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1 CTEP Study \#: 9243 Abbreviated Title: Phase I/II XL184 in mCRPC CTEP Protocol \#: 9243 CC **Protocol \#:** 12-C-0204 Q
Version Date: February 27, 2017 Title: A Phase I and Randomized Phase II Multicenter Study of Cabozantinib (XL184) plus Docetaxel and Prednisone in Metastatic Castrate Resistant Prostate Cancer Coordinating Center: Center for Cancer Research  
Principal Investigator: William Dahut, M.D. A-F  
Genitourinary Malignancies Branch (GMB)  
Center for Cancer Research  
National Cancer Institute Building 10, Room 3-2571 9000 Rockville Pike Bethesda, MD 20892 Phone: 240-760-6187 Email: dahutw@mail.nih.gov
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co-investigators

| Fatima Karzai, M.D., NIMHD A-F 10 Center Drive, Room 13N240 Bethesda, MD 20892 Phone: 301-402-9134 Email: Fatima.karzai@nih.gov                                                                              | Ravi Madan, M.D., GMB, CCR, NCI A-F 10 Center Drive, Room 13N240 Bethesda, MD 20892 Phone: 301-480-7168 Email: madanr@mail.nih.gov                                                  |
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| Andrea Apolo, M.D., GMB, CCR, NCI A-F 10 Center Drive, Room 13N240 Bethesda, MD 20892 Phone: 301-480-0536 Email: andrea.apolo@nih.gov                                                                        | James Gulley, M.D., Ph.D., GMB, CCR, NCI A-F 10 Center Drive, Room 13N240 Bethesda, MD 20892 Phone: 301-480-7164 Email: gulleyj@mail.nih.gov                                        |
| Howard Parnes, M.D. A-F Prostate and Urologic Cancer Research Group Division of Cancer Prevention, NCI 9609 Medical Center Dr, Room 5E302 Rockville MD 20850 Phone: 240-276-7045 Email: parnesh@mail.nih.gov | John Wright, M.D., Ph.D. A-F Investigational Drug Branch, CTEP, DCTD, NCI 9609 Medical Center Dr, Room 5W454 Rockville MD 20850 Phone: 240-276-6565 Email: wrightj@ctep.nci.nih.gov |  
2 CTEP Study #: 9243  
| CTEP Study #: 9243 *Liang Cao, Ph.D. GB, CCR, NCI E, F 37 Convent Drive, Room 6134 Bethesda, MD 20892-1906 Phone: 301-435-9039  E-mail: caoli@mail.nih.gov                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | *William Figg, Pharm.D., GMB, CCR, NCI E, F 10 Center Drive, Room 5A01 Bethesda, MD 20892 Phone: 240-760-6179 Email: wdfigg@mail.nih.gov                                                                                                                                                     |
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| *Donald P Bottaro, PhD, UOB, CCR, NCI E, F 10 Center Drive, Room 1W-5832 Bethesda, MD 20892 Phone: 301-402-0922 Email: bottarod@mail.nih.gov                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | *Cindy Chau, Pharm.D., Ph.D., GMB, CCR, NCI E, F 10 Center Drive, Room 5A01 Bethesda, MD 20892 Phone: 301-402-3622 Email: chauc@mail.nih.gov                                                                                                                                                 |
| *Jane Trepel, Developmental Therapeutics  Branch, (DTB), CCR, NCI E, F 10 Center Drive, Room 2N230 Bethesda MD, 20892 Phone: 301-496-1547 Email: trepelj@mail.nih.gov                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | *Douglas Price, Ph.D., GMB, CCR, NCI E, F 10 Center Drive, Room 5A01 Bethesda, MD 20892 Phone: 301-451-5860 Email: dkprice@mail.nih.gov Guinevere Chun, R.N., OCD, CCR, NCI A, B, C, E, F 10 Center Drive, Room 12N226 Bethesda, MD 20892-1906 Phone: 240-760-6065 Email: gchun@mail.nih.gov |
| Anna Couvillon, N.P., GMB, CCR, NCI A-F 10 Center Drive, Room 13N224 Bethesda, MD 20892 Phone: 301-443-6211 Email: couvilla@mail.nih.gov Helen Owens, R.N., OCD, CCR, NCI A, B, C, E, F  *Seth Steinberg, PhD E, F 10 Center Drive, Room 12N226 Biostatistics and Data Management Section Bethesda, MD 20892-1906 National Cancer Institute Phone: 240-760-6068 9609 Medical Center Drive, Room 2W334 Email: howens@mail.nih.gov Rockville, MD 20850  Phone: 240-276-5563   Email: steinbes@mail.nih.gov Responsible Research Nurse: Helen Owens, R.N., OCD, CCR, NCI Referral Contact/Study Coordinator: Helen Owens, R.N., OCD, CCR, NCI  10 Center Drive, Room 12N226  Bethesda, MD 20892-1906  Phone: 240-760-6068  Email: howens@mail.nih.gov * not responsible for patient care |                                                                                                                                                                                                                                                                                              |  
3 CTEP Study \#: 9243 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 de-identified data or specimens for research purposes* G. *Some/all research activities performed outside NIH*  
| Multi-Institution Contacts:  Institutional PI:   | Joseph Kim, M.D. Prostate and Urologic Cancers Program,  Signal Transduction Program Institution: Yale Comprehensive Cancer Center Institution FWA #: 2577 Yale School of Medicine 333 Cedar St, Fitkin 1, Rm 121 New Haven, CT 06520 Phone Number: 203-737-1600 E-mail: joseph.kim@yale.edu   |
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| IRB Contact:                                     | Christine Early IRB of Record Name: Yale University Human  Investigations Committee IORG #: 4296 55 College Street New Haven, CT 06510 Phone Number: 203-785-4688 Email: hrpp@yale.edu                                                                                                         |
| Pharmacy Contact:                                | Thomas Ferencz, RPh, BCOP Smillow Cancer Center at Yale New Haven Hospital 266 So, Frontage Road, Room 8-110 New Haven, CT, 06510 Phone Number: 203-200-4455 Email: Thomas.ferencz@ynhh.org                                                                                                    |
| Institutional Contact:                           | Matthew Piscatelli, BS CCRP 2 Church Street South, Suite 507  New Haven, CT, 06519 Phone Number: 203-737-8367 Email: matthew.piscatelli@yale.edu                                                                                                                                               |  
4 CTEP Study \#: 9243
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ctep supplied agents

| Drug Name:    | Cabozantinib (XL184)   |
|---------------|------------------------|
| IND Number:   | 116059                 |
| NSC Number:   | 761968                 |
| Sponsor:      | CTEP                   |
| Manufacturer: | Exelixis               |
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commercially available agents

Docetaxel and prednisone will be supplied by the local site pharmacy.
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subjects of study

| Number   | Sex   | Age-Range   |
|----------|-------|-------------|
| 81       | Male  | ≥18 - 100   |
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precis background

- Docetaxel is established as first-line chemotherapy in patients with metastatic castrate resistant prostate cancer (CRPC). However; it is increasingly recognized that combining docetaxel with other agents of clinical activities without overlapping toxicities could simultaneously target different cellular signaling pathways vital for tumor survival, producing either additive or synergistic activities.  
- Inhibition of angiogenesis, either as a stand-alone approach or in combination with chemotherapy, has demonstrable antitumor efficacy against CRPC and there are several antiangiogenic agents that are now in clinical trials in this population of patients.  
- Cabozantinib (XL184) was developed as an inhibitor of both angiogenesis and of its resistance mechanism. It is an inhibitor of multiple receptor tyrosine kinases including cMet, VEGFR2 and RET.  
- In single agent clinical studies, cabozantinib demonstrated, broad anti-tumor activities across many solid tumor types.
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objectives

- To determine the safety profile of cabozantinib in combination with docetaxel and prednisone, and to determine the maximal tolerated dose (MTD) as recommended phase II dose in combination with docetaxel.  
- To determine the relative efficacy (in terms of PFS) of docetaxel and cabozantinib compared to docetaxel alone
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eligibility

- Patients must have progressive metastatic CRPC. There must be radiographic evidence of disease after primary treatment with surgery or radiotherapy. If patients had been on flutamide, they must have disease progression at least 4 weeks after withdrawal. Patients on bicalutamide or nilutamide must have progression at least 6 weeks after withdrawal. Withdrawal criteria apply only to patients on the above anti-androgens for at least the prior 6 months.  
- Patients must be at least 18 years of age and able to give informed consent. - Patients in the Phase II portion of the study must have progressed on abiraterone or enzalutamide
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design

- The initial phase I portion of this study will test fixed dose docetaxel and prednisone in combination with cabozantinib at three escalating doses. Using a standard 3 + 3 design, three patients will initially be treated at each dose level until MTD has been defined.  
- An expansion cohort will then be enrolled at the MTD to further characterize safety, toxicity and pharmacokinetic data and to obtain preliminary information on the efficacy of the combination treatment.  
6 CTEP Study \#: 9243  
- In Phase II, patients will be enrolled to a randomized two-arm cohort comparing docetaxel in combination with cabozantinib to docetaxel alone with a primary endpoint of PFS.  
- The accrual ceiling for the study, including the Phase I dose escalation and the expansion phases as well as the Phase II randomized phase, is set at 81.
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schema

| Phase I portion                              |                          |
|----------------------------------------------|--------------------------|
| Dose Escalation Schedule to determine MTD    |                          |
| Dose Level                                   | Dose of cabozantinib     |
| Level -1                                     | 20 mg PO every other day |
| Level 1                                      | 20 mg PO daily           |
| Level 2                                      | 40* mg PO daily          |
| Level 3                                      | 60 mg PO daily           |
| At all dose levels, subjects will also take: |                          |  
- Docetaxel: 75 mg/m2IV day 1 of each 21 day cycle
- Prednisone: 5 mg PO, twice daily
- *40mg PO daily has been determined to be the MTD for the dose expansion cohort.
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randomized phase ii portion unblinded

| Unblinded Randomization   |                                                                                                                    |
|---------------------------|--------------------------------------------------------------------------------------------------------------------|
| Arm A*                    | Docetaxel 75 mg/m2 Prednisone 5 mg BID                                                                             |
| Arm B                     | Docetaxel 75 mg/m2 Prednisone 5 mg BID Cabozantinib 40 mg PO daily Patients treated until radiographic progression |  
| TABLE OF CONTENTS            |                                                                                                                                         |                        |
|------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------|------------------------|
| PRÉCIS .                     |                                                                                                                                         |                        |
| SCHEMA                       |                                                                                                                                         |                        |
| 1                            | OBJECTIVES                                                                                                                              |                        |
| Primary Objective            |                                                                                                                                         |                        |
| 1.1                          |                                                                                                                                         |                        |
| 1.2                          | Secondary Objectives                                                                                                                    |                        |
| 2                            | BACKGROUND .                                                                                                                            |                        |
| 2.1                          | Castrate Resistant Prostate Cancer                                                                                                      |                        |
| 2.2                          | IND Agent - Cabozantinib (XL184) ................................................................................................... 13 |                        |
| 2.3                          | O OTHER AGENTS .                                                                                                                        |                        |
| 2.4                          | RATIONALE                                                                                                                               |                        |
| 2.5                          | Correlative Studies Background .                                                                                                        |                        |
| PATIENT SELECTION            |                                                                                                                                         |                        |
| 3                            | 3.1                                                                                                                                     | Eligibility Criteria . |
| 3.2                          | Screening Evaluation .                                                                                                                  |                        |
| 4                            | REGISTRATION AND RANDOMIZATION PROCEDURES                                                                                               |                        |
| Registration .               |                                                                                                                                         |                        |
| 4.1                          |                                                                                                                                         |                        |
| 4.2                          | Randomization (Phase II Only)                                                                                                           |                        |
| S                            | TREATMENT PLAN                                                                                                                          |                        |
| 5.1                          | Phase I (Closed to Accrual as of Amendment dated 06-11-2014)................................... 32                                      |                        |
| 5.2                          | Phase II                                                                                                                                |                        |
| 5.3                          | Agent Administration                                                                                                                    |                        |
| 5.4                          | Definition of Dose-Limiting Toxicity .                                                                                                  |                        |
| 5.5                          | General Concomitant Medication and Supportive Care Guidelines .............................. 36                                         |                        |
| 5.6                          | ON Study Assessments .                                                                                                                  |                        |
| 5.7                          | D Duration of Therapy                                                                                                                   |                        |
| 5.8                          | D Duration of Follow Up                                                                                                                 |                        |
| 5.9                          | Criteria for Removal from Protocol Therapy and Off Study Criteria ........................... 42                                        |                        |
| 6                            | DOSING DELAYS/DOSE MODIFICATIONS ..................................................................................44                   |                        |
| 6.1                          | Cabozantinib .                                                                                                                          |                        |
| Docetaxel Dose Modifications |                                                                                                                                         |                        |
| 6.2                          |                                                                                                                                         |                        |
| 6.3                          | Study drug dose holidays .                                                                                                              |                        |
| 7                            | ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .....................................59                                                |                        |
| 7.1                          | Comprehensive Adverse Events and Potential Risks List (CAEPR)                                                                           |                        |  
Version Date: 2/27/2017  
| CTEP Study #: 9243                                                                                                                                |                                                                                                                                      |                                      |
|---------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------|
| 7.2                                                                                                                                               | Definitions                                                                                                                          |                                      |
| 7.3                                                                                                                                               | Expedited Adverse Event Reporting to CTEP                                                                                            |                                      |
| 7.4                                                                                                                                               | Routine Adverse Event Reporting to CTEP                                                                                              |                                      |
| 7.5                                                                                                                                               | NHLBI IRB and NHLBI Clinical Director (CD) Reporting............................................ 70                                  |                                      |
| 7.6                                                                                                                                               | Secondary Malignancy                                                                                                                 |                                      |
| Second Malignancy                                                                                                                                 |                                                                                                                                      |                                      |
| 7.7                                                                                                                                               |                                                                                                                                      |                                      |
| 7.8                                                                                                                                               | DATA AND SAFETY MONITORING Plan                                                                                                      |                                      |
| PHARMACEUTICAL INFORMATION .......................................................................................................72              |                                                                                                                                      |                                      |
| 8                                                                                                                                                 | 8.1                                                                                                                                  | Cabozantinib (XL184) (NSC# 761968) . |
| 8.2                                                                                                                                               | Commercial Agents                                                                                                                    |                                      |
| 9                                                                                                                                                 | PHARMACOKINETIC, BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES                                                                         |                                      |
| (NCI SITE ONLY)                                                                                                                                   |                                                                                                                                      |                                      |
| Pharmacokinetic Studies                                                                                                                           |                                                                                                                                      |                                      |
| 9.1                                                                                                                                               |                                                                                                                                      |                                      |
| 9.2                                                                                                                                               | Biomarker Studies                                                                                                                    |                                      |
| Sample Storage, Tracking and Disposition                                                                                                          |                                                                                                                                      |                                      |
| 9.3                                                                                                                                               |                                                                                                                                      |                                      |
| STUDY CALENDAR ................................................................................................................................84 |                                                                                                                                      |                                      |
| 10                                                                                                                                                |                                                                                                                                      |                                      |
| 11                                                                                                                                                | MEASUREMENT OF EFFECT ............................................................................................................86 |                                      |
| 1.1 Antitumor Effect - Solid Tumors                                                                                                               |                                                                                                                                      |                                      |
| 12                                                                                                                                                | DATA COLLECTION / DATA REPORTING ................................................................................92                  |                                      |
| 12.1 Data Collection                                                                                                                              |                                                                                                                                      |                                      |
| 12.2 Data Reporting                                                                                                                               |                                                                                                                                      |                                      |
| 12.3 CTEP Multicenter Guidelines .                                                                                                                |                                                                                                                                      |                                      |
| 12.4 Collaborative Agreements Language                                                                                                            |                                                                                                                                      |                                      |
| STATISTICAL CONSIDERATIONS .........................................................................................96                            |                                                                                                                                      |                                      |
| 13                                                                                                                                                | 13.1 Study Design/Endpoints                                                                                                          |                                      |
| 13.2 Sample Size/Accrual Rate                                                                                                                     |                                                                                                                                      |                                      |
| 13.3 Analysis of Secondary Endpoints .                                                                                                            |                                                                                                                                      |                                      |
| 14                                                                                                                                                | HUMAN SUBJECTS PROTECTIONS ...........................................................................................97             |                                      |
| 14.1 Rationale For Subject Selection .                                                                                                            |                                                                                                                                      |                                      |
| 14.2 Participation of Children .                                                                                                                  |                                                                                                                                      |                                      |
| 14.3 Participation of Subjects Unable to Give Consent                                                                                             |                                                                                                                                      |                                      |
| 14.4 Evaluation of Benefits and Risks/Discomforts .................................................................................. 98           |                                                                                                                                      |                                      |
| 14.5 Risks/Benefits Analysis .                                                                                                                    |                                                                                                                                      |                                      |
| 14.6 Consent and Assent Process and Documentation                                                                                                 |                                                                                                                                      |                                      |
| 15                                                                                                                                                | PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS ........................100                                                      |                                      |  
9  
| 16   | REFERENCES 101                                                                                                                                                                                                                                                                                                                                                                                                                                   |
|------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 17   | APPENDICES 106 17.1 Appendix A: Performance Status Criteria 106 17.2 Appendix B: Patient Information on Possible Drug Interactions 107 17.3 Appendix C: Guidelines for Prophylaxis and Treatment for Hypersensitivity Reactions  (HSR) Associated with Docetaxel 109 17.4 Appendix D: CCR Patient Self-Administered Study Agent Compliance Log 114 17.5 Appendix E: CTEP Multicenter Guidelines 116 17.6 Appendix F: CCR Problem Report Form 117 |
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1 objectives 1.1 primary objective

- To determine the safety profile of cabozantinib in combination with docetaxel and prednisone, and to determine the maximal tolerated dose (MTD) as the recommended phase II dose in combination with docetaxel  
- To determine the relative efficacy (in terms of progression free survival) of docetaxel and cabozantinib compared to docetaxel alone
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1.2 secondary objectives

- To assess pharmacokinetics of each agent during combination therapy. - To evaluate antitumor activities of combination therapy via measurable disease as determined by Response Evaluation Criteria in Solid Tumors (RECIST) and Prostate Cancer Clinical Trials Working Group Criteria 21.  
- To assess changes in molecular biomarkers in the pathways of receptor tyrosine kinases and angiogenesis, as well as the biomarkers for bone metabolism.
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2 background 2.1 castrate resistant

Prostate cancer is the most common malignancy and the second leading cause of cancer-related deaths in American men. It is estimated that 217,730 men were diagnosed with prostate cancer and 32,050 died from this disease in 2010.  
2 Although the disease is initially responsive to androgen deprivation therapy, it invariably progresses and becomes resistant to androgen ablation in the majority of patients. This leads to the development of CRPC, which is defined as tumor growth despite castrate levels of androgens (serum testosterone < 50 ng/dL).1 Advanced CRPC carries significant morbidity and mortality, and often necessitates a transition to the treatment with chemotherapy to control tumor growth and prevent disseminated organ involvement. The role of chemotherapy in metastatic CRPC was limited until 2004 when two pivotal phase III randomized trials, TAX 327 and SWOG 99-16, demonstrated an overall survival benefit of docetaxel (with prednisone or estramustine) compared to mitoxantrone and prednisone.  
3,4 Based on its modest survival benefit, docetaxel obtained FDA approval and was established as first-line chemotherapy in patients with metastatic CRPC.
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strategies to improve clinical efficacy

It is increasingly recognized that combining docetaxel with other agents of clinical activities without overlapping toxicities could simultaneously target different cellular signaling pathways vital for tumor survival, producing either additive or synergistic activities. Given the survival benefit conferred by docetaxel, it is encouraging that further studies using docetaxel-based combination therapies targeting multiple cellular mechanisms concurrently could be a viable option for this patient population. In fact, numerous trials have been conducted combining docetaxel with different agents of distinct mechanisms of action, including TKIs, angiogenic inhibitors, bone-targeted agents, BCL-2 inhibitors, immunologic agents, and vitamin D analogs.  
5 The available data so far has produced inconsistent results. Several phase II trials of combination treatment have indicated enhanced anti-tumor activity beyond docetaxel alone, whereas others have been proven to be futile. To consolidate the conflicting results published on docetaxelbased therapies, a recent meta-analysis from 12 randomized combination trials with 2,244 patients was performed. The trials were selected in the meta-analysis if they were randomized control trials studying first-line chemotherapy of histologically confirmed CRPC with docetaxel plus prednisone as the control arm. It demonstrated higher PSA response rate and longer overall survival in favor of docetaxel-based combinational therapies,6thus, provided evidence for further endeavor to pursue docetaxel-based combination therapies. This opens up to a question that which molecular pathways are the most appropriate targets which can be incorporated into docetaxel-based regimen for metastatic CRPC patients.
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anti-angiogenic agents as potential partners

The significance of angiogenesis in promoting prostate cancer growth and metastasis has been well established. Microvessel density was reported to be substantially higher in prostate cancer samples from patients with metastatic disease when compared with those without metastatic disease.7 Elevated plasma and urine levels of VEGF-A was found to be associated with metastatic progression and reduced survival in patients with prostate cancer,8thus demonstrated the potential to serve as an independent prognostic factor in men with metastatic prostate cancer.9 Blocking tumor neovascularization via anti-angiogenic agents, e.g. bevacizumab, has been determined as an appealing approach in reducing proliferation and metastatic potential of various tumors, including prostate cancer.10 In an attempt to improve patient's outcome in the first-line treatment setting, the benefit of addition of bevacizumab was assessed in the CALGB phase III trial (90401), where docetaxel, prednisone and bevacizumab was compared with docetaxel and prednisone in 1,050 men with metastatic CRPC. Although addition of bevacizumab led to significant improvements in PFS and PSA response rate but no significant difference in overall survival was noted.11 The negative result from this seemingly promising combination indicates refractoriness and resistance do occur during the course of anti-angiogenic treatment. Multiple mechanisms for acquired resistance have been postulated with supportive preclinical and clinical evidence. Controlling the escape from anti-angiogenesis Angiogenesis is a complex process and multiple mediators are involved at different cellular interface. The examples of these molecules are the families of VEGF, PDGF, FGF, ANG and TIE signaling system, TGF-β signaling, and the NOTCH and WNT signaling pathway, etc.12 Resistance to VEGF inhibitor, such as bevacizumab, usually ensues as inhibition of angiogenesis via a single target which can be potentially overcome by shifting the balance to the production of other pro-angiogenic mediators given the redundancy of angiogenic system.  
12 Indeed, blocking neovascularization by VEGF antibody was found to induce hypoxia which in turn up-regulate angiogenic factors such as bFGF, chemokines and ephrin, and angiopoietin families, leading to anti-angiogenesis rescue.13 To overcome the hurdle of multiple pre-existing or induced proangiogenic factors, we previously took the strategy of dual inhibition of angiogenesis by combining docetaxel, prednisone with two other agents of distinct anti-angiogenic properties, thalidomide and bevacizumab, in chemotherapy-naïve CRPC patients in a single arm phase II trial. Striking results were observed in that 90% of patients achieved PSA decline of > 50% with a 60% objective response rate among patients with measurable disease.14 The median time to progression was 18.2 months and median OS was 28.2 months, comparing favorably to what was observed in TAX 327 and SWOG 9916.14 Subsequent ongoing phase II trial utilizing same strategy of dual angiogenic inhibition (phase II trial of docetaxel, bevacizumab, lenalidomide and prednisone in patients with metastatic CRPC) yielded similar activity as of last analysis in August 2011 (unpublished data). All patients developed Grade ¾ neutropenia, due to overlapping toxicity profiles of docetaxel and thalidomide, in the first trial, which necessitate the use of pegfilgrastim in the second trial. The superior antitumor activities from these two trials supports further research into this strategy, however, new targets lacking overlapping toxicities with docetaxel need to be sought to improve tolerability profile. Another mechanism of VEGF-independent tumor angiogenesis was elucidated by Pennacchietti et al. in cultured cells and mouse xenograft tumor model. Receptor tyrosine kinase c-Met, a protooncogene capable of cell invasion and metastasis upon binding to hepatocyte growth factor (HGF), was found overexpressed under hypoxic condition and this overexpression was inversely proportional to the blood vessel proximity.15 The up-regulation of c-Met sensitized it to HGF
stimulation and resulted in increased cell motility and invasiveness (invasive switch).15 Hypoxiainducible factors (HIFs)-induced c-Met overexpression is considered a cellular coping mechanism in response to low oxygen levels upon selective inhibition of VEGF pathway. However, it potentially can serve as an effective outlet for tumor to escape anti-angiogenesis. In fact, a paracrine mechanism for HGF stimulation of c-Met has been largely implicated in the progression of prostate cancer.  
16 Upregulation of c-Met expression is frequently observed in prostate cancer tissues, particularly in metastatic tumor samples.16 Interestingly, the bone metastases expressed significantly more c-Met than did the lymph node metastases.  
17 AR
signaling appears to negatively regulate the expression of c-Met as significantly elevated c-Met expression was observed during androgen deprivation therapy.  
18 This may potentiate c-Metdriven metastasis resulting in the development of more aggressive CRPC. The fact that suppression of c-Met via RNA interference resulted in loss of hypoxia-enhanced, HGFstimulated cell branching,15 supports the use of combination of anti-angiogenic agents with cMet blocking agents for the prevention of both angiogenic and invasive switch and overcome the resistance to anti-angiogenesis.
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2.2 ind agent - cabozantinib

The search for dual inhibition of both angiogenesis and its resistance mechanism led to the development of XL 184 (Cabozantinib), a potent inhibitor of multiple receptor tyrosine kinases including c-Met, vascular endothelial growth factor receptor 2 (VEGFR2) and RET. Cabozantinib is orally bioavailable as demonstrated by PK studies in rodent and non-rodent models. In vitro assays showed that cabozantinib was a substrate of CYP3A4-mediated metabolism. It 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. It is highly protein-bound (99%) to human plasma proteins and its terminal-phase half-life (t1/2, z) values are 59.1 to 136 hours. In in-vivo target modulation studies, administration of cabozantinib to mice resulted in dose-dependent inhibition of MET, and VEGFR2 with IC50 values of 1.8 nM and 0.035 nM (Investigator Brochure).
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2.2.1 nonclinical development of cabozantinib

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 tumors19. 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 20. 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 21. 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 22. XL184 increased tumor hypoxia (13-fold) and apoptosis (TUNEL; 2.5fold) at 8 and 4 hours after the first and second doses, respectively, when compared to vehicletreated tumors. In addition, XL184 disrupted tumor vasculature by inducing endothelial cell death that negatively affected tumor viability. XL184 treatment resulted in significant tumor growth inhibition of MDA-MB-231 tumors (P <0.001) at all doses (1, 3, 10, 30, or 60 mg/kg) when compared to vehicle-treated tumors. Dose-dependent inhibition was observed for the 3 and 10 mg/kg doses (P <0.01), and complete inhibition was observed at the 30 and 60 mg/kg doses. A single 100 mg/kg dose resulted in sustained MDA-MB-231 tumor growth inhibition for ~8 days after which tumors began growing at a rate similar to vehicle-treated control tumors. In addition, XL184 inhibited tumor growth (P <0.001) in the MET-expressing rat C6 glioma cell line for all doses (1, 3, 10, 30, or 60 mg/kg) when compared with vehicle-treated tumors. The 3 mg/kg and 10 mg/kg doses resulted in significant tumor regression (62% and 85%, P <0.0001) when compared with predose tumor weights. Subchronic administration of XL184 was well tolerated in mice and rats with no signs of toxicity, as determined by stable and/or increasing body weights during the treatment period. ARCaP-M is a human prostate cancer model which expresses both c-Met and VEGF co-receptor NP-1 used in a human prostate tumor xenograft study in mouse bone23. 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 treatment24.  
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. 2.2.1.2 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 trials25. XL184 produced prolonged inhibition of receptor phosphorylation, such as sustained inhibition of c-Met and VEGFR2 for 10 hours after administration of a single dose of XL184. This extended inhibition occurred in a manner that was generally predicted by plasma exposure, i.e., inhibition was diminished when plasma levels fell below approximately 20 μM for c-Met, 5 μM for VEGFR2, and 23 μM for TIE-2. Once daily administration of XL184 resulted in significant inhibition of c-Met phosphorylation in TT tumors, relative to tumors from vehicle control-treated mice, with maximal inhibition of 70% seen at 60 mg/kg,25. 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-Met22. This effect was reversible, as c-Met phosphorylation returned to basal levels by 48 hours after treatment.
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2.2.1.3 nonclinical pharmacokinetics

In the various xenograft models, plasma exposures were similar and plasma concentrations in the range of 3 to 27 μM were associated with efficacy 25. 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 rats25. 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) 25. 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 24. 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. 2.2.1.4 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 24. Histopathological changes present in the bone and pancreas were considered secondary to XL184 administration. Adverse effects following oral exposure to XL184 were generally dose-related, clinically monitorable, and self-resolving upon discontinuation of dosing. In 6-month chronic toxicity studies, treatment-related changes were present only in kidney (rats) and reproductive tissues (dog). In reproductive/developmental toxicity studies, XL184 administration resulted in decreased fertility in male and female rats, in embryotoxicity when given to pregnant rats, and in a visceral tissue malformation (small spleen) when given to pregnant rabbits. The no-observable-adverse-effect-levels (NOAELs) for the chronic toxicity and reproductive/developmental toxicity studies occurred at plasma exposures (AUC) below steady-state values measured in subjects with solid tumors administered 175 mg XL184 capsule form daily (Study XL184-001).  
In definitive genotoxicity bioassays, XL184 was negative in an *S. typhimurium/E.coli* bacterial mutagenicity study, an *in vitro* chromosome aberration study using human peripheral blood lymphocytes, and an *in vivo* mouse bone marrow micronucleus study25. In safety pharmacology studies, no adverse effects occurred on neurobehavioral or respiratory functions in XL184treated rats or on cardiovascular function in XL184-treated dogs.
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2.2.2 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 Lmalate salt (or approximately 138 mg freebase equivalent weight).  
Detailed information for each of these studies, including pharmacokinetic data, can be found in the Investigator's Brochure (2011)24. Safety and efficacy information, from the 2011 Investigator's Brochure, is summarized below.
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2.2.2.1 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 qd26. 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 XL184-014. One additional subject was enrolled as of May 2011 at 50 mg PO qd. Study **XL184-202** was a phase 1b/2 trial that evaluated the safety and tolerability of cabozantinib and erlotinib administered in combination in non-small-cell lung cancer (NSCLC) subjects. Of the 64 subjects enrolled in the phase 1 dose-escalation portion of the study, all but two had been previously treated with and progressed on erlotinib therapy. A cPR was observed in 5 subjects
(8%) and 24 subjects (37%) had SD/PR ≥4 months. The most common grade 3 or higher AEs in the phase 1 portion included diarrhea (44%), fatigue (22%), hypokalemia (11%), decreased appetite (6%), dyspnea (14%), lipase increase (6%), hypomagnesemia (6%), and dehydration
(5%). Twenty-eight subjects were enrolled in the phase 2 portion of the study, in which subjects who had received clinical benefit from erlotinib and subsequently experienced progressive disease (PD), received single-agent cabozantinib or cabozantinib with erlotinib. AEs ≥grade 3 included dehydration (8%) and hypertension (8%). One patient, who was treated with singleagent cabozantinib, had a cPR.  
In the phase I part of this trial (study 9243/12C0204), 20 patients were treated at 3 dose levels (4 at 20 mg, 8 at 40 mg, and 7 at 60 mg) of cabozantinib in combination with docetaxel and prednisone. The MTD of cabozantinib in combination with docetaxel and prednisone was determined to be 40mg. Two DLTs occurred in the 60 mg cabozantinib cohort. One DLT was febrile neutropenia and the other was grade 2 intolerable hand/foot syndrome. The median age was 68 years old (44-84 yrs). The median baseline PSA was 94.7 ng/mL (0.01-754.1 ng/mL). Median Gleason score was 9 (7-10). Median number of cycles was 9.5 (1-33). Common grade 2 and grade 3 adverse events possibly related to cabozantinib were: hand/foot syndrome (4/16), oral mucositis (4/16), hypophosphatemia (4/16), and fatigue (3/16).  
2.2.2.2 Phase 2 Studies In a phase 2 study, **XL184-201**, subjects with progressive or recurrent GB in first or second relapse were enrolled to receive cabozantinib qd as a single agent. Group A received an initial dose of 175 mg (Group A), subsequent cohorts (Groups B and C) received an initial dose of 125 mg. Forty-six subjects were enrolled in Group A, and a total of 176 subjects were enrolled in Groups B/C. Fifty-seven subjects experienced one or more serious adverse events (SAEs) that were assessed to be related to treatment, including five fatal related.  
Study **XL184-203** is a phase 2 randomized discontinuation trial. Subjects are enrolled into one of nine tumor-specific cohorts: breast cancer, gastric/gastroesophageal (GEJ) cancer, hepatocellular carcinoma (HCC), melanoma, NSCLC, ovarian cancer, pancreatic cancer, prostate cancer, and small cell lung cancer (SCLC). Eligible subjects with advanced solid tumors receive open-label cabozantinib at starting dose of 100 mg qd for 12 weeks. Of the 531 subjects enrolled in this study as of May 2011, 92 experienced one or more SAEs that were assessed to be related to treatment with cabozantinib, including seven fatal related SAEs. Randomization was suspended in the CRPC and ovarian cancer cohorts based on observed high rates of clinical activity, and randomized subjects were unblinded. At the last interim analysis, 171 patients with CRPC had been accrued to the study. DCR at week 12 was 68% with 0 of 171 subjects achieving CR, 7 achieving confirmed PR and the remainder with stable disease. Given the encouraging result, a non randomized extension (NRE) cohort was opened for CRPC patients to be evaluated at 100 mg and 40 mg daily doses sequentially. As of June 2012, results were available for 93 CRPC patients treated at 100 mg daily cabozantinib in the extension cohort, 62
(67%) had a bone scan response27. 4 were CRs and 58 were PRs. 15 of these patients also showed stable disease on bone scan. The median duration of response was 5.4 (5.0 - 6.9) months. 84 % of patients experienced at least one dose reduction due to adverse events. One patient with extensive liver disease experienced a related grade 3 portal vein thrombosis with grade 5 liver failure. Preliminary evidence supports clinical activity at 40 mg28. Study **XL184-**
205 is a randomized phase 2 trial for subjects with grade IV astrocytic tumors in first or second relapse. Subjects received one of four regimens: 25 mg qd (Arm 1) continuously, 75 mg qd (Arm 2) continuously, 125 mg qd for 2 weeks followed by 50 mg qd continuously (Arm 3), and 125 mg qd on an intermittent 3 week on/1 week off schedule (Arm 4). A total of 19 subjects were accrued before the study was terminated. Three subjects were rolled over to maintenance Study XL184-900. One subject experienced an SAE assessed to be related to treatment with cabozantinib. Study **XL184-301** is a blind trial for subjects with unresectable, locally advanced or metastatic MTC, randomized 2:1 to cabozantinib or placebo. SAEs reported in Study XL184-301 are: one grade 4 reversible posterior leukoencephalopathy syndrome (RPLS), one grade 5 cardiac arrest following asystolic vagal reaction after aspiration on study medication, and three SAEs of acquired trachea-esophageal fistula (two grade 3, one grade 5).
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2.2.2.3 phase 3 studies

COMET-1 is a randomized, double blind phase 3 trial of cabozantinib in men with metastatic castration-resistant prostate cancer (mCRPC) who had previously been treated with and progressed after treatment with docetaxel, abiraterone and/or enzalutamide. The primary endpoint of the trial was overall survival, and the secondary endpoint was bone scan response as assessed by an independent radiology committee. All patients in the trial had bone metastases, and there was no limit to the number or type of prior treatments. Patients were randomized 2:1 to receive cabozantinib (60 mg daily) or prednisone (5 mg twice daily). The trial did not meet its primary endpoint of demonstrating a statistically significant increase in overall survival for patients treated with cabozantinib as compared to prednisone. The median overall survival for the cabozantinib arm of the trial was 11.0 months versus 9.8 months for the prednisone arm
(hazard ratio 0.90; 95% confidence interval 0.76 - 1.06; p value 0.212).29 In the randomized, double-blind phase 3 COMET-2 trial ((NCT01522443), 119 men with progressive mCRPC after treatment with docetaxel, abiraterone, and/or enzalutamide, with moderate to severe pain were were randomized in a 1:1 fashion to cabozantinib 60 mg po once daily or mitoxantrone and prednisone (12 mg/m2 every 3 weeks and prednisone 5 mg every 12 hours).30 The primary endpoint was pain response. The secondary endpoints were bone scan response and overall survival. The primary endpoint of improving pain was not achieved with pain response rates of 15% for cabozantinib vs. 17% for mitoxantrone and prednisone (P = 0.773). The bone scan response rates were 31% for cabozantinib vs. 5.2 % for mitoxantrone and prednisone. The median overall survival was 9 months for cabozantinib vs 7.9 months for mitoxantrone and prednisone. While the results of both the COMET-1 and COMET-2 trials were negative, both of these studies utilized cabozantinib as a single agent. We hypothesize the addition of the multikinase inhibitor cabozantinib to docetaxel and prednisone could potentially minimize tumor resistance by targeting different cellular signaling pathways without overlapping toxicities. Additionally, emerging clinical data suggests mCRPC patients treated with anti-androgen therapy like abiraterone or enzalutamide have decreased responses to subsequent therapy with docetaxel due to cross-resistance in the androgen pathway targeted by docetaxel, abiraterone, or enzalutamide.31 2.2.2.4 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, palmarplantar 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.  
2.2.2.5 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)26. 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 steadystate plasma levels were reached by Day 1526. Steady-state clearance for the 175 mg capsule dose derived from repeat dose data was 4.2 ± 1.5 L/h. Patients who received 175 mg capsules had four- to five-fold higher steady-state exposure (AUC) compared with Day 1 (7.68 ± 2.85 mcg∙h/mL; n = 23 vs. 41.6 ± 15.3 mcg∙h/mL; n = 23), indicating that XL184 accumulated with repeat daily dosing. There was no significant difference in exposure between patients with MTC and those without MTC. Based on the preliminary PK data from 23 subjects in **XL184-005** who completed both treatments, after a single oral dose of cabozantinib at 100 mg, the terminal t1/2, z of cabozantinib appeared to be similar for both tablet and capsule formulations, with approximately mean values of 110 hours (Exelixis Communication, 2012). The median time to the maximum plasma concentration (tmax) was 4 hours for the tablet formulation and 5 hours for the capsule formulation. High inter-subject variability for Cmax and the area under the plasma drug 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 AUC0inf]: 40-43% for the tablet formulation, 43% for the capsule formulation). The geometric mean Cmax of the tablet formulation was approximately 39% higher than the value observed for the capsule formulation. The geometric mean AUC0-last and AUC0-inf values for the tablet formulation were also higher (15% and 19%, respectively) than those observed for the capsule formulation. However, due to the high within-formulation variability observed, no statistical difference in exposure between the two formulations was apparent. Based on the preliminary PK data from 46 subjects who completed both treatments on trial XL184-004, a high-fat meal did not appear to alter the terminal t1/2, z of cabozantinib [mean t1/2, z
: 131 hours (fed) vs. 128 hours (fasted)]. The high-fat meal significantly increased the median tmax to 6 hours from 4 hours (fasted). The high-fat meal also significantly increased both the cabozantinib Cmax and AUC values by 39% and 56%, respectively. The geometric mean ratio of Cmax fed/fasted was 1.39 (90% CI: 1.16-1.67), and the geometric mean ratio of AUC0-last fed/fasted was 1.56 (90% CI: 1.34-1.80). Based on this result, cabozantinib must be taken on an empty stomach (fasting is required 2 hours before and 1 hour after each cabozantinib dose).
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2.3 other agents 2.3.1 docetaxel

Docetaxel, a semi-synthetic taxane with the ability to disrupt microtubule dynamics, possesses potent antitumor activity in a variety of malignancies. Its mechanism in prostate cancer is thought to be two-fold. First, it acts as a microtubule stabilizer by binding preferentially to Betatubulin, leading to assembly of microtubules without GTP and other various cofactors. This leads to static polymerization, which disrupts the normal mitotic process, causing cell arrest in G2/M phase and ultimately leads to apoptosis. A second mechanism involves BCL-2, which is an oncoprotein that enhances tumor activity via inhibition of apoptosis. The stabilization of microtubule structure by docetaxel results in inactivation of BCL2 function via phosphorylation, which prevents binding to BAX. Increased free BAX induces activation of the caspase cascade leading to apoptosis.  
32 In 2004, both Tannock et al. and Petrylak et al. simultaneously published positive results from two randomized trials using docetaxel as backbone in metastatic CRPC. In TAX 327, the median survival improved from 16.5 months to 18.9 months in patients receiving docetaxel and prednisone every three weeks, as compared to patients who received mitoxantrone and prednisone. Docetaxel also effectively decreased PSA (P<0.001), relieved pain associated bone metastases (P=0.01), as well improved quality of life (P=0.005).  
33 With an extended follow-up, this survival benefit has persisted. In an updated report, median survival was 19.2 months in the docetaxel arm, as compared to 16.3 months in the mitoxantrone arm. More patients survived at 3 years in the docetaxel arm (18.6%) compared with those in the mitoxantrone arm (13.5%).  
4 Similar benefit was also observed in SWOG 9616 where the median survival in docetaxel and estramustine arm surpassed that of mitoxantrone arm by 1.9 months (17.5 vs. 15.6 months; P=0.02).3 These two large randomized studies were the first to demonstrate survival benefit after long battle for active chemotherapeutic agents for men with metastatic CRPC. Undoubtedly, docetaxel is effective in this disease. However, the survival improvement is modest with only 5.9% (86.5% vs. 81.4%) reduction in the rate of death at 3 years with limited survival advantage of 2.9 months 4. New strategies are clearly needed to increase the number and duration of the response. More recently, trials have examined the use of intermittent taxane therapy as a possible mechanism to overcome resistance to these agents33,34. Perhaps more practically, "drug holidays" may improve the quality of life for patients and allow them to recover from the cumulative toxicity of the chemotherapeutic agents during this period35-37. There have been several trials in prostate cancer that have examined this intermittent approach to chemotherapy and have seen favorable results. In a study of 250 patients randomized to 36 mg/m2of docetaxel weekly with high dose calcitriol vs. placebo, arbitrary guidelines were set to have a PSA decline
>50% and PSA ≤ 4 in order to qualify for a drug holiday. Of the 20% of patients who qualified, 90.9% were responsive to docetaxel up resumption of treatment38. The NCI results from a phase II study involving docetaxel combined with antiangiogenic agents report a median OS of > 28 months, which exceeds any contemporary trial that does not employ this intermittent strategy11,14.  
Extensive preclinical and clinical research is ongoing in the identification of the drivers of disease progression. Multiple novel agents with distinct cellular or molecular targets or implications in tumor microenvironment are being assessed in clinical trials either as single agent or in combination with other effective agents.
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2.4 rationale

Given the superior clinical activity and unique molecular mechanism of cabozantinib in CRPC patients, we hypothesize that addition of cabozantinib to docetaxel and prednisone, in patients with metastatic CRPC, will bear acceptable toxicity profile given significant non-overlapping range of AEs and potentially minimize tumor resistance and improve survival by targeting different cellular pathways simultaneously. This combinational therapy with allowances for the incorporation of treatment holidays will represent a safe and effective strategy to maximize patients' benefit and further extend their survival. In phase II randomized discontinuation trial, cabozantinib, as a single agent, was dosed at 100 mg once daily. No recommended dose for combination therapy has been defined. At 100 mg dose level, high incidence of fatigue (9%), hand-foot syndrome (8%), and HTN (5%) were noted in all advanced solid tumors patients 39. Similar rate of adverse events (AEs) were also observed in CRPC cohort with Grade 3/4 AEs being fatigue (11%), HTN (7%), and hand-foot syndrome (5%).  
40 The rate of dose reductions and permanent discontinuations of cabozantinib for AEs occurred in 41% and 12% of all patients, and 51% and 10% in CRPC cohort, respectively.  
39,40 Thus, we propose to conduct a phase I study to define the MTD of cabozantinib when in combination with docetaxel and prednisone. In particular, cabozantinib will be examined at three dose levels (20 mg, 40 mg, and 60 mg qd) with an expansion cohort at MTD. A dose (-1) of 20 mg qod will be studied if DLT is seen at the 20 mg dose level.
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2.4.1 rationale for evaluating docetaxel

Emerging clinical data suggests that mCRPC patients treated with modern anti-androgen therapy such as enzalutamide or abiraterone have decreased responses to subsequent therapy. This is likely due to cross-resistance in the androgen pathway which is targeted by these agents as well as docetaxel31. Three separate retrospective analyses demonstrated a median progression free survival of 4.6 months or less in patients who were treated with docetaxel after progression on abiraterone41-43. The median overall survival in two of these studies was found to be less than 13 months41,42. Although these studies are small and retrospective, they share a consistent and uniform finding that docetaxel and prednisone have limited benefits after disease progression on abiraterone. On the phase I portion of this study, a total of 19 patients were enrolled. Seventeen patients were evaluable (one patient withdrew due to travel and a second patient was not evaluable due to a fall injury). For the 17 patients, median progression free survival is 12.1 months; 6 month PFS is 76.0% (95% CI: 52.0%-90.3%), 12 month PFS is 55.3% (95% CI: 31.9% - 76.6%). For the 14 patients who received abiraterone or enzalutamide, median PFS is 13.6 months; 6 month PFS is 77.9% (95% CI: 51.3% - 92.2%), 12 month PFS is 62.3% (95% CI: 36.3% - 82.8%). PFS results seen in this trial compare favorably to historical previously published data of treatment with docetaxel after progression on abiraterone in mCRPC, suggesting the addition of cabozantinb to docetaxel may help overcome acquired resistance. Further studies will assess if there is a molecular signature that identifies patients benefiting from the cabozantinib plus docetaxel combination.
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2.4.2 chaarted trial (rationale for

High-volume hormone-sensitive metastatic prostate cancer has historically been treated using hormonal therapy followed by chemotherapy. The disease however remained poorly prognostic in nature. A shift in the treatment paradigm of these patients occurred with the results of the Eastern Cooperative Oncology Group (ECOG) phase III randomized CHAARTED trial, which looked at whether the addition of upfront chemotherapy to hormonal therapy improved overall survival in patients with hormone-sensitive metastatic prostate cancer. A retrospective subanalysis from this trial was reported by Dr. Christopher Sweeney from the Dana Farber Cancer Institute, at the 2014 American Society of Clinical Oncology (ASCO)
Plenary Session.44 In the CHAARTED trial, men with metastatic castrate-sensitive prostate cancer were randomized 1:1 to receive androgen deprivation therapy (ADT) alone or to ADT with chemotherapeutic drug docetaxel at 75 mg/m2 every 3 weeks for 6 cycles to be started within 4 months of starting ADT. ADT plus docetaxel resulted in a median overall survival of 57.6 months (HR= 0.61; P = .0003) compared to 44 months in the ADT arm. Patients were stratified according to high-volume vs low-volume disease and the benefit for docetaxel therapy was found to be more apparent in the high-volume metastatic group vs the low-volume metastatic group.  
Most patients with metastatic castrate-sensitive prostate cancer will progress to a castrateresistant state. Previous evidence has also shown that upon progression, docetaxel confers an overall survival benefit.33 However, it is unlikely that such survival benefit would be achieved in cases where a patient has already been treated with 6 cycles of docetaxel while castrate-sensitive. Given the very positive results of the CHAARTED trial and current shift towards initial treatment with docetaxel for high-volume hormone-sensitive metastatic disease, we propose amending protocol 12-C-0204 to address the initial treatment with docetaxel. If a patient has progressed on docetaxel chemotherapy in the castrate-sensitive state, then they will be excluded from this trial on the basis that re-treatment with docetaxel will not confer benefit to the metastatic castrate resistant patient. Additionally, if a patient has progressed to a castrationresistant state and received docetaxel, they will be excluded from this trial as re-treatment with docetaxel has not found to be of benefit in this patient population. Lastly, a time period of 6 months will be required between a patient's completion of the 6th cycle of docetaxel based on CHAARTED and the first dose of study treatment (cycle 1, day 1). This time period is based upon data seen in other solid tumor types, such as retreatment in ovarian cancer with platinumbased chemotherapies.
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2.5 correlative studies background

In addition to the studies listed below, eligible subjects on this protocol may participate in NCI protocol 12-C-0080. Participants in this study will undergo F-18 NaF PET/CT scanning at baseline (within 7 days prior to starting therapy). A subset of these patients (approximately 20) will undergo a second baseline scan within 2-5 days of the initial scan. All participants will then undergo subsequent NaF PET/CT scanning at week 8. These research imaging procedures will be conducted in addition to the clinical imaging procedures listed in the study calendar in section 10. The research radiation risks are discussed in the imaging protocol.
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2.5.1 genetic biomarkers

Single nucleotide polymorphisms (SNPs) in genes that play an important role in the drug metabolism and disposition of docetaxel and cabozantinib (via cytochrome P450 3A4 and ABCB1-mediated pathways) will be evaluated to correlate with efficacy and clinical outcomes. Functional SNPs in 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 sorafenib.  
45
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2.5.2 pharmacodynamic biomarkers

Plasma levels of several angiogenic biomarkers, including vascular endothelial growth factor-A (VEGF-A), soluble VEGFR2 (sVEGFR2), soluble c-Met (sMET), and placental growth factor (PIGF), have been shown to be significantly altered after single agent cabozantinib treatment (Investigator's Brochure). Plasma samples will be obtained to measure changes in the molecular markers of angiogenesis, as well as c-Met before and after administration of the combination. Urinary levels of c-met will also be measured as previous studies have reported it to be a potential marker of metastatic prostate cancer. The change in HGF, which is the only known ligand of c-Met, will be also measured as a marker for c-Met inhibition. The potential relationship between biomarker expression and tumor/PSA response will be explored.
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2.5.3 markers for bone activities

Crosslinked C-telopeptide of type I collagen (CTx) is a marker of osteoclast activity and bone resorption, while total Alkaline phosphatase (t-ALP) is a marker for osteoblast activity. The significant reduction of serum CTx and t-ALP by cabozantinib was reported in the CRPC cohort from a phase II randomized discontinuation trial.  
40 Osteoclast mediated bone resorption can also be assessed by measuring urine N-telopeptide (uNTx), which has been reported as an independent prognostic factor for overall survival in patients with bone metastases from CRPC.46 Samples will be obtained to determine changes in bone turnover from activation of both osteoblasts and osteoclasts.
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2.5.4 circulating tumor cells (ctc)

The changes in CTC counts have been shown to be the most accurate and independent predictor of OS in CRPC. CTC enumeration at baseline and post-treatment is prognostic of survival and the shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease. Thus, CTC will be investigated before and after drug administration as an experimental endpoint. The data will be used to correlate with clinical response. Molecular determinants can also be identified and characterized in CTCs as potential predictive biomarkers of tumor sensitivity to therapeutic treatments. CTCs will be isolated at baseline and genetic analysis will be performed to determine androgen receptor (AR) expression and activity in tumor cells to further understand the clinical response to the combination treatment.
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3 patient selection 3.1 eligibility

3.1.1 *Inclusion Criteria* 3.1.1.1 Must have metastatic, progressive, castrate resistant prostate cancer (CRPC). There must be radiographic evidence of disease after primary treatment with surgery or radiotherapy that has continued to progress radiographically or biochemically (rising PSA levels on successive measurements) despite adequate androgen-deprivation therapy, which is defined as having undergone bilateral surgical castration or continued treatment on GnRH agonists or antagonists..
Progression must be evidenced and documented by any of the following parameters:  
1. Two consecutively rising PSA values, above the baseline, at a minimum of 1week intervals 2. Appearance of one or more new lesions on bone scan 3. Progressive measurable disease by RECIST 1.1 The use of androgen receptor inhibitors is not required prior to study entry. For those patients receiving an anti-androgen agent (flutamide, bicalutamide, or nilutamide), for at least 6 consecutive months immediately prior to study entry, and are entering the trial due to a rise in PSA, they must demonstrate a continued rise in PSA within 4 weeks after stopping flutamide and within 6 weeks after stopping bicalutamide or nilutamide. Flutamide, nilutamide and bicalutamide disease progression requirements only apply to patients who have been on these drugs for at least the prior 6 months.  
3.1.1.2 Histopathological confirmation of prostate cancer by the Laboratory of Pathology of the NCI, Pathology Department of the Walter Reed National Military Medical Center or Yale is required prior to entering this study. Patients whose pathology specimens are no longer available may be enrolled if the patient has a clinical course that is consistent with prostate cancer and available documentation from an outside pathology laboratory of the diagnosis. All efforts should be made to have the material forwarded to the research team for use in correlative studies in cases where original tissue blocks or archival biopsy material is available.  
3.1.1.3 Patients must have metastatic disease, defined as at least one lesion on bone scan or at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam.  
3.1.1.4 Patients must have a performance status of 0 to 2 according to the ECOG criteria (see Appendix A)
3.1.1.5 Patients must have adequate bone marrow, hepatic, and renal function with:
- Hemoglobin ≥ 9 g/dL
- Leukocytes ≥ 3000/μL - ANC ≥ 1500/μL, without CSF support
Confidential
- Platelets ≥ 100,000/μL - AST(SGOT) ≤ 2.5 x upper limit of normal (ULN); - ALT(SGPT) ≤ 2.5 x upper limit of normal (ULN);
- Total serum bilirubin ≤ the upper limit of normal (ULN). - Serum albumin ≥ 2.8 g/dL
- Serum phosphorus, calcium, magnesium, and potassium ≥ LLN
- Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of pancreatitis
- Creatinine ≤ 1.5 X institutional upper limits of normal OR
- Creatinine clearance of ≥ 50 ml/min/1.73 m2 for patients with creatinine levels above institutional normal by 24 hour urine.
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- urine protein/urine creatinine

ratio (UPCR) ≤ 1 3.1.1.6 Patients must be at least 18 years of age. Because no dosing or adverse event data are currently available on the use of cabozantinib in combination with docetaxel and prednisone in patients <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.  
3.1.1.7 Patient must be capable of understanding and complying with protocol requirements and is willing to give informed consent 3.1.1.8 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 and their female partners must agree to use medically accepted barrier methods of contraception (eg, 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 also 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). Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately.  
3.1.1.9 Patients enrolled on the randomized portion of the study must have had disease progression on arbiraterone or enzalutamide.  
3.1.2 *Exclusion Criteria* 3.1.2.1 The subject has had evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment 3.1.2.2 The subject is unable to swallow tablets. 3.1.2.3 The subject has tumor invading (or there is concern for invasion of) major blood vessel.  
3.1.2.4 The subject has active brain metastases or epidural disease Subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible. 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.  
3.1.2.5 The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel). Low dose aspirin (≤81 mg/day), low-dose warfarin (≤1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted.  
3.1.2.6 The subject has a corrected QT interval calculated by the Fridericia formula (QTcF)
>500 ms within 28 days before initiation of protocol therapy. Note: if initial QTcF is found to be > 500 ms, two additional EKGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is ≤500 ms, the subject meets eligibility in this regard.  
3.1.2.7 Patients with contraindication to steroid use 3.1.2.8 Prior treatment with cabozantinib 3.1.2.9 The patient has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or nitrosoureas or mitomycin within 6 weeks before the first dose of study treatment.  
3.1.2.10 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 with the exception of patients receiving prior abiraterone or ketoconazole. For patients receiving prior abiraterone or ketoconazole, they must discontinue the medication within 5 half-lives of the compound before the first dose of study treatment in order to participate in this study. Note: Subjects with prostate cancer currently receiving LHRH or GnRH agonists must be maintained on these agents.  
3.1.2.11 The subject has received any other type of investigational agent within 28 days before the first dose of study treatment.  
3.1.2.12 The subject has received radiation therapy:
- to the thoracic cavity or gastrointestinal tract within 3 months before the first dose of study treatment
- to bone or brain metastasis within 14 days before the first dose of study treatment
- to any other site(s) within 28 days before the first dose of study treatment 3.1.2.13 The subject has received radionuclide treatment within 6 weeks prior to the first dose of the study treatment 3.1.2.14 The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies, including surgery, except alopecia and other non-clinically significant AEs.  
3.1.2.15 The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin time (PTT) test results at screening ≥ 1.3  the laboratory ULN
within 7 days before the first dose of study treatment.  
3.1.2.16 The subject has experienced any of the following:
- clinically-significant hematemesis or gastrointestinal bleeding within 6 months before the first dose of study treatment
- hemoptysis of ≥ 0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment
- any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment 3.1.2.17 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 >140 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:
- unstable angina pectoris - clinically-significant cardiac arrhythmias - stroke (including TIA, or other ischemic event)
- myocardial infarction
- thromboembolic event requiring therapeutic anticoagulation (Note:
subjects with a venous filter (e.g. vena cava filter) are not eligible for this study)
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 study treatment
- intra-abdominal tumor/metastases invading GI mucosa - active peptic ulcer disease - inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
- malabsorption syndrome ii. Any of the following within 6 months before the first dose of study treatment:
(1) history of 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 or concurrent evidence of intraluminal tumor involving the trachea and esophagus.  
d. Other clinically significant disorders such as:
i. active infection requiring intravenous treatment within 10 days of starting protocol treatment 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 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.  
3.1.2.20 Patients who require taking drugs that are strong inhibitors/inducers of CYP3A4 and cannot be switched to an alternative medication.  
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-thecounter medicine or herbal product. Please refer to patient information sheet in Appendix B.  
3.1.2.21 Patients with greater than or equal to grade 2 peripheral neuropathy at baseline.  
3.1.2.22 The subject has had treatment with docetaxel for the treatment of metastatic castratesensitive prostate cancer within 6 months before the first dose of study treatment.  
3.1.2.23 The subject has had progression of prostate cancer during 6 cycles of prior docetaxel treatment for castrate sensitive disease.  
3.1.2.24 The subject has received chemotherapy for castration-resistant prostate cancer.
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3.1.3 inclusion of women and

Men of all races and ethnic groups are eligible for this trial. Women are excluded as prostate cancer does not exist in this population.
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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.  
➢ To be performed 1 week prior to enrollment
- History and physical exam including weight and vital signs
- Tumor marker profile: PSA
➢ To be performed within 16 days prior to enrollment
- CBC with differential and platelet count, prothrombin time/INR, activated partial thromboplastin time
- Urinalysis and UPCR
31 CTEP Study \#: 9243  
- Electrolytes, BUN, creatinine, glucose, AST, ALT, bilirubin, calcium, phosphorous, albumin, magnesium, alkaline phosphatase, LDH, ionized calcium, amylase, lipase, total protein, GGT
- Thyroid function tests - TSH, total T3, T4
- 12 lead ECG
➢ To be performed within 4 weeks prior to enrollment
- CT scan of chest, abdomen, and pelvis - Technetium 99 bone scintigraphy scan
- Testosterone (baseline only, test must be repeated if more than 8 weeks have elapsed between evaluation and C1D1); not required for patients with prior bilateral orchiectomy
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4 registration and randomization 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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4.1.1 for participating site registration

Registration will be a two-part process as patients are screened on this protocol. A protocol registration form will be supplied by the CCR study coordinator and updates will be provided as needed. Subject eligibility and demographic information is required for registration. To initially register a subject, after the participant has signed consent, complete the top portion of the form and send to CCR study coordinator. Once eligibility is confirmed, after completion of screening studies, complete the remainder of the form which is the eligibility checklist, indicating that the patient is being registered for treatment and send to CCR study coordinator. In addition, source documents supporting the eligibility criteria must be sent to the CCR study coordinator. The CCR study coordinator will notify you either by e-mail or fax that the protocol registration form has been received which will include the unique patient/subject ID number. Questions about eligibility should be directed to the CCR study coordinator or PI. Questions related to registration should be directed to the CCR study coordinator. Subjects that do not meet screening criteria should be removed from the study following the procedure in section **5.9.2**.
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4.2 randomization (phase ii only)

After confirming eligibility, patients will be randomized on a 1:1 basis to receive either docetaxel alone or docetaxel with cabozantinib. Randomization will be performed by the CRO.
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5 treatment plan 5.1 phase

There are two components to this study. A Phase 1, single-arm, open-label, dose-escalation component will study cabozantinib combined with fixed dose docetaxel and prednisone in subjects with metastatic CRPC. This component will consist of two parts:  
- A Dose Escalation part to determine the maximum tolerated dose (MTD). Subjects will accrue using a "3 plus 3" design. The evaluation of dose-limiting toxicity (DLT) as defined in Section 5.4 occurring within the first 6 weeks of treatment will be used to determine changes in dose levels. However, all available safety, PK, and pharmacodynamic data will be considered in the decision to dose escalate, dose de-escalate, or expand the current cohort.  
All patients will be treated with docetaxel at 75 mg/m2intravenously every three weeks on day 1 of each cycle as a cycle, and prednisone 5 mg PO BID on days 1-21. Patients will receive a daily cabozantinib dose of 20 mg in dose level 1, 40 mg in dose level 2, and 60 mg in dose level 3 throughout the cycle. If there are 2 or more DLTs at dose level 1, subjects will be enrolled on dose level -1 at 20 mg every other day. All patients will receive 8 mg of oral dexamethasone, 12 hours, 3 hours, and 1 hour before docetaxel infusion.  
- An Expansion Stage. Once the MTD is determined, the study will enter the Expansion Stage in which up to an additional 6 subjects will be accrued (to a total of up to 24) in order to obtain additional safety, PK, and pharmacodynamic data at the MTD.
Patients will continue to receive study treatment as long as they do not experience disease progression and/or unmanageable side effects from the treatment.
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5.2 phase ii

A second component of this study will attempt to determine the relative efficacy of docetaxel, prednisone and cabozantinib at the MTD as compared to docetaxel and prednisone (standard of care) in mCRPC patients. In this study patients will be randomized to either of the two treatment regimens and then treated until disease progression.
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5.3 agent administration

Treatment will be administered primarily on an outpatient basis. Reported adverse events and potential risks are described in Section 7. Appropriate dose modifications are described in Section 6. No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the patient's malignancy.  
| Dose Escalation Schedule   |                       |
|----------------------------|-----------------------|
| Dose Level                 | Dose Cabozantinib     |
| Level -1                   | 20 mg every other day |
| Level 1                    | 20 mg daily           |
| Level 2                    | 40* mg daily          |
| Level 3                    | 60 mg daily           |  
*40mg daily has been determined to be the MTD and will be the dose in the dose escalation phase **and the phase II randomized phase.**  
| REGIMEN DESCRIPTION                                                                                                                                                                                                                 |                              |                      |       |                     |               |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|----------------------|-------|---------------------|---------------|
| Agent                                                                                                                                                                                                                               | Premedications;  Precautions | Dose                 | Route | Schedule            | Cycle  Length |
| ** every                                                                                                                                                                                                                            |                              |                      |       |                     |               |
| Cabozantinib***                                                                                                                                                                                                                     | none                         | ** mg                | PO    | other day or  daily |               |
| 8 mg of oral  dexamethasone, 12  hours, 3 hours, and  1 hour before  infusion                                                                                                                                                       | 21 days                      |                      |       |                     |               |
| 75mg/m2                                                                                                                                                                                                                             | IV over 1 hour               | Day 1 of  each cycle |       |                     |               |
| Docetaxel                                                                                                                                                                                                                           | (3 weeks)                    |                      |       |                     |               |
| Take with food or                                                                                                                                                                                                                   |                              |                      |       |                     |               |
| Prednisone                                                                                                                                                                                                                          | with milk to reduce          | 5 mg                 | PO    | Twice daily         |               |
| stomach irritation.                                                                                                                                                                                                                 |                              |                      |       |                     |               |
| **Doses and intervals as appropriate for assigned dose level. *** Not all patients in the phase II portion will be treated with Cabozantinib - 20 patients will be on the  combination arm and 20 on the single agent docetaxel arm |                              |                      |       |                     |               |
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5.3.1 cabozantinib

Subjects will be instructed to take cabozantinib orally at the appropriate dose level once daily or every other day on a 21 day cycle. As indicated in section 9.1, the first dose of cabozantinib should be withheld until the last PK blood draw 24 hours after the docetaxel infusion; the cycle 2 day 1 dose should be taken just prior to the docetaxel infusion before PK samples are drawn. 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, 2 hours before taking cabozantinib and 1 hour after each cabozantinib dose patients should not eat. Subjects should be instructed not to crush or chew and to avoid both grapefruit and Seville orange products while on the study drug. 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.
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5.3.2 docetaxel prepare as indicated

Docetaxel 75mg/m2 will be administered intravenously over approximately 60 minutes on cycle 1 day 1 and repeated every 21 days (i.e. a 3-week cycle). All patients will receive 8 mg of dexamethasone orally 12 hours 3 hours and 1 hour prior to docetaxel infusion. If a patient misses a pretreatment dose of dexamethasone, he may receive dexamethasone 8 mg intravenously prior to docetaxel. In the event of a hypersensitivity reaction, infusion times may be longer. Hypersensitivity reactions may be managed clinically according to PI discretion. Please see **Appendix C** for suggested management guidelines (optional). To minimize patient exposure to phthalate plasticizers (e.g., DEHP), which may be leached from PVC containers and administration sets, administer docetaxel only through polyethylene-lined administration sets
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5.3.3 prednisone

Prednisone should be taken orally twice a day, at 5mg for each dose. Prednisone should be taken at approximately the same time every day. The doses should be taken about 12 hours apart ± 2 hours. Gastric irritation may be reduced if taken before, during, or immediately after meals or with milk. If a dose of prednisone is missed (more than 14 hours have passed since the last dose), patients should be instructed not to make up the dose and to resume taking prednisone at the next scheduled dose.
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5.3.4 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 reconciled, returned or destroyed in accordance with applicable state and federal regulations. Drug accountability and subject compliance will be assessed with drug dispensing and return records.
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5.4 definition of dose-limiting toxicity

Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) (v4.0). Dose limiting toxicities (DLTs) are defined as adverse events occurring during the first two cycles of therapy and related to the study medications (attributions: possible, probable, and definite) while fulfilling one of the following criteria:  
1. Any Grade 3 or greater non-hematologic toxicity except asymptomatic grade 3 hypertension, hypomagnesemia, hyponatremia, hypophosphatemia, hypocalcemia, and asymptomatic grade 4 uric acid.  
2. A treatment delay of > 2 weeks due to an adverse event (delays due to dental procedures are not included)
3. Grade 4 neutropenia (ANC<500/uL) lasting >5 days. 4. Febrile neutropenia 5. Grade 3 thrombocytopenia lasting for 7 days or more or thrombocytopenia < 50K/uL
requiring platelet transfusion for bleeding will be considered dose limiting.  
6. Any treatment related AEs that lead to dose reduction of either agent (duration or dose) in cycles 1 and 2 will be considered a DLT.  
Anemia will not be considered a DLT.
Hypertension will only be considered a DLT if it is a grade 4 or if clinical management of hypertension as defined in **6.1.7.1** mandates a dose reduction. With the exception of grade ≤ 3 fatigue and grade ≤ 3 reversible asymptomatic labs, the occurrence of a cabozantinib related DLT will lead to removal from protocol therapy unless patients can recover to grade 1 or baseline within 2 weeks. In such cases, patients may continue with protocol treatment with a dose reduction. In the cases of these exceptions, only 1 dose reduction will be permitted during the DLT evaluation period. A subject will be replaced if the subject does not have a DLT but is not fully evaluable for DLT due to missing more than 25% in total of the dosing days due to progressive disease or reasons other than cabozantinib-related toxicity. Because of the long half-life of cabozantinib, DLTs will be monitored for the first 6 weeks (during the first two cycles). Management and dose modifications associated with the above adverse events are outlined in Section 6. Dose escalation will proceed in cohorts of 3–6 patients as defined in the table below. Patients may be accrued concurrently within a single dose level. Patients may be enrolled on the next higher dose level, provided that at least three patients on the previous dose level have completed at least 6 weeks of the combination treatment, and none have experienced a DLT. If one instance of DLT is observed among the initial 3 patients, 3 additional patients must be treated at this dose level without further DLT before escalation can proceed to the next dose level. If two instances of DLT are observed at a dose level, the MTD has been surpassed, and a total of 6 patients must be treated at the previous dose level. The MTD is defined at the dose level at which no more than 1 of 6 patients experiences DLT at the level below that which had two instances of DLT. If a patient did not experience DLT and did not finish treatment, he or she will not be evaluable for toxicity and will be replaced in the dose level. Intrapatient dose escalation may be allowed at the discretion of the principal investigator if the following conditions are met:  
a. there is no drug-related toxicity > grade 2 after 3 courses of study treatment at the initial dose level; b. the higher dose level has been completed by all patients in that cohort and no patients experienced a DLT
c. there is no evidence of disease progression.
In addition, patients who have their dose escalated will not be evaluated for DLTs as they will have previously been evaluated for DLT at their initial dose level and will be more than 3 cycles into therapy.  
| Dose Escalation Table Number of Patients with DLT  at a Given Dose Level   | Escalation Decision Rule                                                                                                                                                                                                                                                                                                                                                                                      |
|----------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0 out of 3                                                                 | Enter 3 patients at the next dose level.                                                                                                                                                                                                                                                                                                                                                                      |
| >2                                                                         | Dose escalation will be stopped. This dose level  will be declared the maximally administered  dose (highest dose administered). Three (3)  additional patients will be entered at the next  lowest dose level if only 3 patients were treated  previously at that dose.                                                                                                                                      |
| 1 out of 3                                                                 | Enter at least 3 more patients at this dose level. - If 0 of these 3 patients experience DLT,  proceed to the next dose level. - If 1 or more of this group suffer DLT, then  dose escalation is stopped, and this dose is  declared the maximally administered dose.  Three (3) additional patients will be entered at  the next lowest dose level if only 3 patients  were treated previously at that dose. |
| <1 out of 6 at highest dose level  below the maximally  administered dose  | This is generally the recommended phase 2 dose.  At least 6 patients must be entered at the  recommended phase 2 dose.                                                                                                                                                                                                                                                                                        |
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5.5 general concomitant medication and

Subjects must inform the investigators of the current or planned use or all other medications during the study (including prescription medications, vitamins, herbal and nutritional supplements, and over-the-counter medications).
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5.5.1 concurrent medications/interventions 5.5.1.1 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.  
5.5.1.2 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)
administered as dictated by safety purposes are acceptable while the subject is enrolled on study. Pain medications administered as dictated by standard practice are acceptable while the patient is enrolled on the study. No concurrent investigational agents are permitted.  
5.5.1.3 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. Strong CYP3A4 inducers such as rifampin, cabamezepine, phenobarbital, phenytoin, pioglitazone, rifabutin, St. John's wort and troglitazone 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. 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 should be avoided 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. Please consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/ for a list of agents that interact with CYP3A4. Because in vitro studies only assessed the metabolizing capacity of the CYP3A4, CYP2C9, and CYP2D6 pathways, the potential for drugs that inhibit/induce other CYP450 pathways (*e.g.*,
CYP2C8, CYP2C19, CYP2B6, CYP1A2) to alter cabozantinib exposure is not known. Therefore, these drugs should be used with caution when given with cabozantinib. Please refer to the Flockhart drug interaction tables for lists of substrates, inducers, and inhibitors of selected CYP450 isozyme pathways (Flockhart 2007; http://medicine.iupui.edu/clinpharm/ddis/).  
Protein Binding: Cabozantinib is highly protein bound (approximately 99.9%) to human plasma proteins. Therefore, highly protein bound drugs should be used with caution with cabozantinib because there is a potential displacement interaction that could increase free concentrations of cabozantinib and/or a co-administered highly protein-bound drug (and a corresponding increase in pharmacologic effect). Factors that influence plasma protein binding may affect individual tolerance to cabozantinib. Therefore, concomitant medications that are highly protein bound (*e.g.*, diazepam, furosemide, dicloxacillin, and propranolol) should be used with caution. Because warfarin is a highly protein bound drug with a low therapeutic index, administration of warfarin at therapeutic doses should be avoided in subjects receiving cabozantinib due to the potential for a protein binding displacement interaction. Drugs Associated with QTc Prolongation: Treatment with cabozantinib has been associated with a mild prolongation of the QTc interval. Caution should be used when treating subjects on cabozantinib with other drugs associated with QTc prolongation (see http://www.qtdrugs.org). Additional QTc monitoring is suggested for subjects who are treated concomitantly with QTc prolonging drugs. Other Interactions: H2 blockers may be taken concomitantly with cabozantinib with the exception of cimetidine, which should be avoided because of its potential to interfere with CYP3A4 mediated metabolism of cabozantinib. In vitro data suggest that cabozantinib is unlikely to be a substrate for P glycoprotein (P-gp), but it does appear to have the potential to inhibit the P-gp transport activity. Additional details related to these overall conclusions are provided in the Investigators Brochure.
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5.5.2 supportive care

General guidelines for the management of cabozantinib related non-hematologic toxicities are provided in Section **6.1.1** . 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. 5.5.2.1 Prophylaxis See section **5.3.2** for information on dexamethasone prophylaxis with docetaxel administration. 5.5.2.2 Neutropenia Growth factors may be used as medically indicated if patient develops fever and neutropenia. Dose reduction or interruption of docetaxel is also recommended as described in section 6.2. Grade 4 febrile neutropenia will result in being removed from protocol therapy. See section 5.4.  
5.5.2.3 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 octreotide47. 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 tolerable levels, a dose reduction and/or dose interruption of cabozantinib should be implemented as described in Section **6.1.2.1**. 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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5.5.2.4 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 **6.1.2** 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 recommended48-50. 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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5.5.2.5 stomatitis and mucositis

Preventive measures may include a comprehensive dental examination to identify any potential complications before study treatment is initiated. Appropriate correction of local factors should be instituted as indicated, such as modification of ill-fitting dentures and appropriate care of gingivitis. During treatment with cabozantinib, good oral hygiene and standard local treatments such as non-traumatic cleansing, and oral rinses (e.g., with a weak solution of salt and baking soda) should be maintained. The oral cavity should be rinsed and wiped after meals, and dentures should be cleaned and brushed often to remove plaque. Local treatment should be instituted at the earliest onset of symptoms. When stomatitis interferes with adequate nutrition and local therapy is not adequately effective, dose reduction or temporary withholding of cabozantinib should be considered.
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5.5.2.6 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 **6.1.3.1** for additional information.
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5.5.2.7 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 (e.g., abscess, cellulitis, or impetigo). In the case of study treatment-related skin changes (e.g., rash, hand-foot syndrome), the investigator may request that additional assessments be conducted with the subject's consent. These assessments may include digital photographs of the skin changes and/or a biopsy of the affected skin and may be repeated until the skin changes resolve.
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5.5.2.8 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. 5.5.2.9 Hypertension See instructions in Section **6.1.7.1**
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5.6 on study assessments

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

ECG assessments will be performed with standard 12-lead ECG equipment according to standard procedures. 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 (e.g., 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 blood draw will be obtained at the scheduled time point, and the ECG will be collected first, followed by vital signs.
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5.6.2 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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5.6.3 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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5.6.4 laboratory assessments

Laboratory assessments will include the following:
- Hematology:
CBC with differential Reticulocytes (if indicated) Erythrocyte sedimentation rate (if indicated)
- 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
-glutamyltransferase (GGT)
- Urinalysis and UPCR - Thyroid function tests - TSH, total T3 and T4 - PT/INR or PTT - PSA
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5.7 duration of therapy

In the absence of treatment delays due to adverse event(s), treatment may continue until one of the following criteria applies:
- Disease progression  
- Intercurrent illness that prevents further administration of treatment, - Unacceptable adverse event(s), - Patient decides to withdraw from the study, or - General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.
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5.8 duration of follow up

Once the patient is no longer receiving treatment (as per section **5.9.1**), follow up evaluations as listed in the study calendar in section 10 will be conducted as appropriate per standard of care at the NCI or by the patient's physician. The patient may also receive follow-up calls to monitor his well-being and progress. For patients who are taken off treatment due to treatment toxicities, a follow up evaluation will be conducted within a month and if appropriate, the subject will be taken off study.
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5.9 criteria for removal from

Prior to removal from study, effort must be made to have all subjects complete a safety visit approximately 30 days following the last dose of study therapy.
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5.9.1 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 require withdrawal of the subject from study treatment:  
- An AE or intercurrent illness that in the opinion of the investigator warrants the subject's withdrawal from treatment
- Necessity for treatment with other investigational drug or other anticancer medications prohibited by protocol
- Noncompliance with the protocol schedule
- Participation in another clinical study using anticancer agent(s)
- Occurrence of cabozantinib related DLT as defined in section 5.4 with the exceptions of grade 4 neutropenia lasting > 5 days, grade ≤ 3 fatigue and grade ≤ 3 reversible asymptomatic laboratory abnormalities
- Occurrence of any grade 3 or grade 4 non hematologic AE (except asymptomatic grade 3 hypomagnesemia, hyponatremia, hypophosphatemia, hypocalcemia, and asymptomatic grade 4 uric acid) during cycles 3 and beyond unless the subject is unequivocally deriving clinical benefit
- Occurrence of grade 4 febrile neutropenia - Request by regulatory agencies for termination of treatment of an individual subject or all subjects under this protocol
- Sexually active subjects who refuse to use medically accepted barrier methods of contraception (e.g., male condom, female condom) during the course of the study and for 4 months following discontinuation of study treatment
- Inability to tolerate the administration of cabozantinib
- Cabozantinib treatment delays > 2 weeks during the DLT evaluation period
- Cabozantinib treatment delays > 2 weeks during cycles 3 and beyond unless the subject was unequivocally benefitting from cabozantinib treatment
- Progressive disease (PD) - Investigator Discretion 5.9.2 *Off Study Criteria*
- Investigator Discretion
- Manufacturer no longer able to supply study agent - Completion of all study procedures
- Participant requests to be withdrawn from study
- Death
- Screen failure
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5.9.3 off study procedure

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. 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.  
Authorized staff must notify Central Registration Office (CRO) when a subject is taken offstudy. An off-study 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 (HOIS) ncicentralregistrationl@mail.nih.gov.
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for participating sites

All subjects must be registered through the NCI Central Registration Office (CRO). The CRO is open from 8:30am to 5:30pm EST Monday through Friday, excluding federal holidays. An offstudy form will be supplied by the CCR study coordinator. Send the completed off-study form to the CCR study coordinator.
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6 dosing delays/dose modifications

In general, the PI will attempt to attribute the toxicity to the most likely agent. In cases of overlapping toxicities (with the exception of hematologic toxicities) of cabozantinib and docetaxel, toxicities will be attributed to cabozantinib. Hematologic toxicities will be attributed to docetaxel due to the infrequency of their occurrence in studies with single agent cabozantinib. Patients who require a treatment delay of >2 weeks, due to toxicities related to treatment, will permanently discontinue treatment on study. Patients will remain on study in the case of unavoidable dental procedures that require a treatment delay of >2 weeks.
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6.1 cabozantinib

Subjects will be monitored continuously for AEs throughout the study. Subjects must be instructed to notify their physician immediately for any and all toxicities.  
General guidelines for the management of non-hematologic are provided in Table **6.1.1**. As a general approach, it is suggested that all AEs be managed with supportive care when possible at the earliest signs of toxicity. Calcium, magnesium, potassium and phosphorus should be kept above the lower limits of the laboratory normal values. For more specific guidelines on gastrointestinal AEs (diarrhea, nausea/vomiting, stomatitis/mucositis), hepatobiliary disorders, pancreatic disorders including lipase and amylase elevations, skin disorders (PPE), embolism and thrombus, hypertension, proteinurea, hemorrhage, rectal and perirectal abscess, gastrointestinal (GI) perforation and GI fistula, non-GI fistula, wound healing and surgery, osteonecrosis of the jaw (ONJ), endocrine disorders and management of treatment-emergent prolongation of the QTc interval, refer to the appropriate below. Guidance for the management of fatigue, anorexia, weight loss, eye disorders, musculoskeletal and connective tissue disorders, nervous system disorders, respiratory/thoracic/mediastinal disorders and congenital, familial and genetic disorders can be found in the Cabozantinib Investigator's Brochure. 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.  
45 CTEP Study \#: 9243 Dosing delays and modification instructions for cabozantinib non-hematologic toxicities are below. 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 ≤ 2 weeks, the subject will have study treatment permanently discontinued. The minimum dose of study treatment will be 20 mg every other day. Subjects who cannot tolerate 20 mg every other day will have study treatment discontinued. The reason for treatment delay and reduced dose must be recorded on the case report form (CRF).  
6.1.1 General Guidelines for *the Management of Cabozantinib-Related non-Hematologic*  
Toxicities  
| Toxicities                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                             |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|
| CTCAE Version 4 Grade                                                                                                                                                                | Guidelines/Intervention                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                             |
| Grade 1:                                                                                                                                                                             | Add supportive care as indicated. Continue cabozantinib at the current  dose level                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                             |
| Grade 2: Grade 2 AEs considered related to  cabozantinib that are subjectively  tolerable or easily managed                                                                          | Add supportive care as indicated. Continue cabozantinib at the current  dose level.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                             |
| Grade 2 AEs considered related to  cabozantinib that are intolerable to the  subject or deemed unacceptable in the  investigator's judgment; or are not  easily managed or corrected | Dose Interruption and/or Dose Reduction - After dose reduction, 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.  - If the AE resolves to baseline or Grade ≤ 1, after dose interruption,  cabozantinib may be resumed at either the same reduced dose or  with another dose reduction at the discretion of the investigator. - If this is a recurring event the dose should be reduced. 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  cabozantinib which occurred without  optimal prophylaxis or which is easily  managed by medical intervention or  resolved quickly        | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Interrupt cabozantinib and add supportive care as indicated |
| -                                                                                                                                                                                    | For AEs that are easily managed (e.g., correction of electrolytes)  with resolution to baseline or Grade ≤1 within 24 hours,  cabozantinib may be resumed at either the same dose or with a  dose reduction at the discretion of the investigator unless this is a  recurring event at which time the dose should be reduced                                                                                                                                                                                                                                                              |                                                             |
| -                                                                                                                                                                                    | For AEs that require supportive care, the dose should be held  while supportive care is initiated and optimized. Then upon  resolution of the AE to baseline or Grade ≤1, cabozantinib may be  resumed at either the same dose or with a dose reduction at the  discretion of the investigator unless this is a recurring event at  which time the dose should be reduced                                                                                                                                                                                                                 |                                                             |
| Grade 3 AEs considered related to  study treatment that occurred despite  optimal prophylaxis or is not easily  managed by medical intervention                                      | Interrupt study treatment until recovery to ≤ Grade 1 or baseline, and  resume treatment with a dose reduction                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                             |
| Grade 4: Grade 4 AEs considered related to                                                                                                                                           | Permanently discontinue study treatment unless determined that the                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                             |
| study treatment                                                                                                                                                                      | subject is unequivocally deriving clinical benefit and the subject is not  within the DLT evaluation period (cycles 1 & 2). In this case, upon  recovery to Grade ≤ 1 or baseline, the subject may be re-treated at a  reduced dose that is to be determined by the investigator and sponsor  but only with sponsor approval.                                                                                                                                                                                                                                                             |                                                             |  
Dose reductions or delays may occur in the setting of lower grade toxicity than defined above if the investigator believes that it is in the interest of the subject's safety.
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6.1.2 diarrhea nausea vomiting stomatitis

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 **6.1.1** should be followed. In addition, general supportive measures should be implemented including continuous oral hydration, correction of fluid and electrolyte abnormalities, small frequent meals, and stopping lactose-containing products, high fat meals and alcohol.
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6.1.2.2 nausea and vomiting

Anti-emetic agents along with supportive care are recommended as clinically appropriate at the first sign of nausea and vomiting. 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. 6.1.2.3 Dehydration As of 26 August 2013 dehydration events have been identified with comparable incidence (9%) and occurring in a shorter time to onset in the blinded prostate cancer studies (median time to onset 38-46 days) than previously experienced with cabozantinib in the MTC development program (median time to onset 114.6 days). Extra monitoring/medical management including electrolyte monitoring and/or early dose reduction of patients exhibiting dehydration symptoms and those with risk factors for dehydration is indicated.
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6.1.2.4 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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6.1.3 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:  
| 6.1.3.1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Transaminase Elevations   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------|
| Transaminase elevation                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Interventions             |
| CTCAE v4.0 Subjects with AST and ALT less than or equal to the ULN at baseline Grade 1 Continue cabozantinib with weekly monitoring of liver function tests (LFTs) for at  least 4 weeks. Then resume the standard protocol-defined monitoring of LFTs. Grade 2 Continue cabozantinib with at least twice weekly monitoring of LFTs for 2 weeks.  Then weekly for 4 weeks. If LFTs continue to rise within Grade 2, interrupt  cabozantinib treatment. Then continue with at least weekly LFTs until resolution  to Grade ≤ 1. Study treatment may then be resumed at a one-dose-level reduction  of cabozantinib Grade 3 Interrupt cabozantinib treatment and monitor with at least twice weekly LFTs until  Grade ≤ 2. Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  Cabozantinib may then be resumed at a one-dose-level reduction. Grade 4 Discontinue study treatment permanently. LFTs should be monitored as clinically  indicated, at least 2-3 times per week, until resolution to Grade ≤ 1. If the subject  was unequivocally deriving clinical benefit and the subject is not within the DLT  evaluation period (cycles 1 & 2), 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 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 and the subject is not within the DLT  evaluation period (cycles 1 & 2), 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   |
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Cabozantinib treatment should also be interrupted when transaminase increases are accompanied by progressive elevations of total bilirubin, and/or elevations of coagulation tests (e.g., International Normalized Ratio [INR]). Monitoring of transaminases should be intensified (2–3 times per week) and cabozantinib should be held until the etiology of the abnormalities is determined and these abnormalities are corrected or stabilize at clinically acceptable levels (INR
< 1.5  ULN, total bilirubin < 1.5  ULN, aminotransferases < 2.5  ULN or baseline).  
Subjects must have cabozantinib permanently discontinued if transaminase elevations are accompanied by evidence of impaired hepatic function (bilirubin elevation >2xULN), in the absence of evidence of biliary obstruction (i.e., significant elevation of alkaline phosphatase [ALP]) 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 2 weeks after 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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6.1.4 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.  
| Asymptomatic Lipase or Amylase Elevations Grade 1 or Grade 2 Continue at current dose level. More frequent monitoring is recommended Grade 3 - Interrupt treatment - Monitor lipase and amylase twice weekly - Upon resolution to Grade ≤1 or baseline, cabozantinib may be restarted at  the same dose or at a reduced dose provided that this occurs within 2 weeks. - If retreatment following Grade 3 lipase or amylase elevation is at the same  dose and Grade 3 or Grade 4 elevations recur, then treatment must be  interrupted again until lipase and amylase levels have resolved to  Grade ≤1 or baseline and retreatment must be at a reduced dose Grade 4 - If occurring within the DLT evaluation period, permanently discontinue  cabozantinib Otherwise: - Interrupt treatment - Monitor lipase and amylase twice weekly - Upon resolution to Grade ≤ 1 or baseline and if resolution occurred within  4 days, cabozantinib may be restarted at the same dose or a reduced dose.  If resolution took more than 4 days, the dose must be reduced upon  retreatment provided that resolution occurred within 2 weeks. - If retreatment following Grade 4 lipase or amylase elevation is at the same  dose and Grade 3 or 4 elevations recur, then treatment must be interrupted  again until lipase and amylase have resolved to Grade ≤ 1 or baseline and  retreatment must be at a reduced dose.   |
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| Pancreatitis Grade 2 and asymptomatic                                                                                                                                                                        | Continue at current dose level. More frequent monitoring of lipase and amylase and  radiographic evaluation is recommended - If grade 3 pancreatitis occurs during DLT evaluation period, permanently                                                                                                               |
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| Grade 2 symptomatic and  Grade 3                                                                                                                                                                             | discontinue cabozantinib                                                                                                                                                                                                                                                                                            |
| Otherwise: - Interrupt treatment - Monitor lipase and amylase twice weekly - Upon resolution to Grade ≤1 or baseline, cabozantinib may be restarted at  a reduced dose if resolution occurred within 2 weeks |                                                                                                                                                                                                                                                                                                                     |
| Grade 4                                                                                                                                                                                                      | Permanently discontinue treatment. However, if the subject was unequivocally  deriving benefit from cabozantinib therapy and the subject is not within the DLT  evaluation period (cycles 1 & 2), treatment may resume at a reduced dose agreed to  by the investigator and sponsor but only with sponsor approval. |
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6.1.5 skin disorders

Palmar-plantar erythrodysesthesia syndrome (PPE; also known as hand-foot syndrome), skin rash (including blister, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, and papular rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been reported in cabozantinib-treated subjects. All subjects on study should be advised to use prophylactic measures for skin care. These measures include the use of hypoallergenic moisturizing creams, ointment for dry skin, sunscreen with SPF ≥30; avoidance of exposure of hands and feet to hot water; protection of pressure-sensitive areas of hands and feet; and use of thick cotton gloves and socks to prevent injury and to keep the palms and soles dry. Subjects with skin disorders should be carefully monitored for signs of infection (*e.g.*, abscess, cellulitis, or impetigo). Early signs of hand-foot syndrome can include tingling, numbness, and slight redness or mild hyperkeratosis. Early manifestations include painful, symmetrical red and swollen areas on the palms and soles. The lateral sides of the fingers or periungual zones may also be affected. Adequate interventions are required to prevent worsening of skin symptoms such as blisters, desquamations, ulcerations, or necrosis of affected areas. Aggressive management of symptoms is recommended, including early dermatology referral. Treatment guidelines for PPE related to study treatment are presented in the table below. In the case of study treatment-related skin changes (*e.g.*, rash, hand-foot syndrome), the investigator may request that additional assessments be conducted with the subject's consent. These assessments may include digital photographs of the skin changes and/or a biopsy of the affected skin and may be repeated until the skin changes resolve.  
| 6.1.5.1                                                                                                        | Hand-Foot Skin Reaction and Hand Foot Syndrome (PPE)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
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| 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 unless the subject  was unequivocally deriving clinical benefit. In this situation, the subject may be  able to resume treatment at a lower dose as determined by the investigator /  principal investigator and Sponsor, but only with Sponsor approval.                                                                                                                                                                                      |
| GABA, γ-aminobutyric acid; NSAID, nonsteroidal anti-inflammatory drugs; PPE, palmar-plantar erythrodysesthesia |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
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6.1.6 thromboembolic events

Deep vein thrombosis and PE have been observed in clinical studies with cabozantinib; including fatal events (please refer to the IB). Unless DLT as defined in Section 5.4, 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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6.1.7 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).  
| Criteria for Dose Modifications                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Treatment/cabozantinib Dose Modification   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------|
| Subjects not receiving optimized anti-hypertensive therapy - Increase antihypertension therapy (i.e., increase dose of  existing medications and/or add new antihypertensive  medications)  - Maintain dose of cabozantinib - If optimal antihypertensive therapy (usually to include  3 agents) does not result in blood pressure < 150 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 > 150 mm Hg (systolic) and < 160 mm Hg OR > 100 mm Hg (diastolic) and < 110 mm Hg - Interrupt and/or reduce cabozantinib by one dose level; - Increase antihypertension therapy (ie, increase dose of existing  medications and/or add new antihypertensive medications); - Monitor subject closely for hypotension; - If optimal antihypertensive therapy (usually to include  3 agents) does not result in blood pressure < 150 systolic or <  100 diastolic, dose of cabozantinib should be reduced further. ≥ 160 mm Hg (systolic) OR - Interrupt treatment with cabozantinib ≥ 100 mm Hg (diastolic)  - Increase anti-hypertension therapy (i.e., increase dose of  existing medications and/or add new antihypertensive  medications)  - Monitor subject closely for hypotension. - When SBP <150 and DBP <100, restart cabozantinib |                                            |  
| Criteria for Dose Modifications                                                                                                                                                                                                       | Treatment/cabozantinib Dose Modification                                                                                                                                                                                                                      |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| treatment at the same dose level.                                                                                                                                                                                                     |                                                                                                                                                                                                                                                               |
| -                                                                                                                                                                                                                                     | Once treatment is restarted, if optimal antihypertensive  therapy (usually to include 3 agents) does not result in blood  pressure < 150 systolic or < 100 diastolic, cabozantinib should  be held and restarted at a lower dose when SBP <150 and  DBP <100. |
| - Discontinue all study treatment                                                                                                                                                                                                     |                                                                                                                                                                                                                                                               |
| Hypertensive crisis or hypertensive  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 |                                                                                                                                                                                                                                                               |
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6.1.8 proteinuria

Proteinuria has been reported with approved drugs that inhibit VEGF pathways as well as with cabozantinib. Any level of proteinuria diagnosed by dipstick should be quantified by a UPCR (mg/dL protein / mg/dL creatinine). When a UPCR exceeds 1, a repeat UPCR or a 24-hour urine protein and creatinine should be performed to confirm the result. Cabozantinib should be discontinued in subjects who develop nephrotic syndrome (proteinuria >3.5 g/day in combination with hypoalbuminemia, edema and hyperlipidemia) or any other relevant renal disease. Also, given the nephrotoxic potential of bisphosphonates, these agents should be used with caution in patients receiving treatment with cabozantinib. Details of management are described in Table **6.1.8.1** below.  
| Urine Protein/Creatinine Ratio             | Action To Be Taken                                                                                                                                                                                                                                                                                                                                                          |                                                                                  |
|--------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------|
| ≤ 1                                        | -                                                                                                                                                                                                                                                                                                                                                                           | No change in treatment or monitoring                                             |
| > 1 and < 3.5                              | -                                                                                                                                                                                                                                                                                                                                                                           | No change in study treatment required                                            |
| -                                          | Consider confirming with a 24-hour protein excretion within 7  days                                                                                                                                                                                                                                                                                                         |                                                                                  |
| -                                          | Repeat UPCR within 7 days and once every week. If UPCR is < 1  on two consecutive readings, then UPCR monitoring can revert to  protocol specific time points. (The second reading is a  confirmatory reading and can be done within 1 week of the first  reading.).                                                                                                        |                                                                                  |
| ≥ 3.5                                      | -                                                                                                                                                                                                                                                                                                                                                                           | Hold cabozantinib immediately and confirm with 24 hour urine protein  excretion. |
| -                                          | If proteinuria of ≥ 3.5 g/24 hours is confirmed without diagnosis of  nephrotic syndrome, continue to hold cabozantinib and monitor UPCR  weekly. If UPCR decreases to < 2, restart cabozantinib at a reduced  dose. Continue monitoring UPCR once every week until two  consecutive readings are < 1, then revert to UPCR monitoring  frequency specified in the protocol. |                                                                                  |
| Nephrotic Syndrome                         | -                                                                                                                                                                                                                                                                                                                                                                           | Discontinue cabozantinib treatment.                                              |
| UPCR; urine protein/urine creatinine ratio |                                                                                                                                                                                                                                                                                                                                                                             |                                                                                  |