Randomized, Double-Blinded Phase III Study of CABozantinib Versus Placebo IN Patients With Advanced NEuroendocrine Tumors After Progression on Prior Therapy (CABINET)
Phase: PHASE3
Conditions: Functioning Pancreatic Neuroendocrine Tumor, Intermediate Grade Lung Neuroendocrine Neoplasm, Locally Advanced Digestive System Neuroendocrine Neoplasm, Locally Advanced Digestive System Neuroendocrine Tumor G1, Locally Advanced Lung Neuroendocrine Neoplasm, Locally Advanced Pancreatic Neuroendocrine Tumor, Locally Advanced Unresectable Digestive System Neuroendocrine Neoplasm, Low Grade Lung Neuroendocrine Neoplasm, Lung Neuroendocrine Tumor, Lung Neuroendocrine Tumor G2, Metastatic Digestive System Neuroendocrine Neoplasm, Metastatic Digestive System Neuroendocrine Tumor G1, Metastatic Lung Neuroendocrine Neoplasm, Metastatic Lung Neuroendocrine Tumor, Metastatic Pancreatic Neuroendocrine Neoplasm, Metastatic Pancreatic Neuroendocrine Tumor, Metastatic Thymus Neuroendocrine Neoplasm, Neuroendocrine Neoplasm, Neuroendocrine Tumor, Neuroendocrine Tumor G2, Non-Functioning Pancreatic Neuroendocrine Tumor, Pancreatic Serotonin-Producing Neuroendocrine Tumor, Thymus Neuroendocrine Tumor, Unresectable Digestive System Neuroendocrine Neoplasm, Unresectable Digestive System Neuroendocrine Tumor G1, Unresectable Lung Neuroendocrine Neoplasm, Unresectable Pancreatic Neuroendocrine Neoplasm, Unresectable Thymus Neuroendocrine Neoplasm
Sponsor: National Cancer Institute (NCI)

 
Version Date: 12/07/2022 
 
 
Update #04 
1 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
ALLIANCE A021602 
RANDOMIZED, DOUBLE-BLINDED PHASE III STUDY OF CABOZANTINIB VERSUS PLACEBO IN 
PATIENTS WITH ADVANCED NEUROENDOCRINE TUMORS AFTER PROGRESSION ON PRIOR THERAPY 
(CABINET) 
NCI-supplied agent(s): Cabozantinib (NSC #761968, IND# 137656); IND holder: DCTD, NCI 
Industry-supplied agent(s): NONE 
Commercial agent(s): NONE 
 
This is an FDA Registration Study. 
ClinicalTrials.gov Identifier: NCT03375320 
Study Chair 
 
 
 
 
 
 
 
 
Community Oncology Co-Chair 
 
Imaging Co-Chair 
Health Outcomes Co-Chair 
and Statistician 
 
Pathology Co-Chair 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alliance GI Committee Co-Chairs 
Correlative Science Committee Co-Chairs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Statistician 
Secondary Statistician 
Protocol Coordinator 
Data Manager 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics Co-Chair 
ECOG-ACRIN Champion 
NRG Champion 
SWOG Champion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Participating NCTN Groups: 
Alliance/Alliance for Clinical Trials in Oncology (lead), ECOG-ACRIN / ECOG-ACRIN Cancer Research Group, 
NRG / NRG Oncology, SWOG / SWOG 
 

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Study Resources 
Expedited Adverse Event Reporting 
 
 Medidata Rave iMedidata Portal 
  
OPEN (Oncology Patient Enrollment Network) 
  
 Biospecimen Management System (BioMS) 
  
 
Protocol Contacts: 
A021602 Nursing Contact 
 
 
 
 
A021602 Pharmacy Liaison 
   
  
 
 
Drug Distribution Contact 
 
 
 
 
Alliance Biorepository at Ohio State University 
 
 
 
 
 
 
IROC Ohio (Alliance Imaging Core Lab) 
 
 
 
 
 
 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modifications 
Study Chair, Nursing Contact, Protocol 
Coordinator, and (where applicable) Data Manager 
Questions regarding data submission, RAVE, or 
patient follow-up 
Data Manager  
Questions regarding the protocol document and 
model informed consent 
Protocol Coordinator 
Questions regarding IRB review 
Alliance Regulatory Inbox 
  
Questions regarding CTEP-AERS reporting 
Alliance Pharmacovigilance Inbox 
  
Questions regarding specimens/specimen 
submissions 
Appropriate Alliance Biorepository  
Questions regarding drug supply 
Pharmaceutical Management Branch (PMB)  
Questions regarding drug administration 
Pharmacy Liaison 
 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the Cancer Trials 
Support Unit (CTSU)  via the 
Regulatory Submission Portal. 
(Sign in at 
 
and select the Regulatory > 
Regulatory Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately by phone or 
email: 
 
to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 
 
for regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
 
 
Contact the CTSU Help Desk 
with any OPEN related questions 
by phone or email: 
 
 
Data collection for this study 
will be done exclusively 
through Medidata Rave. 
Refer to the data submission 
section of the protocol for 
further instructions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website (
). Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires log in with a CTEP-
IAM username and password. 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).  
Institutions will order the following supplies from the CTSU Operations Office: patient-completed 
questionnaire booklets. Supplies can be ordered by downloading and completing the CTSU Supply 
Request Form (available on the protocol-specific page on the CTSU website) and submitting it as 
instructed on the form. 
For clinical questions (i.e. patient eligibility or treatment-related) see Protocol Contacts, Page 2. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 
All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
 
 
 
 

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RANDOMIZED, DOUBLE-BLINDED PHASE III STUDY OF CABOZANTINIB VERSUS 
PLACEBO IN PATIENTS WITH ADVANCED NEUROENDOCRINE TUMORS AFTER 
PROGRESSION ON PRIOR THERAPY 
 
Registration Eligibility Criteria (see Section 3.2 for full descriptions) 
- Histologic documentation of well- or moderately-differentiated neuroendocrine tumor of 
pancreatic or non-pancreatic origin 
- Locally advanced/unresectable tumor(s) or metastatic disease 
- Target lesion disease progression by RECIST v1.1 within 12 months 
- Patients must have measurable disease per RECIST 1.1 
- Progression or intolerance of ≥ 1 prior FDA approved therapy (except somatostatin 
analogs) 
- Prior treatment must be completed ≥ 28 days prior to registration 
- Prior use (and concurrent use at stable dose) of somatostatin analogs is allowed  
- Prior treatment with cabozantinib is not allowed 
- Resolution of toxic effects from prior therapy to grade 1 or less 
- Major surgery must be completed ≥ 12 weeks and minor surgery must be completed ≥ 28 
days prior to registration 
- No class III or IV CHF, clinically significant cardiac arrhythmia, unstable angina, MI, or 
thromboembolic events (incl. stroke, TIA, DVT, and PE) within 6 months of registration 
- No known history of congenital long QT syndrome 
- No uncontrolled hypertension within 14 days of registration 
- No clinically significant GI bleeding or GI abnormalities that may increase risk for GI 
bleeding or GI perforation within 6 months of registration 
- No known tumor with invasion into GI tract from the outside causing increased risk of perforation or bleeding within 28 days of registration 
- No radiologic or clinical evidence of pancreatitis 
- No known cavitary lung lesions 
- No known endobronchial lesions involving main or lobar bronchi 
- No hemoptysis > 2.5 mL or signs of pulmonary hemorrhage within 3 months of registration 
- No known tumor invading or encasing any major blood vessels 
- No history of non-healing wounds or ulcers or history of fracture within 28 days of registration 
- No active brain metastases or cranial epidural disease 
- No known medical condition causing an inability to swallow oral formulations of agents 
- No history of allergic reaction attributed to compounds of similar chemical or biological composition to cabozantinib/placebo 
- No currently active second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ 
- Other concurrent investigational agents or other tumor directed therapies (chemotherapy, radiation) are not allowed 
- No full dose oral anticoagulation/antiplatelet therapy or any dose of warfarin. Aspirin ≤ 81mg and therapeutic LMWH are allowed, except in 
patients with brain metastases. 
- Chronic concomitant treatment with strong inhibitors or strong inducers of CYP3A4 is not allowed 
- Not pregnant and not nursing. Women of childbearing potential must have a negative pregnancy test ≤ 14 days prior to registration 
- Age ≥ 18 Years and ECOG Performance Status: 0-2 
 
Re-Registration Eligibility Criteria 
(see Section 3.3 for full descriptions) 
- Centrally-confirmed radiographic disease progression per 
RECIST v1.1 
- Not pregnant and not nursing. Women of childbearing 
potential must have a negative pregnancy test ≤ 14 days of 
re-registration. 
 
 
Required Initial Laboratory Values (Section 3.2.9) 
Absolute Neutrophil Count (ANC) ≥ 1500/mm3 
Hemoglobin ≥ 9 g/dL 
Platelet Count ≥ 100,000/mm3 
PT/INR, PTT < 1.3 x ULN 
AST/ALT ≤ 3 x ULN 
Total Bilirubin ≤ 1.5 ULN* 
Creatinine ≤ 1.5 mg/dL  
OR  
Creatinine Clearance ≥ 45 mL/min 
Albumin ≥ 2.8 g/dL 
Potassium, Phosphorus, Calcium, Magnesium WNL** 
UPC Ratio ≤ 1 
QTcF ≤ 500 msec 
TSH WNL** 
* Except in the case of Gilbert disease, in which case 
Total Bilirubin ≤ 3 x ULN 
** Supplementation is acceptable to achieve WNL 
Required Laboratory Values (Section 3.3.3) 
Absolute Neutrophil Count (ANC) ≥ 1500/mm3 
Hemoglobin ≥ 9 g/dL 
Platelet Count ≥ 100,000/mm3 
PT/INR, PTT < 1.3 x ULN 
AST/ALT ≤ 3 x ULN 
Total Bilirubin ≤ 1.5 ULN* 
Creatinine ≤ 1.5 mg/dL OR Creatinine Clearance ≥ 45 mL/min 
Albumin ≥ 2.8 g/dL 
Potassium, Phosphorus, Calcium, Magnesium WNL** 
UPC Ratio ≤ 1 
QTcF ≤ 500 msec 
TSH WNL** 
* Except in the case of Gilbert disease, in which case Total Bilirubin ≤ 3 x ULN 
** Supplementation is acceptable to achieve WNL 

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Schema 
 
1 Cycle = 28 Days 
 
 
 
 
 
 
 
 
 
* Randomization will be done separately for the pancreatic NET and carcinoid tumor cohorts. 
** Treatment is to continue until disease progression, unacceptable toxicity, or withdrawal of consent. Patients initially randomized to 
placebo who experience centrally confirmed progressive disease (PD) may elect to crossover to open-label cabozantinib; see Section 
3.3 and Section 4.8. Patients will be followed for survival and progression every 12 weeks until progression or start of new anticancer 
therapy, and then for survival every 6 months until 8 years after registration or until death, whichever comes first. 
NOTE: imaging scans must be submitted for real-time central review within 24 hours of local determination of PD; see Section 6.3. 
 
Imaging after cessation of therapy may be performed at a non-registering institution. If the Group credited for enrollment is a non-
Alliance Group, then other requirements from the credited Group may apply. All protocol conduct must be followed, and the 
registering institution is responsible for ensuring all data is reported per protocol. 
Please see full protocol text for a complete description of the eligibility criteria (Section 3.0) and treatment plan (Section 7.0). 
 
 
2:1 
Pancreatic 
NET 
Carcinoid 
Tumor 
Randomize
* 
Cabozantinib 
60mg daily ** 
Placebo 
60mg daily ** 
Central confirmation 
of PD by IROC Ohio 
Re-Registration 

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TABLE OF CONTENTS 
_________________________________________________________ ..................................................... 4 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY ..................................................................... 1 
SCHEMA ..................................................................................................................................................... 6 
TABLE OF CONTENTS ........................................................................................................................... 7 
1.0 
BACKGROUND ............................................................................................................................. 9 
1.1 Background ...................................................................................................................................... 9 
1.2 Pertinent Existing Data .................................................................................................................. 10 
1.3 Rationale for Trial Design ............................................................................................................. 12 
1.4 Importance and Impact of the Trial ............................................................................................... 12 
2.0 
OBJECTIVES ............................................................................................................................... 13 
2.1 Primary Objectives......................................................................................................................... 13 
2.2 Secondary Objectives..................................................................................................................... 13 
2.3 Other Objective .............................................................................................................................. 13 
2.4 Quality of Life Substudy Objective – A021602-HO1 ................................................................... 13 
2.5 Population Pharmacokinetics Substudy Objective – A021602-PP1 .............................................. 13 
3.0 
PATIENT SELECTION............................................................................................................... 14 
3.1 On-Study Guidelines ...................................................................................................................... 14 
3.2 Registration Eligibility Criteria (Step 1) ........................................................................................ 15 
3.3 Re-Registration Eligibility Criteria (Step 2) .................................................................................. 18 
4.0 
PATIENT REGISTRATION ....................................................................................................... 19 
4.1 Investigator and Research Associate Registration with CTEP ...................................................... 19 
4.2 Cancer Trials Support Unit Registration Procedures ..................................................................... 20 
4.3 Patient Registration Requirements ................................................................................................. 23 
4.4 Patient Registration/Randomization (Step 1) Procedures .............................................................. 23 
4.5 Registration to Correlative and Companion Studies ...................................................................... 24 
4.6 Stratification and Grouping Factors and Treatment Assignments ................................................. 25 
4.7 Patient Re-Registration Requirements ........................................................................................... 25 
4.8 Patient Re-Registration/Crossover (Step 2) Procedures ................................................................ 25 
5.0 
STUDY CALENDAR ................................................................................................................... 27 
6.0 
DATA AND SPECIMEN SUBMISSION ................................................................................... 29 
6.1 Data Collection and Submission .................................................................................................... 29 
6.2 Specimen Collection and Submission ............................................................................................ 31 
6.3 Imaging Submission....................................................................................................................... 37 
7.0 
TREATMENT PLAN/INTERVENTION ................................................................................... 39 
7.1 Cabozantinib/Placebo .................................................................................................................... 39 
7.2 Imaging .......................................................................................................................................... 40 
8.0 
DOSE AND TREATMENT MODIFICATIONS, UNBLINDING ........................................... 44 
8.1 Ancillary Therapy, Concomitant Medications, and Supportive Care ............................................ 44 
8.2 Dose Modifications ........................................................................................................................ 47 
8.3 Unblinding Procedures................................................................................................................... 53 
9.0 
ADVERSE EVENTS .................................................................................................................... 54 
9.1 Routine Adverse Event Reporting (Rave-CTEP-AERS) ............................................................... 54 
9.2 CTCAE Routine Reporting Requirements ..................................................................................... 56 
9.3 Expedited Adverse Event Reporting (Rave-CTEP-AERS) ........................................................... 57 
9.4 Comprehensive Adverse Events and Potential Risks List (CAEPR) for Cabozantinib ................. 60 
10.0 
DRUG INFORMATION .............................................................................................................. 64 
10.1 Cabozantinib (Cabometyx, XL184, IND# 137656, NSC #761968, IND Holder: DCTD, NCI) ... 64 
11.0 
MEASUREMENT OF EFFECT ................................................................................................. 70 
11.1 Schedule of Evaluations ................................................................................................................. 70 

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11.2 Definitions of Measurable and Non-Measurable Disease .............................................................. 70 
11.3 Guidelines for Evaluation of Measurable Disease ......................................................................... 70 
11.4 Measurement of Treatment/Intervention Effect ............................................................................. 71 
11.5 Definitions of Analysis Variables .................................................................................................. 74 
12.0 
END OF TREATMENT/INTERVENTION .............................................................................. 74 
12.1 Duration of Treatment.................................................................................................................... 74 
12.2 Follow-up for Patients Who Stop Protocol Therapy ...................................................................... 74 
12.3 Managing Ineligible Patients and Registered Patients Who Never Receive Protocol Intervention
 
75 
12.4 Extraordinary Medical Circumstances ........................................................................................... 76 
13.0 
STATISTICAL CONSIDERATIONS ........................................................................................ 76 
13.1 Accrual Time and Study Duration ................................................................................................. 76 
13.2 Sample Size .................................................................................................................................... 76 
13.3 Study Endpoints ............................................................................................................................. 77 
13.4 Stratification ................................................................................................................................... 78 
13.5 Analysis Plan ................................................................................................................................. 78 
13.6 Monitoring ..................................................................................................................................... 82 
13.7 Descriptive Factors ........................................................................................................................ 84 
13.8 Inclusion of Women and Minorities .............................................................................................. 84 
14.0 
CORRELATIVE AND COMPANION STUDIES ..................................................................... 85 
14.1 Quality of Life Substudy (Alliance A021602-HO1) ...................................................................... 85 
14.2 Population Pharmacokinetics of Cabozantinib (Alliance A021602-PP1) ..................................... 89 
14.3 Biobanking for Future Correlative Science Studies ....................................................................... 92 
15.0 
REFERENCES .............................................................................................................................. 96 
APPENDIX I 
QUALITY OF LIFE MEASURES ......................................................................... 100 
APPENDIX II 
PATIENT MEDICATION DIARY ........................................................................ 109 
APPENDIX III 
PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD ......... 110 
 ..................................................................................................................... 112 
CLINCIAL TRIAL WALLET CARD .................................................................................................. 112 
SHOW THIS CARD TO ALL OF YOUR HEALTHCARE PROVIDERS AND KEEP IT WITH 
YOU IN CASE YOU GO TO THE EMERGENCY ROOM. ............................................................. 112 
PATIENT NAME:   ................................................................................................................................ 112 
DIAGNOSIS:   ......................................................................................................................................... 112 
STUDY DOCTOR:  ................................................................................................................................ 112 
STUDY DOCTOR PHONE #:  .............................................................................................................. 112 
NCI TRIAL #:  A021602 ........................................................................................................................ 112 
STUDY DRUG(S):  CABOZANTINIB/PLACEBO ............................................................................ 112 
FOR MORE INFORMATION: 1-800-4-CANCER ............................................................................. 112 
CANCER.GOV | CLINICALTRIALS.GOV ........................................................................................ 112 
APPENDIX IV 
PATIENT PHARMACOKINETICS FORM – A021602-PP1 .............................. 113 
APPENDIX V 
DRUGS WITH RISK OF TORSADES DE POINTES/QTC PROLONGATION
 
114 
APPENDIX VI 
COLLABORATIVE AGREEMENTS LANGUAGE ........................................... 116 
 
 
 

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1.0 
BACKGROUND 
1.1 
Background 
The treatment of advanced neuroendocrine tumors (NET) has undergone a rapid evolution in 
recent years. For patients with advanced pancreatic NET, the somatostatin analog lanreotide, 
the mTOR inhibitor everolimus, and the tyrosine kinase inhibitor sunitinib have been shown to 
improve progression-free survival (PFS) compared to placebo and are approved therapies for 
patients with advanced disease [1-3]. For patients with advanced gastrointestinal NET, the 
somatostatin analogs octreotide and lanreotide have been shown to improve time to progression 
or PFS compared with placebo [1, 4]. In addition, 177Lu-Dotatate recently was shown to improve 
PFS compared to high-dose octreotide in patients with midgut NET whose disease had 
progressed on standard-dose octreotide [5]. Everolimus also improves PFS in patients with non-
functional GI and lung NET and is an approved therapy for these indications [6]. However, there 
currently is no standard therapy for patients with advanced NET whose disease has progressed 
on prior therapy. Furthermore, although everolimus and sunitinib are both approved agents for 
pancreatic NET, the phase III studies that demonstrated improved PFS with these agents 
compared with placebo were conducted primarily in patients who had not received prior 
molecularly targeted therapy; thus, the benefits of sunitinib following progression on everolimus 
have not been established. 
Novel therapies to control disease in patients with progressive NET are needed. A key role for 
angiogenesis and the vascular endothelial growth factor (VEGF) pathway signaling in NET is 
suggested by clinical observations that neuroendocrine tumors are vascular tumors. Expression 
of VEGF has been demonstrated in carcinoid and pancreatic NET [7, 8]. Increased expression 
of VEGF receptor-2 (VEGFR-2) has been demonstrated in tissue from gastrointestinal carcinoid 
tumors and a carcinoid cell line [9, 10]. Additionally, pancreatic neuroendocrine tumors show 
widespread expression of VEGFR-2 and -3 in addition to platelet-derived growth factor 
receptors (PDGFRs) α and β, stem-cell factor receptor (c-kit) [11-13].  
Sunitinib, which inhibits VEGFRs, PDGFRs, and c-kit, was evaluated in a randomized, phase 
III study in pancreatic NET that demonstrated improved PFS with sunitinib (median PFS 11.4 
months with sunitinib, as compared with 5.5 months for placebo (HR 0.42, 95% CI 0.26-0.66)) 
[3].  
Other tyrosine kinase inhibitors (TKIs) with activity against VEGFR, including sorafenib and 
pazopanib, have been evaluated in prospective phase II trials of patients with advanced carcinoid 
and pancreatic NET (Table 1). These studies have demonstrated evidence of activity with 
observed objective radiographic responses and encouraging PFS results. 
Table 1 
Agent 
Molecular 
Target(s) 
No. 
Patients 
Tumor Type 
Tumor 
Response 
Rate (%) 
Median 
PFS 
Reference 
Sunitinib 
VEGFR-1, -
2, -3; 
PDGFR–α, -
β; KIT; 
RET; CSF– 
1R; FLT3 
41 
Carcinoid 
2 
10.2 mo 
(TTP) 
Kulke et al., 
2008 [14] 
66 
Pancreatic 
NET 
17 
7.7 mo 
(TTP) 
Sorafenib 
VEGFR, 
PDGFR, 
BRAF 
50 
Carcinoid 
7 
7.8 mo 
Hobday et 
al., 2007 [15] 
43 
Pancreatic 
NET 
11 
11.9 mo 

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Agent 
Molecular 
Target(s) 
No. 
Patients 
Tumor Type 
Tumor 
Response 
Rate (%) 
Median 
PFS 
Reference 
Pazopanib 
VEGFR-1, -
2, -3; 
PDGFR-α, -
β; c-kit 
22 
Carcinoid 
0 
12.2 mo 
Phan et al., 
2015[16] 
33 
Pancreatic 
NET 
22 
14.4 mo 
Pazopanib 
VEGFR-1, -
2, -3; 
PDGFR-α, -
β; c-kit 
15 
Carcinoid (GI) 
9 
10 mo 
Grande et al., 
2015 [17] 
7 
Carcinoid 
(lung, thymus) 
3.4 mo 
17 
Pancreatic 
NET 
12.8 mo 
 
Preclinical data also have demonstrated a role for mesenchymal-epithelial transition factor 
(MET) activation in stimulating growth of neuroendocrine tumors and a role for inhibition of 
MET in treatment of this disease [18-21]. Tumor expression of MET has been correlated with 
reduction in overall survival in patients with pancreatic NET [20]. In the RIP-Tag2 model of 
spontaneous pancreatic NET, treatment with an anti-VEGF antibody or sunitinib increases 
hypoxia, expression of HIF-1α, and activation of MET. This is associated with increased tumor 
invasion and metastasis, which can be reduced by either combining anti-VEGF pathway therapy 
with an inhibitor of MET or treatment with cabozantinib, a small-molecule TKI that targets 
VEGFR-2 as well as c-MET [19]. 
1.2 
Pertinent Existing Data 
1.2.1 
Cabozantinib 
Cabozantinib is an inhibitor of tyrosine kinase receptors known to influence tumor growth, 
metastasis, and angiogenesis including MET, VEGFR-2, AXL, and RET [22]. MET, 
VEGFR-2, AXL, and RET all play important roles in cancer biology. VEGFR-2, expressed 
on endothelial cells, is a well-established key mediator of VEGF signaling in the process 
of tumor angiogenesis [23]. MET, expressed on tumor cells and endothelial cells, mediates 
HGF signaling leading to increased cell motility, proliferation, and survival [24]. 
Upregulation of MET is found in a wide range of malignancies—including thyroid, kidney, 
liver, prostate, ovarian, lung, and breast cancers—and is associated with more aggressive 
and invasive phenotypes of cancer cells in vitro and with metastases in vivo [25, 26]. MET-
driven metastasis may be exacerbated by a number of factors, including tumor hypoxia 
caused by selective inhibition of the VEGF pathway [27, 28]. In addition, the RTK AXL 
has also recently been implicated in invasion and metastasis in VHL-dysregulated clear 
cell renal cell carcinoma (RCC) [29]. Activated forms of the RTK RET are expressed in 
several cancers, including medullary thyroid cancer (MTC) [30] and non-small cell lung 
cancer (NSCLC) [31], and are believed to play an important role in these diseases.  
Clinical Experience 
Cabozantinib is available as both capsules and tablets, but the two formulations are not 
interchangeable.  
Cabozantinib as a capsule formulation was approved by the United States FDA on 
November 29, 2012 for the treatment of patients with progressive, metastatic MTC. 
In a phase III, randomized, double-blind, placebo-controlled including 330 patients with 
medullary thyroid carcinoma (219 cabozantinib, 111 placebo), a significant increase in the 

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primary endpoint of PFS was seen in the cabozantinib arm compared with placebo (median 
of 11.2 vs. 4.0 months; HR = 0.28; 95 CIs: 0.19, 0.40) [32].  
On April 25, 2016, cabozantinib as a tablet formulation was approved by FDA for patients 
with advanced RCC who had received prior anti-angiogenic therapy. 
In a phase III, randomized, open-label, active-controlled study (METEOR) including 658 
patients (330 cabozantinib, 328 everolimus) with advanced RCC who had received prior 
treatment with at least one VEGFR-TKI, cabozantinib demonstrated a statistically 
significant improvements in the primary endpoint, PFS, and both secondary endpoints, 
ORR and OS, compared with the standard-of-care control treatment (everolimus). In the 
primary PFS analysis performed in the first 375 subjects randomized, the hazard ratio (HR) 
adjusted for stratification factors was 0.58 (95% CI: 0.45, 0.74; stratified log-rank p-value 
< 0.0001), and the Kaplan-Meier estimates for median duration of PFS were 7.4 months in 
the cabozantinib arm vs. 3.8 months in the everolimus arm [33]. The PFS analysis was 
repeated among all randomly assigned patients assess by intention-to-treat (658 subjects), 
and results (stratified HR = 0.51 [95% CI: 0.42, 0.62]) were similar to those obtained for 
the primary PFS analysis [34]. In the primary analysis of objective response rate (ORR) at 
the time of the primary analysis of PFS, the ORRs for the cabozantinib and everolimus 
arms were 17% (95% CI: 13, 22) and 3% (95% CI: 2, 6), respectively (unstratified p-value 
<0.0001). A pre-specified interim analysis of OS was conducted for the intention-to-treat 
population at the time of the primary analysis of PFS. The interim analysis demonstrated a 
strong trend for improvement in duration of OS for subjects in the cabozantinib arm 
compared with the everolimus arm (HR = 0.68 [95% CI: 0.51, 0.90; stratified log-rank p-
value = 0.006]) [33]. The final overall-survival analysis confirmed an overall-survival 
benefit for cabozantinib. Median overall-survival was 21.4 months (95% CI: 18.7, not 
estimable) with cabozantinib compared to 16.5 months (95% CI: 14.7, 18.8) with 
everolimus (Hazard Ratio [HR] = 0.66 [95% CI: 0.53, 0.83]; p = 0.00026) [34].    
Cabozantinib also has been evaluated in clinical trials in multiple other tumor types.  
Detailed information for each of these studies, including pharmacokinetic data, can be 
found in the Investigator’s Brochure.   
1.2.2 
Cabozantinib in Neuroendocrine Tumors 
In preclinical studies, cabozantinib has demonstrated activity in NET [19, 21].  
The clinical activity of cabozantinib in patients with NET has been evaluated in a phase II 
study that included patients with advanced pancreatic NET and carcinoid tumors, many of 
whom had progressed on prior therapy [35]. Patients were treated with cabozantinib 
starting at a dose of 60 mg daily and continued treatment until disease progression or 
development of unacceptable toxicity or withdrawal of consent. The primary endpoint of 
the study was radiographic response rate, as measured by RECIST 1.1 criteria. Objective 
radiographic responses to treatment were observed in 3/20 (15%) patients with pancreatic 
NET and 6/41 (15%) patients with carcinoid tumors. Progression-free survival was 21.8 
mo (95% CI, 8.5-32.0 mo) in patients pancreatic NET and 31.4 mo (95% CI, 8.5 mo – not 
reached) in patients with carcinoid. 
Treatment-related adverse events associated with cabozantinib in patients with NET were 
similar to what has been reported in other diseases [35]. Dose modification was commonly 
required; 81% of patients completing at least 1 cycle of therapy eventually required 
reduction from the starting dose of 60 mg daily to either 40 mg or 20 mg daily.  Of note, a 
relationship between dose modification and disease control or disease progression was not 
observed. 

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1.3 
Rationale for Trial Design 
Because of differences in biology and potential responsiveness to treatment, it has been 
recommended that pancreatic NET and non-pancreatic NET (i.e. carcinoid tumors) be evaluated 
as separate entities in clinical trials [36]. Therefore, patients in this trial will be enrolled into two 
separate cohorts -- one for pancreatic NET and one for carcinoid tumors -- to independently test 
the hypothesis. Furthermore, at the NCI NET Clinical Trials Planning Meeting, it was 
recognized that OS is not a practical endpoint for most clinical trials in patients with advanced 
NET and that PFS be used as an endpoint in phase III studies [36]. 
A comparison with placebo has been chosen since there is no approved therapy for patients with 
pancreatic NET or carcinoid tumors whose disease has progressed on prior lines of FDA-
approved therapy. Randomization to cabozantinib vs. placebo will occur in a 2:1 fashion. As of 
Update #02, upon disease progression confirmed by central radiology review, patients will be 
unblinded, and those who were receiving placebo may elect to crossover to open-label therapy 
with cabozantinib.  
1.4 
Importance and Impact of the Trial 
There currently is no standard treatment for patients with advanced NET whose disease has 
progressed on prior lines of FDA-approved therapy. Although everolimus and sunitinib are both 
approved agents for pancreatic NET, the phase III studies demonstrating improved PFS 
compared with placebo were conducted primarily in patients who had not received prior 
molecularly targeted therapy; therefore, the benefits of sunitinib following progression on 
everolimus have not been established [2, 3]. Similarly, in patients with GI NET, there is no 
approved therapy following progression on a somatostatin analog and everolimus or lutetium 
Lu 177 dotatate. In lung NET, there is no currently approved therapy following progression on 
everolimus. Thus, there remains a need for clinical trials evaluating the efficacy of therapy in 
patients with NET whose disease has progressed on prior lines of approved therapy. There also 
is a need for studies examining the activity of novel agents that have the potential to improve 
outcomes for these patients. 
If the proposed phase III study reveals significant improvement in PFS with cabozantinib 
compared with placebo, it could change clinical practice by establishing an effective therapy for 
patients with pancreatic NET and carcinoid tumors. 

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2.0 
OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 
To determine whether cabozantinib can significantly improve progression-free survival 
(PFS) compared to placebo in patients with advanced pancreatic NET whose disease has 
progressed after prior therapy. 
2.1.2 
To determine whether cabozantinib can significantly improve progression-free survival 
(PFS) compared to placebo in patients with advanced carcinoid tumors whose disease has 
progressed after prior therapy. 
2.2 
Secondary Objectives 
2.2.1 
To determine whether cabozantinib can significantly improve overall survival (OS) 
compared to placebo in patients with advanced pancreatic NET whose disease has 
progressed after prior therapy. 
2.2.2 
To determine whether cabozantinib can significantly improve overall survival (OS) 
compared to placebo in patients with advanced carcinoid tumors whose disease has 
progressed after prior therapy. 
2.2.3 
To evaluate safety and tolerability of cabozantinib versus placebo in patients with 
advanced pancreatic NET using CTCAE and PRO-CTCAE. 
2.2.4 
To evaluate safety and tolerability of cabozantinib versus placebo in patients with 
advanced carcinoid tumors using CTCAE and PRO-CTCAE. 
2.2.5 
To evaluate the overall radiographic response rate of cabozantinib versus placebo in 
patients with advanced pancreatic NET whose disease has progressed after prior therapy. 
2.2.6 
To evaluate the overall radiographic response rate of cabozantinib versus placebo in 
patients with advanced carcinoid tumors whose disease has progressed after prior 
therapy. 
2.3 
Other Objective 
Results of the primary analysis will be examined for consistency, while taking into account the 
stratification factors and/or covariates of baseline QOL and fatigue. 
2.4 
Quality of Life Substudy Objective – A021602-HO1  
To compare overall quality of life (primary endpoint: HRQL scale of the EORTC QLQ-C30 
post-randomization), disease-related symptoms, and other domains between the two treatment 
groups (cabozantinib vs. placebo) within each cohort of patients (pancreatic NET vs. carcinoid 
tumor); see Section 14.1.3 for detailed primary, secondary, and exploratory objectives as well 
as primary and secondary hypotheses. 
2.5 
Population Pharmacokinetics Substudy Objective – A021602-PP1  
To describe the population pharmacokinetic and exposure-response relationships of 
cabozantinib in patients with advanced neuroendocrine tumors; see Section 14.2.2 for detailed 
primary objectives. 
 
 

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3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements.  
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate.  
Physicians should consider whether any of the following may render the patient inappropriate 
for this protocol: 
• 
Medical condition such as uncontrolled infection (including HIV), uncontrolled 
diabetes mellitus or cardiac disease which, in the opinion of the treating physician, 
would make this protocol unreasonably hazardous for the patient. 
In addition: 
• 
Drugs that prolong the QTc interval should be avoided if possible, as cabozantinib 
can prolong the QTc interval. Drugs that are generally accepted to have a risk of 
causing Torsades de Pointes (see Appendix V) should be discontinued or replaced 
with drugs that do not carry this risk if at all possible. Patients who receive potential 
QTc-prolonging medications (see Appendix V) should be monitored closely. 
• 
Women and men of reproductive potential must agree to use an appropriate method 
of birth control throughout their participation in this study and for four months 
after completing study treatment due to the teratogenic potential of the therapy 
utilized in this trial. Appropriate methods of birth control include: abstinence, oral 
contraceptives, implantable hormonal contraceptives or double barrier method 
(diaphragm plus condom). 
 
 

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3.2 
Registration Eligibility Criteria (Step 1) 
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following page(s). 
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday one week later would 
be considered Day 7. 
___ 
3.2.1 
Documentation of Disease 
• 
Histologic Documentation: Well- or moderately-differentiated neuroendocrine 
tumors of pancreatic and non-pancreatic (i.e. carcinoid) origin by local pathology. 
The pathology report must state ONE of the following: 1) well- or moderately-
differentiated 
neuroendocrine 
tumor, 
2) 
low- 
or 
intermediate-grade 
neuroendocrine tumor, or 3) carcinoid tumor or atypical carcinoid tumor. 
Documentation of histology from a primary or metastatic site is allowed.  
Patients with poorly differentiated neuroendocrine carcinoma, high-grade 
neuroendocrine carcinoma without specification of differentiation status, 
adenocarcinoid tumor, or goblet cell carcinoid tumor are not eligible. Patients with 
well-differentiated grade 3 neuroendocrine tumor are eligible. 
• 
Stage: Locally advanced/unresectable or metastatic disease. 
• 
Tumor Site: Histological documentation of neuroendocrine tumor of pancreatic, 
gastrointestinal (GI), lung, thymus, other, or unknown primary site. GI, lung, 
thymus, other, and unknown primary NETs will enroll in the carcinoid tumor 
cohort of the study.   
Functional (i.e. associated with symptoms or a clinical syndrome related to 
hormone secretion by tumor) or nonfunctional tumors are allowed. 
• 
Radiologic Evaluation: Target lesions must have shown evidence of disease 
progression by RECIST v1.1 criteria in the 12 months prior to registration. The 
radiologic images, imaging reports, and clinic notes indicating growth of existing 
lesions, development of new lesions, or treatment changes must be submitted per 
Section 6.1.1.  
___ 
3.2.2 
Measurable Disease 
Patients must have measurable disease per RECIST 1.1 by computer tomography (CT) 
scan or magnetic resonance imaging (MRI) (see Section 11.0). 
Lesions must be accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 1 cm with CT or MRI (or ≥ 1.5 cm for lymph nodes). Non-measurable 
disease includes disease smaller than these dimensions or lesions considered truly non-
measurable including: leptomeningeal disease, ascites, pleural or pericardial effusion, 
lymphangitic involvement of skin or lung. See Section 11.0 for additional details. 
___ 
3.2.3 
Prior Treatment 
Patient must have experienced disease progression after receiving or intolerance leading to 
treatment discontinuation of at least one FDA-approved line of therapy (except 
somatostatin analogs). Prior lines of therapy must include one of the following: everolimus, 
sunitinib, or lutetium Lu 177 dotatate in patients with pancreatic NET; everolimus in 

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patients with lung NET; everolimus or lutetium Lu 177 dotatate in patients with 
gastrointestinal NET. 
Prior treatment (except somatostatin analogs) with biologic therapy, immunotherapy, 
chemotherapy, investigational agent for malignancy, and/or radiation must be completed 
at least 28 days prior to registration. 
Prior treatment with somatostatin analogs is allowed, and continuation of treatment with 
somatostatin analogs while on cabozantinib/placebo is allowed provided that the patient 
has been on a stable dose for at least two months. 
Prior systemic treatment with radionuclide therapy must be completed at least 6 weeks 
prior to registration. 
Prior treatment with hepatic artery embolization (including bland embolization, 
chemoembolization, and selective internal radiation therapy) or ablative therapies is 
allowed if measurable disease remains outside of the treated area or if there is documented 
disease progression in a treated site. Prior liver-directed or other ablative treatment must 
be completed at least 28 days prior to registration. 
Prior treatment with cabozantinib is not allowed. 
Patients should have resolution of any toxic effects of prior therapy (except alopecia and 
fatigue) to NCI CTCAE, version 5.0, grade 1 or less.  
Patients must have completed any major surgery at least 12 weeks prior to registration and 
any minor surgery (including uncomplicated tooth extractions) at least 28 days prior to 
registration. Complete wound healing from major surgery must have occurred at least 28 
days prior to registration, and complete wound healing from minor surgery must have 
occurred at least 10 days prior to registration.  
___ 
3.2.4 
Patient History 
No class III or IV CHF within 6 months of registration. 
No clinically significant cardiac arrhythmia within 6 months of registration. 
No unstable angina or MI within 6 months of registration. 
No thromboembolic events within 6 months of registration (incl. stroke, TIA, DVT, & PE).  
No known history of congenital long QT syndrome.  
No uncontrolled hypertension within 14 days of registration (defined as SBP ≥150 mmHg 
and/or DBP ≥ 90 mmHg despite optimal medical management).  
No clinically significant GI bleeding within 6 months of registration. 
No clinically significant gastrointestinal abnormalities that may increase the risk for 
gastrointestinal bleeding within 6 months of registration including, but not limited to: 
active peptic ulcer, known endoluminal metastatic lesion(s) with history of bleeding, 
inflammatory bowel disease, or other gastrointestinal conditions with increased risk of 
perforation. 
No GI perforation within 6 months of registration. 
No known tumor with invasion into the GI tract from the outside causing increased risk of 
perforation or bleeding within 28 days of registration. 
No radiologic or clinical evidence of pancreatitis. 

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No known cavitary lung lesions. 
No known endobronchial lesions involving the main or lobar bronchi and/or lesions 
infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage. (CT 
with contrast is recommended to evaluate such lesions.) 
No hemoptysis greater than ½ teaspoon (2.5 mL) or any other signs of pulmonary 
hemorrhage within the 3 months prior to registration. 
No known tumor invading or encasing any major blood vessels. 
No history of non-healing wounds or ulcers within 28 days of registration. 
No history of fracture within 28 days of registration. 
No brain metastases or cranial epidural disease unless adequately treated, stable, and off 
steroid support for at least 4 weeks prior to registration. 
No known medical condition causing an inability to swallow oral formulations of agents. 
No history of allergic reaction attributed to compounds of similar chemical or biological 
composition to cabozantinib/placebo. 
No “currently active” second malignancy other than non-melanoma skin cancers or 
cervical carcinoma in situ. Patients are not considered to have a “currently active” 
malignancy if they have completed therapy and are free of disease for ≥ 3 years. 
___ 
3.2.5 
Concomitant Medications 
Other planned concurrent investigational agents or other tumor directed therapies 
(chemotherapy, radiation) are not allowed while on this study.  
Concurrent use of somatostatin analogs while on cabozantinib/placebo is allowed provided 
that the patient has been on a stable dose for at least two months. 
Full dose oral anticoagulation/antiplatelet therapy is not permitted. Low dose aspirin ≤ 81 
mg/day is allowed. Anticoagulation with therapeutic doses of LMWH is allowed in patients 
who are on a stable dose of LMWH for at least 6 weeks prior to registration. Treatment 
with warfarin is not allowed. Anticoagulation in patients with brain metastases is not 
permitted. 
Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed. Patients 
must discontinue the drug at least 14 days prior to registration on the study. See Section 
8.1.12 for more information. 
Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must 
discontinue the drug at least 14 days prior to registration on the study. See Section 8.1.13 
for more information. 
___ 
3.2.6 
Not pregnant and not nursing  
Women of childbearing potential must have a negative pregnancy test done ≤ 14 days prior 
to registration. 
A female of childbearing potential is a sexually mature female who: 1) has not undergone 
a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for 
at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 
consecutive months). 

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___ 
3.2.7 
Age ≥ 18 years  
___ 
3.2.8 
ECOG Performance Status: 0-2 
___ 
3.2.9 
Required Initial Laboratory Values:  
Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 
Hemoglobin 
≥ 9 g/dL 
Platelet Count ≥ 100,000/mm3 
PT/INR, PTT 
< 1.3 x upper limit of normal (ULN) 
AST/ALT  
≤ 3 x ULN 
Total Bilirubin ≤ 1.5 x ULN* 
Creatinine 
≤ 1.5 mg/dL OR Creatinine Clearance ≥ 45 mL/min 
Albumin 
≥ 2.8 g/dL 
Potassium 
within normal limits (WNL)** 
Phosphorus 
WNL** 
Calcium 
WNL** 
Magnesium 
WNL** 
Urine Protein to Creatinine (UPC) Ratio ≤ 1 
QTcF  
≤ 500 msec 
TSH  
 
WNL** 
 
*Except in the case of Gilbert disease, in which case Total Bilirubin must be ≤ 3 x ULN 
**Supplementation is acceptable to achieve a value WNL. In patients with low albumin levels, a 
corrected calcium value WNL is acceptable. In patients with abnormal TSH, if Free T4 is normal 
and patient is clinically euthyroid, patient is eligible. 
3.3 
Re-Registration Eligibility Criteria (Step 2) 
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following page(s). 
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday one week later would 
be considered Day 7. 
___ 
3.3.1 
Documentation of Disease 
Patients must have centrally-confirmed radiographic disease progression per RECIST v1.1. 
___ 
3.3.2 
Not pregnant and not nursing  
Women of childbearing potential must have a negative pregnancy test done ≤ 14 days prior 
to re-registration. 
A female of childbearing potential is a sexually mature female who: 1) has not undergone 
a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for 
at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 
consecutive months). 
___ 
3.3.3 
Required Laboratory Values:  
Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 
Hemoglobin 
≥ 9 g/dL 

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Platelet Count ≥ 100,000/mm3 
PT/INR, PTT 
< 1.3 x upper limit of normal (ULN) 
AST/ALT  
≤ 3 x ULN 
Total Bilirubin ≤ 1.5 x ULN* 
Creatinine 
≤ 1.5 mg/dL OR Creatinine Clearance ≥ 45 mL/min 
Albumin 
≥ 2.8 g/dL 
Potassium 
within normal limits (WNL)** 
Phosphorus 
WNL** 
Calcium 
WNL** 
Magnesium 
WNL** 
Urine Protein to Creatinine (UPC) Ratio ≤ 1 
QTcF  
≤ 500 msec 
TSH  
 
WNL** 
 
*Except in the case of Gilbert disease, in which case Total Bilirubin must be ≤ 3 x ULN 
**Supplementation is acceptable to achieve a value WNL. In patients with low albumin levels, a 
corrected calcium value WNL is acceptable. In patients with abnormal TSH, if Free T4 is normal 
and patient is clinically euthyroid, patient is eligible. 
4.0 
PATIENT REGISTRATION 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
at 
 In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
    
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System [RUMS], OPEN, Rave, acting as a 
primary site contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 

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Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
 
 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering 
their practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
Additional 
information 
is 
located 
on 
the 
CTEP 
website 
at 
 For questions, please contact the 
RCR Help Desk by email at 
 
4.2 
Cancer Trials Support Unit Registration Procedures 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU Regulatory Support System 
(RSS). 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval   
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open at 
the site under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) for 
Local Context to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 

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Office, 
but 
sites 
are 
required 
to 
contact 
the 
CTSU 
Regulatory 
Office 
at 
 to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by email or calling 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB approval 
record to be completed: 
• 
Holds an active CTEP status; 
• 
Active status at the site(s) on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating organization’s roster; 
• 
If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB Signatory 
Institution’(s) record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; 
• 
Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO); 
• 
An active roster affiliation with the NCI CIRB roster under at least one CIRB signatory 
Institution (US sites only); and  
• 
Compliance with all protocol-specific requirements (PSRs). 
Protocol-Specific Requirements for A021602 Site Registration 
• 
This is a study with a radiation and/or imaging (RTI) component and the enrolling site 
must be aligned to an RTI provider. To manage provider associations or to add or 
remove associated providers, access the Provider Association page from the Regulatory 
section 
on 
the 
CTSU 
members’ 
website 
at 
Sites must be linked to at least one 
Imaging and Radiation Oncology Core (IROC) provider to participate on trials with an 
RTI component. Enrolling sites are responsible for ensuring that the appropriate 
agreements and IRB approvals are in place with their RTI provider. An individual with 
a primary role on any roster is required to update provider associations, though all 
individuals at a site may view provider associations. To find who holds primary roles at 
your site, view the Person Roster Browser under the RUMS section on the CTSU 
website. 
4.2.1 
Downloading Site Registration Documents  
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 

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documents is restricted to institutions and its associated investigators and staff on a 
participating roster.  To view/download site registration forms:   
• 
Log in to the CTSU members’ website
using your CTEP-
IAM username and password; 
• 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; 
or 
o Click on the By Lead Organization folder to expand, then select Alliance, 
and protocol number A021602. 
• 
Click on Documents, Protocol Related Documents, and use the Document Type 
filter and select Site Registration to download and complete the forms provided. 
(Note: For sites under the CIRB, IRB data will load automatically to the CTSU.) 
4.2.2 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: 
 in order to receive further instruction and 
support. 
NOTE: Until institutions receive a formal notice from the Alliance regarding termination 
to patient follow-up, institutions must not close this trial with the IRB of record for the 
study without first receiving approval from Alliance Regulatory.  Please contact the 
Alliance Regulatory team at 
 with any questions. 
4.2.3 
Checking Site’s Registration Status  
Site registration status may be verified on the CTSU members’ website. 
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the sites 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks.. 
4.2.4 
Delegation of Task Log (DTL) 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the DTL 
application in the Delegation Log section on the CTSU members’ website. The Clinical 
Investigator (CI) is required to review and electronically sign the DTL prior to the site 
receiving an approved site registration status and enrolling patients to the study. To 

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maintain an approved site registration status the CI must re-sign the DTL at least annually 
and when a new version of the DTL is released; and activate new task assignments 
requiring CI sign-off. Any individual at the enrolling site on a participating roster may 
initiate the site DTL. Once the DTL is submitted for CI approval, only the designated DTL 
Administrators or the CI may update the DTL. Instructions on completing the DTL are 
available in the Help Topics button in the DTL application and include a Master Task List, 
which describes DTL task assignments, CI signature, and CTEP registration requirements. 
4.3 
Patient Registration Requirements 
Informed Consent: the patient must be aware of the neoplastic nature of his/her disease and 
willingly consent after being informed of the procedure to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Current 
human protection committee approval of this protocol and a consent form is required prior to 
patient consent and registration. 
Patients with impaired decision making capacity may be enrolled on this study, where 
institutional policy and IRB of record allow.  
Patient Completed Booklets: patient questionnaire booklets are to be ordered prior to the 
registration of any patients. Patient-completed booklets can be ordered by downloading and 
completing the CTSU supply request form (located under the site registration documents section 
of the A021602 CTSU site) and submitting it as instructed on the form. Samples of the booklets 
are found in Appendix I, which are to be used for reference and IRB submission only; they are 
not to be used for patient completion. 
Protected Health Information: the H&E slide collected for this study will be sent to the 
Pathology Co-Chair, 
 at OSU from the Alliance Biorepository. The slide will 
be labeled with patient initials, study ID, and collection date/time. The plasma specimens 
collected for patients consented to the A021602-PP1 substudy will be sent to 
of 
the Alliance Pharmacology/Pharmacokinetic Core Laboratory at the University of Pittsburgh. 
The specimens will be labeled with patient initials, study ID, and collection date/time. The drug 
company supporting this study may retrospectively review the de-identified images submitted 
to IROC after DSMB release. 
4.4 
Patient Registration/Randomization (Step 1) Procedures 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access: 
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 

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To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer 
in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or NPIVR must be assigned 
the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and 
• 
All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records.  
Access OPEN at 
 or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
 For any additional questions, contact the CTSU 
Help Desk at 
 
To receive site reimbursement for specific tests and/or bio-specimen submissions, completion 
dates must be entered in the OPEN Funding screen post registration. Please refer to the protocol-
specific funding page on the CTSU members’ website for additional information. Timely entry 
of completion dates is recommended as this will trigger site reimbursement. 
Initial blinded, patient-specific clinical supplies of cabozantinib/placebo will be shipped from 
the Pharmaceutical Management Branch (PMB) to the registering investigator at the time of 
patient randomization and should arrive within 7 to 10 days after randomization (see Section 
10.1). Treatment is to begin within 14 days of registration. 
4.5 
Registration to Correlative and Companion Studies 
4.5.1 
Registration to Substudies Described in Section 14.0  
There are two substudies within Alliance A021602. The correlative studies must be offered 
to all patients enrolled on Alliance A021602 (although patients may opt to not participate). 
The substudies do not require separate IRB approval. The substudies included within 
Alliance A021602 are: 
• 
Quality of Life Substudy, Alliance A021602-HO1 (Section 14.1) 
• 
Population Pharmacokinetics Substudy, Alliance A021602-PP1 (Section 14.2) 
If a patient answers “yes” to “I choose to take part in the Quality of Life study and will fill 
out the surveys,” Question #1 in the model consent, then they have consented to participate 
in the substudy described in Section 14.1. The patient should be registered to Alliance 
A021602-HO1 at the same time they are registered to the treatment trial (A021602). 
Questionnaires should be submitted per Section 6.1. 
If a patient answers “yes” to “I agree to have my blood collected, and I agree that my blood 
samples and related information may be used for the laboratory study described above,” 
Question #2 in the model consent, then they have consented to participate in the substudy 
described in Section 14.2. The patient should be registered to Alliance A021602-PP1 at the 
same time they are registered to the treatment trial (A021602). Specimens should be 
submitted per Section 6.2.    
 
 

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4.6 
Stratification and Grouping Factors and Treatment Assignments 
Grouping Factors: Pancreatic NET vs. Carcinoid Tumor (i.e. non-pancreatic NET) 
Randomization will be done separately within each cohort, pancreatic NET vs. carcinoid tumor. 
Permuted Block 
After a patient is registered, they will be assigned to one of the two treatment arms (cabozantinib 
vs. placebo) in a 2:1 ratio utilizing a permuted block schedule [37]. The goal of the algorithm is 
to maintain arm balance with respect to the following important stratification factors: 
Stratification Factors for the Pancreatic NET Cohort: 
• 
Concurrent Somatostatin Analog Use: Yes vs. No 
• 
Prior Sunitinib Therapy: Yes vs. No 
Stratification Factors for the Carcinoid Tumor Cohort: 
• 
Concurrent Somatostatin Analog Use: Yes vs. No 
• 
Primary Site: Midgut (jejunum, ileum, appendix, cecum, ascending, colon, hepatic 
flexure)/Unknown primary site vs. Non-midgut GI (stomach, duodenum, 
transverse 
colon, 
splenic 
flexure, 
descending 
colon, 
sigmoid 
colon, 
rectum)/Lung/Other known primary site not listed 
When combined, these stratification factors create four stratum levels for each cohort, and each 
stratum level will have its own patient allocation schedule. The possible block size for this study 
is six. 
4.7 
Patient Re-Registration Requirements 
Patient-completed Booklets: patient questionnaire booklets are to be ordered as outlined in 
Section 4.3.  
Re-registration must occur ≤ 28 days of local determination of disease progression. 
4.8 
Patient Re-Registration/Crossover (Step 2) Procedures 
Patients who meet the criteria for centrally-confirmed radiologic disease progression will may 
be unblinded to treatment assignment. If the patient was on placebo, then they will be allowed 
to crossover to receive open-label cabozantinib provided that all criteria in Section 3.3 are met. 
If the patient was on cabozantinib, then the patient should be followed per Section 5.0. 
Patients receiving placebo who choose to crossover and receive open-label cabozantinib must 
be registered to the cabozantinib arm of the study, as follows: 
1) Log into OPEN registration system and select the appropriate patient. 
2) Select the next registration step. 
3) Complete OPEN Enrollment Form for the patient to change arms. 
4) Enter Cycle # of the last treatment received on the placebo arm, on the OPEN 
Enrollment Form. 
5) OPEN will determine eligibility for the patient to crossover to the new arm. If patient is 
not eligible, OPEN will indicate this. 
6) Once the new arm assignment has been successfully completed, a confirmation email 
will be sent to the site staff. 

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7) If assistance is needed with this process, contact the Alliance Registration Office at
 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all re-registration eligibility criteria within the protocol stated 
timeframes (see Section 3.3). 
Note: The OPEN system will provide the site with a printable confirmation of re-registration 
and treatment information. Please print this confirmation for your records.  
Access OPEN at 
 or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
 For any additional questions, contact the CTSU 
Help Desk at 
  
Open-label, patient-specific clinical supplies of cabozantinib will be shipped from the 
Pharmaceutical Management Branch (PMB) to the registering investigator at the time of patient 
re-registration and should arrive within 7 to 10 days of re-registration (see Section 10.1). 
Treatment is to begin within 14 days of re-registration. 
 
 
 

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5.0 
STUDY CALENDAR   
The pre-study testing intervals are guidelines only. Laboratory and clinical parameters during 
treatment are to be followed using individual institutional guidelines and the best clinical judgment 
of the responsible physician. It is expected that patients on this study will be cared for by oncology 
providers experienced in the treatment and supportive care of patients on this trial.  
Pre-Study Testing Intervals:  
To be completed ≤ 14 DAYS before registration: All laboratory studies, history and physical 
To be completed ≤ 28 DAYS before registration: Any X-ray or scan of any type which is utilized for 
tumor measurement per protocol 
**Calendar should be followed for both blinded therapy and for cross over patients. Crossover 
patients WILL NOT complete the Quality of Life and Pharmacokentic substudies. Re-registration 
should occur ≤ 28 days of local determination of disease progression while receiving blinded therapy 
with central confirmation of progressive disease. 
 
Prior to 
Registration* 
Day 1 of each 
cycle* 
Day 15 of 
Cycles 1 and 2 
(+/- 3 days) 
At progression 
or cessation of 
protocol 
treatment** 
Tests & Observations 
 
History and Physical, PS 
X 
X 
X 
X 
Pulse, BP, Height, Weight 
X(1) 
X(1) 
X(1) 
 
ECG 
X 
A 
 
 
Adverse Event Assessment – 
CTCAE 
X 
X 
X 
B 
Adverse Event Assessment – 
PRO-CTCAE 
X(2) 
X(2) 
 
X(2) 
Patient Medication Diary 
 
X(3) 
 
 
Registration Fatigue/Uniscale 
Assessment 
X(4) 
 
 
 
Laboratory Studies 
 
CBC w/ Differential, Platelets 
X 
X 
X 
 
PT/INR, PTT 
X 
 
 
 
Serum Creatinine  
X 
X 
X 
 
Albumin, ALT, AST, Alk. 
Phos., Bilirubin 
X 
X 
X 
 
Electrolytes (incl. Ca, Cl, CO2, 
K, Na, Mg, P), Glucose 
X 
X 
X 
 
TSH 
X 
C 
 
 
Serum or Urine HCG 
X(5) 
 
 
 
Urine Protein and Creatinine 
X 
D 
 
 
Serum Chromogranin A 
X 
C 
 
 
Hormone Assessment 
E 
E 
 
 
Staging 
 
CT Chest/Abd/Pelvis (or equiv.) 
F 
F 
 
F 
Real-time Central Review 
 
 
 
X(6) 
For patients who consent to participate in A021602-HO1, A021602-PP1, and A021602 Biobanking: 
Quality of Life Substudy7 
At registration and every 12 weeks (+/- 1 week) (i.e. every 3 cycles) 
until progression or start of new anticancer therapy; see Section 14.1 

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Pharmacokinetic Substudy7 
Submission of plasma specimens on Day 1 of Cycles 1, 2, and 3 and 
on Day 15 of Cycles 1 and 2; see Section 6.2, Section 14.2. 
Biobanking 
Submission of specimens within 28 days of registration, Cycle 1 Day 
1, Cycle 2 Day 1, and at the time of progression; see Section 6.2 
* 
Labs completed prior to registration may be used for Day 1 of Cycle 1 tests if obtained ≤ 14 days prior to 
treatment. For subsequent cycles, all labs, scans, tests, and observations may be obtained +/- 3 days of 
scheduled clinic visit. Labs completed prior to re-registration must be completed ≤ 28 days. 
** 
If protocol therapy is discontinued for reasons other than disease progression, physical examination, 
performance status, and radiologic imaging studies should be performed every 12 weeks (+/- 1 week) until 
disease progression or start of new anticancer therapy, whichever comes first. Patients who discontinue study 
treatment due to disease progression (or who start a new anticancer therapy after discontinuing study 
treatment for reasons other than disease progression) should be followed every 6 months for survival until 8 
years after registration. See Section 12.0.  
1 
Height only collected at baseline; weight only measured at baseline, on Day 1 of Cycles 1, 2, and 3, and on 
Day 15 of Cycles 1 and 2. 
2 
Patients complete PRO-CTCAE by paper booklet ordered through the CTSU website. See Section 4.3 and 
Section 4.7 for ordering instructions. See Section 9.1 for administration instructions. See Appendix I for 
PRO-CTCAE assessments for IRB submission and review only. PRO-CTCAE booklets should be 
administered at the following time points: ≤ 21 days prior to treatment, Day 1 of every cycle, and at the time 
of progression (or cessation of protocol treatment). PRO-CTCAE should not be collected after patients 
crossover. 
3 
The diary must begin the day the patient starts taking the medication and must be completed per protocol and 
returned to the treating institution (or compliance must be documented in the medical record by any member 
of the care team). See Appendix II. 
4 
To be completed after registration but ≤ 21 days prior to treatment.  
5 
For women of childbearing potential, see Section 3.2.6; must be done ≤ 14 days prior to registration and re-
registration. 
6 
Restaging scan documenting progressive disease while on blinded therapy must be submitted for real-time 
central review within 24 hours of local determination; see Section 6.3 and Section 7.2.2 for instructions 
regarding imaging submission and IROC notification of cases when there is a local determination of 
progressive disease and request for real-time central review. 
7.  
Crossover patients will not participate in the Quality of Life or the Pharmacokentic substudies.  
A 
To be performed at baseline, on Day 1 of Cycle 2, and on Day 1 of Cycle 3. 
B 
Any adverse events that occur within 30 days of discontinuation of study treatment should be recorded in the 
last treatment cycle form. 
C 
To be performed at baseline, and then every 12 weeks (+/- 1 week) (i.e. every 3 cycles). Any measurements 
of biochemical response should occur in conjunction with the radiographic assessments for disease status. 
D 
To be performed every other cycle (i.e. Cycle 1, Cycle 3, Cycle 5, etc.). 
E 
For patients with a history of carcinoid syndrome only: perform 24-hour urine 5-HIAA at baseline and then 
every 12 weeks (+/- 1 week) (i.e. every 3 cycles). Other hormones, such as gastrin, insulin, glucagon, and 
VIP should be assessed, if clinically indicated, at baseline and then every 12 weeks (+/- 1 week) if elevated. 
Any measurements of biochemical response should occur in conjunction with the radiographic assessments 
for disease status. For patients with functional neuroendocrine tumors (i.e. patients with symptoms related to 
hormone production) only: perform hormone assessment, if clinically indicated, at baseline and then every 
12 weeks (+/- 1 week) if elevated. 
F 
Baseline scans and scans within the 12 months prior to registration used to determine progression for 
eligibility should be submitted within 3 days; see Section 3.2.1, Section 6.3, and Section 7.2.3. Restaging 
scans will be performed after every 12 weeks (+/- 1 week) (i.e. every 3 cycles) until evidence of progression; 
restaging scan used for local determination of progression while on blinded therapy must be submitted for 
real-time central review within 24 hours; see Section 6.3 and Section 7.2.2.  

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Multiphase CT scan (chest/abdomen/pelvis) is the preferred imaging modality. Equivalent modalities (MRI 
scan of the abd/pelvis with either CXR or non-contrast chest CT) may be used at the discretion of the treating 
physician. The CT component of a PET-CT is also acceptable if the CT is of diagnostic quality (using oral 
and IV contrast). The same imaging modality used at baseline should be used for all subsequent evaluations. 
CT scans should be of diagnostic quality and performed with oral and IV contrast unless there is a medical 
contraindication. MRI scans should be of diagnostic quality and performed with IV contrast unless there is a 
medical contraindication. MRI is the preferred imaging modality for patients with a medical contraindication 
to contrast. See Section 7.2.1 for further details. Octreotide scan or Gallium-68-Dotatate scans cannot be used 
for tumor measurements. Supporting documentation is to be submitted per Section 6.1.1. Imaging and reports 
are to be submitted per Section 6.3. 
6.0 
DATA AND SPECIMEN SUBMISSION 
6.1 
Data Collection and Submission 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and 
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (Lab Admin), Rave SLA, or Rave Investigator. 
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration 
type. 
Refer to 
 for registration types and 
documentation required. 
This study has a Delegation of Tasks Log (DTL). Therefore, those requiring write access to 
Rave must also be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata. To accept the invitation, site staff must either click on the link in the email or 
login to iMedidata via the CTSU members’ website under Data Management > Rave Home, 
and click to accept the invitation in the Tasks pane located in the upper right-corner of the 
iMedidata screen. Site staff will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings) and can be accessed by clicking on the eLearning link in the Tasks pane 
located in the upper right corner of the iMedidata screen. If an eLearning is required for the 
study and has not yet been taken, the link to the eLearning will appear under the study name in 
the Studies pane located in the center of the iMedidatascreen; once the successful completion of 
the eLearning has been recorded, access to the study in Rave will be granted, and a Rave EDC 
link will replace the eLearning link under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will receive a separate invitation from iMedidata 

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to activate their account. Account activation instructions are located on the CTSU website in the 
Data Management section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at 
or 
by contacting the CTSU Help Desk at 
   
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered 
queries and form delinquencies, monitor data quality and timeliness, generate reports, and 
review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave Home 
section displays a table providing summary counts of Total Delinquencies and Total Queries. 
DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, forms with 
current status, and timeliness reports. Review the DQP modules on a regular basis to manage 
specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct link on 
the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, 
DQP Queries, DQP Delinquent Forms, DQP Form Status and DQP Reports modules. 
Data Submission Schedule 
A Data Submission Schedule is available on the Alliance study webpage within the Case Report 
Forms section. The Data Submission Schedule is also available on the CTSU website within the 
study-specific folders. 
Patient-completed Booklets 
Patient-completed questionnaire booklets for this study are to be ordered prior to the registration 
of any patients (see Section 4.3). Samples of questionnaire booklets are available in Appendix I 
for reference and IRB submission only. They are not to be used for patient completion. Booklets 
must be given to patients to complete and patients should be instructed to return the booklets to 
site staff in person, and site staff will enter patient responses into Rave.  
Note: There are two mandatory quality of life items included in the main study: 
Registration Fatigue/Uniscale and PRO-CTCAE Adverse Event Assessments; see Section 4.3 
for booklet ordering instructions, Section 5.0 and Section 9.1 for administration instructions, 
and Appendix I for examples of the assessments for IRB submission and review. There are two 
additional quality of life items included as part of the optional A021602-HO1 substudy: 
EORTC Tools and Global Impression of Change Assessments; see Section 4.3 for booklet 
ordering instructions, Section 5.0 and Section 14.1 for administration instructions, and 
Appendix I for examples of the assessments for IRB submission and review.  
 
 

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6.1.1 
Supporting Documentation to be Submitted to the Alliance 
This study requires supporting documentation for diagnosis, response, and progression. 
Additional source documentation is required for the enhanced centralized data monitoring 
plan; see Section 13.6 of this protocol and the Data Submission Schedule accompanying 
the All Forms Packet for further guidance. Supporting documentation will include local 
pathology reports, radiologic images (to be submitted to IROC Ohio per Section 6.3), 
imaging reports, and other documents/notes/reports, and these must be submitted at the 
following time points: 
• 
Prior-to-baseline – radiologic images (submit to IROC Ohio), imaging reports, and 
other reports/notes within the 12 months prior to registration that were used to 
determine progression for eligibility (see Section 3.2.1) 
• 
Baseline – local pathology report, radiologic images (submit to IROC Ohio), and 
imaging reports 
• 
Restaging – radiologic images (submit to IROC Ohio) and imaging reports 
• 
Progression – radiologic images (submit to IROC Ohio) and imaging reports (or 
clinical note documenting clinical progression) 
All supporting documentation is to be submitted via Rave (with the exception of radiologic 
images, which should be submitted to IROC Ohio per Section 6.3). Imaging reports should 
be submitted via Rave and to IROC Ohio per Section 6.3 along with radiologic images. 
6.2 
Specimen Collection and Submission  
For all patients registered to Alliance A021602: Retrospective histopathology review will be 
conducted using the tumor tissue from the diagnostic biopsy or surgical specimens. The 
submission of this sample for histopathology review is required for all patients registered to this 
study, including those who are found to be ineligible and those who do not receive protocol 
therapy. 
For patients consented to A021602-PP1: All participating institutions must ask patients for their 
consent to participate in the pharmacokinetic substudy, although patient participation is 
optional. Pharmacokinetic (PK) analyses will be performed; rationale and methods for the 
scientific components of the PK study are described in Section 14.2. For patients who consent 
to participate, blood will be collected at the time points below for the PK studies. 
For patients consented to A021602 Biobanking: All participating institutions must ask patients 
for their consent to participate in the biobanking for future correlative studies, although patient 
participation is optional. Future biomarker studies will be performed; rationale for the scientific 
components of these future studies are described in Section 14.3. For patients who consent to 
participate, blood and tissue will be collected at the following time points for these future 
studies: 

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Blinded Therapy 
Open-label Therapy 
 
 
 
Within 28 
Days after 
Registration 
Cycle 1 Day 
1 
Cycle 1 
Day 15 
Cycle 2 Day 
1 
Cycle 2 
Day 15 
Cycle 3 
Day 1 
At PD/ End 
of 
Treatment* 
Cycle 1 Day 
1 
Cycle 2 Day 
1 
At PD/ End 
of 
Treatment* 
Storage/ 
Shipping 
Conditions 
Submit 
to: 
Mandatory for all patients registered to A021602: 
One H&E 
Slide 
X 
 
 
 
 
 
 
 
 
 
Ambient/ 
overnight 
ABOSU 
For patients consented to A021602-PP1**, please submit the following: 
Plasma from 
Whole Blood 
(Lavender)1 
 
1 x 5 mL 
1 x 5 mL 
1 x 5 mL 
1 x 5 mL 
1 x 5 mL 
 
 
 
 
Dry ice/ 
overnight 
PITT 
For patients consented to biobanking***, please submit the following: 
FFPE Tumor 
Block2 
X 
 
 
 
 
 
A 
 
 
 
Ambient/ 
overnight 
ABOSU 
Plasma from 
Whole Blood 
(Lavender)3 
 
2 x 10 mL 
 
2 x 10 mL 
 
 
2 x 10 mL 
2 x 10 mL 
2 x 10 mL 
2 x 10 mL 
Dry ice/ 
overnight 
ABOSU 
Whole Blood 
(Lavender)4 
 
1 x 10 mL 
 
 
 
 
 
 
 
 
Cool pack/ 
overnight 
ABOSU 
* 
Blood samples are to be collected  in the event of progression or end of treatment; progression samples may be collected and submitted up to 60 days 
after progression. 
** 
Patients who consented to A021602-PP1 are those who answered “YES” to the model consent question “I agree to have my blood collected, and I agree that 
my blood samples and related information may be used for the laboratory study described above.”  
*** 
Patients who consented to biobanking are those who answered “YES” to the model consent question “I agree to have my blood and tissue collected, and 
I agree that my blood and tissue samples and related information may be kept in a Biobank for use in future health research.”  
1 
The Cycle 1 Day 1 sample should be collected prior to the initiation of treatment; all subsequent samples should be collected prior to the patient 
receiving that day’s scheduled daily dose, preferably 24 hours (+/- 4 hours) after receiving the previous day’s scheduled daily dose. See Section 6.2.3 for 
cryovial ordering suggestions. Samples will be used for the pharmacokinetic substudy detailed in Section 14.2. 
2 
Blocks are strongly preferred over slides, but if a block cannot be submitted due to institutional policy, then 10 unstained, uncharged slides at 5 microns 
cut from the FFPE primary (or metastatic) tumor are acceptable. See Section 6.2.4 for labeling and submission instructions.   
3 
See Section 6.2.5 for cryovial suggestions. Samples will be used for the future plasma biomarker studies detailed in Section 14.3. 
4 
If possible, the sample should be collected prior to the initiation of treatment, however, collection at any point during protocol treatment is acceptable. 
This sample will serve as a germline DNA control for the future studies described in Section 14.3. 
A 
For patients consented to biobanking who have a biopsy or surgery performed due to tumor progression: please submit a tissue block (or alternative of 
10 unstained, uncharged slides at 5 microns) from the progression sample within 60 days per Section 6.2.4. For patients consented to biobanking who 
have a biopsy or surgery performed due to potential treatment toxicities: please submit a tissue block (or alternative of 10 unstained, uncharged slides at 
5 microns) from the potential toxicity sample within 60 days per Section 6.2.4. 

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6.2.1 
Specimen Submission Using the Alliance Biospecimen Management System  
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA 
THIS SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on 
Alliance trials. Authorized individuals may access BioMS at the following URL:  
 using most standard web browsers 
(Safari, Firefox, Internet Explorer, etc.). For information on using the BioMS system, 
please refer to the ‘Help’ links on the BioMS webpage to access the on-line user manual, 
FAQs, and training videos. To report technical problems, such as login issues or application 
errors, please contact: 
 For assistance in 
using the application or questions or problems related to specific specimen logging, please 
contact: 
 
After logging collected specimens in BioMS, the system will create a shipping manifest.  
This shipping manifest must be printed and placed in the shipment container with the 
specimens. 
A copy of the Shipment Packing Slip produced by BioMS must be printed and placed in 
the shipment with the specimens. 
Instructions for the collection of samples are included below. Please be sure to use a method 
of shipping that is secure and traceable. Extreme heat precautions should be taken when 
necessary.  
Specimens for the A021602-PP1 substudy should be sent to the following address: 
 
 
 
 
 
 
Ship specimens to the Alliance Laboratory at the University of Pittsburgh (PITT) with 
Priority Overnight on Monday through Thursday for next day delivery. Do not ship 
specimens the day before a holiday. PITT does not accept Saturday deliveries. 
All other specimens should be sent to the following addresses: 
 
 
 
 
 
  
 
Ship specimens to the Alliance Biorepository at Ohio State University (ABOSU) with 
Priority Overnight on Monday through Thursday for next day delivery. Do not ship 
specimens the day before a holiday. ABOSU does not accept Saturday deliveries. 

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6.2.2 
Tumor Submission for Histopathology Review 
Consistent and accurate histologic grading is important for this study. Submission of one 
H&E slide from the diagnostic tumor biopsy or surgery is required for all patients enrolled 
to this study.  
While local institutional pathology interpretation will be used to determine patient 
eligibility, a retrospective review of the histologic slides used for diagnosis of 
neuroendocrine tumor on these patients will be performed. Central pathology review is not 
required prior to registration.  
A de-identified surgical pathology report should be sent with all archival specimens. 
Usually, this is generated by obscuring all PHI (names and dates) with white-out or a black 
magic marker, labeling each page of the report with the Alliance patient ID, and 
photocopying the report. The surgical pathology case number and block identifier (if 
applicable) should be maintained on the report so that it can be matched with the physical 
labeling on the sample. Please ensure neuroendocrine (chromogranin, synaptophysin) 
and Ki67 staining results are included in the pathology report. 
Label the H&E slide with the following information: 
1) Patient Initials 
2) Alliance Study Number (i.e. A021602) 
3) Institutional Surgical Pathology Number/Block ID either via your institution’s 
standard method for labeling clinical slides or using a permanent marker. Please 
DO NOT use sticky labels. 
It is also important that H&E slides are shipped in appropriately padded and secure 
containers to avoid physical damage.  
Ship specimens to the Alliance Biorepository at OSU with Priority Overnight on Monday 
through Thursday for next day delivery. Do not send specimens the day before a holiday. 
6.2.3 
Blood Submission for Pharmacokinetic Studies in A021602-PP1 
There is NOT a study kit for this trial; see below for cryovial ordering suggestions. 
Cryovial Ordering Suggestions: Some examples of acceptable 1.8-2.0 mL cryovials are 
Nalgene (Cat #5012-0020), Fisher (Cat #10-500-26), Corning (Cat #430488), and Nunc 
(Cat #347627). 
For patients who consent to participate in the A021602-PP1 substudy, blood samples will 
be used for the pharmacokinetic analyses described in Section 14.2. 
Plasma from Whole Blood in EDTA Lavender Top Tube: 
Prior to receiving protocol therapy on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, 
Cycle 2 Day 15, and Cycle 3 Day 1 patients consented to the A021602-PP1 substudy will 
be asked to complete a Patient Pharmacokinetics Form (see Appendix IV) which will 
provide information about the previous 48-hours of cabozantinib/placebo dosing (i.e. 
details on dose and time). After completion, the form should be collected, and the data 
should be reported in Rave on the Specimen Submission Form for A021602-PP1. 
Collect 1 x 5 mL of peripheral venous blood in a lavender top tube prior to the patient 
receiving the daily dosage of cabozantinib/placebo on Cycle 1 Day 1, Cycle 1 Day 15, 
Cycle 2 Day 1, Cycle 2 Day 15, and Cycle 3 Day 1. Invert the tubes approximately 8-10 
times to mix the EDTA, and then centrifuge at room temperature for 15 minutes at ~2500 

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x g (in accordance with local standard operating procedure for plasma isolation). Aliquot 
approximately 1.0 mL of plasma into each 1.8-2.0 mL cryovial (see above for cryovial 
ordering suggestions). 
Immediately label and freeze cryovials at –70°C or colder. If –70°C or colder freezer is not 
available, temporary storage on dry ice or at –20°C prior to shipping is acceptable for up 
to approximately 48 hours. The samples should be placed in a biohazard bag surrounded 
by paper toweling prior to placing them in dry ice so the plasma-containing plastic tubes 
will not crack. Samples should be shipped on dry ice by overnight courier service to the 
University of Pittsburgh within 30 days of collection. Batch shipping is acceptable when 
feasible. Sample handling from collection to storage should not exceed 60 minutes. 
Label all plasma samples with the following identification information: 
1) Date of Collection 
2) Time of Collection (i.e. actual time the blood sample was obtained) 
3) Alliance Patient ID Number 
4) Patient Initials 
5) Alliance Study Number (i.e. A021602-PP1) 
6) Sample Type (e.g. Plasma) 
If labels are used, please ensure labels are carefully attached to the tubes and are not likely 
to fall off when frozen or during shipping. 
6.2.4 
Collection of Paraffin Blocks of Archived Tumor Tissue for A021602 Biobanking 
For patients who consent to participate in A021602 biobanking, tumor blocks from the 
archival, diagnostic tissue sample will be used for the analyses described in Section 14.3. 
For patients who consent to participate in A021602 biobanking, tissue blocks from biopsies 
or surgery due to tumor progression, if obtained, are also to be submitted. In addition, tissue 
blocks from biopsies or surgeries related to potential treatment toxicities should also be 
submitted. 
Paraffin blocks of primary and, when available, metastatic tissue obtained from archival 
tumor specimens should be sent to the Alliance Biorepository at Ohio State (ABOSU). 
Please specify the source of the tumor block (primary or metastatic site).  
Label the blocks with the following information: 
1) Alliance Patient ID Number 
2) Patient Initials 
3) Alliance Study Number (i.e. A021602) 
4) Institutional Surgical Pathology Number/Block ID 
Please DO NOT use sticky labels, and DO NOT put labels/tape on top of the actual tissue. 
The Alliance has instituted special considerations for the small percentage of hospitals 
whose policy prohibits long-term storage of blocks, and the smaller percentage of hospitals 
whose policies prohibit release of any block. If a block can’t be submitted due to 
institutional policy, 10 unstained, uncharged slides at 5 microns cut from the formalin-
fixed, paraffin embedded (FFPE) primary (or metastatic) tumor are required. However, 
blocks are strongly preferred over slides.  

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Label the slides with the following information: 
1) Thickness (e.g. 5 microns) 
2) Institutional Surgical Pathology Number/Block ID (either via your institution’s 
standard method for labeling clinical slides or using a permanent marker). Please 
DO NOT use sticky labels, and DO NOT put labels/tape on top of the actual tissue. 
The slide container should have a label affixed with the following information: 
1) Date of Collection 
2) Alliance Patient ID Number 
3) Patient Initials 
4) Alliance Study Number (i.e. A021602) 
When shipping FFPE tissues (blocks or unstained slides) it is important to avoid extreme 
heat. If environmental conditions indicate, FFPE tissues should be shipped in containers 
containing cold packs. It is also important that tissues are shipped in appropriately padded 
and secure containers to avoid physical damage. 
Ship specimens to the Alliance Biorepository at OSU with Priority Overnight on Monday 
through Thursday for next day delivery. Do not send specimens the day before a holiday. 
The Alliance Biorepositories would like to maintain the integrity of the tissue so that 
quality histology sections may be provided to investigators sometime after the study closes 
when they are ready to perform their research. It is preferred that the Alliance Biorepository 
bank the block until the study investigator is ready to perform the research since it is best 
to use freshly cut tissue sections from the blocks. Please contact the Alliance Biorepository 
at Ohio State University if additional assurances with your hospital pathology department 
are required. 
6.2.5 
Blood Sample Submission for A021602 Biobanking 
There is NOT a study kit for this trial; see below for cryovial ordering suggestions. 
Cryovial Ordering Suggestions: Some examples of acceptable 1.8-2.0 mL cryovials are 
Nalgene (Cat #5012-0020), Fisher (Cat #10-500-26), Corning (Cat #430488), and Nunc 
(Cat #347627). 
For patients who consent to participate in A021602 biobanking, blood samples will be used 
for the biomarker analyses described in Section 14.3.  
Plasma from Whole Blood in EDTA Lavender Top Tubes: 
Collect 2 x 10 mL of peripheral venous blood in lavender top tubes on Cycle 1 Day 1, 
Cycle 2 Day 1, and at the time of progression/end of treatment during both blinded and 
open-label therapy. Invert the tubes approximately 8-10 times to mix the EDTA and then 
centrifuge at room temperature for 15 minutes at ~2500 x g (in accordance with the 
centrifuge manufacturer’s instructions). Transfer the upper layer of plasma from the two 
tubes into a 15 mL conical tube. Repeat the centrifugation of the plasma in the 15 mL 
conical tube at room temperature for 15 minutes at ~2500 x g (in accordance with the 
centrifuge manufacturer’s instructions). Aliquot approximately 1.0 mL of plasma into each 
1.8-2.0 mL cryovial (see above for cryovial ordering suggestions). 
Immediately label and freeze cryovials at –70°C or colder. If –70°C or colder freezer is not 
available, temporary storage on dry ice or at –20°C prior to shipping is acceptable for up 
to approximately 48 hours. The samples should be placed in a biohazard bag and shipped 

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according to IATA Guidelines within approximately 30 days of the blood draw on dry 
ice by overnight courier service to the Alliance Biorepository at Ohio State University. 
Batch shipping is acceptable when feasible. 
Whole Blood in EDTA Lavender Top Tube: 
Collect 1 x 10 mL of peripheral venous blood in one lavender top tube on Cycle 1 Day 1 
during blinded therapy (preferably collected prior to the initiation of treatment, however, 
collection at any point during protocol treatment is acceptable). The tube should be inverted 
approximately 8-10 times to mix the EDTA. Refrigerate sample until shipping. The blood 
sample should be placed in a biohazard bag and shipped the same day as the blood is 
drawn on a cold pack by overnight courier service to the Alliance Biorepository at Ohio 
State University, where it will then be processed for germline DNA. 
Label all blood samples with the following identification information: 
1) Date of Collection 
2) Alliance Patient ID Number 
3) Patient Initials 
4) Alliance Study Number (i.e. A021602) 
5) Sample Type (e.g. Whole Blood, Plasma) 
6.3 
Imaging Submission 
Collection of CT or MRI and CXR (or MRI and non-contrast CT chest) images is required for 
all patients consented on A021602. Quality images will be collected digitally for archival and 
retrospective purposes (see Section 7.2.1 for definitions of quality images). The same imaging 
modality (i.e. multiphase CT or MRI [and CXR or non-contrast chest CT]) used at baseline for 
each patient should be used for all subsequent evaluations to ensure accurate comparison. 
Images and local interpretation reports will be collected digitally at the following time points: 
• 
Prior-to-baseline (scan within the 12 months prior to registration that was used to 
determine progression for eligibility; see Section 3.2.1) 
• 
Baseline (completed within 28 days prior to patient registration) 
• 
Restaging* (performed every 12 weeks until disease progression) 
• 
Progression 
* For patients who discontinue protocol treatment prior to disease progression, continue 
to submit every 12 weeks until disease progression (or start of new anticancer therapy). 
• 
For patients who cross-over to receive open-label therapy, continue to submit ever 12 
weeks until progression on open-label therapy. 
The complete CT or MRI (and CXR or non-contrast CT) scan data in digital DICOM format 
should be submitted electronically to the Imaging and Radiation Oncology Core at Ohio (IROC 
Ohio) within no more than 3 business days upon patient registration (baseline and prior-to-
baseline scans) or upon image acquisition completeness (restaging), and within no more than 
24 hours upon local determination of progression (for real-time central review, see Section 
7.2.2). BMP files, JPG files, or hard copies (films) are not acceptable.  
Imaging data should be submitted electronically to IROC Ohio via TRIAD (Section 6.3.1). The 
standard TRIAD based data transfer approach will be provided separately through IROC efforts 

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via the specific trial e-mail, 
, per the request of participating sites 
before their first imaging data submission. 
If the TRIAD approach is not achievable at a site, alternatively the site needs to de-identify the 
patient data using institutional procedures to remove patient name and medical record number 
while preserving the Alliance patient ID number (e.g. 112136) and protocol number (e.g. 
A021602), and use the following electronic approaches for data submission: 
1) Web Transfer 
 
Any PCs with internet access and web browser (e.g. Internet Explorer, Mozilla Firefox) 
can be used to web transfer DICOM images and other required files to IROC Ohio. The 
standard Web Transfer information will be provided separately through the specific trial 
e-mail, 
 per the request of participating sites before the 
first imaging data submission.  
2) FTP Transfer 
Any FTP software can be used to initiate access to the secure FTP Server of IROC Ohio. 
The standard FTP access information will be provided separately through the specific 
trial e-mail, 
per the request of participating sites before 
the first imaging data submission. 
3) Mail/CD Shipment 
If neither of the electronic data transfer approaches can be achieved, then the de-
identified images in digital DICOM format may be burned to a CD and mailed to IROC 
Ohio (however, electronic submission is preferred). Submit only one of the patient’s 
images per CD, with the Alliance patient ID number, study type, date of scans, and 
name of submitting institution. 
Submit these data to:  
 
 
 
 
 
 
 
 
 
 
If the imaging data submission is done via web transfer, FTP transfer, or mail/CD shipment, 
send an e-mail to IROC Ohio at the specific trial email, 
 to 
inform them that the study has been submitted from the institution. Please include the following 
basic information of submitted data sets: 
1) Alliance Patient ID Number 
2) Scan Time Point (i.e. Baseline) 
3) Date of Scans 
4) Institution Name  

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IROC Ohio will notify the site within 2 business days of the data receipt and within 3 business 
days following the data receipt of the quality check report via the trial specific email 
  
For any questions about or problems with data submission to IROC Ohio, please call the IT 
Group at 
for help. 
6.3.1 
Digital Imaging Data Submission Using Transfer of Images and Data 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s (ACR) 
image exchange application. TRIAD provides sites participating in clinical trials a secure 
method to transmit images. TRIAD anonymizes and validates the images as they are 
transferred. 
6.3.1.1 TRIAD Access Requirements 
TRIAD Access Requirements: 
• 
A valid CTEP-IAM account. 
• 
Registration and Credential Repository (RCR) registration type of: Associate (A), 
Associate Plus (AP), Non-Physician Investigator (NPIVR), or Investigator (IVR) 
registration type. Refer to the CTEP Registration Procedures section for 
instructions on how to request a CTEP-IAM account and complete registration in 
RCR. 
• 
TRIAD Site User role on an NCTN or ETCTN roster. 
All individuals on the Imaging and Radiation Oncology Core provider roster have access 
to TRIAD and may submit images for credentialing purposes, or for enrollments to which 
the provider is linked in OPEN. 
6.3.1.2 TRIAD Installation 
To submit images, the individual holding the TRIAD Site User role will need to install the 
TRIAD application on their workstation. TRIAD installation documentation is available at 
 
This process can be done in parallel to obtaining your CTEP-IAM account and RCR 
registration. 
For questions, contact TRIAD Technical Support staff via email 
 
or
 
6.3.1.3 Procedures for Data Submission via TRIAD 
The standard TRIAD-based data transfer approach will be provided separately through 
IROC efforts via the specific trial e-mail, 
 per the request 
of participating sites before their first imaging data submission.  
7.0 
TREATMENT PLAN/INTERVENTION 
7.1 
Cabozantinib/Placebo 
Protocol treatment is to begin ≤ 14 days of registration or re-registration.  
For questions regarding treatment, please see the study contacts page.  
Blinded Therapy 

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This is a 2:1 randomized, double-blind trial. The initial blinded, patient-specific clinical supplies 
of cabozantinib/placebo will be requested by the Alliance Statistics and Data Management 
Center at the time of randomization and should arrive at the clinical site ≤ approximately 7-10 
days after randomization (see Section 10.1). 
Protocol therapy will consist of 60 mg oral cabozantinib/placebo (three 20 mg tablets) taken 
once daily during each 28-day treatment cycle. Patients should not eat for at least 2 hours before 
and for at least 1 hour after taking cabozantinib/placebo.  
Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of 
consent. Crossover from placebo to open-label cabozantinib at the time of centrally-confirmed 
radiologic disease progression is permitted; see Section 3.3, Section 4.8, Section 6.3, and 
Section 7.2. Patients will be monitored for treatment response and toxicity.  
Open-label Therapy 
The open-label, patient-specific clinical supplies of cabozantinib will be requested by the 
Alliance Statistics and Data Management Center at the time of re-registration and should arrive 
at the clinical site ≤ approximately 7-10 days after re-registration (see Section 10.1). 
Protocol therapy will consist of 60 mg oral cabozantinib (three 20 mg tablets) taken once daily 
during each 28-day treatment cycle. Patients should not eat for at least 2 hours before and for at 
least 1 hour after taking cabozantinib. 
Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of 
consent. Patients will be monitored for treatment response and toxicity. 
7.2 
Imaging 
Collection of CT or MRI and CXR (or MRI and non-contrast CT chest) images is required for 
all patients consented on A021602. Quality images will be collected digitally for archival and 
retrospective purposes (see Section 7.2.1 for definitions of quality images). The same imaging 
modality (i.e. multiphase CT or MRI [and CXR or non-contrast chest CT]) used at baseline for 
each patient should be used for all subsequent evaluations to ensure accurate comparison. 
Images and local interpretation reports will be collected digitally at the following time points: 
• 
Prior-to-baseline (scan within the 12 months prior to registration that was used to 
determine progression for eligibility; see Section 3.2.1) 
• 
Baseline (completed within 28 days prior to patient registration) 
• 
Restaging* (performed every 12 weeks until progression) 
• 
Progression 
* For patients who discontinue protocol treatment prior to disease progression, continue 
to submit every 12 weeks until disease progression (or start of new anticancer therapy).  
If diagnostic CT imaging is performed in conjunction with a PET/CT, that is allowable. 
Images submitted for the progression time point (i.e. local determination of progressive disease) 
while patient is on blinded therapy will be reviewed by the A021602 Imaging Central Review 
Panel in real time; see Section 7.2.2. Images submitted for the progression time point while the 
patient is on open-label therapy are being collected for documentation purposes and will not be 
reviewed by the A021602 Imaging Central Review Panel at this time. 
Images submitted for the baseline time point and the restaging time points while patient is on 
blinded therapy will be reviewed by the A021602 Imaging Central Review Panel retrospectively 
in batches; see Section 7.2.3. Images submitted for the progression time point while the patient 

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is on open-label therapy are being collected for documentation purposes and will not be 
reviewed by the A021602 Imaging Central Review Panel at this time. 
Images submitted for the prior-to-baseline time point are being collected for documentation 
purposes and will not be reviewed by the A021602 Imaging Central Review Panel at this time. 
See Section 6.3 for digital image submission instructions.  
If a patient discontinues protocol therapy prior to disease progression, then the follow-up 
imaging required per Section 5.0 may be performed at a non-registering institution. All protocol 
conduct must be followed, and the registering institution is responsible for ensuring all data is 
reported per protocol. Please refer to the Alliance policy and procedures document posted on 
the Alliance website for the policy on engagement in research by non-registering institutions. If 
the NCTN Group credited for enrollment is a non-Alliance Group, then other requirements from 
the credited Group may apply.  
7.2.1 
Definition of Quality Imaging 
CT Scan Recommendations 
Optimal Technique: The recommendations listed below should be followed if possible 
for the multiphase CT scan of chest/abdomen/pelvis, whenever possible: 
• 
Scanning Mode: Helical 
• 
Patient Position: Supine, arms up 
• 
Scan Extent: Thoracic inlet through pubic symphysis 
• 
Scan Time: Single breath-holding period, in full inspiration 
• 
Section Thickness: 2.5 mm or less 
• 
Enhancement: Intravenous contrast unless medical contraindication 
• 
Reconstruction: Contiguous or overlapping sections; no gaps 
• 
Consistency: Same technique is to be used between baseline and restaging scans 
Minimum Technique: The recommendations listed below should be followed if possible 
for the multiphase CT scan of the chest/abdomen/pelvis, whenever possible (any CT scan 
that does not meet these minimal recommendations should be repeated):  
• 
Scanning Mode: Helical 
• 
Patient Position: Supine, arms up if possible 
• 
Scan Extent: Thoracic inlet through pubic symphysis 
• 
Scan Time: Single breath-holding period, in full inspiration 
• 
Section Thickness: 5 mm or less 
• 
Enhancement: Required if not clinically contraindicated. 
• 
Reconstruction: Contiguous or overlapping sections; no gaps 
• 
Consistency: Same technique is to be used between baseline and restaging scans 
Note: For both optimal and minimum CT recommendations, if contrast is used for baseline scans 
but it is contraindicated at a restaging time point while on protocol therapy, then the scans 

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obtained at all future restaging time points should be obtained as both contrast and non-contrast 
in order to maintain consistency, unless there is a medical contraindication. 
MRI Scan Recommendations 
MRI may be performed instead of CT, and it is the preferred imaging modality for patients with 
a medical contraindication to contrast. It is of the utmost importance that the same imaging 
modality be used at baseline and for all subsequent follow up visits if clinically able. 
The MRI should be performed with routine slice thickness generally not to exceed 5 mm. T1-
weighted, T2-weighted as well as pre- and post-contrast enhanced T1-weighted images should 
be obtained. The precise TR and TE values as well as other pulse sequence parameters can be 
determined based upon local site preferences. At subsequent time points, the same imaging 
technique and sequences should be consistently used unless the patient can no longer receive IV 
contrast. The MRI should be performed of the abdomen and pelvis, and the chest should be 
scanned with CT chest or alternatively, AP and lateral CXR. 
CXR Scan Recommendations 
At minimum, AP chest should be optimal. PA and lateral views are preferred if CT chest is not 
obtained. 
If there is a need to switch imaging modalities, for example, from CT to MRI, then a best attempt 
should be made to account for differences in imaging techniques and care should be taken not 
to progress a patient because of a potentially more sensitive imaging test. 
7.2.2 
Real-time Imaging Central Review 
The following images and local interpretation reports will be collected and submitted for 
centralized, real-time review by the A021602 Imaging Central Review Panel: 
• 
Local determination of progressive disease (PD) while on blinded therapy 
o NOTE: Participating sites must notify IROC Ohio of local radiology 
assessment at the time of site determination of PD (either by trial email at 
 and submit 
locally-determined PD scans within no more than 24 hours (see Section 
6.3), and all imaging studies will be centrally reviewed to evaluate for 
efficacy on a per time point basis and to confirm the presence of PD. 
Sites must notify IROC Ohio preferrable by email, alternate by phone. Please indicate in 
your message to IROC that the scans demonstrate progressive disease to trigger the real-
time review of scans and include the patient ID and scan date of the images. To perform 
the real-time read of scans with local determinations of PD, IROC Ohio must have all prior 
imaging in addition to the PD scan. 
IROC Ohio will contact the A021602 Imaging Central Review Panel within 24 hours 
(except weekends and holidays) of images being received for scheduling a real-time remote 
review. The Imaging Central Review Panel will be blinded to the patient’s treatment 
assignment. IROC Ohio notifies both the participating site and Alliance of the central 
review results within 24 hours after receiving the results from the Imaging Central Review 
Panel. The overall turn-around time between imaging data receipt and central review 
results notification is within 24-72 hours after the imaging data receipt (except weekends 
and holidays). The radiology reviewer or designated team member will enter the central 
review results into Rave. Local review results in Rave should NOT be changed based on 
the results of the central review. 

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The patient should continue taking cabozantinib/placebo while the results of the 
central review are pending, unless the treating investigator believes a change in 
therapy is medically necessary.  
The final treatment decision (remaining blinded versus crossing over to open label) is 
determined by the central review.  
• 
If radiographic progressive disease is the final determination by the central review, 
then protocol treatment will be discontinued, and the patient should be followed 
for survival per Section 5.0. 
• 
If radiographic progressive disease is not the final determination by the central 
review, then protocol treatment should be continued. Sites should communicate 
with IROC Ohio if there are questions regarding the real-time central review 
results. 
Per protocol, the real time central review readers will be blinded to patients’ treatment 
assignment but may have access to clinical history. Reviewers will evaluate the provided 
imaging based on RECIST 1.1, basing lesion involvement and target selection on their 
individual expertise with this disease, and therefore differences in interpretation may arise. 
Central review results will be reported back to the site PI for further evaluation and 
determination of patient status.  
In the event of disagreement between the local and central reads, adjudication may be 
requested by the local site. Notify the IROC Ohio and the Alliance study team that an 
adjudication is requested. Provide relevant clinical documentation as well as information 
regarding how the local determination was recorded to IROC Ohio for further review, and 
IROC Ohio will assign an adjudicator. If requested locally or centrally, the adjudicator may 
be put in touch with the local treating physician. This process may take an additional 24-
72 hours of turnaround time, and the result will be used as the final central review decision 
for the interpretation and treatment/response determinations. 
The A021602 Imaging Central Review Panel will initially consist of 
of 
the University of California, San Francisco and 
 of The Ohio State 
University; other qualified radiologists may be added to the panel in the future upon 
approval by IROC Ohio, the Alliance, and the Study Chair. 
For any questions related to central review, participating sites may directly contact IROC 
Ohio instead of the central reviewer(s), preferably by the trial email at 
 
7.2.3 
Retrospective Imaging Central Review 
To ensure the highest standards and consistency, the following complete CT or MRI (and 
CXR or non-contrast CT) imaging data sets will be collected and submitted for quality 
checks and retrospective centralized primary endpoint assessment image reviews by the 
A021602 Imaging Central Review Panel: 
• 
Baseline scan 
• 
Restaging scans with local determination of CR, PR, or SD during blinded therapy 
The centralized image reviews by the A021602 Imaging Central Review Panel will be 
performed every 6 months for each patient starting from the date of patient registration 
until the date of centrally-confirmed radiographic disease progression or start of new 
anticancer therapy, whichever comes first. At minimum, the central reviewer will assess 

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the scans from the two time points within the 6-month period, however, scans from any 
previous periods may also be reviewed if desired by the central reviewer to ensure an 
accurate interpretation. Scans will be reviewed in batches every quarter for any patients 
who have reached the 6-month benchmark within the preceding three calendar months. 
IROC Ohio will contact the A021602 Imaging Central Review Panel 3 days ahead (except 
weekends and holidays) for scheduling the batched centralized image reviews. Reviewers’ 
availabilities should be sent (at least quarterly) to IROC Ohio in advance for this purpose. 
The batched centralized image reviews will be performed using an IROC Ohio established 
thin-client remote review approach. 
In the event there is disagreement between central reviewers with previously recorded 
central review measurements, a blinded adjudication by another central reviewer will 
occur; the adjudicator will not be the same radiologist that performed either of the central 
reviews in question. The adjudicator’s decision will be used as the retrospective, batched 
central review decision for the purposes of the primary study endpoint. 
Results of the batched centralized image reviews will not be reported back to the site PI. 
There will be no comparison between the real-time image central review results and the 
retrospective image central review results. 
The A021602 Imaging Central Review Panel will initially consist of 
of 
the University of California, San Francisco and 
 of The Ohio State 
University; other qualified radiologists may be added to the panel in the future upon 
approval by IROC Ohio, the Alliance, and the Study Chair. 
For any questions related to central review, participating sites may directly contact IROC 
Ohio 
instead 
of 
the 
central 
reviewer(s), 
either 
by 
the 
trial 
email 
at 
 
8.0 
DOSE AND TREATMENT MODIFICATIONS, UNBLINDING  
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care 
8.1.1 
Patients should not receive any other agent which would be considered treatment 
for the primary neoplasm or impact the primary endpoint. 
8.1.2 
Patients should receive full supportive care while on this study.   
This includes blood product support, antibiotic treatment, and treatment of other newly 
diagnosed or concurrent medical conditions. All blood products and concomitant 
medications such as antidiarrheals, analgesics, and/or antiemetics received from the first 
day of study treatment administration until 30 days after the final dose must be recorded in 
the medical records. 
8.1.3 
Treatment with other chemotherapeutic agents is not permitted.  
8.1.4 
Antiemetics may be used at the discretion of the treating physician. 
Antiemetic agents, along with supportive care, may be used as clinically appropriate at the 
first sign of nausea and vomiting. 5-HT3 receptor antagonists are recommended over 
chronic use of NK-1 receptor antagonists and dexamethasone due to possible CYP3A4 
interactions. 
8.1.5 
Diarrhea management is per the discretion of the treating physician.  
Diarrhea may need to be managed conservatively with medications such as loperamide, 
diphenoxylate/atropine, deodorized tincture of opium, or octreotide as clinically 

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appropriate at the first sign of diarrhea. Treating physicians may wish to instruct patients 
to notify their physician immediately at the first signs of poorly-formed or loose stool or 
an increased frequency of bowel movements. 
Patients with severe diarrhea may need to be assessed for intravenous hydration, correction 
of electrolyte imbalances, and dietary adjustments. 
8.1.6 
Prevention of Skin Toxicity 
Patients could be advised to use prophylactic measures for skin care. These measures may 
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. Treating physicians may wish to carefully monitor 
patients with skin disorders 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. Treating physicians may wish to consider adequate 
interventions to prevent worsening of skin symptoms such as blisters, desquamations, 
ulcerations, or necrosis of affected areas, including aggressive management of symptoms 
and an early dermatology referral. 
Recommendations for treatment of palmar-plantar erythrodysesthesia (hand-foot) 
syndrome include urea 20% cream twice daily and clobetasol 0.05% cream once daily. 
Analgesics (e.g. NSAID, GABA agonist, narcotic) can be used for pain control if needed.  
8.1.7 
Prevention of GI Perforation/Fistula and Non-GI Fistula Formation 
Treating physicians may wish to consider carefully monitoring patients for episodes of 
abdominal pain, especially in patients with known risk factors for developing GI 
perforation/fistula or non-GI fistula, to allow for early diagnosis. 
8.1.8 
Prevention of Mucositis and Stomatitis 
Comprehensive dental examination may be used as a preventative measure to identify any 
potential complications prior to initiation of protocol therapy, and, if indicated, the 
appropriate correction may need to be implemented such as modification of ill-fitting 
dentures and appropriate care of gingivitis. During treatment with cabozantinib/placebo, 
treating physicians may wish to advise patients to maintain 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), as well as noting that the oral cavity should be rinsed and wiped 
after meals, and dentures should be cleaned and brushed often to remove plaque.  
8.1.9 
Prevention of Osteonecrosis of the Jaw (ONJ) 
Patients using concomitant antiangiogenic drugs, bisphosphonates, or denosumab may 
need to be monitored for ONJ more frequently, and treating physicians may wish to advise 
patients who have previously been treated with or concomitantly receive these medications 
to avoid invasive dental procedures if possible. In cases where dental procedures are 
unavoidable, treating physicians may wish to consider the risks and benefits of a dental 
procedure, the extent of the procedure, as well as the risk of developing osteonecrosis of 
the jaw when deciding how long to hold protocol therapy.  
8.1.10 Palliative radiation therapy may not be administered while on protocol therapy.  
Patients who require radiation therapy during protocol treatment will be removed from 
protocol therapy due to disease progression. 

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8.1.11 Alliance Policy Concerning the Use of Growth Factors 
The following guidelines are applicable unless otherwise specified in the protocol. 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations. The use of growth factors should follow 
published guidelines of the American Society of Clinical Oncology Clinical Practice 
Guideline Update. J Clin Oncol 33: 3199-3212, 2015 and American Society of Clinical 
Oncology – American Society of Hematology Clinical Practice Guideline Update on the 
Use of Epoetin and Darbepoetin in Adult Patients with Cancer. J Clin Oncol 28:4996-5010, 
2010. 
Epoetin (EPO): Use of epoetin in this protocol is permitted at the discretion of the treating 
physician. The use of FDA-approved biosimilar WBC growth factor products is acceptable. 
White Blood Cell Growth Factors and other FDA-approved White Blood Cell Growth 
Factor biologics): 
• 
White Blood Cell Growth Factor may not be used: 
o To avoid dose reductions, delays or to allow for dose escalations specified 
in the protocol. 
o For the treatment of febrile neutropenia the use of CSFs should not be 
routinely instituted as an adjunct to appropriate antibiotic therapy.  
o If white blood cell growth factors are used, they must be obtained from 
commercial sources. Selection of white blood cell growth factor products 
should be per institutional guidelines.   
8.1.12 CYP3A4 Inhibitors 
Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed during on 
this trial. The following drugs are EXAMPLES of strong inhibitors of CYP3A4 and are 
not allowed during treatment with cabozantinib. 
• 
Indinavir 
• 
Clarithromycin 
• 
Ketoconazole 
CYP3A4 inhibiting foods such as grapefruit/grapefruit juice and Seville oranges may 
increase plasma concentrations of cabozantinib and should be avoided during treatment 
with cabozantinib. 
Because lists of these agents are constantly changing, please consult and review any drugs 
for their potential to inhibit CYP3A4. Examples of resources that may be utilized include 
the product information for the individual concomitant drug in question, medical reference 
texts such as the Physicians’ Desk Reference, the FDA website, or your local institution’s 
pharmacist. 
8.1.13 CYP3A4 Inducers 
Chronic concomitant treatment with strong inducers of CYP3A4 is not allowed during on 
this trial. The following drugs are EXAMPLES of strong inducers of CYP3A4 and are not 
allowed during treatment with cabozantinib 
• 
Rifampin 

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• 
Carbamazepine 
Because lists of these agents are constantly changing, please consult and review any drugs 
for their potential to induce CYP3A4. Examples of resources that may be utilized include 
the product information for the individual concomitant drug in question, medical reference 
texts such as the Physicians’ Desk Reference, the FDA website, or your local institution’s 
pharmacist. 
8.1.14 Concomitant Medications 
Concurrent use of somatostatin analogs is allowed, given that the patient has been on a 
stable dose for at least two months. 
Full dose oral anticoagulation/antiplatelet therapy is not permitted. Low dose aspirin ≤ 
81mg/day is allowed. Anticoagulation with therapeutic doses of LMWH is allowed in 
patients who are on a stable dose of LMWH for at least 6 weeks. Treatment with warfarin 
is not allowed. Anticoagulation in patients with brain metastases is not permitted. 
Bisphosphonates should be used with caution due to the nephrotic potential of these agents.  
Drugs that prolong the QTc interval should be avoided if possible, as cabozantinib can 
prolong the QTc interval. Drugs that are generally accepted to have a risk of causing 
Torsades de Pointes (see Appendix V) should be discontinued or replaced with drugs that 
do not carry this risk if at all possible. Patients who receive potential QTc-prolonging 
medications (see Appendix V) should be monitored closely. 
Drugs known to be P-glycoprotein substrates (e.g. fexofenadine, aliskiren, ambrisentan 
digoxin, colchicine, maraviroc, posaconazole, tolvaptan, etc.) should be used with caution 
as cabozantinib can cause increased P-glycoprotein substrate plasma concentrations. 
MRP2 inhibitors such as cyclosporine, delavirine, efavirenz, and emtricitabine should be 
used with caution during treatment with cabozantinib as coadministration can cause 
increased cabozantinib plasma concentrations.  
Highly protein-bound medications (e.g. diazepam, furosemide, dicloxacillin, propranolol, 
etc.) should be used with caution during treatment with cabozantinib.  
8.2 
Dose Modifications 
• 
As a general approach, it is suggested that, when possible, all toxicities be managed 
with supportive care at the earliest sign of toxicity and modifying the dose as necessary. 
• 
No dose reductions below level -2 are allowed. If dose reductions below 20 mg once 
daily are required (i.e. level -2), then cabozantinib/placebo will be discontinued.  
• 
Cabozantinib/placebo will not be re-escalated once reduced. 
• 
If cabozantinib/placebo is held for more than 4 weeks, then patients must 
discontinue protocol treatment. Any missed or delayed doses should be considered 
skipped, and the Study Calendar requirements in Section 5.0 should be maintained. 
• 
If multiple adverse events are seen, administer dose based on the greatest reduction 
required for any single adverse event observed. Reductions apply to treatment given in 
the preceding cycle and are based on adverse events observed since the prior dose. 
• 
If more than one of these apply, use the most stringent (i.e. the greatest dose reduction). 
• 
AERS reporting may be required for some adverse events (see Section 9.0). 

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• 
NOTE: PRO-CTAE data should not be used for determining attribution, dose 
modifications, or reporting serious adverse events.  
8.2.1 
Dose Levels 
Dose Level 
Cabozantinib/Placebo 
0* 
60 mg once daily 
-1 
40 mg once daily 
-2 
20 mg once daily 
*Dose level 0 refers to the starting dose 
8.2.2 
Hematologic Toxicities 
For grade 3 neutropenia with documented infection, grade 3 neutropenia ≥ 5 days, or 
grade 4 neutropenia, delay cabozantinib/placebo until toxicity resolves to grade ≤ 1, then 
resume cabozantinib/placebo with one dose level reduction. 
For grade 3 febrile neutropenia, delay cabozantinib/placebo until ANC grade ≤ 1 and 
temperature to ≤ 38.0⁰C, then resume cabozantinib/placebo with one dose level reduction. 
For grade 4 febrile neutropenia, discontinue cabozantinib/placebo. 
For grade 3 thrombocytopenia with clinically significant bleeding or grade 4 
thrombocytopenia, delay cabozantinib/placebo until platelet count ≥ 100,000/mm3, then 
resume cabozantinib/placebo with one dose level reduction. 
For grade 4 anemia, delay cabozantinib/placebo and use supportive care (e.g. red blood 
cell transfusions) as clinically indicated according to institutional guidelines until toxicity 
resolves to grade ≤ 1, then resume cabozantinib/placebo with one dose level reduction. 
For grade 4 hematologic toxicities other than anemia, discontinue cabozantinib/placebo. 
8.2.3 
Hepatic Toxicities 
8.2.3.1 For patients with ALT or AST ≤ ULN at the time of registration: 
For grade 1 ALT or AST, continue cabozantinib/placebo and consider checking LFTs in 
two weeks. 
For grade 2 ALT or AST, consider checking LFTs weekly. If ALT or AST continues to 
rise within grade 2, delay cabozantinib/placebo (and consider checking LFTs weekly) 
until grade ≤ 1, then resume cabozantinib/placebo with one dose level reduction. 
For grade 3 ALT, AST, or bilirubin, delay cabozantinib/placebo and check LFTs weekly 
until grade ≤ 1, then resume cabozantinib/placebo with one dose level reduction. If LFT 
abnormalities are related to a biliary obstruction that has resolved and have returned to 
grade ≤ 1, cabozantinib/placebo treatment may be resumed with the previous dose. 
For grade 3 bilirubin recurring after a dose level reduction or grade 4 bilirubin 
without biliary obstruction, discontinue cabozantinib/placebo. If LFT abnormalities are 
related to a biliary obstruction that has resolved and values have returned to grade ≤ 1, 
cabozantinib/placebo treatment may be resumed with the previous dose. 
For grade 4 ALT or AST, discontinue cabozantinib/placebo. 

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For grade 3 or 4 hepatic failure, discontinue cabozantinib/placebo. 
8.2.3.2 For patients with ALT or AST above the ULN but ≤ 3.0 x ULN (i.e. grade 1) 
at the time of registration: 
For ≥ 1.5 fold increase of ALT or AST and both ALT and AST are ≤ 5.0 x ULN, 
continue cabozantinib/placebo and consider weekly monitoring of LFTs. If LFTs continue 
to rise, delay cabozantinib/placebo (and consider checking LFTs weekly) until grade ≤ 1, 
then resume cabozantinib/placebo with one dose level reduction. 
For ≥ 1.5 fold increase of ALT or AST and 5.0 < ALT or AST ≤ 20.0 x ULN (i.e. either 
ALT or AST is grade 3), delay cabozantinib/placebo (and consider checking LFTs 
weekly) until grade ≤ 1, then resume cabozantinib/placebo with one dose level reduction. 
8.2.3.3 For all patients: 
For ALT or AST increases accompanied by progressive elevations of total bilirubin 
and/or elevations of coagulation tests, delay cabozantinib/placebo (and consider 
checking LFTs weekly) until total bilirubin < 1.5 x ULN, INR < 1.5 x ULN, and ALT or 
AST grade ≤ 1, then resume cabozantinib/placebo with one dose level reduction. 
For ALT or AST increases accompanied by bilirubin > 2 x ULN in the absence of 
biliary obstruction or other explanation, discontinue cabozantinib/placebo. 
8.2.4 
Proteinuria 
The UPC (urine protein to creatinine) Ratio directly correlates with the grams of protein 
found in a 24-hour urine. The UPC ratio based on a random urine sample can be used in 
place of a 24-hour urine. If the UPC Ratio is > 1, then a repeat UPC Ratio and a 24-hour 
urine protein and creatinine may need to be performed to confirm the result.  
UPC Ratio = Urine Protein Concentration (mg/dL) 
                       Creatinine Concentration (mg/dL) 
For UPC Ratio < 3.5 or urine protein < 3.5 g/24 hours, continue the same dose of 
cabozantinib/placebo.  
For UPC Ratio ≥ 3.5 or urine protein ≥ 3.5 g/24 hours, delay cabozantinib/placebo and 
check UPC weekly until proteinuria resolves to UPC < 1.5 or urine protein < 1.5 g/24 
hours, then resume cabozantinib/placebo with one dose level reduction. If treatment is 
delayed for more than one cycle (4 weeks) due to proteinuria, discontinue 
cabozantinib/placebo. 
For Nephrotic Syndrome (proteinuria ≥ 3.5 g/24 hours in combination with 
hypoalbuminemia, edema, and hyperlipidemia) or other relevant renal disease, 
discontinue cabozantinib/placebo. 
8.2.5 
Hypertension (HTN) 
• 
For patients who require a delay of greater than 4 weeks for management of 
hypertension, discontinue cabozantinib/placebo. 
• 
Patients may have up to 3 agents for management of hypertension prior to any dose 
reduction in cabozantinib/placebo. 
• 
24 to 48 hours should elapse between modifications of anti-hypertensive therapy. 

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• 
Treating physicians should not add antihypertensive medications that are strong 
inducers or inhibitors of CYP3A4. 
8.2.5.1 Persistent Grade 2 HTN (Systolic 140-159 mmHg, Diastolic 90-99 mmHg) 
Continue cabozantinib/placebo at the same dose level without interruption; however, 
please see below for recommendations on adding anti-hypertensive therapy agents. 
Recommended Antihypertensive Therapy 
1. Increase existing antihypertensive therapy or initiate a new antihypertensive agent 
if needed after 24-48 hours of treatment; increase dose in stepwise fashion every 
24-48 hours until BP is controlled or at the maximum dose of therapy. 
2. If BP is still not controlled, add another antihypertensive agent; increase dose of 
this drug as described in Step 1.   
3. If BP is still not controlled, add a 3rd agent; increase dose of this drug as described 
in Step 1. 
4. If BP is still not controlled after maximal medical management, proceed with one 
dose level reduction.  
8.2.5.2 Persistent Grade 3 HTN (Systolic ≥ 160 mmHg, Diastolic ≥ 100 mmHg)  
Delay cabozantinib/placebo until systolic BP ≤ 159 mmHg and diastolic BP ≤ 99 mmHg. 
Once blood pressure is controlled to this level, resume cabozantinib/placebo with one dose 
level reduction and consider the recommended antihypertensive therapy outlined above in 
Section 8.2.5.1. However, if the patient requires hospitalization for management of 
symptomatic systolic BP >180 or diastolic BP >110, then discontinue cabozantinib/placebo 
and recommend inpatient management as clinically indicated with IV medications. 
NOTE: Discontinuing or reducing the dose of cabozantinib/placebo is expected to cause a 
decrease in BP. The treating physician should monitor the patient for hypotension and 
adjust the number and dose of antihypertensive medication(s) accordingly. 
8.2.5.3 Grade 4 HTN (Life-threatening Consequences of Hypertension) 
Discontinue cabozantinib/placebo. Recommended management is in inpatient setting with 
ICU support and IV medication as clinically indicated; notify the hospital staff that 
discontinuing cabozantinib/placebo may result in a decrease in BP. 
8.2.6 
Thrombosis 
For grade 2 or 3 venous thrombosis requiring anticoagulation, delay 
cabozantinib/placebo. If the planned duration of full dose anticoagulation is ≤ 2 weeks, 
then delay cabozantinib/placebo until anticoagulation is completed. If the planned duration 
of full dose anticoagulation is > 2 weeks, then resume cabozantinib/placebo during 
anticoagulation therapy if all of the following are met: 
• 
The patient must have been on a stable dose of LMWH prior to restarting 
cabozantinib/placebo. Warfarin or a novel oral anticoagulation drug may not be 
used for anticoagulation. 
• 
The patient must not have any pathological condition that carries a high risk of 
bleeding.  
• 
The patient must not have had any hemorrhagic events while on study.  

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For 
recurrent/worsening 
venous 
thromboembolic 
events 
after 
resuming 
cabozantinib/placebo, discontinue cabozantinib/placebo. 
For grade 4 venous thromboembolic events, discontinue cabozantinib/placebo.  
For any grade arterial thromboembolic events including cerebrovascular ischemia, 
cardiac ischemia/infarction, peripheral or visceral arterial ischemia, discontinue 
cabozantinib/placebo. 
8.2.7 
Hemorrhage 
For grade 2 CNS or pulmonary hemorrhage, discontinue cabozantinib/placebo. 
For any other grade 3 or 4 hemorrhage, discontinue cabozantinib/placebo. 
8.2.8 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) 
For signs and symptoms suggestive of RPLS (e.g. confusion, headache, seizures, 
cortical blindness), delay cabozantinib/placebo. Suspected RPLS should be investigated 
with MRI. If RPLS is confirmed, discontinue cabozantinib/placebo.  
If RPLS is ruled out via MRI, then the decision to resume cabozantinib/placebo should be 
based on the signs and symptoms:  
• 
For grade 3 events, if symptoms resolve, resume cabozantinib/placebo with one 
dose level reduction. 
• 
For 
grade 
4 
events 
considered 
at 
least 
possibly 
related 
to 
cabozantinib/placebo, discontinue cabozantinib/placebo.  
8.2.9 
Fistula, Perforation, Bowel Obstruction, or Wound Dehiscence 
For any grade perforation of any organ, GI leak, or any fistula, discontinue 
cabozantinib/placebo.  
For any grade bowel obstruction requiring medical intervention, delay 
cabozantinib/placebo 
until 
obstruction 
resolves 
completely, 
then 
resume 
cabozantinib/placebo at the previous dose.  
For any grade bowel obstruction requiring surgery, delay cabozantinib/placebo for 28 
days (with full healing for at least 10 days), then resume cabozantinib/placebo at the 
previous dose.  
If cabozantinib/placebo is delayed for > 28 days due to any grade of bowel obstruction, 
discontinue cabozantinib/placebo.  
For wound dehiscence requiring medical or surgical intervention, discontinue 
cabozantinib/placebo. 
8.2.10 Gastrointestinal Toxicities 
For grade 2 diarrhea or nausea/vomiting that worsens or lasts ≥ 10 days, delay 
cabozantinib/placebo 
until 
toxicity 
improves 
to 
grade 
≤ 
1, 
then 
resume 
cabozantinib/placebo with one dose level reduction. 
For grade 3 diarrhea or nausea/vomiting, delay cabozantinib/placebo until toxicity 
improves to grade ≤ 1, then resume cabozantinib/placebo with one dose level reduction. 
For grade 4 diarrhea or nausea/vomiting, discontinue cabozantinib/placebo. 

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8.2.11 Thyroid Dysfunction 
For grade 3 hyper- or hypothyroidism, delay cabozantinib/placebo until toxicity 
improves to grade ≤ 2, then resume cabozantinib/placebo with one dose level reduction. 
For grade 4 hyper-or hypothyroidism, discontinue cabozantinib/placebo. 
8.2.12 Pancreatic Enzyme Increase/Pancreatitis 
For grade 2 pancreatitis, lipase, or amylase (see CTCAE version 5.0, Gastrointestinal 
Disorder), continue cabozantinib/placebo and consider more frequent monitoring of lipase 
and amylase and radiographic evaluation. 
For grade 3 pancreatitis, lipase, or amylase, delay cabozantinib/placebo until toxicity 
improves to grade ≤ 2, then resume cabozantinib/placebo with one dose level reduction. 
For grade 4 pancreatitis, lipase, or amylase, discontinue cabozantinib/placebo. 
8.2.13 Skin Toxicity 
Refer to Section 8.1.6 for guidance regarding supportive management of skin toxicity. 
For grade 1 palmar-plantar erythrodysesthesia (PPE) syndrome (hand-foot 
syndrome) that does not improve within 2 weeks or grade 2 PPE syndrome, continue 
cabozantinib/placebo 
with 
one 
dose level reduction 
and 
consider delaying 
cabozantinib/placebo treatment until PPE syndrome improves to grade ≤ 1. 
For grade 2 PPE syndrome that does not improve within 2 weeks or grade 3 PPE 
syndrome, delay cabozantinib/placebo until PPE syndrome improves to grade ≤ 1, then 
resume cabozantinib/placebo with one dose level reduction. 
For grade 3 PPE syndrome that does not improve within 4 weeks, discontinue 
cabozantinib/placebo. 
8.2.14 Mucositis and Stomatitis 
Refer to Section 8.1.8 for guidance regarding supportive care of mucositis and stomatitis. 
For grade 2 mucositis or stomatitis that is subjectively tolerable, continue 
cabozantinib/placebo and consider providing supportive care. 
For grade 2 mucositis or stomatitis that worsens, lasts ≥ 10 days, or interferes with 
adequate nutrition (and supportive care is insufficient), delay cabozantinib/placebo 
until toxicity improves to grade ≤ 1, then resume cabozantinib/placebo with one dose level 
reduction. 
For grade 3 mucositis or stomatitis that interferes with adequate nutrition (and 
supportive care is insufficient), delay cabozantinib/placebo until toxicity improves to 
grade ≤ 1, then resume cabozantinib/placebo with one dose level reduction. 
For grade 4 mucositis or stomatitis that interferes with adequate nutrition (and 
supportive care is insufficient), discontinue cabozantinib/placebo. 
8.2.15 Osteonecrosis of the Jaw 
To minimize the risk of osteonecrosis of the jaw, it is recommended that, if possible, 
cabozantinib/placebo be stopped at least 4 weeks prior to dental procedures such as tooth 
extractions, implants, and major jaw surgery whenever possible. In this scenario, 
cabozantinib/placebo may be held for up to 8 weeks. Cabozantinib/placebo does not need 
to be held for routine dental fillings and cleanings.  

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8.2.16 Cardiac Toxicity 
For QTc interval > 500 msecs, delay cabozantinib/placebo, stop any medications that may 
prolong the QTc interval (if possible), and consider checking calcium, potassium, and 
magnesium levels and correcting any abnormalities. Once QTc interval ≤ 500 msecs, 
correction of electrolyte abnormalities has been considered, and symptoms have resolved, 
cabozantinib/placebo may be resumed with one dose level reduction. 
8.2.17 Other Non-Hematologic Grade 3 or 4 Toxicity 
For other grade 3 non-hematologic toxicity not described above and considered at 
least possibly related to protocol treatment, delay cabozantinib/placebo until toxicity 
improves to grade ≤ 1, then resume cabozantinib/placebo with one dose level reduction.  
For patients on dose level -2 who experience recurrent other grade 3 non-hematologic 
toxicity (not described above), discontinue cabozantinib/placebo. 
For other grade 4 non-hematologic toxicity (not described above), discontinue 
cabozantinib/placebo. 
8.3 
Unblinding Procedures  
Unblinding can be done only in the event of an emergency or upon centrally-confirmed disease 
progression. Follow the directions below to unblind patient treatment. Please note that if a 
treatment assignment is unblinded due to an emergency, the patient must discontinue protocol 
therapy. 
8.3.1 
Emergency Unblinding Procedures 
Examples of emergencies include: 
• 
A life-threatening unexpected adverse event that is at least possibly related to the 
investigational agent and for which unblinding would influence treatment 
decisions 
• 
A medication error, such as accidental overdose  
Expected adverse events are listed in Section 9.0.  
Contact the Alliance Executive Officer on call by calling 
 
  
The institution must provide the following information to the Alliance Executive Officer:  
• 
Alliance Study ID (i.e. “A021602”)  
• 
Alliance Patient ID Number (e.g. “999999”)  
• 
Patient Initials (e.g. “L,FM”)  
• 
Institution Name  
• 
Name and telephone number of treating physician  
• 
Name and contact information of person requesting the unblinding procedure  
• 
Name and contact information of person to inform of treatment assignment  
• 
Reason for emergency unblinding  
Please remember that emergency unblinding request may be authorized only by an Alliance 
Executive Officer, and emergency unblinding applies only if unblinding would influence 

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management of the medical situation. After the Executive Officer deems unblinding is 
warranted, the treatment assignment will be provided to the contact person at the treating 
site. 
8.3.2 
Protocol-specified Unblinding Procedures 
The steps for unblinding a patient upon progression are as follows: 
1) Patient has an imaging scan that shows progression by RECIST v1.1 (except 
symptomatic deterioration) 
2) Site submits the radiologic images and local imaging report documenting 
progression to IROC Ohio within 24 hours of local determination of disease 
progression. Scans with a local determination of progressive disease should be 
labeled as “progression” when submitted to IROC. Sites should also communicate 
with IROC via email to inform IROC of the need for real-time radiology review 
for a case of progressive disease. IROC contact information can be found on the 
Study Resources page. 
3) IROC Ohio confirms disease progression by RECIST v1.1. 
4) The confirmation of disease progression is received by the site and the Alliance 
Statistics and Data Management Center. 
5) Site emails the Alliance Registration Office to unblind the patient; Registration 
Office confirms receipt of central confirmation of disease progression with 
Statistics and Data Management Center in order to communicate patient treatment 
assignment to site. 
Contact the Alliance Registration Office at 
. Upon confirmation by 
the Primary Statistician (or designee) that the criteria for progression have been met, the 
treatment assignment may be unblinded. No Alliance Executive Officer (or designee) 
approval is required. 
9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events 
(CTCAE), 
Version 
5.0. 
The 
CTCAE 
is 
available 
at 
 
Attribution 
to 
protocol treatment for each adverse event must be determined by the investigator and reported on the 
required forms. Please refer the NCI Guidelines: Adverse Event Reporting Requirements for further 
details on AE reporting procedures. 
To complement CTCAE reporting, patients will self-report their side effects using the PRO-CTCAE.  
The specific PRO-CTCAE items for this protocol can be found in Appendix I. They can also be found 
at: 
 
NOTE: PRO-CTCAE data should not be used for determining attribution, dose modifications, or 
reporting of serious adverse events.  
9.1 
Routine Adverse Event Reporting (Rave-CTEP-AERS) 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 

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times according to the Study Calendar in Section 5.0. For this trial, Adverse Events: Solicited is 
the Form used for routine AE reporting in Rave. 
PRO-CTCAE paper booklets ordered from the CTSU website are to be administered by a 
nurse/CRA and completed by the patient at scheduled times according to the Study Calendar in 
Section 5.0, and then entered into Rave by site staff. 
9.1.1 
Rave-CTEP-AERS Integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) Integration enables evaluation of post-baseline Adverse Events (AE) entered in 
Rave to determine whether they require expedited reporting and facilitates entry in CTEP-
AERS for those AEs requiring expedited reporting.    
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period and used to collect 
AEs that start during the period or persist from the previous reporting period. CRA will 
enter AEs that occur prior to the start of treatment on a baseline form that is not included 
in the Rave-CTEP-AERS integration. AEs that occur prior to enrollment must begin and 
end on the baseline Adverse Events form and should not be included on the standard 
Adverse Events form that is available at treatment unless there has been an increase in 
grade. 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
• 
The reporting period (course/cycle) is correct; and 
• 
AEs are recorded and complete (no missing fields) and the form is query free.  
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form. Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting. A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs that 
meet reporting requirements. The CRA completes the report by accessing CTEP-AERS via 
a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to be made 
to CTEP by telephone at 
Once internet connectivity is restored, the 24-hour 
notification that was phoned in must be entered immediately into CTEP-AERS using the 
direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the CTSU 
website: 
• 
Study specific documents: Protocols > Documents> Education and Promotion; and 
• 
Expedited Safety Reporting Rules Evaluation user guide: Resources > CTSU 
Operations Information> User Guides & Help Topics. 
NCI requirements for SAE reporting are available on the CTEP website: 
NCI Guidelines for Investigators: Adverse Event Reporting Requirements is available at 
 

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9.1.2 
Solicited Adverse Events 
The following adverse events are considered "expected" and their presence/absence should 
be solicited, and severity graded, at baseline and for each cycle of treatment by CTCAE, 
PRO-CTCAE, or both (with the exception of Day 15 of Cycles 1 and 2 for CTCAE). 
CTCAE v5.0 Term 
PRO-CTCAE v1.0 Term 
CTCAE v5.0 System Organ 
Class (SOC) 
Neutrophil count decreased 
 
Investigations 
Platelet count decreased 
 
Investigations 
Alanine aminotransferase increased 
 
Investigations 
Aspartate aminotransferase increased  
Investigations 
Palmar-plantar erythrodysesthesia 
syndrome 
Hand-foot syndrome (a rash 
of the hands or feet that can 
cause cracking, peeling, 
redness, or pain) 
Skin and subcutaneous tissue 
disorders 
Rash maculo-papular 
Rash 
Skin and subcutaneous tissue 
disorders 
Hyperglycemia 
 
Metabolism and nutrition 
disorders 
Hypothyroidism 
 
Endocrine disorders 
Hypertension 
 
Vascular disorders 
Fatigue 
Fatigue, tiredness, or lack of 
energy 
General disorders and 
administration site conditions 
Diarrhea 
Loose or watery stools 
(diarrhea) 
Gastrointestinal disorders 
Mucositis oral 
Mouth or throat sores 
Gastrointestinal disorders 
 
Problems with tasting food or 
drink 
Gastrointestinal disorders 
 
Decreased appetite 
Gastrointestinal disorders 
 
Nausea 
Gastrointestinal disorders 
9.2 
CTCAE Routine Reporting Requirements 
In addition to the solicited adverse events listed in Section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to the 
Alliance Statistics and Data Management Center. Questions about routine reporting should be 
directed to the Data Manager.  
NOTE: PRO-CTCAE data should not be used for determining attribution, dose modifications, 
or reporting of serious adverse events. 
Combinations of CTCAE Grade & Attribution Required for Routine AE Data Submission on 
Case Report Forms (CRFs) 
 
 

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Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
a 
a 
a 
a 
Unlikely 
 
a 
a 
a 
a 
Possible 
 
a, b 
a, b 
a, b 
a, b 
Probable 
 
a, b 
a, b 
a, b 
a, b 
Definite 
 
a, b 
a, b 
a, b 
a, b 
a) 
Adverse Events: Other CRF - Applies to AEs occurring between registration and within 30 
days of the patient’s last treatment date, or as part of the Clinical Follow-Up Phase. 
b) 
Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date. 
9.3 
Expedited Adverse Event Reporting (Rave-CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. Alliance investigators are required to notify the Alliance Central Protocol 
Operations Program, the Study Chair, and their Institutional Review Board if a patient has a 
reportable serious adverse event. The descriptions and grading scales found in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. 
The 
CTCAE 
is 
identified 
and 
located 
on 
the 
CTEP 
website 
at: 
All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0.  
For further information on the NCI requirements for SAE reporting, please refer to the ‘NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements’ document published by 
the NCI.  
Note: All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause should be provided. 
NOTE: PRO-CTCAE data should not be used for determining attribution, dose modifications, 
or reporting of serious adverse events.  
9.3.1 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE ≤ 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
5) A congenital anomaly/birth defect  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6) 

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ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via electronic submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours 
of learning of the AE, followed by a complete expedited report within 5 calendar days of the 
initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted electronically 
within 10 calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4 and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-
lives, rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote 
“1” above applies after this reporting period. 
Effective Date: May 5, 2011 
 
9.3.2 
Expedited AE Reporting Timelines Defined 
“24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS ≤ 24 hours of learning of the event followed by a complete CTEP-AERS report ≤ 5 
calendar days of the initial 24-hour report. 
“10 calendar days” - A complete CTEP-AERS report on the AE must be submitted ≤ 10 
calendar days of the investigator learning of the event.  
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 

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designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions (see below). 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs following 
treatment with an agent under a CTEP IND. 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
9.3.3 
Additional Instructions or Exclusion to CTEP-AERS Expedited Reporting 
Requirements for Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or 
non-CTEP IND 
All adverse events reported via CTEP-AERS (i.e. serious adverse events) should also be 
forwarded to your local IRB. 
Alliance A021602 uses a drug under a CTEP IND. The reporting requirements for 
investigational agents under a CTEP IND should be followed for all agents (any arm) in 
this trial. 
Grade 3/4 hematosuppression and hospitalization resulting from such do not require CTEP-
AERS, but should be submitted as part of study results. All other grade 3, 4, or 5 adverse 
events that precipitate hospitalization or prolong an existing hospitalization must be 
reported via CTEP-AERS. 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.” 
Evidence that the death was a manifestation of underlying disease (e.g. radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours.  
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, 
probably, or definitely related to the investigational agent/intervention. 
All new malignancies must be reported via CTEP-AERS whether or not they are thought 
to be related to either previous or current treatment. All new malignancies should be 
reported, i.e. solid tumors (including non-melanoma skin malignancies), hematologic 
malignancies, myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors. 
In CTCAE version 5.0, the new malignancies (both second and secondary) may be reported 
as one of the following: (1) Leukemia secondary to oncology chemotherapy, (2) 
Myelodysplastic syndrome, or (3) Treatment-related secondary malignancy. Whenever 
possible, the CTEP-AERS reports for new malignancies should include tumor pathology, 
history or prior tumors, prior treatment/current treatment including duration, any associated 
risk factors or evidence regarding how long the new malignancy may have been present, 
when and how the new malignancy was detected, molecular characterization or 
cytogenetics of the original tumor (if available) and of any new tumor, and new malignancy 
treatment and outcome, if available. New primary malignancies should also be reported 
using study Form, Notice of New Primary. 
Treatment expected adverse events include those listed in Section 10.0 and in the package 
insert. 

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CTEP-AERS reports should be submitted electronically. 
Pregnancy loss: 
• 
Pregnancy loss is defined in CTCAE as “Death in utero.” 
• 
Any Pregnancy loss should be reported expeditiously, as Grade 4 “Pregnancy loss” 
under the Pregnancy, puerperium and perinatal conditions SOC. 
• 
A Pregnancy loss should NOT be reported as a Grade 5 event under the Pregnancy, 
puerperium and perinatal conditions SOC, as currently CTEP-AERS recognizes 
this event as a patient death. 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the 
General disorders and administration SOC. 
9.4 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Cabozantinib 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that 
are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer 
to 
the 
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
for 
further clarification. Frequency is provided based on 3219 patients. Below is the CAEPR for 
XL184 (Cabozantinib). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next 
to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
Version 2.4, December 17, 20181 
 
 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
ENDOCRINE DISORDERS 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
 
Gastrointestinal fistula2 
  
 
 
Gastrointestinal 
hemorrhage3 
  

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 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
 
 
Gastrointestinal 
perforation4 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Oral pain 
 
 Oral pain (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Lipase increased 
 
 Lipase increased (Gr 4) 
 
Platelet count decreased 
 
 Platelet count decreased  
(Gr 3) 
Weight loss 
 
 
 Weight loss (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
  
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
 
Hypophosphatemia 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Generalized muscle 
weakness 
 
  
 
Muscle cramp 
 
  
 
 
Osteonecrosis of jaw 
  
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
Dysgeusia 
 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
  
 
 
Intracranial hemorrhage    
 
 
Ischemia 
cerebrovascular 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
 
 
Stroke 
  

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 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
 
 
Transient ischemic 
attacks 
  
RENAL AND URINARY DISORDERS 
  
 
Hematuria 
 
  
 
 
Proteinuria 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
 
 
Pneumothorax6 
  
 
 
Respiratory fistula7 
  
 
Respiratory hemorrhage8 
 
  
 
Voice alteration 
 
 Voice alteration (Gr 3) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Hair color changes 
 
 Hair color changes (Gr 1) 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
 
 Palmar-plantar 
erythrodysesthesia 
syndrome (Gr 3) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event9 
 
  
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
 Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Enterovesical fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, 
Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS 
SOC. 
 
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
5Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
6Pneumothorax has been observed at a higher than expected frequency (15-20%) in a study treating 
patients with relapsed Ewing sarcoma and osteosarcoma all of whom had pulmonary metastases. 

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7Respiratory fistula includes Bronchial fistula, Bronchopleural fistula, Laryngeal fistula, Pharyngeal fistula, 
Pulmonary fistula, and Tracheal fistula under the RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS SOC. 
 
8Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Hemoptysis, Laryngeal 
hemorrhage, Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS SOC. 
 
9Thromboembolic event includes pulmonary embolism which may be life-threatening.  
 
Adverse events reported on XL184 (Cabozantinib) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that XL184 (Cabozantinib) caused the 
adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Eosinophilia; Febrile neutropenia; Hemolytic 
uremic syndrome 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Cardiac arrest; Cardiac 
disorders - Other (hypokinetic cardiomyopathy); Chest pain - cardiac; Heart failure; Left ventricular 
systolic dysfunction; Myocardial infarction; Myocarditis; Sinus bradycardia; Sinus tachycardia; 
Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (autoimmune thyroiditis); Endocrine disorders - 
Other (thyroiditis); Endocrine disorders - Other (thyrotoxicosis); Hyperthyroidism; Hypopituitarism 
EYE DISORDERS - Blurred vision; Cataract; Eye disorders - Other (corneal epithelium defect) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal fissure; Anal mucositis; Anal pain; 
Anal ulcer; Cheilitis; Colitis; Colonic obstruction; Duodenal ulcer; Dysphagia; Enterocolitis; Esophageal 
ulcer; Esophagitis; Flatulence; Gastric ulcer; Gastroesophageal reflux disease; Gastrointestinal disorders 
- Other (glossitis); Gastrointestinal disorders - Other (pneumoperitoneum); Gastrointestinal pain; Gingival 
pain; Hemorrhoids; Ileus; Pancreatitis; Periodontal disease; Rectal pain; Rectal ulcer; Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Edema face; 
Fever; Gait disturbance; General disorders and administration site conditions - Other (general physical 
health deterioration); General disorders and administration site conditions - Other (implant site 
inflammation); Hypothermia; Malaise; Multi-organ failure; Non-cardiac chest pain; Pain; Sudden death 
NOS 
HEPATOBILIARY DISORDERS - Budd-Chiari syndrome; Cholecystitis; Hepatic failure; Hepatobiliary 
disorders - Other (cholelithiasis); Hepatobiliary disorders - Other (hepatic cirrhosis); Hepatobiliary 
disorders - Other (hepatic thrombus); Hepatobiliary disorders - Other (hepatitis toxic); Hepatobiliary 
disorders - Other (hepatorenal syndrome); Portal vein thrombosis 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Autoimmune disorder 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and procedural 
complications - Other (post procedural hemorrhage); Injury, poisoning and procedural complications - 
Other (tendon injury); Wound dehiscence; Wrist fracture 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Blood lactate 
dehydrogenase increased; CPK increased; Cardiac troponin I increased; Creatinine increased; Ejection 
fraction decreased; Electrocardiogram QT corrected interval prolonged; GGT increased; Investigations - 
Other (D-dimer); Investigations - Other (urine ketone body present); Lymphocyte count decreased; 
Neutrophil count decreased; Serum amylase increased; Thyroid stimulating hormone increased; White 
blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Glucose intolerance; Hyperglycemia; Hypernatremia; 
Hyperuricemia; Hypoalbuminemia; Hyponatremia; Metabolism and nutrition disorders - Other (failure to 
thrive); Metabolism and nutrition disorders - Other (hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Buttock pain; Chest wall 
pain; Flank pain; Muscle weakness lower limb; Musculoskeletal and connective tissue disorder - Other 
(muscle hemorrhage); Myalgia; Neck pain; Osteonecrosis; Osteoporosis; Rhabdomyolysis 

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NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (lip and/or oral cavity cancer); Tumor 
hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Concentration impairment; Dysarthria; 
Dysesthesia; Dysphasia; Encephalopathy; Lethargy; Memory impairment; Nervous system disorders - 
Other (hemiparesis); Nervous system disorders - Other (vocal cord paralysis); Peripheral motor 
neuropathy; Peripheral sensory neuropathy; Presyncope; Seizure; Somnolence; Spinal cord 
compression; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; Insomnia; 
Psychiatric disorders - Other (mental status changes) 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Glucosuria; Renal 
and urinary disorders - Other (hemorrhage urinary tract); Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain; Reproductive system and breast 
disorders - Other (scrotal ulcer/erythema/edema); Scrotal pain; Vaginal fistula; Vaginal inflammation; 
Vaginal perforation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Aspiration; Atelectasis; Hoarseness; Hypoxia; Laryngeal edema; Oropharyngeal pain; 
Pharyngeal mucositis; Pleural effusion; Pneumonitis; Productive cough; Pulmonary hypertension; 
Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (nasal septum perforation); 
Respiratory, thoracic and mediastinal disorders - Other (pneumomediastinum); Respiratory, thoracic and 
mediastinal disorders - Other (rales); Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Nail changes; Pain of skin; 
Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (pain, sloughing of skin and 
erythema); Skin and subcutaneous tissue disorders - Other (psoriasis); Skin hypopigmentation; Skin 
ulceration 
VASCULAR DISORDERS - Hematoma; Hypotension; Superior vena cava syndrome; Vascular disorders 
- Other (bleeding varicose vein); Vasculitis 
 
Note: XL184 (Cabozantinib) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
10.0 DRUG INFORMATION 
10.1 
Cabozantinib (Cabometyx, XL184, IND# 137656, NSC #761968, IND Holder: DCTD, 
NCI) 
Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by eligible participating Investigators (or their authorized 
designee) at each participating institution. The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents. The eligible participating investigators at 
each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF). If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead participating investigator at that institution. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application. 
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status, a “current” password, and active 
person registration status. For questions about drug orders, transfers, returns, or accountability, 
call or email PMB any time. Refer to the PMB’s website for specific policies and guidelines 
related to agent management.   

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Availability 
Cabozantinib and matching placebo will be provided free of charge by Exelixis and distributed 
by the Pharmaceutical Management Branch (PMB), Cancer Therapy Evaluation Program 
(CTEP), Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI).  
Cabozantinib (NSC 761968) is supplied as 20 mg tablets. The 20 mg and matching placebo 
tablets are round, yellow film coated containing microcrystalline cellulose, lactose anhydrous, 
hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, 
and Opadry yellow film coating. Cabozantinib and placebo tablets are packaged as 30 tablets 
per bottle. 
Each blinded, patient-specific bottle will be labeled with: 
• 
The protocol number (i.e. A021602) 
• 
The bottle number (i.e. “Bottle 1 of 6”, “Bottle 2 of 6”, etc.) 
• 
The number of tablets (i.e. “30 tablets”) 
• 
The patient ID number (e.g. "999999") 
• 
The patient initials (i.e. Last initial, First initial, Middle initial [e.g. “L, FM”]) 
• 
The agent identification (i.e. “Cabozantinib 20 mg or Placebo”) 
• 
A blank line for the pharmacist to enter the patient’s name 
• 
Administration instructions (i.e. “Take ____ tablets daily.”) 
• 
Storage instructions (i.e. “Store at Controlled Room Temperature 20° to 25°C.”) 
• 
Emergency contact instructions 
• 
A Julian date 
 
Julian Dating 
The Julian date indicates the day the bottle was labeled and shipped and is composed of the last 
two digits of the calendar year (e.g. 2017 = 17, 2018 = 18) and a day count (e.g. January 1 = 
001, December 31 = 365). For example, a bottle labeled and shipped on January 1, 2017 would 
have a Julian date of ‘17001’ and a bottle labeled and shipped on December 31, 2017 would 
have a Julian date of ‘17365’. The Julian date will be used by PMB for recalls. When a lot 
expires, PMB will determine the last date the expired lot was shipped and will recall all bottles 
(i.e. both cabozantinib and placebo) shipped on or before that date thus eliminating any chance 
of breaking the blind. The Julian Date – Order number (e.g. 17352-0003) from the patient-
specific label must be used as the Lot number on the NCI Oral DARF. 
Storage and Stability 
Store intact bottles at controlled room temperature, 20⁰C to 25⁰C; excursions permitted from 
15⁰C to 30⁰C (59⁰F to 86⁰F). Stability testing of the intact bottles is on-going. Dispense 
cabozantinib (XL 184)/placebo in the original container. Cabozantinib/placebo is stable for up 
to 24 hours when dispensed in an open container, such as a pill cup, and for up to 7 days when 
dispensed in a closed container, such as a pharmacy bottle other than the original container. 

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Administration 
Cabozantinib/placebo is taken orally on an empty stomach. Fasting is required for at least 2 
hours before and at least 1 hour after each dose of cabozantinib/placebo. Do not crush or chew. 
Do not take a missed dose within 12 hours of the next dose. Cabozantinib/placebo should not 
be taken with grapefruit/grapefruit juice or Seville oranges. 
Initial Supply 
No blinded starter supplies will be available for this study. Blinded, patient specific clinical 
supplies will be sent to the registering investigator at the time of randomization and should arrive 
within approximately 7 to 10 days. This randomization will be performed by the Alliance 
Statistics and Data Management Center. The assigned Alliance patient ID number must be 
recorded by the registering institution for proper bottle dispersion. Once a patient has been 
registered, the Alliance Statistics and Data Management Center will electronically transmit a 
clinical drug request for that patient to the PMB. This request will be entered and transmitted 
by the Alliance Statistics and Data Management Center the day the patient is registered and will 
be processed by the PMB the next business day and shipped the following business day. 
Shipments within the United States will be sent by FedEx Ground and shipments to Canada (if 
participating) will be sent by FedEx (generally one to two day delivery). For example, if a patient 
is randomized on Monday, PMB will receive the order Tuesday and ship Wednesday. Shipments 
to United States sites can be expedited (i.e. receipt on Thursday in example above) by the 
provision of an express courier account name and number to the Alliance Statistics and Data 
Management Center at the time the patient is registered. Orders to destinations within the United 
States are shipped Monday through Thursday. Orders to destinations within Canada are shipped 
Monday through Wednesday. 
The initial request will be for 6 bottles of cabozantinib/placebo 20 mg. Approximately 2 weeks 
after Cycle 2 begins (2 weeks before needed), sites may reorder an additional 6 bottles [a 2 cycle 
(8 week) supply at a dose of 3 tablets given once daily] of cabozantinib/placebo 20 mg using 
the 
PMB 
Online 
Agent 
Order 
Processing 
(OAOP) 
application 
 Access to OAOP requires the establishment of a 
CTEP Identity and Access Management (IAM) account 
 
the maintenance of an “active” account status, and a “current” password. The assigned patient 
ID number (e.g. "999999") and the patient initials (e.g. "L, FM") must be entered in the "Patient 
or Special Code" field. A separate order is required for each patient ID number (e.g. "999999") 
being ordered. All drug orders will be shipped directly to the physician responsible for treating 
the patient. 
Study drug cannot be shipped post-distribution. 
In the event of a patient institution transfer, the site to which the patient transferred cannot order 
study drug until the patient is officially transferred through the CTSU. 
Initial Supply – Open-Label (Unblinded): For Crossover Patients Only 
No open-label starter supplies will be available for this study. Open-label (unblinded), patient 
specific clinical supplies will be sent to the registering investigator at the time of re-registration 
and should arrive within approximately 7 to 10 days. Once a patient has been re-registered, the 
Alliance Statistics and Data Management Center will electronically transmit a clinical drug 
request for that patient to the PMB. This request will be entered and transmitted by the Alliance 
Statistics and Data Management Center the day the patient is re-registered and will be processed 
by the PMB the next business day and shipped the following business day. Shipments within 
the United States will be sent by FedEx Ground and shipments to Canada (if participating) will 
be sent by FedEx (generally one to two day delivery). For example, if a patient is reregistered 

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on Monday, PMB will receive the order Tuesday and ship Wednesday. Shipments to United 
States sites can be expedited (i.e. receipt on Thursday in example above) by the provision of an 
express courier account name and number to the Alliance Statistics and Data Management 
Center at the time the patient is re-registered. Orders to destinations within the United States are 
shipped Monday through Thursday. Orders to destinations within Canada are shipped Monday 
through Wednesday. 
The initial request will be for 6 bottles of cabozantinib 20 mg. Approximately 2 weeks after the 
second cycle begins (2 weeks before needed), sites may reorder an additional 6 bottles [a 2 cycle 
(8 week) supply at a dose of 3 tablets given once daily] of cabozantinib 20 mg using the PMB 
Online 
Agent 
Order 
Processing 
(OAOP) 
application 
 Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
the maintenance of an “active” account status, and a “current” password. 
The assigned patient ID number (e.g. "999999") and the patient initials (e.g. "L, FM") must be 
entered in the "Patient or Special Code" field. A separate order is required for each patient ID 
number (e.g. "999999") being ordered. All drug orders will be shipped directly to the physician 
responsible for treating the patient. 
Study drug cannot be shipped post-distribution. 
In the event of a patient institution transfer, the site to which the patient transferred cannot order 
study drug until the patient is officially transferred through the CTSU. 
Drug Transfers 
Tablets MAY NOT be transferred from one patient to another patient or from one protocol to 
another protocol. All other transfers (e.g. a patient moves from one participating clinical site to 
another participating clinical site, the principal investigator at a given clinical site changes) must 
be approved in advance by the PMB. To obtain an approval for transfer, investigators should 
complete and submit to the PMB 
a Transfer Investigational Agent 
Form available on the CTEP home page 
or by calling the PMB at 
 
The patient ID number (e.g. "99999"') and the patient initials (e.g. "L, FM") should 
be entered in the "Received on NCI Protocol No." and the "Transferred to NCI Protocol No." 
fields in addition to the protocol number (i.e. "A021602"). 
Drug Returns 
When it is necessary to return undispensed study drug (e.g. sealed or partial bottles remaining 
when a patient permanently discontinues protocol treatment, expired bottles recalled by the 
PMB), Investigators should return the study drug to the PMB using the NCI Return Drug List 
available on the CTEP home page 
 or by calling the PMB at 
 
The patient ID number (e.g. "99999") and the patient initials (e.g. "L, FM") should be 
entered in the "Lot Number" field. 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing, and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page. Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation, and ordering investigator on this protocol. 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application. Access to OAOP requires the establishment of a 

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CTEP IAM account and the maintenance of an “active” account status, and a “current” password 
and active person registration status. Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents: 
 
• 
NCI CTEP Investigator Registration: 
  
• 
PMB Online Agent Order Processing (OAOP) Application: 
   
• 
 
 
• 
CTEP Associate Registration and IAM Account Help: 
   
• 
IB Coordinator: 
  
• 
PMB Email: 
 
• 
PMB Phone and Hours of Service: 
 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
Drug Interactions 
Cabozantinib is a substrate of CYP3A4. Coadministration of cabozantinib with medications that 
are strong inhibitors/inducers of CYP3A4 should be avoided. Administration of a strong 
CYP3A4 inducer, rifampin (600 mg daily for 31 days), to healthy subjects decreased single-
dose plasma cabozantinib exposure (AUC) by 77%. Examples of strong CYP3A4 inducers are 
carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampentin, rifampin, and 
St. John’s Wort. Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 
27 days), to healthy subjects increased single-dose plasma cabozantinib exposure (AUC) by 
38%. Strong CYP3A4 inhibitors are boceprevir, clarithromycin, conivaptan, grapefruit juice, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telithromycin, and voriconazole. Avoid grapefruit/grapefruit juice and 
Seville oranges while participating in this trial.  
Coadministration of gastric pH modifying drugs such as PPIs, H2-blockers, or antacids has no 
clinically-relevant effect on cabozantinib plasma PK in healthy volunteers; thus, concomitant 
use of these drugs with XL184 (cabozantinib) is allowed. 
Cabozantinib is highly protein bound, 99.9%. Use caution when coadministering cabozantinib 
with medications that are highly protein-bound (e.g. diazepam, furosemide, dicloxacillin, and 
propranolol). Administration of warfarin with cabozantinib is not allowed as warfarin is highly 
protein-bound and has a very narrow therapeutic index. 
Drugs that prolong the QTc interval should be avoided or replaced if possible, as cabozantinib 
can prolong the QTC interval. Patients who receive potential QTc-prolonging medications (see 
Appendix V) should be monitored closely. 
P-glycoprotein (P-gp) substrates (e.g. fexofenadine, aliskiren, ambrisentan digoxin, colchicine, 
maraviroc, posaconazole, tolvaptan, etc.) should be used with caution during treatment with 
cabozantinib as coadministration can cause increased P-gp substrate levels. 
MRP2 inhibitors (e.g. cyclosporine, delavirine, efavirenz, emtricitabine, etc.) should be used 
with caution during treatment with cabozantinib as coadministration can cause increased 
cabozantinib plasma concentrations.   

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Pharmacokinetics 
Distribution: Vd: ~319 L 
Protein Binding: ≥ 99.7% to plasma proteins 
Metabolism: Hepatic via CYP3A4 
Half-life Elimination: ~99 hours 
Time to Peak: ~2-5 hours 
Excretion: Feces (54%); urine (27%) 
Adverse Events 
Please refer to the CAEPR in Section 9.4. 
Nursing Guidelines 
Instruct patients to take on an empty stomach. They should be fasting 2 hours prior and 1 hour 
after taking the agent. 
Instruct patients to not crush or chew tablets. 
Do not take the agents with grapefruit/grapefruit juice or Seville oranges. 
The agent has many drug-to-drug interactions. Assess patient’s medication list including OTC 
and herbal products. Instruct patient to report any new medications to the study team 
immediately. 
Surgery (including dental work) should be avoided with 28 days of last dose of agent, if at all 
possible.  
Patients may experience hypertension. Monitor BP as required per protocol and instruct patients 
to make sure they continue any prescribed antihypertensives. 
Warn patients of possible changes to hair color.  
Monitor electrolytes closely, especially calcium as hypocalcemia is common. 
Patients may experience GI side effects including, but not limited to: abdominal pain, 
constipation, anorexia, dysgeusia, diarrhea, and nausea/vomiting. Treat symptomatically and 
monitor for effectiveness of any intervention. Diarrhea may be treated with loperamide 4 mg po 
at the first onset of diarrhea, and then with loperamide 2 mg po every 2 hours until the patient 
is diarrhea-free for 12 hours. 
Monitor CBC with diff. as cytopenias are common. Instruct patients to report any signs or 
symptoms of infection and/or bruising/bleeding to the study team immediately. 
Monitor LFTs. 
Warn of possible hand-foot syndrome (PPE). Instruct patient to report pain, skin changes, etc. 
to the study team. 
Rarely, pulmonary embolism and other arterial thromboembolism has been reported.  
 
 
 

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11.0 MEASUREMENT OF EFFECT 
Response and progression will be evaluated in this study using the new international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1).  
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the short 
axis measurements in the case of lymph nodes are used in the RECIST guideline [38]. 
11.1 
Schedule of Evaluations 
For the purposes of this study, patients should be reevaluated every 12 weeks (+/- 1 week).   
Supporting documentation of response should be submitted per Section 6.1.1, and radiologic 
images and local interpretation reports should be submitted per Section 6.3.  
11.2 
Definitions of Measurable and Non-Measurable Disease 
11.2.1 Measurable Disease 
A non-nodal lesion is considered measurable if its longest diameter can be accurately 
measured as ≥ 2.0 cm with chest x-ray, or as ≥1.0 cm with CT scan or MRI. 
A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm in diameter 
as assessed using calipers (e.g. skin nodules) on imaging. In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
A malignant lymph node is considered measurable if its short axis is >1.5 cm when 
assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm).   
Tumor lesions in a previously irradiated area are considered measurable disease if there 
has been evidence of disease progression in the previously irradiated area in the 6 months 
prior to registration. 
11.2.2 Non-measurable Disease 
Non-measurable disease includes disease smaller than these dimensions or lesions 
considered truly non-measurable including: leptomeningeal disease, ascites, pleural or 
pericardial effusion, lymphangitic involvement of skin or lung.  
11.3 
Guidelines for Evaluation of Measurable Disease 
11.3.1 Measurement Methods 
All measurements should be recorded in metric notation (i.e. decimal fractions of 
centimeters) using a ruler or calipers. 
The same method of assessment and the same technique must be used to characterize each 
identified and reported lesion at baseline and during restaging. For patients having only 
lesions measuring at least 1 cm to less than 2 cm must use CT imaging for both pre- and 
post-treatment tumor assessments.   
Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used at the same evaluation to assess the antitumor effect of a treatment.  
11.3.2 Acceptable Modalities for Measurable Disease 
• 
Conventional CT and MRI: This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less.  

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o As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type 
and site of disease. The lesions should be measured on the same pulse 
sequence. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
• 
Chest X-ray: Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung. However, CT scans are 
preferable. 
11.3.3 Measurement at Follow-up Evaluation   
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
Cytologic and histologic techniques can be used to differentiate between PR and CR in rare 
cases (e.g. residual lesions in tumor types such as germ cell tumors, where known residual 
benign tumors can remain.) 
11.4 
Measurement of Treatment/Intervention Effect 
11.4.1 Target Lesions & Target Lymph Nodes 
Measurable lesions (as defined in Section 11.2.1) up to a maximum of 5 lesions, 
representative of all involved organs, should be identified as “Target Lesions” and recorded 
and measured at baseline. These lesions can be non-nodal or nodal (as defined in Section 
11.2.1), where no more than 2 lesions are from the same organ and no more than 2 
malignant nodal lesions are selected.  
Note: If fewer than 5 target lesions and target lymph nodes are identified (as there often 
will be), there is no reason to perform additional studies beyond those specified in the 
protocol to discover new lesions.   
Target lesions and target lymph nodes should be selected on the basis of their size, be 
representative of all involved sites of disease, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, 
the largest lesion (or malignant lymph node) does not lend itself to reproducible 
measurements in which circumstance the next largest lesion (or malignant lymph node) 
which can be measured reproducibly should be selected.   
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all target lesions 
plus the sum of the short axis of all the target lymph nodes will be calculated and reported 
as the baseline sum of dimensions (BSD). The BSD will be used as reference to further 
characterize any objective tumor response in the measurable dimension of the disease.   
Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will be calculated 
and reported as the post-baseline sum of dimensions (PBSD). If the radiologist is able to 
provide an actual measure for the target lesion (or target lymph node), that should be 
recorded, even if it is below 0.5 cm. If the target lesion (or target lymph node) is believed 
to be present and is faintly seen but too small to measure, a default value of 0.5 cm should 

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be assigned. If it is the opinion of the radiologist that the target lesion or target lymph node 
has likely disappeared, the measurement should be recorded as 0 cm. 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and the PBSD. 
11.4.2 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease are classified as non- target lesions or non-target lymph 
nodes and should also be recorded at baseline. These lesions and lymph nodes should be 
followed in accord with Section 11.4.3. 
11.4.3 Response Criteria 
All target lesions and target lymph nodes followed by CT/MRI/Chest X-ray must be 
measured on re-evaluation at evaluation times specified in Section 11.1. Specifically, a 
change in objective status to either a PR or CR cannot be done without re-measuring target 
lesions and target lymph nodes.  
Note: Non-target lesions and non-target lymph nodes should be evaluated at each 
assessment, especially in the case of first response or confirmation of response. In selected 
circumstances, certain non-target organs may be evaluated less frequently. For example, 
bone scans may need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
• 
Evaluation of Target Lesions 
o Complete Response (CR): All of the following must be true: 
▪ 
Disappearance of all target lesions. 
▪ 
Each target lymph node must have reduction in short axis to < 1.0 
cm. 
o Partial Response (PR): At least a 30% decrease in PBSD (sum of the 
longest diameter for all target lesions plus the sum of the short axis of all 
the target lymph nodes at current evaluation) taking as reference the BSD 
(see Section 11.4.1). 
o Progression (PD): At least one of the following must be true: 
▪ 
At least one new malignant lesion, which also includes any lymph 
node that was normal at baseline (< 1.0 cm short axis) and 
increased to ≥ 1.0 cm short axis during follow-up.  
▪ 
At least a 20% increase in PBSD (sum of the longest diameter for 
all target lesions plus the sum of the short axis of all the target 
lymph nodes at current evaluation) taking as reference the MSD 
(Section 11.4.1).  In addition, the PBSD must also demonstrate an 
absolute increase of at least 0.5 cm from the MSD.  
o Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor 
sufficient increase to qualify for PD taking as reference the MSD. 
• 
Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
o Complete Response (CR): All of the following must be true: 
▪ 
Disappearance of all non-target lesions.  
▪ 
Each non-target lymph node must have a reduction in short axis 
to <1.0 cm. 

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o Non-CR/Non-PD: Persistence of one or more non-target lesions or non-
target lymph nodes  
o Progression (PD): At least one of the following must be true: 
▪ 
At least one new malignant lesion, which also includes any lymph 
node that was normal at baseline (< 1.0 cm short axis) and 
increased to ≥ 1.0 cm short axis during follow-up.   
▪ 
Unequivocal progression of existing non-target lesions and non-
target lymph nodes.  (NOTE:  Unequivocal progression should not 
normally trump target lesion and target lymph node status.  It must 
be representative of overall disease status change.)  
11.4.4 Overall Objective Status 
The overall objective status for an evaluation is determined by combining the patient’s 
status on target lesions, target lymph nodes, non-target lesions, non-target lymph nodes, 
and new disease as defined in the following table:  
For Patients with Measurable Disease  
Target Lesions & 
Target Lymph Nodes 
Nontarget Lesions & 
Nontarget Lymph Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated (NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
* 
See Section 11.4.3 

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11.4.5 Symptomatic Deterioration  
Patients with global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time, and not either related to 
study treatment or other medical conditions, should be reported as “symptomatic 
deterioration” on the corresponding Case Report Form in Rave. Every effort should be 
made to document the objective progression even after discontinuation of treatment due to 
symptomatic deterioration, and radiologic imaging should continue to be collected every 
12 weeks until disease progression (or start of a new anticancer therapy); see Section 5.0. 
11.5 
Definitions of Analysis Variables 
Formal definitions of variables used in analyses can be found in the Statistical Considerations 
section (Section 13.0) of the protocol. 
12.0 END OF TREATMENT/INTERVENTION 
12.1 
Duration of Treatment  
Patients will receive treatment until disease progression, unacceptable toxicity, or withdrawal 
of consent. Patients initially randomized to placebo who experience centrally-confirmed 
progressive disease (PD) may elect to crossover to open-label cabozantinib; see Section 3.3 and 
Section 4.8. 
12.1.1 CR, PR, or SD 
Patients who are in CR, PR or SD will continue treatment at the highest tolerable dose until 
the appearance of disease progression, unacceptable toxicity, or withdrawal of consent.   
After treatment is discontinued, patients will be followed per Section 12.1.3. 
12.1.2 Disease Progression 
Patients should be given a minimum of 3 cycles of protocol therapy. 
Patients who progress on blinded therapy may be unblinded, and, if randomized to placebo, 
they will be allowed to crossover to open-label cabozantinib; see Section 8.3.  
Document details of progression, including tumor measurements, on data forms. 
Patients who progress on blinded therapy who do not crossover and patients who 
experience disease progression on open-label cabozantinib should be followed for survival 
per Section 5.0.  
12.1.3 Discontinuation of Study Agent 
If the patient discontinues cabozantinib/placebo due to disease progression, then the patient 
should crossover to open-label cabozantinib (if applicable) or the patient should be 
followed for survival per the Study Calendar (Section 5.0). If the patient discontinues 
cabozantinib/placebo for a reason other than disease progression, then the patient should 
be followed every 12 weeks (+/- 1 week) for progression and survival per Section 5.0. 
12.2 
Follow-up for Patients Who Stop Protocol Therapy 
If the patient discontinues cabozantinib/placebo due to disease progression and does not 
crossover to open-label therapy, then the patient should be followed for survival every 6 months 
per the Study Calendar (Section 5.0). 
If the patient discontinues open-label cabozantinib due to disease progression, then the patient 
should be followed for survival every 6 months per the Study Calendar (Section 5.0). 

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12.2.1 Withdrawal of Consent 
If the patient no longer wishes to continue cabozantinib/placebo and withdraws his/her 
consent for protocol therapy, then the patient should be asked if he/she may be followed 
for disease progression and survival per Section 5.0. The reason for discontinuation and 
the patient’s response should be documented. 
If the patient no longer wishes to continue disease progression follow-up and withdraws 
his/her consent for follow-up, then the patient should be asked if he/she may be followed 
for survival per Section 5.0. The reason for discontinuation and the patient’s response 
should be documented. 
If the patient no longer wishes to continue survival follow-up and withdraws his/her 
consent, then no additional follow-up is required. The reason for discontinuation should be 
documented. 
If the patient is consented to either the optional substudies or biobanking (Section 14.0) 
and no longer wishes to have his/her specimens collected or quality of life reported and 
withdraws his/her consent for future collections, then no additional collections should 
occur. The reason for discontinuation should be documented.  
If the patient is consented to either the optional substudies or biobanking (Section 14.0) 
and no longer wishes to have his/her specimens biobanked for use in future research or 
quality of life responses analyzed and withdraws his/her consent for future use, then no 
future analyses should occur, and his/her related health information should no longer be 
collected. The reason for discontinuation should be documented. 
12.2.2 Stopping Study Treatment due to Toxicity 
If the patient discontinues cabozantinib/placebo due to unacceptable toxicity, then the 
patient should be followed for disease progression and survival per the Study Calendar in 
Section 5.0. The date on which the patient begins a new treatment should be recorded. 
12.3 
Managing Ineligible Patients and Registered Patients Who Never Receive Protocol 
Intervention  
Definition of Ineligible Patient 
A study participant who is registered to the trial but does not meet all of the eligibility criteria 
is deemed to be ineligible.  
Follow-up for Ineligible Patients Who Continue with Protocol Treatment 
Patients who are deemed ineligible after registering may continue protocol treatment, provided 
the treating physician, Study Chair, and Executive Officer agree there are no safety concerns if 
the patient continues protocol treatment. All scans, tests, and data submission are to continue as 
if the patient were eligible. Notification of the local IRB may be necessary per local IRB 
policies. 
Follow-up for Ineligible Patients Who Discontinue Protocol Treatment 
For patients who are deemed ineligible after registering to the trial, who start treatment, but then 
discontinue study treatment, the same data submission requirements are to be followed as for 
those patients who are eligible and who discontinue study treatment. 
Follow-up for Patients Who are Registered, but Never Start Study Treatment 
For all study participants who are registered to the trial but who never receive study intervention 
(regardless of eligibility), the follow-up requirements are as follows: Baseline, off-treatment, 

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and post-treatment follow up (i.e. progression and survival) data submission required. See the 
Data Submission Schedule accompanying the All Forms Packet. 
12.4 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 
13.0 STATISTICAL CONSIDERATIONS 
This study is a two-arm randomized, double-blinded, placebo-controlled phase III trial comparing the 
outcomes of treatment with 1) cabozantinib or 2) placebo in patients with advanced neuroendocrine 
tumors after progression on prior therapy. Patients will be separated into 2 cohorts: pancreatic NET 
vs. carcinoid tumors. Patients will be randomized in 2:1 fashion to either cabozantinib or placebo. 
The randomization will be done separately within each cohort. Efficacy analyses will be based on the 
intention to treat principle, and all randomized patients will be included for the analysis, i.e. patients 
will be assigned to the treatment group they were randomized to regardless of the actual treatment 
received. Analysis related to adverse events will be based on the safety population. All patients who 
were randomized and received any amount of protocol therapy will be considered in the safety 
population, and patients will be assigned to the treatment group they actually received. 
13.1 
Accrual Time and Study Duration 
Pancreatic NET Cohort 
We aim to accrue 6 patients per month for 31 months for a total of 185 patients, which translates 
to an accrual rate of 72 patients per year. After a minimum follow-up of 8 months, the total time 
to primary analysis is 3.25 years (39 months).  
CALGB 80701, a randomized phase II study of everolimus and octreotide with or without 
bevacizumab in advanced pancreatic NET, enrolled 150 patients from October 2010-October 
2012. This translates to enrollment of 6.25 patients per month on average. ECOG 2211, a 
randomized phase II study of temozolomide plus capecitabine versus temozolomide in advanced 
pancreatic NET, accrued as many as 6 patients per month. Both of these studies included a 
patient population that is similar to the pancreatic NET cohort in this study. 
Carcinoid Tumor Cohort 
We aim to accrue 6 patients per month for 35 months for a total of 210 patients, which translates 
to an accrual rate of 72 patients per year. After a minimum follow-up of 11 months, the total 
time to primary analysis is 3.8 years (46 months).  
Alliance A021202 (NCT 01841736), a randomized phase II study of pazopanib versus placebo 
in patients with progressive carcinoid tumors, enrolled 171 patients from June 2013-October 
2015. A021202 included patients similar to the carcinoid tumor cohort in this study. 
13.2 
Sample Size 
Pancreatic NET Cohort 
The best historical data available on the outcome of patients with pancreatic NET and 
progressive disease comes from the results of the placebo arms of the RADIANT-3 study and 

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the randomized study of sunitinib vs. placebo. In these studies, the progression-free survival 
(PFS) in patients receiving placebo was approximately 5 months. 
We assume an accrual period of 2.6 years (31 months), 6 patients per month, 4.32% of dropout, 
minimum follow-up in all other patients of 8 months, exponential survival, and that a one-sided 
log-rank test for superiority will be conducted at level 0.025. We also assume PFS of 5 months 
for patients receiving placebo. Based on these assumptions, a sample size of 185 patients (124 
in cabozantinib arm and 61 in placebo arm) will result in 149 events which are required to 
provide 90% power to detect a hazard ratio (HR) of 0.568 between the two treatment arms. The 
PFS estimate corresponding to this HR is 8.8 months. 
Carcinoid Tumor Cohort 
The best historical data available on the outcome of patients with carcinoid tumors and 
progressive disease comes from the results of the placebo arms of the RADIANT-2 and 
RADIANT-4 studies. In the RADIANT-2 study, the PFS according to investigator review in 
patients receiving placebo was 8.6 months. In the RADIANT-4 study, the PFS in patients 
receiving placebo was 3.9 months. 
We assume an accrual period of 2.9 years (35 months), 6 patients per month, 4.286% of dropout, 
minimum follow-up in all other patients of 11 months, exponential survival, and that a one-sided 
log-rank test for superiority will be conducted at level 0.025. We also assume PFS of 7 months 
for patients receiving placebo. Based on these assumptions, a sample size of 210 patients (141 
in cabozantinib arm and 69 in placebo arm) will result in 164 events which are required to 
provide 90% power to detect a hazard ratio (HR) of 0.583 between the two treatment arms. The 
PFS estimate for the cabozantinib corresponding to this HR is 12 months. 
For Both Cohorts 
The rate of PFS events and censoring will be monitored over the course of the study; if it appears 
that the study will not reach the requisite number of PFS events within the planned study 
timeframe, the protocol may be amended to increase the total sample size. 
13.3 
Study Endpoints 
13.3.1 Primary Endpoint 
For both cohorts: The primary endpoint of this trial is progression-free survival (PFS), 
defined as the time from randomization to the first radiographic documentation of disease 
progression, per RECIST 1.1 determined by retrospective independent central review (i.e. 
IROC; see Section 7.2.3), or death from any cause. Symptomatic deterioration alone does 
not constitute a PFS event. Patients who do not have a PFS event will be censored for PFS 
at the last disease assessment date which is prior to initiation of new anticancer therapy. 
13.3.2 Secondary Endpoints 
For both cohorts: overall survival, adverse events, and radiographic response rate. 
Overall Survival (OS) 
The secondary endpoint of this study is overall survival, defined as the time from 
randomization to death, from any cause. Patients who do not have an OS event will be 
censored for OS at the date they were last known to be alive. 
Adverse Events (AEs) 

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CTCAE AEs and the maximum grade for each type of AE will be recorded for each patient. 
Similarly, scores (0-4) and the maximum score for each PRO-CTCAE item will be 
recorded for each patient. 
Radiographic Response Rate 
A secondary endpoint of this study is (confirmed) radiographic response rate, defined as 
the proportion of patients in each arm whose best response is either complete response 
(CR) or partial response (PR) prior to crossover. 
13.4 
Stratification 
The analysis will be done separately for the pancreatic NET and carcinoid tumor cohorts and 
will be stratified by the stratification factors listed in Section 4.6. 
13.5 
Analysis Plan 
13.5.1 Primary Endpoint 
Treatment Efficacy Decision Rules 
Interim analysis for both cohorts: Two interim analyses for futility only will be 
performed at the time at which 33% and 66% of the projected number of events have 
occurred. Gamma family spending function with parameter -6 will be used for futility 
boundary. The futility boundary will be considered non-binding. The specific critical p-
values for declaring futility at each analysis are specified in the tables below. Specifically, 
at 2nd interim analysis in the pancreatic NET cohort: if p-value > 0.343, then the 
cabozantinib will be considered inefficacious. When progression-free survival (PFS) 
crosses futility boundary, the accrual will be suspended (if still ongoing), the enrolled 
patients will be followed per protocol, and the data will be reported. 
Final analysis for both cohorts: The primary efficacy analysis will be performed at the 
time at which 100% of the projected number of events have occurred (149 PFS events for 
the pancreatic NET cohort, and 164 PFS events for the carcinoid tumor cohort). The 
specific critical p-values for declaring superiority or futility at each analysis are specified 
in the tables below. Specifically, at the final analysis for the pancreatic NET cohort: if the 
p-value ≤ 0.023, then the cabozantinib will be deemed effective; if not, then the 
cabozantinib will be considered to have not met the criteria for efficacy. Per FDA 
instruction, the critical p-value of 0.023 is used for analysis, even though the statistical 
design has a Type I error of 0.025; therefore, we are spending 0.001 alpha for efficacy at 
each of the two interim analyses. 
 
Pancreatic NET Cohort – Decision Boundary 
Analysis 
time point 
(% events) 
Number of 
events 
Critical p-
value for 
efficacy 
HR for 
efficacy 
Critical p-
value for 
futility 
HR for 
futility 
33% 
50 
N/A 
N/A 
0.856 
1.375 
66% 
99 
N/A 
N/A 
0.343 
0.917 
100% (Final) 
149 
0.023* 
0.711 
0.023* 
0.711 
 
 

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Carcinoid Tumor Cohort – Decision Boundary 
Analysis 
time point 
(% events) 
Number of 
events 
Critical p-
value for 
efficacy 
HR for 
efficacy 
Critical p-
value for 
futility 
HR for 
futility 
33% 
55 
N/A 
N/A 
0.856 
1.356 
66% 
109 
N/A 
N/A 
0.343 
0.921 
100% (Final) 
164 
0.023* 
0.723 
0.023* 
0.723 
* 
Alpha spending of 0.001 (for efficacy) per interim analysis (overall level = 0.025) 
is employed per FDA instruction. 
 
Operating characteristics for both cohorts: The tables below show the operating 
characteristics assuming the PFS follows exponential survival functions, and they include 
the operating characteristics according to the monitoring plan outlined above. The 
proportion of times that: 1) the study would stop early at 1st or 2nd interim analyses due to 
futility of cabozantinib, and 2) the study would conclude the cabozantinib is superior to 
placebo at the final analysis, are tabulated by true median PFS and equivalent true hazard 
ratio for PFS by treatment groups. 
 
Pancreatic NET Cohort – Operating Characteristics 
True median PFS 
(months) † 
True 
Hazard 
Ratio 
%‡ of times the 
study will be 
stopped early for 
futility 
%‡ of times the 
study will be 
stopped early for 
efficacy 
%‡ of times 
that 
cabozantinib 
is declared 
superior 
Placebo 
Cabozantinib 
1st 
interim 
analysis 
2nd 
interim 
analysis 
1st 
interim 
analysis 
2nd 
interim 
analysis 
5 
8.8 
0.568 
0.12 
1.04 
NA 
NA 
90.89 
5 
8 
0.625 
0.36 
3.4 
NA 
NA 
77.92 
5 
7 
0.714 
1.34 
10.53 
NA 
NA 
50.15 
5 
6 
0.833 
4.61 
28.04 
NA 
NA 
18.92 
5 
5 
1 
14.47 
51.1 
NA 
NA 
2.58 
† 
Although we use median PFS to illustrate each scenario, the hypothesis testing is 
based on the entire survival curve.  
‡ 
Proportions are based on 10,000 replicates in the simulation study. 
 
 
 

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Carcinoid Tumor Cohort – Operating Characteristics 
True median PFS 
(months) † 
True 
Hazard 
Ratio 
%‡ of times the 
study will be 
stopped early for 
futility 
%‡ of times the 
study will be 
stopped early for 
efficacy 
%‡ of times 
that 
cabozantinib 
is declared 
superior 
Placebo 
Cabozantinib 
1st 
interim 
analysis 
2nd 
interim 
analysis 
1st 
interim 
analysis 
2nd 
interim 
analysis 
7 
12 
0.583 
0.14 
1.04 
NA 
NA 
90.67 
7 
11 
0.636 
0.38 
3.23 
NA 
NA 
78.55 
7 
9 
0.778 
2.74 
18.07 
NA 
NA 
34.02 
7 
8 
0.875 
6.47 
33.6 
NA 
NA 
12.70 
7 
7 
1 
14.25 
51.63 
NA 
NA 
2.42 
† 
Although we use median PFS to illustrate each scenario, the hypothesis testing is 
based on the entire survival curve.  
‡ 
Proportions are based on 10,000 replicates in the simulation study. 
 
Analysis plan for both cohorts: PFS will be compared between treatment arms using the 
stratified log rank test at one-sided level 0.023. The stratification factors listed in Section 
4.6, as collected on the OPEN Enrollment Form, will be used for the analysis. The HR for 
PFS will be estimated using a stratified Cox proportional hazards model, and the 95% CI 
for the HR will be provided. Results from an unstratified analysis will also be provided.  
Kaplan-Meier methodology will be used to estimate the median PFS for each treatment 
arm, and Kaplan-Meier curves will be produced. Brookmeyer Crowley methodology will 
be used to construct the 95% CI for the median PFS for each treatment arm [39]. 
Sensitivity analysis plan for both cohorts: 
• 
The PFS according to investigator assessment will be used as the endpoint for a 
sensitivity analysis.  
• 
For patients with a PFS event related to the results of a scan performed prior to the 
time of scheduled restaging, the PFS event will be dated on the date of the next 
scheduled radiology restaging assessment. 
Carcinoid Tumor Cohort – Pre-planned Subgroup Analysis 
In the carcinoid tumor cohort, we will perform the subgroup analysis by the subgroups 
specific below to evaluate whether the treatment effect is consistent across different 
subgroups. Interaction p-value (interaction between treatment arms and specific 
subgroups) will be used to determine whether the treatment effect is consistent. A p-value 
of < 0.1 will indicate that there is a differential treatment effect across different subgroups. 
The pre-planned subgroups are: 
• 
Prior Anti-VEGF Therapy: Yes vs. No 
• 
Prior Targeted Radionucleotide Therapy (PRRT): Yes vs. No 
 
 

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13.5.2 Secondary Endpoints 
Overall survival (OS) for both cohorts: The analyses for OS will follow ITT principle and 
will be conducted separately within each cohort (pancreatic NET and carcinoid tumor). 
The distribution of OS will be estimated using the method of Kaplan-Meier. The median 
OS, along with the 95% confidence intervals, will be estimated for the two treatment 
groups. Additionally, 3-year OS rate, along with the 95% confidence intervals, will be 
estimated for the two treatment groups. 
Overall survival will be compared between treatment arms using the stratified log-rank test 
at a one-sided cumulative 2.3% level of significance. The stratified Cox regression will be 
used to estimate the hazard ratio (HR) of OS, along with the 95% confidence interval. A 
hierarchical approach will be used to control for family-wise type-I error rate, therefore OS 
will be formally statistically tested only if the primary efficacy endpoint, PFS, is 
statistically significantly different between the two treatment groups.  
The best historical data related to OS outcome in patients with pancreatic NET and 
progressive disease comes from the results of the placebo arms of the RADIANT-3 study 
and the randomized study of sunitinib vs. placebo. In the RADIANT-3 study, median OS 
was 37.7 months in patients who received placebo. In the phase III study of sunitinib vs. 
placebo in patients with pancreatic NET, median OS was 29.1 months in patients who 
received placebo.  
The best historical data available related to OS outcome in patients with carcinoid tumors 
and progressive disease comes from the results of the placebo arm of the RADIANT-2 
study. In the RADIANT-2 study, median OS was 35.8 months in patients who received 
octreotide with placebo. The final OS analysis has not been reported for the RADIANT-4 
study, which included patients with nonfunctional carcinoid tumors who were randomized 
to receive everolimus or placebo. 
Because patients in this trial are required to have experienced disease progression on at 
least one line of prior systemic therapy not including somatostatin analogs, we anticipate 
that the median OS time in patients receiving placebo in both cohorts of this trial may be 
shorter than what has been reported in the clinical trials mentioned above.  
The OS analyses within each cohort will be conducted when approximately 155 OS events 
have been observed. Based on the assumed accrual rate and target sample size specified in 
previous sections, the anticipated analysis times for the final OS analysis are approximately 
86 months and 68 months for the pancreatic NET and carcinoid tumor cohorts, 
respectively. 
13.5.3 Adverse Events (AEs) 
AEs and the maximum grade for each type of adverse event will be recorded for each 
patient. Similarly, scores (0-4) and the maximum score for each PRO-CTCAE item will be 
recorded for each patient. For patients who elect to crossover to open-label cabozantinib at 
centrally-confirmed PD, only adverse events that occur prior to crossover will be 
considered for endpoint. Any AEs that occur after crossover for these patients will be 
analyzed separately in a descriptive fashion. 
For CTCAE data, the frequency tables will be reviewed to determine the patterns. The 
overall adverse event rates will be compared between treatment groups using Chi-square 
test (or Fisher’s exact test if the data in contingency table is sparse). 
PRO-CTCAE data will, at minimum, be analyzed similarly to CTCAE data.  Reasons for 
missed PRO-CTCAE assessments will be collected, and we will describe the extent of 

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missing data as well as its patterns and causes. The initial analysis of each PRO-CTCAE 
item will use all available scores in an analysis which mirrors the approach used for the 
CTCAE data. Supplemental analysis will use model-based multiple imputation 
incorporating baseline patient characteristics and physician-rated performance status 
(which is collected at each cycle). CTCAE data may be incorporated as auxiliary data into 
multiple imputation models for AEs which are captured by both PRO-CTCAE and 
CTCAE. Results from supplemental analysis will be descriptively compared to the results 
of the initial analysis to assess the robustness of results to missing data. Since a preferred 
or optimal statistical methodology for PRO-CTCAE data is yet to be determined, additional 
analyses of PRO-CTCAE data beyond those specified above may be undertaken based on 
the current state of the science at time of data maturity for this study. 
13.5.4 Radiographic Response Rate 
Radiographic response rate for both cohorts: the analyses for (confirmed) radiographic 
response rate will follow the ITT principle and will be conducted separately within each 
cohort (pancreatic NET and carcinoid tumor). 
The proportion of patients with either (confirmed) CR or (confirmed) PR as their best 
response will be estimated using point estimates and 95% confidence intervals . For 
patients who elect to crossover to open-label cabozantinib at centrally-confirmed PD, only 
disease assessments prior to crossover will be considered for this endpoint. Any 
radiographic responses that occur after crossover will be analyzed separately in a 
descriptive fashion. Radiographic response rate will be compared between treatment arms 
using the 2-sample z-test to compare sample proportion at a one-sided 2.5% level of 
significance. 
13.6 
Monitoring 
Safety Monitoring: 
This study will be monitored by the Alliance Data and Safety Monitoring Board (DSMB), an 
NCI-approved functioning body. Reports containing efficacy, adverse event, and administrative 
information will be provided to the DSMB every six months as per NCI guidelines. In addition, 
the Study Chair and Study Statistician will review the accrual and safety data periodically, as 
well as the Alliance Group Meeting Reports, in order to identify any feasibility problems 
associated with accrual rates and adverse events.  
Any data release, whether at the time of interim analysis or at the time of final analysis, must be 
approved by the Alliance DSMB prior to execution. 
CDUS Monitoring: This study has been assigned CDUS Abbreviated monitoring. 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis by FTP burst of data. Reports are due January 31, April 30, July 31, and 
October 31. Instructions for submitting data using the CDUS can be found on the CTEP Web 
site 
 
Note: If your study has been assigned to CDUS-Complete reporting, all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS reporting 
guidelines must be reported via the monitoring method identified above. If your study has been 
assigned to CDUS-Abbreviated reporting, no adverse event reporting (routine or expedited) is 
required to be reported via CDUS, but expedited adverse events are still required to be submitted 
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Enhanced Centralized Data Monitoring: This trial will utilize central monitoring in order to 
ensure complete and consistent data collection. 
Enhanced centralized data monitoring will be performed for the first two cycles of treatment for 
all patient cases enrolled from each site (as identified by a unique NCI Institution Code). The 
cases selected for central monitoring will be reviewed for completeness and consistency with 
the eligibility criteria via source data verification (SDV) with source documents compared to 
data reported via the electronic Case Report Forms in Rave. Centralized data monitoring with 
SDV will be performed for all patients for key eligibility and response/disease outcomes.  
A source document is a document in which data collected for a clinical trial is first recorded. 
This data is usually later entered in the Case Report Forms. The ICH-GCP guidelines define 
source documents as original documents, data, and records. 
The pretreatment documents that should be uploaded within two weeks after registration for 
central review include: 
1) Pathology report 
2) Baseline imaging reports used to confirm radiographic progression for eligibility 
3) Documentation of one or more prior lines of FDA-approved systemic therapy (as 
specified in Section 3.2.3) not including somatostatin analogs and documentation of 
disease progression or treatment intolerance 
4) Labs to include baseline CBC, chemistry, urine protein to creatinine (UPC) ratio, TSH 
5) ECG 
6) Clinic source documents to verify initial performance status 
7) Deidentified last page of the signed and dated informed consent document including 
any pages with responses indicated by patient for optional studies (with patient’s full 
signature and any other PHI redacted, but date should be retained) 
8) Documentation of the first two courses of treatment (submitted within two weeks of 
completion) to include, medication orders, medication compliance records 
See the Data Submission Schedule, available on the Alliance and CTSU websites, for additional 
details regarding source data verification of key eligibility criteria. 
Sites should ensure that patient identifiers have been removed from all pages that will be 
uploaded and add study-specific identifying information (i.e. Alliance Patient ID) and then scan 
and upload all document into Rave. Please ensure that all pages are legible and correct. 
In the event that enhanced central monitoring or review of key performance indicators (KPIs) 
identifies unacceptable enrollment procedures or significant deviations from eligibility criteria,  
treatment administration, or other significant protocol requirements, then the site will need to 
submit a corrective and preventative action plan (CAPA) within two weeks of being notified of 
the findings of the central monitoring.   
 
 

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Additional cases may be selected for centralized monitoring or an audit visit may be conducted 
when deviations are noted or for sites will high enrollment (note: audit visits will be conducted 
according to the NCI Clinical Trials Monitoring Branch guidelines). Deficiencies or KPIs that 
may elicit one of these responses include, but are not limited to: 
• 
Accrual rate 
• 
Eligibility 
• 
Early termination 
• 
Data submission timeliness 
• 
Outstanding forms 
• 
Outstanding queries 
• 
Query responsiveness 
• 
Protocol deviations 
13.7 
Descriptive Factors 
Tumor Grade: grade 1 vs. grade 2 vs. grade 3 vs. unknown 
Functional (Hormone Secretion) Status: functional vs. non-functional 
Tumor Site: pancreatic vs. lung vs. stomach vs. duodenum vs. jejunum vs. ileum vs. appendix 
vs. cecum vs. ascending colon vs. hepatic flexure vs. transverse colon vs. splenic flexure vs. 
descending colon vs. sigmoid colon vs. rectum vs. unknown vs. other 
13.8 
Inclusion of Women and Minorities 
Pancreatic NET Cohort 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
2 
2 
0 
0 
4 
Asian 
6 
7 
0 
0 
13 
Native Hawaiian or 
Other Pacific Islander 
8 
10 
0 
0 
18 
Black or African 
American 
3 
3 
1 
1 
8 
White 
63 
66 
5 
4 
138 
More Than One Race 
2 
2 
0 
0 
4 
Total 
84 
90 
6 
5 
185 
 
 
 
 
 

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Carcinoid Tumor Cohort 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
3 
3 
1 
1 
8 
Asian 
6 
7 
0 
0 
13 
Native Hawaiian or 
Other Pacific Islander 
8 
10 
0 
0 
18 
Black or African 
American 
4 
4 
2 
2 
12 
White 
69 
73 
6 
5 
153 
More Than One Race 
2 
2 
1 
1 
6 
Total 
92 
99 
10 
9 
210 
 
14.0 CORRELATIVE AND COMPANION STUDIES  
There will be one substudy and one biobanking for future correlative science studies, and all patients 
are encouraged to participate.  
14.1 
Quality of Life Substudy (Alliance A021602-HO1) 
14.1.1 Background 
We will evaluate quality of life and disease-related symptoms in patients with advanced 
pancreatic NET and carcinoid tumors treated with cabozantinib versus placebo. For 
patients who opt in, patients will complete the EORTC QLQ-C30 and EORTC QLQ-
GI.NET21 at baseline and every 12 weeks until disease progression or the start of a new 
anticancer therapy. The hypothesis is that cabozantinib will improve quality of life and 
decrease disease-related symptoms as compared to placebo and will be important in the 
current study to investigate potential treatment benefits in the setting where no effective 
treatments exist. We are using the same tools as were used in A021202 (randomized phase 
II study of pazopanib versus placebo in patients with progressive carcinoid tumors) to allow 
for cross-study comparison and to further our current work in understanding quality of life 
and disease symptomatology of these patients. In A021202, the EORTC QLQ-C30, 
GI.NET21, and Linear Analog Self-Assessment (LASA) items were administered at 
baseline, weekly during the first cycle of treatment, at 3 months, and at 1 year with a plan 
to compare the longer questionnaires (EORTC QLQ-C30 and GI.NET21) to a brief 
approach (LASA items). We have modified our approach somewhat in the present study 
maintaining the longer questionnaires (as results indicating comparability of approaches is 
not available at this time) but capturing less acute data and more frequent long-term data 
on the same schedule as disease assessments to better estimate and compare the trajectory 
of disease impact over time as well as to begin to explore possible symptom response 
endpoints for use in future clinical trials. Note, patient-reported treatment-related toxicities 
will be captured in the main body of the protocol using PRO-CTCAE on a more frequent 
interval. 
Recently, Pearman et al. [40] reported a large cross-sectional study using the PROMIS-29 
questionnaire reported on the quality of life outcomes of patients with NET. The authors 
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are correlated with decreased quality of life. Also, patients with recurrent disease reported 
poorer physical, social, and mental functions. This study was consistent with a previous 
study reported by Beaumont et al. [41]. 
A major limitation of these studies was their cross-sectional approaches in heterogeneous 
patient populations. Investigation of quality of life in this patient population in the setting 
of therapeutic clinical trials remains lacking. The present study allows us to estimate the 
within-patient trajectory of disease impact over time and compare trajectories between 
arms in a well-defined clinical trial population. We also aim to explore possible symptom 
response endpoints to begin to develop criteria for evaluating future therapies in clinical 
trials in this patient population. 
14.1.2 Methods 
For the schedule of assessments for this quality of life study, see Section 5.0. All 
participating institutions must ask patients for their consent to participate in this quality of 
life study (A021602-HO1), although patient participation is optional. Paper booklets will 
be used for this study. For information regarding ordering the booklets, see Section 4.3. 
For all patients who consent to participate in the quality of life study (A021602-HO1), a 
booklet will be given to the patient to complete at the specified, planned clinic visits before 
any procedures/tests are initiated at the site visit and prior to any discussion of their status 
with healthcare personnel at the site. For assessments after cessation of protocol-treatment 
but prior to disease progression or the start of a new anticancer therapy, a member of the 
site study staff may administer the booklet over the phone if no clinic visit is available for 
in-person completion. Booklets will be collected at the following time points: at baseline 
and every 12 weeks until disease progression or initiation of new anticancer therapy (i.e. 
every 3 cycles approximately coinciding with disease assessments). The booklet contains 
52 questions, and it is anticipated that the booklet will take approximately 10-15 minutes 
for the patient to complete at each administration time point. The questionnaires will be 
available in pre-printed booklets in English at time of study activation. Booklets containing 
other languages may be added depending on patient demand.  Patients who consent to 
participate in this quality of life study (A021602-HO1) may decline to complete a booklet 
at any time. The primary reason for each missed booklet will be collected on a case report 
form. 
The European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 (EORTC QLQ-C30) is a 30-item questionnaire about patient ability 
to function (measured via five functional scales), symptoms related to the cancer and its 
treatment (via eight symptom scales/items), overall health and quality of life, and perceived 
financial impact of the cancer and its treatment. Each item is measured on a 1-4 scale 
(1=not at all; 4=very much). Seven of nine scales had Cronbach’s alpha greater than 0.70 
and the test-retest reliability for all scales and one single item was 0.78 or higher. These 
instruments are available in other languages upon request. 
The GI.NET21 module is intended for use among patients with gastrointestinal-related 
neuroendocrine tumors, who vary in disease stage and treatments. The module comprises 
21 questions assessing disease symptoms, side effects of treatment, body image, disease-
related worries, social functioning, communication and sexuality. The questionnaire results 
in the following scale scores: endocrine symptoms [3 questions], gastrointestinal 
symptoms [5 questions], treatment-related side effects [3 questions], bone/muscle pain [1 
question], concern about weight loss [1 question], social function [3 questions], disease-
related worries [3 questions], sexuality [1 question], and communication [1 question]. The 
measure is presently in phase IV validation testing as set out in the EORTC module 

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development process, indicative that initial content and construct validity has been 
achieved, but that further data are needed to demonstrate responsiveness and discriminant 
validity. Given the lack of an alternative fully validated NET-specific questionnaire, and 
the EORTC’s rigorous development process and high rate of ultimately successful 
validation, we have selected to use this questionnaire for the current study. We believe that 
this questionnaire will become the gold standard for assessment of quality of life issues in 
patients with NET. 
Perception of change will be evaluated with a Patient Global Impression of Change item. 
Global Impression of Change Scale (also called the Subjective Significance Scale) has been 
used as an anchor for determination of minimally clinically significant differences in 
numerous oncology clinical trials within Alliance legacy trials (N00C3, N01C3, N01CB, 
and N03CA) and beyond [42-44]. The patient rates the change in his/her overall status 
(ranging from very much improved, much improved, minimally improved, no change, 
minimally worse, much worse, to very much worse). 
14.1.3 Objectives/Hypotheses 
Primary Objective 
Compare health-related quality of life (HRQL) as assessed by the EORTC QLQ-C30 
between patients randomized to cabozantinib vs. placebo by patient cohort (pancreatic 
NET vs. carcinoid tumor).  
Hypothesis: HRQL (based on the EORTC QLQ-C30 HRQL summary score) will be better 
in patients randomized to cabozantinib compared to placebo from initiation of protocol-
treatment until disease progression or start of new anticancer therapy. 
Secondary Objective 
Compare NET disease-related symptoms and other domains as assessed by EORTC QLQ-
GI.NET21 between patients randomized to cabozantinib vs. placebo by patient cohort 
(pancreatic NET vs. carcinoid tumor).  
Hypothesis: NET disease-related symptoms and other domains (based on the EORTC 
QLQ-GI.NET21 scale scores excluding treatment-related side effects and communication) 
will be better in patients randomized to cabozantinib compared to placebo from initiation 
of protocol-treatment until disease progression or start of new anticancer therapy. 
Exploratory Objectives 
1) Assess the relationship between EORTC QLQ-GI.NET21 symptoms, EORTC 
QLQ-C30 functioning domains, and EORTC QLQ-C30 Global Health 
Status/Quality of Life score. 
2) Explore possible symptom response definitions through estimation of meaningful 
changes in EORTC QLQ-GI.NET21 scale and summary scores and compare rates 
of symptom response between arms. 
14.1.4 Statistical Considerations 
All questionnaires will be scored according to published scoring algorithms. The primary 
analysis will involve a mixed model of the EORTC QLQ-C30 HRQL summary score 
within each patient cohort. The mixed model will compare the post-randomization HRQL 
between randomized arms. In addition to a randomized arm covariate, each model will 
include a covariate for baseline HRQL and will use the planned month of assessment as 
the categorical time value. Unstructured covariance will initially be used, though 
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selected based on minimization of the Akaike information criterion. The statistical 
significance of the randomized arm covariate between arms will be employed for 
hypothesis testing. Within this model, this covariate represents the estimated average 
difference between randomized arms across post-randomization time points. We have 
chosen this approach to reduce the number of hypothesis tests to one for each patient 
cohort.  We feel that this is a reasonable approach because we anticipate a consistent effect 
across time points. In supplemental analysis, we will modify this approach to include a 
time-by-arm interaction effect and report time-specific comparisons between arms as well 
as model-based estimation of the area-under-the-curve throughout treatment based on 
mixed model contrasts. 
Primary patient-reported outcome analysis will be conducted at the time that all consented 
patients have completed 24 weeks of treatment (or are no longer being followed for quality 
of life). Release of the data for presentation will be at the discretion of the DSMB. Patients 
will be analyzed according to the randomized treatment arm assignment. All patients who 
consent for participation in the HO1 component with a baseline endpoint value and at least 
one endpoint value post-randomization will be included in the primary analysis. In the 
primary analysis, all observations available will be used. See below for information 
regarding analyses to account for missing data. 
In secondary analysis, similar mixed model comparisons of EORTC QLQ-GI.NET21 scale 
scores will be conducted within each patient cohort. Graphical procedures will include 
plots of average values over time by arm for each primary and secondary endpoint. 
Exploratory analysis will include computation of Pearson correlations among patient-
reported endpoints at fixed time points and univariate and multivariate linear mixed models 
of EORTC QLQ-C30 Global Health Status/Quality of Life score to investigate the impact 
of symptoms and functioning on quality of life. 
Possible symptom response endpoints will be explored. Candidate summary scores include 
the average of all EORTC QLQ-GI.NET21 scale scores and the average of all EORTC 
QLQ-GI.NET21 scale scores excluding treatment-related side effects and communication. 
Meaningful change for each will be explored using common distribution-based and anchor-
based approaches. Data will be pooled across patient cohorts for this analysis. For 
distribution-based approaches, meaningful changes will be estimated as 0.5 and 0.3 times 
the baseline standard deviation, 12-week standard deviation, 24-week standard deviation, 
standard deviation of the change-from-baseline scores at 12 weeks, and standard deviation 
of the change-from-baseline scores at 24 weeks. The anchor-based approach will employ 
the global impression of change items at 12 and 24 weeks. Candidate symptom response 
endpoints with triangulated meaningful change criteria will be applied to each treatment 
arm and rates of symptom response will be compared between arms within each patient 
cohort using a chi-squared test. Finally, cumulative distribution plots will be used to 
visually simultaneously assess arm comparisons across all possible meaningful change 
criteria within each patient cohort. 
For all statistical analyses, p-values <0.05 will be considered statistically significant 
(though interpretation will take into consideration that the type I error is not strictly 
controlled across primary and secondary endpoints). For interpreting the clinical 
significance of effects, 0.2, 0.5, and 0.8 standard deviation (SD) effects will be considered 
as small, moderate, and large based on Cohen throughout [45]. 
Missing data will be handled in a number of ways. Missing items within a summary or 
scale score will be handled according to each questionnaire’s published scoring algorithms. 
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patient/disease characteristics will be compared between patients who do and do not 
provide data for the primary analysis. We will also graphically explore patterns of missing 
data. All analyses will be completed using all available data, followed by analyses 
completed using a range of imputation methods. Lastly, we will employ pattern mixture 
models for longitudinal analyses. Output from all analyses will be tabulated and 
descriptively compared to assess the degree to which missing data impacts study results. 
Power  
Within the pancreatic NET cohort, we assume that 138 of the 185 enrolled patients will 
be progression-free at 12 weeks (based on median PFS of 5 months in the placebo arm and 
8.8 months in the cabozantinib arm). Allowing up to 15% additional missing data due to 
non-compliance, we based power estimation on having baseline and at least one follow-up 
assessment in 117 patients (83 on the cabozantinib arm, 34 on the placebo arm) in this 
cohort. The primary analysis in this cohort has 80% and 90% power to detect a 0.58 and a 
0.67 standard deviation difference between arms, respectively, assuming no correlation 
between baseline and follow-up HRQL (conservatively based on a power calculation for a 
two-sample t-test). With correlation of 0.5 between baseline and a single follow-up HRQL, 
the detectable effect size shrinks to 0.52 and 0.61, respectively, which can still be thought 
of as a conservative estimate based on a single follow-up time point.  
Within the carcinoid tumor cohort, we assume that 169 of the 210 enrolled patients will 
be progression-free at 12 weeks (based on median PFS of 7 months in the placebo arm and 
12 months in the cabozantinib arm). Allowing up to 15% additional missing data due to 
non-compliance, we based power estimation on having baseline and at least one follow-up 
assessment in 143 patients (100 on the cabozantinib arm, 43 on the placebo arm) in this 
cohort. The primary analysis in this cohort has 80% and 90% power to detect a 0.51 and a 
0.60 standard deviation difference between arms, respectively, assuming no correlation 
between baseline and follow-up HRQL (conservatively based on a power calculation for a 
two-sample t-test). With correlation of 0.5 between baseline and a single follow-up HRQL, 
the detectable effect size shrinks to 0.47 and 0.55, respectively, which can still be thought 
of as a conservative estimate based on a single follow-up time point.  
The planned analyses will incorporate all available data to maximize power. Thus, we 
anticipate having 80% power for detecting an effect size between 0.4 and 0.5 standard 
deviations within each cohort which is considered as clinically meaningful based on the 
work of Cohen. 
Overall power across both cohorts is expected to be 81% (i.e. 0.90 x 0.90 = 0.81) for effect 
sizes of 0.67 and 0.60 in the pancreatic NET and carcinoid tumor cohorts, respectively, 
assuming no correlation between baseline and follow-up HRQL, and for effect sizes of 
0.61 and 0.55 in the pancreatic NET and carcinoid tumor cohorts, respectively, assuming 
a correlation of 0.5 between baseline and follow-up HRQL. These effect sizes are 
considered moderate to large and clinically-meaningful based on the work of Cohen. 
14.2 
Population Pharmacokinetics of Cabozantinib (Alliance A021602-PP1) 
14.2.1 Background 
The absolute bioavailability of cabozantinib tablet or capsule formulations has not been 
determined. As noted by Lacy et al., the median time to maximum plasma concentration 
(Tmax) values across healthy volunteer (HV) studies was 3 to 5 hours, although individual 
subjects did show prolonged absorption phases with maximum plasma concentration (Cmax) 
occurring as late as 120 hours after dosing [46]. Following the absorption peak, plasma 
concentrations declined slowly with a mean terminal half-life of 111–131 hours across the 

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studies. Cabozantinib accumulates approximately fivefold by day 15 following daily 
dosing based on area under the plasma concentration-time curve (AUC). A population 
pharmacokinetics (PK) analysis was performed on pooled data for 289 cabozantinib-
treated cancer patients (including medullary thyroid cancer [MTC]) receiving daily 
administration of the cabozantinib capsule formulation at a dose of 140 mg FBE/day (FBE, 
free base equivalents), except for five subjects that were dosed at 200 mg FBE/day. The 
data were adequately described by a one-compartment model with first-order absorption 
and first-order elimination with a small lag time. The mean clearance of distribution (CL/F) 
and apparent volume of distribution (Vc/F) were estimated to be 106 L/day (standard error 
% [SE%] = 2.98%) and 349 L (SE% = 2.73%), respectively, resulting in an estimated 
effective half-life of 2.28 days (55 hours). 
Hepatobiliary elimination appears to be the major route of elimination of cabozantinib and 
its inactive metabolites, while urinary excretion is a route of elimination exclusively for 
cabozantinib metabolites. Four identified inactive metabolites constitute approximately 
65% of total cabozantinib-related AUC following a single 140-mg FBE dose. 
The protein binding of cabozantinib is approximately 99.77%. The percentage of 
cabozantinib unbound to plasma protein appeared to be correlated with serum albumin 
concentration; subjects with low serum albumin concentrations exhibited a higher 
percentage of unbound plasma protein and lower total Cmax. The mean values of systemic 
exposures, AUC0–24 and AUC0–72, in plasma were around 1.6 times higher than those in 
whole blood. 
Single doses of cabozantinib tablets at 20-, 40-, and 60-mg FBE dose strengths showed 
dose-proportional increases in mean plasma cabozantinib Cmax and AUC0–t values, 
suggesting linear pharmacokinetics. 
Cabozantinib AUC was increased by 63-81% or 7-30% in subjects with mild/moderate 
hepatic or renal impairment, respectively, by 34-38% with concomitant administration of 
the CYP3A4 inhibitor ketoconazole, and by 57% following a high-fat meal. Cabozantinib 
AUC was decreased by 76-77% with concomitant administration of the CYP3A4 inducer 
rifampin and was unaffected following administration of the proton pump inhibitor 
esomeprazole. Cabozantinib is a potent in vitro inhibitor of P-glycoprotein and multidrug 
and toxin extrusion transporters 1 and 2-K, and it is a substrate for multidrug resistance 
protein 2. 
Patients with medullary thyroid cancer with low model-predicted apparent clearance were 
more likely to dose hold/reduce cabozantinib early and had a lower average dose through 
day 85. However, longitudinal tumor modeling suggests that cabozantinib dose reductions 
from 140 to 60 mg/day did not markedly reduce tumor growth inhibition in medullary 
thyroid cancer patients. 
PK parameter values at a single 140-mg FBE dose were generally consistent for capsule 
and tablet formulations administered in HVs and for the capsule formulation administered 
in subjects with advanced malignancies. 
In a population pharmacokinetic analysis, no clinically significant covariates affecting 
cabozantinib pharmacokinetics were identified. Sex and body mass index (BMI) on oral 
clearance were the only covariates retained in the final model. Cabozantinib CL/F was 
shown to decrease by approximately 22% at the 95th percentile of BMI relative to the 
median, which translates to an approximately 28% increase in steady-state AUC. Female 
individuals cleared cabozantinib slower than male individuals by 22%, resulting in a 
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combined contributed to 15% of the variability in cabozantinib CL/F. Cabozantinib 
pharmacokinetics were not affected by age (20-86 years). The effect of race on 
cabozantinib pharmacokinetics could not be concluded based on the low percentages of 
non-white patients in the study population. Inter-individual variability in CL/F was modest 
(coefficient of variability [CV] = approximately 35%).  
The inter-subject variability (%CV) in HVs following a single capsule or tablet dose ranged 
from 20-59% for AUC values and from 28-72% for Cmax values across the studies. The 
%CV was estimated to be 39% for Cmax and 28% for AUC values in the capsule-tablet 
bioequivalence study. The %CV in cancer patients was 42-43% for Cmax and 34% for AUC 
after a single dose, and 37-43% for Cmax and 38-43% for AUC at steady state. 
In the pivotal phase III study for MTC, 79% of patients who received the 140-mg FBE 
cabozantinib dose eventually dose reduced. Forty-two percent of subjects received 60 
mg/day as their final dose. Exposure-response analyses showed an increased risk for time-
to-first-cabozantinib-dose-modification to be highly correlated with higher AUCss, pred. 
However, Kaplan–Meier analyses of progression-free survival (PFS) stratified by time-to-
first-dose-modification (tertiles) showed no clear association between early and late 
cabozantinib dose modifications and reduced PFS. These findings suggest that, although 
MTC patients who clear cabozantinib slower may have a higher risk of early dose reduction 
relative to the faster-clearing patients, the dose reduction paradigm used in the phase III 
study allowed individual MTC patients to ultimately attain a tolerated exposure providing 
clinical benefit [46]. 
14.2.2 Objectives 
To determine the intra-patient and inter-patient variability of cabozantinib exposure (C0) 
in patients with advanced neuroendocrine tumors receiving cabozantinib. 
To correlate cabozantinib exposure (C0) and AUC, as determined by population 
pharmacokinetic analysis, with toxicity and efficacy in patients with advanced 
neuroendocrine tumors. 
14.2.3 Methods 
Approximately 5 mL of peripheral blood for cabozantinib trough concentrations will be 
obtained from consenting patients prior to receiving their first cabozantinib dosage on 
Cycle 1 Day 1 and then obtained during clinic visits on Cycle 1 Day 15, Cycle 2 Day 1, 
Cycle 2 Day 15, and Cycle 3 Day 1 while still on protocol therapy but before receiving the 
scheduled daily dose (trough sample). The time of day the samples were obtained will be 
documented. Plasma will be extracted by local hospitals and shipped to the Alliance 
Pharmacology/Pharmacokinetic Core Laboratory at the University of Pittsburgh in a frozen 
condition. During the clinic visits, a Patient Pharmacokinetics Form (see Appendix IV) 
will be completed which will collect information about the timing of the previous 48-hours 
of cabozantinib dosing; this will detail the time the last two doses of study drug were 
received. 
Drug concentrations will be measured in plasma using an LC-MS/MS assay implemented 
by the Alliance Pharmacology/Pharmacokinetic Core Laboratory at the University of 
Pittsburgh using a modification of the assay published by Su et al. [47]. 
Both frequentist and population modeling approaches will be employed. 
14.2.4 Analyses 
For the first objective, we will calculate the intra- and inter-subject variability in exposure. 
Population pharmacokinetic approaches will be employed to achieve this. 

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For the second objective, population pharmacokinetic approaches will be used to explore 
the relationships of exposure versus dose modification, toxicity, and efficacy. 
Factors such as patient weight, height, albumin levels, etc. will be used as covariants in the 
analyses. 
The data collected from the samples, as outlined above, will be sent using encrypted secure 
spreadsheets to the Alliance SDC A021602 Statistician. Statistical analyses will be a 
collaboration between the Alliance SDC and Alliance Pharmacology/Pharmacokinetic 
Core Laboratory teams. 
14.3 
Biobanking for Future Correlative Science Studies 
NOTE: Testing of banked samples will not occur until an amendment to this treatment protocol 
(or separate correlative science protocol) is reviewed and approved in accordance with National 
Clinical Trials Network (NCTN) policies. 
Note: All laboratory correlates are classified as exploratory, and the specimens requested for 
submission in Section 6.2 will be collected for banking-only at this time. 
14.3.1 Potential Plasma Biomarkers of Cabozantinib 
Background 
Previous phase II studies in patients with breast cancer and cholangiocarcinoma treated 
with cabozantinib have evaluated baseline and on-treatment levels of pro-angiogenic and 
pro-inflammatory biomarkers [48, 49]. Treatment with cabozantinib was associated with 
significant increases in VEGF, PlGF, and SDF1α and decreases in Ang-2 and sVEGFR2. 
Cabozantinib also led to decreases in HGF and TIMP-1, both of which are associated with 
stellate cell activation and fibrosis and decreases in the inflammatory cytokines IFN-c, 
TNF- α, IL-8, and IL-10.   
These studies have also demonstrated that baseline biomarker levels may be associated 
with patient outcomes. In patients with cholangiocarcinoma treated with cabozantinib, a 
low baseline plasma TIMP-1 level was associated with longer PFS, and a low IL-6 level 
and a high soluble MET (sMET) level were correlated with longer OS [49]. In patients 
with breast cancer treated with cabozantinib, a high baseline sMET level was also 
correlated with longer PFS [48]. In contrast, data from a phase II study of patients with 
castrate resistant prostate cancer did not reveal a relationship between plasma biomarkers 
and radiographic response to cabozantinib [50]. 
Other studies examining on-treatment changes in biomarker levels in patients treated with 
anti-VEGF pathway inhibitors have demonstrated that changes may correlate with 
outcome. For example, in patients with renal cell carcinoma treated with the anti-VEGF 
antibody bevacizumab, elevated HGF levels at baseline were associated with worse OS.  
Patients experiencing a decline in HGF level following 4 weeks of treatment had improved 
OS compared to those with persistently elevated HGF levels [51]. 
Based on this data, there is a strong biological rationale to examine the association of 
circulating biomarkers both at baseline and in the setting of response and resistance to 
cabozantinib. We hypothesize that baseline levels of plasma inflammatory and angiogenic 
markers will predict likelihood of response to cabozantinib in NET. Similarly, treatment-
related changes in biomarker levels will predict outcomes.  
Although assessment of biomarker levels at baseline may identify factors that predict 
benefit or lack of benefit from cabozantinib, evaluation of changes in biomarker levels 
following initiation of therapy may identify responders to treatment. Reassessment of 

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biomarkers at the time of progression also may reveal markers and mechanisms of 
resistance. As such, it may be possible to use such biomarkers to risk-stratify individuals 
and their response to treatment, providing a more personalized approached to therapy.      
Methods 
Peripheral blood will be collected at baseline (Cycle 1 Day 1), during treatment (Cycle 2 
Day 1), and at the time of disease progression. To identify blood-based markers of anti-
angiogenic inhibition, the Duke multiplex ELISA-based plasma angiome panel will be 
tested. Results of prior studies utilizing this platform have identified strong candidate 
predictors of benefit for bevacizumab, including VEGF-D in patients with pancreatic 
cancer and IL-6 in patients with clear cell renal carcinoma. We anticipate being able to 
identify and validate or refute candidate plasma biomarkers of benefit that are specific for 
cabozantinib using this methodology. 
Table 1 below lists the panel of key angiogenic and inflammatory markers currently 
optimized. The “Angiome” multiplex array has gone through a rigorous evaluation to 
ensure data quality and has recently been approved by the NCI Biomarker Review 
Committee (BRC) as an integrated biomarker for use in two phase III studies of cediranib 
and olaparib in both platinum-sensitive and platinum-resistant ovarian cancer. Because 
cabozantinib also inhibits the activity of MET and AXL, we also aim to examine levels of 
members of these families, including s-MET, s-AXL, and GAS6. 
Table 1 – Plasma-based Marker Identification 
14.3.2 Determination of Mutation Spectrum in ct-DNA 
Background 
Mutations in pancreatic neuroendocrine tumors are well established and include alterations 
in MEN1, DAXX, ATRX, and SETD2, among other genes [52, 53]. Far less understood 
are GI carcinoid genetics, but mutations in CDKN1B are found most commonly [54, 55].  
Investigation of the mutational spectrum in lung carcinoid tumors has disclosed mutations 
in chromatin remodeling genes [56]. Drug sensitivity based on genotype in NET is 
unknown at this time. Additionally, mechanisms of resistance to cabozantinib have not 
been well studied.  
Changes in the mutational profile of circulating tumor DNA (ctDNA) may provide an 
opportunity to better understand tumor biology and genetic mechanisms of response and 
resistance to therapy. In a study examining the mutational profile in ctDNA in patients with 
metastatic renal cell carcinoma, ctDNA was observed to be altered between first- and 
second-line treatments [57]. The highest disparity in genomic alteration frequencies in 
post-first-line versus first-line were in TP53 (49% vs. 24%), VHL (29% vs. 18%), NF1 
(20% vs. 3%), EGFR (15% vs. 8%), and PIK3CA (17% vs. 8%).  Restricting the analysis 
to later lines versus first-line vascular endothelial growth factor inhibitors, these 
Soluble Angiogenic Factors Matrix-derived Factors 
Markers of Vascular 
Activation and Inflammation 
ANG-2 
VEGF-A 
BMP-9 
CD73 
bFGF 
VEGF-C 
OPN 
ICAM-1 
HGF 
VEGF-D 
TGFβ1 
IL-6 
PDGF-AA 
sVEGFR1 
TGFβ2 
IL-6R 
PDGF-BB 
sVEGFR2 
TGFβR3 
IL-6ST (GP130) 
PlGF 
sVEGFR3 
TIMP1 
SDF-1 
 
 
TSP2 
VCAM-1 

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differences were even more prominent, particularly for TP53 (64% vs. 31%) and NF1 (29% 
vs. 4%). These results suggest that events leading to these changes may underlie unknown 
mechanisms of resistance. In addition, assessment of ctDNA may reveal relevant 
biomarkers to facilitate selection of novel targeted therapies. 
In this study, we aim to characterize changes in the tumor mutation profile that occur in 
NET following therapy with cabozantinib and at the time of disease progression. These 
results will be correlated with response and resistance to cabozantinib. Sequencing results 
from ctDNA will also be compared to results from FFPE tumor tissue when available.  
Methods 
Peripheral blood will be collected at baseline (Cycle 1 Day 1), during treatment (Cycle 2 
Day 1), and at progression. Circulating tumor DNA (ctDNA) and DNA from buffy coat 
will be extracted using standard methods. Select samples (representative responders, non-
responders, and those with acquired resistance) will undergo sequencing and copy number 
assessment with a 410 CLIA-certified gene panel test (MSKCC-IMPACT) to determine 
changes in the mutation spectrum with drug treatment. The MSKCC-IMPACT platform 
has been used on over 16,000 patients to assess somatic and germline mutations. 
14.3.3 Evaluation of c-MET and phospho-c-MET Expression in FFPE Tumor Tissue  
The receptor tyrosine kinase MET is known target of cabozantinib. To determine baseline 
MET expression and phosphorylation of the receptor, FFPE tissue sections will be 
deparaffinized prior to antigen retrieval, blocking, and incubation with primary antibodies. 
Patients will be dichotomized as to whether or not their tumor expresses c-MET and the 
association between expression and response to cabozantinib will be evaluated. 
14.3.4 Next-Generation Sequencing (NGS) of Tumor DNA and of Matching Germline 
DNA Collected from Peripheral Blood 
Background 
NGS of tumor DNA is crucial to obtain a comprehensive genetic molecular basis to inform 
hypotheses related to the biology of this disease and its treatment. Among the different 
approaches for NGS, whole-exome sequencing (WES) of tumor DNA combined with that 
of germline DNA from a matching peripheral blood sample is the most cost-effective one. 
WES will provide a systematic analysis of the tumor genome of each patient, thus 
establishing genomic signatures for testing of their predictive and prognostic value. The 
WES output from the germline DNA will allow, in addition to providing novel candidate 
genes for outcome testing, new genes associated with the side effects of the study drug. 
Methods 
This analysis is very comprehensive and exploratory and will be used to generate a set of 
novel hypotheses and test their clinical significance. 
Whole exome libraries will be prepared in the Pre-Clinical Genomic Pathology (gPATH) 
laboratory at UNC. We will use a DNA input of 750 ng. For WES, we will utilize the 
Agilent SureSelect All-Exon bait set, which is optimized to target uniform coverage of the 
human exome, followed by the Illumina DNA TruSeq library preparation kit. Currently, 
we are using a 150 base paired-end sequencing strategy. To accurately identify somatic 
gene variants, we sequence cancer samples to an average depth of 200x coverage. With 
current computational protocols, this depth achieves 100% sensitivity for SNPs and small 
indels and >90% sensitivity for large indels, assuming the allele is present in at least 10% 
of the sample. At this depth, specificity for somatic events is also very high (>99.999%) 
when a paired normal is available. 

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Targeted sequencing in this manner is fast, reproducible, economical, and has excellent 
performance characteristics (sensitivity and specificity). Sequencing of DNA from FFPE 
and frozen samples is generally performed using the same protocol with the following 
minor modifications: FFPE samples will be sequenced using the paired end protocol with 
PCR duplicates removed to address the greater problem of lower complexity and PCR 
artifacts in paraffin samples. The UNC laboratory has extensive experience with WES from 
tumor samples and matching germline DNA [58-61]. 
Sequencing data are routed through an automated pipeline, SeqWare, managed by the UNC 
Bioinformatics Core Facility. SeqWare initiates processing of the raw data based on the 
protocols specified in gPATH’s Laboratory Information Management System. Initial 
alignment to the genome is performed using Stampy, a highly-sensitive DNA alignment 
algorithm [62]. Currently, the resulting alignments are then processed with UNCseqR to 
generate somatic mutation calls, all while following standard quality control procedures 
[63].  
Once mutations, structural variations, or copy number variations are detected, they are 
annotated. High-quality variants will be carried on to annotate for genomic features, 
including known genes, exonic function, predicted amino acid changes, predicted allele 
frequencies based upon the 1,000 Genomes Project [64] and the NHLBI Exome 
Sequencing Project [65], variant functions (loss of function, gain of function, no change), 
and COSMIC IDs etc. by Variant Effect Predictor (VEP) [66] combined with the UniPort 
database 
Specifically, the call on loss-of-function or gain-of-
function will be based on existing experimental data from the UniPort database, while 
harmful or tolerated effects on protein structure will be predicted using SIFT 
 embedded in the VEP analysis. In addition, other bioinformatic 
analyses will be conducted to detect regulatory changes potentially affecting gene 
expression using publicly-accessible repositories such as ENCODE, as well as other 
repositories that have been utilized in the past [67-70]. 
 
 

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22. 
Yakes, F.M., et al., Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously 
suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther, 2011. 10(12): p. 2298-
308. 
23. 
Carmeliet, P. and R.K. Jain, Principles and mechanisms of vessel normalization for cancer and 
other angiogenic diseases. Nat Rev Drug Discov, 2011. 10(6): p. 417-27. 
24. 
Trusolino, L., A. Bertotti, and P.M. Comoglio, MET signalling: principles and functions in 
development, organ regeneration and cancer. Nat Rev Mol Cell Biol, 2010. 11(12): p. 834-48. 
25. 
Birchmeier, C., et al., Met, metastasis, motility and more. Nat Rev Mol Cell Biol, 2003. 4(12): p. 
915-25. 
26. 
Comoglio, P.M., S. Giordano, and L. Trusolino, Drug development of MET inhibitors: targeting 
oncogene addiction and expedience. Nat Rev Drug Discov, 2008. 7(6): p. 504-16. 
27. 
Rini, B.I., Metastatic renal cell carcinoma: many treatment options, one patient. J Clin Oncol, 
2009. 27(19): p. 3225-34. 
28. 
Giubellino, A., W.M. Linehan, and D.P. Bottaro, Targeting the Met signaling pathway in renal 
cancer. Expert Rev Anticancer Ther, 2009. 9(6): p. 785-93. 
29. 
Rankin, E.B., et al., Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis 
through SRC and MET. Proc Natl Acad Sci U S A, 2014. 111(37): p. 13373-8. 
30. 
Moura, M.M., et al., Correlation of RET somatic mutations with clinicopathological features in 
sporadic medullary thyroid carcinomas. Br J Cancer, 2009. 100(11): p. 1777-83. 
31. 
Ju, Y.S., et al., A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from 
whole-genome and transcriptome sequencing. Genome Res, 2012. 22(3): p. 436-45. 
32. 
Elisei, R., et al., Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol, 2013. 31(29): 
p. 3639-46. 
33. 
Choueiri, T.K., et al., Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl 
J Med, 2015. 373(19): p. 1814-23. 
34. 
Choueiri, T.K., et al., Cabozantinib versus everolimus in advanced renal cell carcinoma 
(METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol, 2016. 17(7): 
p. 917-27. 
35. 
Chan, J., et. al.,, Phase II trial of cabozantinib in patients with carcinoid and pancreatic 
neuroendocrine tumors. J Clin Oncol, 2017. 35. 
36. 
Kulke, M.H., et al., Future directions in the treatment of neuroendocrine tumors: consensus report 
of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. J Clin 
Oncol, 2011. 29(7): p. 934-43. 
37. 
Zelen, M., The randomization and stratification of patients to clinical trials. J Chronic Dis, 1974. 
27(7-8): p. 365-75. 
38. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
39. 
Brookmeyer, R. and J. Crowley, A Confidence-Interval for the Median Survival-Time. Biometrics, 
1982. 38(1): p. 29-41. 
40. 
Pearman, T.P., et al., Health-related quality of life in patients with neuroendocrine tumors: an 
investigation of treatment type, disease status, and symptom burden. Support Care Cancer, 2016. 
24(9): p. 3695-703. 
41. 
Beaumont, J.L., et al., Comparison of health-related quality of life in patients with neuroendocrine 
tumors with quality of life in the general US population. Pancreas, 2012. 41(3): p. 461-6. 
42. 
Osoba, D., et al., Interpreting the significance of changes in health-related quality-of-life scores. J 
Clin Oncol, 1998. 16(1): p. 139-44. 
43. 
Guyatt, G.H., et al., Methods to explain the clinical significance of health status measures. Mayo 
Clin Proc, 2002. 77(4): p. 371-83. 
44. 
Dueck, A.C., et al., Validity and Reliability of the US National Cancer Institute's Patient-Reported 
Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). JAMA 
Oncol, 2015. 1(8): p. 1051-9. 

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45. 
Cohen, J., Statistical power analysis for the behavioral sciences. 1988, Hillsdale, N.J.: L. Erlbaum 
Associates. 
46. 
Lacy, S.A., D.R. Miles, and L.T. Nguyen, Clinical Pharmacokinetics and Pharmacodynamics of 
Cabozantinib. Clin Pharmacokinet, 2017. 56(5): p. 477-491. 
47. 
Su, Q., et al., An LC-MS/MS method for the quantitation of cabozantinib in rat plasma: application 
to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci, 2015. 985: p. 119-
23. 
48. 
Tolaney, S.M., et al., Phase II and Biomarker Study of Cabozantinib in Metastatic Triple-Negative 
Breast Cancer Patients. Oncologist, 2017. 22(1): p. 25-32. 
49. 
Goyal, L., et al., A phase 2 and biomarker study of cabozantinib in patients with advanced 
cholangiocarcinoma. Cancer, 2017. 
50. 
Leibowitz-Amit, R., et al., Changes in plasma biomarkers following treatment with cabozantinib 
in metastatic castration-resistant prostate cancer: a post hoc analysis of an extension cohort of a 
phase II trial. J Transl Med, 2016. 14: p. 12. 
51. 
George, D.J., Halabi, S., Starr, M. D., Hurwitz, H., Association of on-treatment plasma HGF levels 
with overall survival (OS) in patients (pst) with advanced renal cell carcinoma (RCC) treated with 
interferon alpha (INF) +/- bevacizumab (BEV): Results from CALGB 90206 (Alliance). J Clin 
Oncol, 2017. 35. 
52. 
Scarpa, A., et al., Whole-genome landscape of pancreatic neuroendocrine tumours. Nature, 2017. 
543(7643): p. 65-71. 
53. 
Jiao, Y., et al., DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic 
neuroendocrine tumors. Science, 2011. 331(6021): p. 1199-203. 
54. 
Francis, J.M., et al., Somatic mutation of CDKN1B in small intestine neuroendocrine tumors. Nat 
Genet, 2013. 45(12): p. 1483-6. 
55. 
Karpathakis, A., et al., Prognostic Impact of Novel Molecular Subtypes of Small Intestinal 
Neuroendocrine Tumor. Clin Cancer Res, 2016. 22(1): p. 250-8. 
56. 
Simbolo, M., et al., Lung neuroendocrine tumours: deep sequencing of the four World Health 
Organization histotypes reveals chromatin-remodelling genes as major players and a prognostic 
role for TERT, RB1, MEN1 and KMT2D. J Pathol, 2017. 241(4): p. 488-500. 
57. 
Pal, S.K., et al., Evolution of Circulating Tumor DNA Profile from First-line to Subsequent Therapy 
in Metastatic Renal Cell Carcinoma. Eur Urol, 2017. 
58. 
Jeck, W.R., et al., Targeted next generation sequencing identifies clinically actionable mutations 
in patients with melanoma. Pigment Cell Melanoma Res, 2014. 27(4): p. 653-63. 
59. 
Zhao, X., et al., Combined Targeted DNA Sequencing in Non-Small Cell Lung Cancer (NSCLC) 
Using UNCseq and NGScopy, and RNA Sequencing Using UNCqeR for the Detection of Genetic 
Aberrations in NSCLC. PLoS One, 2015. 10(6): p. e0129280. 
60. 
Montgomery, N.D., et al., Identification of Human Papillomavirus Infection in Cancer Tissue by 
Targeted Next-generation Sequencing. Appl Immunohistochem Mol Morphol, 2016. 24(7): p. 490-
5. 
61. 
Seifert, B.A., et al., Germline Analysis from Tumor-Germline Sequencing Dyads to Identify 
Clinically Actionable Secondary Findings. Clin Cancer Res, 2016. 22(16): p. 4087-94. 
62. 
Lunter, G. and M. Goodson, Stampy: a statistical algorithm for sensitive and fast mapping of 
Illumina sequence reads. Genome Res, 2011. 21(6): p. 936-9. 
63. 
Cancer Genome Atlas Research, N., Comprehensive genomic characterization of squamous cell 
lung cancers. Nature, 2012. 489(7417): p. 519-25. 
64. 
Genomes Project, C., et al., An integrated map of genetic variation from 1,092 human genomes. 
Nature, 2012. 491(7422): p. 56-65. 
65. 
Tennessen, J.A., et al., Evolution and functional impact of rare coding variation from deep 
sequencing of human exomes. Science, 2012. 337(6090): p. 64-9. 
66. 
McLaren, W., et al., The Ensembl Variant Effect Predictor. Genome Biol, 2016. 17(1): p. 122. 

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67. 
Glubb, D.M., et al., Novel Functional Germline Variants in the VEGF Receptor 2 Gene and Their 
Effect on Gene Expression and Microvessel Density in Lung Cancer. Clinical Cancer Research, 
2011. 17(16): p. 5257-5267. 
68. 
Glubb, D.M., et al., Functional FLT1 Genetic Variation is a Prognostic Factor for Recurrence in 
Stage I-III Non-Small-Cell Lung Cancer. Journal of Thoracic Oncology, 2015. 10(7): p. 1067-1075. 
69. 
Innocenti, F., et al., A genome-wide association study (GWAS) of overall survival (OS) in 609 
metastatic colorectal cancer (mCRC) patients treated with chemotherapy and biologics in CALGB 
80405. Journal of Clinical Oncology, 2015. 33(15_suppl): p. 3599-3599. 
70. 
Crona, D., et al., 494 Novel Prognostic and Predictive Germline Genetic Markers of Overall 
Survival in Renal Cell Carcinoma Patients Treated with Sorafenib. European Journal of Cancer. 
48: p. 153. 
 
 

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APPENDIX I 
QUALITY OF LIFE MEASURES 
 
Registration Fatigue/Uniscale Assessments 
 
At patient registration, this form is to be administered by a nurse/CRA, completed by the patient, 
and entered into Medidata Rave at the time of registration. 
 
If needed, this appendix can be adapted to use as a source document. A booklet containing this 
assessment does not exist – please do not order this booklet. 
 
 
 
 
How would you describe: 
 
your level of fatigue, on the average in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Fatigue 
 
 
 
 
 
 
 
 
 
Fatigue 
as bad  
as it can be 
 
your overall quality of life in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
it can be 
 
 
 
 
 
 
 
 
 
As good as 
it can be 
 
 
 
 
 

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National Cancer Institute PRO-CTCAE 
 
_____________________________________________________________________________________ 
 
You have been given a booklet to complete for this study. The booklet contains some questions about 
your ‘quality of life’ and the side effects you are experiencing as a patient receiving treatment for 
cancer. Your answers will help us to better understand how the treatment you are receiving is 
affecting the way you feel. 
 
 
1. This booklet contains one set of questions:  
 
a. National Cancer Institute PRO-CTCAE (12 questions) 
 
2. Please follow the directions at the top of this questionnaire. 
 
3. You may choose not to answer any questions that make you feel uncomfortable. 
 
4. Please complete the booklet during your scheduled clinical visit and return it to your nurse, 
physician, or research coordinator. 
 
 
Thank you for taking the time to help us. 
 
 

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NCI PRO-CTCAETM ITEMS 
Item Library Version 1.0 
_____________________________________________________________________________________ 
 
As individuals go through treatment for their cancer they sometimes experience different symptoms and 
side effects. For each question, please check or mark an X in the one box that best describes your 
experiences over the past 7 days… 
 
1. 
In the last 7 days, what was the SEVERITY of your MOUTH OR THROAT SORES at their 
WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did MOUTH OR THROAT SORES INTERFERE with your usual 
or daily activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
2. 
In the last 7 days, what was the SEVERITY of your PROBLEMS WITH TASTING FOOD OR 
DRINK at their WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
 
3. 
In the last 7 days, what was the SEVERITY of your DECREASED APPETITE at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did DECREASED APPETITE INTERFERE with your usual or 
daily activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
4. 
In the last 7 days, how OFTEN did you have NAUSEA? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost 
constantly 
In the last 7 days, what was the SEVERITY of your NAUSEA at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
 
5. 
In the last 7 days, how OFTEN did you have LOOSE OR WATERY STOOLS (DIARRHEA)? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost 
constantly 
 
6. 
In the last 7 days, did you have any RASH? 
○ Yes 
○ No 
 
7. 
In the last 7 days, what was the SEVERITY of your HAND-FOOT SYNDROME (A RASH OF 
THE HANDS OR FEET THAT CAN CAUSE CRACKING, PEELING, REDNESS, OR 
PAIN) at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
 
The PRO-CTCAE™ items and information herein were developed by the NATIONAL CANCER 
INSTITUTE at the NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the 
PRO-CTCAE™ is subject to NCI's Terms of Use. 
 

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8. 
In the last 7 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR LACK OF 
ENERGY at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did FATIGUE, TIREDNESS, OR LACK OF ENERGY 
INTERFERE with your usual or daily activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
 
Do you have any other symptoms that you wish to report? 
○ Yes 
○ No 
 
Please list any other symptoms: 
1. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very 
severe 
2. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very 
severe 
3. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very 
severe 
4. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very 
severe 
5. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very 
severe 
 
The PRO-CTCAE™ items and information herein were developed by the NATIONAL CANCER 
INSTITUTE at the NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the 
PRO-CTCAE™ is subject to NCI's Terms of Use. 
 
 
 
 
 

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Patient Booklet 
 
_____________________________________________________________________________________ 
 
You have been given a booklet to complete for this study. The booklet contains some questions about 
your ‘quality of life’ and the side effects you are experiencing as a patient receiving treatment for 
cancer. Your answers will help us to better understand how the treatment you are receiving is 
affecting the way you feel. 
 
 
1. This booklet contains three sets of questions:  
 
a. EORTC QLQ-C30 (30 questions) 
b. EORTC QLQ-GI.NET21 (21 questions) 
c. Patient Global Impression of Change (1 question) 
 
2. Please follow the directions at the top of each questionnaire. 
 
3. You may choose not to answer any questions that make you feel uncomfortable. 
 
4. Please complete the booklet during your scheduled clinical visit and return it to your nurse, 
physician, or research coordinator. 
 
 
Thank you for taking the time to help us. 
 
 

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EORTC QLQ - C30 (Version 3) 
_____________________________________________________________________________________ 
We are interested in some things about you and your health. Please answer all of the questions yourself by 
circling the number that best applies to you. There are no "right" or "wrong" answers. The information 
that you provide will remain strictly confidential. 
 
 
 
Not at 
A 
Quite Very 
 
 
All 
Little 
a Bit Much 
1. Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
2.  Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
3.  Do you have any trouble taking a short walk outside 
 
of the house? 
1 
2 
3 
4 
 
4.  Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
 
5.  Do you need help with eating, dressing, washing 
 
yourself or using the toilet? 
1 
2 
3 
4 
 
 
During the past week: 
Not at 
A 
Quite Very 
 
 
All 
Little 
a Bit Much 
 
6.  Were you limited in doing either your work or other 
 
daily activities? 
1 
2 
3 
4 
 
7.  Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
 
8.  Were you short of breath? 
1 
2 
3 
4 
 
9.  Have you had pain? 
1 
2 
3 
4 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
15. Have you vomited? 
1 
2 
3 
4 
 
Please go to next page 

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EORTC QLQ - C30 (Version 3) 
_____________________________________________________________________________________ 
 
During the past week: 
Not at 
A 
Quite Very 
 
 
All 
Little 
a Bit Much 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
18. Were you tired? 
1 
2 
3 
4 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
20. Have you had difficulty in concentrating on things, 
 
like reading a newspaper or watching television? 
1 
2 
3 
4 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
22. Did you worry? 
1 
2 
3 
4 
 
23. Did you feel irritable? 
1 
2 
3 
4 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
 
For the following questions please circle the number between 1 and 7 that best applies to you. 
 
29. How would you rate your overall health during the past week? 
 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
 
 
 
 
 
Excellent 
 
30. How would you rate your overall quality of life during the past week? 
 
 
1 
2 
3 
4 
5 
6 
7 
     Very poor 
 
 
 
 
 
 
                   Excellent 
 
Please go to next page 

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EORTC QLQ – GI.NET21 
___________________________________________________________________________________________________________________ 
Patients sometimes report that they have the following symptoms or problems. Please indicate the extent 
to which you have experienced these symptoms or problems during the past week. Please answer by 
circling the number that best applies to you. 
 
During the past week: 
Not at 
A 
Quite Very 
 
 
All 
Little 
a Bit Much 
 
31. Did you have hot flushes? 
1 
2 
3 
4 
 
32.  Have you noticed or been told by others that you  
 
looked flushed/red? 
1 
2 
3 
4 
 
33.  Did you have night sweats? 
1 
2 
3 
4 
 
34.  Did you have abdominal discomfort? 
1 
2 
3 
4 
 
35.  Did you have a bloated feeling in your abdomen? 
1 
2 
3 
4 
 
36.  Have you had a problem with passing wind/gas/flatulence? 
1 
2 
3 
4 
 
37.  Have you had acid indigestion or heartburn? 
1 
2 
3 
4 
 
38.  Have you had difficulties with eating? 
1 
2 
3 
4 
 
39.  Have you had side-effects from your treatment? 
 
(If you are not on treatment please circle N/A) 
N/A 
1 
2 
3 
4 
 
40. Have you had a problem from repeated injections? 
 
(If not having injections please circle N/A) 
N/A 
1 
2 
3 
4 
 
41. Were you worried about the tumour recurring in other  
 
areas of the body? 
1 
2 
3 
4 
 
42. Were you concerned about disruption of home life? 
1 
2 
3 
4 
 
43. Have you worried about your health in the future? 
1 
2 
3 
4 
 
44. How distressing has your illness or treatment been to  
 
those close to you? 
1 
2 
3 
4 
 
45. Has weight loss been a problem for you? 
1 
2 
3 
4 
 
46. Has weight gain been a problem for you? 
1 
2 
3 
4 
 
47. Did you worry about the results of your tests? 
 
(If you have not had tests please circle N/A) 
N/A 
1 
2 
3 
4 
 
48. Have you had aches or pains in your muscles or bones? 
1 
2 
3 
4 
 
49. Did you have any limitations in your ability to travel? 
1 
2 
3 
4 
 
During the past four weeks: 
 
50. Have you had problems receiving adequate information  
 
about your disease and treatment? 
1 
2 
3 
4 
 
51. Has the disease or treatment affected your sex life (for the worse)? 
 
(If not applicable please circle N/A) 
N/A 
1 
2 
3 
4 
 
Please go to next page 
 

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If you have not started treatment on this study, please stop here. 
 
 
 
 
 
If you have started treatment on this study, 
please complete the one question below. 
 
 
_____________________________________________________________________________________ 
 
Patient Global Impression of Change (PGIC) 
_____________________________________________________________________________________ 
1. Since the start of the study, my overall status is: 
X one box only: 
□ Very Much Improved 
□ Much Improved 
□ Minimally Improved 
□ No Change 
□ Minimally Worse 
□ Much Worse 
□ Very Much Worse 
 
 
 
 
 
 
Thank you for taking the time to help us. 
 
 
 

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APPENDIX II 
PATIENT MEDICATION DIARY 
Patient Initials: __________ Patient ID Number: __________ Study Number: __________ 
Cycle #: _________ Dose: _________   Blinded   
Open-label 
Patient Instructions 
• 
Please fill in on the table below every day that you take your study medication by writing in the 
number of tablets you take, and the date on which you take them. Please bring this sheet with you 
to all appointments. 
• 
Cabozantinib/placebo should be taken by mouth (orally) without food. Do not eat for at least 2 
hours before and at least 1 hour after each dose of cabozantinib/placebo. Grapefruit/juice and 
Seville oranges should be avoided while on cabozantinib/placebo. 
• 
If you miss a dose, please take the missed dose as soon as possible, but only if there are 12 or 
more hours remaining before the next scheduled dose. 
• 
If you miss a dose and the next dose is due (scheduled) in less than 12 hours, then place a “0” for 
the “Number of Tablets” you took that day, and do not take the “missed” dose. Please take the 
next dose as scheduled. 
• 
If vomiting occurs after taking cabozantinib/placebo (even if it appears that an intact or whole 
tablet has been vomited), then do NOT take a replacement dose on that day. Start taking 
cabozantinib/placebo again with the next scheduled dose. If consistent vomiting occurs, please 
notify your study doctor. 
• 
Cabozantinib/placebo tablets should be stored at room temperature; do not crush or chew tablets.   
 
 
 
 
Comments: ___________________________________________________________________________ 
 
Patient Signature: _______________________________________________ 
Date: ______________ 
 
The table below is to be completed ONLY by Site Staff (Nurse/CRP) after the cycle is completed: 
Pill Bottle Returned (Circle) 
Yes            No 
Date of Pill Count (MM/DD/YYYY) 
/            /  
Number of Tablets Given 
 
Number of Tablets Returned 
 
Discrepancy (Circle) 
Yes            No 
Site Staff Initials 
 
Cabozantinib/Placebo 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Number of Tablets 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
Cabozantinib/Placebo 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Number of Tablets 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
Cabozantinib/Placebo 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Number of Tablets 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
Cabozantinib/Placebo 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Number of Tablets 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 

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APPENDIX III PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the experimental study 
drug, XL184 (cabozantinib).  This clinical trial is sponsored by the National Cancer Institute. This form is 
addressed to the patient, but includes important information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
XL184 (cabozantinib) interacts with a specific enzyme in your liver, certain transport proteins that help 
move drugs in and out of cells, and the heart’s electrical activity (QTc prolongation).  
 
• The enzyme in question is CYP3A4. XL184 (cabozantinib) is metabolized by CYP3A4 and may be 
affected by other drugs that inhibit or induce this enzyme. 
• The proteins in question are P-glycoprotein (P-gp) and MRP2.  XL184 (cabozantinib) is an inhibitor 
of P-gp and may be affected by other drugs that are “substrates.” XL184 is also a substrate of MRP2 
and may be affected by other drugs that are “inhibitors” or “inducers” of MRP2.  
• XL184 (cabozantinib) may affect the heart’s electrical activity causing QTc prolongation. The study 
doctor may be concerned about QTc prolongation and any other medicine that is associated with 
greater risk for having QTc prolongation.   
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
XL184 (cabozantinib) may interact with other drugs which can cause side effects. For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this clinical 
trial. It is also very important to tell your doctors if you stop taking any regular medicines, or if you start 
taking a new medicine while you take part in this study. When you talk about your current medications with 
your doctors, include medicine you buy without a prescription (over-the-counter remedy), or any herbal 
supplements such as St. John’s Wort. It is helpful to bring your medication bottles or an updated medication 
list with you. 
 
Many health care providers can write prescriptions. You must tell all of your health care providers (doctors, 
physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical trial.  
 
These are the things that you and they need to know:  
 
XL184 (cabozantinib) must be used very carefully with other medicines that use certain liver enzyme 
transport proteins to be effective or to be cleared from your system or that may affect your heart’s 
electrical activity. Before you enroll onto the clinical trial, your study doctor will work with your regular 
health care providers to review any medicines and herbal supplements that are considered “strong 
inducers/inhibitors of CYP3A4, substrates of P-gp, or any medicines associated with greater risk for 
having QTc prolongation.” 
 
• Please be very careful! Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug. Speak to your doctors or pharmacist to 
determine if there could be any side effects.  

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• Do not drink or eat grapefruit/juice or Seville oranges. 
o Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any medicine. 
o Your study doctor’s name is _____________________________________ and he or she 
can be contacted at _____________________________________. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CLINCIAL TRIAL WALLET 
CARD 
Show this card to all of your 
healthcare providers and 
keep it with you in case you 
go to the emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:  A021602 
Study Drug(S):  Cabozantinib/Placebo 
 
 
 
 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 

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APPENDIX IV PATIENT PHARMACOKINETICS FORM – A021602-PP1 
 
Note: This form is required to be completed at all blood draw time points associated with the 
pharmacokinetic substudy (A021602-PP1). 
 
On Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, and Cycle 3 Day 1, this form is to be 
administered by a nurse/CRP, completed by the patient, and entered into Rave by site staff. 
 Note: study medication should be taken after providing the blood sample. 
 
Patient Initials: ___________  
Patient ID #: _____________  
Study #: _________________ 
Cycle #: _______ 
Day #: _________  
Date: __________ 
 
 
The following question refers to the day before yesterday (2 days ago): 
What time did you take your study medication (cabozantinib/placebo)? __ __:__ __ 
AM / PM 
 
The following question refers to yesterday (1 day ago): 
What time did you take your study medication (cabozantinib/placebo)? __ __:__ __ 
AM / PM 
 
The following question refers to today (THIS ONLY APPLIES IF YOU HAVE TAKEN YOUR 
STUDY MEDICATION BEFORE BEING SEEN IN THE CLINIC TODAY): 
What time did you take your study medication (cabozantinib/placebo)? __ __:__ __ 
AM / PM 
 
 
 
 
 
 
 
 
 
 

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APPENDIX V 
DRUGS WITH RISK OF TORSADES DE POINTES/QTC PROLONGATION 
The following table presents a list of drugs that have a known risk, possible risk, or conditional risk of 
causing Torsades de Pointes. Please note that this list is frequently updated; for the most current list of 
medications, sites should visit the following website: 
  
Known Risk: Drugs that can 
prolong the QT 
interval AND are associated 
with a known risk of Torsades 
de Pointes, even when taken 
as recommended 
Possible Risk: Drugs that can cause 
QT prolongation but currently lack 
evidence for a risk of Torsades de 
Pointes when taken as 
recommended 
Conditional Risk: Drugs that are 
associated with Torsades de 
Pointes BUT only under certain 
conditions of their use (e.g. excessive 
dose, in patients with conditions such as 
hypokalemia, or when taken with 
interacting drugs) OR by creating 
conditions that facilitate or induce 
Torsades de Pointes (e.g. by inhibiting 
metabolism of a QT-prolonging drug or by 
causing an electrolyte disturbance that 
induces Torsades de Pointes). 
Generic/Brand Name 
Generic/Brand Name 
Generic/Brand Name 
Amiodarone /Cordarone® 
Alfuzosin /Uroxatral® 
Amantadine /Symmetrel® 
Amiodarone /Pacerone® 
Aripiprazole / Abilify® 
Amitriptyline /Elavil® 
Arsenic trioxide /Trisenox® 
Chloral hydrate /Noctec® 
Atazanavir /Reyataz® 
Astemizole /Hismanal® 
Clozapine /Clozaril® 
Clomipramine /Anafranil® 
Azithromycin /Zithromax® 
Dolasetron /Anzemet® 
Desipramine /Pertofrane® 
Bepridil /Vascor® 
Dronedarone /Multaq® 
Diphenhydramine /Benadryl® 
Chloroquine /Aralen® 
Efavirenz / Sustiva® 
Diphenhydramine /Nytol® 
Chlorpromazine /Thorazine® 
Famotidine / Pepcid® 
Doxepin /Sinequan® 
Cisapride /Propulsid® 
Felbamate /Felbatrol® 
Esomeprazole / Nexium® 
Cilostazol / Pletal® 
Flecainide /Tambocor® 
Fluconazole /Diflucan® 
Ciprofloxacin / Cipro® 
Foscarnet /Foscavir® 
Fluoxetine /Sarafem® 
Citalopram / Celexa® 
Fosphenytoin /Cerebyx® 
Fluoxetine /Prozac® 
Clarithromycin /Biaxin® 
Gatifloxacin /Tequin® 
Galantamine /Reminyl® 
Disopyramide /Norpace® 
Gemifloxacin /Factive® 
Imipramine /Norfranil® 
Dofetilide /Tikosyn® 
Granisetron /Kytril® 
Itraconazole /Sporanox® 
Domperidone /Motilium® 
Hydroxyzine / Atarax® 
Ketoconazole /Nizoral® 
Donepezil / Aricept® 
Lithium /Lithobid® 
Loperamide / Imodium® 
Droperidol /Inapsine® 
Lithium /Eskalith® 
Paroxetine /Paxil® 
Erythromycin /Erythrocin® 
Moexipril/HCTZ /Uniretic® 
Protriptyline /Vivactil® 
Erythromycin /E.E.S.® 
Moxifloxacin /Avelox® 
Quetiapine /Seroquel® 
Escitalopram / Cipralex® 
Nicardipine /Cardene® 
Ranolazine /Ranexa® 
Fluconazole / Diflucan® 
Nilotinib /Tasigna® 
Sertraline /Zoloft® 

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Known Risk: Drugs that can 
prolong the QT 
interval AND are associated 
with a known risk of Torsades 
de Pointes, even when taken 
as recommended 
Possible Risk: Drugs that can cause 
QT prolongation but currently lack 
evidence for a risk of Torsades de 
Pointes when taken as 
recommended 
Conditional Risk: Drugs that are 
associated with Torsades de 
Pointes BUT only under certain 
conditions of their use (e.g. excessive 
dose, in patients with conditions such as 
hypokalemia, or when taken with 
interacting drugs) OR by creating 
conditions that facilitate or induce 
Torsades de Pointes (e.g. by inhibiting 
metabolism of a QT-prolonging drug or by 
causing an electrolyte disturbance that 
induces Torsades de Pointes). 
Gatifloxacin / Tequin® 
Nortriptyline /Pamelor® 
Solifenacin /VESIcare® 
Grepafloxacin / Raxar® 
Ofloxacin /Floxin® 
Torsemide / Demadex® 
Halofantrine /Halfan® 
Oxytocin /Pitocin® 
Trazodone / Desyrel® 
Haloperidol /Haldol® 
Paliperidone /Invega® 
Trimipramine /Surmontil® 
Ibutilide /Corvert® 
Risperidone /Risperdal® 
 Voriconazole /VFend® 
Levofloxacin / Levaquin® 
Sertindole /Serlect® 
 
Levomethadyl /Orlaam® 
Sertindole /Serdolect® 
 
Mesoridazine /Serentil® 
Sunitinib /Sutent® 
 
Methadone /Dolophine® 
Tacrolimus /Prograf® 
 
Methadone /Methadose® 
Tamoxifen /Nolvadex® 
 
Moxifloxacin / Avelox® 
Telithromycin /Ketek® 
 
Ondansetron / Zofran® 
Tizanidine /Zanaflex® 
 
Pentamidine /Pentam® 
Vardenafil /Levitra® 
 
Pentamidine /NebuPent® 
Venlafaxine /Effexor® 
 
Pimozide /Orap® 
 
 
Probucol /Lorelco® 
 
 
Procainamide /Pronestyl® 
 
 
Procainamide /Procan® 
 
 
Quinidine /Cardioquin® 
 
 
Quinidine /Quinaglute® 
 
 
Roxithromycin / Rulide® 
 
 
Sotalol /Betapace® 
 
  
Sparfloxacin /Zagam® 
 
 
Terfenadine /Seldane® 
  
Thioridazine /Mellaril® 
 
  
 
Note: the above list is not all-inclusive.   
Reference: 
accessed on March 24, 2017. 
 

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APPENDIX VI COLLABORATIVE AGREEMENTS LANGUAGE 
NCI/DCTD Collaborative Agreements Language 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) (hereinafter 
referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the 
following obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to 
Collaborator” 
 contained within 
the terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for 
Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the 
investigators. The protocol documents for studies utilizing Agents contain confidential information 
and should not be shared or distributed without the permission of the NCI. If a copy of this protocol 
is requested by a patient or patient’s family member participating on the study, the individual 
should sign a confidentiality agreement. A suitable model agreement can be downloaded from: 
 
2. For a clinical protocol where there is an investigational Agent used in combination with (an)other 
Agent(s), each the subject of different Collaborative Agreements, the access to and use of data by 
each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be 
referred to as “Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree 
in writing prior to the commencement of the trials that it will use the Multi-Party Data 
solely for development, regulatory approval, and commercialization of its own Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be 
made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional 
disclosure is required by law or court order as described in the IP Option to Collaborator 
 
Additionally, 
all 
Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all 
applicable federal statutes and regulations for the protection of human subjects, including, if 
applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 
45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or 
PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the guidelines 
and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this 
clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group 
office for Cooperative Group studies or by the principal investigator for non-Cooperative Group 
studies for immediate delivery to Collaborator(s) for advisory review and comment prior to 
submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. 
Collaborator shall have the right to request that publication be delayed for up to an additional 30 

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days in order to ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator(s)’s intellectual property rights, are protected. Copies of abstracts must be provided 
to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably 
at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings. Press releases and other media presentations must also be forwarded 
to CTEP prior to release. Copies of any manuscript, abstract, and/or press release/media 
presentation should be sent to: 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, manuscript, or 
other form of public disclosure shall contain any of Collaborator’s confidential/proprietary information.