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| Abbreviated Title: Ph 2 XL184 in urothelial CA  CTEP Protocol #: 9236  CC Protocol #: 12-C-0205 P  Version Date: May 10, 2019  NCT Number: NCT01688999  Title: A Phase II Study of Cabozantinib (XL184) in Patients with Advanced/Metastatic Urothelial  Carcinoma  NCI Principal Investigator: Andrea B. Apolo, M.D. A-E Genitourinary Malignancies Branch (GMB)  National Cancer Institute 10 Center Drive Room 12N226 Bethesda, MD 20892 Phone: 301-480-0536  Fax: 301-402-0172  Email: andrea.apolo@nih.gov Lead Associate Investigator: William Dahut, M.D., GMB, CCR, NCI A-E NIH Associate Investigators: Peter Choyke, M.D., MIP, CCR, NCI B, E James Gulley, M.D., Ph.D., GMB, CCR, NCI A-E Ravi Madan, M.D., GMB, CCR, NCI A-E Howard Parnes, M.D., Prostate and Urologic Cancer Research  Group A-E John Wright, M.D., Ph.D., IDB, CTEP, DCTD, NCI B, E *Donald Bottaro, Ph.D., UOB/CCR/NCI B, E *William Figg, Pharm.D., GMB, CCR, NCI B, E *Douglas Price, Ph.D., GMB, CCR, NCI B, E *Les R. Folio, D.O., MPH, MSc, MAS B, E *Jane Trepel, DTB, CCR, NCI B, E *Mark Raffeld, M.D., LP, CCR, NCI B, E *Maria Merino, M.D., LP, CCR, NCI B, E *Michael Dean, Ph.D., Laboratory of Translational Genomics,  DCEG, NCI B, E Statistician: *Seth Steinberg, Ph.D. B, E Biostatistics and Data Management Section National Cancer Institute 9609 Medical Center Drive, Room 2-W-334, MSC 9716  Bethesda, MD 20892-9716  Phone: 240-276-5563  Email: steinbes@mail.nih.gov Responsible Research Nurse /  Corrine M. Keen, R.N., M.S., CCRP A,B,C Study Coordinator: 10 Center Drive, Room 13N230 1   |
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Phone: 240-760-6097 Email: ckeen@mail.nih.gov Referral Contact: Corrine M. Keen, R.N., M.S., CCRP
* not responsible for patient care Roles: A. Obtain information by intervening or interacting with living individuals for research purposes B. Obtaining identifiable private information about living individuals C. *Obtaining the voluntary informed consent of* individuals to be subjects D. *Makes decisions about subject eligibility* E. *Studying, interpreting, or analyzing identifiable private* information or data/specimens for research purposes F. Studying, interpreting, or analyzing coded, linked data or specimens for research purposes  
| CTEP Supplied Agents:  Drug Name: Cabozantinib (XL184)  IND Number: 116059  NSC Number: 761968  Sponsor: CTEP  Manufacturer: Exelixis   |
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G. *Some/all research activities performed outside NIH*
Commercially available agents:
18FDG and Na18F will be supplied from commercial sources by the NCI Molecular Imaging Program
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precis background objectives eligibility design

x In the United States, urothelial carcinoma (UC) of the bladder is the fourth most common malignancy in men and the ninth most common in women with an estimated 69,250 new cases and 14,990 deaths in the year 2011 x There is no FDA-approved second line drug for patients with metastatic UC
x Multiple lines of evidence support targeting angiogenesis in UC x In human bladder cancer, overexpression of c-Met/Axl/PDGFR-α or c-Met alone showed significant correlation with poor survival x Cabozantinib is a new chemical entity that inhibits multiple receptor tyrosine kinases with growth-promoting and angiogenic properties.  
x The primary targets of cabozantinib are MET, VEGFR2, and RET
x To determine the response rate of cabozantinib in patients with progressive urothelial cancer who have received prior cytotoxic chemotherapy x Patients in cohort 1 must have a histologically confirmed diagnosis of metastatic, progressive urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.  
x Patients in cohort 2 must have a histologically confirmed diagnosis of bone only metastatic, urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.  
x Patients in cohort 3 must have a histologically confirmed diagnosis of non-transitional cell carcinoma cancer (including but not limited to squamous cell, neuroendocrine, adenocarcinoma including urachal and sarcomatoid) of the bladder, urethra, ureter, or renal pelvis.  
x Patients must have been previously treated, as defined by treatment with at least one prior cytotoxic chemotherapy regimen or agent. Patients may have received any number of prior cytotoxic agents.  
x 18 years of age or older. x A maximum of 71 subjects will be enrolled in this open label, non-randomized, phase II trial of 60 mg each day of cabozantinib. Up to 50 patients will be accrued to cohort 1 (metastatic, progressive urothelial cancer). The remainder will be enrolled on exploratory cohorts 2 & 3, bone only metastatic urothelial disease and non TCC bladder cancer respectively, during the time the study is accruing patients for cohort 1. Note: Patients who tolerate cabozantinib at 60 mg daily during the first 2 cycles (first restaging time period) without ≥ grade 2 toxicity may undergo dose escalation to 80 mg daily at the discretion of the Principal Investigator.  
x A Simon 2 stage design with alpha=0.05 and beta = 0.10 as acceptable error probabilities.  
Initially 21 subjects will be enrolled and followed for progression. If 2 or more of cohort 1 subjects experiences a response, enrollment will continue until a total of 41 evaluable  
subjects with progressive urothelial cancer have been entered. 2-3 patients per month may enroll on this trial; thus, 2 to 3 years is anticipated as the accrual period.  
x Each patient will undergo response evaluation assessments with CAP CT (or MRI) with or without Na18F PET CT every 8 weeks while on active protocol therapy starting at baseline.  
Patients will undergo investigational FDG PET/CT and PET/MRI (optional) at baseline, week 4 and week 8.
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schema treatment and imaging schedule

| TABLE OF CONTENTS                                                                                                                                       |                                                                                                                                                                       |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| PRÉCIS .                                                                                                                                                |                                                                                                                                                                       |
| SCHEMA................................................................................................................................................4 |                                                                                                                                                                       |
| TABLE OF CONTENTS                                                                                                                                       |                                                                                                                                                                       |
| OBJECTIVES .                                                                                                                                            |                                                                                                                                                                       |
| 1                                                                                                                                                       | Primary Objective                                                                                                                                                     |
| 1.1                                                                                                                                                     |                                                                                                                                                                       |
| 1.2                                                                                                                                                     | Secondary Objectives                                                                                                                                                  |
| Exploratory Objectives                                                                                                                                  |                                                                                                                                                                       |
| 1.3                                                                                                                                                     |                                                                                                                                                                       |
| 2                                                                                                                                                       | BACKGROUND .                                                                                                                                                          |
| 2.1                                                                                                                                                     | Urothelial Cancer ................................................................................................................................................. 8 |
| 2.2                                                                                                                                                     | IND Agent - Cabozantinib (XL184) .                                                                                                                                    |
| 2.3                                                                                                                                                     | RATIONALE                                                                                                                                                             |
| Correlative Studies Background .                                                                                                                        |                                                                                                                                                                       |
| 2.4                                                                                                                                                     |                                                                                                                                                                       |
| 3                                                                                                                                                       | PATIENT SELECTION                                                                                                                                                     |
| 3.1                                                                                                                                                     | Eligibility Criteria .                                                                                                                                                |
| 3.2                                                                                                                                                     | Screening Evaluation .                                                                                                                                                |
| 4                                                                                                                                                       | REGISTRATION PROCEDURES                                                                                                                                               |
| 4.1                                                                                                                                                     | Treatment Assignment Procedures                                                                                                                                       |
| S                                                                                                                                                       | TREATMENT PLAN                                                                                                                                                        |
| 5.1                                                                                                                                                     | Agent Administration                                                                                                                                                  |
| 5.2                                                                                                                                                     | General Concomitant Medication and Supportive Care Guidelines ............................... 31                                                                      |
| 5.3                                                                                                                                                     | ON Study Assessments .                                                                                                                                                |
| 5.4                                                                                                                                                     | D Duration of Therapy                                                                                                                                                 |
| 5.5                                                                                                                                                     | D Duration of Follow Up                                                                                                                                               |
| Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 37                                                       |                                                                                                                                                                       |
| 5.6                                                                                                                                                     |                                                                                                                                                                       |
| 6                                                                                                                                                       | DOSING DELAYS/DOSE MODIFICATIONS .............................................................................39                                                      |
| 6.1                                                                                                                                                     | Cabozantinib .                                                                                                                                                        |
| 6.2                                                                                                                                                     | Cabozantinib drug holiday                                                                                                                                             |
| 7                                                                                                                                                       | ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ....................................53                                                                               |
| 7.1                                                                                                                                                     | Comprehensive Adverse Events and Potential Risks List (CAEPR)                                                                                                         |
| 7.2                                                                                                                                                     | Definitions                                                                                                                                                           |
| 7.3                                                                                                                                                     | Expedited Adverse Event Reporting to CTEP                                                                                                                             |
| 7.4                                                                                                                                                     | Routine Adverse Event Reporting to CTEP                                                                                                                               |
| 7.5                                                                                                                                                     | NIH Intramural IRB and Clinical Director Reporting ........................................................ 62                                                        |
| 7.6                                                                                                                                                     | Secondary Malignancy                                                                                                                                                  |
| S                                                                                                                                                       |                                                                                                                                                                       |  
| Version Date: 05/10/2019                                                                                                                  |                                                                                                                                                                            |
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| 7.7                                                                                                                                       | Second Malignancy                                                                                                                                                          |
| DATA AND SAFETY MONITORING Plan                                                                                                           |                                                                                                                                                                            |
| 7.8                                                                                                                                       |                                                                                                                                                                            |
| 8                                                                                                                                         | PHARMACEUTICAL AND IMAGING AGENT INFORMATION ...................................63                                                                                         |
| 8.1                                                                                                                                       | Cabozantinib (XL184) (NSC 761968)                                                                                                                                          |
| 9                                                                                                                                         | BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ................................................66                                                                             |
| 9.1                                                                                                                                       | Biomarker Studies                                                                                                                                                          |
| 9.2                                                                                                                                       | Correlative Studies                                                                                                                                                        |
| 9.3                                                                                                                                       | Sample Storage, Tracking and Disposition .                                                                                                                                 |
| Samples for Genetic/Genomic Analysis .                                                                                                    |                                                                                                                                                                            |
| 9.4                                                                                                                                       |                                                                                                                                                                            |
| 10                                                                                                                                        | STUDY CALENDAR ...................................................................................................................................80                       |
| 11                                                                                                                                        | MENT OF EFFECT .........................................................................................................................83                                 |
| 1.1 Antitumor Effect - Solid Tumors                                                                                                       |                                                                                                                                                                            |
| DATA COLLECTION / DATA REPORTING / REGULATORY REQUIREMENTS ......89                                                                       |                                                                                                                                                                            |
| 12                                                                                                                                        | DATA COLLECTION                                                                                                                                                            |
| 12.1                                                                                                                                      |                                                                                                                                                                            |
| 12.2                                                                                                                                      | Genomic Data Sharing Plan                                                                                                                                                  |
| 12.3                                                                                                                                      | DATA Reporting .                                                                                                                                                           |
| 12.4                                                                                                                                      | CC                                                                                                                                                                         |
| Collaborative Agreements Language .................................................................................................... 91 |                                                                                                                                                                            |
| 12.5                                                                                                                                      |                                                                                                                                                                            |
| 12.6                                                                                                                                      | Material Transfer Agreement (MTA) for Samples Sent to HTG Molecular ............. 92                                                                                       |
| 12.7                                                                                                                                      | MMTA for Samples Sent to Baylor College ........................................................................................ 92                                        |
| 13                                                                                                                                        | STATISTICAL CONSIDERATIONS ..........................................................................................93                                                    |
| 13.1                                                                                                                                      | Study Design/Endpoints                                                                                                                                                     |
| Sample Size/Accrual Rate                                                                                                                  |                                                                                                                                                                            |
| 13.2                                                                                                                                      |                                                                                                                                                                            |
| 13.3                                                                                                                                      | Stratification Factors .                                                                                                                                                   |
| 13.4                                                                                                                                      | Analysis of Secondary Endpoints ............................................................................................................ 94                            |
| 13.5                                                                                                                                      | Reporting and Exclusions .                                                                                                                                                 |
| 14                                                                                                                                        | HUMAN SUBJECTS PROTECTIONS ...........................................................................................95                                                   |
| 14.1 Rationale For Subject Selection .                                                                                                    |                                                                                                                                                                            |
| 14.2                                                                                                                                      | Participation of Children ............................................................................................................................................. 95 |
| 14.3                                                                                                                                      | Participation of Subjects Unable to Give Consent ..................................................................... 95                                                  |
| 14.4 Evaluation of Benefits and Risks/Discomforts                                                                                         |                                                                                                                                                                            |
| Risks/Benefits Analysis                                                                                                                   |                                                                                                                                                                            |
| 14.5                                                                                                                                      |                                                                                                                                                                            |
| 14.6 Consent and Assent Process and Documentation                                                                                         |                                                                                                                                                                            |
| 15                                                                                                                                        | REFERENCES ................................................................................................................................................98              |
| APPENDICES .                                                                                                                              |                                                                                                                                                                            |
| 16                                                                                                                                        |                                                                                                                                                                            |  
| 16.1   | Appendix A: Performance Status Criteria 103                              |
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| 16.2   | Appendix B: Patient Information on Possible Drug Interactions 104        |
| 16.3   | Appendix C: Patient Medication Diary 106                                 |
| 16.4   | Appendix D: CCR Patient Self-Administered Study Agent Compliance Log 107 |
| 16.5   | Appendix E: Blood Pressure Monitoring Form 109                           |
| 16.6   | Appendix F: Sample Collection for Correlative Studies 110                |
| 16.7   | Appendix G: MDASI Quality of Life Assessment 113                         |
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1 objectives 1.1 primary objective

x To determine the response rate of cabozantinib in patients with progressive urothelial cancer who have received prior cytotoxic chemotherapy.  
x To measure the PFS of cabozantinib as determined by RECIST (version 1.1). x To determine the safety and toxicity of cabozantinib in this previously treated patient population.  
x To estimate overall survival of patients with metastatic urothelial carcinoma of the bladder treated with cabozantinib.  
x To explore the relationship between the biodistribution changes in FDG PET/CT
parameters and the clinical response.  
x To assess RECIST criteria semi-automated volume (SAV), SACT, MASS criteria and Choi criteria in metastatic target lesions.  
x To compare the change in Hounsfield units (HU) with the SUV change with treatment response in metastatic lesions.  
x To perform correlative studies assessing potential biomarkers of response to XL184.  
x To perform exploratory evaluation of response criteria in urothelial cancer patients who have not progressed by RECIST, but have developed bone lesions.  
x To perform exploratory evaluation of response criteria in patients with non-transitional cell carcinoma of the bladder.  
x To conduct preliminary studies in genetic changes in tumor vs. normal tissue in order to begin to identify specific genetic or chromosomal changes that lead to cancer.  
x To assess quality of life in patients treated with cabozantinib.  
In the United States, urothelial carcinoma (UC) of the bladder is the fourth most common malignancy in men and the ninth most common in women with an estimated 69,250 new cases and 14,990 deaths in the year 2011.1 Worldwide, 386,300 new cases and 150,200 deaths occurred from bladder cancer in 20081. Although UC is a chemosensitive malignancy with response proportions of over 50% with conventional cytotoxic regimens, the response durations are short and the median survival of patients with metastatic disease is approximately 14 months2. There is no FDA-approved second line drug for patients with metastatic UC and no standard conventional chemotherapy agent(s) have demonstrated a survival benefit in patients that have progressed after first line platinum-based chemotherapy. Second-line trials with cytotoxic agents have generally yielded discouraging response rates (see **Table 1** below) with a median progression-free survival between 2 to 3 months and a median survival in the range of 6 to 9 months3-6. Furthermore, many patients receive these agents as part of first-line therapy leaving few available options for patients 8 with progressive or recurrent disease. This highlights the need for the development of novel therapies for the treatment of patients with metastatic UC.  
| Agent            | Activity  Overall Response   | 95% CI   |
|------------------|------------------------------|----------|
| Paclitaxel4,7,8  | 9-10%                        | 0-17%    |
| Docetaxel3,9     | 13%                          | 4-30%    |
| Ifosfamide10-12  | 20%                          | 10-32%   |
| Gemcitabine13,14 | 23%                          | 8-38%    |
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targeting angiogenesis in uc

Several processes central to tumor progression, including tumor growth, invasion, and metastasis are dependent on an adequate blood supply. Angiogenesis, the process by which the neovascular blood supply is recruited, is orchestrated by a balance of stimulatory and inhibitory factors released by tumor and host cells. Over twenty years ago, Chodak et al first demonstrated that the urine of patients with UC contained pro-angiogenic substances 15. Multiple lines of evidence support targeting angiogenesis in UC:  
x Microvessel density, a histological measure of angiogenesis, has been correlated with stage, recurrence, and survival, in UC. 16,17, 18 x Several reports have described increased expression of vascular endothelial growth factor
(VEGF), a mediator of angiogenesis, in the tissue, serum, and urine of patients with UC
and correlated these markers with stage and prognosis.19-21 x Inhibitors of angiogenesis have shown activity in preclinical murine models of UC.22-24 x A functional autocrine loop involving VEGF/VEGFR2 may be important in the pathogenesis of some bladder cancers. In a recent non-clinical study, 6 of 13 bladder tumor cell lines examined expressed VEGFR2 (Flk-1). Further analysis of the T24 bladder tumor cell line revealed a functional autocrine loop involving VEGF and VEGFR2.25,26 Clinical studies in bladder cancer with anti-angiogenic agents.
A phase II study of single agent Sunitinib 27 in 77 patients on one of two schedules (50 mg per day for 4 weeks on and 2 weeks off [cohort A], 37.5 mg per day continuously [cohort B]), found a partial response in three of 45 patients in cohort A, and in one of 32 patients in cohort B. Clinical regression or stable disease was achieved in 33 of 77 patients (43%) with 29% of patients achieving stable disease lasting longer than 3 months. Antitumor responses were observed, identifying the vascular endothelial growth factor axis as a viable pathway for UC treatment. A phase II study of 43 metastatic or unresectable chemo naïve UC patients treated with cisplatin, gemcitabine, and bevacizumab as first-line chemotherapy reported complete response 19%, partial response 53%; with overall response rate of 72%. Stable disease lasting greater than 12 weeks was observed in 9%. With a median follow-up of 27.2 months (range, 3.5 to 40.9 months), median progression-free survival (PFS) was 8.2 months (95% CI, 6.8 to 10.3 months) with a median overall survival (OS) time of 19.1 months (95% CI, 12.4 to 22.7 months). This combination demonstrates significant clinical activity in the first-line treatment of metastatic UC patients. A phase III trial to further define the toxicity risk vs. clinical benefit of bevacizumab addition to platinum-based doublets is currently ongoing in this population.
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met expression in bladder cancer

The c-met proto-oncogene encodes a receptor tyrosine kinase (Met) and has been shown to play a role in oncogenesis. High titers of hepatocyte growth factor, the specific ligand for Met, are excreted in the urine and tend to reflect disease activity of bladder cancer. The clinical significance of Met in human bladder cancer was examined in bladder cancer cell lines and human bladder cancer tumors. The mRNA expression and genomic alteration of c-met was studied in five bladder cancer cell lines. Met overexpression was then compared with p53 nuclear accumulation (TP53) in primary bladder cancer (n = 142 patients). Expression of c-met tended to correlate with differentiation of cancer cell lines in the absence of point mutations. Expression of Met was positively associated with histologic grade, stage classification, tumor size, and nodular tumor growth (P <.05, respectively). Indicators for poor long-term survival were invasive cancer, multiple tumors, and Met overexpression (P =.0006, .01, and.04, respectively). In these studies, the c-met proto-oncogene demonstrated that it plays an important role in the progression of bladder carcinogenesis28.  
The clinical significance of the expression of phosphorylated c-Met in bladder cancer, and its correlation with cancer cell progression-related molecules has also been investigated by Miyata et al.29. The expression levels of 2 tyrosine residues of c-Met (pY1234/1235 and pY1349) were examined immunohistochemically (IHC) in 133 specimens with non-metastatic bladder cancer and their correlation with matrix metalloproteinase–1, –2, –7, and –14; urokinase-type plasminogen activator; E-cadherin; CD44 standard, variant 3, and variant 6; and vascular endothelial growth factor. Expression of phosphorylated c-Met was detected in cancer cells, but was rare in normal urothelial cells. c-Met, pY1349 was associated with high pathologic T stage in a multivariate analysis. Expression of pY1349 c-Met was a marker of metastasis and (P = .001) and causespecific survival (P = .003). Expressions of matrix metalloproteinase–2, matrix metalloproteinase–
7, and E-cadherin correlated with pY1349 c-Met expression. This demonstrates that pY1349 cMet plays an important role in tumor development, and its expression is a significant predictor of metastasis and survival of patients with bladder cancer. A study using antibody arrays that selected antibodies against targets differentially expressed in bladder tumors, found serum protein, c-met, to be top ranked at identifying bladder cancer patients from controls30. C-met expression was validated by immunohistochemistry of tissue microarrays containing bladder tumors (n = 173) and was associated with pathological stage and tumor grade (p<0.001), and over-all survival (P=0.044). NIH-Met5 and T24-Met3 cell lines harboring an inducible human c-Met gene were established. C-Met-related receptor tyrosine kinases were screened by microarray analysis. The potential clinical importance was examined in a cohort of 65 cases of locally advanced and metastatic bladder cancer patients. A positive association of Axl or platelet-derived growth factor receptoralpha (PDGFR-α) with c-Met expression was demonstrated at translational level, and confirmed by specific siRNA knock-down. The transactivation of c-Met on Axl or PDGFR-α in vitro was through a ras- and Src-independent activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathway. In human bladder cancer, co-expression of these receptor tyrosine kinases was associated with poor patient survival (p < 0.05), and overexpression of c-Met/Axl/PDGFR-α or c-Met alone showed the most significant correlation with poor survival
(p < 0.01)31.
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c-met inhibitor in bladder cancer

Met overexpression occurs in bladder cancer28,29,31,32. The effects of a small, orally available, highly selective Met tyrosine kinase inhibitor, PF-2341066, was studied in a pre-clinical model of bladder cancer. Bladder cancer cell lines (HT 1376, T24 and TCC-sup) were treated with PF2341066 to determine its effects on cellular proliferation and migration. Migration was inhibited in a dose dependent manner when the cells were treated with PF-2341066 (Bottaro, NCI, UOB, unpublished).
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dual targeting vegf and c-met

Hypoxia has been shown to result in the upregulation of both MET and VEGF, and activated MET
can indirectly promote angiogenesis and tumor growth by upregulating VEGF expression 33, 34.  
Evidence from the literature 34 also supports cooperative roles for MET and VEGFR2 in the proliferation and survival of the tumor endothelium. Thus, simultaneous inhibition of both MET and VEGFR2 should result in near-complete inhibition of major survival pathways that are induced in tumors by hypoxia.
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2.2 ind agent - cabozantinib

XL184 (cabozantinib) inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor growth, metastasis, and angiogenesis (Investigator's Brochure, 2011). The primary targets of XL184 are MET (c-MET) and vascular endothelial growth factor receptor 2 (VEGFR2); additional targets include RET, AXL, KIT, and TIE-2. Both c-Met and VEGFR2 are important mediators of tumor growth and tumor angiogenesis, and in *vivo* pharmacodynamic activity of XL184 against cMet and VEGFR2 has been demonstrated in both preclinical and clinical studies.  
RTKs regulate many processes including cell growth and survival, organ morphogenesis, neovascularization, and tissue repair35. Dysregulation of RTKs by mutation, gene rearrangement, gene amplification, and overexpression of both receptor and ligand has been implicated as causative factors in the development and progression of numerous human cancers. The RTK c-Met, encodes the high-affinity receptor for hepatocyte growth factor (HGF) or scatter factor (SF)35. c-Met and HGF are each required for normal mammalian development and have been shown to be important in cell migration, morphogenic differentiation, and organization of three-dimensional tubular structures (*e.g.*, renal tubular cells, gland formation, *etc.*), as well as cell growth, angiogenesis, and tumor invasiveness and metastasis. Upregulation of MET is found in a wide range of malignancies including thyroid, prostate, ovarian, lung, and breast cancers, and is associated with more aggressive and invasive phenotypes of cancer cells *in vitro* and metastases in vivo (Investigator's Brochure, 2011). c-Met-driven metastasis may be exacerbated by a number of factors, including tumor hypoxia caused by selective inhibition of the VEGF pathway. Evidence linking c-Met and HGF as causative or progression factors in human cancers include: (1) the overexpression of both receptor and ligand in neoplasms relative to surrounding tissues; (2) the correlation of receptor and ligand overexpression with disease severity and outcome; (3) genetic alteration of c-Met by mutation of gene amplification in multiple cancer types; (4) introduction of c-Met and HGF (or mutant c-Met) into cell lines, conferred the properties of tumorigenicity and metastatic propensity on engineered cells; (5) introduction of c-Met or HGF as transgenes into the germline of mice resulted in primary and secondary neoplasms; and (6) the inhibition of c-Met or HGF function with dominant-negative receptors, antibody antagonists (both Met and HGF), and biologic antagonists (e.g., NK4) have reversed cancer-associated phenotypes such as motility, invasion and proliferation of tumor cells, and tumor growth and dissemination in vivo35.  
A wide variety of human cancers, including brain, colorectal, gastric, and lung, demonstrate dysregulated c-Met activity36, either by means of c-Met kinase overexpression37, activating c-Met gene mutations and/or amplification37-39, or increased autocrine and/or paracrine secretion of the c-Met ligand, HGF/SF. These alterations have been implicated in tumor progression and metastasis, and a high constitutive activation of c-Met has been correlated with poor clinical prognosis40.  
VEGFR2 is the predominant mediator of VEGF-stimulated endothelial cell migration, proliferation, survival, and enhanced vascular permeability41. Increased expression of VEGFR2, often in combination with VEGFR3, has been observed in the tumor vascular endothelium in most common human solid tumor types, on tumor cells in melanoma and hematological malignancies, and in colitis-associated colon cancer42. High VEGFR2 expression is an unfavorable prognostic biomarker in hepatocellular carcinoma (HCC), and correlated with triple-negative (*i.e.*, therapyresistant) breast cancer and poor survival.
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nonclinical development of xl184 in

Inhibition of VEGF signaling pathway was previously shown to result in more invasive tumors in the transgenic RIP-Tag2 mouse model of pancreatic neuroendocrine cancer that spontaneously develops aggressive tumors43. In RIP-Tag2 transgenic mice, tumors treated with XL184 were smaller (P <0.05) than in mice treated with vehicle or an anti-VEGF antibody, but were also less invasive (P <0.05) and had no liver metastases 44. 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 45. Tumors were 35% smaller after XL184 treatment than corresponding values for vehicle control mice. c-Met protein expression in tumors was slightly decreased, but phosphorylated c-Met was markedly reduced after treatment for 7 days. Mice bearing MDA-MB-231 cells (expressing MET and VEGF) were administered four oral doses of 100 mg/kg 46. XL184 increased tumor hypoxia (13-fold) and apoptosis (TUNEL; 2.5-fold) at 8 and 4 hours after the first and second doses, respectively, when compared to vehicle-treated tumors. In addition, XL184 disrupted tumor vasculature by inducing endothelial cell death that negatively affected tumor viability. XL184 treatment resulted in significant tumor growth inhibition of MDA-MB-231 tumors (P <0.001) at all doses (1, 3, 10, 30, or 60 mg/kg) when compared to vehicle-treated tumors. Dose-dependent inhibition was observed for the 3 and 10 mg/kg doses (P <0.01), and complete inhibition was observed at the 30 and 60 mg/kg doses. A single 100 mg/kg dose resulted in sustained MDA-MB-231 tumor growth inhibition for ~8 days after which tumors began growing at a rate similar to vehicle-treated control tumors. In addition, XL184 inhibited tumor growth (P <0.001) in the MET-expressing rat C6 glioma cell line for all 12 doses (1, 3, 10, 30, or 60 mg/kg) when compared with vehicle-treated tumors. The 3 mg/kg and 10 mg/kg doses resulted in significant tumor regression (62% and 85%, P <0.0001) when compared with predose tumor weights. Subchronic administration of XL184 was well tolerated in mice and rats with no signs of toxicity, as determined by stable and/or increasing body weights during the treatment period. ARCaP-M is a human prostate cancer model which expresses both c-Met and VEGF co-receptor NP-1 used in a human prostate tumor xenograft study in mouse bone47. ARCaP-M cells were injected into the tibia of nude mice on Day 1, and on Day 31 animals with established bone lesions were randomized to receive XL184 or vehicle daily (qd) for 7 weeks of treatment48. Tibiae from vehicle-treated animals exhibited both osteoblastic and osteolytic lesions, whereas tibiae from XL184 treated animals appeared mostly normal. Thus, XL184 treatment blocked both osteoblastic and osteolytic progression of ARCaP-M xenograft tumors in bone.
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nonclinical pharmacodynamics

In mice, the effective dose resulting in 50% inhibition (ED50) of targets was achieved at well tolerated doses of XL184 and at plasma exposures comparable to exposure observed in clinical trials49. XL184 produced prolonged inhibition of receptor phosphorylation, such as sustained inhibition of c-Met and VEGFR2 for 10 hours after administration of a single dose of XL184. This extended inhibition occurred in a manner that was generally predicted by plasma exposure, *i.e.*, inhibition was diminished when plasma levels fell below approximately 20 μM for c-Met, 5 μM for VEGFR2, and 23 μM for TIE-2. Once daily administration of XL184 resulted in significant inhibition of c-Met phosphorylation in TT tumors, relative to tumors from vehicle control-treated mice, with maximal inhibition of 70%
seen at 60 mg/kg49. Dose-dependent inhibition of phosphorylation of c-Met and RET was observed among the 3, 10, and 30 mg/kg dose groups as well. c-Met phosphorylation was inhibited by a single 100 mg/kg oral dose of XL184, 2–8 hours post dose in H441 tumors (human lung papillary adenocarcinoma) that harbor constitutively phosphorylated c-Met 46. This effect was reversible, as c-Met phosphorylation returned to basal levels by 48 hours after treatment.
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nonclinical pharmacokinetics

In the various xenograft models, plasma exposures were similar and plasma concentrations in the range of 3 to 27 μM were associated with efficacy49. In rats, plasma concentrations in the range of 5 to 15 μM were associated with maximal anti-tumor activity. Despite the apparent requirement for high peak concentrations, trough concentrations as low as 0.1 μM were observed at highly efficacious doses in mice. These results were consistent with *in vivo* target modulation studies in mice which demonstrated long (4- to 10-hour) durations of action, and indicated that continuous high exposure was not required to maintain efficacy. Dose proportional increases in exposure occurred at oral doses of 3–100 mg/kg in mice and at 3–
30 mg/kg in rats49. In rats, the oral bioavailability of XL184 dosed as a solid was approximately 100% of XL184 dosed as a liquid. In comparison, oral bioavailability was much lower in dogs (20%) and monkeys (18%) for the solid versus liquid dosage forms.  
Systemic drug exposure parameters (maximum plasma concentration [Cmax] and area under the time-concentration curve from 0 to t hours post-dose [AUC0-t] values) associated with single XL184 oral doses in rats increased less than dose-proportionally with increasing dose (100–900 mg/kg) 49. With repeat daily oral dosing in rats, systemic exposure (AUC0-t values) increased generally dose-proportionally following 14 and 178 dosing days (dose ranges 1–15 mg/kg/day and 0.1–1 mg/kg/day, respectively). The Cmax and AUC0-t values in rats administered 100 mg/kg were approximately 2-fold and 3-fold higher, respectively, than for dogs given 2000 mg/kg; therefore, the higher systemic exposure to XL184 in rats correlated with the greater toxicity observed in this species at lower administered doses.  
Systemic drug exposure parameters (Cmax and AUC0-t values) associated with single XL184 oral doses in dogs increased less than dose-proportionally with increasing XL184 dose (400–2000 mg/kg), suggesting possible saturation of systemic absorption 48. With repeat daily dosing, exposure (Cmax and AUC0-24 values) both increased greater than dose-proportionally from 10 to 100 mg/kg and less than dose proportionally from 100 to 1000 mg/kg following 14 dosing days.
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toxicology

In rodents and non-rodents, histopathological changes associated with XL184 administration were observed in gastrointestinal (GI) tract, bone marrow, lymphoid tissues, kidney, and adrenal and reproductive tract tissues 48. 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 steadystate 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 study49. In safety pharmacology studies, no adverse effects occurred on neurobehavioral or respiratory functions in XL184-treated rats or on cardiovascular function in XL184-treated dogs.
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clinical experience

As of May 4, 2011, 1003 patients have been studied in 12 ongoing Exelixis-sponsored clinical trials with XL184 treatment 1) as a single agent at does ranging from 0.08 to 11.52 mg/kg on an intermittent dosing schedule, 2) from 25 to 265 mg (19.7-209 mg freebase equivalent weight) on a fixed daily dosing schedule and 3) in combination with temozolomide (TMZ) and radiation therapy (RT), or with erlotinib (Exelixis Communication, 2011). The maximum tolerated dose (MTD) on once daily (qd) by mouth (PO) dosing schedule was determined to be 175 mg L-malate salt (or approximately 138 mg freebase equivalent weight).  
14 Detailed information for each of these studies, including pharmacokinetic data, can be found in the Investigator's Brochure48. Safety and efficacy information, from the 2011 Investigator's Brochure, is summarized below.
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phase i studies

Study **XL184-001** was a phase 1 dose-escalation study in subjects with solid tumors. Eighty-five subjects, across 13 dosing levels (DL) ranging from 0.08 mg/kg qd (using powder-in-bottle [PIB] suspension on a 5 days on, 9 days off schedule) to 265 qd (using capsules [25 and/or 100mg] for two, 14-day cycles) were enrolled. The capsule MTD was determined to be 175 mg qd50. Of the 35 subjects with medullary thyroid cancer (MTC) and measureable disease enrolled in the dose expansion phase, 10 (29%, 95% CI) had confirmed partial responses (cPR) (with a duration up to 48+ months), 17 (49%) had tumor shrinkage of ≥30%, and stable disease (SD) of at least 6 months was observed in 15/37 (41%) of the MTC subjects. In Study **XL184-002**, treatment of subjects with newly diagnosed glioblastoma (GB) consisted of cabozantinib in combination with TMZ with or without radiation therapy. Enrollment has been terminated and no clinical efficacy data is presented in the 2011 Investigator's Brochure. All adverse events (AEs) were assessed with respect to combination treatment and not the individual components. Nineteen patients were evaluated for AEs, the most common grade 3 or higher included neutropenia (21%), thrombocytopenia (16%), leucopenia (16%), and hypertension (11%). Myelosuppression, including prolonged pancytopenia, is a dose-limiting toxicity (DLTs) associated with TMZ use. The frequency at which bone marrow toxicity was observed in this study is consistent with the TMZ prescribing information. Study **XL184-004** is a Phase 1, open-label, randomized, single-dose, two-treatment, two-way crossover study to assess the effect of food on the bioavailability of cabozantinib in healthy adult subjects. According to a randomization scheme, 56 subjects received single oral doses of the assigned treatment of Test (175 mg cabozantinib, dosed as one 100-mg capsule and three 25-mg capsules 30 minutes after administration of a high-fat breakfast) or Reference (175 mg cabozantinib, dosed as one 100-mg capsule and three 25-mg capsules under fasting conditions).  
Blood samples were collected up to 504 hours post-dose for each subject after each treatment to assess plasma cabozantinib pharmacokinetics. See "Pharmacokinetics" section for results. Study **XL184-005** is a Phase 1, open-label, randomized, single-dose, two-treatment, two-way crossover comparative bioavailability study of cabozantinib tablet and capsule formulations in healthy volunteers. Subjects received single oral doses of the assigned treatment of Test (100 mg cabozantinib, dosed as one 100-mg tablet) or Reference (100 mg cabozantinib, dosed as two 50-mg capsules), according to a randomization scheme. Each dosing was administered under fasting conditions, and blood samples were collected up to 504 hours post-dose for each subject after each treatment to assess plasma cabozantinib PK. See "Pharmacokinetics" section for results. In Study **XL184-008**, subjects with advanced solid tumors (particularly renal cell carcinoma [RCC] and differentiated thyroid cancer [DTC]) are evaluated for any potential clinically significant drug-drug interaction of cabozantinib on the CYP isozyme CYP2C8. The effect of qd dosing of 175 mg cabozantinib and a single dose of rosiglitazone will be evaluated. In 11 patients evaluated for AEs, the most common grade 3 or higher AEs were fatigue (9%), hypophosphatemia (27%), blood amylase increase (9%), and hyponatremia (9%). In a phase 1 study, **CA205-001**, Japanese subjects with advanced or metastatic solid tumors for whom the standard of care is ineffective or inappropriate, received cabozantinib at a starting dose of 75 mg PO qd. Two of the three subjects in the first cohort experienced DLTs of proteinuria and thrombocytopenia. Because of a change in study sponsor, this study was reinitiated as XL184014. One additional subject was enrolled as of May 2011 at 50 mg PO qd. Study **XL184-202** was a phase 1b/2 trial that evaluated the safety and tolerability of cabozantinib and erlotinib administered in combination in non-small-cell lung cancer (NSCLC) subjects. Of the 64 subjects enrolled in the phase 1 dose-escalation portion of the study, all but two had been previously treated with and progressed on erlotinib therapy. A cPR was observed in 5 subjects
(8%) and 24 subjects (37%) had SD/PR ≥4 months. The most common grade 3 or higher AEs in the phase 1 portion included diarrhea (44%), fatigue (22%), hypokalemia (11%), decreased appetite (6%), dyspnea (14%), lipase increase (6%), hypomagnesemia (6%), and dehydration (5%). Twenty-eight subjects were enrolled in the phase 2 portion of the study, in which subjects who had received clinical benefit from erlotinib and subsequently experienced progressive disease
(PD), received single-agent cabozantinib or cabozantinib with erlotinib. AEs ≥grade 3 included dehydration (8%) and hypertension (8%). One patient, who was treated with single-agent cabozantinib, had a cPR.
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phase 2 studies

In a phase 2 study, **XL184-201**, subjects with progressive or recurrent GB in first or second relapse were enrolled to receive cabozantinib qd as a single agent. Group A received an initial dose of 175 mg (Group A), subsequent cohorts (Groups B and C) received an initial dose of 125 mg. Forty-six subjects were enrolled in Group A, and a total of 176 subjects were enrolled in Groups B/C. Fifty-seven subjects experienced one or more serious adverse events (SAEs) that were assessed to be related to treatment, including five fatal rSAEs. Study **XL184-203** is a phase 2 randomized discontinuation trial. Subjects are enrolled into one of nine tumor-specific cohorts: breast cancer, gastric/gastroesophageal (GEJ) cancer, hepatocellular carcinoma (HCC), melanoma, NSCLC, ovarian cancer, pancreatic cancer, prostate cancer, and small cell lung cancer (SCLC). Eligible subjects with advanced solid tumors receive open-label cabozantinib at starting dose of 100 mg qd for 12 weeks. Of the 531 subjects enrolled in this study as of May 2011, 92 experienced one or more SAEs that were assessed to be related to treatment with cabozantinib, including seven fatal SAEs. Study **XL184-205** is a randomized phase 2 trial for subjects with grade IV astrocytic tumors in first or second relapse. Subjects received one of four regimens: 25 mg qd (Arm 1) continuously, 75 mg qd (Arm 2) continuously, 125 mg qd for 2 weeks followed by 50 mg qd continuously (Arm 3), and 125 mg qd on an intermittent 3 week on/1 week off schedule (Arm 4). A total of 19 subjects were accrued before the study was terminated. Three subjects were rolled over to maintenance Study XL184-900. One subject experienced an SAE assessed to be related to treatment with cabozantinib. Study **XL184-301** is a blind trial for subjects with unresectable, locally advanced or metastatic MTC, randomized 2:1 to cabozantinib or placebo. SAEs reported in Study XL184-301 are: one 16 grade 4 reversible posterior leukoencephalopathy syndrome (RPLS), one grade 5 cardiac arrest following asystolic vagal reaction after aspiration on study medication, and three SAEs of acquired trachea-esophageal fistula (two grade 3, one grade 5).
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adverse events

The clinical studies with XL184 are ongoing and thus the AE data from the clinical database as of March 1, 2011 and May 4, 2011 do not yet include all SAEs (Exelixis Communication, 2011). As of March 2011, AE data are available for 913 subjects who have been dosed with XL184 (806 in single-agent studies and 107 in combination studies of XL184 with erlotinib, rosiglitazone, or TMZ ± radiation) (Investigator's Brochure, 2011). Data from the 806 subjects who received single-agent XL184 show that the most frequently (>20%) observed AEs regardless of causality were fatigue, diarrhea, nausea, decreased appetite, constipation, palmar-plantar erythrodysesthesia (PPE) syndrome, vomiting, dysphonia, and hypertension. Effects that may be related to the inhibition of VEGF, including hypertension, thromboembolic events, GI perforation, fistula formation, hemorrhage, wound dehiscence, and proteinuria, have been observed in the single-agent and combination XL184 studies. The most commonly reported SAEs that were assessed as related to study treatment with XL184 (as a single-agent or combination) were pulmonary embolism (PE), diarrhea, dehydration, deep vein thrombosis (DVT), vomiting, nausea, thrombocytopenia, fatigue, wound dehiscence, and PPE syndrome. Grade 5 AE data are available for 1404 subjects who have been dosed with cabozantinib as a single agent (1286) or in combination (118) through June 1, 2012. There have been 27 grade 5 AEs related to study treatment: GI hemorrhage (two subjects), pulmonary hemorrhage (one subject), esophageal hemorrhage (one subject), PE (two subjects), respiratory failure (three subjects), respiratory disorder (one subject), hemoptysis (one subject), death due to unknown cause (four subjects), intracranial hemorrhage (one subject), intestinal perforation (one subject), enterocutaneous fistula (one subject), tracheo-esophageal fistula (one subject), esophageal fistula (one subject), hemorrhage (two subjects), hepatic failure (one subject), bronchopneumonia (one subject) cardiac arrest (one subject), sepsis (one subject), and diverticular perforation, peritonitis (one subject) (Exelixis Communication). The initial daily doses of drug in these subjects were 100 mg (8 subjects), 125 mg (8 subjects), 175 mg (11 subjects). In 2 subjects, the initial dose of 125 mg was reduced to 50 and 75 mg respectively prior to death.
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pharmacokinetics

Pharmacokinetic analysis of 74 patients in trial **XL184-001** showed dose proportional increases in maximum plasma concentration (Cmax) and AUC both for PIB (dose range 0.08-11.52 mg/kg) and the capsule formulation (dose range: 125 to 175 mg) (Kurzrock, 2011). Terminal-phase half-life
(t1/2,z) values were 59.1 to 136 hours (Investigator's Brochure, 2011). After repeat dosing, t1/2,z values (mean ± standard deviation) for XL184 were 91.3 ± 33.3 hours (n = 23), and apparent steady-state plasma levels were reached by Day 15 (Kurzrock, 2011). Steady-state clearance for the 175 mg capsule dose derived from repeat dose data was 4.2 ± 1.5 L/h. Patients who received 175 mg capsules had four- to five-fold higher steady-state exposure (AUC) compared with Day 1 (7.68 ± 2.85 mcg∙h/mL; n = 23 vs. 41.6 ± 15.3 mcg∙h/mL; n = 23), indicating that XL184 accumulated with repeat daily dosing. There was no significant difference in exposure between patients with MTC and those without MTC. Based on the preliminary PK data from 23 subjects in **XL184-005** who completed both treatments, after a single oral dose of cabozantinib at 100 mg, the terminal t1/2, z of cabozantinib appeared to 17 be similar for both tablet and capsule formulations, with approximately mean values of 110 hours
(Exelixis Communication, 2012). The median time to the maximum plasma concentration (tmax)
was 4 hours for the tablet formulation and 5 hours for the capsule formulation. High inter-subject variability for Cmax and the area under the plasma drug concentration time curve (AUC) values were observed for both formulations (coefficient of variation [CV]% Cmax: 51% for the tablet formulation, 61% for the capsule formulation; CV% for the AUC from time zero to the last quantifiable timepoint or to infinity [AUC0-last or AUC0-inf]: 40-43% for the tablet formulation, 43%
for the capsule formulation). The geometric mean Cmax of the tablet formulation was approximately 39% higher than the value observed for the capsule formulation. The geometric mean AUC0-last and AUC0-inf values for the tablet formulation were also higher (15% and 19%,
respectively) than those observed for the capsule formulation. However, due to the high withinformulation variability observed, no statistical difference in exposure between the two formulations was apparent. Based on the preliminary PK data from 46 subjects who completed both treatments on trial XL184004, a high-fat meal did not appear to alter the terminal t1/2, z of cabozantinib [mean t1/2, z : 131 hours (fed) vs. 128 hours (fasted)]. The high-fat meal significantly increased the median tmax to 6 hours from 4 hours (fasted). The high-fat meal also significantly increased both the cabozantinib Cmax and AUC values by 39% and 56%, respectively. The geometric mean ratio of Cmax fed/fasted was 1.39 (90% CI: 1.16-1.67), and the geometric mean ratio of AUC0-last fed/fasted was 1.56 (90%
CI: 1.34-1.80). Based on this result, cabozantinib must be taken on an empty stomach (fasting is required 2 hours before and 1 hour after each cabozantinib dose).
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2.3 rationale 2.3.1 rationale for

Bladder cancer is a highly vascular malignancy that produces high levels of pro-angiogenic factors including VEGF, bFGF and IL-8. Microvessel density, a histological measure of angiogenesis, has been correlated with stage, recurrence, and survival in this disease. Clinical studies in bladder cancer with anti-VEGF pathway agents have shown anti-tumor activity. While these studies validate the potential for an anti-angiogenic approach to UC, they also indicate the need to investigate alternative ways to target the tumor vasculature. Of particular interest are agents that target more than one mechanism for tumor growth and development and have activity in tumors resistant to existing therapies. Cabozantinib is an oral, potent inhibitor of MET and VEGFR2 that produces robust antiangiogenic, antiproliferative, and antiinvasive effects in preclinical models. MET and VEGFR2 are key mediators of angiogenesis. Preliminary results of randomized phase II studies with cabozantinib in CRPC and ovarian cancer have demonstrated clinical activity. MET activation is common in solid tumors including UC and promotes proliferation, invasion, and metastasis. For these reasons, co-targeting of the MET and VEGF signaling pathways using cabozantinib may represent a promising treatment strategy.
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2.3.2 rationale for a pfs

Pertinent to the issue of discovering new drugs active in urothelial cancers is that identifying clinical benefit should not be limited to response. Some of the newer "targeted therapy" agents approved by the FDA have been approved on the basis of improved progression-free survival (PFS) and not response rate (e.g., sorafenib in renal cell carcinoma with a response rate of approximately 10% but a major impact in PFS and, eventually, an improvement in survival). This being said, the median progression-free survival for bladder cancer patients treated with chemotherapy is modest at only 2-3 months and response rates are in the 10-20% range. In a second-line trial of weekly paclitaxel in 31 patients with progressive urothelial cancer, the median time to progression was 2.2 months4. In an ECOG trial evaluating the epothilone analog BMS247550 in patients with relapsed urothelial cancer, the median progression-free survival was 2.7 months (95% CI, 1.8, 4.1)5. In a phase 3 randomized second-line trial of vinflunine versus best supportive care, the PFS for patients treated with vinflunine was 3.0 months (95% CI, 2.1, 4.0)51.  
Novel therapies are desperately needed for these patients and identifying activity in the refractory setting by using PFS is considered an acceptable approach with these new targeted agents.
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2.3.3 rationale for cabozantinib dose

A cabozantinib starting dose of 100 mg qd has been studied in 171 CRPC subjects enrolled to the Phase 2 XL184-203 RDT. Despite relatively high rates of cabozantinib dose reductions to the next lowest dose of 60 mg qd within the first 12 weeks of therapy (51%), this starting dose resulted in high rates of pain relief, bone scan improvement, and overall disease control. Preliminary data from a separate and ongoing dose-ranging study looking at lower doses of cabozantinib in CRPC coupled with results from a retrospective review of the Phase 2 XL184-203 RDT indicate that lower doses below 100 mg qd are likely to retain efficacy while improving upon tolerability: Preliminary results from an ongoing dose-ranging study: To date, 9 subjects with metastatic CRPC enrolled to the first cohort (starting dose of 40 mg qd) are evaluable for bone scan response. All 9 subjects exhibit evidence of response on bone scan including two complete responses. Although most subjects did not have pain at baseline, one subject reported pain at baseline which resolved by Week 6. No dose reductions or interruptions have been reported to date, although one subject discontinued study treatment for fatigue that was present at baseline and another subject discontinued because of a pathologic fracture. This provides preliminary evidence that lower doses are pharmacologically active in a patient population with advanced CRPC. Retrospective review of Phase 2 XL184-203 RDT: While the overall rate of dose reduction from 100 mg to 60 mg was 51%, only 14% required an additional reduction in dose from 60 mg to the next lowest dose of 40 mg, which is consistent with an overall improvement in tolerability profile at the 60-mg dose level. The majority (69%) of subjects with pain at baseline who experienced early dose reduction (before Week 6) to 60 mg went on to report pain improvement at Week 6. Moreover, 80% of these subjects remained progression-free and continued to report pain relief at the Week 12 time point. Thus the dose of 60 mg qd appears to offer improved tolerability while maintaining efficacy in a patient population with advanced CRPC and cancer-related pain at baseline. Further analysis of the timing of AEs that led to dose reductions or interruptions was conducted. The median time to first AE triggering a dose reduction or interruption at 100 mg qd was 29 days, with very few subjects experiencing significant toxicity in the first 2 weeks of study treatment. As such this study will adopt a starting cabozantinib dose of 60 mg qd. The goal of this regimen is to improve the overall tolerability of cabozantinib while maintaining efficacy in this patient population
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2.4 correlative studies background 2.4.1

CEC, CEP and CTC may serve as markers for assessment of treatment's antiangiogenic activity. CEC, CEP and CTC will be analyzed by multiparameter flow cytometry. Mononuclear cells will be isolated and run fresh or viably frozen. Immune subsets, including MDSC and Tregs, may be analyzed if sample permits.
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2.4.2 c-met analysis by real-time

The c-met proto-oncogene encodes a receptor tyrosine kinase (Met) and has been shown to play a role in oncogenesis. The clinical significance of Met in human bladder cancer was examined in bladder cancer cell lines and human bladder cancer tumors. The mRNA expression and genomic alteration of c-met was studied in five bladder cancer cell lines. Met overexpression was then compared with p53 nuclear accumulation (TP53) in primary bladder cancer (n = 142 patients). Expression of c-met tended to correlate with differentiation of cancer cell lines in the absence of point mutations. Expression of Met was positively associated with histologic grade, stage classification, tumor size, and nodular tumor growth (P <.05, respectively). Indicators for poor long-term survival were invasive cancer, multiple tumors, and Met overexpression (P =.0006, .01, and.04, respectively). In these studies, the c-met proto-oncogene demonstrated that it plays an important role in the progression of bladder carcinogenesis28.  
We hypothesize that the c-Met analysis by real-time RT-PCR correlates with the C-met level found in the serum and is of prognostic significance.
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2.4.3 il-8 circulating cytokine levels

IL-8 is a proinflammatory chemokine, which belongs to the chemokine receptors family and which stimulates neutrophil chemotaxis and degranulation52,53. IL-8 is a potent pro-angiogenic factor, which has been shown to initiate tumor angiogenesis in xenograft models in which VEGF
signaling was regulated54. Its expression has been reported to enhance angiogenesis through the induction of MMP-9 and to induce metastases of human transitional cancer cell lines55. In animal models of urothelial cancer, high expression of IL-8 was associated with a significant increase in tumor growth and metastases56 A recent study has associated increased IL-8 plasma levels in xenograft renal cell carcinoma (RCC) models with resistance to sunitinib treatment.57 In the same study, IL-8 was overexpressed in tumors from patients refractory to sunitinib. Increased expression of IL-8, MMP-9, and VEGF in non-small-cell lung cancer patients, treated with the oral inhibitor of VEGFR2 tyrosine kinase vandetanib, correlated with a higher risk of progression.58 In mRCC patients treated with pazopanib, baseline levels of IL-8 correlated with tumor burden,59 and different polymorphisms of the IL-8 gene were significantly associated with treatment activity.60 The role for IL-8 baseline levels as a predictive serum biomarker of sunitinib activity in patients with urothelial cancer was studied and it was found that low IL-8 baseline levels were significantly associated with increased time to progression.61
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2.4.4 genetic biomarkers

Single nucleotide polymorphisms (SNPs) in genes that play an important role in the drug metabolism and disposition of cabozantinib (via cytochrome P450 3A4 and ABCB1-mediated pathways) will be evaluated to correlate with efficacy and clinical outcomes. Functional SNPs in 20 the *VEGFR2* gene could alter antiangiogenic treatment response or outcome by affecting the VEGF signaling pathways. Thus, we will determine if *VEGFR2* genetic variants may be correlated to toxicity and clinical outcomes as we have previously shown in patients treated with bevacizumab and sorafenib62.
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2.4.5 angiogenesis markers

Plasma levels of several angiogenic biomarkers, including VEGF-A, soluble VEGFR2 (sVEGFR2), and placental growth factor (PIGF), have been shown to be significantly altered after single agent cabozantinib treatment (Investigator's brochure). Post-treatment changes in soluble MET (sMET), a potential biomarker for MET inhibition, were observed to be of statistical significance in clinical studies. Plasma samples will be obtained to measure changes in the molecular markers of angiogenesis, as well as sMET/KIT before and after administration of the combination. The potential relationship between biomarker expression and tumor response will be explored.
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2.4.6 plasma and urinary hgf

We will collect urine and blood from patients on this study in order to determine whether urinary hepatocyte growth factor (HGF), urinary soluble MET receptor (sMet), plasma HGF and plasma Met levels are biomarkers of bladder cancer (transitional cell carcinoma; TCC) and/or response to systemic treatment with the experimental Met/VEGFR inhibitor cabozantinib. Soluble Met levels are determined by electrochemiluminescence immunoassay and normalized to urinary creatinine values.
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2.4.7 met expression in tissue

We will investigate the expression and prognostic role of the receptor tyrosine kinase MET, phosphorylated MET, and the ligand hepatocyte growth factor (HGF) in patients with urothelial cancer enrolled in this study. MET, pMET, and HGF expression will be assessed using immunohistochemistry. MET, pMET, and HGF will be correlated with extent of disease, therapy response rate, progression free and overall survival. Tissue blocks and slides obtained from outside pathology departments will be analyzed as available. Tissue biopsies will be encouraged but done strictly on a voluntary basis. Biopsies will be obtained from primary tumor sites and/or metastatic sites.
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2.4.8 immune subsets and angiogenesis

Circulating and intratumoral immune subsets and other markers of the microenvironment, hypoxia-inducible factor (HIF) 1α and 2α and other angiogenesis and/or immunologic markers will be analyzed at baseline and 8-18 weeks after treatment. At 8 weeks (after 2 cycles of treatment), the potential for biopsy will be discussed with the patient. Tissue blocks and slides obtained from outside pathology departments will be analyzed as available. Tissue biopsies will be encouraged but done strictly on a voluntary basis. Biopsies will be obtained from primary tumor sites and/or metastatic sites.
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2.4.9 imaging with pet/ct and

Fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been approved for imaging in many malignancies but not for bladder cancer. A retrospective analysis FDG-PET/CT in patients with metastatic urothelial cancer demonstrated 21 that it has excellent sensitivity and specificity in the detection of metastatic bladder cancer63. FDGPET/CT scans may provide better accuracy in clinical information for directing therapy. We will prospectively explore the utility of FDG-PET CT and FDG-PET MRI in this study.
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2.4.10 comparison of target lesion

At present, conventional imaging evaluation of tumor burden in metastatic disease is limited to axial measurements of select target lesions, which serves as a surrogate assessment for three dimensional changes in tumor size. Rigorous quantitative assessment of tumor response to cancer therapy is dependent upon assessment of these three dimensional changes in size. Recent image processing algorithms allow for formal RECIST reporting within clinical radiology reports, as well as tumor volumetric assessment and HU analysis within PACS and radiologist workflow. Advanced algorithms allow for rapid SA volumetric and tumor density measurements that more accurately reflect tumor burden/ treatment response compared to single dimensional axial measurements alone. Radiologists and information processing IP technologists can use PACS to record RECIST reports that include this information as accurate as existing team measurements. RECIST and volumetric analysis with data integrated has the potential to improve metastatic lesion quantification over existing reporting standards. Ability to produce RECIST and volumetric calculations in reports in PACS, RIS and HIS should improve quality of patient care in facilities treating cancer patients.
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2.4.11 quality of life assessment

In the second line setting, chemotherapy is given with the intent of hindering disease progression and prolonging quality of life. As more treatments for solid tumor malignancies evolve, particularly for the palliative setting, their efficacy will be measured and agents compared not only by the traditional overall and progression free survival standards, but by the effect upon patient quality of life64. "Symptom Inventory" developed by Charles Cleeland at MDACC is a questionnaire that attempts to assess the degree to which various symptoms "interfere with life."
This cancer symptom measurement tool will be utilized at baseline and following cycle 3 of XL184 to informally evaluate its impact upon health related quality of life parameters in this population, to better measure the benefit of therapy against the risk of decline is quality of life.
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3 patient selection 3.1 eligibility

Cohort 1 only (urothelial progressive disease)  
3.1.1.1 Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. Confirmation may be obtained from any CLIA certified lab.  
3.1.1.2 Patients must have progressive metastatic disease. Progressive disease will be defined as new or progressive lesions on cross-sectional imaging.  
3.1.1.3 Patients must have at least one measurable site of disease (according to RECIST (version 1.1) criteria)
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cohort 2 only (bone-only)

3.1.1.4 Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. Confirmation may be obtained from any CLIA certified lab.  
3.1.1.5 Patients must *not* have measurable progressive disease (RECIST 1.1) 3.1.1.6 Patient must have appearance of at least one new bone lesion. Cohort 3 (Rare histologies) 3.1.1.7 Patient must have a histologically confirmed diagnosis of non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis including but not limited to squamous cell, neuroendocrine, adenocarcinoma including urachal and sarcomatoid. Confirmation may be obtained from any CLIA certified lab.  
3.1.1.8 Patients must have progressive metastatic disease. Progressive disease will be defined as new or progressive lesions on cross-sectional imaging.  
3.1.1.9 Patients must have at least one measurable site of disease (according to RECIST (version 1.1) criteria)
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all cohorts

3.1.1.10 Patients must have been previously treated, as defined by treatment with at least one prior cytotoxic regimen or agent.  
3.1.1.11 Age > 18 years. Because no dosing or adverse event *data are cu*rrently available on the use of cabozantinib in patients <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.  
3.1.1.12 ECOG performance status <2 (Karnofsky >60%, (see **Appendix A**) 3.1.1.13 Adequate organ function as defined by the following criteria:
x Hemoglobin ≥ 9 g/dL x Absolute neutrophil count (ANC) ≥ 1500/μL x Platelets ≥ 75,000/μL x Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase
[SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) ≤3.0 x upper limit of normal (ULN); ≤ 5.0 x ULN in cases of liver metastases x Total serum bilirubin ≤ 1.5 u the upper limit of normal (ULN). For subjects with known Gilbert's disease or similar syndrome with slow conjugation of bilirubin, total bilirubin ≤ 3.0 mg/dL
x Serum creatinine ≤ 1.5 X institutional upper limits of normal or for patients with creatinine levels above 1.5 x institutional normal: creatinine clearance ≥
50 mL/min/1.73 m2 by 24 hour urine collection or estimated creatinine clearance of ≥ 50 mL/min. For creatinine clearance estimation , the Cockcroft and Gault equation should be used:
o Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72)
o Female: Multiply above result by 0.85 23 x Urine protein/creatinine ratio (UPCR) ≤ 2  
3.1.1.14 Patient must be able to provide either archival tumor samples (H&E slides and one paraffin block or 10 unstained slides) or undergo tumor biopsy.  
3.1.1.15 Patient must be capable of understanding and complying with protocol requirements and is willing to give informed consent 3.1.1.16 The effects of XL184 on the developing human fetus are unknown. For this reason and because tyrosine kinase inhibitors agents are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (see below) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of XL184 administration.  
Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (*e.g.*, male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s).  
3.1.1.17 Women of childbearing potential must have a negative pregnancy test at screening.  
Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopause is defined as amenorrhea ≥ 12 consecutive months. Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible reason.
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3.1.2 exclusion criteria

3.1.2.1 The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (eg, cytokines or antibodies) within 3 weeks, or nitrosoureas or mitomycin within 6 weeks before the first dose of study treatment.  
3.1.2.2 Prior treatment with cabozantinib 3.1.2.3 Prior treatment with other small molecule inhibitors of VEGFR within ≤ 2 years of study enrollment.  
3.1.2.4 The subject has received radiation therapy:
x to the thoracic cavity or gastrointestinal tract within 3 months before the first dose of study treatment x to brain metastases within 14 days before the first dose of study treatment x to any other site(s), with the exception of bone, within 28 days before the first dose of study treatment 3.1.2.5 The subject has received radionuclide treatment within 6 weeks before the first dose of study treatment 3.1.2.6 The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment.  
3.1.2.7 The subject has received any other type of investigational agent within 28 days before the first dose of study treatment.  
3.1.2.8 The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs.  
3.1.2.9 The subject has a primary brain tumor 3.1.2.10 The subject has active brain metastases, leptomeningeal or epidural disease (Note:
Subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible. Neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment. Baseline brain scans are not required to confirm eligibility.)
3.1.2.11 The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin time (PTT) test ≥1.3 u the laboratory ULN within 7 days before the first dose of study treatment.  
3.1.2.12 The subject requires treatment, in therapeutic doses, with oral anticoagulants such as warfarin prior to initiation of protocol therapy. Low dose aspirin (≤81 mg/day), low-dose warfarin (≤1 mg/day), and low molecular weight heparin (LMWH) are permitted. Subjects will be permitted to use anticoagulation as described in section **5.2.2.6** if treatment is required while they are enrolled on the protocol.  
3.1.2.13 The subject requires chronic concomitant treatment of strong CYP3A4 inducers (*e.g.*,
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's Wort).  
Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/ medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product. Please refer to patient information sheet in **Appendix B**.  
3.1.2.14 The subject has experienced any of the following within 3 months before the first dose of study treatment:
x clinically-significant hematemesis or gastrointestinal bleeding x hemoptysis of ≥ 0.5 teaspoon (≥2.5 mL) of red blood x any other signs indicative of pulmonary hemorrhage 3.1.2.15 The subject has tumor invading (or concern for invasion) major blood vessels 3.1.2.16 Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the 25 judgment of the Investigator would make the patient inappropriate for entry into this study.  
3.1.2.17 The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib.  
3.1.2.18 The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
a. Cardiovascular disorders including  
i. Congestive heart failure (CHF): New York Heart Association (NYHA) Class III
(moderate) or Class IV (severe) at the time of screening ii. Concurrent uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment (BP must be controlled at screening)
iii. Any history of congenital long QT syndrome
iv. Any of the following within 6 months before the first dose of study treatment:
x unstable angina pectoris  
x clinically-significant cardiac arrhythmias x stroke (including TIA, or other ischemic event) x myocardial infarction
b. Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including: i. Any of the following within 28 days before the first dose of cabozantinib  
x active peptic ulcer disease, x active inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
x active malabsorption syndrome ii. Any of the following within 6 months before the first dose of study treatment:
(1) abdominal fistula (2) gastrointestinal perforation (3) bowel obstruction or gastric outlet obstruction  
(4) 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 ago.  
c. Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy.
d. Other clinically significant disorders such as:
i. No active systemic infection requiring parenteral antibiotics ii. serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment iii. history of organ transplant iv. concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment v. history of major surgery as follows:
(1) 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.  
(2) 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 3.1.2.19 The subject is unable to swallow tablets 3.1.2.20 The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >500 ms within 28 days before treatment initiation.  
3.1.2.21 The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation.  
3.1.2.22 The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.  
3.1.2.23 The subject has had within 2 years before the start of study treatment evidence of another malignancy which required systemic treatment 3.1.2.24 HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the study agents. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
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3.1.3 inclusion of women and

Men and women of all races and ethnic groups are eligible for this trial.  
| 3.1.3.1                                   | Accrual Targets  Ethnic Category   | Sex/Gender   |      |    |        |        |      |      |
|-------------------------------------------|------------------------------------|--------------|------|----|--------|--------|------|------|
| Females                                   | Males                              | Total        |      |    |        |        |      |      |
| Hispanic or Latino                        | 2                                  | +            | 4    | =  | 6      |        |      |      |
| Not Hispanic or Latino                    | 15                                 | +            | 44   | =  | 59     |        |      |      |
| Ethnic Category: Total of all subjects    | 17                                 | (A1)         | +    | 48 | (B1) = | 65     | (C1) |      |
| Racial Category                           |                                    |              |      |    |        |        |      |      |
| American Indian or Alaskan Native         | 0                                  | +            | 1    | =  | 1      |        |      |      |
| Asian                                     | 3                                  | +            | 4    | =  | 7      |        |      |      |
| Black or African American                 | 4                                  | +            | 9    | =  | 13     |        |      |      |
| Native Hawaiian or other Pacific Islander | 0                                  | +            | 1    | =  | 1      |        |      |      |
| White                                     | 10                                 | +            | 33   | =  | 43     |        |      |      |
| Racial Category: Total of all subjects    |                                    | 17           | (A2) | +  | 48     | (B2) = | 65   | (C2) |
| (A1 = A2)                                 | (B1 = B2)                          | (C1 = C2)    |      |    |        |        |      |      |
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3.1.4 recruitment strategies

The study will be posted on the CCR website and on clinicaltrials.gov
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3.2 screening evaluation

Study eligibility is based on meeting all of the study inclusion criteria and none of the exclusion criteria at screening before study treatment administration. Screening evaluations may be performed as part of an NIH Screening protocol. This does not include the baseline correlative studies that will only be performed after the patient has signed the consent form.  
The following assessments will be conducted prior to subjects receiving their first dose of cabozantinib on this protocol:
x History including performance status assessment  
x Physical examination including height, weight, vital signs
x Laboratory assessments: acute care panel (sodium, potassium, chloride, total CO2
(Bicarbonate), creatinine, glucose, urea nitrogen), mineral panel (albumin, calcium total, magnesium total, phosphorus), hepatic panel(alkaline phosphatase, ALT/GPT, AST/GOT, total bilirubin, direct bilirubin), ionized calcium, amylase, lipase, LDH, total protein, GGT
x 24 hour urine collection if needed (see section **3.1.1.13**) x Urinalysis including UPCR x PT/INR, PTT x Thyroid function tests - TSH, total T3, T4
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x 12 lead ecg

x Urine or serum HCG (in women of childbearing potential)
x CT Scan of chest, abdomen and pelvis (MRI may be performed in subjects unable to tolerate contrast for CT)
x Pathology evaluation/confirmation of urothelial carcinoma
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4 registration procedures

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. A recorder is available during non-working hours.
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4.1 treatment assignment procedures

| Number               | Name                        | Description                                                                                                                                                                                                     |
|----------------------|-----------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1                    | Cohort 1 (urothelial        | Patients with urothelial progressive disease of the bladder, urethra,                                                                                                                                           |
| progressive disease) | ureter, or renal pelvis.    |                                                                                                                                                                                                                 |
| 2                    | Cohort 2 (Bone-only)        | Patients with bone-only urothelial carcinoma of the bladder,  urethra, ureter, or renal pelvis.                                                                                                                 |
| 3                    | Cohort 3 (Rare histologies) | Patients with non-transitional cell carcinoma of the bladder,  urethra, ureter, or renal pelvis including but not limited to squamous  cell, neuroendocrine, adenocarcinoma including urachal and  sarcomatoid. |
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arms

1 Cabozantinib Administered orally at a dose of 60 mg once daily on each day of a  
28-day cycle.  
| Number   | Name   | Description   |
|----------|--------|---------------|
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5 treatment plan

This is a Phase 2, single-arm, open-label study of cabozantinib in subjects with advanced/metastatic urothelial carcinoma that has progressed despite treatment with cytotoxic chemotherapy. The primary endpoint is to determine the activity of cabozantinib as determined by response rate. A Simon 2-stage design will be used. In the first stage, 21 subjects will be accrued. If there are at least 2 responses, accrual will continue to the second stage and an additional 20 evaluable subjects will be enrolled. If there are a total of 6 or more responses among the total of 41 evaluable subjects, Cabozantinib will be considered of clinical interest in progressive urothelial carcinoma. The primary objective of the study will be to determine the activity of cabozantinib as determined by progression free survival by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Cabozantinib will be administered orally at a daily dose of 60 mg. Patients may continue on study as long as they are tolerating therapy. Patients who achieve and maintain a response of CR by RECIST per section **11.1.4.4** for over 3 years, may have the drug held (drug holiday) as described in section 6.2.
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5.1 agent administration 5.1.1 cabozantinib

Treatment will be administered primarily on an outpatient basis. Subjects will be instructed to take cabozantinib orally at a dose of 60 mg once daily on each day of a 28 day cycle. If a dose is missed, subjects should be instructed not to make it up on the following day. Cabozantinib should be taken on an empty stomach; patients must fast for 2 hours before and 1 hour following each dose of cabozantinib. Subjects should be instructed not to crush or chew and to avoid both grapefruit and Seville orange products while on the study drug. Patients will be provided a pill diary (**Appendix C**) to track the oral study agents, instructed in its use, and asked to bring it with them to each appointment. A new copy of the pill diary will be given to patients whose dose is reduced due to adverse events. Pill counts will also be maintained by study personnel. Subjects will be instructed to notify their physician immediately of any and all AEs. Subjects experiencing one or more AEs due to the study treatment may require a dosing delay or reduction(s) in their dose in order to continue with study treatment. Reported adverse events and potential risks are described in Section 0. 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.  
| Agent        | Premedications;  Precautions   | Dose   | Route   | Schedule   | Cycle  Length  28 days   |
|--------------|--------------------------------|--------|---------|------------|--------------------------|
| Cabozantinib | none                           | 60 mg  | PO      | Daily      | (4                       |
| weeks)       |                                |        |         |            |                          |  
Patients who tolerate cabozantinib at 60 mg daily during the first 2 cycles (first restaging time period) without ≥ grade 2 toxicity may undergo dose escalation to 80 mg daily at the discretion of the Principal Investigator.
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5.1.2 study drug accountability &

All oral self-administered investigational agents will be properly accounted for, handled, and disposed in accordance with existing federal regulations and principles of Good Clinical Practice. The investigator will maintain accurate records of receipt of all cabozantinib, including dates of receipt (compliance form available in **Appendix D**). In addition, accurate records will be kept regarding when and how much study treatment is dispensed and used by each subject in the study. Reasons for deviation from the expected dispensing regimen must also be recorded. At completion of the study, to satisfy regulatory requirements regarding drug accountability, all unused cabozantinib will be returned to the NCI Clinical Repository for proper destruction as per the NCI guidelines. Drug accountability and subject compliance will be assessed with drug dispensing and return records.
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5.2 general concomitant medication and

Because there is a potential for interaction of XL184 with other concomitantly administered drugs through the cytochrome P450 system, the case report form must capture the concurrent use of all other drugs, over-the-counter medications, or alternative therapies. The Principal Investigator should be alerted if the patient is taking any agent known to affect or with the potential to affect selected CYP450 isoenzymes.
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5.2.1 concurrent medications/interventions 5.2.1.1 anticancer

If a subject requires additional systemic anticancer treatment, study treatment must be discontinued. Local intervention is discouraged unless medically unavoidable. Subjects receiving local intervention (*e.g.*, palliative radiation) are allowed to continue to receive study treatment at the investigator's discretion.
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5.2.1.2 other medications

Subjects must be instructed to inform the investigators of the current or planned use or all other medications during the study (including prescription medications, over-the-counter medications, vitamins and herbal and nutritional supplements). It is the responsibility of the investigator to ensure that details regarding all medications are documented. Bisphosphonates started prior to screening activities or initiated during the course of the study to control bone pain may be used with caution. Colony stimulating factors (*e.g.*, erythropoietin and granulocyte colony-stimulating factors) and pain medications administered as dictated by standard practice are acceptable while the subject is enrolled in the study. However, colony stimulating factors should not be administered prophylactically prior to the first dose of study treatment. No concurrent investigational agents are permitted. 5.2.1.3 Potential Drug Interactions Cytochrome P450: Preliminary data from a clinical drug interaction study (Study XL184-008) show that clinically relevant steady-state concentrations of cabozantinib appear to have no marked effect on the AUC of co-administered rosiglitazone, a CYP2C8 substrate. Therefore, cabozantinib is not anticipated to markedly inhibit CYP2C8 in the clinic, and by inference, is not anticipated to markedly inhibit other CYP450 isozymes that have lower [I]/Ki values compared to CYP2C8 (*i.e.*, CYP2C9, CYP2C19, CYP2D6, CYP1A2, and CYP3A4). In vitro data indicate that cabozantinib is unlikely to induce cytochrome P450 enzymes, except for possible induction of CYP1A1 at high cabozantinib concentrations (30 μM). Cabozantinib is a CYP3A4 substrate (but not a CYP2C9 or CYP2D6 substrate), based on data from in vitro studies using CYP-isozyme specific neutralizing antibodies. Preliminary results from a clinical pharmacology study, XL184-006, showed that concurrent administration of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an approximately 80% reduction in cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy volunteers. Co-administration of cabozantinib with strong inducers of the CYP3A4 family (*e.g.*, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's wort) may significantly decrease cabozantinib concentrations. The chronic use of strong CYP3A4 inducers should be avoided. Other drugs that induce CYP3A4 should be used with caution because these drugs have the potential to decrease exposure (AUC) to cabozantinib (*e.g.*, chronic use of modafinil) should be avoided because of its potential to reduce cabozantinib exposure. Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme induction potential is recommended. In addition, caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a subject who has been concurrently receiving a stable dose of cabozantinib, as this could significantly increase the exposure to cabozantinib. Preliminary results from a clinical pharmacology study, XL184-007, showed that concurrent administration of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 3339% increase in the cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy volunteers. Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family (*e.g.*, ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir) may increase cabozantinib concentrations. Grapefruit / grapefruit juice and Seville oranges may also increase plasma concentrations of cabozantinib. Strong CYP3A4 inhibitors and other drugs that inhibit CYP3A4 should be used with caution because these drugs have the potential to increase exposure (AUC) to cabozantinib. Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is recommended. Because in vitro studies only assessed the metabolizing capacity of the CYP3A4, CYP2C9, and CYP2D6 pathways, the potential for drugs that inhibit/induce other CYP450 pathways (*e.g.*, CYP2C8, CYP2C19, CYP2B6, CYP1A2) to alter cabozantinib exposure is not known. Therefore, these drugs should be used with caution when given with cabozantinib. Please refer to the Flockhart drug interaction tables for lists of substrates, inducers, and inhibitors of selected CYP450 isozyme pathways (Flockhart 2007; http://medicine.iupui.edu/clinpharm/ddis/. Protein Binding: Cabozantinib is highly protein bound (approximately 99.9%) to human plasma proteins. Therefore, highly protein bound drugs should be used with caution with cabozantinib because there is a potential displacement interaction that could increase free concentrations of 32 cabozantinib and/or a co-administered highly protein-bound drug (and a corresponding increase in pharmacologic effect). Factors that influence plasma protein binding may affect individual tolerance to cabozantinib. Therefore, concomitant medications that are highly protein bound (*e.g.*, diazepam, furosemide, dicloxacillin, and propranolol) should be used with caution. Because warfarin is a highly protein bound drug with a low therapeutic index, administration of warfarin at therapeutic doses should be avoided in subjects receiving cabozantinib due to the potential for a protein binding displacement interaction. Drugs Associated with QTc Prolongation: Treatment with cabozantinib has been associated with a mild prolongation of the QTc interval. Caution should be used when treating subjects on cabozantinib with other drugs associated with QTc prolongation (see http://www.qtdrugs.org). Additional QTc monitoring is suggested for subjects who are treated concomitantly with QTc prolonging drugs. Other Interactions: In a relative bioavailability study in dogs, cabozantinib exposure was not significantly affected by drugs that alter gastric pH. Nevertheless, drugs such as proton pump inhibitors (PPIs) and H2-antagonists produce profound suppression of gastric acid secretion and significant increases in gastric pH. By elevating gastric pH, PPIs and H2-antagonists may decrease cabozantinib plasma exposure levels and its effectiveness in vivo, resulting in clinically significant drug interactions. The use of PPIs (*e.g.*, omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole) and/or H2-antagonists (*e.g.*, ranitidine, famotidine, and nizatidine) is discouraged during this study. If antacids are not adequate, the use of H2 blockers is preferred over PPIs (Note:
Cimetidine should be avoided because of its potential to interfere with CYP3A4 mediated metabolism of cabozantinib). Antacids, H2 blockers, or PPIs should be taken at least 2 hours
(preferably 4 hours) after taking cabozantinib but at least 14 hours before the next dose of cabozantinib if possible. In vitro data suggest that cabozantinib is unlikely to be a substrate for P glycoprotein (P-gp), but it does appear to have the potential to inhibit the P-gp transport activity. Additional details related to these overall conclusions are provided in the Investigators Brochure
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5.2.2 supportive care

General guidelines for the management of non-hematologic and hematologic toxicities are provided in Sections **6.1.1** and **6.1.2**, respectively. As a general approach, it is suggested that all AEs be managed with supportive care when possible at the earliest signs of toxicity. For more specific guidelines on gastrointestinal AEs (diarrhea, nausea/vomiting, stomatitis/mucositis), hepatobiliary disorders, skin disorders (PPE), embolism and thrombus, and hypertension, see below.
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5.2.2.1 diarrhea

Subjects should be instructed to notify their physician immediately at the first signs of poorly formed or loose stool or an increased frequency of bowel movements. Administration of antidiarrheal agents is recommended at the first sign of diarrhea as initial management. Loperamide is recommended as standard first line therapy. Alternatively, diphenoxylate/atropine can be used. Additional agents to consider in subjects with diarrhea that is refractory to the above include deodorized tincture of opium and octreotide65. Some subjects may require concomitant therapy with loperamide, diphenoxylate/atropine, and deodorized tincture of opium to control diarrhea. When combination therapy with antidiarrheal agents does not control the diarrhea to 33 tolerable levels, a dose reduction and/or dose interruption of cabozantinib should be implemented as described in **Table 2**. In addition, general supportive measures should be implemented including continuous oral hydration, correction of fluid and electrolyte abnormalities, small frequent meals, and stopping lactose-containing products not including cabozantinib, high fat meals and alcohol.
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5.2.2.2 nausea and vomiting

Anti-emetic agents along with supportive care are recommended as clinically appropriate at the first sign of nausea and vomiting. A dose reductions and/or dose interruption of cabozantinib may be required as described in Section **6.1.1** if antiemetic treatment and/or prophylaxis alone is not adequate. Agents classified as having the highest therapeutic index (such as 5-HT3 receptor antagonists) per ASCO or MASCC/ESMO guidelines for anti-emetics in oncology or dexamethasone are recommended66-68. Caution is recommended with the use of aprepitant or fosaprepitant and nabilone as cabozantinib exposure may be affected by concomitant administration because aprepitant and fosaprepitant are both inhibitors and inducers of CYP3A4, and nabilone is a weak inhibitor of CYP3A4.
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5.2.2.3 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 (eg, 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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5.2.2.4 hepatobiliary disorders

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. See section **6.1.4** for additional information.
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5.2.2.5 skin disorders

All subjects on study should be advised on prophylactic measures for hand-foot syndrome including the use of emollients (Ammonium lactate 12% cream or heavy moisturizer twice daily), removal of calluses, avoidance of exposure of hands and feet to hot water leading to vasodilatation, protection of pressure-sensitive areas of hands and feet, and use of cotton gloves and socks to prevent injury and keep the palms and soles dry. The onset of PPE is variable with paresthesia (tingling, numbness) being the characteristic initial manifestation, which can be accompanied by slight redness or mild hyperkeratosis. PPE advances with symmetrical painful erythema and swollen areas (edema) 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. Urea 20% cream twice daily and clobetasol 0.05% cream once daily should be used in subjects that exhibit toxicity. NSAIDS, GABA agonists and opioids may be used for pain control. Aggressive management of symptoms is recommended, including early dermatology referral. Subjects with skin disorders should be carefully monitored for signs of infection (eg, abscess, cellulitis, or impetigo). In the case of study treatment-related skin changes (eg, rash, hand-foot syndrome), the investigator may request that additional assessments be conducted with the subject's consent. These assessments may include digital photographs of the skin changes and/or a biopsy of the affected skin and may be repeated until the skin changes resolve.
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5.2.2.6 embolism and thrombosis

Low molecular weight heparin should be used to establish full anticoagulation in subjects on the first occurrence of a PE and/or DVT. Full anticoagulation with warfarin is not permitted and venous filters are not recommended. Treatment can be restarted at the discretion of the investigator. Subjects should permanently discontinue after a second thrombotic event. Although routine prophylactic anticoagulation is not necessary for all subjects, prophylactic anticoagulation is allowed for individual subjects at the discretion of the investigator. 5.2.2.7 Hypertension See instructions in section **6.1.8**.
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5.3 on study assessments

Please see study calendar (section 10) for schedule of the study assessments.
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5.3.1 electrocardiogram (ecg) assessments

ECG assessments will be performed with standard 12-lead ECG equipment according to standard procedures. Pre-treatment ECGs should be performed after vital signs are obtained and before any blood draws. At any time point, if there is an increase in QTc interval to an absolute value > 500 msec using the Fridericia correction formula, two additional ECGs should be performed approximately 2 minutes apart, within 30 minutes. If the average QTc interval calculated by the Fridericia formula from the three ECGs is > 500 msec, study treatment must be withheld and a cardiology consultation is recommended for evaluation and subject management. Study treatment may only be continued if the QTc resolves to 500msec or less and per investigator judgment that continued treatment is appropriate. Abnormalities in the ECG that lead to a change in subject management (eg, dose reduced or withheld, requirement for additional medication or monitoring) or result in clinical signs and symptoms are considered clinically significant for the purposes of this study and will be recorded on the AE CRF. If values meet criteria defining them as serious, they must be reported as SAEs. When an ECG time point coincides with other activities, the ECG will be collected first, followed by vital signs.
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5.3.2 vital signs

Vital signs (body temperature, respiratory rate, and blood pressure and pulse) will be conducted at regular intervals. Blood pressure and pulse will be measured after the subject has been sitting for at least 5 minutes. When vital signs are scheduled at the same time as blood draws, the blood draws will be obtained at the scheduled time point, and the vitals will be obtained as close to the scheduled blood draw as possible.
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5.3.3 physical examinations

A physical examination will include assessments of general appearance, skin, HEENT, thorax/lungs, cardiovascular, abdominal, genitourinary, musculoskeletal and neurological findings. Any pertinent findings should be documented either in the subject's medical history (if determined to be prior to the first dose of cabozantinib) or as an AE (if new or worsening after the first dose of cabozantinib).
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5.3.4 laboratory assessments

Laboratory assessments will include the following: 5.3.4.1 Hematology:
CBC with differential Reticulocytes (if indicated) Erythrocyte sedimentation rate (if indicated)
5.3.4.2 Serum chemistries:
Hepatic panel (alkaline phosphatase, ALT/GPT, AST/GOT, total bilirubin, direct bilirubin)
Acute care panel (sodium, potassium, chloride, total CO2 (Bicarbonate), creatinine, glucose, urea nitrogen)
Mineral panel (albumin, calcium total, magnesium total, phosphorus) Ionized calcium Amylase Lipase Lactate dehydrogenase (LDH) Total protein J-glutamyltransferase (GGT)
5.3.4.3 Urinalysis including urine creatinine and UPCR 5.3.4.4 Thyroid function tests - TSH, total T3 and T4 5.3.4.5 PT/INR or PTT 5.3.4.6 24 hour urine collection for protein 5.3.4.7 Urine or serum HCG (in women of childbearing potential)
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5.4 duration of therapy

In the absence of treatment delays due to adverse event(s), treatment may continue until one of the following criteria applies:
x Disease progression (unless patients are on drug holiday in which case disease progression will prompt resuming the treatment),
x Intercurrent illness that prevents further administration of treatment, x Unacceptable adverse event(s), x Patient decides to withdraw from the study, or x General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.  
x Necessity for treatment with other anticancer treatment prohibited by the protocol, x 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, x Women who become pregnant or are breast feeding, x Request by regulatory agencies for termination of treatment of an individual subject or all subjects under the protocol, or x Significant noncompliance with the protocol schedule in the opinion of the investigator.  
x The minimum dose of study treatment will be 20 mg once per day. Subjects who cannot tolerate 20 mg once per day will have study treatment discontinued.
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5.5 duration of follow up

Patients will be contacted by telephone 30 - 37 days after the last dose of cabozantinib for a safety assessment. Patients on drug holiday do not need to be contacted. Any study drug remaining in the patient's possession at this time will be returned by mail and treatment compliance will be documented. Additional follow-up will occur for subjects with AEs related to study treatment that are ongoing at the time of this phone call, and for subjects with SAEs related to study treatment that occur after the time of this phone call. The Investigator or designees will make every possible attempt every 2 months (±7 days) after the follow-up phone call to contact the patient or family to obtain the survival information of the patient and start date of additional anticancer treatment.
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5.6 criteria for removal from

Prior to removal from study, effort must be made to have all subjects complete a safety phone call approximately 30 days following the last dose of study therapy.
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5.6.1 criteria for removal from

Subjects may discontinue study treatment or withdraw their consent to participate in the study at any time without prejudice. The investigator may withdraw a subject from study treatment or from the study if, in his or her clinical judgment, it is in the best interest of the subject or if the subject cannot comply with the protocol. In addition, any of the following conditions unless they occur during the drug holiday require withdrawal of the subject from study treatment:  
x An AE or intercurrent illness that in the opinion of the investigator warrants the subject's withdrawal from treatment x Hemorrhage within 30 days of agent administration x Necessity for treatment with other investigational drug or other anticancer medications prohibited by protocol x Noncompliance with the protocol schedule x Participation in another clinical study using anticancer agent(s)
x Occurrence of any grade 4 non hematologic AE unless the subject is unequivocally deriving clinical benefit x Occurrence of grade 4 febrile neutropenia unless the subject is unequivocally deriving clinical benefit x Inability to tolerate a 20 mg daily dose of cabozantinib x Request by regulatory agencies for termination of treatment of an individual subject or all subjects under this protocol x Sexually active subjects who refuse to use medically accepted barrier methods of contraception (eg, male condom, female condom) during the course of the study and for 4 months following discontinuation of study treatment x Women who become pregnant or are breast feeding x Cabozantinib treatment delays > 6 weeks unless the subject was unequivocally benefitting from cabozantinib treatment x Progressive disease (PD)
x Investigator Discretion The reason for study treatment discontinuation will be documented. For subjects who discontinue or are withdrawn from study treatment, every effort must be made to undertake protocol-specified follow-up procedures and end-of-treatment assessments, if possible, unless consent to participate in the study is also withdrawn. If a subject fails to return for the protocol-defined visits, an effort must be made to determine the reason. If the subject cannot be reached by telephone, at the minimum a registered letter should be sent to the subject (or the subject's legal guardian) requesting contact with the clinic. If a subject is discontinued from study treatment because of an AE considered to be related to study treatment and the event is ongoing 30 days after the last dose of study treatment, the event must be followed until resolution or determination by the investigator that the event has become stable or irreversible. 5.6.2 *Off Study Criteria* x Investigator Discretion x Manufacturer no longer able to supply study agent x Participant requests to be withdrawn from study
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x death

If a subject withdraws consent to participate in the study, the reason for withdrawal will be documented, no further study procedures or assessments will be performed, and no further study data will be collected for this subject, other than the determination of survival status from public records such as government vital statistics or obituaries.
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5.6.3 off protocol therapy and

Authorized staff must notify Central Registration Office (CRO) when a subject is off protocol therapy and when a subject is taken off-study. A Participant Status Update Form from the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and sent via encrypted email to: NCI Central Registration Office ncicentralregistrationl@mail.nih.gov.
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6 dosing delays/dose modifications 6.1

Subjects will be monitored continuously for AEs throughout the study and for 30 days after the last dose of study treatment and for any serious adverse event (SAE) assessed as related to study treatment or study procedures, even if the SAE occurs more than 30 days after the last dose of study treatment. Subjects will be instructed to notify their physician immediately of any and all AEs. Subjects experiencing one or more AEs due to the study treatment may require a dosing delay or reduction(s) in their dose in order to continue with study treatment. General guidelines for the management of non-hematologic and hematologic toxicities are provided in section **6.1.1** and section **6.1.2**, respectively. As a general approach, it is suggested that all AEs be managed with supportive care when possible at the earliest signs of toxicity. Calcium, magnesium, potassium and phosphorus should be kept above the lower limits of the laboratory normal values. For more specific guidelines on gastrointestinal AEs (diarrhea, nausea/vomiting, stomatitis/mucositis), hepatobiliary disorders, pancreatic disorders including lipase and amylase elevations, skin disorders (PPE), embolism and thrombus, hypertension, proteinurea, hemorrhage, rectal and perirectal abscess, gastrointestinal (GI) perforation and GI
fistula, non-GI fistula, wound healing and surgery, osteonecrosis of the jaw (ONJ), endocrine disorders and management of treatment-emergent prolongation of the QTc interval, refer to the appropriate section below. Guidance for the management of fatigue, anorexia, weight loss, eye disorders, musculoskeletal and connective tissue disorders, nervous system disorders, respiratory/thoracic/mediastinal disorders and congenital, familial and genetic disorders can be found in the Cabozantinib Investigator's Brochure. Re-escalating study treatment after a dose reduction:
x Subjects who required a dose reduction for Grade 4 non-hematologic toxicity should not be re-escalated x For other related AEs, subjects may be re-escalated to the previous dose at the discretion of the investigator but not sooner than 2 weeks after resolution to Grade ≤ 1 or to the baseline value of AEs.  
x If a subject has been dose-reduced more than once, dose re-escalation can only occur to the next higher dose level. Further dose escalation to higher well-tolerated dose levels is allowed only if clinically indicated per investigator's judgment and dose escalation criteria are met with each escalation (e.g. a minimum 2 week interval between escalations)
x If the AEs that previously led to dose reduction(s) recur upon re-escalation, the dose should be reduced again and no further dose escalation will be permitted.  
x Dose re-escalation is not allowed for dose reduction triggered by neutropenia or thrombocytopenia.  
Dosing may need to be interrupted for AEs considered not related to cabozantinib if this is clinically indicated or if causality is initially uncertain. Study treatment may be resumed at the same dose (or a lower dose per investigator judgment) if the AE is determined not to be related to cabozantinib once the investigator determines that retreatment is clinically appropriate and the subject meets the protocol re-treatment criteria. Dosing delays and modification instructions for cabozantinib hematologic and non-hematologic toxicities are below. Please consult **Table 2** for the appropriate dose at each dose reduction. If study treatment of cabozantinib is restarted after being withheld or interrupted, the subject should be instructed not to make up the missed doses of cabozantinib. If the subject does not recover from his or her toxicities to tolerable Grade ≤ 2 within 6 weeks, the subject will have study treatment discontinued unless there is unequivocal evidence that the subject is benefitting. In this situation, a subject may be able to restart therapy with a dose reduction upon resolution of the toxicity. Baseline CT and bone scans must be repeated at the time the study drug is reinitiated. The minimum dose of study treatment will be 20 mg daily. Subjects who cannot tolerate 20 mg daily will have study treatment discontinued. Table 2: Dose Levels  
| Dose Level   | Cabozantinib dose   |
|--------------|---------------------|
| -2           | 20 mg               |
| -1           | 40 mg               |
| 1            | 60 mg               |
| 2            | 80 mg               |  
The reason for treatment delay and reduced dose must be recorded on the case report form (CRF).  
| CTCAE Version 5 Grade   | Guidelines/Intervention                                                     |
|-------------------------|-----------------------------------------------------------------------------|
| Grade 1:                | Add supportive care as indicated. Continue study treatment at 60 mg  daily. |  
| Version Date: 05/10/2019  CTCAE Version 5 Grade                                                                                                                                         | Guidelines/Intervention                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------|
| Grade 2:  Grade 2 AEs considered related to  study treatment that are subjectively  tolerable or easily managed                                                                         | Add supportive care as indicated. Continue study treatment at 60 mg  daily.                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                |
| Grade 2 AEs considered related to  study treatment that are intolerable to  the subject or deemed unacceptable in  the investigator's judgment; or are not  easily managed or corrected | Dose reduce  x 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.  x If the AE resolves to Grade ≤ 1 or baseline without a dose  interruption, continue the reduced dose.                                                                                                                                                |                                                                |
| Grade 3:  Grade 3 AEs considered related to  study treatment which occurred  without optimal prophylaxis or which  is easily managed by medical  intervention or resolved quickly       | x                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Interrupt study treatment and add supportive care as indicated |
| x                                                                                                                                                                                       | For AEs that are easily managed (e.g., correction of electrolytes)  with resolution to baseline or Grade ≤ 1 within 24 hours,  treatment 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                                                                                                                                                                                |                                                                |
| x                                                                                                                                                                                       | 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, treatment should be  restarted with a dose reduction. Note: if the investigator believes  the likelihood of a reoccurrence of the same Grade 3 AE is small  due to continued prophylaxis or other effective intervention,  treatment may be resumed without a dose reduction and with very  careful monitoring of the subject. |                                                                |
| Grade 3 AEs considered related to  study treatment that occurred despite  optimal prophylaxis or is not easily  managed by medical intervention                                         | Interrupt study treatment until recovery to ≤ Grade 1 or baseline, and  resume treatment with a dose reduction                                                                                                                                                                                                                                                                                                                                                                                            |                                                                |
| Grade 4:  Grade 4 AEs considered related to                                                                                                                                             | Permanently discontinue study treatment unless determined that the                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                |
| 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.                                                                                                                                                                                                                                                                                                 |                                                                |
| 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.         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                |  
| 6.1.2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Hematologic Toxicities                                                                                                                                                                                                                                                                                                     |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 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 one dose level reduction.                                                                                                                                                                                          |
| Thrombocytopenia  Grade 3 thrombocytopenia with clinically  significant bleeding or Grade 4  thrombocytopenia                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Interrupt cabozantinib treatment until resolution to ≤ Grade 1, and  resume cabozantinib treatment at a one dose level reduction                                                                                                                                                                                           |
| 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  one dose level reduction.                                                                                                                                                         |
| Grade 4 febrile neutropenia                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Permanently discontinue study treatment unless determined that the  subject is unequivocally deriving clinical benefit. In this case, upon  recovery to Grade ≤ 1 or baseline, the subject may be re-treated at a  reduced dose that is to be determined by the investigator and  sponsor, but only with sponsor approval. |
| Other Grade 4 Hematologic Toxicities  Grade 4 hematologic toxicities                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Permanently discontinue study treatment unless determined that the                                                                                                                                                                                                                                                         |
| other than anemia                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | 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 u 109/L; Grade 2 (1 u 109/L ≤ ANC <1.5 x 109/L),  Grade 3 (0.5 u 109 /L ≤ ANC < 1 u 109/L), Grade 4 (ANC < 0.5 u 109/L).  Febrile Neutropenia: Grade 3 (present); Grade 4 (Life-threatening consequences; urgent intervention indicated).  Thrombocytopenia: Grade 1 (<LLN - 75 x 109/L); Grade 2 (<75.0 - 50.0 x 109/L);  Grade 3 (Platelet count ≤ 50 - 25 u 109/L); Grade 4 (Platelet count < 25 x 109/L).  No dose modifications are required for grade 1, grade 2 or other grade 3 hematological toxicities. |                                                                                                                                                                                                                                                                                                                            |  
6.1.3 *Diarrhea, Nausea, Vomiting, Stomatitis, and Mucositis* 6.1.3.1 Diarrhea Subjects should be instructed to notify their physician immediately at the first signs of poorly formed or loose stool or an increased frequency of bowel movements. Administration of antidiarrheal agents is recommended at the first sign of diarrhea as initial management. Loperamide is recommended as standard first line therapy. Alternatively, diphenoxylate/atropine can be used. Additional agents to consider in subjects with diarrhea that is refractory to the above include deodorized tincture of opium and octreotide (Benson *et al.,* 2004). Some subjects may require concomitant therapy with loperamide, diphenoxylate/atropine, and deodorized tincture of opium to control diarrhea. The dose modification guidance in Table 6-1 should be followed. In addition, general supportive measures should be implemented including continuous oral hydration, correction of fluid and electrolyte abnormalities, small frequent meals, and stopping lactosecontaining products, high fat meals and alcohol.
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6.1.3.2 nausea and vomiting

Anti-emetic agents along with supportive care are recommended as clinically appropriate at the first sign of nausea and vomiting. The dose modification guidance in Table **6.1.1** 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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6.1.3.3 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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6.1.4 hepatobiliary disorders

Elevations of transaminases have also been observed during treatment with cabozantinib. In general, it is recommended that subjects with elevation of ALT, AST, and/or bilirubin have more frequent laboratory monitoring of these parameters. If possible, hepatotoxic concomitant medications and alcohol should be discontinued in subjects who develop elevated transaminases. Since subjects may enter the study with elevations of AST/ALT at baseline, the following guideline should be used for dose modifications:  
| Transaminase elevation  CTCAE v5.0                                                                                                                                                                                                               | Intervention   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|
| Subjects with AST and ALT less than or equal to the ULN at baseline  Grade 1 Continue cabozantinib with weekly monitoring of liver function tests (LFTs) for at  least 4 weeks. Then resume the standard protocol-defined monitoring of LFTs. 43 |                |  
| Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Continue cabozantinib with at least twice weekly monitoring of LFTs for 2 weeks.  Then weekly for 4 weeks. If LFTs continue to rise within Grade 2, interrupt  cabozantinib treatment. Then continue with at least weekly LFTs until resolution  to Grade ≤ 1. Study treatment may then be resumed at a one-dose-level reduction  of cabozantinib                                |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Interrupt cabozantinib treatment and monitor with at least twice weekly LFTs until  Grade ≤ 2. Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  Cabozantinib may then be resumed at a one-dose-level reduction.                                                                                                                                           |
| Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Discontinue study treatment permanently. LFTs should be monitored as clinically  indicated, at least 2-3 times per week, until resolution to Grade ≤ 1. If the subject  was unequivocally deriving clinical benefit, the subject may be able to resume  treatment at a lower dose of cabozantinib as determined by the investigator and  sponsor but only with sponsor approval. |
| Subjects with AST or ALT above the ULN but ≤ 3.0 x ULN (i.e., Grade 1) at baseline  ≥ 1.5 fold increase of AST or  ALT AND both AST and  ALT are ≤ 5.0 x ULN Continue cabozantinib treatment with at least twice weekly monitoring of LFTs  for 4 weeks and weekly for 4 weeks. If LFTs continue to rise, interrupt study  treatment. Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  Study treatment may then be resumed at a one-dose-level reduction of  cabozantinib  ≥ 1.5 fold increase of AST or  ALT and at least one of  AST or ALT is Grade 3 (i.e.  AST or ALT > 5.0 but ≤ 20.0 x ULN)  Interrupt study treatment and monitor with at least twice weekly LFTs until  Grade ≤ 2. Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  Study treatment may then be resumed at a one-dose-level reduction of  cabozantinib. Grade 4 Discontinue study treatment permanently. LFTs should be monitored as clinically  indicated, at least 2-3 times per week, until resolution to Grade ≤ 1. If the subject  was unequivocally deriving clinical benefit, the subject may be able to resume  treatment at a lower dose as determined by the investigator and sponsor but only  with sponsor approval. |                                                                                                                                                                                                                                                                                                                                                                                  |  
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 u ULN, total bilirubin < 1.5 u ULN, aminotransferases ≤ baseline grade).  
Subjects must have cabozantinib permanently discontinued if transaminase elevations are accompanied by evidence of impaired hepatic function (bilirubin elevation >2 uULN), 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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6.1.5 pancreatic conditions

Amylase and lipase elevations have been observed in clinical studies with cabozantinib. The clinical significance of asymptomatic elevations of enzymes is not known but in general has not been associated with clinically apparent sequelae. It is recommended that subjects with lipase elevation and/or symptoms of pancreatitis have more frequent laboratory monitoring of lipase and/or amylase (2-3 times per week). Subjects with symptomatic pancreatitis should be treated with standard supportive measures.  
| 6.1.5.1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Asymptomatic Lipase or Amylase Elevations   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------|
| Asymptomatic Lipase or Amylase Elevations  Grade 1 or Grade 2 Continue at current dose level. More frequent monitoring is recommended  Grade 3 x Interrupt treatment  x Monitor lipase and amylase twice weekly  x 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.  x 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 x Interrupt treatment  x Monitor lipase and amylase twice weekly  x 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.  x 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. |                                             |  
6.1.5.2 Pancreatitis  
| Pancreatitis  Grade 2 and asymptomatic   | x                                                                                                                                                                                                                                                         | Continue at current dose level. More frequent monitoring of lipase and  amylase and radiographic evaluation is recommended.   |
|------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------|
| Grade 2 symptomatic and                  | x                                                                                                                                                                                                                                                         | Interrupt treatment                                                                                                           |
| Grade 3                                  | x                                                                                                                                                                                                                                                         | Monitor lipase and amylase twice weekly                                                                                       |
| x                                        | 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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6.1.6 skin disorders

Palmar-plantar erythrodysesthesia syndrome (PPE; also known as hand-foot syndrome), skin rash (including blister, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, and papular rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been reported in cabozantinib-treated subjects. All subjects on study should be advised to use prophylactic measures for skin care. These measures includes the use of hypoallergenic moisturizing creams, ointment for dry skin, sunscreen with SPF ≥30; avoidance of exposure of hands and feet to hot water; protection of pressure-sensitive areas of hands and feet; and use of thick cotton gloves and socks to prevent injury and to keep the palms and soles dry. Subjects with skin disorders should be carefully monitored for signs of infection (*e.g.*, abscess, cellulitis, or impetigo). Early signs of hand-foot syndrome can include tingling, numbness, and slight redness or mild hyperkeratosis. Early manifestations include painful, symmetrical red and swollen areas on the palms and soles. The lateral sides of the fingers or periungual zones may also be affected. Adequate interventions are required to prevent worsening of skin symptoms such as blisters, desquamations, ulcerations, or necrosis of affected areas. Aggressive management of symptoms is recommended, including early dermatology referral. Treatment guidelines for PPE related to study treatment are presented in the table below. In the case of study treatment-related skin changes (*e.g.*, rash, hand-foot syndrome), the investigator may request that additional assessments be conducted with the subject's consent. These assessments may include digital photographs of the skin changes and/or a biopsy of the affected skin and may be repeated until the skin changes resolve.  
| 6.1.6.1                                                                                                        | Hand-Foot Skin Reaction and Hand Foot Syndrome (PPE)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
|----------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 1                                                                                                        | Continue cabozantinib at current dose. Start urea 20% cream twice daily AND  clobetasol 0.05% cream once daily. Assess subject at least weekly for changes in  severity. Subjects should be instructed to notify investigator immediately if  severity worsens.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| Grade 2                                                                                                        | If tolerable, continue cabozantinib at current dose. If intolerable, reduce  cabozantinib dose to next lower level and/or interrupt dosing. Start/continue urea  20% cream twice daily AND clobetasol 0.05% cream once daily. Add analgesics  for pain control with NSAIDs/GABA agonists/narcotics if needed. Assess subject  at least weekly for changes in severity. If treatment was interrupted (but not  reduced), treatment may be restarted at the same dose or at one dose level lower  when reaction decreases to Grade 1 or 0. If a treatment interruption is again  required, the dose must be reduced when treatment resumes. Subjects should be  instructed to notify investigator immediately if severity worsens. If severity  worsens at any time, or affects self-care, proceed to the management guidelines  for Grade 3 PPE. |
| Grade 3                                                                                                        | Interrupt study treatment until severity decreases to Grade 1 or 0. Start/continue  urea 20% cream twice daily AND clobetasol 0.05% cream once daily. Pain  control with NSAIDs/GABA agonists/narcotics. Treatment may restart at one  dose level lower when reaction decreases to Grade 1 or 0. Permanently  discontinue subject from study if reactions worsen or do not improve within 6  weeks.                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| GABA, γ-aminobutyric acid; NSAID, nonsteroidal anti-inflammatory drugs; PPE, palmar-plantar erythrodysesthesia |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
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6.1.7 embolism and thrombosis

Deep vein thrombosis and PE have been observed in clinical studies with cabozantinib; including fatal events (please refer to the IB). Subjects who develop a PE or DVT should have study treatment held until therapeutic anticoagulation with heparins is established. Study treatment may be resumed with a one dose-level reduction in subjects who have uncomplicated PE or DVT and are deriving clinical benefit from study treatment. During treatment with anticoagulants, subjects need to be monitored on an ongoing basis for bleeding risk and signs of bleeding. Subjects with life-threatening PE or DVT should have study treatment discontinued unless toxicity can be managed and subject is deriving clear clinical benefit as determined by the investigator and agreed by the Sponsor. Venous filters (*e.g.* vena cava filters) are not recommended due to the high incidence of complications associated with their use. Once a subject is fully anticoagulated, treatment can be restarted per investigator judgment at one dose lower. Subjects should permanently discontinue after a second thrombotic event. Although routine prophylactic anticoagulation is not necessary for all subjects, prophylactic anticoagulation is allowed for individual subjects at the discretion of the investigator. Arterial thrombotic events (*e.g.*, transient ischemic attack, myocardial infarction) have been observed rarely in studies with cabozantinib. Cabozantinib should be discontinued in subjects who develop an acute MI or any other clinically significant arterial thromboembolic complication.
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6.1.8 hypertension

Hypertension is a relatively common complication of other VEGF-pathway inhibitors and has been observed in cabozantinib clinical studies. Decisions to decrease or hold the dose of study treatment must be based on BP readings taken by a medical professional and must be confirmed with a second measurement at least 5 minutes following the first measurement. Subjects with known hypertension should be optimally managed prior to study entry. Clinical judgment should be used in deciding whether new or worsened hypertension emerging during treatment with cabozantinib requires immediate therapy, or whether therapeutic intervention can be delayed in order to confirm the finding of new or worsened hypertension at a second visit before taking new therapeutic action. It is recommended that this second visit occur within 1 week. Blood pressure should be monitored in a constant position visit to visit, either sitting or supine. Cabozantinib dosing should be interrupted in subjects with severe hypertension (≥180 mm Hg systolic or ≥120 mm Hg diastolic; or sustained ≥160 mm Hg systolic or ≥110 diastolic) who cannot be controlled with medical interventions and discontinued in subjects with hypertensive crises or hypertensive encephalopathy (see next Table below).  
| 6.1.8.1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Management of Hypertension Related to Cabozantinib  Criteria for Dose Modifications Treatment/cabozantinib Dose Modification   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------|
| Subjects not receiving optimized anti-hypertensive therapy  > 140 mm Hg (systolic) and < 160 mm Hg  x Increase antihypertension therapy (i.e., increase dose of  existing medications and/or add new antihypertensive  medications)  x Maintain dose of cabozantinib  x 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  OR > 90 mm Hg (diastolic) and < 110 mm Hg  x Reduce cabozantinib by one dose level.  x Increase antihypertension therapy (i.e., increase dose of  existing medications and/or add new antihypertensive  medications)  x Monitor subject closely for hypotension.  x 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. |                                                                                                                                |  
| Criteria for Dose Modifications                                                                                                                                                                                                                                                                                               | Treatment/cabozantinib Dose Modification                                                                             |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------|
| ≥ 180 mm Hg (systolic) OR                                                                                                                                                                                                                                                                                                     | x Interrupt treatment with cabozantinib Add new or additional  anti-hypertensive medications and/or increase dose of |
| ≥ 120 mm Hg (diastolic)                                                                                                                                                                                                                                                                                                       | existing medications.                                                                                                |
| x Monitor subject closely for hypotension.  x When SBP < 140 and DBP < 90, restart cabozantinib  treatment at one dose level lower  x 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                                                                                                                                                                                                                                                                                           | Discontinue all study treatment                                                                                      |
| encephalopathy  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                                                                                                                            |                                                                                                                      |  
Patients with a history of hypertension should be instructed to record their blood pressure once per week during each cycle of cabozantinib on the form provided in **Appendix E** and to bring the form with them at each clinic visit.
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6.1.9 proteinuria

Proteinuria has been reported with approved drugs that inhibit VEGF pathways as well as with cabozantinib. Any level of proteinuria diagnosed by dipstick should be quantified by a UPCR (mg/dL protein / mg/dL creatinine). When a UPCR exceeds 2, a repeat UPCR or a 24-hour urine protein and creatinine should be performed to confirm the result. Cabozantinib should be discontinued in subjects who develop nephrotic syndrome (proteinuria >3.5 g/day in combination with hypoalbuminemia, edema and hyperlipidemia) or any other relevant renal disease. Also, given the nephrotoxic potential of bisphosphonates, these agents should be used with caution in patients receiving treatment with cabozantinib. Details of management are described in the next Table below.  
| Urine Protein/Creatinine Ratio   | Action To Be Taken                                                                                                                                                                                                                                                   |                                       |
|----------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------|
| ≤ 2                              | x                                                                                                                                                                                                                                                                    | No change in treatment or monitoring  |
| > 2 and < 3.5                    | x                                                                                                                                                                                                                                                                    | No change in study treatment required |
| x                                | Consider confirming with a 24-hour protein excretion within 7  days                                                                                                                                                                                                  |                                       |
| x                                | Repeat UPCR within 7 days and once every week. If UPCR is <  2 on two consecutive readings, then UPCR monitoring can revert  to protocol specific time points. (The second reading is a  confirmatory reading and can be done within 1 week of the first  reading.). |                                       |