Clinical trial NCT04497038
Conditions: Advanced Adult Hepatocellular Carcinoma
Sponsor: University of Michigan Rogel Cancer Center
Start date: 2021-08-06; Completion date: 2023-05-02
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The aim of this study is to determine the safety and efficacy of cabozantinib in the management of unresectable or metastatic hepatocellular carcinoma (HCC) with underlying Child-Pugh class B cirrhosis.

Detailed description:

Arms: arm 1: Cabozantinib 20-60 mg by mouth once daily.
Interventions: intervention 1: Cabozantinib
Intervention descriptions: intervention 1: Patients will receive therapy with cabozantinib. Dosage in the trial will start at 40 mg PO daily. Each patient will be assessed for the development of toxicity according to the NCI Common Terminology Criteria for Adverse Events, version 5.0. Dose adjustments may be made per the Time-To-Event modification of the Continual Reassessment Method (TITE-CRM). The maximum dosage will be 60 mg PO daily and the minimum will be 20 mg PO daily.

Protocol documents:
Prot_SAP_000.pdf: 
ID: UMCC 
2020.007 
    Cabozantinib in Patients With Advanced 
Hepatocellular Carcinoma With Child Pugh Class B 
Cirrhosis After First-Line Therapy 
    NCT04497038 
 


Page 1 of 50 
 
UMCC 2020.007 
 
 
Phase 1/2 Trial to Evaluate Cabozantinib in Patients with Advanced Hepatocellular Carcinoma with 
Child Pugh Class B Cirrhosis after First-Line Therapy 
 
Principal/Sponsor-Investigator: 
Vaibhav Sahai, MBBS, MS 
Division of Hematology/Oncology 
Department of Internal Medicine 
University of Michigan 
C412 Med Inn Building 
1500 E. Medical Center Drive 
Ann Arbor, MI 48109 
Phone: 734-936-4991 
Fax: 734-936-4940 
Email: vsahai@med.umich.edu 
 
Co-Principal Investigator: 
Neehar Parikh, MD 
Division of Gastroenterology 
Department of Internal Medicine 
University of Michigan 
1500 E. Medical Center Drive 
Ann Arbor, MI 48109 
Phone: 734-936-8643 
Fax: 734-936-7722 
Email: ndparikh@med.umich.edu 
 
Coordinating Center: 
University of Michigan 
 
 
Biostatistician: 
Kent Griffith, MPH, MS 
University of Michigan 
Center for Cancer Biostatistics 
School of Public Health 
Email: kentg@med.umich.edu 
 
Study Drug: 
Cabozantinib (Cabometyx®) 
 
IND: 
Exempt status 
 
Version: 
01/21/2020 
08/19/2020 
04/19/2023 


Page 2 of 48 
 
 
TABLE OF CONTENTS 
STUDY SYNOPSIS ............................................................................................... 6 
1.0 
BACKGROUND AND RATIONALE ..................................................... 8 
1.1 
Hepatocellular Carcinoma - Background .......................................................................... 8 
1.2 
Management of HCC Patients with Child-Pugh B Cirrhosis ............................................. 8 
1.3 
Rationale .......................................................................................................................... 9 
2.0 
STUDY OBJECTIVES .......................................................................... 9 
2.1 
Primary Objectives ........................................................................................................... 9 
2.2 
Secondary Objectives ...................................................................................................... 9 
2.3 
Exploratory Objectives ..................................................................................................... 9 
2.4 
Endpoints Assessment ..................................................................................................... 9 
3.0 
PATIENT ELIGIBILITY ....................................................................... 10 
3.1 
Eligibility Criteria ............................................................................................................. 10 
4.0 
SUBJECT SCREENING AND ENROLLMENT PROCEDURES ......... 12 
5.0 
TREATMENT PLAN ........................................................................... 13 
5.1 
Treatment Dosage and Administration ........................................................................... 13 
5.2 
Toxicities and Dosing Delays/Dose Modifications .......................................................... 14 
5.3 
Concomitant Medications/Treatments ............................................................................ 21 
5.4 
Other Modalities or Procedures ...................................................................................... 21 
5.5 
Duration of Therapy ....................................................................................................... 21 
5.6 
Off Treatment Criteria..................................................................................................... 22 
5.7 
Duration of Follow-Up..................................................................................................... 22 
5.8 
Off Study Criteria ............................................................................................................ 22 
5.9 
Patient Replacement ...................................................................................................... 22 
6.0 
STUDY PROCEDURES ..................................................................... 22 


Page 3 of 48 
 
 
6.1 
Screening/Baseline Procedures ..................................................................................... 22 
6.2 
Time and Events Table/Schedule of Events/Study Calendar ......................................... 24 
7.0 
MEASUREMENT OF EFFECT ........................................................... 26 
7.1 
Antitumor Effect- Solid Tumors ...................................................................................... 26 
7.2 
Safety/Tolerability ........................................................................................................... 30 
8.0 
ADVERSE AND OTHER REPORTABLE EVENTS ............................ 30 
8.1 
Adverse Event Reporting Requirements ........................................................................ 30 
8.2 
Definitions ...................................................................................................................... 30 
8.3 
Adverse Event Characteristics ....................................................................................... 32 
8.4 
Serious Adverse Event Reporting Guidelines ................................................................ 32 
8.5 
Routine Reporting .......................................................................................................... 33 
8.6 
Reporting of Pregnancy ................................................................................................. 33 
8.7 
Reporting of Unanticipated Problems ............................................................................. 33 
8.8 
Safety Report Reconciliation .......................................................................................... 34 
8.9 
Stopping Rules ............................................................................................................... 34 
9.0 
DRUG INFORMATION ....................................................................... 34 
9.1 
Cabozantinib .................................................................................................................. 34 
10.0 
CORRELATIVES/TRANSLATIONAL STUDIES ................................ 36 
10.1 
Pharmacokinetic Analysis .............................................................................................. 36 
10.2 
Tissue Collection ............................................................................................................ 36 
10.3 
Blood Collection ............................................................................................................. 37 
10.4 
Centralized Imaging ....................................................................................................... 37 
10.5 
Specimen Banking ......................................................................................................... 37 
11.0 
STATISTICAL CONSIDERATIONS ................................................... 37 
11.1 
Study Design/Study Endpoints ....................................................................................... 37 
11.2 
Sample Size and Accrual ............................................................................................... 37 


Page 4 of 48 
 
 
11.3 
Dose Allocation .............................................................................................................. 39 
11.4 
Data Analyses Plans ...................................................................................................... 40 
12.0 
ADMINISTRATIVE PROCEDURES ................................................... 40 
12.1 
Ethics and Good Clinical Practice .................................................................................. 40 
12.2 
Data Management .......................................................................................................... 40 
12.3 
Record Retention ........................................................................................................... 41 
13.0 
DATA AND SAFETY MONITORING .................................................. 41 
14.0 
QUALITY ASSURANCE AND AUDITS .............................................. 41 
15.0 
CLINICAL MONITORING PROCEDURES ......................................... 42 
16.0 
REFERENCES ................................................................................... 43 
17.0 
APPENDICES .................................................................................... 44 


Page 5 of 48 
 
 
ABBREVIATIONS: 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSU 
Clinical Trials Support Unit 
DILI 
Drug Induced Liver Injury 
DLT 
Dose Limiting Toxicity 
DSMC 
Data and Safety Monitoring Committee 
H&P 
History & Physical Exam 
HCC 
Hepatocellular Carcinoma 
HRPP 
Human Research Protections Program 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
MSPM 
Multi-Site Project Manager 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
PO 
per os/by mouth/orally 
PR 
Partial Response 
PRC 
Protocol Review Committee 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
TiTE-CRM 
Time-To-Event modification of the Continual Reassessment Method 
TTP 
Time to Progression 
UaP 
Unanticipated Problem 
WBC 
White Blood Cells 


Page 6 of 48
STUDY SCHEMA
Title
Phase 1/2 Trial to Evaluate Cabozantinib
in Patients with Advanced 
Hepatocellular Carcinoma with Child Pugh Class B Cirrhosis after First-Line 
Therapy
Phase
Phase I/II
Methodology
Single arm
Study Duration
3 years
Study Center(s)
Multi-Center: up to 4 sites total including lead site: University of Michigan
Objectives
Primary Objectives
1.
Determine the maximum tolerated dose/recommended phase 2 dose 
(RP2D) for cabozantinib in patients with HCC with underlying Child-Pugh B 
cirrhosis
Secondary Objectives
1.
Evaluate the overall response rate, median TTP, PFS and OS of patients 
with advanced HCC.
2.
Evaluate the safety and tolerability of cabozantinib in this patient population.
3.
Characterize the pharmacokinetic (PK) profile of cabozantinib in this patient 
population
Exploratory Objectives
1.
To explore predictors of biomarker response and mechanisms of resistance 
based on the exploratory analysis of tumor tissue obtained through serial 
biopsies and blood, when available.
a.
Levels of PD-L1 (B7-H1), PD-L2, T cell subset, myeloid-derived cell 
subset infiltration by immunohistochemistry (IHC) at baseline, at 2 
months and progression.
b.
Whole exome genomic and transcriptomic (RNAseq) analysis for 
MET, VEGF, AXL and immune signature at baseline, and 
progression, if tissue is available.
c.
Collection of blood in Streck tubes for plasma and PBMC collection 
for future cfDNA and immune cell subset analysis, respectively
Number of 
Subjects
32
Eligibility Criteria
See Section 3.1 for Eligibility Criteria.
Advanced HCC with Child-
Pugh B cirrhosis that have 
either progressed or
STUdeDeYmSeYdNinOtoPleSrIaSnt of
STUDY SYNOPSIS
first-line systemic therapy
Continual Reassessment
Method (N=32)
Dose level 0 – 20 mg PO daily 
Dose level 1 – 40 mg PO daily 
Dose level 2 – 60 mg PO daily


Page 7 of 48 
 
 
 
Study Product(s), 
Dose, Route, 
Regimen 
 
Cabozantinib 20-60 mg by mouth once daily 
Duration of 
Administration 
 
Patients may be treated on study for no longer than 2 years. 
 
 
 
 
 
 
 
Statistical 
Methodology 
This protocol will enroll patients with unresectable or metastatic, Child-Pugh B7 
or B8 HCC to receive cabozantinib in a Phase 1/2 study to confirm the safety 
profile and the recommended Phase 2 dose (RP2D) in this patient population. 
The primary endpoint is the assessment of dose-limiting toxicity during the first 
29-days of therapy. The secondary endpoints include ORR (PR+CR) per RECIST 
v1.1 criteria during active study treatment, safety, PFS and OS. PK assessment 
will also be completed for this cohort. 
 
The trial will be monitored using the Time-To-Event modification of the Continual 
Reassessment Method (TITE-CRM). This method assumes a model for the time 
to occurrence of toxic responses as a function of the dose. The time-to-event 
modification allows information from all patients enrolled and treated (even those 
with only partial observation) to contribute information for calculating the dose- 
toxicity relationship. This method is flexible with regard to the number of patients 
treated at each dose level, patients may be continuously recruited throughout the 
trial, without recruitment pauses, as long as patients are assigned a dose deemed 
safe at the time of enrollment. 


Page 8 of 48 
 
 
1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Hepatocellular Carcinoma - Background 
Hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer related death worldwide 
(El-Serag and Rudolph 2007). In the U.S. it is increasing in frequency and highly morbid, 
accounting over 30,000 deaths per year. HCC typically develops in patients with cirrhosis, 
which partially accounts for the high mortality seen in this population, with 5-year survival 
estimates at 18-20%. Patients with early stage disease may be eligible for curative 
therapies, however the majority of patient present with late stage HCC. The first-line 
systemic therapies for HCC include multikinase inhibitors, sorafenib and lenvatinib. The 
phase 3 SHARP trial randomized patients with untreated HCC with underlying Child-Pugh 
A cirrhosis to either sorafenib or placebo and noted a median overall survival of 10.7 and 
7.9 months (HR 0.69; P, <.001), respectively (Llovet, Ricci et al. 2008). More recently, a 
non-inferiority phase 3 trial randomized patients to either lenvatinib or sorafenib in the same 
patient population, and showed that overall survival was 13.6 versus 12.3 months (HR 
0.92), respectively (Kudo, Finn et al. 2018). 
 
After progression on sorafenib, five medications have received FDA approval in HCC. The 
phase 3 RESORCE trial evaluated regorafenib versus placebo in patients with HCC after 
sorafenib failure with Child-Pugh A cirrhosis and an ECOG performance status score of 0- 
1, and noted a median overall survival (OS) of 10.6 and 7.8 months (HR, 0.63; P, <.0001), 
respectively (Bruix, Qin et al. 2017). Nivolumab, an anti-PD1 immune checkpoint inhibitor, 
was evaluated in patients with unresectable HCC previously treated with sorafenib with 
Child-Pugh class A cirrhosis on the CheckMate040 trial, and was found to have an overall 
response rate (ORR) of 18.2%, and thus has gained FDA approval as a second-line 
therapy for unresectable HCC (El-Khoueiry, Sangro et al. 2017). Pembrolizumab, another 
anti-PD1 immune checkpoint inhibitor was also approved for second-line HCC therapy 
based on a 17% ORR in the phase-2 KEYNOTE 224 study (Zhu, Finn et al. 2018). 
Ramucirumab, a monoclonal antibody targeting VEGFR2, gained second line approval for 
patients with HCC and an alpha fetoprotein level greater than 400 based on the results of 
the Phase 3 REACH-2 study (Zhu, Kang et al. 2019). The phase 3 CELESTIAL trial 
evaluated cabozantinib versus placebo in patients with HCC after sorafenib failure with 
Child-Pugh A cirrhosis and an ECOG performance status score of 0-1, and noted a median 
overall survival (OS) of 10.2 and 8.0 months (HR, 0.76; P, .005), respectively (Abou-Alfa, 
Meyer et al. 2018). 
 
1.2 
Management of HCC Patients with Child-Pugh B Cirrhosis 
There are no approved second-line systemic therapies in patients with more advanced 
cirrhosis (Child-Pugh classes B or C), which represents a significant proportion of patients 
who present with advanced HCC. In the GIDEON study, an international observational 
study of patients on sorafenib, over 20% of patients had Child-Pugh B cirrhosis at 
presentation (Lencioni, Kudo et al. 2014). There are minimal prospective data to evaluate 
the safety and efficacy of the currently approved second-line therapies for HCC in Child- 
Pugh B cirrhosis. An Italian prospective database on the use of sorafenib in patients with 
HCC with no prior therapy and underlying Child-Pugh A (n=234) and B (n=63) patients 
showed the Child-Pugh class B patients, regardless of disease spread, had a higher risk of 
death than those with Child-Pugh class A function (OS 3.8 versus 10.0 months (P, <.001), 
respectively). Moreover, Child-Pugh class B patients with a B8 + B9 score did worse in 
terms of OS compared with those with a B7 score. However, the median time to 
progression (TTP) in each respective arm was 4.2 and 3.8 months with no statistical 
significance. Additionally, the median daily dose between the 2 arms was also not 
statistically different and the study concluded that the drug is tolerable and patients with 
Child-Pugh class B may be safely treated with sorafenib (Pressiani, Boni et al. 2013). 


Page 9 of 48 
 
 
However, there are no prospective trial data, and thus there is a significant unmet need for 
systemic therapeutic options in this patient population. 
 
1.3 
Rationale 
Patients with unresectable HCC with underlying Child-Pugh class B cirrhosis have no 
options for systemic therapy based on current guidelines and available evidence. The aim 
of this study is to determine the safety and efficacy of cabozantinib in the management of 
HCC in this patient population. 
 
 
2.0 
STUDY OBJECTIVES 
 
2.1 
Primary Objectives 
 
2.1.1 
Determine the maximum tolerated dose/recommended phase 2 dose (RP2D) for 
cabozantinib in patients with HCC with underlying Child-Pugh B cirrhosis 
 
2.2 
Secondary Objectives 
 
2.2.1 
Evaluate the overall response rate, median TTP, PFS and OS of patients with 
advanced HCC. 
 
2.2.2 
Evaluate the safety and tolerability of cabozantinib in this patient population. 
 
2.2.3 
Characterize the pharmacokinetic (PK) profile of cabozantinib in this patient 
population 
 
2.3 
Exploratory Objectives 
2.3.1 
To explore predictors of biomarker response and mechanisms of resistance 
based on the exploratory analysis of tumor tissue obtained through serial 
biopsies and blood, when available. 
a) Levels of PD-L1 (B7-H1), PD-L2, T cell subset, myeloid-derived cell 
subset infiltration by immunohistochemistry (IHC) at baseline, at 2 
months and progression. 
b) Whole exome genomic and transcriptomic (RNAseq) analysis for MET, 
VEGF, AXL and immune signature at baseline, and progression, if tissue 
is available. 
c) Collection of blood in Streck tubes for plasma and PBMC collection for 
future cfDNA and immune cell subset analysis, respectively 
 
2.4 
Endpoints Assessment 
2.4.1 
Primary Endpoint Assessment: Determine the maximum tolerated 
dose/recommended phase 2 dose by assessment of dose-limiting toxicities 
(DLTs). 
 
2.4.2 
Secondary Endpoint Assessment: The progression-free survival (PFS) will be 
defined as time from date of treatment to date of radiological or clinical 
progression (leading to withdrawal from the study), or death from any cause, 
whichever comes first. The time to progression (TTP) will be defined as time from 
date of treatment to date of radiological or clinical progression (leading to 
withdrawal from the study). Follow-up time will be censored at the date of last 
disease evaluation. Overall survival (OS) will be defined from the date of 
treatment to either date of death or censoring. Adverse events and reportable 
serious events are defined by the study protocol (NCI Common Toxicity Criteria 
for Adverse Events (CTCAE) v5.0). 


Page 10 of 48 
 
 
 
 
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the eligibility criteria to be enrolled to the study. Study treatment may 
not begin until a subject is enrolled. 
 
3.1 
Eligibility Criteria 
 
3.1.1 
Patients must have a radiologically consistent (early enhancement and delayed 
enhancement washout) or pathologically confirmed diagnosis of hepatocellular 
carcinoma that is not eligible for curative resection, transplantation, or ablative 
therapies. 
 
3.1.2 
Prior radiation, liver directed therapy (including bland, chemo- or radio- 
embolization, or ablation), or hepatic resection are permitted if >4 weeks from 
start of therapy. Extra-hepatic palliative radiation is permitted if completed >2 
weeks prior to first dose of study therapy and the patient has recovered to < 
grade 1 toxicity. 
 
3.1.3 
Patients must have radiographically measurable disease (RECIST1.1) in at least 
one site not previously treated or with progression after radiation or liver directed 
therapy (including bland, chemo- or radio-embolization, or ablation) either within 
the liver or in a metastatic site. 
 
3.1.4 
Patients must have either progressed or deemed intolerant of first-line systemic 
therapy. More than one line of systemic therapy is not permitted. The last dose 
should be at least 2 weeks from first dose of study therapy. Prior treatment may 
not contain cabozantinib. 
 
3.1.5 
Recovery to ≤ grade 1 from toxicities related to any prior treatments, unless the 
AEs were clinically non-significant and/or stable on supportive therapy 
 
3.1.6 
Must be ≥ 18 years of age. 
 
3.1.7 
Must have a Child-Pugh score of B7 or B8 
 
3.1.8 
Must have an ECOG performance status of 0-1. 
 
3.1.9 
Ability to understand and willingness to sign IRB-approved informed consent. 
 
3.1.10 Willing to provide archived tissue, if available, from a previous diagnostic biopsy. 
 
3.1.11 Must be able to tolerate CT and/or MRI with contrast. 
 
3.1.12 Adequate organ function obtained ≤ 2 weeks prior to enrollment: 
 
absolute neutrophil count 
≥ 1200/mm3 
hemoglobin 
≥ 8.5 g/dL 
platelets 
≥ 60,000/mm3 
serum creatinine 
≤ 1.5 x ULN 
creatinine clearance 
≥ 40 mL/min 
albumin 
≥ 2.8 g/dL 
AST/ALT 
≤ 5.0 x ULN 
total bilirubin 
≤ 3.0 mg/dL 
INR 
≤ 2.3 


Page 11 of 48 
 
 
 
 
3.1.13 Must not have uncontrolled ascites (requiring paracentesis within 3 months of 
screening) or hepatic encephalopathy requiring hospitalization (within 6 months 
of screening) 
 
3.1.14 Must not have prior history of organ transplantation. 
 
3.1.15 No known brain metastasis unless adequately treated with radiotherapy and/or 
surgery and stable for at least 4 weeks before registration. Eligible subjects must 
have been without corticosteroid treatment at the time of registration. 
 
3.1.16 Must not have undergone a major surgery (e.g., GI surgery, removal or biopsy of 
brain metastasis) within 8 weeks before first dose of study treatment. Complete 
wound healing from major surgery must have occurred 1 month before first dose 
and from minor surgery (e.g., simple excision, tooth extraction) at least 10 days 
before first dose. Subjects with clinically relevant ongoing complications from 
prior surgery are not eligible. 
 
3.1.17 Must not have an active second malignancy other than non-melanoma skin 
cancer or cervical carcinoma in situ. Patients with history of malignancy are 
eligible provided primary treatment of that cancer was completed > 1 year prior to 
enrollment and the patient is free of clinical or radiologic evidence of recurrent or 
progressive malignancy. 
 
3.1.18 Must not have uncontrolled, significant intercurrent or recent illness including, but 
not limited to the following conditions: 
a. Cardiovascular disorders: 
i. Congestive heart failure New York Heart Association Class 3 or 4, 
unstable angina pectoris, serious cardiac arrhythmias. 
ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 
150 mm Hg systolic or > 100 mm Hg diastolic despite optimal 
antihypertensive treatment. 
iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction 
(MI), or other ischemic event, or thromboembolic event (e.g., deep venous 
thrombosis, pulmonary embolism) within 6 months before first dose. 
iv. Presence of known arterial aneurysm. 
b. Gastrointestinal (GI) disorders including those associated with a high risk of 
perforation or fistula formation: 
i. The subject has evidence of tumor invading the GI tract, active peptic 
ulcer disease, inflammatory bowel disease (e.g., Crohn’s disease), 
diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute 
pancreatitis, acute obstruction of the pancreatic duct or common bile duct, 
or gastric outlet obstruction. 
ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal 
abscess within 6 months before first dose. Note: Complete healing of an 
intra-abdominal abscess must be confirmed before first dose. 
c. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 
teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., 
pulmonary hemorrhage) within 12 weeks before first dose. 
d. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial 
disease manifestation. 
e. Lesions invading or encasing any major blood vessels except thromboses of 
portal/hepatic vasculature attributed to underlying liver disease and/or liver 
tumor. 
f. 
Other clinically significant disorders that would preclude safe study 
participation. 


Page 12 of 48 
 
 
i. Serious non-healing wound/ulcer/bone fracture. 
ii. Uncompensated/symptomatic hypothyroidism. 
iii. Known HIV 
 
3.1.19 Must not have untreated or incompletely treated varices with bleeding or high risk 
for bleeding. Subjects treated with adequate endoscopic therapy (in accordance 
with institutional standards) without any episodes of recurrent overt GI bleeding 
requiring transfusion or hospitalization for at least 6 months prior to study entry 
are eligible. 
 
3.1.20 Must not have a psychiatric illness, other significant medical illness, or social 
situation (such as involuntary incarceration) which, in the investigator’s opinion, 
would limit compliance or ability to comply with study requirements. 
 
3.1.21 Women must not be pregnant or breastfeeding since cabozantinib may harm the 
fetus or child. All females of childbearing potential (not surgically sterilized and 
between menarche and 1-year post menopause) must have a blood or urine test 
to rule out pregnancy within 2 weeks prior to registration. 
 
3.1.22 Women of child-bearing potential (not surgically sterilized and between 
menarche and 1-year post menopause) and men must agree to use 2 methods 
of adequate contraception (hormonal plus barrier or 2 barrier forms) OR 
abstinence prior to study entry, for the duration of study participation, and for 4 
months following completion of study therapy. Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she should 
inform her treating physician immediately. 
 
3.1.23 Prisoners or subjects who are involuntarily incarcerated, or compulsorily detained 
for treatment of either a psychiatric or physical (e.g. infectious disease) illness 
would be excluded. 
 
3.1.24 Concomitant treatment with strong inducers or inhibitors of CYP3A4 is not allowed 
(see Appendix III). Patients must discontinue the drug(s) at least 14 days prior to 
first study dose on the study. 
 
3.1.25 Concomitant anticoagulation with oral anticoagulants (e.g. warfarin, direct 
thrombin and factor Xa inhibitors), or platelet inhibitors (e.g. clopidogrel) is not 
allowed. The following anticoagulants are allowed: 
 
a. Low dose aspirin 
b. Prophylactic dose low molecular weight heparin 
c. Therapeutic dose low molecular weight heparin is allowed in subjects without 
brain metastasis who have been on a stable dose for at least 6 weeks before 
the first dose of study therapy, and have had no clinically significant 
hemorrhagic complications from the anticoagulation regimen. 
 
3.1.26 Must not have corrected QT interval calculated by the Fridericia formula (QTcF) > 
500 ms per electrocardiogram (ECG) within 28 days before first dose of study 
treatment. Note: If a single ECG shows a QTcF with an absolute value > 500 ms, 
two additional ECGs at intervals of approximately 3 min must be performed within 
30 min after the initial ECG, and the average of these three consecutive results for 
QTcF will be used to determine eligibility. 
 
 
4.0 
SUBJECT SCREENING AND ENROLLMENT PROCEDURES 


Page 13 of 48 
 
 
Patient enrollment for this trial will be centrally managed by the Oncology Clinical Trials Support 
Unit (i.e. the Coordinating Center) of The University of Michigan Rogel Cancer Center as 
described below: 
 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on the Screening and 
Enrollment Log provided by the Coordinating Center. 
 
It is the responsibility of the local site investigator to determine patient eligibility prior to submitting 
patient enrollment request to the Coordinating Center. After patient eligibility has been 
determined, a copy of the completed Eligibility Worksheet together with all the pertinent de- 
identified source documents will be submitted by the requesting site to the Coordinating Center, 
by email to CTSU-Oncology-Multisite@med.umich.edu. 
 
A Multi-Site Coordinator of the Coordinating Center, who acts as the registrar, will review the 
submitted documents and process the enrollment. Sites should inform the Multi-Site Coordinator 
of a potential enrollment by 5 p.m. on the day prior to enrollment. Same day enrollments cannot 
be guaranteed. 
 
The registrar will send an email to the requesting site registrar to confirm patient enrollment and 
randomization and to provide the study identification number and randomization number assigned 
to the patient. In addition, a copy of the completed Eligibility Worksheet signed and dated by the 
registrar will be sent back to the requesting site registrar. 
 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in the Screening and Enrollment Log. These patients will not 
have study identification number assigned to them, and will not receive study treatment. 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Treatment Dosage and Administration 
Protocol treatment must start within 14 calendar days of enrollment otherwise the patient 
will be taken off study. Re-screening is allowed. 
 
5.1.1 
Dose Levels 
Patients will receive therapy with cabozantinib starting at dose level 1. The safety 
profile of this agent has been previously evaluated in patients with HCC with 
underlying Child-Pugh A cirrhosis (6). Patients may continue treatment in 
absence of disease progression or unacceptable toxicity for no longer than 2 
years. 
 
Table 1. Dose Levels 
Dose Level 
Cabozantinib Dose (Q28 days) 
0 
20 mg PO Daily 
1* 
40 mg PO Daily 
2 
60 mg PO Daily 
*starting dose level 
 
Cabozantinib must be taken on an empty stomach. Subjects must be instructed 
not to eat for at least 2 hours before and at least 1 hour after taking cabozantinib. 


Page 14 of 48 
 
 
Subjects should be instructed to take their cabozantinib dose at approximately 
the same time every day. If a subject misses a dose, the dose may be taken later 
only if it is within 12 hours of when the missed dose should have been taken. The 
missed dose should not be made up if it is within 12 hours of the next scheduled 
dose. 
 
Cabozantinib tablets should be swallowed whole with at least 8 ounces of water. 
The tablets should not be crushed. Grapefruit, grapefruit juice, seville oranges 
and their products should be avoided by subjects taking cabozantinib. 
 
5.1.2 
Dose Limiting Toxicities 
A DLT will be any of the following occurring during the first 29 days of therapy, 
attributed (possibly, probably, or definitely) to the drug following day 1 treatment 
as assessed per the NCI CTCAE v5.0. 
 
1. Grade 4 or greater hematological toxicity with the exception of uncomplicated 
grade 4 leukopenia/ neutropenia lasting <7 days) 
2. Grade 3 or higher thrombocytopenia with bleeding 
3. Grade 3 or greater febrile neutropenia. 
4. Grade 3 or greater non-hematological toxicity, except nausea, vomiting, 
diarrhea (exception only when lasting <3 days, or without supportive care 
measures, such as anti-diarrheal medications), hyperbilirubinemia (secondary 
to biliary obstruction), alopecia, fatigue, and hypersensitivity reaction 
5. Any death not clearly due to the underlying disease or extraneous causes. 
6. Grade 3 or higher electrolyte abnormality that lasts >72 hours, or is clinically 
complicated, or does not resolve spontaneously or with conventional medical 
interventions. 
 
Any dose modifications deemed necessary for patient safety during this period by 
the treating investigator would constitute a DLT for that patient – even if not 
meeting the explicit DLT definition as reported in Section 5.1.2. With completion 
of cycle 1, and following DLT determination (yes vs. no) on cycle 2 day 1, cycle 2 
may begin. 
 
Information on dose limiting toxicity events must be entered within one business 
day, recorded locally and entered into Case Report Forms (CRFs) on the web- 
based electronic data capture (EDC) system of the University of Michigan. 
 
5.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Dose 
modifications are not allowed during cycle 1, days 0-29, during DLT determination. Any 
dose modifications deemed necessary for patient safety during this period by the treating 
investigator would constitute a DLT for that patient – even if not meeting the explicit DLT 
definition as reported in Section 5.1.2. Each patient will be assessed for the development 
of toxicity according to the Time and Events Table (Section 6.2). Toxicity will be assessed 
according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 
5.0. Dose adjustments should be made according to the system showing the greatest 
degree of toxicity. 
 
Table 2. Cabozantinib Dose Modifications 
Current Dose 
Adjusted Dose 
60 mg 
40 mg 
40 mg 
20 mg 


Page 15 of 48 
 
 
 
20 mg 
Discontinue 
 
 
5.2.1 
Dose re-escalation to previous dose may be considered at the discretion of the 
investigator for grade 2-3 AEs which have resolved or recovered to grade 1 (or 
baseline) and deemed tolerable and easily managed by optimized supportive 
treatment. All dose reductions for grade 4 AEs will be permanent unless 
otherwise noted. 
 
5.2.2 
If more than one toxicity occurs requiring dose reduction, the dose administered 
should be based on the most severe toxicity. 
 
5.2.3 
Treatment delay of more than 42 days from last intended therapy will result in 
treatment discontinuation unless there is unequivocal evidence that the subject is 
benefitting. In this situation, a subject may be able to restart therapy with a dose 
reduction upon resolution of the toxicity per the discretion of the investigator. 
 
5.2.4 
If a patient experiences neutropenic fever at any point in the treatment cycle, 
chemotherapy will be delayed until ANC > 1,000 and antibiotic treatment of the 
event is completed. When treatment resumes, consider one dose level reduction 
as per Table 2. 
 
5.2.5 
Dose will not be modified for cholangitis attributable to biliary obstruction/stent 
occlusion unless this occurs in the setting of > grade 3 neutropenia. 
 
5.2.6 
Laboratory abnormalities that are not directly attributable to treatment (i.e., 
hyperglycemia) or not clinically relevant (i.e., lymphopenia) do not require 
modification of dosing. 


Page 16 of 48 
 
 
 
Table 3. Dose Modifications for Hematologic Toxicity 
Hematologic Toxicity 
Dose Adjustment for Cabozantinib 
ANC ≥ 1000/mm3 
AND 
Platelets ≥ 60,000/mm3 
 
Treat as scheduled 
ANC 500-999/mm3 
OR 
Platelets 40-59,999/mm3 
Hold cabozantinib up to a maximum of 28 days until ANC ≥ 1000/mm3 AND platelets 
≥ 60,000/mm3 then consider resuming at next lower dose level as detailed in Table 2. If not 
resolved, then discontinue treatment. 
ANC < 500/mm3 
OR 
Platelets < 40,000/mm3 
Hold cabozantinib up to a maximum of 28 days until ANC ≥ 1000/mm3 AND platelets 
≥ 60,000/mm3 then resume at next lower dose level as detailed in Table 2. If not resolved, then 
discontinue treatment. 
Note: Laboratory abnormalities that are not directly attributable to treatment (i.e., basophilia), anemia, or not clinically relevant (i.e., 
lymphopenia) do not require dose modification. All dose adjustments for toxicity will be described in the clinical record. 
 
 
Table 4. Dose Modifications for Non-Hematologic Toxicity 
Non-Hematologic 
Toxicity 
Criteria 
Dose Adjustment for Cabozantinib 
Alopecia 
Any Grade 
No modification to doses 
 
Venous 
thromboembolism 
 
 
Any Grade 
Hold cabozantinib until anticoagulation has been established. No modification to doses. 
Low molecular weight heparins are the preferred management for thrombotic events; oral 
anticoagulants (e.g., warfarin or other coumarin-related agents, direct thrombin or direct 
FXa inhibitors, or antiplatelet agents, or chronic use of aspirin above low dose levels for 
cardioprotection per local applicable guidelines) are not allowed. 
Arterial 
thromboembolism 
Grade >3 
Discontinue cabozantinib 
Visceral perforation 
or fistula formation 
Any Grade 
Discontinue cabozantinib 
Reversible posterior 
leukoencephalopathy 
syndrome 
 
Any Grade 
 
Discontinue cabozantinib 


Page 17 of 48 
 
 
Wound dehiscence 
Any Grade 
Hold cabozantinib until complete healing has taken place 
 
Nausea and vomiting 
Grade >3 (ongoing 
after maximal anti- 
emetic therapy) 
 
Consider decrease or discontinuation of cabozantinib 
 
Hyperbilirubinemia 
 
Grade >3 
Hold cabozantinib up to a maximum of 42 days until toxicity resolves to Grade ≤ 2, then 
consider resuming at same dose as before. If not resolved, then discontinue all treatment. 
Dose will not be modified for cholangitis attributable to biliary obstruction/stent occlusion 
unless this occurs in the setting of >grade 3 neutropenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
Tolerable 
Grade 1-2 
x 
Continue with study treatment and consider dose reduction 
x 
Initiate treatment with an antidiarrheal agent (e.g., loperamide 4 mg followed by 2 mg 
after each episode of diarrhea [maximum: 16 mg loperamide per day]) 
x 
Dietary modifications (e.g., small lactose-free meals, bananas and rice) 
x 
Intake of isotonic fluids (1-1.5 L/day) 
x 
Re-assess after 24 hours: 
o 
Diarrhea resolving to baseline bowel habits: gradually add solid foods and 
discontinue or decrease antidiarrheal treatment after 12 h diarrhea-free interval 
o 
Diarrhea not resolving: Continue/resume antidiarrheal treatment 
 
 
 
 
 
 
 
Intolerable Grade 2, 
Grade 2 > 48 h, 
or ≥ Grade 3 
x 
Interrupt study treatment 
x 
Ask subject to attend clinic 
x 
Rule out infection (e.g., stool sample for culture) 
o 
Administer antibiotics as needed (e.g., if fever or Grade 3-4 neutropenia 
persists > 24 h) 
x 
Administer fluids (1-1.5 L/day orally or IV, as appropriate) for hydration or to correct 
electrolyte abnormalities 
x 
For Grade 3-4 or complicated lower grade diarrhea consider hospitalization and IV 
hydration 
x 
Re-assess after 24 h 
o 
Diarrhea resolving to baseline bowel habits or Grade ≤ 1: consider restarting 
study treatment at reduced dose 
Diarrhea not resolving: Start and or continue antidiarrheal treatment (e.g., loperamide 4 mg 
followed by 2 mg after each episode of diarrhea [maximum: 16 mg loperamide per day]). 
Consider starting second line antidiarrheal or referral to gastroenterologist 


Page 18 of 48 
 
 
 
 
Hemorrhage 
Serious and life- 
threatening bleeding 
events or recent 
hemoptysis (≥ 2.5 mL 
of red blood) 
 
 
Cabozantinib should be discontinued. 
 
 
 
 
 
 
 
 
 
 
 
Hypertension 
> 150 mm Hg 
(systolic) and < 160 
mm Hg 
OR 
> 100 mm Hg 
(diastolic) and < 110 
mm Hg 
x 
Optimize antihypertensive medications by adding new or additional antihypertensive 
medications and/or increase dose of existing medications. 
x 
Reduce cabozantinib treatment by one dose level if optimal antihypertensive therapy 
(usually to include 3 agents) does not result in BP <150 mm Hg systolic or 
<100 mm Hg diastolic 
x 
If subject is symptomatic interrupt cabozantinib treatment 
 
 
 
 
≥ 160 mm Hg 
(systolic) 
OR 
≥ 110 mm Hg 
(diastolic) 
x 
Reduce cabozantinib by one dose level or interrupt cabozantinib treatment per 
investigator discretion 
x 
Add new or additional anti-hypertensive medications and/or increase dose of existing 
medications and monitor subject closely for hypotension. If optimized antihypertensive 
therapy (usually to include 3 agents) does not result in BP < 150 mm Hg systolic or 
< 100 mm Hg diastolic, cabozantinib treatment should be dose reduced further or 
interrupted 
x 
Cabozantinib treatment should be dose interrupted if upper limits of systolic BP (≥ 160 
mm Hg) are sustained and not adequately manageable or if systolic BP is > 180 mm 
Hg or diastolic BP > 110 mm Hg, or if subject is symptomatic 
x 
Re-start cabozantinib treatment at the most tolerable dose and re-escalate only if BP 
falls to and is sustained at < 150 mm Hg systolic and < 100 mm Hg diastolic 
Hypertensive 
emergency 
x 
Discontinue cabozantinib treatment 
 
 
Hand-Foot Syndrome 
 
 
Grade 1 
x 
Cabozantinib treatment may be continued at the current dose if PPES is clinically 
insignificant and tolerable. Otherwise, cabozantinib should be reduced to the next 
lower dose level. Start urea 20% cream twice daily AND clobetasol 0.05% cream once 
daily. Reassess at least weekly; if PPES worsens at any time or does not improve after 
2 weeks, proceed to the intervention guidelines for Grade 2. 


Page 19 of 48 
 
 
 
 
 
 
Grade 2 
x 
Cabozantinib treatment may be continued if PPES is tolerated. Cabozantinib should be 
dose reduced or interrupted if PPES is intolerable. Continue urea 20% cream twice 
daily AND high potency steroid cream (e.g., clobetasol 0.05%) once daily and add 
analgesics (e.g., NSAIDs/gamma-aminobutyric acid agonists) for pain control if 
needed. Reassess at least weekly; if PPES worsens or affects self-care, proceed to 
the intervention guidelines for Grade 3. 
 
 
Grade 3 
x 
Interrupt cabozantinib treatment until severity decreases to Grade 1 or 0. Continue 
treatment of skin reaction with high potency steroid cream (e.g., clobetasol 0.05%) 
twice daily AND analgesics. Resume study drug at a reduced dose if PPES recovers to 
Grade ≤ 1. Discontinue subject from study treatment if PPES does not improve within 
6 weeks. 
Proteinuria 
≤ 1 mg/mg 
(≤ 113.1 mg/mmol) 
x 
No change in cabozantinib treatment or monitoring 
 
 
 
 
 
 
 
> 1 and < 3.5 mg/mg 
(> 113.1 and < 395.9 
mg/mmol) 
x 
Consider confirming with a 24-h protein assessment within 7 days 
x 
No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg or urine protein ≤ 2 
g/24 h on 24-h urine collection. 
x 
Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg on repeat UPCR 
testing or urine protein > 2 g/24 h on 24-h urine collection. Continue cabozantinib on a 
reduced dose if UPCR decreases to < 2 mg/mg. Consider interrupting cabozantinib 
treatment if UPCR remains > 2 mg/mg despite a dose reduction until UPCR decreases 
to < 2 mg/mg. Restart cabozantinib treatment at a reduced dose after a dose 
interruption. 
x 
Repeat UPCR within 7 days and once per week. If UPCR < 1 mg/mg on 2 consecutive 
readings, UPCR monitoring can revert to protocol-specific times. (Second reading is 
confirmatory and can be done within 1 week of first reading.) If UPCR remains > 1 
mg/mg and < 2 mg/mg for 1 month or is determined to be stable (< 20% change) for 1 
month, check urine protein/creatinine per protocol or as clinically indicated. 
Nephrotic syndrome 
x 
Discontinue cabozantinib treatment 
Osteonecrosis 
(including jaw) 
Grade 1-4 
x 
Discontinue cabozantinib treatment 


Page 20 of 48 
 
 
 
 
 
 
Other toxicity 
possibly attributable 
to study treatment 
Intolerable Grade 2 
that cannot be 
adequately managed 
x 
Hold treatment or dose reduction at discretion of treating investigator. 
x 
Note: It is recommended that dose holds be as brief as possible. 
 
Grade 3 
x 
Hold treatment and monitor toxicity every 1-2 weeks. If toxicity resolves to ≤ Grade 1 
(or baseline) within 6 weeks, treatment may be resumed with one dose level reduction. 
x 
Note: It is recommended that dose holds be as brief as possible. 
 
 
Grade 4 
x 
Discontinue cabozantinib unless the following criteria are met: 
o 
Subject is deriving clear clinical benefit as determined by the investigator 
o 
Toxicity can be managed with a dose reduction following recovery to Grade 1 (or 
baseline) and optimal medical care 
Note: Laboratory abnormalities that are not directly attributable to treatment (i.e., hyperglycemia), or can be managed easily (e.g. 
hypokalemia), or are not clinically relevant do not require dose modification. All dose adjustments for toxicity will be described in the clinical 
record. 


Page 21 of 48 
 
 
 
 
5.3 
Concomitant Medications/Treatments 
The following concomitant medications or treatments are not permitted while the patient 
is currently receiving therapy on the protocol: 
x 
Other investigational agents or anticancer treatment 
x 
Concurrent radiation or other locoregional therapy 
x 
Strong CYP3A4 inhibitors and inducers (see Appendix III) 
x 
Oral anticoagulants (e.g., warfarin or other coumarin-related agents, direct 
thrombin or direct FXa inhibitors, or antiplatelet agents such as clopidogrel, or 
chronic use of aspirin above low dose levels for cardioprotection per local 
applicable guidelines). 
x 
Erythropoietic stimulating agents (e.g., epoetin alfa and darbepoetin alfa) 
 
The following concomitant medications or treatments are to be used with caution while 
the patient is currently receiving therapy on the protocol: 
 
x 
Drugs that prolong the QTc interval should be avoided if possible, as 
cabozantinib can prolong the QTc interval 
x 
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. 
x 
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. 
x 
Highly protein-bound medications (e.g. diazepam, furosemide, dicloxacillin, 
propranolol, etc.) should be used with caution during treatment with cabozantinib. 
x 
Grapefruit, star fruit, and seville oranges may also increase plasma 
concentrations of cabozantinib and should be avoided. 
 
5.4 
Other Modalities or Procedures 
None 
 
5.5 
Duration of Therapy 
Treatment may continue for a total of 2 years or until one of the following criteria apply: 
x 
Disease progression as defined in Section 7.0 
x 
Inter-current illness that prevents further administration of treatment 
x 
Unacceptable adverse event(s) 
x 
Sexually active subjects who refuse to use medically accepted barrier 
methods of contraception (e.g., male condom, female condom) during the 
course of the study and for 4 months after discontinuation of study treatment 
x 
Patient who becomes pregnant or is breastfeeding 
x 
Patient who cannot tolerate the minimum protocol-specified dose of study 
treatment 
x 
Request by regulatory agencies for termination of treatment of an individual 
subject or all subjects under the protocol 
x 
Significant noncompliance with the protocol schedule in the opinion of the 
investigator 
x 
Patient voluntarily withdraws from treatment OR 
x 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 


Page 22 of 48 
 
 
5.6 
Off Treatment Criteria 
Patients will be removed from protocol therapy when any of the criteria listed in Section 
5.5 apply. Document in the source the reason for ending protocol therapy and the date 
the patient was removed from treatment. All patients who discontinue treatment should 
comply with protocol specific follow-up procedures as outlined in Section 5.7. The only 
exception to this requirement is when a subject withdraws consent for all study 
procedures or loses the ability to consent freely. 
 
5.7 
Duration of Follow-Up 
After treatment discontinuation, follow-up for survival and initiation of any other anti- 
cancer therapies will be documented every 3 months (+/- 1 week) via telephone or office 
visit documentation for up to 2 years from treatment discontinuation or until death, 
whichever comes first, or 3 years after first date of treatment initiation for those that 
remain on treatment. Patients removed from treatment for unacceptable adverse events 
will also be followed more closely until resolution or stabilization of the adverse event. 
 
5.8 
Off Study Criteria 
Patients can be taken off study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or administrative 
reasons. The reason(s) for discontinuation from study will be documented and may 
include: 
 
5.8.1 
Patient withdraws consent (termination of treatment and follow-up); 
 
5.8.2 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment; 
 
5.8.3 
Termination of the study by the Sponsor, the University of Michigan, or the FDA; 
 
5.8.4 
Patient completes protocol treatment and follow-up criteria; 
 
5.9 
Patient Replacement 
All patients who receive at least one dose of study therapy will be considered evaluable 
for primary endpoint and safety/toxicity. 
 
Patients enrolled in the study will be considered non-evaluable for efficacy under the 
following case scenarios and replaced by additional patients: 
 
1. Patients who received no investigational therapy. 
 
2. Patients meeting off study criteria 5.8.1 and 5.8.2. As this trial assigns the dose level 
based upon real-time assessment of the experience of those treated on trial, any 
partial data from a patient stopping trial therapy early while still within the observation 
period for dose-limiting toxicity due to criteria 5.8.1 and 5.8.2, will continue to have 
their partial data used for dose assignments for future patients. However, this type of 
patient, stopping treatment due to 5.8.1 and 5.8.2 would be replaced to reach the 
trial’s total sample size. 
 
 
6.0 
STUDY PROCEDURES 
 
6.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be 
done only after obtaining informed consent. Assessments performed for clinical 


Page 23 of 48 
 
 
indications (not exclusively to determine study eligibility) may be used for 
baseline values even if the studies were done before informed consent was 
obtained. 


Page 24 of 48 
 
 
 
6.2 
Time and Events Table/Schedule of Events/Study Calendar 
 
Table 5. Study Calendar 
 
Procedures 
 
Screening1 
Cycle 1 
Cycle X 
EOT 
Visit8 
Follow-Up 
Q3 months +/- 
1 week9 
Day 1 
Day 15 
Day 1 
Day 15 
Informed Consent 
X 
 
History, Physical 
Examination 
X 
X 
X 
X 
Weight, BSA 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
Performance Status 
X 
X 
X 
X 
Toxicity Evaluations 
 
X 
X 
X 
Scans with Tumor 
Measurements 
X 
 
X5 
CBC with differential 
X 
X 
X 
X 
CMP2 
X 
X 
X 
X 
AFP 
 
X 
X10 
X 
PT/INR, PTT 
X 
 
Pregnancy Test3 
X 
 
UPCR11 
 
X 
X 
TSH, Free T4 and T3 
 
X 
X 
Concomitant 
Medication Review 
X 
X 
X 
12 lead ECG 
X 
 
PK Blood12 
 
 
X 
X12 
X12 
Research Blood4 
 
X 
X 
X 
Tissue6 
X 
 
X 
Study Drug 
Administration7 
 
X 
X 
X 
Survival Follow-up 
 
 
X 
 
1. All screening procedures to be completed within 2 weeks of enrollment, except imaging which should be ≤ 4 weeks. Protocol 
treatment is to begin <14 days of enrollment. 


Page 25 of 48 
 
 
2. Comprehensive metabolic panel includes BUN/creatinine, sodium, potassium, chloride, glucose, calcium, alkaline phosphatase, AST, 
ALT, total bilirubin and total protein. 
3. Required for females of childbearing potential. Serum or urine pregnancy test per site investigator discretion. 
4. Cycle 1 Day 1 specimens will be collected prior to administration of initial dose, and Cycle X Day 1 specimens will be collected on 
Cycle 4 Day 1. Refer to the lab manual for sample collection and processing details. 
5. MRI or CT (abdomen/pelvis) with contrast along with CT chest with/without contrast will be assessed every 8 + 1 weeks starting from 
C1D1. Imaging assessment of scans at the site should be completed by either a radiologist or an imaging core, and not by the 
oncologist nor via abstraction of data from the subjective/clinical radiology report. 
6. Pre-treatment, diagnostic pathology specimens obtained in the course of standard biopsy or surgery, if available. Procurement of tissue 
is mandatory for enrollment, if available. If tissue from initial biopsy is not available, a repeat biopsy is NOT required and patient will be 
eligible for enrollment. Post-treatment tissue collection, if available. Refer to the lab manual for sample collection and processing details. 
7. See Section 5.1 for details. Study drug administration with associated labs will have a window of + 3 days. 
8. End of treatment (EOT) visit should be completed within 30 days of last treatment. 
9. Patients will be followed every 3 months via telephone or office visit documentation for up to 2 years from treatment discontinuation or 
until death, whichever comes first, or 3 years after first date of treatment initiation for those that remain on treatment. 
10. Check AFP every 8 +/- 1 weeks. May be delayed if drug is not administered within the window. 
11. Urine protein/creatinine ratio 
12. Pharmacokinetic blood draws (pre-dose) prior to Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15 and Cycle 3 Day 1. See lab manual 
for details. 


Page 26 of 48 
 
 
 
7.0 
MEASUREMENT OF EFFECT 
 
7.1 
Antitumor Effect- Solid Tumors 
Objective response assessment will be determined by review of CT or MR scans 
of the chest, abdomen and pelvis using RECIST v1.1 every 8 weeks +/- 1 week 
while patients are on treatment (Eisenhauer, Therasse et al. 2009) . 
 
7.1.1 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with study drug. 
 
Evaluable for primary endpoint, DLT/MTD assessment. All patients that receive 
at least one dose of study therapy will be considered evaluable. Patients 
enrolled to therapy but that never receive study therapy will be replaced. 
 
Evaluable for objective response. All enrolled patients who received at least 1 
cycle(s) of therapy, and had their disease re-evaluated will be considered 
evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
7.1.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
 
x 
10 mm by CT scan (irrespective of scanner type) for studies with a slice 
thickness of <5mm or twice the slice thickness or MRI 
x 
10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non- 
measurable) 
x 
20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Note: Tumor lesions that are situated in a previously irradiated area will only be 
considered measurable, if they have had subsequent progression by at least 5 
mm. 
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm using CT scan), are considered non- 
measurable disease. Bone lesions without measurable soft tissue component, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed 
by CT or MRI), and cystic lesions are all non-measurable. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total should be identified as target lesions and recorded and 


Page 27 of 48 
 
 
measured at baseline. Target lesions should be selected on the basis of their 
size (non-nodal lesions with the longest diameter), be representative of all 
involved organ(s), but in addition should be those that lend themselves to 
reproducible repeated measurements. 
 
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor. Pathological nodes 
that are defined as measurable and may be identified as target lesions must 
meet the criterion of a short axis of ≥15 mm by CT scan. Only the short axis of 
these nodes will contribute to the baseline sum. The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI 
the plane of acquisition may be axial, sagittal or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as 
being 20 mm x 30 mm has a short axis of 20 mm and qualifies as a malignant, 
measurable node. In this example, 20 mm should be recorded as the nodal 
measurement. All other pathological nodes (those with short axis ≥10mm but <15 
mm) should be considered non-target lesions. Nodes that have a short axis 
<10mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
of diameters. If lymph nodes are to be included in the sum, then as noted above, 
only the short axis is added into the sum. The baseline sum of diameters will be 
used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including pathological 
lymph nodes should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required, and these lesions should 
be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. 
‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
 
7.1.3 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start date and never more than 4 weeks before the 
beginning of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during 
subsequent follow-up studies. Imaging-based evaluation should always be done 
rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they 
are superficial and >10 mm diameter as assessed using calipers (e.g. skin 
nodules). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is suggested. As noted above, 
when lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 


Page 28 of 48 
 
 
CT, MRI: MR is the best currently available and reproducible method to measure 
lesions selected for response assessment in HCC. If CT is completed, the 
guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5mm or less. When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because 
they are operator dependent, it cannot be guaranteed that the same technique 
and measurements will be taken from one assessment to the next. If new lesions 
are identified by ultrasound in the course of the study, confirmation by CT or MRI 
is advised. 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in 
trials where recurrence following complete response or surgical resection is an 
endpoint. 
 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. 
 
 
7.1.4 
Response Criteria 
 
7.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted not less than 4 
weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline 
sum LD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD 
of target lesions (with a minimum absolute increase of 5 mm), taking as 
reference the smallest sum LD recorded since the treatment started, or 
the appearance of one or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR (taking 
as reference the baseline sum LD) nor sufficient increase to qualify for 
PD (taking as reference the smallest sum LD since the treatment 
started). 
 
 
7.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions. All 
lymph nodes should be non-pathological in size (<10 mm short axis) 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions. 


Page 29 of 48 
 
 
 
Although a clear progression on non-target lesions in absence of stable 
target lesions is exceptional, the opinion of the treating physician should 
prevail in such circumstances. 
 
7.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 
treatment started). The patient's best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
 
 
Table 6. Response Evaluation as per RECISTv1.1 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response per 
RECISTv1.1 
Confirmed Response 
for this Category 
Requires: 
CR 
CR 
No 
CR 
>4 wks. confirmation 
CR 
CR 
Non-CR/PD 
No 
PR 
>4 wks. confirmation 
PR 
CR 
Non-CR/PD 
No 
 
SD 
CR 
Non-CR/PD 
No 
SD 
Documented at least 
once >4 wks. from 
baseline 
PD 
Any 
Any 
PD 
   
Any 
PD* 
Any 
Any 
Any 
Yes 
* 
Only in exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression 
at that time should be reported as “symptomatic deterioration”. Every effort 
should be made to document the objective progression even after 
discontinuation of treatment. 
NA=not applicable 
 
Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery. 
 
 
7.1.5 
Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started. 


Page 30 of 48 
 
 
7.2 
Safety/Tolerability 
 
Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the CTCAE version 5.0 for reporting of adverse events 
(http://ctep.cancer.gov/reporting/ctc.html). 
 
 
8.0 
ADVERSE AND OTHER REPORTABLE EVENTS 
 
8.1 
Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is 
done to ensure the safety of subjects enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Data on adverse events will be collected from 
the time of the initial study treatment administration through 100 days after the last dose 
of study treatment. Any serious adverse event that occurs more than 100 days after the 
last study treatment and is considered related to the study treatment or intervention must 
also be reported. Serious Adverse Events (SAEs) will continue to be followed until: 
 
x 
Resolution or the symptoms or signs that constitute the serious adverse event 
return to baseline; 
x 
There is satisfactory explanation other than the study treatment for the changes 
observed; or 
x 
Death. 
 
The investigator is responsible for the detection, documentation, grading and assignment 
of attribution of events meeting the criteria and definition of an AE or SAE. The definitions 
of AEs and SAEs are given below. It is the responsibility of the principal investigator to 
ensure that all staff involved in the trial is familiar with the content of this section. 
 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment administration is considered to be pre-existing in nature. Any known pre- 
existing conditions that are ongoing at time of study entry should be considered medical 
history. 
 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 8.3, 
occurring from the initial study treatment administration through 100 days following the 
last dose of the study treatment must be recorded as an adverse event in the patient’s 
source documents and on the CRF regardless of frequency, severity (grade) or assessed 
relationship to the study treatment or intervention. However, with regards to laboratory 
and vital sign abnormalities, only those which require protocol treatment to be modified or 
treatment to be rendered should be reported as AEs 
 
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of 
a pre-existing condition that occurs after the patient begins study treatment is also 
considered an adverse event. However, anticipated fluctuations of pre-existing 
conditions, including the disease under study, that don’t represent a clinically significant 
exacerbation or worsening, need not be reported as AEs. 
 
8.2 
Definitions 
 
8.2.1 Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can be any unfavorable and unintended sign (including an 


Page 31 of 48 
 
 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an experimental intervention, whether or not related to the intervention. 
 
x 
Diagnostic and therapeutic non-invasive and invasive (i.e., surgical) 
procedures will not be reported as adverse events. However, the medical 
condition for which the procedure was performed must be reported if it 
meets the definition of an adverse event unless it is a pre-existing (prior 
to protocol treatment) condition. 
 
8.2.2 Serious Adverse Event 
An adverse event is considered “serious” if, in the view of either the investigator 
or sponsor-investigator, it results in any of the following outcomes: 
 
x 
Death 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
x 
A life-threatening adverse event 
An adverse even is considered ‘life-threatening’ if, in the view of either 
the investigator [or sponsor], its occurrence places the patient or subject 
at immediate risk of death. It does not include an adverse event that, had 
it occurred in a more severe form, might have caused death. 
x 
Inpatient hospitalization or prolongation of existing hospitalization for > 
24 hours 
x 
A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
x 
A congenital anomaly/birth defect 
x 
Important medical event: Any event that may not result in death, be life- 
threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the 
patient and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition of “Serious Adverse Event”. 
Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; 
convulsions that do not result in inpatient hospitalization or the 
development of drug dependency or drug abuse. 
 
Previously planned (prior to signing the informed consent form) surgeries should 
not be reported as SAEs unless the underlying medical condition has worsened 
during the course of the study. Preplanned hospitalizations or procedures for 
preexisting conditions that are already recorded in the patient’s medical history at 
the time of study enrollment should not be considered SAEs. Hospitalization or 
prolongation of hospitalization without a precipitating clinical AE (for example, for 
the administration of study therapy or other protocol-required procedure) should 
not be considered SAEs. However, if the preexisting condition worsened during 
the course of the study, it should be reported as an SAE. 
 
8.2.3 Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory 
abnormalities should occur prior to the reporting of a potential DILI event. All 
occurrences of potential DILIs, meeting the defined criteria, must be reported as 
SAEs. 
 
Potential drug induced liver injury is defined as: 
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 


Page 32 of 48 
 
 
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase) 
AND 
3. No other immediately apparent possible causes of AT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to 
be hepatotoxic. 
 
8.2.4 Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
 
x 
For approved and marketed drugs or devices, those adverse events are 
described in the approved Package Insert (Label). 
x 
For investigational new drugs or devices, those adverse events are 
described in the FDA Investigator’s Brochure. 
x 
In clinical research studies, information on expected adverse events is 
also summarized in the protocol and in the consent document. See 
section 9.1.9 for the list of expected adverse events related to the drug 
under study. 
 
8.2.5 Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in the 
Package Insert, Investigator’s Brochure, in published medical literature, in the 
protocol, or in the informed consent document. 
 
8.3 
Adverse Event Characteristics 
 
8.3.1 CTCAE Term 
(AE description) and grade: 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. All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be down 
loaded from the CTEP web site. (http://ctep.cancer.gov) 
 
8.3.2 Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
RELATED 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
UNRELATED 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study 
treatment/intervention. 
 
8.4 
Serious Adverse Event Reporting Guidelines 
 
8.4.1 Reporting procedures for multi-site trials 
All serious adverse events (SAEs) and unanticipated problems (UPs), regardless 
of causality to study drug, will be reported to the Principal Investigator and also to 
the Coordinating Center. All SAEs and UPs must be reported to the Coordinating 
Center within 1 business day of first awareness of the event. Events should be 


Page 33 of 48 
 
 
reported using the Coordinating Center’s SAE form as available in the study 
database. A copy of the SAE form as available in the study database should be 
sent to the Coordinating Center via fax at 734-232-0744 or via email to CTSU- 
Oncology-Multisite@med.umich.edu within 1 business day of the site’s knowledge 
of the event. 
 
Follow-up information must also be reported within 1 business day of receipt of the 
information by the investigator. 
 
All SAEs and UPs will be reported to the IRB per current institutional standards. 
 
The Coordinating Center will disseminate information regarding SAEs and UPs to 
the participating sites within 5 business days of review of the information by the 
Coordinating Center’s Principal Investigator (or designee in the event of extended 
absence) only in the case that the event(s) is believed to be related (i.e., possibly, 
probably, or definitely) to the study drug. The Coordinating Center will be 
responsible for reporting of events to the FDA and supporters, as appropriate 
(outlined below). 
 
8.4.2 
Reporting procedures to Exelixis 
All Serious Adverse Events (SAEs) occurring from the initial study treatment 
administration through 30 days following the last dose of the study treatment will 
be reported by the Coordinating Center to Exelixis. Any SAEs occurring after 30 
days following the last dose of the study treatment that are believed to be related 
to study drug will also be reported to Exelixis. 
The Coordinating Center will send the initial completed SAE Form within 1 
business day of receipt via email to drugsafety@exelixis.com or fax 650-837- 
7392. 
If only limited information is initially available or an ongoing SAE changes in its 
intensity or relationship to the study drug, or if new information becomes 
available, a follow-up report will be generated and sent to Exelixis within 1 
business day of receipt. 
Pregnancy (in subject or partner) or lactation exposure, although not an SAE, 
should be reported to Exelixis. Forms will be provided to the study sites upon 
request. The outcome of a pregnancy (for a subject or for the partner of a 
subject) and the medical condition of any resultant offspring must be reported to 
Exelixis. Any birth defect or congenital anomaly must be reported as an SAE, 
and any other untoward events occurring during the pregnancy must be reported 
as AEs or SAEs, as appropriate. 
 
8.5 
Routine Reporting 
All other adverse events- such as those that are expected, or are unlikely or definitely not 
related to the study participation- are to be reported annually as part of regular data 
submission. 
 
8.6 
Reporting of Pregnancy 
Pregnancies that occur during study participation or within 6 months of last study dose 
should be reported to the Coordinating Center via e-mail at CTSU-Oncology- 
Multisite@med.umich.edu immediately upon site’s knowledge of the event. 
 
8.7 
Reporting of Unanticipated Problems 
There are types of incidents, experiences and outcomes that occur during the conduct of 
human subjects research that represent unanticipated problems but are not considered 


Page 34 of 48 
 
 
adverse events. For example, some unanticipated problems involve social or economic 
harm instead of the physical or psychological harm associated with adverse events. In 
other cases, unanticipated problems place subjects or others at increased risk of harm, but 
no harm occurs. 
 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse 
event) that may represent an unanticipated problem, the investigator should assess 
whether the incident, experience, or outcome represents an unanticipated problem. The 
incident, experience or outcomes is considered unanticipated if it meets all of the following 
criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency); 
2. Related or possibly related to participation in the research; and 
3. Suggests that the research places subjects or others at a greater risk of harm than was 
previously known or recognized. 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the IRB within 14 calendar days of 
the study team becoming aware of the problem. 
 
8.8 
Safety Report Reconciliation 
The Sponsor will reconcile the clinical database SAE reports transmitted to Exelixis. 
Frequency of reconciliation should be every 3 months and prior to the database lock or final 
data summary. Exelixis will email, upon request from the Investigator, the reconciliation 
report. Requests for reconciliation should be sent via email. The data elements listed on 
the reconciliation report will be used for identification purposes. 
 
8.9 
Stopping Rules 
The DSMC comprised of the principal investigators, co-investigators at University of 
Michigan, study statistician, and multi-site coordinator will be responsible for the continuous 
monitoring of the study for treatment tolerability and efficacy. During the monthly meetings 
current study data will be reviewed and the decision to continue, hold, or stop accrual to 
this study will be formally considered. 
 
 
9.0 
DRUG INFORMATION 
 
9.1 
Cabozantinib 
 
9.1.1 
Other Names 
Cabometyx® 
 
9.1.2 
Classification 
Tyrosine kinase inhibitor/Antineoplastic agent 
 
9.1.3 
Mechanism of Action 
Inhibition of the tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, 
ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2. 
 
9.1.4 
Pharmacokinetics 
1. Distribution: The oral volume of distribution (Vz/F) of cabozantinib is 
approximately 319 L. Cabozantinib is highly protein bound in human plasma 
(≥ 99.7%). 


Page 35 of 48 
 
 
2. Elimination: The predicted terminal half-life is approximately 99 hours and the 
clearance (CL/F) at steady state is estimated to be 2.2 L/hr. 
 
9.1.5 
Storage, Preparation and Stability 
Cabozantinib can be stored at 20°C to 25°C (68°F to 77°F); excursions are 
permitted from 15°C to 30°C (59°F to 86°F). 
 
9.1.6 
Dose and Administration 
1. Dosage: See Section 5.1 
2. Administration: Cabozantinib must be taken on an empty stomach. Subjects 
must be instructed not to eat for at least 2 hours before and at least 1 hour 
after taking cabozantinib. Subjects should be instructed to take their 
cabozantinib dose at approximately the same time every day. If a subject 
misses a dose, the dose may be taken later only if it is within 12 hours of 
when the missed dose should have been taken. The missed dose should not 
be made up if it is within 12 hours of the next scheduled dose. 
 
Cabozantinib tablets should be swallowed whole with at least 8 ounces of 
water. The tablets should not be crushed. Grapefruit, grapefruit juice, Seville 
oranges and their products should be avoided by subjects taking 
cabozantinib. 
 
9.1.7 
Availability 
Cabozantinib tablets are supplied as film coated tablets containing cabozantinib 
malate equivalent to 20 mg and 60 mg of cabozantinib and contain 
microcrystalline cellulose, lactose anhydrous, hydoxypropyl cellulose, 
croscarmellose sodium, colloidal silicon dioxide, magnesium stearate and 
Opadry® yellow. 
 
60 mg tablets are yellow film-coated, oval shaped with no score, debossed with 
“XL” on one side and “60” on the other side of the tablet; available in bottles of 30 
tablets: NDC 42388-023-26 
 
20 mg tablets are yellow film-coated, round shaped with no score, debossed with 
“XL” on one side and “20” on the other side of the tablet; available in bottles of 30 
tablets: NDC 42388-024-26 
 
Doses of 40 mg will comprise of two 20-mg tablets. 
 
9.1.8 
Handling and Disposal 
Cabozantinib disposal should occur in accordance with recommendation from the 
Food and Drug Administration. (https://www.fda.gov/drugs/safe-disposal- 
medicines/disposal-unused-medicines-what-you-should-know) 
 
9.1.9 
Adverse Effects 
1. Adverse Effects: Adverse reactions occurring in ≥ 20% of cabozantinib- 
treated patients in the CELESTIAL clinical trial in patients with HCC, in order 
of decreasing frequency were: diarrhea, decreased appetite, palmar-plantar 
erythrodysesthesia (PPES), fatigue, nausea, hypertension, and vomiting 
(Abou-Alfa, Meyer et al. 2018). Grade 3-4 adverse reactions which occurred 
in ≥ 5% of patients were PPES, hypertension, fatigue, diarrhea, asthenia, 
and decreased appetite. There were 6 adverse reactions leading to death in 
patients receiving cabozantinib (hepatic failure, hepatorenal syndrome, 
esophagobronchial fistula, portal vein thrombosis, pulmonary embolism, 


Page 36 of 48 
 
 
upper gastrointestinal hemorrhage). Other described AEs include GI fistulas 
and perforation (1%), thrombotic events (7%), jaw osteonecrosis (<1%), 
wound complications in the perioperative period, and Reversible Posterior 
Leukoencephalopathy Syndrome. 
 
For a full description of the safety profile of cabozantinib across multiple 
cancers, refer to the Cabozantinib Investigator’s Brochure. 
 
Adverse events may occur within the first few weeks in the course of 
treatment with cabozantinib, as cabozantinib is expected to reach steady 
state exposure at approximately 2 weeks following first dose. Events that 
generally have an early onset include hypocalcemia, hypokalemia, 
thrombocytopenia, hypertension, PPES, abdominal pain, mucosal 
inflammation, constipation, diarrhea, and vomiting. 
 
2. Pregnancy and Lactation: Category D. Based on animal data cabozantinib 
can cause fetal harm when administered to a pregnant woman. 
 
3. Drug Interactions: 
Strong CYP3A4 Inhibitors: Coadministration of a cabozantinib capsule 
formulation with a strong CYP3A4 inhibitor increased the exposure of 
cabozantinib, which may increase the risk of exposure-related adverse 
reactions. Avoid coadministration of cabozantinib with strong CYP3A4 
inhibitors. Reduce the dosage of cabozantinib if coadministration with strong 
CYP3A inhibitors. Reduce the dosage of CABOMETYX if coadministration 
with strong CYP3A4 inhibitors cannot be avoided. Avoidance of grapefruit 
or grapefruit juice is recommended due to the potential for increased 
exposure of cabozantinib. 
 
Strong CYP3A4 Inducers: Coadministration of a cabozantinib capsule 
formulation with a strong CYP3A4 inducer decreased the exposure of 
cabozantinib, which may reduce efficacy. Avoid coadministration of 
cabozantinib with strong CYP3A4 inducers. Increase the dosage of 
cabozantinib if coadministration with strong CYP3A4 inducers cannot be 
avoided. Avoidance of St. John’s Wort is recommended which may lead to 
decreased exposure of cabozantinib. 
 
 
10.0 
CORRELATIVES/TRANSLATIONAL STUDIES 
We will aim to study the HCC tumor microenvironment through the use of pre-treatment tissue 
collection (mandatory, if available, at all sites) as well as post-treatment tissue collection (optional 
for patients enrolled at all sites). Identification of important biologic subsets of HCC patients that 
may have clinical efficacy from cabozantinib will be the overarching goal of this translational 
science. Tissue (previously collected via core biopsy, surgical excision) may be examined by 
whole exome analysis, RNA seq and histologically by immunohistochemistry (IHC). Biologic 
markers and RNA expression will be examined in the context of patient efficacy. 
 
10.1 Pharmacokinetic Analysis 
The pharmacokinetic blood draws occur prior (pre-dose) to Cycle 1 Day 15, Cycle 2 Day 1, 
Cycle 2 Day 15 and Cycle 3 Day 1. See lab manual for details. 
 
10.2 Tissue Collection 
Tissue will be collected at the time points specified in section 6.2 Study Calendar. Please 
refer to the lab manual for sample collection and processing details. 


Page 37 of 48 
 
 
10.3 Blood Collection 
Blood samples will be collected at the time points specified in section 6.2 Study Calendar. 
Please refer to the lab manual for sample collection and processing details. 
 
10.4 Centralized Imaging 
All CT scans will be coded using trial patient and site IDs and shipped or electronically 
uploaded for banking and exploratory endpoint assessment. Please see the lab manual for 
details regarding shipping address and/or information for electronic upload. 
 
10.5 Specimen Banking 
Patient samples collected for this study will be retained at University of Michigan. 
Specimens will be stored indefinitely or until they are used up. If future use is denied or 
withdrawn by the patient, best efforts will be made to stop any additional studies and to 
destroy the specimens. 
 
Specimens being stored long-term for potential use not outlined in the protocol are subject 
to University Policy Governing Tissue Sample Collection, Ownership, Usage, and 
Disposition within all UMMS Research Repositories. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 Study Design/Study Endpoints 
This protocol will enroll patients with unresectable or metastatic HCC to cabozantinib in a 
Phase 1b/2 study design. The trial will be monitored using the Time-To-Event modification 
of the Continual Reassessment Method (TITE-CRM) (Cheung and Chappell 2000) 
(O'Quigley, Pepe et al. 1990). This method assumes a model for the time to occurrence of 
toxic responses as a function of the dose. The time-to-event modification allows 
information from all patients enrolled and treated (even those with only partial observation) 
to contribute information for calculating the dose-toxicity relationship. This method is 
flexible with regard to the number of patients treated at each dose level, patients may be 
continuously recruited throughout the trial, without recruitment pauses, as long as patients 
are assigned a dose deemed safe at the time of enrollment. 
 
The primary endpoint is the occurrence/lack thereof of dose-limiting toxicity (defined in 
Section 5.1.2) during the first 29-days of therapy to identify the maximum tolerated 
dose/recommended Phase 2 dose (RP2D) in this patient population. 
 
11.2 Sample Size and Accrual 
The study will enroll 32 patients for the estimates of the dose-toxicity function. Patients will 
be recruited as available and assigned to treatment according to the estimate probability of 
DLT as described above. No formal cohort size is required; however, at least two patients 
must be observed for their entire acute toxicity period (29 days) before dose escalation is 
allowed. 
 
The operating characteristics of this trial design were evaluated through simulation, both 
near to and far from our expectations for toxicity. Table 7 lists our prior expectations for 
toxicity at each dose level and the simulated ‘truth’ for the four simulation scenarios. The 
simulation scenarios are: 1 – our prior expectations for toxicity are correct, 2 – our prior 
expectations moderately underestimate the true probability of toxicity at all dose levels, 3 – 
our prior expectations moderately overestimate the true probability for toxicity at all dose 
levels, and finally 4 – our prior expectation severely underestimated the true probability for 
toxicity. The MTD or RP2D is in gray; the dose level with the highest estimated probability 
of dose-limiting toxicity not exceeding 0.35. 


Page 38 of 48 
 
 
 
Table 7. Operating Characteristics for Trial Schema 
 
Dose Level 
Expectation 
for probability 
of DLT 
Scenario 
1 
Scenario 
2 
Scenario 
3 
Scenario 
4 
0 
20% 
20% 
20% 
15% 
45% 
1* 
27% 
27% 
35% 
20% 
60% 
2 
35% 
35% 
50% 
30% 
75% 
Other Variables 
Scenario 
1 
Scenario 
2 
Scenario 
3 
Probability of early termination (PET) 
17% 
32% 
7% 
Expected number (EN) of patients 
treated at MTD 
16 
12 
22 
Probability of selecting correct dose 
level as MTD 
70% 
40% 
90% 
*starting dose level 
 
 
The following figure displays the operating characteristics for this trial design under the four 
scenarios. The simulations indicate that this design does a good job of choosing the MTD 
or RP2D and treats a majority of patient at that dose level under scenarios both near to and 
far from expectations. The trial also stops early and protects the patient from the possibility 
of unjustifiable probability of DLT when the reality of the probability of DLT is moderately to 
severely higher than what we expect. 


Page 39 of 48 
 
 
 
 
 
11.3 Dose Allocation 
The dose level for each patient treated on this trial will be determined by the study 
statistician based upon selecting the dose level with the highest estimated probability of 
dose-limiting toxicity not to exceed or threshold of 35%, based upon our prior expectation 
and accumulating trial data; subject to the following constraints: 
x 
The 1st and 2nd patients will be assigned to receive dose level 1
x 
Intra-subject dose escalation is not permitted
x 
The dose may be escalated only 1 dose level between adjacently accrued and 
treated patients. Dose de-escalated between adjacently accrued and treated 
patients is not restricted.
x 
At a minimum two patients at a given dose level are required to be completely 
observed for the DLT observation period (Cycle 1, days 1-28, D1C2 (day 29)) 
before escalation is allowed.
x 
Patients will be recruited as available and assigned to treatment according to the 
TiTE-CRM algorithm. No formal cohort sizes or accrual rate limits are required.


Page 40 of 48 
 
 
11.4 Data Analyses Plans 
The TiTE-CRM estimates for the probability of DLT will be reported with 95% Bayesian 
Credible intervals, once the 32nd evaluable patient has completed the DLT observation 
period. The MTD/RP2D will be determined at that time as the dose level with the highest 
probability of DLT not exceeding 35%. 
 
We will record ORR as a yes/no outcome for each patient for the period of active study 
treatment and report the estimate and exact 95% binomial confidence intervals. We will 
estimate PFS and OS using the product-limit method of Kaplan and Meier. Follow-up time 
will be defined as time from date of first study treatment until the date of radiological or 
clinical progression (leading to withdrawal from the study), or death from any cause, 
whichever comes first for PFS and for only death from any cause for OS. For patients 
without events, we will censor the follow-up time at the date of last disease evaluation at 
the time of analysis. We will report estimates for the median and 75th percentiles with 95% 
confidence intervals. We will summarize additional safety data (e.g., laboratory safety 
parameters, vital signs, concomitant medications and new physical examination findings) 
descriptively by reporting counts and percentages, with exact binomial confidence intervals 
where appropriate. ORR will be determined as per the RECISTv1.1 guidelines. We will 
report adverse events per the NCI CTCAE v5.0. 
 
12.0 
ADMINISTRATIVE PROCEDURES 
 
12.1 Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and be consistent with Good 
Clinical Practice (GCP), as defined by the International Conference on Harmonization 
(ICH), WHO and any local directives. 
 
The protocol, any amendments, and the subject informed consent will receive Institutional 
Review Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion before 
initiation of the study. 
 
12.2 Data Management 
All information will be recorded locally and entered into Case Report Forms (CRFs) on the 
web-based electronic data capture (EDC) system of the University of Michigan. Online 
access will be provided to each site by the Coordinating Center. 
 
CRFs will be reviewed and source verified by the multi-site project manager (MSPM) during 
annual monitoring visits and prior to and between visits. Discrepant, unusual and 
incomplete data will be queried by the MSPM. The investigator or study coordinator will be 
responsible for providing resolutions to the data queries, as appropriate. The investigator 
must ensure that all data queries are dealt with promptly. 
 
The data submission schedule is as follows: 
x At the time of enrollment 
o 
Subject entry into the EDC 
 Subject Status 
 Demographics 
x During study participation 
o 
All data should be entered online within 10 business days of data acquisition. 
[Information on dose limiting toxicity events must be entered within one 
business day.] Information on Serious Adverse Events must be entered 
within the reporting timeframe specified in Section 8.4 of the protocol. 
 
All study information should be recorded in an appropriate source document (e.g. clinic 
chart). 


Page 41 of 48 
 
 
12.3 Record Retention 
The Investigators must retain all study records and source documents for the maximum 
period required by applicable regulations and guidelines, or institution procedures, 
whichever is longer. 
 
 
13.0 
DATA AND SAFETY MONITORING 
This study will be monitored in accordance with the NCI approved University of Michigan Rogel 
Cancer Center Data and Safety Monitoring Plan, with oversight by the Rogel Cancer Center Data 
and Safety Monitoring Committee (DSMC). 
 
The Sponsor-Investigator (S-I)/Study Principal Investigator will provide ongoing monitoring of data 
and patient safety in this trial and conduct regular data review with participating sites. 
 
The Sponsor-Investigator (S-I)/Study Principal Investigator and/or the Project Manager/Delegate 
will review data and patient safety issues with participating sites in a monthly meeting. 
Depending on the protocol activity, the meeting cadence may be more frequent. This data review 
meeting may be achieved via a teleconference or another similar mechanism to discuss matters 
related to: 
 
¾ Enrollment rate relative to expectations, characteristics of participants 
¾ Safety of study participants (SAE reporting, unanticipated problems) 
¾ Adherence to protocol (protocol deviations) 
¾ Completeness, validity and integrity of study data 
¾ Retention of study participants 
 
Participating sites are required to ensure all pertinent data for the review period are available in 
the database at the time of the discussion. 
 
Participating sites unable to participate in the data review meeting are required to provide written 
confirmation that their site has reviewed the relevant data and patient safety issues for the review 
period and their site’s data are in alignment with the data reported in the database. Written 
confirmation is to be provided to the Project Manager/Delegate within the timeline requested to 
retain compliance with monitoring timelines. 
 
Documentation of the teleconference or alternate mechanism utilized to review items above is to 
be retained in the Trial Master File. 
 
The Project Manager/Delegate is responsible for collating the data from all participating sites and 
completing the Protocol Specific Data and Safety Monitoring Report (DSMR) form to document 
the data review meeting discussion. 
 
The DSMR will be signed by the Sponsor-Investigator (S-I)/Study Principal Investigator or 
designated Co-Investigator and submitted to the DSMC on a monthly basis for independent 
review. 
 
14.0 
QUALITY ASSURANCE AND AUDITS 
The Data and Safety Monitoring Committee can request a ‘for cause’ quality assurance audit of 
the trial if the committee identifies a need for a more rigorous evaluation of study-related issues. 
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform the Coordinating Center that such a 
request has been made. 


Page 42 of 48 
 
 
15.0 
CLINICAL MONITORING PROCEDURES 
Clinical studies coordinated by The University of Michigan Rogel Cancer Center must be 
conducted in accordance with the ethical principles that are consistent with Good Clinical 
Practices (GCP) and in compliance with other applicable regulatory requirements. 
 
This study will be monitored by a representative of the Coordinating Center of the Rogel Cancer 
Center. Monitoring visits will be made during the conduct of the study and at study close-out. 
 
Prior to subject recruitment, a participating site will undergo site initiation meeting to be conducted 
by the Coordinating Center. This will be done as an actual site visit; teleconference, 
videoconference, or web-based meeting after the site has been given access to the study 
database and assembled a study reference binder. The site’s principal investigator and his study 
staff should make every effort in attending the site initiation meeting. Study–related questions or 
issues identified during the site initiation meeting will be followed-up by the appropriate Rogel 
Cancer Center personnel until they have been answered and resolved. 
 
Monitoring of this study will include both ‘Centralized Monitoring’, the review of source documents 
at the Coordinating Center and ‘On-site Monitoring’, an actual site visit. The first ‘Centralized’ 
visit should occur after the first subject enrolled completes [first treatment cycle/course]. The 
study site will send the de-identified source documents to the Coordinating Center for monitoring. 
‘Centralized’ monitoring may be requested by the Coordinating Center if an amendment requires 
changes to the protocol procedures. The site will send in pertinent de-identified source 
documents, as defined by the Coordinating Center for monitoring. 
 
The first annual ‘On-site’ monitoring visit should occur after the first five study participants are 
enrolled or twelve months after a study opens, whichever occurs first. The annual visit may be 
conducted as a ‘Centralized’ visit if less than three subjects have enrolled at the study site. The 
type of visit is at the discretion of the Coordinating Center. At a minimum, a routine monitoring 
visit will be done at least once a year, or once during the course of the study if the study duration 
is less than 12 months. The purpose of these visits is to verify: 
 
¾ 
Adherence to the protocol 
¾ 
Completeness and accuracy of study data and samples collected 
¾ 
Proper storage, dispensing and inventory of study medication 
¾ 
Compliance with regulations 
 
During a monitoring visit to a site, access to relevant hospital and clinical records must be given 
by the site investigator to the Coordinating Center representative conducting the monitoring visit 
to verify consistency of data collected on the CRFs with the original source data. While most 
patient cases will be selected from patients accrued since the previous monitoring visit, any 
patient case has the potential for review. At least one or more unannounced cases will be 
reviewed, if the total accruals warrant selection of unannounced cases. 
 
The Coordinating Center expects the relevant investigational staff to be available to facilitate the 
conduct of the visit, that source documents are available at the time of the visit, and that a 
suitable environment will be provided for review of study-related documents. Any issues identified 
during these visits will be communicated to the site and are expected to be resolved by the site in 
a timely manner. For review of study-related documents at the Coordinating Center, the site will 
be required to ship or fax documents to be reviewed. 
 
Participating site will also undergo a site close-out upon completion, termination or cancellation of 
a study to ensure fulfillment of study obligations during the conduct of the study, and that the site 
Investigator is aware of his/her ongoing responsibilities. In general, a site close-out is conducted 
during a site visit; however, site close-out can occur without a site visit. 


Page 43 of 48 
 
 
16.0 
REFERENCES 
 
Abou-Alfa, G. K., T. Meyer, A. L. Cheng, A. B. El-Khoueiry, L. Rimassa, B. Y. Ryoo, I. Cicin, P. Merle, Y. 
Chen, J. W. Park, J. F. Blanc, L. Bolondi, H. J. Klumpen, S. L. Chan, V. Zagonel, T. Pressiani, M. H. Ryu, 
A. P. Venook, C. Hessel, A. E. Borgman-Hagey, G. Schwab and R. K. Kelley (2018). "Cabozantinib in 
Patients with Advanced and Progressing Hepatocellular Carcinoma." N Engl J Med 379(1): 54-63. 
Bruix, J., S. Qin, P. Merle, A. Granito, Y. H. Huang, G. Bodoky, M. Pracht, O. Yokosuka, O. Rosmorduc, V. 
Breder, R. Gerolami, G. Masi, P. J. Ross, T. Song, J. P. Bronowicki, I. Ollivier-Hourmand, M. Kudo, A. L. 
Cheng, J. M. Llovet, R. S. Finn, M. A. LeBerre, A. Baumhauer, G. Meinhardt, G. Han and R. Investigators 
(2017). "Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment 
(RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial." Lancet 389(10064): 56-66. 
Cheung, Y. K. and R. Chappell (2000). "Sequential designs for phase I clinical trials with late-onset 
toxicities." Biometrics 56(4): 1177-1182. 
Eisenhauer, E. A., P. Therasse, J. Bogaerts, L. H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. 
Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe and J. Verweij (2009). 
"New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)." Eur J Cancer 
45(2): 228-247. 
El-Khoueiry, A. B., B. Sangro, T. Yau, T. S. Crocenzi, M. Kudo, C. Hsu, T. Y. Kim, S. P. Choo, J. Trojan, T. 
H. R. Welling, T. Meyer, Y. K. Kang, W. Yeo, A. Chopra, J. Anderson, C. Dela Cruz, L. Lang, J. Neely, H. 
Tang, H. B. Dastani and I. Melero (2017). "Nivolumab in patients with advanced hepatocellular carcinoma 
(CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial." Lancet 
389(10088): 2492-2502. 
El-Serag, H. B. and K. L. Rudolph (2007). "Hepatocellular carcinoma: epidemiology and molecular 
carcinogenesis." Gastroenterology 132(7): 2557-2576. 
Kudo, M., R. S. Finn, S. Qin, K. H. Han, K. Ikeda, F. Piscaglia, A. Baron, J. W. Park, G. Han, J. Jassem, J. 
F. Blanc, A. Vogel, D. Komov, T. R. J. Evans, C. Lopez, C. Dutcus, M. Guo, K. Saito, S. Kraljevic, T. Tamai, 
M. Ren and A. L. Cheng (2018). "Lenvatinib versus sorafenib in first-line treatment of patients with 
unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial." Lancet 391(10126): 
1163-1173. 
Lencioni, R., M. Kudo, S. L. Ye, J. P. Bronowicki, X. P. Chen, L. Dagher, J. Furuse, J. F. Geschwind, L. L. 
de Guevara, C. Papandreou, T. Takayama, S. K. Yoon, K. Nakajima, R. Lehr, S. Heldner and A. J. Sanyal 
(2014). "GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its 
treatment with sorafeNib): second interim analysis." Int J Clin Pract 68(5): 609-617. 
Llovet, J. M., S. Ricci, V. Mazzaferro, P. Hilgard, E. Gane, J. F. Blanc, A. C. de Oliveira, A. Santoro, J. L. 
Raoul, A. Forner, M. Schwartz, C. Porta, S. Zeuzem, L. Bolondi, T. F. Greten, P. R. Galle, J. F. Seitz, I. 
Borbath, D. Haussinger, T. Giannaris, M. Shan, M. Moscovici, D. Voliotis, J. Bruix and S. I. S. Group (2008). 
"Sorafenib in advanced hepatocellular carcinoma." N Engl J Med 359(4): 378-390. 
O'Quigley, J., M. Pepe and L. Fisher (1990). "Continual reassessment method: a practical design for phase 
1 clinical trials in cancer." Biometrics 46(1): 33-48. 
Pressiani, T., C. Boni, L. Rimassa, R. Labianca, S. Fagiuoli, S. Salvagni, D. Ferrari, E. Cortesi, C. Porta, C. 
Mucciarini, L. Latini, C. Carnaghi, M. Banzi, S. Fanello, M. De Giorgio, F. R. Lutman, G. Torzilli, M. A. 
Tommasini, R. Ceriani, G. Covini, M. C. Tronconi, L. Giordano, N. Locopo, S. Naimo and A. Santoro (2013). 
"Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective 
feasibility analysis." Ann Oncol 24(2): 406-411. 
Zhu, A. X., R. S. Finn, J. Edeline, S. Cattan, S. Ogasawara, D. Palmer, C. Verslype, V. Zagonel, L. Fartoux, 
A. Vogel, D. Sarker, G. Verset, S. L. Chan, J. Knox, B. Daniele, A. L. Webber, S. W. Ebbinghaus, J. Ma, A. 
B. Siegel, A. L. Cheng, M. Kudo and K.-. investigators (2018). "Pembrolizumab in patients with advanced 
hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label 
phase 2 trial." Lancet Oncol 19(7): 940-952. 
Zhu, A. X., Y. K. Kang, C. J. Yen, R. S. Finn, P. R. Galle, J. M. Llovet, E. Assenat, G. Brandi, M. Pracht, H. 
Y. Lim, K. M. Rau, K. Motomura, I. Ohno, P. Merle, B. Daniele, D. B. Shin, G. Gerken, C. Borg, J. B. Hiriart, 
T. Okusaka, M. Morimoto, Y. Hsu, P. B. Abada, M. Kudo and R.-s. investigators (2019). "Ramucirumab 
after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein 
concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial." Lancet Oncol 
20(2): 282-296. 


Page 44 of 48 
 
 
17.0 
APPENDICES 
 
Appendix I 
ECOG Performance Status 
Appendix II 
Child-Pugh Status 
Appendix III 
List of Strong Inhibitors and Inducers of CYP3A4 
Appendix IV 
Investigator’s Statement 


Page 45 of 48 
 
 
Appendix I 
ECOG Performance Status 
 
 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature e.g. light house work, office work. 
 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
Source: Eastern Cooperative Oncology Group 


Page 46 of 48 
 
 
Appendix II 
Child-Pugh Score 
 
 
Measure 
1 point 
2 points 
3 points 
Total Bilirubin (mg/dL) 
<2 
2-3 
>3 
Serum Albumin (g/dL) 
>3.5 
2.8-3.5 
<2.8 
Prothrombin Time 
x 
PT >ULN (sec) 
x 
INR 
 
1-3 
<1.7 
4-6 
1.7-2.3 
>6 
>2.3 
Ascites 
Absent 
Slight 
Moderate to Severe 
Hepatic 
Encephalopathy 
 
None 
Grade 1-2 
(or suppressed with 
medication) 
Grade 3-4 
(or refractory) 
 
Source: R.N.H. Pugh, I.M. Murray-Lyon, J.L. Dawson, M.C. Pietroni, Roger Williams. Transection of 
the esophagus for bleeding esophageal varices. British Journal of Surgery. Volume 60. Issue 8, 
pages 646-649, August 1973 
Encephalopathy grades: 
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram 
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves 
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves 
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves 
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity 


Page 47 of 48 
 
 
Appendix III 
List of Strong Inhibitors and Inducers of CYP3A4 
Strong Inhibitors 
Clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, grapefruit/grapefruit juice, 
atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir. 
 
Strong Inducers 
 
Rifampin, carbamazepine, oxcarbazepine, nevirapine, fosphenytoin, pentobarbital, phenobarbital, , 
phenytoin, primidone, enzalutamide, lumacaftor, St John’s Wort, mitotane, apalutamide, rimexolone, 
rifaximin, and rifamycin. 


Page 48 of 48 
 
 
Appendix IV 
Investigator’s Statement 
 
1. I have carefully read this protocol entitled “Phase 1/2 Trial to Evaluate Cabozantinib in Patients with 
Advanced Hepatocellular Carcinoma with Child Pugh Class B Cirrhosis after First-Line Therapy”, 
Version 08/19/2020 and agree that it contains all the necessary information required to conduct 
the study. I agree to conduct the study as outlined in the protocol. 
 
2. I agree to conduct this study according to the moral, ethical and scientific principles governing 
clinical research as set out in the Declaration of Helsinki, the principles of Good Clinical Practice 
(GCP) as described in 21 Code of Federal Regulations (CFR) and any applicable local 
requirements. 
 
3. I understand that this trial and any subsequent changes to the trial will not be initiated without 
approval of the appropriate Institutional Review Board, and that all administrative requirements of 
the governing body of the institution will be complied with fully. 
 
4. Informed written consent will be obtained from all participating patients in accordance with 
institutional and Food and Drug Administration (FDA) requirements as specified in Title 21, CFR, 
Part 50. 
 
5. I understand that my signature on the electronic Case Report Form (eCRF) indicates that I have 
carefully reviewed each page and accept full responsibility for the contents thereof. 
 
6. I understand that the information presented in this study protocol is confidential, and I hereby 
assure that no information based on the conduct of the study will be released without prior consent 
from University of Michigan unless this requirement is superseded by the FDA. 
 
 
Site PI Name: 
 
 
 
Site Name: 
 
 
 
Signature of Site PI: 
 
 
 
Date of Signature: 
 
\ 
\ 
 

ICF_001.pdf: 
ID: UMCC 
2020.007 
    Cabozantinib in Patients With Advanced 
Hepatocellular Carcinoma With Child Pugh Class B 
Cirrhosis After First-Line Therapy 
    NCT04497038 
 


Page 1 of 22
Consent Subtitle Sahai-1390 HCC
Consent Version: 08MAY2023 
UNIVERSITY OF MICHIGAN
CONSENT TO BE PART OF A RESEARCH STUDY
1. KEY INFORMATION ABOUT THE RESEARCHERS AND THE STUDY
Study title: Phase 1/2 Trial to Evaluate Cabozantinib in Patients with Advanced Hepatocellular Carcinoma with 
Child Pugh Class B Cirrhosis after First-Line Therapy
Company or agency sponsoring the study: The University of Michigan along with support from Exelixis, Inc.
Names, degrees, and affiliations of the principal investigator and study coordinator (if applicable):
Principal Investigator: Vaibhav Sahai, MBBS, MS, Department of Internal Medicine, University of Michigan
Co-Principal Investigator: Neehar Parikh, MD, Department of Internal Medicine, University of Michigan
Site Principal Investigator: Thomas Enzler, MD, PhD, Department of Internal Medicine, University of Michigan
1.1 Key Study Information
You may be eligible to take part in a research study. All information in this form is important. This form contains 
information that will help you decide whether to join the study. All information in this form is important. Take 
time to carefully review this information. After you finish, you should talk to the researchers about the study and 
ask them any questions you have. You may also wish to talk to others such as your friends, family, or other 
doctors about your participation in this study. If you decide to take part in this study, you will be asked to sign this 
form. Before you do, be sure you understand what the study is about.
A research study is different from the regular medical care you receive from your doctor. Research studies hope 
to make discoveries and learn new information about diseases and how to treat them. You should consider the 
reasons why you might want to join a research study or why it is not the best decision for you at this time. 
Research studies do not always offer the possibility of treating your disease or condition. Research studies also 
have different kinds of risks and risk levels, depending on the type of the study. You may also need to think about 
other requirements for being in the study. For example, some studies require you to travel to scheduled visits at 
the study site in Ann Arbor, Michigan or elsewhere. This may require you to arrange travel, change work 
schedules, find child care, or make other plans. In your decision to participate in this study, consider all of these 
matters carefully. 
This research is studying the use of a new drug in small numbers of people to learn about its safety, tolerability 
and its effect on your body at certain doses as a treatment for Advanced Hepatocellular Carcinoma with Child 
Pugh B cirrhosis after First-Line Therapy. Researchers want to understand how the drug works in your body and 
how your body will react to it. This study will be using the drug cabozantinib. You will take cabozantinib by mouth. 
Others procedures that will take place throughout the course of the study include physical exams, blood draws, 
scans of your cancer, urine collection (females) along with other items listed later in this document. Your health-
related information and biospecimens (blood and tissue) will be collected for this research study.
There can be risks associated with joining any research study. The type of risk may impact whether you decide to
Study ID: HUM00184276   IRB: IRBMED   Date Approved: 8/23/2023   Expiration Date: 2/2/2024


Page 2 of 22
Consent Subtitle Sahai-1390 HCC
Consent Version: 08MAY2023 
join the study. For this study, a brief list of some of most commonly seen risks may include weakness, diarrhea, 
hypertension, nausea, vomiting, loss of appetite, blisters, rash, or pain in hands or feet and changes to the way 
things taste. More detailed information will be provided later in this document.
This study may not offer any benefit to you now but may benefit others in the future by helping people to live
longer or improve the quality of life.
We expect the amount of time you will participate in the study to vary depending on how your disease responds
to the study intervention and if you have any major side effects and could be up to three years.
You can decide not to be in this study. Alternatives to joining this study include receiving standard of care
treatment for this disease, taking part in a different study, receiving palliative care, or having no treatment.
Even if you decide to join the study now, you are free to leave at any time if you change your mind.
More information about this study continues in Section 2 of this document.
2. PURPOSE OF THIS STUDY
2.1 Study purpose:
This is a Phase I/II study which means that the goals are to see if the investigational drug cabozantinib is safe as 
well as whether it is effective in improving outcomes. The first part of the study will try to find out what effects, 
good and/or bad, this drug has on you and your cancer, and to find a dose to use in the second part of the trial.
Hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer related death worldwide. Patients with 
advanced hepatocellular cancer with Child-Pugh B cirrhosis, that is unable to be removed with surgery, have no 
options for treatment based on current guidelines and available evidence. 
The purpose of this study is to determine the safety and effectiveness (how well the drug works) of cabozantinib 
in the management of HCC in this patient population. 
On January 14, 2019, the Food and Drug Administration approved cabozantinib for patients with advanced HCC 
with Child-Pugh A who have been previously treated with sorafenib. This approval was based on the CELESTIAL 
clinical trial that looked at cabozantinib versus placebo in 707 patients with HCC, and the patients taking 
cabozantinib showed an increase in overall survival versus the patients who received placebo. The patients in the 
CELESTIAL study had mild liver impairment (Child-Pugh Class A) so this study will be considered research as it is 
looking at how well cabozantinib works in HCC patients with moderate liver impairment (Child-Pugh Class B).
3. WHO MAY PARTICIPATE IN THE STUDY
Taking part in this study is completely voluntary. You do not have to participate if you don't want to. You may also 
leave the study at any time. If you leave the study before it is finished, there will be no penalty to you, and you 
will not lose any benefits to which you are otherwise entitled. 
Study ID: HUM00184276   IRB: IRBMED   Date Approved: 8/23/2023   Expiration Date: 2/2/2024


Page 3 of 22
Consent Subtitle Sahai-1390 HCC
Consent Version: 08MAY2023 
3.1 Who can take part in this study?
Adult men and women with hepatocellular carcinoma that cannot be treated with surgery, transplant, or ablative 
therapies (therapies that destroy abnormal tissue without destroying the tissue).
There are many other inclusion and exclusion criteria which the doctors will use to determine if you can
participate in this study. It is important that you discuss your full medical history and all of your medications with
your doctor.
3.2 How many people are expected to take part in this study?
A total of approximately 32 subjects at several institutions will take part in this study, including approximately 10
from the University of Michigan.
4. INFORMATION ABOUT STUDY PARTICIPATION
4.1 What will happen to me in this study? 
The study team will explain the research study and answer any questions you have about the study. If you want to 
participate in the study, the study team will request you sign the consent form prior to any activities that pertain 
to the study. Once your consent is obtained, the study team will look through your medical chart, ask you 
questions, and begin scheduling tests and procedures to determine if you are eligible for the study. The study 
team will inform you of the types of tests and procedures required before the study begins.
Many of the procedures that will be performed during the study, including routine blood tests, tumor evaluations 
(radiology scans), physical examinations, vital signs (blood pressure, heart rate, breathing rate, and temperature) 
and measurement of height and weight, would normally be done as part of your standard of care regardless of 
study participation. However, some of these may be done more frequently as a result of your participation in this 
study. Administration of the study drug, tissue and some blood sample collection and analysis are solely for 
research purposes.  Tests and procedures that are done more often than your regular medical care because of 
your study participation and that are solely for research purposes will be identified below. The study staff will 
inform you of the types of tests and procedures you have to undergo during the study.
During the study you must:

Follow the instructions you are given.

Come to the study center for your visits with the study doctor.

Tell the study doctor or study staff about any changes in your health and/or medications you are taking.

Tell the study doctor or study staff if you want to stop being in the study at any time.
Before starting the study:
Some exams, tests, and procedures will be required to find out if you can be in this study. If you have had some of 
them recently, they may not need to be repeated. The screening tests and procedures do not have to be
completed in one day and you are allowed to take breaks if you have multiple procedures in one day.
The following tests and procedures will be performed during screening and/or at one or more study visits. Refer 
to the study calendar below for information about which procedures will be performed at certain study visits.

Medical history: including any past treatments, surgeries, infection and autoimmune diseases.
Study ID: HUM00184276   IRB: IRBMED   Date Approved: 8/23/2023   Expiration Date: 2/2/2024


Page 4 of 22
Consent Subtitle Sahai-1390 HCC
Consent Version: 08MAY2023 

Medications: It is important that you tell your doctor about all of the medications that you have been
taking, including over the counter medicines, vitamins or herbal treatments.

Physical exam/Vital Signs: including measurement of your height, weight, blood pressure, heart rate,

respiratory rate and temperature.

Performance status: Your ability to perform day to day activities and care for yourself

Routine blood tests (approximately 2 teaspoons): will be drawn for tests to check blood counts,
chemistry, health and blood markers for cancer

Pregnancy test: (urine or blood – approximately 1 teaspoon): if you are a woman able to have children

Scans of your cancer: these could include Computed tomography (CT) of the chest, CT or magnetic
resonance imaging (MRI) of the upper and lower belly. The scans will be sent to a central location in a
coded format.
o A CT scan uses special x-ray equipment to make detailed pictures of body tissues and organs. For 
the CT scan, you may be given a “contrast material” (a special dye that makes it easier for doctors to 
see different tissues in your body). You will be asked to lie still and may be asked to hold your breath 
for a few seconds. The CT scan is done in the Radiology Department and takes about half an hour.
o A MRI scan takes an image of your head or body to observe the location and size of your tumor.
For the MRI scan, you may be given a “contrast material” (a special dye that makes it easier for
doctors to see different tissues in your body). You will be asked to lie down on a narrow bed
which will slide into a tunnel that is 6 feet long by 22 inches across and is open at each end. You
will be asked to lie quietly for about one hour, during which time you will hear a loud machine-like 
noise. A MRI scan takes about an hour and a half to complete.

Blood for Research: About 4 teaspoons of blood will be collected at each visit listed below. Samples
will be collected at the following time points. This is for research purposes.
o Pre-treatment: Cycle 1 Day 1
o On-Treatment: Cycle 4 Day 1
o Post-Treatment: End of Treatment (EOT)

Blood for Pharmacokinetics (PK): About half a teaspoon of blood will be collected at each visit listed 
below. This is for research purposes.
o Week 3 Predose: Cycle 1 Day 15
o Week 5 Predose: Cycle 2 Day 1
o Week 7 Predose: Cycle 2 Day 15
o Week 9 Predose: Cycle 3 Day 1

Toxicity evaluation: You will be asked about any side effects or illnesses you experience.

ECG: an electrical tracing of your heart rhythm
o Wires or “leads” will be attached to your chest with an adhesive and you will be asked to lie still
while the machine prints out an electrical “record” of your heart activity
Study ID: HUM00184276   IRB: IRBMED   Date Approved: 8/23/2023   Expiration Date: 2/2/2024


Page 5 of 22
Consent Subtitle Sahai-1390 HCC
Consent Version: 08MAY2023 

Tumor tissue: Your doctor will check to see if you have enough stored tissue sample of your tumor that 
was collected previously and submit to study for research analysis. If you do not have enough stored 
tissue, you will not be asked to undergo a fresh tissue biopsy prior to starting treatment. 
o If there is a biopsy done after completion of study treatment the tissue will need to be shared with 
study team.
Study Intervention:
If you qualify to participate in the study based on the results of the screening tests and procedures, you will 
return to the study doctor’s clinic.
You will take cabozantinib by mouth every day.
Below are general rules for taking cabozantinb:

Take without food (Do not eat at least 2 hours before and at least 1 hour after taking the medication). 

Swallow whole (do NOT chew, crush or cut the capsule)

The medication SHOULD NOT be ingested if broken, cracked or otherwise not intact
•
If you miss a dose, take it later only if it is within 12 hours of when the missed dose should have been 
taken. Do NOT make up the missed dose if it’s after 12 hours of when your missed dose should have been 
taken
If you experience adverse events, you may have to stop taking the study drug and if you recover from your 
adverse event, you may be able to restart the study drug. 
You will continue to receive the study intervention for up to two years as long as you are tolerating the 
treatment and your disease hasn’t progressed.
Follow-up:
If you stop the study intervention for any reason you will be asked to return for end of treatment visit 30 days
after your last dose of study intervention.
After you complete the study intervention visit you will have an office visit, or be contacted by a member of 
the study team every 3 months for up to 2 years from when you stopped the study intervention.
See the table below for a summary of the study intervention and procedures.
Study Calendar
Cycle 1 
Cycle X 
Procedures
Screening
Day 1
Day 15
Day 1
Day 15
EOT 
Visit
Follow-Up
Every 3 
months +/- 
1 week
Informed consent
X
History, physical 
Examination
X
X
X
X
Weight, height
X
X
X
X
Vital signs (heart rate, 
temperature, etc.)
X
X
X
X
X
Toxicity evaluation by 
X
X
X
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EOT, end of treatment; ECG, electrocardiogram; CBC, complete blood count; AFP, alpha-feto protein; PT, 
prothrombin time; INR, international normalized ratio; PTT, partial thromboplastin time; TSH, thyroid 
stimulating hormone; PK, pharmacokinetics.
Research Samples Stored for Future Use:
We will keep some of your research blood and tissue samples, as well as medical information (such as gender,
race, and how your cancer responded to the treatment, etc.) so that we may study them in future research. The 
future research may be similar to this study or may be completely different. Your samples would be kept at the 
University of Michigan. Samples will be stored indefinitely or until they are used up.
By taking part in this study, you are giving us your permission to use your blood, tissue and medical information 
for future research. Even if you give us permission now to keep some of your blood, tissue and medical 
information, you can change your mind later and ask us to destroy it. Keep in mind, however, that once we have 
analyzed your blood and tissue, we may not be able to take the information out of our research.
We may share your blood, tissue and medical information with other researchers, so that they can use it in their 
research and evaluations of how the study regimens function in the body with the overall aim of helping future 
patients. No identifiable information that could be directly linked to you will be provided. Their research may be 
similar to this study or may be completely different. Once we have shared your blood, tissue and medical 
information with other researchers, we will not be able to get it back.
You will not find out the results of future research on your blood and tissue samples. Allowing us to do future
research on your blood, tissue and medical information will not benefit you directly.
The University of Michigan, the investigators or a collaborating researcher may benefit financially from future
your physician
Scans with tumor 
measurements
X
Every 8 
weeks
12 lead ECG
X
Follow-up every 3 months 
for survival
X
Routine blood tests
CBC with differential, 
CMP
X
X
X
X
Tumor marker (AFP)
X
X
X
PT/INR, PTT
X
TSH, Free T4 and T3
X
X
Routine urine tests
Pregnancy test (blood or 
urine)
X
Urine protein creatinine 
ratio
X
X
Research procedures
PK blood
X
X
X
Research blood
X
X
X
Tumor tissue collection, if 
available
X
X
Study drug administration
X
X
X
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research on your blood, tissue and medical information.
Loss of Confidentiality
Your samples will be coded however there is a risk of loss of confidentiality of your information. If your samples 
are provided to research collaborators the following information may be made available: your diagnosis and 
treatments, the time the samples were collected in relation to your study regimen, your disease status, and 
demographic data (for example gender, race, age, etc.). Please ask the Study Doctor or Study Nurse if you would 
like to know more about how your information will be protected.
4.2 How much of my time will be needed to take part in this study? 
The initial screening visit will take approximately 2-5 hours. Each study visit is expected to take approximately 4-6 
hours. Patients will be followed every 3 months via telephone or office visit documentation for up to 2 years from 
treatment discontinuation or until death, whichever comes first, or 3 years after first date of treatment initiation 
for those that remain on treatment.
4.3 When will my participation in the study be over? 
The maximum time you will be in the study can be up to 3 years, but will depend on how your disease responds to
the study intervention and how well you tolerate the study intervention. After you stop taking the study
intervention you will be asked to come back for an end of treatment visit and the study team will follow you via
telephone or an office visit every 3 months for up to 2 years from when you stopped taking the study 
intervention, or 3 years after the first date you started the study intervention. Your participation may end sooner 
if you decide to no longer participate, your study doctor feels it is in your best interest to stop your study 
participation, your disease progresses or the study is ended. You can stop participating at any time. However, if 
you decide to stop participating in the study, we encourage you to talk to the study doctor and your regular 
physician first.
4.4 What will happen with my information and/or biospecimens used in this study?
Your biospecimens and collected information may be shared with Exelixis, Inc. 
With appropriate permissions, your biospecimens and collected information may also be shared with other 
researchers, here, around the world, and with companies.
Your identifiable private information or identifiable biospecimens may be stripped of identifiers and used for 
future research studies or distributed to another researcher for future research studies without additional 
informed consent.
5. INFORMATION ABOUT RISKS AND BENEFITS
5.1 What risks will I face by taking part in the study? What will the researchers do to protect me against these 
risks?
The drug used in the study may cause certain side effects and discomforts. You may have all, some, or none of
the known side effects. There is also a risk that other rare or unknown side effects may occur. Your doctors and
nurses will check you closely for side effects, and may give you medicines or other treatments to stop or reduce 
some of these effects. Some side effects may go away soon after the study medication is stopped, but in some 
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cases, side effects may be serious, long lasting, and/or permanent. There is even a chance that a side effect may 
cause death. If you have any side effects, it is important that you report them to your study doctor or research
staff.
These risks will be minimized by monitoring you carefully. We will provide the usual supportive care that would be 
routinely given to someone with your condition. If you have side effects from the study intervention, we will make 
appropriate adjustments as defined by the study protocol. You may need to discontinue the study intervention if 
the side effects are too serious.
The known or expected risks are:
Side Effects ASSOCIATED WITH CABOZANTINIB
Very Common Side Effects that Occurred in ≥ 10% of Cancer Patients (≥ 1 in 10) Treated with Cabozantinib 
(Alone)
•
Abdominal pain 
•
Alteration of thyroid function tests 
•
Blisters, rash, or pain in hands or feet 
•
Changes in blood tests used to monitor the liver, which may indicate liver damage 
•
Change in voice 
•
Changes to the way things taste 
•
Constipation 
•
Diarrhea
•
Fatigue 
•
Hair color changes or hair loss
•
High blood pressure 
•
Inflammation of mucus membranes
•
Loss of appetite
•
Mouth and throat sores or swelling 
•
Nausea
•
Rash
•
Vomiting
•
Weakness 
•
Weight loss
Common Side Effects That Occurred ≥ 1% but < 10% of Cancer Patients (≥ 1 in 100, but < 1 in 10) Treated with 
Cabozantinib (Alone)

Abnormal thickening of the outer layer of the skin 

Change in the feeling of touch 

Cough 

Bleeding, including bleeding from stomach or intestines which may look like coffee grounds or black sticky 
bowel movements and bleeding within the brain 

Blood clot in a large vein, usually in the leg

Blood clot that travels from a vein to the lung 

Confusion and disorientation
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
Decreased amounts of red blood cells (anemia), which may cause feelings of tiredness or shortness of 
breath

Decreased amounts of calcium or sodium in the blood 

Decreased or increased amounts of potassium in the blood

Decreased amounts of magnesium or phosphorus in the blood

Decreased level of albumin in the blood

Decreased platelet counts, which increases the risk of bleeding or make bleeding more difficult to 
stop 

Decreased white blood cell counts, which may increase chances of infection 

Dermatitis acneiform, a type acne

Dehydration

Difficulty swallowing

Dizziness 

Dry mouth

Dry skin

Fever

Fungal infections including mouth, lung, and other locations 

Hemorrhoids and bleeding hemorrhoids

Headache

Increased amounts of pancreas enzymes in the blood, which may indicate damage to the pancreas 

Increased levels of bilirubin in the blood, which may indicate complications with the 

Increased levels of creatinine in the blood, which may indicate complications with the kidneys 

Mouth or throat pain 

Muscle spasm 

Muscle weakness

Pain in a joint or muscle

Pain in extremities

Protein in the urine, which may indicate kidney damage 

Shortness of breath 

Stomach acid coming up from the stomach into the esophagus 

Swelling of the limb(s) 

Ulcer

Upset stomach or indigestion
Uncommon Side Effects That Occurred ≥ 0.1% but < 1% of Cancer Patients (≥ 1 in 1000, but < 1 in 100) Treated 
with Cabozantinib (Alone)

Abnormal electrical activity in the heart that could cause a potentially serious change in heart rhythm 

Abnormal opening between two organs or from an organ to the outside of the body 

Abscesses (infected cavities filled with pus) 

Blood clot in an artery 

Chest discomfort originating from the heart 

Clouding of the lens in the eye that affects vision

Damage to skeletal muscle tissue 
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
Decreased brain function or decreased alertness and ability to think 

Decrease in all blood counts (red blood cells, white blood cells and platelets) 

Destruction of bone tissue, in particular, bone in the jaw

Gallstones 

Heart attack 

Heart failure

Holes in the stomach or intestines 

Infections 

Inflammation of the intestine, appendix, gall bladder or thin tissue lining the inner wall of the abdomen 
and most of the abdominal organs 

Reduced kidney function 

Liver failure 

Loss of consciousness, fainting episode 

Pneumonia and inflammation of the lungs 

Rapid heart rhythm 

Re-opening of wounds after surgery

Respiratory failure 

Seizure

Stroke / mini-stroke 

Tear or inflammation in skin that lines the anus 

Uncoordinated movements 
Side effects that occurred in less than 0.1% of patients but were considered medically important or severe or life-
threatening and rarely fatal are listed in the tables below. These events occurred in studies of cabozantinib given 
alone. If you are at the clinical site and notice any signs or symptoms of the side effects listed below, check with 
the staff in the clinic immediately; if you are no longer at the clinical site, call your doctor or go immediately to the 
nearest hospital.
Rare but Medically Important Side Effects not listed above that Occurred ≥ 0.01% but < 0.1% of Cancer Patients 
(≥ 10000, but < 1 in 1000) Treated with Cabozantinib [Alone)

Air in the chest between lungs and chest wall

Allergic reaction

Anemia caused by destruction of red blood cells

Blocked intestines 

Brain dysfunction caused by brain swelling 

Cancer of the mouth or skin

Damage to the outermost surface of the eye 

Inflammation and blockage of channels that carry bile from the liver 

Severe swelling of the mouth, lips, tongue, eyes and throat, or difficulty swallowing or breathing 

Temporary paralysis of the intestines 

Throat swelling 

Very high blood pressure that comes on suddenly and quickly and which can lead to serious injury to the 
heart and brain

Enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall

Blood vessel inflammation associated with possible bleeding, bruising, and/or rash
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Risks of CT Scan
The contrast substance injected during the CT scan may cause pain, burning feeling, sweating, and rarely a serious
allergic reaction that can be serious. If you know you’re allergic to iodine you must inform your doctor
immediately. The contrast agent used in the CT scan may cause kidney damage, especially if you’re diabetic,
dehydrated and if you’re older. In addition, your thyroid function may be affected. Please inform your doctor if
this is the case.
CT imaging uses ionizing radiation, which increases your risk to develop cancer. Everyone is exposed to naturally
occurring ionizing radiation every day. The amount of radiation exposure from 1 CT scan is approximately
comparable to 1-3 years of natural background radiation. The estimated additional lifetime risk of developing a
fatal cancer from a standard CT scan is approximately 1 in 2,000.
Risks of MRI Scan
Contrast is used to improve the pictures of the inside of the body made by the MRI. Common risks of MRI include:
feeling fearful of being in a small enclosed space (claustrophobia) when you are lying inside the MRI scanner,
feeling uncomfortable because of the loud noises made by the machines, and feeling uncomfortable with the
physical sensations you may feel during the process. You are also exposed to some risk because of the injected
contrast, gadolinium-DTPA, which may cause headache, nausea, and local burning sensation. 
The contrast agent, gadolinium has been linked to development of Nephrogenic Fibrosing Dermopathy (NFD) (also
known as Nephrogenic Systemic Fibrosis (NSF). This causes a thickening of the skin, organs and other tissues, and
is a rare complication in patients with kidney disease that undergo an MRI with contrast material. To help prevent
this, we will check how well your kidneys work before you have any MRIs. Because of the use of contrast, all
female subjects who are able to have children will be required to use adequate birth control. If you have
implanted metal objects such as a pacemaker, artificial limbs, or metal joints, you will not be able to have an MRI
done, and may not be able to take part in this research.
Blood tests
Blood samples will be taken from a vein in your arm during the study. The taking of a blood sample may cause
some discomfort and bruising, and there is a potential for infection. Other risks, although rare, include dizziness
and fainting
Tumor tissue collection
A piece of a tumor will be collected for research, if available from prior surgery or biopsy.

Genetic material, including DNA and RNA, will be obtained from samples, stored in freezers, and used for
profiling and analyzing your cancer. Specifically, the study includes DNA sequencing of your tumor and
normal cells as a comparison. The goal is to identify key changes in the genes important to cancer cells
that could potentially influence clinical decision making for your cancer. However, success or clinical
benefits from the profiling of your cancer DNA is not guaranteed.

Analysis of the sequencing data will be used for research purposes, for example to discover new, 
unknown associations between genes and cancer. This type of research may affect the lives of future 
patients with cancer.
It is possible that a mutation found in the tumor DNA is also a mutation in your normal tissue (inheritable,
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or passed down in families). Since we are not testing normal tissue, we cannot tell if an abnormal gene in
the tumor could also be in your normal (non-tumor) cells. Your study doctor will discuss this result with
you. If your test results show that you have gene mutations that are possibly inherited, your doctor may
recommend that you meet with a genetic counselor and, if warranted, undergo further genetic testing on
non-tumor tissue to determine if the mutation is inherited. This type of testing is considered standard
care and is not part of this study.

As with all medical screening tests, there is a chance of a false positive or a false negative result. A “false
positive” refers to the identification of a genetic change that is not present. A “false negative” is the
failure to find a genetic change that indeed exists. The tests have been designed to ensure that the
possibility of incorrect results is low.
Risks of Electrocardiogram (EKG) or heart trace
Small sticky pads will be stuck to your chest, shoulders and hips and a machine will measure the electrical activity 
of your heart. The study staff may need to clip small patches of your hair in these areas. These sticky pads may 
cause some local irritation and may be uncomfortable to remove.
Risks of Pregnancy
If you are a woman of child bearing potential, you must not have sexual intercourse or you must use reliable birth 
control throughout the study and for 4 months after the last dose of study drug. The study doctor will discuss 
methods of birth control with you if needed.
If you are pregnant or become pregnant or are nursing a child during the study, there may be risks to your unborn 
baby or nursing child. Some drugs cause premature (early) birth or birth defects. Nobody knows what all of these 
risks are right now.
If you become pregnant or think you may be pregnant during the study, immediately stop using the study drug 
and contact the study doctor’s office immediately. You must not breast-feed an infant during the study. 
Please also inform the study doctor if you become pregnant up to 4 months after the completion of the study 
drug.
Women of child-bearing potential (not surgically sterilized and between menarche and 1-year post menopause) 
and men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) OR
abstinence prior to study entry, for the duration of study participation (including study breaks), and for 4 months 
following completion of study therapy. 
You must talk to the doctor before changing any birth control methods you have already agreed to use.
  
Primary forms
Hormonal forms
Barrier forms

Tubal sterilization 
(tubes tied)

Birth control pill

Hormonal intrauterine 
device

Male latex condom with or 
without spermicide

Partner’s vasectomy 

Birth control injections 
(Depo-Provera)

Diaphragm with spermicide

Abstinence 

Vaginal rings (NuvaRing)

Cervical cap with spermicide
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
Birth control implants 
(Nexplanon)

Vaginal sponge (contains 
spermicide)

Birth control patches 
(Ortho Evra)
Any birth control method can fail. The reports of birth control failing are more frequent for female patients who 
use only a single form of birth control. Using two forms of birth control at the same time greatly reduces the 
chances of pregnancy.
MEN
All men must use two acceptable forms of birth control (hormonal plus barrier or 2 barrier forms) OR abstinence 
while taking part in the study and for 4 months after treatment has stopped because the effects on sperm are not 
known. Also, men should not donate sperm or semen while taking part in the study because the effects on sperm 
are not known.
The study doctor must follow up and document the course and the outcome of all pregnancies, even if you 
withdraw from the study or if the study has finished. If you become pregnant during the study, the study doctor 
or his/her staff will ask to contact you and your pregnancy physician for information about the pregnancy until the 
child is born and may share this information with the sponsor.
Genetic Risks:
The federal Genetic Information Nondiscrimination Act (GINA) generally makes it illegal for health insurance 
companies, group health plans, and most employers to discriminate against you based on your genetic 
information. This law does not protect you against genetic discrimination by companies that sell life insurance, 
disability insurance, or long-term care insurance. Under this law:

Health insurance companies and group health plans may not request your genetic information that we 
obtain from this research

Health insurance companies and group health plans may not use your genetic information when making 
decisions regarding your eligibility or premiums

Employers with 15 or more employees may not use your genetic information that we obtain from this 
research when making a decision to hire, promote, or fire you or when setting the terms of your 
employment

GINA does not apply to the following groups; however, these groups have policies in place that provide 
similar protections against discrimination:

Members of the US Military receiving care through Tricare

Veterans receiving care through the Veteran’s Administration (VA)

The Indian Health Service

Federal employees receiving care through the Federal Employees Health Benefits Plans
Let your study doctor know of any questions you have about possible side effects. You can ask the study doctor 
questions about side effects at any time.
Additionally, there may be a risk of loss to confidentiality or privacy. See Section 9 of this document for more 
information on how the study team will protect your confidentiality and privacy.
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As with any research study, there may be additional risks that are unknown or unexpected.
5.2 What happens if I get hurt, become sick, or have other problems as a result of this research?
The researchers have taken steps to minimize the risks of this study. Even so, you may still have problems or side 
effects, even when the researchers are careful to avoid them. Please tell the researchers listed in Section 10 about 
any injuries, side effects, or other problems that you have during this study. You should also tell your regular 
doctors.
5.3 If I take part in this study, can I also participate in other studies?
Being in more than one research study at the same time, or even at different times, may increase the risks to you. 
It may also affect the results of the studies. You should not take part in more than one study without approval 
from the researchers involved in each study. 
5.4 How could I benefit if I take part in this study? How could others benefit? 
You will not receive any direct personal benefits from being in this study. However, others may benefit from the 
knowledge gained from this study.
5.5 Will the researchers tell me if they learn of new information that could change my willingness to stay in this 
study?
Yes, the researchers will tell you if they learn of important new information that may change your willingness to 
stay in this study. If new information is provided to you after you have joined the study, it is possible that you may 
be asked to sign a new consent form that includes the new information.
6. ALTERNATIVES TO PARTICIPATING IN THE STUDY
6.1 If I decide not to take part in this study, what other options do I have?
You do not have to be in this study to get treatment for your cancer. You have the option to receive other
treatment for your cancer, participate in other research trials, receive other care for your disease, or choose not
to receive any treatment. You should talk to your study doctor and your regular physician about each of your
options and their risks and benefits before you decide if you want to take part in this study.
7. ENDING THE STUDY
7.1 If I want to stop participating in the study, what should I do?
You are free to leave the study at any time. If you leave the study before it is finished, there will be no penalty to 
you. You will not lose any benefits to which you may otherwise be entitled. If you choose to tell the researchers 
why you are leaving the study, your reasons for leaving may be kept as part of the study record. If you decide to 
leave the study before it is finished, please tell one of the persons listed in Section 10 “Contact Information”.
7.2 Could there be any harm to me if I decide to leave the study before it is finished? 
If you decide to leave the study early, please notify someone on the study team. They will instruct you on how to 
stop the study safely and you will be advised whether any additional test may need to be done for your safety.
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7.3 Could the researchers take me out of the study even if I want to continue to participate?
Yes. There are many reasons why the researchers may need to end your participation in the study. Some 
examples are:

The researcher believes that it is not in your best interest to stay in the study.

You become ineligible to participate.

Your condition changes and you need treatment that is not allowed while you are taking part in the study.

You do not follow instructions from the researchers.

The study is suspended or canceled.
8. FINANCIAL INFORMATION
8.1 Who will pay for the costs of the study? Will I or my health plan be billed for any costs of the study? 
The study will pay for research-related items or services that are provided only because you are in the study. If 
you are not sure what these are, see Section 4.1 above or ask the researchers for a list. If you get a bill you think is 
wrong, call the researchers’ telephone number listed in Section 10.1.
The study drug cabozantinib will be provided by Exelixis, Inc. free of charge.
You or your health plan will pay for all the things you would have paid for even if you were not in the study, like:

Health care given during the study as part of your regular care

Items or services needed to give you study drugs or devices

Monitoring for side effects or other problems

Deductibles or co-pays for these items or services.
If you do not have a health plan, or if you think your health plan may not cover these costs during the study, 
please talk to the researchers listed in Section 10 below or call your health plan’s medical reviewer.
If you do not have a health plan, or if you think your health plan may not cover these costs during the study,
please talk to the researchers listed in Section 10 below or call your health plan’s medical reviewer. 
The pre-treatment and end of treatment biopsy are mandatory and the cost will be paid for by the study.
The study team has given you instructions about this research study. It is important that you follow these
instructions carefully. If you get sick, have a medical complication, or are injured as a result of your being in the
study, call Dr. Enzler immediately, at 734-647-8902 (Clinic) or 734-936-4000 (Hospital Operator; 24-hour paging).
The doctor will either treat you or send you to another doctor for treatment.
If taking part in the study makes you sick or causes you injury, you or your insurance provider will be billed for all
costs of treatment as the study does not provide compensation for sickness or injury caused by the study. It is
possible that your insurance will not cover these costs.
By signing this form, you do not give up your right to seek payment if you are harmed as a result of being in this 
study.
8.2 Will I be paid or given anything for taking part in this study?
You will be paid to take part in this study. However, to cover your travel cost, you will be eligible to receive $50 
per study visit, up to 12 completed visits (up to 600 US dollars beginning with cycle 1 day 1), via gift card. Initial 
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request is payable at the completion of the first treatment visit, subsequent payments are based on completion of 
study visits. The University of Michigan will be responsible for payments. In order to process your payment, full 
name, completed mailing address, date of birth, and social security number will be required.
8.3 Who could profit or financially benefit from the study results?
Information obtained from this study may help the supporter Exelixis, Inc. and/or the University of Michigan learn 
more about the causes, risks, treatments, or how to prevent this and other health problems. In the interest of 
transparency, we would like you to know that Dr. Parikh has served on an Advisory Board for the sponsor of this 
research. Dr. Parikh is not likely to benefit financially from the results of this research.
Research can lead to new discoveries, such as new tests, drugs, or devices. Researchers, their organizations, and 
other entities, including companies, may potentially benefit from the use of the data or discoveries. You will not 
have rights to these discoveries or any proceeds from them.
9. CONFIDENTIALITY OF SUBJECT RECORDS AND AUTHORIZATION TO RELEASE YOUR PROTECTED HEALTH 
INFORMATION
The information below describes how your privacy and the confidentiality of your research records will be 
protected in this study, and any sub-studies described in this document.
9.1 How will the researchers protect my privacy?
The University of Michigan has rules to protect information about you. Federal and state laws also protect your 
privacy. Upon enrolling in this study, you will be assigned a unique identification number. All records related to 
the study will use this identification number instead of your name or other personally identifying information 
whenever possible. We will take measures to protect the privacy and security of all your personal information, but 
we cannot guarantee complete confidentiality of study data. 
Medical information created by this research study may become part of your hospital medical record and may be 
forwarded to your primary doctor. Information that does not become part of your medical record will be stored in 
your study file. 
You have the right to request access to your protected health information that is used or shared during this
research and that is related to your study treatment or payment for your study treatment, but you may access
this information only after the study is completed. To request this information, please contact the researchers
listed in Section 10 “Contact Information” (below).
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This 
Web site will not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.
9.2 What protected health information (PHI) about me could be seen by the researchers or by other people? 
Why? Who might see it?
Signing this form gives the researchers your permission to obtain, use, and share information about you for this 
study, and is required in order for you to take part in the study.
Study ID: HUM00184276   IRB: IRBMED   Date Approved: 8/23/2023   Expiration Date: 2/2/2024


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Consent Subtitle Sahai-1390 HCC
Consent Version: 08MAY2023 
Medical information and billing records are protected by the privacy regulations of the federal Health Insurance 
Portability and Accountability Act of 1996 (HIPAA). This type of information is called protected health information 
(PHI). PHI about you may be obtained from any hospital, doctor, and other health care provider involved in your 
care, including:

Hospital/doctor's office records, including test results (X-rays, blood tests, urine tests, etc.)

Mental health care records (except psychotherapy notes not kept with your medical records

Alcohol/substance abuse treatment records

HIV/AIDS status

Sexually transmitted disease and/or other communicable disease status

Genetic counseling/genetic testing records

Health plan/health insurance records

All records relating to your condition, the treatment you have received, and your response to the 
treatment

Billing information

Demographic information

Personal identifiers
There are many reasons why information about you may be used or seen by the researchers or others during or 
after this study. Examples include:

The researchers may need the information to make sure you can take part in the study. 

The researchers may need the information to check your test results or look for side effects. 

University, Food and Drug Administration (FDA) and/or other government officials, auditors, and/or the 
IRB may need the information to make sure that the study is done in a safe and proper manner.

Study sponsors or funders, or safety monitors or committees, may need the information to: 
o
Make sure the study is done safely and properly
o
Learn more about side effects 
o
Analyze the results of the study 

Insurance companies or other organizations may need the information in order to pay your medical bills 
or other costs of your participation in the study.

The researchers may need to use the information to create a databank of information about your 
condition or its treatment.

Information about your study participation may be included in your regular UMHS medical record.

If you receive any payments for taking part in this study, the University of Michigan accounting 
department may need your name, address, Social Security number, payment amount, and related 
information for tax reporting purposes. 

Federal or State law may require the study team to give information to government agencies. For 
example, to prevent harm to you or others, or for public health reasons. 
The results of this study could be published in an article, but would not include any information that would let 
others know who you are. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This
Web site will not include information that can identify you. At most, the Web site will include a summary of the
results. You can search this Web site at any time.
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Consent Subtitle Sahai-1390 HCC
Consent Version: 08MAY2023 
9.3 What happens to information about me after the study is over or if I cancel my permission to use my PHI?
As a rule, the researchers will not continue to use or disclose information about you, but will keep it secure until it 
is destroyed. Sometimes, it may be necessary for information about you to continue to be used or disclosed, even 
after you have canceled your permission or the study is over. 
 
Examples of reasons for this include:

To avoid losing study results that have already included your information 

To provide limited information for research, education, or other activities (This information would not 
include your name, social security number, or anything else that could let others know who you are.) 

To help University and government officials make sure that the study was conducted properly
9.4 When does my permission to use my PHI expire? 
Your permission expires at the end of the study, unless you cancel it sooner. You may cancel your permission at 
any time by writing to the researchers listed in Section 10 "Contact Information" (below). If you withdraw your 
permission, you may no longer be eligible to participate in this study.
10. CONTACT INFORMATION
10.1 Who can I contact about this study?
Please contact the researchers listed below to:

Obtain more information about the study

Ask a question about the study procedures or treatments

Talk about study-related costs to you or your health plan 

Report an illness, injury, or other problem (you may also need to tell your regular doctors)

Leave the study before it is finished

Express a concern about the study
Principal Investigator: Thomas Enzler, MD, PhD
Mailing Address: 
University of Michigan
1500 East Medical Center Drive
C437 MIB; SPC 5843
Ann Arbor, MI 48109
Telephone: 734-647-8902 (Clinic)
Emergency Contact: 734-936-4000 (Hospital Operator – 24-hour paging)
You may also express a concern about a study by contacting the Institutional Review Board listed below. 
University of Michigan Medical School Institutional Review Board (IRBMED)
2800 Plymouth Road
Building 520, Room 3214
Ann Arbor, MI 48109-2800
Telephone: 734-763-4768 (For International Studies, include the appropriate calling codes.)
Fax: 734-763-1234
e-mail: irbmed@umich.edu 
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Consent Subtitle Sahai-1390 HCC
Consent Version: 08MAY2023 
If you are concerned about a possible violation of your privacy or concerned about a study you may contact the 
University of Michigan Health System Compliance Help Line at 1-866-990-0111.
When you call or write about a concern, please provide as much information as possible, including the name of the 
researcher, the IRBMED number (at the top of this form), and details about the problem. This will help University 
officials to look into your concern. When reporting a concern, you do not have to give your name unless you want 
to.
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Consent Subtitle Sahai-1390 HCC
Consent Version: 08MAY2023 
11. RECORD OF INFORMATION PROVIDED
11.1 What documents will be given to me?
You will receive a copy of the signed and dated informed consent.
Your signature in the next section means that you have received copies of all of the following documents:

This "Consent to be Part of a Research Study" document. (Note: In addition to the copy you receive, copies 
of this document will be stored in a separate confidential research file and may be entered into your 
regular University of Michigan medical record.)

Other (specify):
Study ID: HUM00184276   IRB: IRBMED   Date Approved: 8/23/2023   Expiration Date: 2/2/2024


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Consent Subtitle Sahai-1390 HCC
Consent Version: 08MAY2023 
12. SIGNATURES
Sig-A
Consent/Assent to Participate in the Research Study
I understand the information printed on this form. I have discussed this study, its risks and potential benefits, and 
my other choices with __________________________________.  My questions so far have been answered. I 
understand that if I have more questions or concerns about the study or my participation as a research subject, I 
may contact one of the people listed in Section 10 (above). I understand that I will receive a copy of this form at the 
time I sign it and later upon request. I understand that if my ability to consent or assent for myself changes, either I 
or my legal representative may be asked to re-consent prior to my continued participation in this study.
Print Legal Name: ________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Sig-D
Consent/Assent to collect for unspecified future research
This project involves the option to allow the study team to keep your identifiable specimens/data for use in future 
research. I understand that it is my choice whether or not to allow future use of my specimens. I understand that if 
my ability to consent or assent for myself changes, either I or my legal representative may be asked to re-consent 
prior to my continued participation in this study.
_____ Yes, I agree to let the study team keep my specimens for future research.
_____ No, I do not agree to let the study team keep my specimens for future research.
Print Legal Name: ___________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ______________________________
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Consent Subtitle Sahai-1390 HCC
Consent Version: 08MAY2023 
Sig-G
Principal Investigator or Designee
I have provided this participant and/or his/her legally authorized representative(s) with information about this 
study that I believe to be accurate and complete. The participant and/or his/her legally authorized 
representative(s) indicated that he or she understands the nature of the study, including risks and benefits of 
participating.
Legal Name: ________________________________________________________________________
Title: ______________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Study ID: HUM00184276   IRB: IRBMED   Date Approved: 8/23/2023   Expiration Date: 2/2/2024