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TITLE: A Phase 2 Study of Cabozantinib (XL184), a Dual Inhibitor of MET and VEGFR, **in Patients with Metastatic Refractory Soft Tissue Sarcoma**  
| VEGFR, in Patients with Metastatic Refractory Soft Tissue Sarcoma   |                                                                                                                                                           |             |                       |
|---------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|-----------------------|
| Abbreviated Title:                                                  | Ph2 Cabozantinib Soft Tissue Sarcoma                                                                                                                      |             |                       |
| Coordinating Center:                                                | Developmental Therapeutics Clinic (NCIDTC) National Cancer Institute 10 Center Drive Bethesda, MD 20892                                                   |             |                       |
| Participating Sites:                                                | City of Hope Stanford University School of Medicine University of Southern California                                                                     |             |                       |
| Principal Investigator:                                             | A. P. Chen, MDA-E Center Drive Bldg 31 Rm 3A44 Bethesda, MD 20892 Phone: (240) 781-3320; Fax: (301) 402-0172 chenali@mail.nih.gov                         |             |                       |
| NCI Associate Investigators:                                        | James H. Doroshow, MDA-E                                                                                                                                  |             | DCTD/NCI              |
| Donald P. Bottaro, PhDE                                             |                                                                                                                                                           | UOB/CCR/NCI |                       |
| Howard Streicher, MDA-E                                             |                                                                                                                                                           | DCTD/NCI    |                       |
| Geraldine O'Sullivan Coyne, MD, PhDA-E                              | DCTD/NCI                                                                                                                                                  |             |                       |
| Elad Sharon, MDA-E                                                  |                                                                                                                                                           | DCTD/NCI    |                       |
| Richard Piekarz, MDA-E                                              |                                                                                                                                                           | DCTD/NCI    |                       |
| Naoko Takebe, MD, PhDA-E                                            |                                                                                                                                                           | DCTD/NCI    |                       |
| Sheila Prindiville, MD, MPHA-E                                      | CCCT, NCI                                                                                                                                                 |             |                       |
| Non-NCI Associate                                                   | Lamin Juwara, CRNPA,B,E                                                                                                                                   |             | Leidos Biomed., FNLCR |
| Investigators:                                                      | Apurva Srivastava, PhDE                                                                                                                                   |             | Leidos Biomed., FNLCR |
| Statistician:                                                       | Larry Rubinstein, PhD, BRB/DCTDE 9609 Medical Center Dr, Room 5W106 Phone: (240) 276-6026 rubinsteinl@mail.nih.gov                                        |             |                       |
| Research Nurse:                                                     | Ashley Bruns, RN, DCTD/NIHA,B,E 10 Center Drive, Bldg 10/Rm 8D53  Bethesda, MD 20892 Telephone: (240) 858-3162  Fax: (301) 451-5625  ashley.bruns@nih.gov |             |                       |  
1  
| City of Hope (CoH): FWA # FWA00000692                                                                                                                                                                                                                                      | Principal Investigator: Warren A. Chow, MD,  FACP City of Hope Medical Center 1500 E. Duarte Rd. Duarte, CA 91010 Phone: 626-256-4673 Fax: 626-301-8233 wchow@coh.org                                                                        |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| IRB: David Holt Director, Clinical Research Protections City of Hope IRB of Record: City of Hope Natl Med Ctr &  the Beckman Rsch Inst IRB#1 IRB IORG#: IORG0000042 1500 E. Duarte Rd, Duarte, CA 91010 Phone: (626) 218-3099; E-mail: daholt@coh.org                      | Pharmacy: Oscar Martin, PharmD Investigational Drug Service, City of Hope 1500 E. Duarte Rd., Duarte, CA 91010 Phone (626) 256-4673 x62398; Fax: (626) 930-5378 E-mail: omartin@coh.org                                                      |
| University of Southern California (USC): FWA #00005906                                                                                                                                                                                                                     | Principal Investigator: James Hu, MD University of Southern California 1441 Eastlake Ave. Los Angeles CA. 90033 Phone: 323-865-0813 Fax: 323-865-0061 jameshu@med.usc.edu                                                                    |
| IRB Director: Sandy Jean University of Southern California Health  Sciences Institutional Review Board  IRB IORG# IRB00000484 LAC+USC Medical Center General Hospital Suite 4700  1200 North State St.  Los Angeles, CA 90033 Phone: (323) 276-2231 Sandy.Jean@med.usc.edu | USC Pharmacy Contact: Charlene Chiu, PharmD USC/Norris Comprehensive Cancer Center /  Investigational Drug Services 1441 Eastlake Avenue, Rm. 2407 Los Angeles, CA. 90033 Phone: (323) 865-3538; Fax: (323) 865-0857 IDSPharmacy@med.usc.edu |
| Stanford University School of Medicine  FWA00000935                                                                                                                                                                                                                        | Principle Investigator: Shivaani Kummar, MD Stanford University School of Medicine 780 Welch Road, Rm CJ250L Palo Alto, CA 94304 (650) 724-9084 skummar@stanford.edu                                                                         |
| Stanford University Administrative Panel on  Human Subject in Medical Research IORG #0000208 3000 El Camino Real, Five Palo Alto Square,  4th Floor,  Palo Alto, CA 94306                                                                                                  | Kristine M. McGlennen, MN, RN Cancer Clinical Trials Office 800 Welch Rd., FC2C19 Stanford, California 94305 Tel: (650) 723-3589 / Pager: (650) 723-8222 ext.  26827 /Fax: (650) 736-8092                                                    |
| Pharmacy contact: Martha "Marty" Hamilton Stanford Hospital and Clinics Investigational Pharmacy 300 Pasteur Drive, Room H0302 Stanford, CA 94305 Phone (650-725-5295) Fax #: 650-725-6262 MaHamilton@stanfordhealthcare.org                                               |                                                                                                                                                                                                                                              |
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california cancer consortium (ccc) participating

| CTEP Monitor:   |
|-----------------|  
Roles: Aobtains information by intervening or interacting with living individuals for research purposes; Bobtains identifiable private information about living individuals; Cobtains the voluntary informed consent of individuals to be subjects; Dmakes decisions about subject eligibility; E*studies,*
interprets, or analyzes identifiable private information or data/specimens for research purposes  
| NCI Supplied Agent:   |
|-----------------------|  
| John J. Wright, MD, PhD   |
|---------------------------|  
| IND number: NCT number: Protocol Version Date:   |
|--------------------------------------------------|  
| NCT01755195 March 18, 2021   |
|------------------------------|  
| Cabozantinib (NSC 761968)   |
|-----------------------------|  
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precis

Background:
- Soft tissue sarcomas (STS) are a relatively rare heterogeneous group of tumors that constitute about 1% of adult cancers.  
- The mainstay of treatment for advanced disease has been palliative chemotherapy with a median overall survival of approximately 12 months. This has not changed considerably in the past years and there is an unmet need for newer targeted therapies.  
- VEGF levels are elevated in patients with STS and various sarcoma cell lines express high levels of activated c-Met receptor.  
- We hypothesize that dual targeting of the VEGF and c-MET pathways with cabozantinib would result in clinical benefit in patients with soft tissue sarcoma.  
Objectives:
Primary:
- Assess the response rate (CR+PR) of cabozantinib in patients with soft tissue sarcomas.  
- Assess the 6 month progression free survival (PFS) of cabozantinib in soft tissue sarcomas.  
Secondary:
- Determine and compare circulating levels of HGF, soluble MET (sMET), VEGF-A, and soluble VEGFR2 (sVEGFR2) prior to and following administration of cabozantinib.  
Eligibility:
- Patients must have had disease progression following one line of standard therapy
- Age ≥ 18 years. - Adequate organ function.  
- Patients will be stratified based on prior VEGFR TKI therapy.  
Design:
- All patients will receive cabozantinib at 60 mg PO daily in 4 week cycles.  
- Tumor response evaluations by imaging will be done every 2 cycles (less frequently for patients on study more than one year).  
- The study will be conducted as a dual-endpoint two-stage Phase II trial to target objective tumor response rate (CR+PR) of 30% against an unacceptably low rate of 10%, and 6-month PFS rate of 65% against an unacceptably low rate of 45% (corresponding to median PFS of 9.6 vs. 5.2 months).  
- The trial will accrue up to 50 evaluable patients.
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schema

aCabozantinib 60 mg po q day continuously throughout. Cabozantinib will be taken on an empty stomach 1 hour before, or 2 hours after, a meal.  
bBlood samples for PD analyses (mandatory at the NCI but optional at participating sites)
collected at baseline (pre-treatment), on C1D1 (3-6 hours post dose), and on C2D1 (3-6 hours post dose).  
cBlood samples for CTC analyses (optional) collected at baseline (pre-treatment), on C1D1 4 hours (+/- 1 hour) post dose, on day 1 of all subsequent cycles before drug administration, and at disease progression.  
| TABLE OF CONTENTS                                                                                                                                      |                                                                                                                                                 |                                                                                       |
|--------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------|
| PRÉCIS ..............................................................................................................................................4 |                                                                                                                                                 |                                                                                       |
| SCHEMA                                                                                                                                                 |                                                                                                                                                 |                                                                                       |
| OBJECTIVES ...................................................................................................................................8        |                                                                                                                                                 |                                                                                       |
| 1                                                                                                                                                      | 1.1                                                                                                                                             | Primary Objectives                                                                    |
| 1.2                                                                                                                                                    | Secondary Objectives                                                                                                                            |                                                                                       |
| 2                                                                                                                                                      | BACKGROUND ...................................................................................................................................8 |                                                                                       |
| 2.1                                                                                                                                                    | Soft Tissue Sarcoma (STS)                                                                                                                       |                                                                                       |
| 2.2                                                                                                                                                    | Cabozantinib (XL184)                                                                                                                            |                                                                                       |
| 2.3                                                                                                                                                    | Correlative Studies                                                                                                                             |                                                                                       |
| 2.4                                                                                                                                                    | RATIONALE                                                                                                                                       |                                                                                       |
| 3                                                                                                                                                      | PATIENT SELECTION                                                                                                                               |                                                                                       |
| Eligibility Criteria ...................................................................................................................18             |                                                                                                                                                 |                                                                                       |
| 3.1                                                                                                                                                    |                                                                                                                                                 |                                                                                       |
| 3.2                                                                                                                                                    | Exclusion Criteria ..................................................................................................................19         |                                                                                       |
| 3.3                                                                                                                                                    | Inclusion of Women and Minorities ...................................................................................23                         |                                                                                       |
| 3.4                                                                                                                                                    | Eligibility Screening Evaluation ...........................................................................................23                  |                                                                                       |
| 4                                                                                                                                                      | REGISTRATION PROCEDURES .....................................................................................24                                 |                                                                                       |
| 4.1                                                                                                                                                    | Registration Process                                                                                                                            |                                                                                       |
| Participating Site Registration ......................................................................................24                               |                                                                                                                                                 |                                                                                       |
| 4.2                                                                                                                                                    |                                                                                                                                                 |                                                                                       |
| 4.3                                                                                                                                                    | Off Protocol Therapy and Off-Study Procedure .............................................................24                                    |                                                                                       |
| S                                                                                                                                                      | TREATMENT PLAN.......................................................................................................................25         |                                                                                       |
| 5.1                                                                                                                                                    | Agent Administration                                                                                                                            |                                                                                       |
| 5.2                                                                                                                                                    | General Concomitant Medication and Supportive Care Guidelines......................27                                                           |                                                                                       |
| 5.3                                                                                                                                                    | Duration of Therapy                                                                                                                             |                                                                                       |
| 5.4                                                                                                                                                    | Duration of Follow Up                                                                                                                           |                                                                                       |
| 5.5                                                                                                                                                    | Criteria for Removal from Study .......................................................................................29                       |                                                                                       |
| 6                                                                                                                                                      | DOSING DELAYS/DOSE MODIFICATIONS                                                                                                                |                                                                                       |
| 6.1                                                                                                                                                    | Management of Cabozantinib-related AE ..................................................................30                                      |                                                                                       |
| ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .................41                                                                                    |                                                                                                                                                 |                                                                                       |
| 7                                                                                                                                                      | 7.1                                                                                                                                             | Comprehensive Adverse Events and Potential Risks List (CAEPR)......................41 |
| 7.2                                                                                                                                                    | CTEP Reporting Requirements                                                                                                                     |                                                                                       |
| 7.3                                                                                                                                                    | NIH Reporting Requirements ........................................................................................49                           |                                                                                       |
| 8                                                                                                                                                      | PHARMACEUTICAL INFORMATION                                                                                                                      |                                                                                       |
| 8.1                                                                                                                                                    | Cabozantinib (NSC 761968)                                                                                                                       |                                                                                       |
| Agent Ordering .                                                                                                                                       |                                                                                                                                                 |                                                                                       |
| 8.2                                                                                                                                                    |                                                                                                                                                 |                                                                                       |
| 8.3                                                                                                                                                    | Agent Accountability .......................................................................................................................52  |                                                                                       |
| 8.4                                                                                                                                                    | Investigator Brochure Availability .....................................................................................52                      |                                                                                       |
| Useful Links and Contacts .............................................................................................................52              |                                                                                                                                                 |                                                                                       |
| 8.5                                                                                                                                                    | CORRELATIVE STUDIES                                                                                                                             |                                                                                       |
| 9                                                                                                                                                      | 9.1                                                                                                                                             | Pharmacodynamics .                                                                    |
| 10                                                                                                                                                     | STUDY CALENDAR ...................................................................................................................57            |                                                                                       |
| 11                                                                                                                                                     | MEASUREMENT OF EFFECT                                                                                                                           |                                                                                       |
| 1.1 Antitumor Effect - Solid Tumors ..................................................................................................59               |                                                                                                                                                 |                                                                                       |
| 1.2 Methods for Evaluation of Measurable Disease .............................................................61                                       |                                                                                                                                                 |                                                                                       |
| 1.3 Response Criteria .................................................................................................................63              |                                                                                                                                                 |                                                                                       |
| 1.4 Duration of Response ........................................................................................................65                    |                                                                                                                                                 |                                                                                       |  
| 11.5 Progression-Free Survival 65                                                                                                                                                                                                                                                                                                                                 |                                             |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------|
| 12                                                                                                                                                                                                                                                                                                                                                                | DATA REPORTING / REGULATORY REQUIREMENTS 65 |
| 12.1 Data Reporting 65 12.2 Data Safety and Monitoring Plan 66 12.3 Multicenter Guidelines 67 12.4 Collaborative Agreements Language 68                                                                                                                                                                                                                           |                                             |
| 13                                                                                                                                                                                                                                                                                                                                                                | STATISTICAL CONSIDERATIONS 70               |
| 13.1 Study Design/Endpoints 70 13.2 Sample Size/Accrual Rate 70 13.3 Stratification Factors 70 13.4 Analysis of Secondary Endpoints 70 13.5 Reporting and Exclusions 71                                                                                                                                                                                           |                                             |
| 14                                                                                                                                                                                                                                                                                                                                                                | HUMAN SUBJECTS PROTECTIONS 71               |
| 14.1 Justification for Subject Selection 71 14.2 Evaluation of Benefits and Risks/Discomforts 72 14.3 Consent and Assent Process and Documentation 72 14.4 Procedure for Protecting Against or Minimizing Any Potential Risks 73 14.5 Patient Advocate 73                                                                                                         |                                             |
| REFERENCES 74 APPENDIX A:PERFORMANCE STATUS CRITERIA 77 APPENDIX B: POTENTIAL DRUG INTERACTIONS 78 APPENDIX C: STUDY DIARY 80 APPENDIX D: DRUG INTERACTIONS 83 APPENDIX E: CTEP MULTICENTER GUIDELINES 84 APPENDIX F: ELIGIBILITY/PRE-REGISTRATION WORKSHEET 86 APPENDIX G: INFORMED CONSENT TEMPLATE FOR MULTICENTER 92 APPENDIX H: PD COLLECTION WORKSHEETS 103 |                                             |  
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1 objectives 1.1 primary objectives

- Assess the response rate (CR+PR) of cabozantinib in patients with soft tissue sarcomas.  
- Assess the 6 month progression free survival (PFS) of cabozantinib in soft tissue sarcomas.
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1.2 secondary objectives

- Determine and compare circulating levels of HGF, soluble MET (sMET), VEGF-A,
and soluble VEGFR2 (sVEGFR2) prior to and following administration of cabozantinib.
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2 background 2.1 soft tissue

Soft tissue sarcomas (STS) are a relatively rare heterogeneous group of tumors that arise mainly from embryonic mesoderm. They constitute about 1% of adult cancers with 10,000 new cases diagnosed every year in the US with an overall mortality rate of 3,920 cases per year including adults and children.  
1 More than 50 different histological types have been identified the most common of which are pleiomorphic sarcoma also known as malignant fibrous histiocytoma (MFH), GIST, liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumors.  
2 Diagnosis at an early stage is crucial since complete surgical resection yields the best prognosis. However, the lack of a screening modality makes it difficult with more than 50% of patients developing metastasis during their course of disease decreasing their 5 yr survival to below 10%.The mainstay of treatment for the advanced disease patients has been palliative chemotherapy. The chemotherapy backbone of an anthracycline with or without ifosfamide has been used for decades and yielded response rates of 20-30% and a median overall survival of approximately 12 months.  
3-10 Anthracycline resistant STS and certain subtypes like leiomyosarcoma appear to have better responses to the combination of gemcitabine and docetaxel which is the only regimen in STS which has demonstrated an overall survival advantage in the phase III randomized setting.  
11-13 With the median survival of these patients having changed very little over the past decade there is an unmet need for newer targeted therapies. One of the targets that have emerged in this setting is the tumor produced angiogenic factor vascular endothelial growth factor (VEGF). It has been shown that VEGF levels are elevated in patients with STS and correlates with the grade of the tumor.14-17 Factors other than VEGF, such as platelet-derived growth factor (PDGF), are also likely to be involved in STS angiogenesis.18 Bevacizumab a monoclonal antibody against VEGF has been studied in combination with chemotherapy regimens including gemcitabine, docetaxel19 and temozolomide20 with promising results. Pazopanib, an oral angiogenesis inhibitor that targets VEGF receptors (VEGFRs), PDGF
receptors (PDGFRs), and c-kit has also been studied in STS in phase II21 and III settings22 to show improvement in PFS by 13 weeks compared to placebo. Hepatocyte growth factor/scatter factor (HGF/SF) activates the c-Met receptor tyrosine kinase and promotes cell proliferation, survival, and invasion and also plays a role in angiogenesis.  
23,24 Various sarcoma cell lines express high levels of activated c-Met receptor and suggesting that HGF/SF signaling pathway may contribute to sarcomagenesis.25 Interruption of autocrine or paracrine HGF/SF c-met signaling with the monoclonal antibody AMG102 in leiomyosarcoma cell line SK-LMS-1 and in mouse xenograft models has shown significant antitumor effect.26 It has also been shown that clear cell sarcoma cells are dependent on HGF/C-Met axis27 for invasion, chemotaxis, and survival.
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2.2 cabozantinib (xl184)

Cabozantinib is a new chemical entity that inhibits the receptor tyrosine kinases MET (hepatocyte growth factor [HGF] receptor) and VEGFR2 (vascular endothelial growth factor receptor 2). Both MET and VEGFR2 are important mediators of tumor growth and tumor angiogenesis, and MET is particularly associated with tumor invasiveness and metastasis. In vivo pharmacodynamic activity of cabozantinib against MET and VEGFR2 has been demonstrated in both preclinical and clinical studies and has been associated with tumor growth inhibition and tumor regression. In preclinical studies, cabozantinib treatment has also been shown to inhibit tumor angiogenesis, tumor invasiveness and metastasis, and the progression of tumors in bone. Cabozantinib inhibits multiple RTKs implicated in tumor growth, metastasis, and angiogenesis (Investigator's Brochure, 2011). The primary targets of cabozantinib are MET and VEGFR2; additional targets include RET, AXL, KIT, and TIE-2. Cabozantinib is a potent inhibitor of MET and VEGFR2 with half-maximal inhibitory concentration (IC50) values of 1.3 nmol/L and 0.035 nmol/L, respectively.  
28 Cabozantinib strongly inhibited several kinases that have also been implicated in tumor pathobiology, including KIT, RET, AXL, TIE2, and FLT3 (IC50 = 4.6, 5.2, 7, 14.3, and 11.3 nmol/L, respectively). Cabozantinib did not potently inhibit kinases such as RON, EGFR, IGFR1, and EphA4/B4. In cellular assays, it inhibited phosphorylation of MET and VEGFR2, as well as KIT, FLT3, and AXL with IC50s of 7.8, 1.9, 5.0, 7.5, and 42 μmol/L, respectively.  
28
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nonclinical development of xl184

In *Vivo Activity* In RIP-Tag2 transgenic mice (model of pancreatic neuroendocrine carcinoma), tumors treated with XL184 were smaller (P <0.05) than in mice treated with vehicle or an antiVEGF antibody, but were also less invasive (P <0.05) and had no liver metastases.  
29 All mice treated with XL184 (n = 6) survived until 20 weeks, but none treated with vehicle (n = 14) or anti-VEGF antibody (n= 8) reached that endpoint. Tumor vascularity decreased after treatment, with reductions ranging from 67% at 3 mg/kg to 83% at 30 mg/kg for 7 days (You *et al.*, 2011). Tumors were 35% smaller after XL184 treatment than corresponding values for vehicle control mice. c-Met protein in tumors was slightly less, 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.  
28 XL184 increased tumor hypoxia (13-fold) and apoptosis
(TUNEL; 2.5-fold) at 8 and 4 hours after the first and second doses, respectively, when compared to vehicle-treated tumors. In addition, XL184 disrupted tumor vasculature by inducing endothelial cell death that negatively impacted tumor viability. XL184 treatment resulted in significant tumor growth inhibition of MDA-MB-231 tumors (P <0.001) at all doses (1, 3, 10, 30, or 60 mg/kg) when compared to vehicle-treated tumors. Dose-dependent inhibition was observed for the 3 and 10 mg/kg doses (P <0.01), and complete inhibition was observed at the 30 and 60 mg/kg doses. A single 100 mg/kg dose resulted in sustained MDA-MB-231 tumor growth inhibition for ~8 days after which tumors began growing at a rate similar to vehicle-treated control tumors. In addition, XL184 inhibited tumor growth (P <0.001) in the MET-expressing rat C6 glioma cell line for all doses (1, 3, 10, 30, or 60 mg/kg) when compared with vehicle-treated tumors. The 3 mg/kg and 10 mg/kg doses resulted in significant tumor regression (62% and 85%, P <0.0001) when compared with pre-dose tumor weights. Subchronic administration of XL184 was well tolerated in mice and rats with no signs of toxicity, as determined by stable and/or increasing body weights during the treatment period.  
28
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pharmacodynamics

In vivo pharmacodynamic experiments showed that XL184 inhibits key RTKs that promote tumor cell proliferation and/or angiogenesis (MET, VEGFR2, TIE-2, and RET) (Investigator's Brochure, 2010). In mice, the effective dose resulting in 50% inhibition (ED50) of targets was achieved at well tolerated doses of XL184 and at plasma exposures comparable to exposure observed in clinical trials. XL184 produced prolonged inhibition of receptor phosphorylation, such as sustained inhibition of MET and VEGFR2 for 10 hours after administration of a single dose of XL184. This extended inhibition occurred in a manner that was generally predicted by plasma exposure, i.e., inhibition was diminished when plasma levels fell below approximately 20 μM for MET, 5 μM for VEGFR2, and 23 μM for TIE-2. Once daily administration of XL184 resulted in significant inhibition of MET phosphorylation in TT tumors, with maximal inhibition of 70% seen at 60 mg/kg, relative to tumors from vehicle control-treated mice (Investigator's Brochure, 2011). Dosedependent inhibition of phosphorylation of MET and RET was observed among the 3, 10, and 30 mg/kg dose groups.  
MET phosphorylation was inhibited by a single 100 mg/kg oral dose of XL184, 2–8 hours post dose in H441 tumors (human lung papillary adenocarcinoma) that harbor constitutively phosphorylated MET 28. This effect was reversible, as MET
phosphorylation returned to basal levels by 48 hours after treatment.
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toxicology

In rodents and non-rodents, histopathological changes associated with XL184 administration were observed in gastrointestinal (GI) tract, bone marrow, lymphoid tissues, kidney, and adrenal and reproductive tract tissues (Investigator's Brochure, 2011). Histopathological changes present in the bone and pancreas were considered secondary to XL184 administration. Adverse effects following oral exposure to XL184 were generally dose-related, clinically monitorable, and self-resolving upon discontinuation of dosing. In 6-month chronic toxicity studies, treatment-related changes were present only in kidney (rats) and reproductive tissues (dog). In reproductive/developmental toxicity studies, XL184 administration resulted in decreased fertility in male and female rats, in embryotoxicity when given to pregnant rats, and in a visceral tissue malformation (small spleen) when given to pregnant rabbits. The no-observable-adverse-effect-levels (NOAELs) for the chronic toxicity and reproductive/developmental toxicity studies occurred at plasma exposures (AUC) below steady-state values measured in subjects with solid tumors administered 175 mg XL184 capsule form daily (Study XL184-001).  
In definitive genotoxicity bioassays, XL184 was negative in an *S. typhimurium/E. coli* bacterial mutagenicity study, an *in vitro* chromosome aberration study using human peripheral blood lymphocytes, and an *in vivo* mouse bone marrow micronucleus study. In safety pharmacology studies, no adverse effects occurred on neurobehavioral or respiratory functions in XL184-treated rats or on cardiovascular function in XL184treated dogs.
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clinical studies with cabozantinib

As of 4 May 2011, 1003 subjects have been enrolled in open-label clinical studies of cabozantinib, and 330 subjects have been enrolled in a placebo-controlled blinded Phase 3 study. Clinical data are available from nine studies of cabozantinib including four Phase 1 studies, one Phase 1b/2 study, three Phase 2 studies, and one Phase 3 study. Doses in the studies listed in Table 1 are in terms of salt-based dosing with the exception of study XL184-203, where the free-base equivalent weight is also noted.  
| Table 1.     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                 |                                                        |
|--------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|--------------------------------------------------------|
| Study #      | Phase                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Patient         | Dose and Response                                      |
| Population   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                 |                                                        |
| XL184-001    | 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Solid tumors    | Single-agent: Capsules: 25 and/or 100 mg PO daily (QD).  10 (29%) of 35 patients with MTC had a cPR31 . Overall, of  85 patients with advanced solid tumors, 18 patients  experienced tumor shrinkage of 30% or more, including 17  (49%) of 35 patients with MTC. In addition, 15 (41%) of  37 patients with MTC had SD for at least 6 months. In the  non-MTC subset, SD of at least 3 months was reported in  38% of patients with the following tumors: colorectal (three  patients); melanoma (two patients); carcinoid (two patients)  tumors; and adenoid cystic, follicular thyroid, papillary  thyroid, HCC, RCC, CTCL, salivary gland, ASPS, clearcell sarcoma, mesothelioma, and neuroendocrine tumor  originating in the thyroid (one patient each).                                                        |
| XL184-002    | 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Newly diagnosed | XL184 qd in combination with TMZ and radiation therapy |
| glioblastoma | in the concurrent phase and with TMZ in the maintenance  phase  Arm 1, XL184: initiated at the start of 6–7 week concurrent  phase of RT, given as a single agent during the 4-week rest  phase, and continued subsequently in the maintenance  phase.  TMZ: starting dose of 75 mg/m2 /day QD with concurrent  RT for 6 weeks. Arm 2, XL184: initiated during the  maintenance phase with TMZ. TMZ: starting dose of 200  mg/m2 /day given 5 consecutive days and repeated every 28  days. MTD Expansion, XL184: initiated at the start of 6–7  week concurrent phase of RT, given as a single agent during |                 |                                                        |  
| Study #      | Phase                                                                                                                                                                                                                                                                                                                                                                                                                      | Patient                                                  | Dose and Response                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
|--------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Population   | the 4-week rest phase, and continued subsequently in the  maintenance phase. XL184 and TMZ will be given at  MTDs determined in Arms 1 and 2.                                                                                                                                                                                                                                                                              |                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| XL184-008    | 1                                                                                                                                                                                                                                                                                                                                                                                                                          | Differentiated  thyroid cancer  (DTC) or  metastatic RCC | Drug-drug interaction study with exploratory objective of  anti-tumor activity. XL184: 175 mg PO QD.  Rosiglitazone: one 4 mg dose followed by a second 4 mg  dose 3 weeks later.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| CA205-001    | 1                                                                                                                                                                                                                                                                                                                                                                                                                          | Advanced or  metastatic solid  tumors (Japan)            | Starting dose: 75 mg PO QD; reduced to 50 mg.  Study closed when collaboration with BMS was terminated                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| XL184-014    | 1                                                                                                                                                                                                                                                                                                                                                                                                                          | Advanced or  metastatic solid  tumors (Japan)            | Starting dose 50 mg                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| XL184-202    | 1                                                                                                                                                                                                                                                                                                                                                                                                                          | b / 2 NSCLC                                              | Multiple dose levels of erlotinib + XL184 were evaluated.  Response: The dose levels in phase 2 study XL184-202 are:  arm B (75 mg XL184 + 150 mg erlotinib and 50 mg XL184  + 150 mg erlotinib [MTD]) and arm A (75 mg XL184 + 100  mg erlotinib; 125 mg XL184 + 100 mg erlotinib; and 125  mg XL184 + 50 mg erlotinib) (Wakelee et al., 2010). Six  of 36 evaluable patients, including at least 3 patients with  prior erlotinib therapy, had 30% reduction in tumor  measurements on at least 1 post-baseline scan, including 3  with a cPR (1 with MET amplification). Prolonged SD of 4  months was observed in some patients, including one  patient for 9+ months and one patient with epidermal  growth factor receptor (EGFR) T790M. A cPR was  achieved in 5 of 64 (8%) evaluable patients enrolled in  phase 1 (Investigator's Brochure, 2011). In phase 2, a cPR  was observed in one patient treated with single-agent  XL184. |
| XL184-201    | 2                                                                                                                                                                                                                                                                                                                                                                                                                          | Progressive or                                           | Group A: initial dose of 175 mg. Groups B and C: initial                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| recurrent GB | dose of 125 mg. Response: at the dose of 125 mg QD,  cPRs were observed in 11 of 37 (30%) patients without  prior anti-angiogenic therapy, with a median duration of  response of 5.1 months (range = 0.9–6.7) (Investigator's  Brochure, 2011). At 175 mg QD, cPRs were observed in 7  of 34 (21%) patients without prior anti-angiogenic therapy,  with a median duration of response of 2.9 months (range =  1.9–12.8). |                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| XL184-203    | 2                                                                                                                                                                                                                                                                                                                                                                                                                          | Nine tumorspecific cohorts:  breast cancer,  gastric/GEJ  adenocarcinoma,                                                          | Starting dose: 125 mg QD (100 mg freebase equivalent  weight) during 12-weeks run-in phase. Patient with CR or  PR continued XL184. Patients with SD were randomized to  placebo or XL184  Patients with PD discontinued treatment. 12                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |  
| Study #                                                                                       | Phase                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Patient                                             | Dose and Response                                                                                                                                                                                                                                                                                                        |
|-----------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Population HCC, melanoma,  NSCLC, ovarian  cancer, pancreatic  cancer, prostate  cancer, SCLC | Non-randomized extension cohorts in CRPC and ovarian  cancer  Response: One hundred seventy one CRPC subjects were  enrolled. Randomization was suspended after 122 subjects  were enrolled due to demonstrated clinical benefit. Seven  patients achieved a cPR at week 12, and three additional  patients achieved PR after the 12-week lead-in stage. The  disease-control rate (rate of response +stable disease) at  week 12 was 68%. Seventeen subjects were randomized to  placebo; 14 to XL184. Among these subjects, the hazard  ratio for PFS was 0.013 (p = 0.007). Of 108 subjects  evaluable for bone scan response, 19% had complete  resolution; 56% had partial resolution; 21% had stable  disease and only 3% had progression as their best response.  Three hundred nineteen subjects with non-CRPC advanced  solid tumors were also enrolled in study XL184-203 .The  overall ORR at week 12 by cohort was: HCC 10% (3/30  patients), NSCLC 10% (6/60 patients), breast 10% (2/20  patients), melanoma 5% (4/77 patients), SCLC 5% (1/21  patients), pancreatic 0% (0/20) and gastric/GEJ 0% (0/21).  In 51 evaluable epithelial ovarian cancer patients, at 12  weeks, the overall RR was 24% (12/51 patients), 21% in  platinum-refractory/resistant patients (7/34)), and 28% in  platinum-sensitive patients (10/36). The highest disease  control rates at week 12 were HCC (73%), ovarian (53%),  melanoma (47%), breast (45%), and NSCLC (40%). |                                                     |                                                                                                                                                                                                                                                                                                                          |
| XL184-205                                                                                     | 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Grade IV                                            | 25 mg QD continuously (Arm 1); 75 mg QD continuously                                                                                                                                                                                                                                                                     |
| astrocytic tumors                                                                             | (Arm 2); 125 mg QD for two weeks followed by 50 mg QD  continuously (Arm 3); and 125 mg QD on an intermittent 3  weeks on/1 week off schedule (Arm 4).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                     |                                                                                                                                                                                                                                                                                                                          |
| XL184-301                                                                                     | 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Unresectable,  locally advanced  or metastatic  MTC | 175 mg QD or placebo administered QD. Response: Randomized, double blind, placebo-controlled  study recently reported top line data indicating that the  primary endpoint of the study, PFS, was met. PFS on the  cabozantinib arm was 11.2 months compared to 4 months  on placebo, hazard ratio [HR] 0.28, p < 0.0001. |  
The dose of 60 mg proposed in this study is based on a recent trial reported at ASCO
2012 30. An adaptive response scheme was used to determine the lowest active daily cabozantinib dose among dose levels +1 (60 mg), 0 (40 mg), and -1 (20 mg). The primary endpoint was wk 6 bone scan response (BSR) assessed with an automated FDA 510(k) approved computer-aided detection system. A ≥30% decrease in total bone scan lesion area (BSLA) was defined as a response. The first cohort was treated at dose level 0. The number of responses (≥8 vs. <8 among 11 evaluable pts) was used to select the dose level (-1 vs. +1) for the second cohort. Based on the observed BSR rate in the second cohort of 11 patients, a dose was selected for expansion to treat 13 more pts. The study completed planned enrollment of 36 pts. Median age was 66; 44% were docetaxelpretreated. Among 12 pts enrolled at dose level 0, there were 10 BSRs at wk 6 including 1 complete response (CR), and 1 pt with stable disease (SD). The median decrease in BSLA was 62%. Ten patients evaluated at wk 12 included 9 BSRs (3 CRs), and 1 sustained SD. Among 11 pts then treated at dose level -1, 10 pts were evaluable at wk 6:
1 BSR, 5 SD, and 4 had progressive disease. No pts in the 2 cohorts required dose reduction or treatment interruption at 12 wks; 1 patient discontinued due to grade 3 AEs (anorexia, fatigue). 6/12 pts with ≥ 6 months follow-up remain on study. 5/5 pts enrolled at 40 mg with CTCs ≥5 per 7.5 mL converted to <5. Thirteen pts accrued to the expansion cohort at 40 mg daily had confirmed high BSR rate. The study concluded that cabozantinib 40 mg daily achieves a high BSR rate in men with CRPC and bone metastases, and is associated with better tolerability than previously reported for cabozantinib 100 mg daily. Hence, the manufacturer is carrying a dose of 60 mg forward in phase III trials, which is the dose that we have chosen in our trial.
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pharmacokinetics

In study XL184-00131, pharmacokinetic (PK) analysis showed dose-proportional increases in plasma exposure (Cmax and AUC) both for the PIB formulation (dose range: 0.08 to 11.52 mg/kg) and the capsule formulation (dose range: 125 mg to 175 mg). After repeat daily dosing, t1/2, z values (mean ± standard deviation) for cabozantinib were 91.3 ± 33.3 hours (n = 23), and apparent steady-state plasma levels were reached by day 15. 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 steadystate exposure (AUC) compared with Day 1 (7.68 ± 2.85 μg·h/mL; n = 23 *vs.* 41.6 ± 15.5 μg·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.
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safety

As of March 1, 2011, the most frequently (>20%) observed adverse events (AEs) in 806 patients treated in single agent, open label cabozantinib studies, regardless of the relationship to drug, were fatigue, diarrhea, nausea, decreased appetite, constipation, palmar-plantar erythrodysesthesia (PPE) syndrome, vomiting, dysphonia and hypertension, (Investigator's Brochure, 2011). Effects that may be related to the inhibition of VEGF, including hypertension, thromboembolic events, GI perforation, fistula formation, hemorrhage, wound healing complications, and proteinuria, have also been observed. As of 4 May 2011, of the 1003 subjects enrolled in open-label clinical trials with cabozantinib (either as a single-agent or in combination with other therapies). Across all open-label studies, the most common SAEs, regardless of causality were PE, dehydration, vomiting, DVT, pneumonia, diarrhea, nausea, convulsion, mental status changes, and abdominal pain. Fatigue (16%), diarrhea (10%), and nausea (6%) were the most common reasons for discontinuation. There have been 15 deaths considered related to cabozantinib treatment within 30 days of the last dose of study treatment: pulmonary embolism (2 patients), respiratory failure (pulmonary embolism) (1 patient), respiratory failure (1 patient), GI hemorrhage (2 patients), unexplained death (2 patients), hemoptysis (1 patient), hemorrhage intracranial (1 patient), enterocutaneous fistula (1 patient), respiratory disorder (1 patient), intestinal perforation (1 patient), hemorrhage (1 patient), and diverticular perforation–peritonitis (1 patient).
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2.3 correlative studies

Substantial inhibition of phosphorylation of MET, RET, and KIT, as well as of downstream signaling molecules AKT and extracellular signal-regulated kinase (ERK), was seen following administration of cabozantinib (Investigator's Brochure, 2011).  
From the first 12 cases in **study XL184-201**, 80% of samples of tumor cells were positive for MET with a lower fraction positive for RET and VEGFR2 (42% and 58%, respectively) (DePrimo *et al.*, 2009). MET signal in blood vessels was limited (33%); whereas, RET and VEGFR2 expression was often seen in tumor-associated blood vessels. Modulation of plasma levels of VEGFA, soluble MET, soluble VEGFR2, soluble KIT, and PlGF, was consistent with multiple on-target effects. Objective response was observed in the presence or absence of tumor EGFR amplification, phosphatase and tensin (PTEN) mutation, and O6-methylguanine-DNAmethyltransferase (MGMT) promoter methylation.  
Phase 1: Study XL184-001 Changes in pharmacodynamic markers consistent with antiangiogenesis activity were observed in Cohorts 6 through 12 and the eMTD Cohort with plasma samples taken on Day 1 pre-dose and Day 29. While small cohort sizes presented a challenge for statistical analysis of pharmacodynamic marker changes the combined data of Cohorts 12 and the eMTD Cohort (i.e., subjects enrolled at the MTD) demonstrated that changes in PlGF (↑), VEGF-A (↑), EPO (↑), and sVEGFR2 (↓) reached statistical significance. Soluble MET as a potential biomarker of MET inhibition was increased upon cabozantinib treatment and changes reached statistical significance. One set of serial skin biopsies was received from a subject enrolled in the eMTD Cohort and was analyzed using fluorescence-based IHC. Changes in total MET, RET and KIT were minimal during the course of cabozantinib treatment but the activity (as assessed by the phosphorylation status) of these cabozantinib targets (decrease compared to baseline: MET: 40%, RET: 40%, KIT: 61%) as well as of the downstream signaling molecules AKT (39%) and ERK (55%) was statistically significantly reduced in this surrogate tissue. These observations support the ontarget inhibitory effect of cabozantinib. Total levels and phosphorylation of VEGFR2 were not affected by cabozantinib treatment in this surrogate tissue.
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circulating levels of hgf soluble

Many proteins are proteolytically released from the cell surface by a process known as ectodomain shedding. Shedding occurs under normal physiologic conditions and can be increased in certain pathologies. MET is among the many receptors for which ectodomain shedding has been demonstrated. HGF stimulates mitogenesis, motogenesis, and morphogenesis in a variety of cellular targets during development, homeostasis, and tissue regeneration. Inappropriate HGF signaling resulting in unregulated cell proliferation, motility, and invasion occurs in several human malignancies. This can occur through paracrine signaling, autocrine loop formation, receptor mutation, gene amplification or gene rearrangement accompanied frequently with overexpression of ligand and/or receptor proteins. Working under the hypothesis that aberrant MET pathway activation in cancer might result in increased ectodomain shedding, MET could be a useful biomarker of tumor progression; Athauda et al. developed a sensitive electrochemiluminescent immunoassay to quantitate MET protein in biological samples.  
32 Their study showed significant direct correlations between malignant potential and sMET production in tumor-derived and genetically engineered cell lines, and between tumor burden and plasma sMET levels in mice harboring human tumor xenografts.  
32 These preclinical studies supported the hypothesis that sMET might indicate malignant potential and/or tumor burden for cancers where the pathway is active. Several studies of human clinical samples are now underway to investigate the potential utility of sMET to aid diagnosis and patient selection, and as a pharmacodynamic marker for drugs that directly target MET kinase activity. Among these is an ongoing collaboration between GlaxoSmithKline (GSK) and the NCI Urologic Oncology Branch to measure plasma sMET, HGF, VEGF-A and sVEGFR2 in patients in Phase I and II
clinical trials of GSK1363089 (GSK089), an inhibitor of MET and VEGFR2 tyrosine kinases. In a Phase II gastric cancer study, patients treated with GSK089 on an intermittent dosing schedule showed significantly increased plasma sMET and VEGF-A during the treatment periods and decreases during drug holidays. Follow-up cell-based studies show that inhibition of MET kinase activity blocks receptor internalization, resulting in increased exposure to cell surface MET shedders(s), suggesting a direct short-term relationship between sMET levels and drug target inhibition. Increased VEGF-A levels have been reported as a response to VEGFR inhibitors in previous clinical studies. Median tumor burden did not change significantly over the course of the gastric study, so it was not possible to determine whether sMET levels could also reflect tumor burden. This question will be better assessed in an ongoing Phase II clinical trial of GSK089 in patients with papillary renal cell carcinoma, where changes in tumor burden meeting RECIST criteria were reported in an interim trial report.33
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circulating tumor cells (ctcs)

CTCs will be isolated from whole blood samples collected at baseline and then throughout the study for assessment of DNA damage response markers such as γH2AX. We will also evaluate whether we can measure changes in the number and phenotype (epithelial-mesenchymal transition) of CTCs in patients over time to explore any correlation with response to treatment or disease progression. This analysis will be performed in Dr. Kinders' lab with the ApoStream instrument, which uses antibodyindependent CTC isolation technology that can isolate viable CTCs from epithelial and non-epithelial cancers.
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2.4 rationale

We propose a clinical trial of cabozantinib, a dual VEGFR and MET inhibitor, in refractory soft tissue sarcoma for the following reasons: 1. It has been shown that VEGF levels are elevated in patients with STS and correlates with the grade of the tumor.14-17 Anti-VEGF agents like bevacizumab have been studied in this disease with promising results.19,20 Pazopanib has also been studied in STS in phase II21 and III settings22; patients showed improvement in PFS by 13 weeks compared to placebo. 2. Various sarcoma cell lines express high levels of activated c-Met receptor suggesting that HGF/SF signaling pathway may contribute to sarcomagenesis.25 Interruption of autocrine or paracrine HGF/SF c-met signaling with the monoclonal antibody AMG102 in leiomyosarcoma cell line SK-LMS-1 and in mouse xenograft models has shown significant antitumor effect.26 It has also been shown that MiT tumors like clear cell sarcoma cells are dependent on HGF/C-Met axis27 for invasion, chemotaxis, and survival.  
3. The MET pathway may play an important role in resistance to VEGF inhibitors like sunitinib.  
34 Treatment with multiple VEGF inhibitors has been reported to be associated with an aggressive phenotype with increased invasiveness and higher MET expression.35-37 Hence, we propose to target the dual arms of the VEGF/MET axis with cabozantinib in the hope to eliminate some of the resistance that has been encountered in the past with angiogenic inhibitors.  
4. In vivo activity of XL184 has been shown in the form of tumor shrinkage in RIP-Tag2  
  
transgenic mice29 and mice bearing MDA-MB-231 cells28. As shown in Figure 3, combination blockade of VEGFR and c-MET with XL184 significantly (P < 0.05) prolongs survival compared to treatment with vehicle or anti-VEGFR antibody alone in the RIPTag2 transgenic mouse model, a spontaneous and highly vascularized pancreatic islet cell cancer.  
Figure 3: Increased survival of RIP-Tag2 transgenic mice following treatment with the VEGFR and c-MET inhibitor XL184 compared to treatment with anti-VEGF antibody or vehicle. The extent of liver metastasis was also less in RIP-Tag2 mice treated with combination blockade of VEGFR and c-MET than in mice treated with anti-VEGF antibody alone.  
5. In the clinical arena, cabozantinib has been shown in Phase 1 study XL184-001 that evaluated the capsule formulation and suspension formulation to achieve SD of at least 3 months in advanced solid tumors (including one patient each of alveolar soft part sarcoma and clear cell sarcoma).31 By targeting the dual VEGF/c-MET pathway with cabozantinib in soft tissue sarcoma we propose to improve on the PFS that was established in the Phase III trial of pazopanib where it improved median PFS by 13 weeks compared to placebo.22 If our proposed trial is positive, we 17  
would anticipate this could lead to a large randomized phase III trial comparing the two targeted agents pazopanib and cabozantinib in STS, thereby establishing a new standard of care in this population.
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3 patient selection 3.1 eligibility

Patients must have histologically or cytologically confirmed soft tissue sarcoma that is metastatic or unresectable and for which standard treatment that prolongs survival does not exist or is no longer effective. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam.  
Patients are allowed prior VEGFR-TKI therapy. Patients will be stratified based on prior VEGFR-TKI therapy. Age ≥18 years. Because no dosing or adverse event data are currently available on the use of cabozantinib in patients <18 years of age, children are excluded from this study. ECOG performance status ≤1 (Karnofsky >70%, see Appendix A). Life expectancy > 3 months.
Patients must have normal organ and marrow function as defined below:  
$\mathcal{L}$  
− leukocytes >3,000/mcL  
− absolute neutrophil count >1,500/mcL  
− platelets >100,000/mcL − total bilirubin ≤1.5 times ULN  
− AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of  
normal  
− creatinine within normal institutional limits  
OR  
− creatinine clearance >60 mL/min/1.73 m2for patients with  
creatinine levels above institutional normal.  
− 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  
Subjects must have blood pressure (BP) no greater than 140 mmHg (systolic) and 90 mmHg (diastolic) for eligibility. Initiation or adjustment of BP medication is permitted prior to study entry provided that the average of three BP readings at the time of enrollment is ≤ 140/90 mmHg  
Patients must be able to swallow whole tablets. Tablets must not be crushed or chewed.
The effects of cabozantinib on the developing human fetus are unknown. For this reason and because receptor tyrosine kinases are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception. 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).  
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.  
Ability to understand and the willingness to sign a written informed consent document.
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3.2 exclusion criteria

Patients who have had anticancer therapy, including kinase inhibitors or any investigational agent within 4 weeks or 5 half-lives (whichever is shorter) (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered to baseline from adverse events (except alopecia and other non-clinically significant AEs). Patients who have received prior cabozantinib or inhibitors of c-MET or HGF are ineligible.  
The subject has received radionuclide treatment within 6 weeks of the first dose of study treatment The subject has received radiation therapy within 4 weeks (≤ 2 weeks for palliative radiation therapy)
Patients with active brain metastases or carcinomatous meningitis or epidural disease are excluded from this clinical trial. Subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation who are asymptomatic and have remained stable for 4 weeks and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible. Neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment. Baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility. Eligibility of subjects receiving any medications or substances known to affect or with the potential to affect the activity of cabozantinib will be determined following review of their cases by the Principal Investigator (see Sections 3.2.8, 3.2.9 and 3.2.10 for further information). Patients who are taking enzymeinducing anticonvulsant agents are not eligible.  
Patients with refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that could interfere with absorption. Uncontrolled intercurrent illness including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women are excluded from this study because cabozantinib has 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. Strong inhibitors and inducers of CYP3A4 can affect levels of cabozantinib and should be avoided whenever possible or switched to alternatives. Subjects requiring chronic concomitant treatment of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's Wort) are not eligible for this study. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new overthe-counter medicine or herbal product.  
HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with cabozantinib. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. 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. (Please note that there may be cases in which patients on study require anticoagulation for DVT/PE management; this does not necessitate taking the patient off study. See Section 6.1.5.) The subject has experienced any of the following
- clinically-significant gastrointestinal bleeding within 3 months before the first dose of study treatment; the participant must be maintained on a prophylactic regimen for management of an upper GI bleeding event with no evidence of recurrence and/or endoscopic confirmation of resolution of the source of a lower GI bleed.  
•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 The subject has radiographic evidence of cavitating pulmonary lesion(s). The subject has tumor invading or encasing any major blood vessels  
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 The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
1. Cardiovascular disorders including:
a) Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening b) Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment c) Any history of congenital long QT syndrome d) Any of the following within 6 months before the first dose of study treatment:
- unstable angina pectoris - clinically-significant cardiac arrhythmias - stroke (including TIA, or other ischemic event) - myocardial infarction - thromboembolic event requiring therapeutic anticoagulation (Note:
subjects with a venous filter (e.g. vena cava filter) are not eligible for this study)
2. Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:
a) Any of the following within 28 days before the first dose of study treatment
- intra-abdominal tumor/metastases invading GI mucosa - active peptic ulcer disease,
- inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
- malabsorption syndrome b) Any of the following within 6 months before the first dose of study treatment:
- abdominal fistula - gastrointestinal perforation - bowel obstruction or gastric outlet obstruction
- intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 6 months before the first dose of study treatment.  
3. Other disorders associated with a high risk of fistula formation including PEG
tube placement within 3 months before the first dose of study therapy
4. Other clinically significant disorders such as:
a) serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment b) history of organ transplant, including allogeneic bone marrow transplant c) concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment d) history of major surgery as follows:
i. Major surgery within 3 months of the first dose of cabozantinib if there were no wound healing complications or within 6 months of the first dose of cabozantinib if there were wound complications ii. Minor surgery within 1 months of the first dose of cabozantinib if there were no wound healing complications or within 3 months of the first dose of cabozantinib if there were wound complications In addition, complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of cabozantinib irrespective of the time from surgery The subject is unable to swallow tablets The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >500 ms within 28 days before enrollment. 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. The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee. The subject has had evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment.  
Patients should not have any clinical evidence of an active infection at the time of enrollment.
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3.3 inclusion of women and

Both men and women of all races and ethnic groups are eligible for this trial.
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3.4 eligibility screening evaluation

Histologic confirmation: A block or stained slides of primary tumor tissue or of known recurrence will be required from each participant to confirm diagnosis. Pathology confirmation will be performed by the Laboratory of Pathology, NIH for patients enrolled at the NCI or by the department of pathology at the site where the patient is enrolled. History and physical examination: Complete history and physical examination (including height, weight, vital signs, and ECOG performance score) will be conducted within 8 days prior to enrollment. Imaging Studies: All patients will be required to undergo a CT scan of the chest/abdomen/pelvis to evaluate sites of disease within 28 days prior to enrollment. MRI or CT scan with contrast of the brain, MRI liver, MRI for other disease sites, or bone scan may be done as clinically indicated.  
Laboratory Evaluation: Laboratory data are to be obtained within 8 days prior to enrollment:
- Hematological Profile: CBC with differential.  
- Biochemical Profile: albumin, alkaline phosphatase, total bilirubin, BUN, sodium, chloride, bicarbonate, calcium, creatinine, glucose, phosphorus, magnesium, potassium, total protein, SGOT [AST], SGPT [ALT], amylase, lipase, TSH.  
- Serum or urine pregnancy test for female participants of childbearing potential.  
- Urinalysis for urine protein/creatinine ratio or 24-hour urine for proteinuria if patients have 1+ or greater urine protein.  
- EKG
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4 registration procedures

Eligible participants will be entered on study by a member of the study team.
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4.1 registration process

Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) within 24 hours of signing consent. A registration Eligibility Checklist from the Web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via encrypted email to: NCI Central Registration Office (HOIS) (ncicentralregistrationl@mail.nih.gov). After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to advise them of the acceptance of the patient on the protocol prior to the release of any investigational agents. Verification of Registration will be forwarded electronically via email to the research team. Please note that it is very important for all registrars to acquire encrypted e-mail from NIH Help Desk, since the verification of registration includes patient's information. A recorder is available during non-working hours.
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4.2 participating site registration

All patients must be registered through the NCI Central Registration Office (CRO) via the Coordinating Center. A protocol registration form will be completed by the Coordinating Center, NCI CCR. To register a participant after they have signed the consent, complete Appendix F (Eligibility/Pre-Registration Worksheet) and fax (or email) it, along with all supporting records, to the Coordinating Center's Research Nurse, Ashley Bruns, Phone: (240) 858-3162, Fax (301) 451-5625, ashley.bruns@nih.gov. The Coordinating Center will notify you either by e-mail or fax that the protocol registration form has been received. The Coordinating Center will register the patient and provide the participating site with the patient's unique patient ID number. This unique ID number is to be used on all research samples and data entry for this patient. Questions about eligibility should be directed to the Coordinating Center's Research Nurse, Ashley Bruns, Phone: (240) 858-3162, Fax (301) 451-5625, ashley.bruns@nih.gov.
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4.3 off protocol therapy and

NCI Clinical Center: Authorized staff must notify the Central Registration Office (CRO) when a patient is taken off protocol therapy and when a patient is taken off-study. A Participant Status Updates Form from the website (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and sent via encrypted email to: NCI Central Registration Office (HOIS) (ncicentralregistration-l@mail.nih.gov).  
Participating sites: Authorized staff must notify the Coordinating Center Central Registration Office (CRO) when a patient is taken off protocol therapy and when a patient is taken off-study. The Participant Status Updates Form included in Appendix F must be completed and sent via encrypted email to: NCI Central Registration Office (HOIS) (ncicentralregistrationl@mail.nih.gov) and faxed or emailed to the Coordinating Center's Research Nurse, Ashley Bruns, Phone: (240) 858-3162, Fax (301) 451-5625, ashley.bruns@nih.gov.
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5 treatment plan

This is a multicenter phase II trial of patients with soft tissue sarcoma. Treatment will be administered on an outpatient basis. Patient evaluations will be performed throughout the study as described below. Baseline history, physical examination, laboratory evaluations, urinalysis, pregnancy test, and EKG must be conducted within 8 days prior to start of protocol therapy. If protocol therapy is started within 8 days of the eligibility screening evaluations (see Section 3.4), the results from these screening evaluations may be used as baseline measurements. If >8 days have passed since the screening evaluations, the medical history, physical examination, laboratory evaluations, urinalysis, pregnancy test, and EKG must be repeated prior to starting protocol therapy. Tumor imaging must be performed within 28 days prior to start of protocol therapy.  
History and physical examination, labs (CBC with differential; serum chemistries), serum or urine pregnancy test (for female participants of childbearing potential), and EKG will be performed at baseline and within 8 days prior to the start of each new cycle after cycle 1. B12 and folate are not part of the screening evaluation but will be measured at baseline (within 8 days prior to start of protocol therapy) and every 12 weeks (every 3 cycles; within 8 days prior to the start of the cycle). Urinalysis for evaluation of urine protein/creatinine ratio should occur at baseline, within 8 days prior to the start of each new cycle after cycle 1, and as clinically indicated. CT scans will be performed at baseline (within 28 days prior to start of protocol therapy), and repeat imaging scans will be performed every 2 cycles (every 3 cycles for patients on study for more than 1 year; every 4 cycles for patients on study more than 3 years). MRI evaluation of site of disease may be performed in lieu of CT evaluation at the discretion of the principal investigator if in the opinion of the investigator this modality would provide a more accurate assessment of disease than a CT would for a given site. The history and physical exam, pregnancy test, CT scan, EKG, and all other protocol-required labs, including blood collections for CTCs, will be done less frequently for patients on study more than one year (every 3 cycles after 1 year on study and every 4 cycles after 3 years on study). B12 and folate (measured at baseline and then every 3 cycles) will be measured every 4 cycles after 3 years on study.
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5.1 agent administration

Adult patients will receive cabozantinib tablets as 60 mg tablets orally once a day in a 28-day cycle. A dose of 100 mg daily was tested and found to have acceptable efficacy albeit greater toxicity and a dose of 40 mg was also tested and found to be efficacious30,38. Patients who tolerate the 60 mg dose with little or minimal toxicity may be dose escalated to 80 mg after the first restaging (after cycle 2) for subsequent cycles. Dose escalation will be decided by the treating physician after discussion with the study PI. 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. Cabozantinib will be taken on an  
empty stomach, 1 hour before or 2 hours after food. Subjects may fast for at least 1 hour before and 2 hours after eating. The drug will be administered once daily at approximately the same time each day. Tablets must be swallowed whole and not crushed. A new cycle may begin up to 1 week later than it would otherwise be scheduled based on the 28-day cycle, to allow for flexibility for days the clinic is closed and other unexpected events. Patients will be provided with a Study Diary (Appendix C), instructed in its use, and asked to bring it with them to each appointment. After cycle 2, a cycle will be considered completed if 90% of the prescribed doses are administered.
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cabozantinib

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.  
Concomitant medications that are inhibitors or inducers of the CYP3A4 pathway should be used with caution. Strong CYP3A4 inducers such as rifampin, carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, St. John's Wort, and troglitazone should be avoided. In addition, 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 (Investigators brochure, 2011). Caution must also 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 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. Appendix B presents guidelines for identifying medications/substances that could potentially interact 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/*). 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. Cabozantinib is highly protein bound, 99.9%. Use caution when co-administering cabozantinib with medications that are highly protein-bound (e.g., diazepam, furosemide, dicloxacillin, and propranolol). Administration of warfarin with cabozantinib is contraindicated as warfarin is highly protein-bound and has a very narrow therapeutic index. 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: In a relative bioavailability study in dogs, cabozantinib exposure was not significantly affected by drugs that alter gastric pH. Nevertheless, drugs such as proton pump inhibitors (PPIs) and H2-antagonists produce profound suppression of gastric acid secretion and significant increases in gastric pH. By elevating gastric pH, PPIs and H2-antagonists may decrease cabozantinib plasma exposure levels and its effectiveness in vivo, resulting in clinically significant drug interactions.  
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.
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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, and two-way crossover study (Study XL184-004). Based on the preliminary PK data, a high fat meal did not appear to alter the terminal t1/2, but significantly increased the median tmax to 6 hours from 4 hours (fasted). The high fat meal also significantly increased both the cabozantinib Cmax and AUC values by 41% and 57%, respectively. Based on this result, cabozantinib should be taken on an empty stomach (fasting is required 1 hour before, and 2 hours after each cabozantinib dose).
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5.2 general concomitant medication and

All patients will be provided with the best available supportive care. No chemotherapeutic drugs other than cabozantinib will be allowed. 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.
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anorexia

Anorexia leading to grade 3 weight loss will be managed according to local standard of care including nutritional support. Pharmacologic therapy such as megestrol acetate or dronabinol may be considered. For Grade 3 weight loss dose reductions will not be done unless pharmacologic interventions have been tried first and fail.
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diarrhea

If diarrhea develops and does not have an identifiable cause other than study drug administration, anti-diarrheals such as Lomotil (diphenoxylate HCl 2.5 mg + atropine sulfate 0.025 mg/tablet) dosed according to package insert or loperamide 4 mg po after the first unformed stool with 2 mg po with every 2 hours (4 mg every 4 hours while asleep), till resolution of episode of at least 12 hours (no more than 16 mg of loperamide during a 24-hour period). This regimen can be repeated for each diarrheal episode. Diarrhea will be considered refractory if it does not resolve within 24 hours to ≤ Grade 2 with the above regimen (maximum of 16 mg of loperamide in a 24-hour period). If the patient develops blood or mucus in the stool, dehydration, or hemodynamic instability, or fever along with the diarrhea, anti-diarrheals will be discontinued and the patient will be treated with IV fluids and antibiotics as medically indicated. The dose modification guidance in Table 6-1 should be followed. In addition, general supportive measures will 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.
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nausea and vomiting

Anti-emetics will not be administered routinely prior to cabozantinib. 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.
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myelosuppression

The use of growth factors will be considered in accordance with ASCO guidelines.
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stomatitis and mucositis

Preventive measures may include a comprehensive dental examination to identify any potential complications before study treatment is initiated. Appropriate correction of local factors should be instituted as indicated, such as modification of ill-fitting dentures and appropriate care of gingivitis. During treatment with cabozantinib, good oral hygiene and standard local treatments such as non-traumatic cleansing, and oral rinses (e.g., with a weak solution of salt and baking soda) should be maintained. The oral cavity should be rinsed and wiped after meals, and dentures should be cleaned and brushed often to remove plaque. Local treatment should be instituted at the earliest onset of symptoms. When stomatitis interferes with adequate nutrition and local therapy is not adequately effective, dose reduction or temporary withholding of cabozantinib should be considered.
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5.3 duration of therapy

In the absence of treatment delays due to adverse events, treatment may continue until one of the following criteria applies:
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5.4 duration of follow up

Patients will be followed for 30 days after the last dose is administered or until one of the following occurs: patient enrolls on another protocol, patient receives standard of care, or death, and whichever comes first. The follow-up will consist of a phone call between Days 27-30 after the last dose to evaluate adverse events that were ongoing and any new events that might be deemed related to the therapy. Toxicities felt to be possibly, probably, or definitely related to the study drugs that have not resolved or stabilized by Day 30 post-treatment will be followed until stabilization or resolution via biweekly phone calls.
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5.5 criteria for removal from

Patients will be removed from study for one of the following reasons: completed 30-day follow up period or toxicities are unresolved but stabilized, patient withdraws from study, and/or patient enrolls on another protocol. The reason for study removal and the date the patient was removed must be documented in the medical record and communicated to Central Registration per Section 4.
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6 dosing delays/dose modifications

Treatment may be delayed for a maximum of 2 weeks for toxicities. In case toxicities do not resolve as stated, the patient will not receive further therapy on this protocol and will be followed for resolution of toxicities. Start of next cycle may be delayed for up to 1 week to accommodate scheduling conflicts. Dose modifications are intended for within-cycle and start-of-next-cycle changes. If administration of study drug is interrupted for any reason, it will not be made up, and counting of the cycle days continues. A maximum of 2 dose reductions will be allowed before patient is taken off treatment. Patients who require a dose reduction will not have the dose reescalated.  
- Disease progression
- Intercurrent illness that prevents further administration of treatment - Significant toxicity occurs despite 2 dose reductions as described in Section 6 or no lower dose level exists
- Patient decides to withdraw from the study
- General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.  
- Necessity for treatment with other anticancer treatment prohibited by the protocol, - Sexually active subjects who refuse to use medically accepted barrier methods of contraception (e.g., male condom, female condom) during the course of the study and for 4 months following discontinuation of study treatment,
- Women who become pregnant or are breast feeding,
- Request by regulatory agencies for termination of treatment of an individual subject or all subjects under the protocol, or
- Significant noncompliance with the protocol schedule in the opinion of the investigator.  
All patients begin at dose level 0. **Patients who tolerate dose level 0 with no or minimal**
toxicity may be escalated to 80 mg daily, sequentially, after the first restaging (after cycle 2). Dose escalation will be decided by the treating physician after discussion with the study PI.  
| Dose Level   | Cabozantinib Dose   |
|--------------|---------------------|
| -2           | 20 mg               |
| -1           | 40 mg               |
| 0            | 60 mg               |
| +1           | 80 mg               |
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6.1 management of cabozantinib-related ae

Subjects will be monitored continuously for AEs throughout the study. Subjects must be instructed to notify their physician immediately for any and all toxicities.  
General guidelines for the management of non-hematologic and hematologic toxicities are provided in Table 6-1 and Table 6-2, respectively.  
These algorithms should be followed unless there are specific clinical circumstances for which the treating physician decides an alternative treatment approach is clinically appropriate. Consultation with the study chair is recommended.  
| CTCAE Version 5                                                                                                                                                                        | Guidelines/Intervention                                                                                                                                                                                                                                                                                                                                                 |                                                             |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|
| Grade                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                                                                         |                                                             |
| Grade 1:                                                                                                                                                                               | Add supportive care as indicated. Continue cabozantinib at the current  dose level.                                                                                                                                                                                                                                                                                     |                                                             |
| Grade 2: Grade 2 AEs considered  related to cabozantinib that  are subjectively tolerable or  easily managed                                                                           | Add supportive care as indicated. Continue cabozantinib at the current  dose level.                                                                                                                                                                                                                                                                                     |                                                             |
| Grade 2 AEs considered  related to cabozantinib that  are intolerable to the subject  or deemed unacceptable in  the investigator's judgment;  or are not easily managed or  corrected | Dose reduce - If the AE dose not resolve to Grade ≤1 or baseline in 7 to 10 days  or worsens at any time, cabozantinib dosing should then be  interrupted. Then upon resolution to baseline or Grade ≤ 1, the  reduced dose should be restarted. - If the AE does resolves to resolves to Grade ≤1 or baseline without  a dose interruption, continue the reduced dose. |                                                             |
| Grade 3: Grade 3 AEs considered  related to cabozantinib which occurred without  optimal prophylaxis or                                                                                | -                                                                                                                                                                                                                                                                                                                                                                       | 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                                                                                                                                                                             |                                                             |  
Table 6-1. General Approach to the Management of Cabozantinib-Related NonHematologic Adverse Events  
| Clinical Center Protocol #13-C-0044 which is easily managed by  medical intervention or  resolved quickly 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  Permanently discontinue study treatment unless determined that the  related to study treatment subject is unequivocally deriving clinical benefit. In this case, upon  recovery to Grade ≤1 or baseline, the subject may be re-treated at a  reduced dose that is to be determined by the investigator and sponsor  but only with sponsor approval. Dose reductions or delays may occur in the setting of lower grade toxicity than defined above if the  investigator believes that it is in the interest of the subject's safety.  Table 6-2. General Approach to the Management of Cabozantinib-Related Hematologic  Adverse Events CTCAE Version 5 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.   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| CTCAE Version 5 Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Intervention   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|
| Other Grade 4 Hematologic Toxicities 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). Grade 4 hematologic  toxicities  other than anemia |                |
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hepatobiliary disorders

Elevations of transaminases have also been observed during treatment with cabozantinib. In general, it is recommended that subjects with elevation of ALT, AST, and/or bilirubin have more frequent laboratory monitoring of these parameters. If possible, hepatotoxic concomitant medications and alcohol should be discontinued in subjects who develop elevated transaminases. Since subjects may enter the study with elevations of AST/ALT at baseline, the following guideline should be used for dose modifications:  
| Transaminase  elevation  CTCAE v5.0                                 | Intervention                                                                                                                                                                                                                                                                                                                                                                    |
|---------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Subjects with AST and ALT less than or equal to the ULN at baseline |                                                                                                                                                                                                                                                                                                                                                                                 |
| Grade 1                                                             | Continue cabozantinib with weekly monitoring of liver function tests (LFTs) for at  least 4 weeks or until LFTs return to baseline or stabilize at grade 1. Then resume  the standard protocol-defined monitoring of LFTs.                                                                                                                                                      |
| Grade 2                                                             | Continue cabozantinib with weekly monitoring of LFTs for 2 weeks or until LFTs  return to ≤ Grade 1 or baseline. If LFTs continue to rise within Grade 2, interrupt  cabozantinib treatment. Then continue with weekly LFTs for 4 weeks or 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 from baseline AND both AST  and ALT are ≤ 5.0  x ULN                                                   | Continue cabozantinib treatment with weekly monitoring of LFTs for 4 weeks or  until LFTs return to baseline or stabilize, whichever occurs first. If LFTs continue  to rise but remain ≤5.0 x ULN continue to monitor LFTs weekly for  4 weeks. If LFTs continue to rise after the additional 4 weeks of monitoring,  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  from baseline 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.                                                                                                                                              |  
Cabozantinib treatment should also be interrupted when transaminase increases are accompanied by progressive elevations of total bilirubin, and/or elevations of coagulation tests (e.g., International Normalized Ratio [INR]). Monitoring of transaminases should be intensified (2–3 times per week) and cabozantinib should be held until the etiology of the abnormalities is determined and these abnormalities are corrected or stabilize at clinically acceptable levels (INR < 1.5  ULN, total bilirubin < 1.5  ULN,
aminotransferases ≤ baseline grade). Subjects must have cabozantinib permanently discontinued if transaminase elevations are accompanied by evidence of impaired hepatic function (bilirubin elevation >2 ULN), in the absence of evidence of biliary obstruction (i.e., significant elevation of alkaline phosphatase) or some other explanation of the injury (e.g., viral hepatitis, alcohol hepatitis), as the combined finding (i.e., Hy's Law cases) represents a signal of a potential for the drug to cause severe liver injury. All subjects who develop isolated bilirubin elevations of Grade 3 should have study treatment held until recovered to Grade ≤1 or baseline (or lower). If this occurs within 6 weeks of the dosing delay, study treatment may continue at a reduced dose. In subjects without biliary obstruction and Grade 4 bilirubin elevation, or with recurrence of Grade 3 bilirubin elevation after a dose reduction, study treatment must be discontinued.
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pancreatic conditions

Amylase and lipase elevations have been observed in clinical studies with cabozantinib. The clinical significance of asymptomatic elevations of enzymes is not known but in general have not been associated with clinically apparent sequelae. It is recommended that subjects with lipase elevation and/or symptoms of pancreatitis have more frequent laboratory monitoring of lipase and/or amylase (2-3 times per week). Subjects with symptomatic pancreatitis should be treated with standard supportive measures.  
| 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.               |                     |
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asymptomatic lipase or amylase elevations

| Pancreatitis                      |                                                                                                                                                                                                                                                           |                                                                        |
|-----------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|
| Grade 2 and                       | -                                                                                                                                                                                                                                                         | Continue at current dose level. More frequent monitoring of lipase and |
| asymptomatic                      | 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 pressuresensitive areas of hands and feet; and use of thick cotton gloves and socks to prevent injury and to keep the palms and soles dry. Subjects with skin disorders should be carefully monitored for signs of infection (e.g., abscess, cellulitis, or impetigo).  
Early signs of hand-foot syndrome can include tingling, numbness, and slight redness or mild hyperkeratosis. Early manifestations include painful, symmetrical red and swollen areas on the palms and soles. The lateral sides of the fingers or periungual zones may also be affected. Adequate interventions are required to prevent worsening of skin symptoms such as blisters, desquamations, ulcerations, or necrosis of affected areas. Aggressive management of symptoms is recommended, including early dermatology referral. Treatment guidelines for PPE related to study treatment are presented in the table below. In the case of study treatment-related skin changes (e.g., rash, hand-foot syndrome), the investigator may request that additional assessments be conducted with the subject's consent. These assessments may include digital photographs of the skin changes and/or a biopsy of the affected skin and may be repeated until the skin changes resolve.  
| Hand-Foot Skin Reaction and Hand Foot Syndrome (PPE)   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
|--------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 1                                                | Continue cabozantinib at current dose. Start urea 20% cream twice daily AND clobetasol  0.05% cream once daily. Assess subject at least weekly for changes in severity. Subjects  should be instructed to notify investigator immediately if severity worsens.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| Grade 2                                                | If tolerable, continue cabozantinib at current dose. If intolerable, reduce cabozantinib  dose to next lower level and/or interrupt dosing. Start/continue urea 20% cream twice  daily AND clobetasol 0.05% cream once daily. Add analgesics for pain control with  NSAIDs/GABA agonists/narcotics if needed. Assess subject at least weekly for changes  in severity. If treatment was interrupted (but not reduced), treatment may be restarted at  the same dose or at one dose level lower when reaction decreases to Grade 1 or 0. If a  treatment interruption is again required, the dose must be reduced when treatment  resumes. Subjects should be instructed to notify investigator immediately if severity  worsens. If severity worsens at any time, or affects self-care, proceed to the management  guidelines for Grade 3 PPE. |
| Grade 3                                                | Interrupt study treatment until severity decreases to Grade 1 or 0. Start/continue urea  20% cream twice daily AND clobetasol 0.05% cream once daily. Pain control with  NSAIDs/GABA agonists/narcotics. Treatment may restart at one dose level lower when  reaction decreases to Grade 1 or 0. Permanently discontinue subject from study if  reactions worsen or do not improve within 6 weeks.                                                                                                                                                                                                                                                                                                                                                                                                                                             |
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embolism and thrombosis

Deep vein thrombosis and PE have been observed in clinical studies with cabozantinib; including fatal events (please refer to the Investigators Brochure). 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 35 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 experimental treatment 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. *Note:* lovenox will be administered as therapeutic anticoagulation; no data exist of an interaction between cabozantinib and lovenox. 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.
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hypertension toxicity

Therapeutic BP monitoring by a health care provider will occur at the beginning of every cycle for the duration of treatment .All patients will be required to monitor their BP at least once a day (preferably BID) throughout the treatment and record the readings in the study diary (Appendix C). Subjects with known hypertension should be optimally managed prior to study entry. 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 4 below). If the readings are abnormal the patient needs to have the BP reconfirmed by a health care provider prior to changes in study drug or antihypertensive medications are made. Table 4 will be used for the management, and for the determination of cabozantinib dose modification. Suggested antihypertensive medications are listed in Appendix D.  
| Table 4 Criteria for Dose                                                            | Treatment/Cabozantinib Dose Modification                                                                                                                                                                                                                                                                                                                                                                      |
|--------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Modifications                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                               |
| Subjects not receiving optimized anti-hypertensive therapy                           |                                                                                                                                                                                                                                                                                                                                                                                                               |
| > 140 mm Hg (systolic)  and < 160 mm Hg OR > 90 mm Hg (diastolic)  and < 110 mm Hg   | - Increase antihypertension therapy (i.e., increase dose of existing  medications and/or add new antihypertensive medications)  - Maintain dose of cabozantinib - If optimal antihypertensive therapy (usually to include 3 agents) does not  result in blood pressure < 140 systolic or < 90 diastolic, or if the subject  is symptomatic, the dose of cabozantinib should be reduced.                       |
| ≥ 160 mm Hg (systolic)  and < 180 mm Hg OR ≥ 110 mm Hg  (diastolic) and < 120  mm Hg | - Reduce cabozantinib by one dose level. - Increase antihypertension therapy (i.e., increase dose of existing  medications and/or add new antihypertensive medications)  - Monitor subject closely for hypotension. - If optimal antihypertensive therapy (usually to include 3 agents) does not  result in blood pressure < 140 systolic or < 90 diastolic, dose of  cabozantinib should be reduced further. |
| ≥ 180 mm Hg (systolic)  OR ≥ 120 mm Hg (diastolic )                                  | - Interrupt treatment with cabozantinib Add new or additional antihypertensive medications and/or increase dose of existing medications. - Monitor subject closely for hypotension.36                                                                                                                                                                                                                                                                                                                                                                                                               |  
| Criteria for Dose                                                                                                                                                                 | Treatment/Cabozantinib Dose Modification                                                                                                                                                                                                                                         |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Modifications                                                                                                                                                                     | - When SBP < 140 and DBP < 90, restart cabozantinib treatment at one  dose level lower - If optimal antihypertensive therapy (usually to include 3 agents) does not  result in blood pressure < 140 systolic or < 90 diastolic, dose of  cabozantinib should be reduced further. |
| Hypertensive crisis or  hypertensive  encephalopathy                                                                                                                              | Discontinue all study treatment                                                                                                                                                                                                                                                  |
| BP, blood pressure, SBP systolic blood pressure, DBP diastolic blood pressure NOTE: If SBP and DBP meet different criteria in table, manage per higher dose-modification criteria |                                                                                                                                                                                                                                                                                  |  
Proteinuria toxicity Evaluation of urine protein/creatinine ratio (UPC) should occur as follows: at baseline and at the start of each cycle. Dose modification should be done according to Table 5 below.  
| Urine Protein/Creatinine Ratio ≤ 1          | -                                                                                                                                                                                                                                                                                                                                | No change in treatment or monitoring                                             |
|---------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------|
| > 1 and < 3.5                               | -                                                                                                                                                                                                                                                                                                                                | Confirm with a 24 hour urine protein excretion  within 7 days.                   |
| -                                           | If proteinuria of > 1 g/24 hours is confirmed, hold  cabozantinib and continue with UPCR monitoring.  When UPCR returns to < 1, 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. |                                                                                  |
| ≥ 3.5                                       | -                                                                                                                                                                                                                                                                                                                                | Hold cabozantinib immediately and confirm with  24 hour urine protein excretion. |
| -                                           | Evaluate for nephritic syndrome. If present,  discontinue cabozantinib treatment permanently,  and monitor subject for resolution of nephritic  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 decreased to < 1, then revert to UPCR  monitoring frequency specified in protocol                                                                                     |                                                                                  |
| UPCR, urine protein/urine creatinine ratio. |                                                                                                                                                                                                                                                                                                                                  |                                                                                  |
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guidelines for the prevention of

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
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following

- Tumor lesions with cavitations or tumor lesions which invade, encase, or abut major blood vessels. The anatomic location and characteristics of primary tumors or metastases as well as the medical history should be carefully reviewed in the selection of subjects for treatment with cabozantinib.  
- Recent or concurrent radiation to the thoracic cavity. - Active peptic ulcer disease, ulcerative colitis, and other inflammatory GI diseases.  
- Underlying medical conditions which affect normal hemostasis (e.g., deficiencies in clotting factors and/or platelet function, or thrombocytopenia).  
- Concomitant medication with anticoagulants or other drugs which affect normal hemostasis.  
- History of clinically significant hemoptysis.  
Cabozantinib should be discontinued in subjects with serious and life-threatening bleeding events or recent hemoptysis (≥ 0.5 teaspoon (2.5 mL) 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.
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rectal and perirectal abscess

Rectal and perirectal abscesses have been reported, sometimes in subjects with concurrent diarrhea. These should be treated with appropriate local care and antibiotic therapy. Cabozantinib should be held until adequate healing has taken place.  
Guidelines for Prevention of GI Perforation/Fistula and Non-GI Fistula Formation GI perforation/fistula and Non-GI fistula formation have been reported with approved drugs that inhibit VEGF pathways as well as with cabozantinib. Carefully monitor for episodes of abdominal pain, especially in subjects with known risk factors for developing GI perforation/fistula or non-GI fistula, to allow for early diagnosis. Such risk factors include (but may not be limited to) the following:
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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.  
38 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.
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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.
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endocrine disorders

Prospective studies of markers of thyroid functions are currently ongoing in two singleagent studies to characterize the effects of cabozantinib on thyroid function. Preliminary data indicate that cabozantinib affects thyroid function tests (TFTs) in a high number of subjects (see Cabozantinib Investigator's Brochure). Routine monitoring of thyroid function and assessments for signs and symptoms associated with thyroid dysfunction is recommended for subjects treated with cabozantinib. Management of thyroid dysfunction (e.g., symptomatic hypothyroidism) should follow accepted clinical practice guidelines. Other endocrine disorders such as hypocalcemia and hyperglycemia, and associated laboratory changes, have been observed in less than 10% of subjects. Monitoring with standard laboratory tests for endocrine disorders and clinical examination prior to initiation and during treatment with cabozantinib is required. Cabozantinib should be discontinued in subjects with severe or life-threatening endocrine dysfunction.  
Guidelines for Prevention of Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported with use of antiangiogenic drugs and bisphosphonates and denosumab in cancer patients. Additional risk factors for ONJ have been identified such as use of corticosteroids, chemotherapy, local radiotherapy, poor oral hygiene, smoking, dental or orofacial surgery procedures, and cancer disease itself. Cases of osteonecrosis have been reported in subjects treated with cabozantinib, the details of which are provided in the current version of Investigator's Brochure. As a preventive measure, invasive dental procedures should be avoided if possible in subjects who have previously been treated with or concomitantly receive bisphosphonates or denosumab. In cases where dental procedures are unavoidable, the risks and benefits of a dental procedure and the extent of the procedure as well as the risk of developing osteonecrosis of the jaw need to be considered when deciding on the duration of a temporary treatment interruption of cabozantinib. If clinically possible, treatment with cabozantinib should be held for at least 2 weeks prior to a dental procedure and resumed after complete wound healing occurred. Subjects with any documented case of osteonecrosis should have study treatment interrupted, and appropriate clinical management should be initiated. Reinitiation of study treatment must be discussed with and approved by the Sponsor on a case by case basis.  
Guidelines for Management of Treatment-Emergent Corrected QT (QTc) Prolongation  
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 EKGs 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 EKGs should be performed within 30 minutes after the initial EKG with intervals not less than 3 minutes apart. If the average QTcF from the three EKGs 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 EKG 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.
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7 adverse events list and

Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine whether the event requires expedited reporting (via CTEP-AERS) **in addition** to routine reporting.