fred hutchinson cancer center university
untitled h2

Current version: December 13, 2021 Title of Protocol:
A Phase 2 trial of cabozantinib and pembrolizumab in the first‐line treatment of advanced hepatocellular carcinoma  
| Investigators List: Principal Investigator                 | Professional Title                               | Phone Number   |
|------------------------------------------------------------|--------------------------------------------------|----------------|
| Gentry King, MD                                            | Assistant Member, FHCRC, Assistant Professor, UW | (206) 606‐2494 |
| Investigator                                               | Professional Title                               | Phone Number   |
| E. Gabriela Chiorean, MD                                   | Member, FHCRC, Professor, UW                     | (206) 606‐6248 |
| Stacey Cohen, MD                                           | Assistant Member, FHCRC, Assistant Professor, UW | (206) 606‐6658 |
| Andrew Coveler, MD                                         | Associate Member, FHCRC, Associate Professor, UW | (206) 606‐7509 |
| William Harris, MD                                         | Associate Member, FHCRC, Associate Professor, UW | (206) 606‐6856 |
| Veena Shankaran, MD                                        | Associate Member, FHCRC, Associate Professor, UW | (206) 667‐7844 |
| David Zhen, MD                                             | Assistant Member, FHCRC, Assistant Professor, UW | (206) 606‐1733 |
| Lindsay Hannan, MD                                         | Assistant Member, FHCRC, Assistant Professor, UW | (206) 667‐4998 |
| Biostatistician: Ted Gooley, PhD                           | Full Member, FHCRC                               |                |
| Supported by: Exelixis (drug and funding) and Merck (drug) |                                                  |                |  
A Phase 2 trial of cabozantinib and pembrolizumab in the first‐line treatment of advanced hepatocellular carcinoma
fred hutchinson cancer center university
project synopsis

| PROJECT SYNOPSIS Title   | A Phase 2 trial of cabozantinib and pembrolizumab in the first‐line treatment  of advanced hepatocellular carcinoma                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
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| Version date             | August 11, 2021                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Study center             | University of Washington/Fred Hutchinson Cancer Center                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Number of subjects       | 29 patients                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| Study duration           | Accrual period: 24 months; follow‐up period: 12 months                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Background and           | Hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer‐related                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| rationale                | mortality globally. Prognosis is poor for patients with advanced disease  despite the recent approval of several new agents. The immune system plays a  critical role in the pathogenesis of HCC. Increased regulatory T cells, decreased  CD8+ and CD4+ tumor‐infiltrating lymphocytes, and high PD‐1/PD‐L1  expression are associated with poorer outcomes. This is supported by the  efficacy of PD‐1 inhibitors currently approved in the second‐line treatment of  HCC, after progression on VEGFR tyrosine kinase inhibitors. Promising early results were noted for combinations of immune checkpoint  inhibitors and VEGF/VEGFR blockade, which may activate synergistic or inhibit  resistance pathways. Lenvatinib and pembrolizumab led to an ORR of 42%,  while bevacizumab and atezolizumab led to an ORR of 61% in the first‐line  treatment of advanced HCC. Furthermore, the role of cMET signaling is  increasingly recognized in HCC. Cabozantinib is a multikinase inhibitor against  cMET, VEGFR1‐3 and AXL. The Phase 3 CELESTIAL trial demonstrated a  significant improvement in OS with cabozantinib compared to placebo in  patients post‐sorafenib (HR 0.76, 95% CI 0.63‐0.92, p=0.0049), leading to FDA  approval for patients with advanced HCC previously treated with sorafenib. Evidence also supports the immunomodulatory effects of cMET and the TAM  receptors including AXL via enhancement of PD‐L1/PD‐L2 expression and  regulation of immune effector and regulatory cells, thus supporting a  combination strategy with cabozantinib and immunotherapy. There is a strong rationale for the combined inhibition of c‐MET/VEGFR and  PD‐1 in HCC. This Phase 2 clinical trial will evaluate the efficacy of cabozantinib  and pembrolizumab in the first‐line treatment of patients with advanced HCC. |
| Design                   | Non‐randomized Phase 2 trial (Simon's optimal two‐stage design)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Objectives               | Primary objective - To determine the objective response rate (ORR) of the combination ofPage 2 of 107                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |  
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| cabozantinib and pembrolizumab in the first‐line treatment of  advanced HCC based on RECIST v1.1.                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                   |                           |
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| Secondary objectives - To assess the disease control rate (DCR) by RECIST v1.1, ORR and DCR  by iRECIST, progression‐free survival (PFS) by RECIST v1.1, and overall  survival (OS). - To assess the safety of the combination of cabozantinib and  pembrolizumab based on NCI CTCAE v5. Exploratory objectives - To explore the predictive biomarkers for cabozantinib and  pembrolizumab in HCC in blood and archival tissue or pre‐treatment  fresh tumor biopsy (if applicable). |                                                                                                                                                                                                                                                                                                                                                                                                   |                           |
| Inclusion and                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Inclusion criteria                                                                                                                                                                                                                                                                                                                                                                                |                           |
| exclusion criteria                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | 1.                                                                                                                                                                                                                                                                                                                                                                                                | At least 18 years of age. |
| 2.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Must have a histologically confirmed diagnosis of HCC or a non‐invasive  diagnosis of HCC as per the American Association for the Study of Liver  Diseases (AASLD) criteria. a. If available, archival tissue must be submitted. b. Mixed HCC‐cholangiocarcinoma is not allowed.                                                                                                                  |                           |
| 3.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Patient has BCLC stage C disease, or BCLC stage B disease that is not  amenable to locoregional therapy orrefractory to locoregional therapy, and  not amenable to curative treatment. a. Previous locoregional therapy is allowed (e.g. surgical resection,  external beam radiation, catheter‐based therapy), and patients must  have evidence of disease progression from locoregionaltherapy. |                           |
| 4.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Must have measurable disease by RECIST v1.1. a. Lesions that were previously radiated or ablated cannot be target  lesions unless there was subsequent radiographic progression at those  sites.                                                                                                                                                                                                  |                           |
| 5.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | No prior systemic therapy for HCC. Prior chemotherapy given locally into  the liver (e.g. TACE) is allowed.                                                                                                                                                                                                                                                                                       |                           |
| 6.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Must have Child‐Pugh class A hepatic function within 7 days prior to first  dose of study intervention (Appendix 6).                                                                                                                                                                                                                                                                              |                           |
| 7.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | ECOG performance status 0‐1 (Appendix 5).                                                                                                                                                                                                                                                                                                                                                         |                           |
| 8.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Life expectancy of at least 12 weeks.                                                                                                                                                                                                                                                                                                                                                             |                           |
| 9.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Recovery to baseline or ≤ Grade 1 toxicities (CTCAE v5) related to any prior  treatments, unless adverse events (AEs) are clinically nonsignificant and/or  stable on supportive therapy.                                                                                                                                                                                                         |                           |
| 10. Adequate organ and marrow function, based upon meeting all of the  following laboratory criteria within 14 days before first dose of study  treatment: a. Absolute neutrophil count (ANC) ≥ 1500/mm3 without granulocyte  colony‐stimulating factor support. b. Platelets ≥ 60,000/mm3 without transfusion within 14 days.Page 3 of 107                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                   |                           |  
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| e.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Total bilirubin ≤ 2 mg/dL OR direct bilirubin ≤ ULN for participants with  total bilirubin levels >2 mg/dL.                  |
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| f.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Serum albumin ≥ 2.8 g/dl (≥ 28 g/L) without albumininfusion.                                                                 |
| g.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≤ 1.5 × ULN.                                             |
| h.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 40 mL/min using the Cockcroft‐Gault equation (Appendix 7). |
| i.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol)or  24h urine protein ≤ 1g.                                 |
| j.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Hemoglobin A1c (HbA1c) ≤ 8% within 28 days before randomization or  fasting serum glucose ≤ 160 mg/dL.                       |
| 11. Patients with positive hepatitis B surface antigen (HBsAg) and/or HBV viral  load >100 IU/mL at the time of enrollment are eligible to enroll on study if  they meet the following criteria: a. Anti‐HBV therapy as per institutional practice must be given at least 4  weeks and HBV viral load must be <100 IU/mL prior to initiating study  treatment. Patients on active HBV therapy with viral loads <100 IU/mL  should remain on the same therapy throughout studytreatment. b. Note: Patients with positive anti‐hepatitis B core antibody (HBcAb),  negative HBsAg, and negative or positive anti‐hepatitis B surface  antibody, and who have an HBV viral load <100 IU/mL do not require  anti‐viral prophylaxis. 12. Patients with past or ongoing hepatitis C infection (HCV) are eligible to  enroll on study, with or without prior anti‐viral treatment, as long as the  other eligibility criteria are met. Treated patients must have completed  their anti‐viral treatment at least 1 month prior to initiating study  treatment. 13. Sexually active fertile subjects and their partners must agree to use  effective methods of contraception (see Appendix 8) during the course of  the study and for at least 4 months after the last dose cabozantinib. They  must also refrain from donating sperm during this time period. 14. Female subjects of childbearing potential must not be pregnant at screening  and not breastfeeding. Females of childbearing potential are defined as  premenopausal females capable of becoming pregnant (i.e. females who  have had any evidence of menses in the past 12 months,with the exception  of those who had prior hysterectomy). a. Women who have been amenorrheic for 12 or more months are still  considered to be of childbearing potential if the amenorrhea is possibly  due to prior chemotherapy, antiestrogens, low body weight, ovarian  suppression or other reasons. 15. Capable of understanding and complying with the protocol requirements  and must provide written informed consent/assent for the study. |                                                                                                                              |  
Exclusion criteria 1. Prior treatment with any systemic therapy for HCC, including anti‐VEGF
therapy or any systemic investigational agent.  
a. If the patient previously received systemic treatment for reasons other than HCC: small molecule kinase inhibitors are not allowed within 2 weeks and cytotoxic/biologic agents are not allowed within 4 weeks of study treatment.  
2. Prior exposure to immune checkpoint inhibitors or other immunotherapeutic agents.  
3. Currently participating in or has participated in a study of an investigational agent or device within 4 weeks prior to the first dose of studytreatment.  
4. Major surgery within 6 weeks or minor surgery (e.g. dental extraction)
within 10 days prior to first dose of study treatment.  
a. Complete wound healing from major surgery must have occurred at least 1 month before first dose and from minor surgery (e.g. simple excision, tooth extraction) at least 7 days before first dose. Subjects with clinically relevant ongoing complicationsfrom priorsurgery are not eligible.  
5. Local liver‐directed therapy within 4 weeks of initiating studytreatment.  
6. Palliative radiation for the purpose of symptomatic relief to non‐liver and non‐CNS disease within 2 weeks of starting treatment. Other radiation treatments within 4 weeks of starting treatment.  
a. Patients must have recovered from all radiation‐related toxicities, not require corticosteroids, and have not had radiationpneumonitis.  
7. Prior liver or other allogenic tissue/organ transplantation. 8. History of primary immunodeficiency.  
9. Active autoimmune or inflammatory disease that has required systemic treatment in the past 2 years (i.e. with use of disease‐modifying agents, corticosteroids or immunosuppressive drugs). This includes, but is not limited to, inflammatory bowel disease, celiac disease, systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, Graves' disease, etc.  
a. The following autoimmune conditions are allowed: vitiligo or alopecia; hypothyroidism on stable hormone replacement therapy; psoriasis/eczema not requiring systemic treatment.  
b. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.  
10. Chronic use of systemic steroid (in dosing exceeding 10 mg daily of prednisone equivalent) or immunosuppressive therapy or use within 14 days prior to enrollment.  
a. The following treatments are allowed: intranasal, inhaled, topical or local steroid injections; systemic corticosteroids at physiologic doses equivalent to no more than prednisone 10 mg/day; steroids as premedication for contrast dye allergy.  
11. History of (non‐infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.  
12. History of hepatic encephalopathy or treatment to prevent or control  
| rifaximin to control hepatic encephalopathy are not allowed.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
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| 13. Esophageal or gastric variceal bleeding within the past 6 months. All  subjects will be screened for esophageal varices unless performed in the  last 6 months before study treatment. If varices are present, they should be  treated according to institutional standards before starting study  treatment. 14. Uncontrolled ascites, clinically significant or symptomatic ascites requiring  paracenteses or increasing doses of diuretics within the past 3months. a. Patients who are on stable diuretic doses for at least 3 months are  eligible if they meet other eligibility criteria. b. Asymptomatic ascites detected on imaging are allowed. 15. Has known history or any evidence of CNS metastases and/or  carcinomatous meningitis. Subjects with previously treated brain  metastases may participate provided they are asymptomatic and  radiologically stable (i.e. without progression for at least 4 weeks byrepeat  imaging (which must be performed during study screening), clinically stable,  and without the need steroidsfor at least 4 weeks priorto first dose ofstudy  treatment). 16. Concomitant anticoagulation with oral anticoagulants (e.g. warfarin, direct  thrombin and Factor Xa inhibitors) or platelet inhibitors (e.g. clopidogrel).  Allowed anticoagulants are the following: a. Low‐dose aspirin for cardioprotection (per local applicable guidelines)  is permitted. b. Low molecular weight heparin (LMWH) ispermitted. c. Anticoagulation with therapeutic doses of LMWH is allowed in subjects  without known brain metastases who are on a stable dose of LMWH for  at least 4 weeks before first dose of study treatment, and who have had  no clinically significant hemorrhagic complications from the  anticoagulation regimen or the tumor. 17. The subject has 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 with risk of  hemodynamic instability within 12 months before the first dose  of study treatment. ii. Uncontrolled hypertension defined as sustained blood pressure  (BP) > 150 mm Hg systolic or > 95 mm Hg diastolic despite optimal  antihypertensive treatment, and/or change in antihypertensive  medications within 1 week before starting treatment. Note:  eligibility of a subject receiving 4 or more antihypertensive  medications prior to study entry will require approval from the PI. iii. Stroke (including transient ischemic attack [TIA]), myocardial  infarction (MI), or other ischemic event, or arterial  thromboembolic within 12 months before the first dose. iv. Asymptomatic venous thromboembolic event (e.g. deep venous |  
| symptomatic cholangitis or appendicitis, acute pancreatitis, acute  obstruction of the pancreatic duct or common bile duct, or gastric  outlet obstruction.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                            |           |           |    |       |              |    |
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| 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, other history ofsignificant bleeding (e.g.  pulmonary hemorrhage) within 12 weeks before first dose, or known  thrombotic disorder. |           |           |    |       |              |    |
| d.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Cavitating                                                                                                                                                                                                                                 | pulmonary | lesion(s) | or | known | endotracheal | or |
| endobronchial disease manifestation.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                            |           |           |    |       |              |    |
| e.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Lesions invading any major blood vessels, including inferior vena cava  or cardiac involvement of HCC based on imaging. Note: Main and branch portal vein and hepatic vein invasion is allowed.                                            |           |           |    |       |              |    |
| f.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Ongoing active infection requiring antibiotics. Antibiotics mustbe  completed at least 7 days before initiating study treatment.                                                                                                           |           |           |    |       |              |    |
| g.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Known active tuberculosis.                                                                                                                                                                                                                 |           |           |    |       |              |    |
| h.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Serious non‐healing wound, ulcer, or bone fracture.                                                                                                                                                                                        |           |           |    |       |              |    |
| 18. Patients with proteinuria >1+ on urine dipstick testing will undergo 24‐hour  urine collection for quantitative assessment of proteinuria. Participants  with urine protein ≥1 g/24 hours will be ineligible. 19. Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms  per electrocardiogram (EKG) within 28 days before first dose of study  treatment. a. Note: If a single EKG shows a QTcF with an absolute value > 500 ms, two  additional EKGs at intervals of approximately 3 min must be performed  within 30 min after the initial EKG, and the average of these three  consecutive results for QTcF will be used to determineeligibility. 20. Inability to swallow tablets or any other condition that might interfere with  oral absorption of medications. 21. Previously identified allergy or hypersensitivity to study drugs and/or any of  their excipients. 22. Ongoing secondary malignancy that is progressing and/or has required |                                                                                                                                                                                                                                            |           |           |    |       |              |    |  
| 23. Has a known history of HIV infection. Note: HIV testing is not mandated for  screening. 24. Co‐infection with HBV (HBsAg (+) and /or detectable HBV DNA) and HCV  (anti‐HCV Ab (+) and detectable HCV RNA) at study entry. 25. Co‐infection with HBV and HDV at study entry. 26. Live vaccine or live attenuated vaccine within 30 days prior to first doseof  study treatment. Administration of killed vaccines is allowed. 27. Pregnant or lactating females. 28. Known psychiatric illness, substance abuse disorder, or other condition that  would interfere with the ability to comply with the requirements of the  study. 29. Has history or current evidence of any condition, therapy, or laboratory  abnormality that might confound the results of the study, interfere with the  subject's participation for the full duration of the study, or is not in the best  interest of the subject to participate, in the opinion of the treating  investigator.   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
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| Study treatments                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | All enrolled patients will receive cabozantinib 40mg PO daily continuously and  pembrolizumab 200mg IV every 3 weeks, in 3‐week cycles. Dose modifications  of cabozantinib and/or pembrolizumab may be made for adverse events (AEs)  (guidelines provided in protocol). Immune‐related AEs will be treated per  published guidelines. If one agent needs to be discontinued due to treatment‐  related toxicity, patients may continue to receive treatment with the other  agent. Treatment will continue until disease progression, intolerance, or patient  withdrawal. Treatment beyond progression will be allowed if pre‐specified  criteria are met (Section 12.1).                                                                                                   |
| Study assessments                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Toxicity assessments (history, physical exam, labs) will occur weekly during  cycle 1, then every 3 weeks on day 1 of each subsequent cycle. AEs will be  graded by NCI CTCAE v5. Disease assessments will be performed by multiphasic contrast CT or MRI of  abdomen/pelvis, as well as CT chest with or without contrast at baseline  (within one month of enrollment) and every 9 weeks on treatment. Tumor  response will be determined by RECIST v1.1 and iRECIST. The tumor marker  alpha‐fetoprotein (AFP) will also be measured at baseline and every 9 weeks if  abnormal at baseline. If patients discontinue treatment due to intolerable or unacceptable toxicity,  they will be followed for progression and for survival at least every 4 months  up to 3 years. |
| Statistical plan and  sample size  calculation                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | This Phase 2 trial uses Simon's optimal two‐stage design. The null hypothesis  that the true ORR by RECIST v1.1 is 20% will be tested against a one‐sided  alternative that the assumed‐true ORR with the tested combination is 38%. In  the first stage, 13 patients will be accrued. If there are 2 or fewer patients withPage 8 of 107                                                                                                                                                                                                                                                                                                                                                                                                                                      |  
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| response (an observed ORR of 15% or less), the study will be suspended for  lack of sufficient efficacy. Otherwise, 16 additional patients will be accrued for  a total of 29 patients. The null hypothesis (ORR 20%) will be rejected if 9 or  more patients have a tumor response out of 29 patients (an observed ORR of  at least 31%). This design yields a type I error rate of 0.10 and power of 80%  when the true ORR is 38%.   |                                                                                                   |
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| Anticipated                                                                                                                                                                                                                                                                                                                                                                                                                             | It is anticipated that the combination of cabozantinib and pembrolizumab will                     |
| findings                                                                                                                                                                                                                                                                                                                                                                                                                                | significantly improve the ORR of patients with advanced HCC in the first‐line  treatment setting. |
fred hutchinson cancer center university
table of contents

| 1.0                                                                                                          | INTRODUCTION .                                                                                                                                 |
|--------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|
| 1.1                                                                                                          | Overview of hepatocellular carcinoma                                                                                                           |
| 1.2                                                                                                          | Systemic therapy in advanced HCC                                                                                                               |
| 1.2.1                                                                                                        | Approved targeted multikinase inhibitors .                                                                                                     |
| 1.2.2                                                                                                        | MMET inhibition and cabozantinib .                                                                                                             |
| 1.2.3                                                                                                        | Immuno-modulation by the PD-1 pathway .................................................................................................16      |
| 1.2.4                                                                                                        | Immune checkpoint inhibition in HCC.........................................................................................................16 |
| Combination therapy with immune checkpoint inhibitors in HCC .............................................17 |                                                                                                                                                |
| 1.2.5                                                                                                        |                                                                                                                                                |
| 1.3                                                                                                          | Rationale for combining cabozantinib and pembrolizumab in HCC.......................................................18                         |
| 1.4                                                                                                          | Study drug information .                                                                                                                       |
| 1.4.1                                                                                                        | Cabozantinib drug profile                                                                                                                      |
| 1.4.2                                                                                                        | Pembrolizumab drug profile .                                                                                                                   |
| 1.5                                                                                                          | Rationale for dose selection                                                                                                                   |
| 1.5.1                                                                                                        | Rationale for cabozantinib dose selection                                                                                                      |
| 1.5.2                                                                                                        | Rationale for pembrolizumab dose selection .                                                                                                   |
| 2.0                                                                                                          | TRIAL DESIGN .                                                                                                                                 |
| STUDY OBJECTIVES                                                                                             |                                                                                                                                                |
| 3.0                                                                                                          |                                                                                                                                                |
| 3.1                                                                                                          | Primary objectives                                                                                                                             |
| 3.2                                                                                                          | Secondary objectives .                                                                                                                         |
| 3.3                                                                                                          | Exploratory objectives                                                                                                                         |
| 4.0                                                                                                          | STUDY ENDPOINTS                                                                                                                                |
| 4.1                                                                                                          | Primary endpoint .                                                                                                                             |
| 4.2                                                                                                          | Secondary endpoints                                                                                                                            |
| 4.3                                                                                                          | Exploratory endpoints                                                                                                                          |
| 5.0                                                                                                          | SUBJECT SELECTION                                                                                                                              |
| 5.1                                                                                                          |                                                                                                                                                |
| 5.2                                                                                                          | Exclusion criteria .                                                                                                                           |
| 5.3                                                                                                          | Re-screening                                                                                                                                   |
| 6.0                                                                                                          | PRE-TREATMENT PROCEDURES .                                                                                                                     |
| Informed consent                                                                                             |                                                                                                                                                |
| 6.1                                                                                                          | Page 10 of 107                                                                                                                                 |  
| RG1007034                             |                                                                                                                                                            |
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| Screening                             |                                                                                                                                                            |
| 6.2                                   |                                                                                                                                                            |
| 6.3                                   | Subject registration .                                                                                                                                     |
| TREATMENT PLAN                        |                                                                                                                                                            |
| 7.0                                   |                                                                                                                                                            |
| 7.1                                   | Cabozantinib administration                                                                                                                                |
| 7.2                                   | Pembrolizumab administration                                                                                                                               |
| D Duration of therapy                 |                                                                                                                                                            |
| 7.3                                   |                                                                                                                                                            |
| 7.4                                   | T Treatment compliance                                                                                                                                     |
| CONCOMITANT MEDICATIONS AND THERAPIES |                                                                                                                                                            |
| 8.0                                   |                                                                                                                                                            |
| 8.1.                                  | Allowed therapy                                                                                                                                            |
| 8.2                                   | Recording concomitant therapy                                                                                                                              |
| 8.3                                   | Palliative radiation .                                                                                                                                     |
| 8.4                                   | Prohibited or restricted therapy .                                                                                                                         |
| 9.0                                   | TOXICITIES AND DOSING MODIFICATIONS                                                                                                                        |
| 9.1                                   | Assessment of adverse events .                                                                                                                             |
| 9.2                                   | General guidelines about toxicity assessment and management incombination therapy .......35                                                                |
| 9.3                                   | Information on cabozantinib toxicity ...................................................................................................................36 |
| Gastrointestinal disorders            |                                                                                                                                                            |
| 9.3.1                                 |                                                                                                                                                            |
| 9.3.2                                 | Non-gastrointestinal fistula                                                                                                                               |
| Hemorrhage .                          |                                                                                                                                                            |
| 9.3.3                                 |                                                                                                                                                            |
| 9.3.4                                 | Thromboembolic events                                                                                                                                      |
| 9.3.5                                 | Hypertension                                                                                                                                               |
| 9.3.6                                 | Stomatitis and mucositis .                                                                                                                                 |
| 9.3.7                                 | Skin and Subcutaneous Tissue Disorders .............................................................................................40                     |
| 9.3.8                                 | OSTEONECROSIS                                                                                                                                              |
| 9.3.9                                 | Proteinuria ............................................................................................................................................41 |
| 9.3.10                                | Nervous system disorders .....................................................................................................................42           |
| 9.3.11                                | Hepatocellular toxicity ........................................................................................................................42         |
| Infections and infestations           |                                                                                                                                                            |
| 9.3.12                                |                                                                                                                                                            |
| 9.3.13                                | Blood and lymphatic system disorders ...............................................................................................43                     |
| 9.3.14                                | Fatigue                                                                                                                                                    |
| 9.3.15                                | Weight loss                                                                                                                                                |
| 9.3.16                                | QTc prolongation                                                                                                                                           |  
| RG1007034                                                                                                                                                |                                                                                                                                                                 |
|----------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 9.3.17                                                                                                                                                   | Electrolyte disorders .........................................................................................................................45               |
| 9.3.18                                                                                                                                                   | Endocrine disorders ............................................................................................................................45              |
| Angioedema ...........................................................................................................................................45 |                                                                                                                                                                 |
| 9.3.19                                                                                                                                                   |                                                                                                                                                                 |
| 9.4                                                                                                                                                      | D Dose levels of cabozantinib                                                                                                                                   |
| 9.5                                                                                                                                                      | Guidance on dose modification of cabozantinib and pembrolizumab for non-immune and                                                                              |
| immune toxicities                                                                                                                                        |                                                                                                                                                                 |
| Non-immune toxicities                                                                                                                                    |                                                                                                                                                                 |
| 9.5.1                                                                                                                                                    |                                                                                                                                                                 |
| 9.5.2                                                                                                                                                    | Diarrhea (immune and non-immune) ..............................................................................................47                               |
| 9.5.3                                                                                                                                                    | Liver toxicity ..............................................................................................................................................49 |
| 9.5.4                                                                                                                                                    | Skin toxicity other than PPES                                                                                                                                   |
| Other immune-related toxicities                                                                                                                          |                                                                                                                                                                 |
| 9.5.5                                                                                                                                                    |                                                                                                                                                                 |
| 9.5.6                                                                                                                                                    | Pembrolizumab-related infusion reaction                                                                                                                         |
| 9.6                                                                                                                                                      |                                                                                                                                                                 |
| 10.0                                                                                                                                                     | STUDY CALENDAR .                                                                                                                                                |
| 1.0                                                                                                                                                      | STUDY ASSESSMENTS                                                                                                                                               |
| 11.1                                                                                                                                                     | Baseline/screening evaluations                                                                                                                                  |
| 1.2                                                                                                                                                      | On study evaluations                                                                                                                                            |
| 1.3                                                                                                                                                      | Assessment of safety parameters at baseline and duringstudy treatment ...............................63                                                         |
| 1.4                                                                                                                                                      | Evaluations at treatment discontinuation (at 30 days [+ 7 days] following last dose of                                                                          |
| cabozantinib or pembrolizumab) .                                                                                                                         |                                                                                                                                                                 |
| Post-study follow-up .                                                                                                                                   |                                                                                                                                                                 |
| 1.5                                                                                                                                                      |                                                                                                                                                                 |
| 12.0                                                                                                                                                     | CRITERIA FOR TREATMENT DISCONTINUATION                                                                                                                          |
|                                                                                                                                                          |                                                                                                                                                                 |
| 12.1                                                                                                                                                     |                                                                                                                                                                 |
| 13.0                                                                                                                                                     | GUIDELINES FOR DISEASE EVALUATION                                                                                                                               |
| Tumor assessment by RECIST v1.1(primary endpoint) ............................................................................68                         |                                                                                                                                                                 |
| 13.1                                                                                                                                                     |                                                                                                                                                                 |
| 13.1.1                                                                                                                                                   | Definitions for measurable disease and target lesions ........................................................................68                                |
| 13.1.2                                                                                                                                                   | Definitions of response                                                                                                                                         |
| 13.1.3                                                                                                                                                   | Evaluation of overall response .                                                                                                                                |
| 13.1.4                                                                                                                                                   | Definitions for response evaluations                                                                                                                            |
| 13.2                                                                                                                                                     | Tumor assessment by iRECIST (secondary endpoints) .......................................................................................71                     |
| 13.2.1                                                                                                                                                   | Similarities and differences between iRECIST andRECIST v1.1 ....................................................71                                              |
| Timepoint response using iRECIST                                                                                                                         |                                                                                                                                                                 |
| 13.2.2                                                                                                                                                   |                                                                                                                                                                 |  
| RG1007034                                                                                                                                                      | Methods of measurement .                                                                                                                            |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------|
| 13.3                                                                                                                                                           | DRUG INFORMATION .                                                                                                                                  |
| 14.0                                                                                                                                                           |                                                                                                                                                     |
| 14.1                                                                                                                                                           | Cabozantinib .                                                                                                                                      |
| 14.1.1                                                                                                                                                         | Composition and formulation                                                                                                                         |
| 14.1.2                                                                                                                                                         | Storage and handling .                                                                                                                              |
| Administration .                                                                                                                                               |                                                                                                                                                     |
| 14.1.3                                                                                                                                                         |                                                                                                                                                     |
| 14.1.4                                                                                                                                                         | Treatment accountability                                                                                                                            |
| Pembrolizumab                                                                                                                                                  |                                                                                                                                                     |
| 14.2                                                                                                                                                           |                                                                                                                                                     |
| 14.2.1                                                                                                                                                         | Formulation and preparation                                                                                                                         |
| 14.2.2                                                                                                                                                         | Storage and handling .                                                                                                                              |
| 14.3.3                                                                                                                                                         | Treatment accountability                                                                                                                            |
| 15.0                                                                                                                                                           | BIOLOGICAL CORRELATIVE STUDIES .                                                                                                                    |
| 15.1                                                                                                                                                           | Tissue collection                                                                                                                                   |
| 15.2                                                                                                                                                           | Immunohistochemistry (IHC) .                                                                                                                        |
| RNA sequencing .                                                                                                                                               |                                                                                                                                                     |
| 15.3                                                                                                                                                           |                                                                                                                                                     |
| 15.4                                                                                                                                                           | Flow cytometry and cytokine assays                                                                                                                  |
| ADVERSE EVENT ASSESSMENT AND REPORTING                                                                                                                         |                                                                                                                                                     |
| 16.0                                                                                                                                                           |                                                                                                                                                     |
| 16.1                                                                                                                                                           | DEFINITIONS                                                                                                                                         |
| Attribution to study treatment .                                                                                                                               |                                                                                                                                                     |
| 16.2                                                                                                                                                           |                                                                                                                                                     |
| 16.3                                                                                                                                                           | Parameters of assessment for AEs and SAEs                                                                                                           |
| Monitoring and recording AEs .                                                                                                                                 |                                                                                                                                                     |
| 16.4                                                                                                                                                           |                                                                                                                                                     |
| 16.4.1                                                                                                                                                         | Responsibility for adverse event monitoring ...........................................................................................80           |
| 16.4.2                                                                                                                                                         | Time frame for AE monitoring.....................................................................................................................80 |
| 16.4.3                                                                                                                                                         | Laboratory data                                                                                                                                     |
| 16.4.4                                                                                                                                                         | Recording AEs                                                                                                                                       |
| 16.5                                                                                                                                                           | Requirements for reporting AEs                                                                                                                      |
| 16.5.1                                                                                                                                                         | SE REPORTING                                                                                                                                        |
| Reporting of pregnancy and lactation .......................................................................................................81                 |                                                                                                                                                     |
| 16.5.2                                                                                                                                                         |                                                                                                                                                     |
| 16.5.3                                                                                                                                                         | Reporting of pembrolizumab overdose ..................................................................................................82            |
| Events of clinical interest ................................................................................................................................82 |                                                                                                                                                     |
| 16.5.4                                                                                                                                                         |                                                                                                                                                     |
| 16.5.5                                                                                                                                                         |                                                                                                                                                     |
| STATISTICAL CONSIDERATIONS                                                                                                                                     |                                                                                                                                                     |
| 17.0                                                                                                                                                           |                                                                                                                                                     |  
| RG1007034                                                                                                                                                        |                                                                                                                                                                              |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 17.1                                                                                                                                                             | Sample size calculation ..............................................................................................................................................83     |
| Statistical methods                                                                                                                                              |                                                                                                                                                                              |
| 17.2                                                                                                                                                             | DATA AND SAFETY MONITORING PLAN                                                                                                                                              |
| 18.0                                                                                                                                                             |                                                                                                                                                                              |
| 18.1                                                                                                                                                             | T Trial monitoring                                                                                                                                                           |
| 18.2                                                                                                                                                             | Data and safety reviews ..................................................................................................................................................84 |
| STUDY DOCUMENTATION AND RECORD-KEEPING                                                                                                                           |                                                                                                                                                                              |
| 19.0                                                                                                                                                             |                                                                                                                                                                              |
| 19.1                                                                                                                                                             | Investigator's files and retention of documents ........................................................................................85                                   |
| Source documents and background data ...........................................................................................................85               |                                                                                                                                                                              |
| 19.2                                                                                                                                                             |                                                                                                                                                                              |
| 19.3                                                                                                                                                             | Audits and inspections .............................................................................................................................................85       |
| Case report forms                                                                                                                                                |                                                                                                                                                                              |
| 19.4                                                                                                                                                             |                                                                                                                                                                              |
| 20.0                                                                                                                                                             | PROTOCOL MODIFICATIONS ......................................................................................................................................86              |
| 2.0                                                                                                                                                              | TERMINATION OF STUDY ...............................................................................................................................................86       |
| ETHICAL ASPECTS                                                                                                                                                  |                                                                                                                                                                              |
| 2.0                                                                                                                                                              | L LOCAL REGULATIONS                                                                                                                                                          |
| 2.1                                                                                                                                                              | Institutional review board/ethics committee ..............................................................................................................86                 |
| 22.2                                                                                                                                                             |                                                                                                                                                                              |
| 2.3                                                                                                                                                              | Confidentiality of trial documents and subject regions .........................................................................87                                           |
| PUBLICATION OF DATA                                                                                                                                              |                                                                                                                                                                              |
| 23.0                                                                                                                                                             |                                                                                                                                                                              |
| 24.0                                                                                                                                                             | APPENDICES .                                                                                                                                                                 |
| Appendix 1: Abbreviations and definitions ................................................................................................................87     |                                                                                                                                                                              |
| Appendix 2. Cabozantinib Drug Diary ..........................................................................................................................91 |                                                                                                                                                                              |
| Appendix 3: Clinical laboratory tests                                                                                                                            |                                                                                                                                                                              |
| Appendix 4: Strong inducers and inhibitors of CYP3A .................................................................................................94          |                                                                                                                                                                              |
| Appendix 5: ECOG performance status scale                                                                                                                        |                                                                                                                                                                              |
| Appendix 6: Child-Pugh score calculation for cirrhosis mortality .....................................................................94                         |                                                                                                                                                                              |
| Appendix 7: Cockcroft-Gault equation for determining creatinine clearance (CrCl) ................................95                                              |                                                                                                                                                                              |
| Appendix 8: Highly effective methods of contraception ..............................................................................96                           |                                                                                                                                                                              |
| 25.0                                                                                                                                                             | REFERENCES                                                                                                                                                                   |
fred hutchinson cancer center university
1.0 introduction 1.1 overview of

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, and is the 5th most common cancer(estimated 841,080 incident casesin 2018 worldwide) and the 3rd leading cause of cancer‐ related mortality globally (estimated 781,631 deaths in 2018 worldwide).1,2 Men are 3.5 times more likely than women to develop HCC. The rate of HCC has risen significantly in the US in the last decade with an annual increase in incidence of 3.64% based on analysis of the SEER data from 2000‐2012.3 Moreover, this trend is projected to continue into the next decade with aging of the baby boomers. It is estimated that the incidence rate (per 100,000 person‐years) of HCC in adults will increase from 13.5 in 2013 to 17.0 in 2020 and 21.2 in 2030.3 Common etiologic factors for HCC include hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol, metabolic disorders (e.g. obesity, non‐alcoholic fatty liver disease, diabetes), and smoking.4 HBV is the most important etiology of HCC worldwide and accounts for >50% of cases, mainly in HBV‐endemic parts ofsoutheast Asia and Africa.5 In the US, HCV, alcohol, and increasingly metabolic disorders are the primary risk factors for HCC.6 HCC is associated with poor prognosis. The 5‐year overall survival (OS) of patients with primary liver malignancy is estimated to be 18%.7 The median OS of patients with advanced HCC remains limited (~18 months) despite recent developments in systemic therapy.8 Thus, there is an ongoing need to develop novel therapeutic strategies in this disease.
fred hutchinson cancer center university
1.2 systemic therapy in advanced

Sorafenib has specificity for RAF, VEGFR1‐3 and PDGFRb, and was the first agent to significantly improve OS compared to placebo in patients with advanced HCC as demonstrated by the Phase 3 SHARP trial, serving as a standard treatment since 2007.9 Recently, several similar multikinase inhibitors with targets including VEGFR, PDGFR, FGFR and other receptors have been approved. In the REFLECT trial, lenvatinib was non‐inferior to sorafenib with respect to OS and is now an additional first‐line therapy option.10 The data also demonstrated that achieving an objective response was an independent predictive factor for increased OS.11 In the RESORCE trial, regorafenib significantly improved OS compared to placebo (10.6 vs. 7.8 months; HR
0.63, 95% CI 0.50‐0.79, p<0.0001) in advanced HCC patients who progressed on and tolerated prior sorafenib.12 Anti‐tumor activity of these multikinase inhibitors comes from their anti‐angiogenic, anti‐
proliferative, and pro‐apoptotic effects.
fred hutchinson cancer center university
1.2.2 met inhibition and cabozantinib

The importance of the MET receptorsignaling pathway, which is activated by its ligand HGF, is increasingly recognized in HCC. MET overexpression is observed in a large subset of HCC tumors and is associated with poorer survival.13,14 MET activation and signaling mediates the epithelial‐to‐mesenchymal transition, invasion, and tumor metastasis.15 In fact, the anti‐tumor activity of MET inhibition in HCC has been well established in both preclinical and early clinical studies.16,17 Particularly, MET activation is believed to be one of the mechanisms of resistance to anti‐VEGF therapy, providing the rationale for concurrently inhibiting VEGFR and MET.18,19 Cabozantinib is a multikinase inhibitor with its primary activity against MET, VEGFR1‐3 and AXL.20 The Phase 3 CELESTIAL trial randomized (2:1) patients with advanced HCC who previously progressed on sorafenib to cabozantinb 60mg orally daily vs. placebo. Cabozantinib demonstrated a significant improvement in OS (10.2 vs. 8.0 months, HR 0.76 (95% CI 0.63‐0.92), p=0.005) and in PFS (5.2 vs. 1.9 months, HR 0.44 (95% CI 0.36‐0.52), p<0.001) compared to placebo. The objective response rate (ORR)
was 4% vs. < 1% (p=0.009).21 In this trial, 68% of patients experienced a grade 3 or 4 AE (vs. 37% in patients receiving placebo). In the cabozantinib arm, dose reduction was required in 62% of patients, while 16% of patients discontinued treatment due to toxicity. Moreover, the median daily dose of cabozantinib received was 35.8 mg daily.  
Based on results of the CELESTIAL trial, cabozantinib was FDA approved for the treatment of advanced HCC post‐sorafenib in January 2019.
fred hutchinson cancer center university
1.2.3 immuno-modulation by the pd-1

The programmed cell death 1 (PD‐1) receptor is essential in the control of the immune system. It is expressed on surface of activated lymphocytes including CD4+ and CD8+ T cells, B cells, T regulatory cells, and natural killer cells. The ligandsfor PD‐1 are PD‐L1 and PD‐L2, which are expressed orinduced in various cell types. Binding of PD‐L1 or PD‐L2 to PD‐1 inhibits T cell activation, therefore modulating immune responses to prevent autoimmune reactions. PD‐L1 expression can be found in the vascular endothelium and other non‐hematopoietic tissues, while PD‐L2 is mainly expressed on antigen‐presentingcells.22,23 PD‐L1 expression occurs at low levels in normal tissues. However, many cancers express high levels of PD‐
L1 in order to inhibit T cell activation and anti‐tumor immune responses.24 Thus, immune checkpoint inhibition of the PD‐1 pathway is one therapeutic strategy to prevent suppression of T cell responses against tumor cells.
fred hutchinson cancer center university
1.2.4 immune checkpoint inhibition inhcc

The immune system plays a critical role in the pathogenesis of HCC.25 The cirrhotic liver is marked by an immunosuppressive state.26 Increased T regulatory cells, decreased CD8+ or CD4+ T cells, and high PD‐ L1/PD‐L2 expression are associated with disease progression and poorer outcomes.27‐33 Immune checkpoint inhibition has been shown to be an active therapeutic strategy in this disease. In the Phase 1/2 trial CheckMate 040 of nivolumab in patients with advanced HCC with or without prior sorafenib, the ORR by modified RECIST (mRECIST) was 20% (95% CI 15‐26) in the dose‐expansion phase, while the 6‐ and 9‐month OS was 83% (95% CI 78‐88) and 74% (95% CI 67‐79), respectively.34 Response was observed independent of PD‐L1 expression and HCC etiology. Likewise, in the Phase 2 trial KEYNOTE‐ 224, patients with advanced HCC who progressed on sorafenib were treated with pembrolizumab and demonstrated an ORR of 17% (95% CI 11‐26) and a disease control rate (DCR) of 62% (95% CI 52‐71) by mRECIST.35 Both nivolumab and pembrolizumab were safe and tolerable; the rate of grade 3 or 4 treatment‐related adverse events (TRAEs) was 25% with both agents. Efficacy and toxicity were both independent of viral infection status. 34,35 Subgroup analyses suggested greater response in tumors with PD‐L1 overexpression by the combined positive score, although further validation studies are needed. Interestingly, the randomized Phase 3 trial KEYNOTE‐240 of pembrolizumab vs. best supportive care in patients with advanced HCC previously treated with sorafenib did not meet its primary endpoints of OS
and PFS.36 However, the study had a stringent pre‐specified p‐value cutoff of 0.0174 for statistical significance, and there was a clear trend towards improved OS with pembrolizumab compared to best supportive care (median OS 13.9 vs. 10.6 months, HR 0.781 (95% CI 0.611‐0.988), p=0.0238). Subsequent therapies received by the two groups also likely affected the results. Similar to prior experience, the ORR
with pembrolizumab was 18.3% (95% CI 14.0‐23.4).36 Moreover, PD‐1 inhibition has been evaluated in the first‐line treatment setting in HCC patients in the CheckMate 459 trial of nivolumab vs. sorafenib. The trial did not meet its primary endpoint of OS, with a median OS of 16.4 vs. 14.7 months (HR 0.85 (95% CI 0.72‐1.02), p=0.0752). ORR was 15% vs. 7%. Subsequent therapies received might have affected the OS, as 38% and 46% of patients in the nivolumab and sorafenib arms, respectively, received subsequent treatments.37 Nivolumab and pembrolizumab are currently approved for the second‐line treatment of advanced HCC.  
Otherimmune checkpoint inhibitors currently in development in HCC include anti‐PD‐L1 (e.g. durvalumab, atezolizumab) and anti‐CTLA4 (e.g. tremelimumab) agents.
fred hutchinson cancer center university
1.2.5 combination therapy with immune

The ORR associated with nivolumab and pembrolizumab monotherapy in refractory HCC was 20% and 17%, respectively.34,35 Thus, there is a need to improve on these outcomes and maximize the efficacy of immune checkpoint inhibitors. Combination approaches have been explored and yielded promising early results.  
There is now growing evidence for the combination of VEGF/VEGFR‐targeting agents and PD‐1/PD‐L1 inhibition, which may lead to increased effector T cell infiltration into tumors.38 The combination of lenvatinib and pembrolizumab was evaluated in a Phase 1b trial of HCC patients in the first‐line treatment setting. There were 6 patients in the DLT evaluation phase (Part 1) and 24 patients in the expansion phase (Part 2). This study demonstrated an ORR of 42% (95%CI 23‐63) by mRECIST criteria
(complete response (CR) 4%, partialresponse (PR) 39%).38 The median progression‐free survival(PFS) was 9.69 (95%CI 5.55‐NE) months. The rate of grade 3‐4 treatment‐emergent adverse events(TEAEs) was 60%,
and the rate of serious adverse events (SAEs) was 27%, including 3 deaths (out of 30 patients). The most common TEAEs were: decreased appetite (53%), hypertension (53%), diarrhea (43%), fatigue (40%),
dysphonia (30%), proteinuria (30%), AST elevation (27%), weight loss (27%), hypothyroidism (20%),
nausea (20%), and palmar‐plantar erythrodyesthesia syndrome (PPES) (20%). The most common grade 3 TEAEs were: hypertension (17%), AST elevation (17%), decreased WBC (13%), hyponatremia (10%). 60%
of patients required dose interruption of lenvatinib or pembrolizumab due to a TEAE, and 60% of patients had a dose reduction of lenvatinib. The rate of discontinuation of lenvatinib or pembrolizumab was 17%.38 Furthermore, a Phase 1b trial of atezolizumab and bevacizumab was conducted in solid tumors, in which Arms A and F enrolled treatment‐naïve patients with unresectable HCC. Arm F was a randomized cohort of atezolizumab/bevacizumab vs. atezolizumab.39 The combination regimen demonstrated a significant improvement in the primary endpoint of PFS compared to atezolizumab monotherapy (median PFS 5.6 vs. 3.4 months; HR 0.55, 80% CI 0.40‐0.74, p=0.0108). TRAEs occurred in 68% in the atezo/bev group (grade 3 TRAEs, 20%) and 41% in the atezo group (grade 3 TRAEs, 5%). In Arm A, 104 patients with treatment‐naïve unresectable HCC received atezolizumab/bevacizumab; its primary endpoint of ORR was 36% (76% of responses were ongoing at the time of data cutoff). There were 88% TRAEs, and 39% grade 3‐4 TRAEs (most commonly hypertension).  
While these were early phase studies with small numbers of patients, theirresults provided strong support for combining VEGF blockade with immune checkpoint inhibitors for increased efficacy in HCC. The combination of atezolizumab plus bevacizumab previously received FDA breakthrough designation for development in HCC.40 In fact, the Phase 3 randomized trial of atezolizumab/bevacizumab vs. sorafenib
(IMbrave 150) for the first‐line treatment of unresectable HCC met its primary endpoint of OS and PFS
(press release October 21, 2019).41 Other similar immunotherapy combination Phase 3 trials in treatment‐naïve advanced HCC patients are currently ongoing: lenvatinib/pembrolizumab vs. lenvatinib (LEEP‐002) (NCT03713593), and cabozantinib/atezolizumab vs. sorafenib vs. cabozantinib (COSMIC‐312) (NCT03755791).
fred hutchinson cancer center university
1.3 rationale for combining cabozantinib

Both cabozantinib and pembrolizumab have clinical activity as monotherapy in advanced refractory HCC,
and there is significant benefit in combining VEGFR and PD‐1 inhibition in the first‐line treatment setting, as discussed above. In addition, MET has been shown to play an immunosuppressive role by interacting with immune checkpoint pathways. For instance, MET mediates immune suppression by upregulating PD‐
L1 expression, while PD‐L1 and PD‐L2 have been associated with increased levels of MET and VEGF.42,43 Co‐expression of MET and PD‐L1/PD‐L2 was observed in squamous cell carcinomas of the lung and esophagus.44,45 Similarly, the TAM family of receptors including AXL have been demonstrated tosuppress the immune system. Cabozantinib has specificity against AXL and has been shown to modulate the tumor microenvironment, as well as immune suppressor and effector cells.46‐49 There is a strong rationale for combining inhibition of MET, AXL/TAM receptors, VEGFR and PD‐1 in HCC
through the combination of cabozantinb and pembrolizumab, which will be explored in this non‐
randomized Phase 2 trial in the first‐line treatment of patients with advanced HCC.
fred hutchinson cancer center university
1.4 study drug information 1.4.1

Please refer to the Investigator's Brochure for complete information on cabozantinib.
fred hutchinson cancer center university
1.4.1.1 targetspecificity

Cabozantinib (XL184) is a multikinase targeted agent with specificity against several receptor tyrosine kinases. The main targets are MET (IC50 8 nM), VEGFR2/KDR (IC50 2 nM), and RET (IC50 85 nM), but it also inhibits KIT (IC50 5 nM), FLT3 (IC50 11 nM), and AXL (IC50 42 nM). Based on cellular and in vivo activity assays, cabozantinib exhibits comparable anti‐tumor activity against MET and VEGFR2, with lesser activity against RET, KIT, AXL and FLT3.
fred hutchinson cancer center university
1.4.1.2 preclinical data

Preclinicalstudies demonstrated that cabozantinib given orally effectively blocked the phosphorylation of MET and VEGFR2 in tumor xenograft models, and the duration of inhibition was over 8 hours at 100 mg/kg.50 In vivo changes in tumor vasculature and apoptosis were observed in xenografts treated with cabozantinib. Moreover, cabozantinib induced significant tumor growth inhibition or regression in xenograft models across various tumor types, including medullary thyroid cancer, breast cancer, lung cancer, and glioblastoma.50 In a MET‐overexpressed HCC xenograft model, cabozantinib prolonged the survival of mice compared to vehicle.51 There is also evidence that cabozantinib has specific anti‐tumor activity in bone metastatic lesions.50,52
fred hutchinson cancer center university
1.4.1.3 pharmacokinetics (pk)

A population PK analysis of cabozantinib at 60 mg daily (dose reduction allowed) in patients with renal cell carcinoma showed it had the following characteristics: terminal half‐life 99 h, terminal volume of distribution (V/F) ~319 L, clearance at steady state 2.2 L/h. Clearance was independent of age and sex.  
Cabozantinb is mostly protein‐bound in circulation.
fred hutchinson cancer center university
cytochrome p450 and potential interactions

Data from a clinical drug interaction study (Study XL184‐008) showed that clinically relevant steady‐state concentrations of cabozantinib appear to have no marked effect on the area under the plasma concentration‐vs‐time curve (AUC) of co‐administered rosiglitazone, a CYP2C8 substrate. Therefore, cabozantinib is not anticipated to markedly inhibit CYP2C8 in the clinic, and by inference, is not anticipated to markedly inhibit other CYP450 isozymesthat have lower [I]/Ki values compared to CYP2C8 (i.e. CYP2C9, CYP2C19, CYP2D6, CYP1A2, and CYP3A4). In vitro data indicate that cabozantinib is unlikely to induce cytochrome P450 enzymes, except for possible induction of CYP1A1 at high cabozantinib concentrations
(30 μM). Based on in vitro studies, cabozantinib is a CYP3A4 substrate and a weak CYP2C9 substrate (but not a CYP2D6, CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate). Results from a clinical pharmacology study
(XL184‐006) showed that concurrent administration of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an approximately 77% reduction in cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy volunteers. Chronic co‐administration of cabozantinib with strong inducers of the CYP3A4 family (see Appendix 4) may significantly decrease cabozantinib concentrations.  
The chronic use of these strong CYP3A4 inducers should be avoided. Other drugs that induce CYP3A4 should be also used with caution due to the potential decreased exposure (AUC) to cabozantinib. Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme induction potential is recommended if possible.  
In addition,resultsfrom a clinical pharmacology study (XL184‐007)showed that concurrent administration of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 38% increase in the cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy volunteers. Co‐
administration of cabozantinib with strong inhibitors of the CYP3A4 family (see Appendix 4) may increase cabozantinib concentrations. Grapefruit, star fruit and Seville oranges may also increase plasma concentrations of cabozantinib and should be avoided. Strong CYP3A4 inhibitors should be avoided and other drugs with inhibitory effects on CYP3A4 should be used with caution because these drugs have the potential to increase exposure (AUC) to cabozantinib. Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is recommended if possible.
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protein-binding

Cabozantinib is highly bound (≥ 99.7%) to human plasma proteins. Therefore, highly protein‐bound drugs should be used with caution with cabozantinib because there is a potential displacement interaction that could increase free concentrations of cabozantinib and/or of the co‐administered highly protein‐bound drug (and a corresponding increase in pharmacologic effect).
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other interactions

Food may increase exposure levels of cabozantinib by 57%. Therefore, fasting recommendations should be followed.  
In vitro data suggest that cabozantinib is unlikely to be a substrate for P‐glycoprotein, but it does appear to have the potential to inhibit the P‐glycoprotein transport activity. Therefore, cabozantinib may have the potential to increase plasma concentrations of co‐administered substrates of P‐glycoprotein.  
Cabozantinib was shown to be a substrate of drug transporter MRP2 in an in vitro assay. Administration of MRP2 inhibitors to subjects may result in increases in cabozantinib plasma concentrations. Administration of the proton pump inhibitor (PPI) esomeprazole resulted in no clinically relevant effect on cabozantinib plasma PK in healthy volunteers. Therefore, concomitant use of gastric pH modifying agents
(e.g. PPIs, H2 receptor antagonists, and antacids) is not contraindicated in subjects administered cabozantinib.  
Additional details regarding potential drug interactions with cabozantinib can be found in the Investigator's Brochure.  
1.4.1.4 Clinical safety in clinical trials of *cabozantinib* Cabozantinib has been studied across multiple malignancies, including HCC, medullary thyroid, prostate, breast and non‐small cell lung cancers, renal cell carcinoma, melanoma, and glioblastoma multiforme.50 The capsule formulation has been approved in the US for refractory metastatic medullary thyroid cancer, and the tablet formulation has been approved for advanced renal cell carcinoma andHCC.  
Please see the Investigator's Brochure for the most updated safety information on cabozantinib. Per Investigator Brochure v13, safety data are available from 2611 subjects who have been dosed with cabozantinib (2453 subjects in single agent cabozantinib studies [2410 subjects in a pooled analysis and 43 subjects in a Japanese study] and 158 subjects in combination studies of cabozantinib with other agents). In prior studies, the most frequent AEs experienced by ≥ 20% of subjects treated with cabozantinib in descending order of frequency were: diarrhea, fatigue, decreased appetite, nausea, weight decreased, PPES, vomiting, constipation, hypertension, dysgeusia, dysphonia, asthenia, and dyspnea. For a full description of the safety profile of cabozantinib, refer to the cabozantinib Investigator's Brochure.  
Other medically important but less frequent AEs included: arterial thrombotic AEs (eg, transientischemic attack [TIA], and myocardial infarction [MI]) and venous thrombotic AEs (e.g. deep vein thrombosis [DVT]
and pulmonary embolism), severe hemorrhagic events, proteinuria, wound healing complications, gastrointestinal (GI) perforation, abscesses including intra‐abdominal and pelvic abscess, GI and non‐GI fistula formation, osteonecrosis, and reversible posterior leukoencephalopathy syndrome(RPLS).  
AEs associated with laboratory abnormalities experienced by ≥ 5% of subjects treated with cabozantinib in descending order of frequency were: anemia, AST increased, ALT increased, hypothyroidism, hypokalemia, hypomagnesemia, thrombocytopenia, hypocalcemia, hypophosphatemia, lactate dehydrogenase (LDH) increased, lipase increased, neutropenia, hyponatremia, ALP increased, leukopenia, and hyperglycemia.  
AEs may occur within the first few weeks in the course of treatment with cabozantinib, as the drug is expected to reach steady state exposure at approximately 2 weeks following the first dose. Events that generally have an early onset include hypocalcemia, hypokalemia, thrombocytopenia, hypertension, PPES, abdominal pain, mucosal inflammation, constipation, diarrhea, and vomiting. AEs should be managed with supportive care at the earliest signs of toxicity. Dose reductions and treatment interruptions/delays should be considered. Dose reductions are recommended for events that, if persistent, could become serious or intolerable (see Section 9.0).
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1.4.1.5 safety of cabozantinib in

The safety profile of cabozantinib in HCC patients was characterized in a Phase 2 randomized discontinuation study and in a Phase 3 clinical trial.21,53 CELESTIAL was a Phase 3 randomized trial of cabozantinib (n=470) vs. placebo (n=237) in patients with HCC and Child‐Pugh class A5 liver function previously treated with sorafenib. The starting dose of cabozantinib was 60 mg daily, and 62% of patients required dose reductions with a median time to first dose reduction of 38 days. The median average daily dose administered was 35.8 mg daily.  
In the CELESTIAL trial, TEAEs occurred in 99% of patients, with grade 3‐4 AEs in 68% of patients and SAEs in 50% of patients. The most common TEAEs in >=20% of patients were: diarrhea (54%), decreased appetite (48%), PPES (46%), fatigue (45%), nausea (31%), hypertension (29%), vomiting (26%), AST
increased (22%), and asthenia (22%). The most common grade 3‐4 TEAEs in >=5% of patients were: PPES
(17%), hypertension (16%), AST elevation (12%), diarrhea (10%), fatigue (10%), asthenia (7%), decreased appetite (6%), ALT elevation (5%).21 16% of patients discontinued cabozantinib due to TRAEs, most commonly for PPES, fatigue, reduced appetite, diarrhea, and nausea. In the study, grade 5 TRAEs were reported in 6 patients in the cabozantinib group, including liver failure, bronchoesophageal fistula, portal vein thrombosis, upper GI hemorrhage, pulmonary embolism, and hepatorenal syndrome.21
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1.4.2 pembrolizumab drug profile

Please refer to the Investigator's Brochure for complete information on pembrolizumab.  
1.4.2.1 Preclinical and clinical trial data Pembrolizumab is a potent and highly selective humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the PD‐1 receptor, thus inhibiting its interaction with PD‐L1 and PD‐L2. Based on preclinical *in vitro* data, pembrolizumab has high affinity and potent receptor blocking activity for PD1. Pembrolizumab has been in clinical development in multiple advanced malignancies and has an acceptable safety profile. Keytruda™ (pembrolizumab) has been approved for advanced or metastatic melanoma, non‐small cell lung cancer, head and neck squamous carcinoma, classical Hodgkin lymphoma, urothelial carcinoma, MSI‐ H or dMMR solid tumors, PD‐L1‐expressing gastric or gastroesophageal cancer, PD‐L1‐expressing cervical cancer, primary mediastinal large B‐cell lymphoma, and Merkel cell carcinoma. Moreover, it was approved on November 9, 2018 for patients with advanced HCC previously treated withsorafenib.  
Please refer to the Investigator's Brochure and the US Prescribing Information on pembrolizumab for more information.
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1.4.2.2 safety of pembrolizumab in

The KEYNOTE‐224 trial was a Phase 2 non‐randomized trial of pembrolizumab in patients with HCC and Child‐Pugh class A hepatic function (n=104).35 Pembrolizumab was safe and tolerable in this population.  
TRAEs occurred in 73% of patients, with grade 3‐4 TRAEs in 25% and SAEs in 15% of patients. The most common TRAES in >=10% of patients were: fatigue (21%), AST elevation (14%), pruritis (12%), diarrhea
(11%), and rash (10%). The most common grade 3‐4 TRAEs were: AST elevation (7%), ALT elevation (4%),
and fatigue (4%). 17% of patients had a dose interruption due to a TRAE, most commonly AST elevation (4%), ALT elevation (3%), hypothyroidism (2%), and rash (2%). Five out of 104 patients discontinued pembrolizumab due to a TRAE, including adrenal insufficiency, increased AST, increased ALT, increased bilirubin, and cholestatic jaundice. One death due to ulcerative esophagitis was thought to be possibly related to pembrolizumab. Immune‐related AEs (irAEs) were reported in 15% of the study population, most commonly hypothyroidism (8%) and adrenal insufficiency (3%). The rate of immune‐mediated hepatitis was 3%; no flares or recurrence of HBV or HCV were observed. Four out of 104 patients had a grade 3 irAE: adrenal insufficiency (n=2), skin toxicity (n=1), and Type 1 diabetes mellitus (n=1). In the Phase 3 trial KEYNOTE‐240 of pembrolizumab vs. best supportive care, TRAEs occurred in 61% and 49% of patients, respectively. In the pembrolizumab arm, the rate of grade 3‐4 TRAEs was 19%, while 7.2%
of patients had a grade 3 immune‐mediated AE, leading to treatment discontinuation in 7%. The most common TRAEs were: pruritis (13%), fatigue (10%), AST elevation (9%), diarrhea (8%), and rash (8%). The most common grade 3‐4 TRAEs were: AST (5%) and ALT (4%) elevations. Hypo‐ (5%) andhyperthyroidism
(3%) were the most common immune‐mediated AEs, mostly grade 1‐2, followed by severe skin reaction
(3%), pneumonitis (2%), hepatitis (2%).36 Please refer to the pembrolizumab Investigator's Brochure for the complete drug safety and toxicity profile in other tumor types.
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1.5 rationale for dose selection

Cabozantinib will be initiated at 40 mg orally once daily continuously. In the CELESTIAL trial, 62% of patients treated with cabozantinib 60 mg required a dose reduction due to toxicities, and the median average daily dose was 35.8 mg.21 Ongoing trials of nivolumab and cabozantinib for triple negative breast cancer and renal cell carcinoma currently use a starting dose of 40 mg.54‐56 In fact, the 40 mg dose is recommended by Exelixis in trials of combination therapy with immune checkpointinhibitors.
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1.5.2 rationale for pembrolizumab dose

The planned fixed dose of pembrolizumab for this study in combination with cabozantinib is 200 mg IV
every 3 weeks (Q3W). Based on the totality of data generated in the Keytruda development program, 200 mgQ3W isthe appropriate dose of pembrolizumab for adults across all indications and regardless oftumor type. As outlined below, this dose is justified by:  
- Clinical data from 8 randomized studies in melanoma and NSCLC indications demonstrating flat dose‐ and exposure‐efficacy relationships from 2 mg/kg Q3W to 10 mg/kg Q2W, representing an approximate 5‐ to 7.5‐fold exposure range (refer to IB, Section 5.2.2)
- Population PK analysis showing that both fixed dosing and weight‐based dosing provides similar control of PK variability with considerable overlap in the distributions of exposures, supporting suitability of 200 mg Q3W
- Clinical data showing meaningful improvement in benefit‐risk including overall survival at 200 mg Q3W across multiple indications, and
- Pharmacology data showing full target saturation in both systemic circulation (inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically‐based PK [PBPK] analysis)at 200 mg Q3W
Recently, the efficacy and safety of pembrolizumab 200 mg IV q3w in combination with the multikinase inhibitor lenvatinib has been evaluated in an investigational multicenter, multi‐indication, open‐label Phase 1b/1 clinical study38 and a Phase 3 study is ongoing.
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2.0 trial design

This is a non‐randomized Phase 2 trial using the Simon's optimal two‐stage design. In the first stage, 13 eligible patients will enroll. If there are 2 or fewer patients with response (CR or PR), the study will be suspended for lack of sufficient efficacy. Otherwise, 16 additional patients will be accrued for a total of 29 patients. An accrual period of 24 months and follow‐up period of 12 months are anticipated. More than 29 patients may be screened and/or enrolled depending on screen fails and dropouts before starting treatment.
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3.0 study objectives 3.1 primary

.  
To determine the objective response rate (ORR) of the combination of cabozantinib and pembrolizumab in the first-line treatment of advanced HCC based on RECISTv1.1.
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3.2 secondary objectives

.  
.  
To assess the disease control rate (DCR) by RECIST v1.1, ORR and DCR by iRECIST, progression-free survival (PFS) by RECIST v1.1, and overall survival(OS).  
To assess the safety of the combination treatment with cabozantinib and pembrolizumab basedon
NCI CTCAE v5.
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3.3 exploratory objectives

To explore the predictive biomarkers for cabozantinib and pembrolizumab in HCC using archival tissue
.  
or pre-treatment fresh tumor biopsy (if available) and pre-treatment peripheralblood.
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4.0 study endpoints 4.1 primary

- Objective response (complete or partial response) per RECIST v1.1 (by blinded centralreview).  
- Objective response (complete or partial response) per iRECIST (blinded centralreview). - Disease control (complete + partial response + stable disease) per RECIST v1.1 andiRECIST. - Progression‐free survival(PFS) is defined astime fromstudy registration to radiographic progression per RECIST v1.1 (blinded central assessment), clinical progression, or death of anycause.  
- Overall survival (OS) is defined as time from study registration to death of anycause. - Safety will be evaluated by assessing AEs according to NCI CTCAEv5.  
Exploratory biomarkers will be assessed using archival tumor tissue or pre‐treatment fresh tumor biopsy
(if available) and peripheral blood and correlated with tumor response. Tumor tissue will be assessed by multiplex immunohistochemistry (IHC) assay for intratumoral immune cell subsets and distribution, RNA sequencing (NanoString) for immune gene expression, and T cell receptor (TCR) clonality. The expression levels of biomarkers including c‐MET, PD‐L1 and PD‐L2 in tumor cells and cells of the tumor microenvironment will also be assessed by IHC. Blood‐based biomarkers will be explored, including circulating T cell subsets and cytokines. To be eligible for the study, the subject must meet all of the inclusion criteria and none of the exclusion criteria.  
1. At least 18 years of age.  
2. Must have a histologically confirmed diagnosis of HCC or a non‐invasive diagnosis of HCC as perthe American Association for the Study of Liver Diseases (AASLD)criteria.  
c. If available, archival tissue must be submitted. d. Mixed HCC‐cholangiocarcinoma is not allowed.  
3. Patient has BCLC stage C disease, or BCLC stage B disease that is not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to curativetreatment.  
a. Previous locoregional therapy is allowed (e.g. surgical resection, external beam radiation, catheter‐based therapy), and patients must have evidence of disease progression from locoregional therapy.  
4. Must have measurable disease by RECIST v1.1.  
a. Lesions that were previously radiated or ablated cannot be target lesions unless there was subsequent radiographic progression at those sites.  
25 of 107 Protocol V4.0 13Dec2021
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4.0 study endpoints 4.1 primary

5. No prior systemic therapy for HCC. Prior chemotherapy given locally into the liver (e.g. TACE) is allowed.  
6. Must have Child‐Pugh class A hepatic function within 7 days prior to first dose of studyintervention
(Appendix 6).  
7. ECOG performance status 0‐1 (Appendix 5).  
8. Life expectancy of at least 12 weeks.  
9. Recovery to baseline or ≤ Grade 1 toxicities(CTCAE v5)related to any priortreatments, unless adverse events (AEs) are clinically nonsignificant and/or stable on supportivetherapy.  
10. Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 14 days before first dose of study treatment:
a. Absolute neutrophil count (ANC) ≥ 1500/mm3 without granulocyte colony‐stimulatingfactor support.  
b. Platelets ≥ 60,000/mm3 without transfusion within 14 days.  
c. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without transfusion or EPO dependency within 14days.  
d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 × upperlimit of normal
(ULN).  
e. Total bilirubin ≤ 2 mg/dL OR direct bilirubin ≤ ULN for participants with total bilirubin levels >2 mg/dL.  
f. Serum albumin ≥ 2.8 g/dl (≥ 28 g/L) without albumininfusion.  
g. Prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≤ 1.5 ×ULN. h. Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 40 mL/min using the Cockcroft‐
Gault equation (Appendix 7).  
i. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) or 24h urine protein ≤1g. j. Hemoglobin A1c (HbA1c) ≤ 8% within 28 days before randomization or fasting serum glucose ≤
160 mg/dL.  
11. Patients with positive hepatitis B surface antigen (HBsAg) and/or HBV viral load >100 IU/mL at the time of enrollment are eligible to enroll on study if they meet the followingcriteria:
a. Anti‐HBV therapy as per institutional practice must be given at least 4 weeks and HBV viral load must be <100 IU/mL prior to initiating study treatment. Patients on active HBV therapy with viral loads <100 IU/mL should remain on the same therapy throughout studytreatment.  
b. Note: Patients with positive anti‐hepatitis B core antibody (HBcAb), negative HBsAg, and negative or positive anti‐hepatitis B surface antibody, and who have an HBV viral load <100 IU/mL do not require anti‐viral prophylaxis.  
12. Patients with past or ongoing hepatitis C infection (HCV) are eligible to enroll on study, with or without prior anti‐viral treatment, as long as the other eligibility criteria are met. Treated patients must have completed their anti‐viral treatment at least 1 month prior to initiating studytreatment.  
13. Sexually active fertile subjects and their partners must agree to use effective methods of contraception (see Appendix 8) during the course of the study and for at least 4 months after the last dose cabozantinib. They must also refrain from donating sperm during this timeperiod.  
14. Female subjects of childbearing potential must not be pregnant at screening and not breastfeeding.  
Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e. females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy).  
a. Women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons.  
15. Capable of understanding and complying with the protocol requirements and must provide written informed consent/assent for the study.
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5.2 exclusion criteria

1. Prior treatment with any systemic therapy for HCC, including anti‐VEGF therapy or any systemic investigational agent.  
a. If the patient previously received systemic treatment for reasons other than HCC: small molecule kinase inhibitors are not allowed within 2 weeks and cytotoxic/biologic agents are not allowed within 4 weeks of study treatment.  
2. Prior exposure to immune checkpoint inhibitors or other immunotherapeuticagents.  
3. Currently participating in or has participated in a study of an investigational agent or device within 4 weeks prior to the first dose of study treatment.  
4. Major surgery within 6 weeks or minor surgery (e.g. dental extraction) within 10 days prior to first dose of study treatment.  
a. Complete wound healing from major surgery must have occurred at least 1 month before first dose and from minor surgery (e.g. simple excision, tooth extraction) at least 7 days before first dose. Subjects with clinically relevant ongoing complications from prior surgery are noteligible.  
5. Local liver‐directed therapy within 4 weeks of initiating studytreatment.  
6. Palliative radiation for the purpose of symptomatic relief to non‐liver and non‐CNS disease within 2 weeks of starting treatment. Other radiation treatments within 4 weeks of startingtreatment.  
a. Patients must have recovered from allradiation‐related toxicities, not require corticosteroids, and have not had radiation pneumonitis.  
7. Prior liver or other allogenic tissue/organ transplantation.  
8. History of primary immunodeficiency.  
9. Active autoimmune or inflammatory disease that has required systemic treatment in the past 2 years
(i.e. with use of disease‐modifying agents, corticosteroids or immunosuppressive drugs). This includes, but is not limited to, inflammatory bowel disease, celiac disease, systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, Graves' disease,etc. a. The following autoimmune conditions are allowed: vitiligo or alopecia; hypothyroidism on stable hormone replacement therapy; psoriasis/eczema not requiring systemic treatment.  
b. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.  
10. Chronic use of systemic steroid (in dosing exceeding 10 mg daily of prednisone equivalent) or immunosuppressive therapy or use within 14 days prior toenrollment.  
a. The following treatments are allowed: intranasal, inhaled, topical or local steroid injections; systemic corticosteroids at physiologic doses equivalent to no more than prednisone 10 mg/day; steroids as premedication for contrast dye allergy.  
11. History of (non‐infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.  
12. History of hepatic encephalopathy or treatment to prevent or control encephalopathy within the past 12months. Subjects on lactulose and/orrifaximin to control hepatic encephalopathy are not allowed.  
13. Esophageal or gastric variceal bleeding within the past 6 months. All subjects will be screened for esophageal varices unless performed in the last 6 months before study treatment. If varices are present, they should be treated according to institutional standards before starting studytreatment.  
14. Uncontrolled ascites, clinically significant orsymptomatic ascites requiring paracenteses or increasing doses of diuretics within the past 3months.  
a. Patients who are on stable diuretic doses for at least 3 months are eligible if they meet other eligibility criteria.  
b. Asymptomatic ascites detected on imaging are allowed.  
15. Has known history or any evidence of CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are asymptomatic and radiologically stable (i.e. without progression for at least 4 weeks by repeat imaging (which must be performed during study screening), clinically stable, and without the need steroidsfor at least 4 weeks prior to first dose of study treatment).  
16. Concomitant anticoagulation with oral anticoagulants (e.g. warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (e.g. clopidogrel). Allowed anticoagulants are thefollowing:
a. Low‐dose aspirin for cardioprotection (per local applicable guidelines) ispermitted.  
b. Low molecular weight heparin (LMWH) ispermitted.  
c. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without known brain metastases who are on a stable dose of LMWH for at least 4 weeks before first dose of study treatment, and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor.  
17. The subject has 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 with risk of hemodynamic instability within 12 months before the first dose of study treatment.  
ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolicor
> 95 mm Hg diastolic despite optimal antihypertensive treatment, and/or change in antihypertensive medications within 1 week before starting treatment. Note: eligibility of a subject receiving 4 or more antihypertensive medications prior to study entry will require approval from the PI.  
iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or otherischemic event, or arterial thromboembolic within 12 months before the firstdose.  
iv. Asymptomatic venous thromboembolic event (e.g. deep venous thrombosis, pulmonary embolism) is allowed if the patient has been stable on anticoagulation with LMWH for at least 4 weeks.  
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), GI malabsorption, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outletobstruction.  
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, other history of significant bleeding (e.g. pulmonary hemorrhage) within 12 weeks before first dose, or known thrombotic disorder.  
d. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial diseasemanifestation.
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5.2 exclusion criteria

f.e. Lesionsinvading any major blood vessels, including inferior vena cava or cardiac involvement of HCC based on imaging.  
Note: Main and branch portal vein and hepatic vein invasion is allowed.  
g.f. Ongoing active infection requiring antibiotics. Antibiotics must be completed at least7 days before initiating study treatment.  
h.g. Known active tuberculosis.  
i.h. Serious non‐healing wound, ulcer, or bone fracture.  
18. Patients with proteinuria >1+ on urine dipstick testing will undergo 24‐hour urine collection for quantitative assessment ofproteinuria.Participantswithurine protein ≥1 g/24 hourswillbe ineligible.  
19. Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms perelectrocardiogram
(EKG) within 28 days before first dose of study treatment.  
a. Note: If a single EKG shows a QTcF with an absolute value > 500 ms, two additional EKGs at intervals of approximately 3 min must be performed within 30 min after the initial EKG, and the average of these three consecutive results for QTcF will be used to determineeligibility.  
20. Inability to swallow tablets or any other condition that might interfere with oral absorption of medications.  
21. Previously identified allergy or hypersensitivity to study drugs and/or any of theirexcipients.  
22. Ongoing secondary malignancy that is progressing and/or has required active treatment within the past year. Adjuvant treatment for resected breast cancer isallowed.  
a. Subjects with basal cell carcinoma of the skin, squamous cell carcinoma or the skin, prostate cancer, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy areallowed.  
23. Has a known history of HIV infection. Note: HIV testing is not mandated forscreening.  
24. Co‐infection with HBV (HBsAg (+) and /or detectable HBV DNA) and HCV (anti‐HCV Ab (+)and detectable HCV RNA) at study entry.  
25. Co‐infection with HBV and HDV at study entry.  
26. Live vaccine or live attenuated vaccine within 30 days prior to first dose of studytreatment.  
Administration of killed vaccines is allowed.  
27. Pregnant or lactating females.  
28. Known psychiatric illness, substance abuse disorder, or other condition that would interfere with the ability to comply with the requirements of the study.  
29. Has history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
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5.3 re-screening

Patients who failed initial screening due to a reversible cause (e.g. biliary obstruction, infection) may have an opportunity to re‐screen after discussion with the Study PI.
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6.0 pre-treatment procedures

This study will be initiated only after the protocol, informed consent form, and any other required documents have been reviewed and approved by the responsible IRB according to applicable regulations. The same applies for the implementation of changes introduced by amendments to the protocol or consent form, except where such changes are necessary to prevent apparent immediate hazards to the research participant(s) or others.
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6.0 pre-treatment procedures

Potential patients will be identified in the GI Oncology outpatient clinics at Fred Hutchinson Cancer Center
(FHCC) and through referrals from outside physicians or the Liver Tumor Clinic at the University of Washington Medical Center (UWMC). Patients who are potentially eligible for this trial will undergo the informed consent process and be screened for eligibility utilizing the Eligibility Criteria (Section 5.0).
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6.1 informed consent

Prior to participation in the study, written informed consent and HIPAA authorization must be obtained by the investigator (or person designated by the investigator) from each subject in accordance with regulatory, legal, and institutional requirements. The protocol will be discussed thoroughly with the subject, and all known risks will be described. The procedures and alternative forms of therapy will be presented as objectively as possible and the risks and hazards of the study explained. The subject will be informed of the planned use, level of confidentiality, and potential disclosure of study data. Consent will be obtained using forms approved by the Institutional Review Board (IRB) of the FHCRC/UW
Cancer Consortium, which will be kept in the medical record. In the case where the subject is unable to read, an impartial witness should be present during the entire informed consent discussion. After the subject has orally consented to participation in the trial, the witness's signature on the form will attest that the information in the consent form was accurately explained and understood. A summary of the consent discussion will be recorded in the patient's medical chart. A signed copy of the informed consent will be given to each subject.  
If new safety information results in significant changes in the risk/benefit assessment, the consent form should be reviewed and updated as necessary. All subjects (including those already being treated) should be informed of the new information, should be given a copy of the revised form, and should give their consent to continue in the study.
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6.2 screening

Written informed consent must be obtained before initiation of any clinical screening procedure that is performed solely for the purpose of determining eligibility for this study. Evaluations performed as part of routine care before informed consent can be considered as screening evaluations if done within the defined screening period.  
Study eligibility is based on meeting all of the study inclusion criteria and none of the exclusion criteria at screening and on Study Day 1 before study treatmentadministration.
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6.3 subject registration

Once screening procedures are completed and eligibility is confirmed, the study subject will be registered and entered into the Clinical Trial Management System (CTMS) at the Fred Hutchinson Cancer Center. All patients must be registered and be assigned a unique study number prior to starting protocol therapy.  
Treatment initiation must occur within 5 working days ofregistration.  
If a patient is consented to the trial but is not registered or is withdrawn prior to initiation of protocol treatment, the reason for screen failure and/or withdrawal will be documented. However, no clinical trial data will be collected beyond the basic demographic data contained on the eligibility checklist. A
registration log with dated entries for each patient registered will bekept.
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7.0 treatment plan

All enrolled patients will be treated with cabozantinib and pembrolizumab in 3‐week treatment cycles.
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7.1 cabozantinib 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 scheduleddose.  
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.  
All patients will be given the Cabozantinib Drug Diary (Appendix 2) to record the date and time of each dose of cabozantinib taken.
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7.2 pembrolizumab administration

Pembrolizumab will be administered at 200 mg intravenously over 30 minutes on Day 1 of each 3‐week cycle (+/‐ 2 days). Every effort should be made to target infusion timing to be as close to 30 minutes as possible. However, a window between ‐5 minutes and +10 minutes is permitted (i.e. infusion time is 30 minutes ‐5 min/+10 min). Pembrolizumab should be infused before cabozantinib when the study drugs are given on the same day. The Pharmacy Manual contains specific instructions for the preparation of pembrolizumab and administration of infusion solution.  
Pembrolizumab may be administered up to 2 days before or after the scheduled day of dosing due to administrative reasons. Dosing interruptions/delays are permitted in the case of medical/surgical events or logistical reasons(i.e. elective surgery, unrelated medical events, patient vacation, holidays) not related to pembrolizumab‐induced toxicity. Patients should resume pembrolizumab therapy within 3 weeks of the scheduled interruption (for reasons other than toxicity), unless approved by the Study PI. The reason for interruption/delay should be documented in the patient's study record.
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7.3 duration of therapy

Patients will begin cabozantinib and pembrolizumab concurrently. Patients may continue study therapy until unequivocal disease progression, unacceptable drug‐related toxicity, or subject withdrawal. If one drug needs to be permanently discontinued due to toxicity, the other agent may be continued. Interval dosing interruption/delay of either or both agents is allowed for AEs (see Section 9.0). Treatment beyond progression with cabozantinib and/or pembrolizumab (depending on patient tolerance) will be allowed based on meeting pre‐specified criteria and after discussion with the study PI
(see Section 12.1).  
Patients may be treated up to a maximum of two years from the time of treatment initiation.
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7.4 treatment compliance

Patients will complete the Cabozantinib Drug Diary (Appendix 2) that helps with tracking of drug doses taken and confirming treatment compliance. Patient compliance with cabozantinib will be assessed at each visit. Compliance will also be confirmed by counting returned capsules. Patients who are significantly noncompliant will be discontinued from the study. A patient will be considered significantly noncompliant if he or she misses 7 or more consecutive days of cabozantinib, or more than 25% cumulative days of cabozantinib during the study for reasons other than toxicity, or if the patient takes more than the prescribed amount of medication. Cabozantinib dose suspensions or delays due to toxicity do not count in compliance assessment.
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8.0 concomitant medications and therapies

During study participation, symptomatic or supportive treatment of tumor‐associated symptoms (e.g.  
pain, nausea) and side effects of treatment is encouraged if appropriate as per the treating investigator.  
Specifically, the following concomitant therapies are permitted, if clinically indicated:  
- Antiemetics and antidiarrheal (for non‐immune diarrhea)medications. - Opioid analgesics.  
- Granulocyte colony‐stimulating factors (G‐CSF) used as per clinical guidelines (e.g. ASCO or ESMO
guidelines).  
- Bisphosphonates can be used for bone metastases or hypercalcemia if the benefit outweighs the risk per the investigator's discretion.  
o Note: Osteonecrosis of the jaw has been reported with the use of bisphosphonates as wellas with cabozantinib. Patients must be informed of this risk and be monitored frequentlyfor
potentially overlapping toxicities. They should be advised regarding oral hygiene practice and to quickly report symptoms to the investigator. Oral examinations are recommended prior to starting bisphosphonates. See Section 9.3.8.  
- Transfusions and hormone replacement as indicated by standard clinical practice. - Individualized anticoagulation therapy with heparin is allowed if it can be provided safely and effectively under the following circumstances:
o *Low dose heparins for prophylactic use* are allowed if clinically indicated and the benefit outweighs the risk per the investigator's discretion.  
o *Therapeutic doses of LMWH* at the time of the first dose of study treatment are allowed if the subject has no evidence of brain metastasis, has been on a stable dose of LMWH for at least 4 weeks, and has had no complications from a thromboembolic event or the anticoagulation regimen.  
o *Therapeutic doses of LMWH* after first dose of study treatment are allowed if clinically indicated (e.g. for the treatment of DVT), and the benefit outweighs the risk per the investigator's discretion. For management of thromboembolic complications while on study, see Section 9.3.4.  
o Standard clinical management of anticoagulation therapy with heparins must be followed. This includes, but is not limited to, subject education regarding potential adverse drug reactions, monitoring laboratory parameters, dose adjustments (e.g. due to kidneydysfunction).  
o For restrictions on oral anticoagulants, seeSection8.4.  
- Premedication is allowed for pembrolizumab‐related infusion reactions (Section9.5.6).  
Patients cannot receive systemic glucocorticoids for any purpose other than to modulate symptoms from an AE that is suspected to have an immunologic etiology. The use of physiologic doses of corticosteroids may be approved after consultation with the Principal Investigator. Exception: steroids may be used for premedication prior to imaging.  
Potential drug interactions with cabozantinib are summarized in Section 1.4.3.
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8.2 recording concomitant therapy

Concomitant medications administered within 28 days before the first dose ofstudy treatment and during the treatment phase until the study discontinuation visit should be recorded, as well as medications administered for SAEs occurring after 30 days after the last dose of trial treatment, as defined in Section 16.1. All premedications, supportive medications, and other concomitant therapy (including all prescription, over‐the‐counter (OTC), herbalsupplements, and IV medications and fluids) that are taken between study consent and the end‐of‐study visit after treatment discontinuation should be recorded in the case report form (CRF), with the start and end of treatment dates, total daily dose, dosage unit, and the reason for use. If changes occur during the trial period, documentation of drug dosage, frequency, route, and date may also be included on the CRF.