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18.0 data and safety monitoring

Institutional support of trial monitoring will be in accordance with the FHCRC/University of Washington Cancer Consortium Institutional Data and Safety Monitoring Plan. Underthe provisions of this plan, FHCRC
Clinical Research Support (CRS) coordinates data and compliance monitoring conducted by consultants, contract research organizations, or FHCRC employees unaffiliated with the conduct of the study.  
Independent monitoring visits occur at specified intervals determined by the assessed risk level of the study and the findings of previous visits per the institutional DSMP. It will be the monitor's responsibility to inspect the CRFs at regular intervals throughout the study to verify both adherence to the protocol and the completeness, consistency, and accuracy of the data being entered onthem.  
In addition, protocols are reviewed at least annually and as needed by the Consortium Data and Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC), and the FHCRC/University of Washington Cancer Consortium Institutional Review Board (IRB). The review committees evaluate accrual, adverse events, stopping rules, and adherence to the applicable data and safety monitoring plan for studies actively enrolling or treating subjects. The IRB reviews the study progress and safety information to assess continued acceptability of the risk‐benefit ratio for human subjects. Approval of committees as applicable is necessary to continue the study.  
The trial will comply with the standard guidelines set forth by these regulatory committees and other institutional, state and federal guidelines.
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18.2 data and safety review

Investigators will conduct continuous review of data and patient safety. At least monthly review meetings are required and will include: PI, data manager, study coordinator, and other members as per the PI's discretion (e.g. sub‐investigators, nurses). Review of data and patient safety will be reviewed during these meetings, including:  
- The number of patients enrolled in the protocol - Any significant toxicities experienced by patients enrolled
- Dose modifications and responses observed
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19.0 study documentation and record-keeping

The investigator must maintain adequate and accurate records to enable the conduct of the study to be fully documented and the study data to be subsequently verified. These documents should be classified into two separate categories as follows: (1) the investigator's study file, and (2) subjects' clinical source documents.  
The investigator'sstudy file will contain the protocol and protocol amendments, CRFs, query forms, IRB/EC
and governmental approvals with correspondence, sample informed consent, drug records, staff curriculum vitae and authorization forms, any other records required under the Protocol, and other appropriate documents and correspondence.  
Subjects' clinical source documents include the subjects' hospital/clinic records; physicians' and nurses' notes; original laboratory, ECG, X‐ray, pathology and special assessment reports;signed informed consent forms; consultant letters; and subject screening and enrollmentlogs. The investigator must keep these two categories of documents on file for at least the latest of (a) 2 years following the marketing application approval date for the study treatment in the indication being investigated, or (b) 2 years after the investigation is completed or discontinued, or (c) for a period of time consistent with local regulatory requirements, whichever is longest. Afterthat period, the documents may be destroyed subject to local regulations with prior written permission from Exelixis/Merck. If the investigator wants to assign the study records to another party or move them to another location, Exelixis/Merck must be notified in advance.
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19.2 source documents and background

Upon request, the investigator will supply its licensees and collaborators with any required background data from the study documentation or clinic records. This is particularly important when CRFs are illegible or when errors in data transcription are suspected. In case of special problems or governmental queries or requests for audit inspections, it is also necessary to have access to the complete study records, provided that subject confidentiality is protected.
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19.3 audits and inspections

The investigator should understand that source documents for this study must be made available, after appropriate notification, to qualified personnel from the Exelixis or Merck Quality Assurance Unit (or designee) or to health authority inspectors. The verification of the CRF data must be by direct inspection of source documents.
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19.4 case report forms

For enrolled subjects, only data from the procedures and assessments required by the CRFs should be entered on the appropriate CRF. Other are recorded only on the source documents and will not be transcribed to CRFs. Additional procedures and assessments may be performed as part of the 85 of 103 Protocol V4.0 13Dec2021 investigator's institution or medical practice standard of care and may not be required for CRF entry. For each subject enrolled, the CRF (paper or electronic) must be completed and signed by the PI or authorized delegate from the study staff.  
All paper forms should be typed or filled out using indelible ink and must be legible. Errors should be crossed out but not obliterated, the correction inserted, and the change initialed and dated by the investigator or his or her authorized delegate.  
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data in the CRFs and in all required reports.
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20.0 protocol modifications

Protocol modifications or amendments must be reviewed and approved by Exelixis and Merck prior to implementation. All protocol modifications must be submitted to the IRB/EC for information and approval in accordance with local requirements and to regulatory agencies if required. Approval must be obtained before any changes can be implemented, except for changes necessary to eliminate an immediate hazard to study subjects or those that involve only logistical or administrative aspects of the trial (e.g. change in monitor or change of telephone number).
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21.0 termination of study

At any time, the study may be terminated prior to completion of planned enrollment and achievement of objectives if there is evidence that the study regimen is not tolerable at the lower dose limits stated in the protocol, or if interim data analysis demonstrates lack of efficacy of study treatment. In terminating the study, the investigator will ensure that adequate consideration is given to the protection of the subjects' interests. Upon study termination, the investigatorshall cease enrolling subjectsinto the study and shall discontinue conduct of the study as soon as is medically practicable. The IRB will be notified about the completion or early termination of the trial.
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22.0 ethical aspects 22.1 local

The study must fully adhere to the principles outlined in ICH Good Clinical Practice (GCP) and local regulations on the conduct of clinical research.).
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22.2 institutional review board/ethics committee

This protocol (and any modifications) and appropriate consent procedures must be reviewed and approved by an IRB/EC. This board must operate in accordance with current local, regional, and federal regulations. The investigator will send a letter or certificate of IRB/EC approval to Exelixis and Merck (or designee) before subject enrollment and whenever subsequent modifications to the protocol are made.
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22.3 confidentiality of trial documents

The investigator must assure that subjects' anonymity will be maintained and that their identities are protected from unauthorized parties. On CRFs or other documents, subjects should be identified by identification codes and not by their names. The investigator should keep a subject enrollment log showing codes, names, and addresses. The investigatorshould maintain documents (e.g. subjects' written consent forms) in strict confidence.  
All tumor scans, research samples, photographs, and results from examinations, tests, and procedures may be sent to Exelixis and Merck, and its partners or designees for review.
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23.0 publication of data

The PI holdsthe primary responsibility for publication ofthe study results,provided thatthe PIwill provide Exelixis and Merck with a copy of any proposed publication orrelease:  
- (a) for abstracts, slide presentations or posters, at least five (5) business day prior to submission
(in the case of abstracts) or first public presentation (in the case of slide presentations and posters); and
- (b) at least thirty (30) days in advance of first submission and each subsequent submission in the case of manuscripts and also comply with any provisions regarding publication that are agreed to between the University of Washington and Exelixis and Merck in the Clinical Trial Agreement related to this study.
fred hutchinson cancer center university
24.0 appendices appendix 1 abbreviations

| Abbreviation or   | Definition                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
|-------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| term              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| AE                | Adverse event: any untoward medical occurrence in a patient or clinical  investigation patient administered a pharmaceutical product and that does not  necessarily have a causal relationship with this treatment. An adverse event can  therefore be any unfavorable and unintended sign (including an abnormal  laboratory finding), symptom, or disease temporally associated with the use of a  medicinal (investigational) product, whether or not related to the medicinal  (investigational) product. |  
| ALP         | alkaline phosphatase                                                                                                                    |
|-------------|-----------------------------------------------------------------------------------------------------------------------------------------|
| ALT         | alanine aminotransferase                                                                                                                |
| ANC         | absolute neutrophil count                                                                                                               |
| AUC         | area under the curve                                                                                                                    |
| AST         | aspartate aminotransferase                                                                                                              |
| BP          | blood pressure                                                                                                                          |
| CBC         | complete blood count                                                                                                                    |
| CI          | confidence interval                                                                                                                     |
| CMV         | Cytomegalovirus                                                                                                                         |
| CR          | complete response                                                                                                                       |
| CRF/eCRF    | case report form/electronic case report form                                                                                            |
| CT          | computed tomography                                                                                                                     |
| CTCAE       | Common Terminology Criteria for Adverse Events                                                                                          |
| CYP         | cytochrome P450                                                                                                                         |
| DCR         | disease control rate                                                                                                                    |
| DILI        | drug‐induced liver injury                                                                                                               |
| DNA         | deoxyribonucleic acid                                                                                                                   |
| DSMC        | data and safety monitoring committee                                                                                                    |
| DVT         | deep venous thrombosis                                                                                                                  |
| EBV         | Epstein‐Barr virus                                                                                                                      |
| eDC:        | Electronic Data Capture. A computer database where clinical trial data are  entered and validated.                                      |
| ECOG        | Eastern Cooperative Oncology Group                                                                                                      |
| EKG         | electrocardiogram                                                                                                                       |
| Enrollment: | The act of assigning a patient to a treatment. Patients who are enrolled in the  trial are those who have been assigned to a treatment. |
| Enter:      | Patients entered into a trial are those who sign the informed consent form  directly.                                                   |
| ERB/IRB     | ethical review board / institutional review board                                                                                       |
| FFPE        | formalin‐fixed, paraffin‐embedded                                                                                                       |
| GCP         | good clinical practice                                                                                                                  |
| GFR         | glomerular filtration rate                                                                                                              |
| GLP         | good laboratory practice                                                                                                                |
| GI          | gastrointestinal                                                                                                                        |
| Hb          | hemoglobin                                                                                                                              |
| HBeAb       | hepatitis B e‐antigen antibody                                                                                                          |
| HBeAg       | hepatitis B e‐antigen antigen                                                                                                           |
| HBcAb       | hepatitis B core antibody                                                                                                               |
| HBsAb       | hepatitis B surface antibody                                                                                                            |
| HBsAg       | hepatitis B surface antigen                                                                                                             |
| HBV         | hepatitis B virus                                                                                                                       |
| HCV         | hepatitis C virus                                                                                                                       |
| HR          | hazard ratio                                                                                                                            |
| i (prefix)  | immune                                                                                                                                  |
| IB          | investigator's brochure                                                                                                                 |
| ICF         | informed consent form                                                                                                                   |  
| iCPD            | immune confirmed progressive disease                                                                                                                                                                                                                                                                                |
|-----------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| IHC             | immunohistochemistry                                                                                                                                                                                                                                                                                                |
| INR             | international normalized ratio                                                                                                                                                                                                                                                                                      |
| Investigational | A pharmaceutical form of an active ingredient or placebo being tested or used as                                                                                                                                                                                                                                    |
| product (IP):   | a reference in a clinical trial, including products already on the market when used  or assembled (formulated or packaged) in a way different from the authorized form, or marketed products used for an unauthorized indication, or marketed  products used to gain further information about the authorized form. |
| irAE            | immune‐related adverse event                                                                                                                                                                                                                                                                                        |
| IRB             | institutional review board                                                                                                                                                                                                                                                                                          |
| iUPD            | immune unconfirmed progressive disease                                                                                                                                                                                                                                                                              |
| IV              | intravenous                                                                                                                                                                                                                                                                                                         |
| LMWH            | low molecular weight heparin                                                                                                                                                                                                                                                                                        |
| NSAIDS          | non‐steroidal anti‐inflammatory drugs                                                                                                                                                                                                                                                                               |
| MI              | myocardial infarction                                                                                                                                                                                                                                                                                               |
| MRI             | magnetic resonance imaging                                                                                                                                                                                                                                                                                          |
| OS              | overall survival                                                                                                                                                                                                                                                                                                    |
| ORR             | objective response rate                                                                                                                                                                                                                                                                                             |
| PI              | principal investigator                                                                                                                                                                                                                                                                                              |
| PD              | progressive disease                                                                                                                                                                                                                                                                                                 |
| PD‐1            | programmed cell death 1                                                                                                                                                                                                                                                                                             |
| PE              | physical exam                                                                                                                                                                                                                                                                                                       |
| PET             | positron emission tomography                                                                                                                                                                                                                                                                                        |
| PFS             | progression‐free survival                                                                                                                                                                                                                                                                                           |
| PK              | pharmacokinetic                                                                                                                                                                                                                                                                                                     |
| PO              | orally                                                                                                                                                                                                                                                                                                              |
| PPES            | palmar‐plantar erythrodyesthesia syndrome                                                                                                                                                                                                                                                                           |
| PR              | partial response                                                                                                                                                                                                                                                                                                    |
| PTT             | partial prothrombin time                                                                                                                                                                                                                                                                                            |
| QTc             | corrected QTc interval (QTcF: QTc calculated by Fredericia formula)                                                                                                                                                                                                                                                 |
| RECIST          | Response Evaluation Criteria In Solid Tumors                                                                                                                                                                                                                                                                        |
| iRECIST         | immune RECIST                                                                                                                                                                                                                                                                                                       |
| mRECIST         | modified RECIST                                                                                                                                                                                                                                                                                                     |
| RBC             | red blood cell                                                                                                                                                                                                                                                                                                      |
| Reporting       | A point‐in‐time copy of the collection database. The final reporting database is                                                                                                                                                                                                                                    |
| database:       | used to produce the analyses and output reports for interim or final analyses of  data.                                                                                                                                                                                                                             |
| Re‐screen:      | To screen a patient who was previously declared a screen failure for the same  study.                                                                                                                                                                                                                               |
| RPLS            | reversible posterior leukoencephalopathy syndrome                                                                                                                                                                                                                                                                   |
| SAE             | serious adverse event                                                                                                                                                                                                                                                                                               |
| Screen:         | The act of determining if an individual meets minimum requirements to become  part of a pool of potential candidates for participation in a clinical study.                                                                                                                                                         |
| Screen failure: | Patient who does not meet one or more criteria required for participation in a  trial.                                                                                                                                                                                                                              |
| SD              | stable disease                                                                                                                                                                                                                                                                                                      |  
| TEAE   | treatment‐emergent adverse event   |
|--------|------------------------------------|
| TIA    | transient ischemic attack          |
| TRAE   | treatment‐related adverse event    |
| TSH    | thyroid‐stimulating hormone        |
| UPCR   | urine protein to creatinine ratio  |
| ULN    | upper limit of normal              |
| WBC    | white blood cell                   |
| WOCP   | women of child‐bearing potential   |  
Today's Date: _ Participant Study ID:
Participant Initials: Cycle Number:
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instructions to the participant

1. Complete one form for each cycle (21 days).  
2. You will take 40 mg of Cabozantinib (2) x (20 mg pills) once a day. Or 20 mg of Cabozantinib if dose reduced (1) x (20 mg pill).  
- Cabozantinib must be taken daily on an empty stomach. You must not to eat for at least 2hours before and at least 1 hour after taking Cabozantinib.  
- Take your Cabozantinib dose at approximately the same time every day.  
- Cabozantinib pills should be swallowed whole with at least 8 ounces of water.  
3. Record the date, the number of pills you took, and the time that you took them.  
4. If you have any comments or notice any side effects, please record them in thecomments column.  
5. Please bring your pill bottle and this form to your physician when you go to your next appointment.  
6. Please record missed or skipped doses. Do not share your drug supply. Wash your hands after touching the pills.  
- The dose may be taken later only if it is within 12 hours of when the missed dose shouldhave been taken.  
- The missed dose should not be made up if it is within 12 hours of the next scheduleddose.  
7. The tablets should not be crushed. Grapefruit, grapefruit juice, Seville oranges, star fruit, and their products should be avoided.  
| and their products should be avoided. DOSE   | Comments              |
|----------------------------------------------|-----------------------|
| Number of Pills                              | Time dose was taken   |
| Taken                                        |                       |
| Date                                         | Day 1 2 3 4 5 6 7 8 9 |  
| RG1007034 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Participant's Signature:                                       | Date:                    |    |
|-----------------------------------------------------------------------------------------------------------------------|--------------------------|----|
| Physician's office will complete this section: Number of tablets dispensed:                                           | Date of pills dispensed: |    |
| Participant's planned daily dose: Total number of pills taken thismonth:  Hasthe patient missed any study medication? | Yes                      | No |
| Comments:  Study Personnel Signature:                                                                                 | Date:                    |    |
| Medical EMERGENCY: 911 (such as chest pain, seizure, sudden shortness of breath, etc.)                                |                          |    |  
Research Coordinator: / Weekday Pager Number:
24‐hour EMERGENCY pager: 206‐598‐6190
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instructions to the participant

Appendix 3: Clinical laboratory tests  
| Hematology (at screening and on study)  Hemoglobin Hematocrit  Leukocytes (WBC) Neutrophils (segmented and bands)  Lymphocytes Monocytes  Eosinophils Basophils  Platelets                                                 | Serum chemistry (at screening and on study)  Sodium Bicarbonate (CO2)  Potassium  Calcium  Magnesium  Phosphate  Glucose  Albumin  Total protein Blood urea nitrogen (BUN) Creatinine Alanine aminotransferase (ALT)  Aspartate aminotransferase (AST)  Alkaline phosphatase (ALP) Total bilirubin HBV/HCV status At screening: − HCV Ab (if positive, obtain HCVRNA) − HBcAb, HbsAg (if either or both are  positive, obtain HBV DNA) On study: − HBcAb+ and HBsAg‐ at baseline:  obtain HBsAg every 2 cyclesstarting at  cycle 3 (and HBV DNA ifpositive) − HBcAb+ and HBsAg+ at baseline: obtain HBV DNA every 2 cycles  starting at cycle 3   |    |            |     |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|------------|-----|
| Other                                                                                                                                                                                                                      | immune‐related                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | AE | monitoring | (at |
| screening and every 2 cycles on study starting at  cycle 3) TSH, free T4 and T3  Cortisol Amylase  Lipase Coagulation (at screening and on study)  International normalized ratio (INR)  Partial thromboplastin time (PTT) | Urine protein (at screening and every 2 cycles  starting at cycle 3) Urine protein to creatinine ratio                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |    |            |     |
| Tumor marker (at screening and every 3 cycles  starting at cycle 4) Alpha fetoprotein                                                                                                                                      | Serum pregnancy test (women of childbearing  potential only) at screening only                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |    |            |     |
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appendix 4 strong inducers and

Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9.  
If possible, strong inducers of CYP3A4 (see below) should be avoided and substituted by alternative medications at the discretion of the treating physician. If they must be used, the patient must be on a stable dose.  
Strong inducers of CYP3A: apalutamide, carbamazepine, enzalutamide, fosphenytoin, lumacafotor, mitotane, phenobarbital, phenotyoin, primidone If possible, strong inhibitors of CYP3A4 (see below) should be avoided and substituted by alternative medications at the discretion of the treating physician. Grapefruit or grapefruit juice should be avoided.  
Strong inhibitors of CYP3A: atazanavir, boceprevir, clarithromycin, cobicistat and cobicista containing coformulations, darunavir, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir, mifepristone, nefazodone, nelfinavir, ombitasvir‐paritaprevir‐ritonavir, ombitasvir‐paritaprevir‐ritonavir plus dasabuvir, posaconazole, ritonavir and ritonavir containing coformulations, saquinavir, telaprevir, telithromycin, voriconazole.  
Please refer to the drug interaction tables at the following websites for lists of substrates, inducers, and inhibitors of selected CYP450 isozyme pathways:
Http://medicine.iupui.edu/clinpharm/ddis/table.aspx http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLab eling/ucm080499.htm).  
Appendix 5: ECOG performance status scale  
| 1   | Strenuous physical activity restricted; fully ambulatory and able to carryout  light work.                      |
|-----|-----------------------------------------------------------------------------------------------------------------|
| 2   | Capable of all selfcare but unable to carry out any work activities. Up and  about >50 percent of waking hours. |
| 3   | Capable of only limited selfcare; confined to bed or chair >50 percent of  waking hours.                        |
| 4   | Completely disabled; cannot carry out any selfcare; totally confined to bed  or chair.                          |  
| Parameter       | Point           |                      |                 |
|-----------------|-----------------|----------------------|-----------------|
| 1               | 2               | 3                    |                 |
| Total bilirubin | <2 mg/dL (<34.2 | 2‐3 mg/dL (34.2‐51.3 | >3 mg/dL (>51.3 |
| umol/L)         | umol/L)         | umol/L)              |                 |  
Appendix 6: Child‐Pugh score calculation for cirrhosis mortality  
| RG1007034 Albumin        | >3.5 g/dL (>35 g/L)   | 2.8‐3.5 g/dL (28‐35 g/L)   | <2.8 g/dL (<28 g/L)   |
|--------------------------|-----------------------|----------------------------|-----------------------|
| INR                      | <1.7                  | 1.7‐2.2                    | >2.2                  |
| Ascites                  | Absent                | Easily controlled          | Poorly controlled     |
| Encephalopathy1          | None                  | Grade 1‐2                  | Grade 3‐4             |
| 1 Encephalopathy grades: |                       |                            |                       |  
Albumin >3.5 g/dL (>35 g/L) 2.8‐3.5 g/dL (28‐35 g/L) <2.8 g/dL (<28 g/L)  
INR <1.7 1.7‐2.2 >2.2  
Ascites Absent Easily controlled Poorly controlled  
Encephalopathy1 None Grade 1‐2 Grade 3‐4 1Encephalopathy grades:  
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram  
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves  
Grade 2: lethargic, time‐disoriented, inappropriate, asterixis, ataxia, slow triphasic waves  
Grade 3: somnolent, stuporous, place‐disoriented, hyperactive reflexes, rigidity, slower waves  
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2‐3 cps delta activity  
| Child‐Pugh score   | Class   | 1‐year survival (%)   | 2‐year survival (%)   |
|--------------------|---------|-----------------------|-----------------------|
| 5‐6                | A       | 100                   | 85                    |
| 7‐9                | B       | 80                    | 60                    |
| 10‐15              | C       | 45                    | 35                    |  
Sources:
Child CG and Turcotte JG. Surgery and portal hypertension. In: The liver and portal hypertension.  
Philadelphia: Saunders 1964:50‐64.  
Pugh et al. Transfection of the oesophagus for bleeding esophageal varices. Br J Surg 1973;60.
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appendix 7 cockcroft-gault equation for

The Cockcroft‐Gault equation is to be used for calculating CrCl from local laboratory results.  
For serum creatinine concentration in mg/dL:
CrCl = (**140 - age**) x (wt) x **0.85** (if female), or x **1.0** (ifmale)
(mL/min) 72 x **serum creatinine** (*mg/dL*)
For serum creatinine concentration in umol/L:
CrCl = (**140 - age**) x (wt) x **0.85** (if female), or x **1.0** (ifmale)
(mL/min) 0.81 x **serum creatinine** (*umol/L*)
Age in years, weight (wt) in kilograms.  
Source: Cockcroft and Gault 1976.
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appendix 8 highly effective methods

- Combined oral contraceptive pill andmini‐pill - NuvaRing® - Implantable contraceptives - injectable contraceptives (such as Depo‐Provera®) - Intrauterine device (such as Mirena® and ParaGard®) - Contraceptive patch for women <90 Kg (<198 pounds) - Bilateral tubal occlusion or hysterectomy with bilateralsalpingo‐oophorectomy - Vasectomy
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25.0 references

1. Cancer IAfRo. Estimated number of incident cases worldwide, both sexes, all ages.  
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253Afalse%252C%2522prev%2522%253Afalse%257D&orientation=horizontal&type_sort=0&typ e_nb_items=%257B%2522top%2522%253Atrue%252C%2522bottom%2522%253Afalse%257D&
population_group_globocan_id=. 2018.  
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18. Sennino B, McDonald DM. Controlling escape from angiogenesis inhibitors. In: Nat Rev *Cancer.*
Vol 12. England2012:699‐709.  
19. You WK, Sennino B, Williamson CW, et al. VEGF and c‐Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. *Cancer Res.*2011;71(14):4758‐4768.  
20. Lacy SA, Miles DR, Nguyen LT. Clinical Pharmacokinetics and Pharmacodynamics of Cabozantinib.  
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