A Single-arm Phase II Study of Cabozantinib and Atezolizumab in Patients With Recurrent or Metastatic Esophageal Squamous Cell Carcinoma Who Failed a Platinum-based Chemotherapy
Phase: PHASE2
Conditions: Esophageal Cancer, Metastatic Cancer, Squamous Cell Carcinoma
Sponsor: National Taiwan University Hospital

Protocol of Cabozantinib-Atezolizumab  
for ESCC, 27-Nov-2020, Version 1.0 
TITLE: A single-arm phase II study of cabozantinib and atezolizumab in 
patients with recurrent or metastatic esophageal squamous cell carcinoma 
(ESCC) who failed a platinum-based chemotherapy                                                                   
 
一項針對已接受過白金類化療之復發或轉移食道鱗狀細胞癌患者， 
合併使用cabozantinib 及atezolizumab 的第二期臨床試驗 
 
 
Principal Investigator: 
 
Chih-Hung Hsu  M.D., Ph.D. 
徐志宏 醫師 
Department of Oncology, National Taiwan University Hospital  
7 Chung-Shan South Road, Taipei, TAIWAN, 100 
 
Tel: 02-23123456 ext.  67680 
Fax: 02-23711174 
E-mail: chihhunghsu@ntu.edu.tw 
 
 
 
 
 

Protocol of Cabozantinib-Atezolizumab  
for ESCC, 27-Nov-2020, Version 1.0 
 
Co-Investigators: 
 
Department of Oncology, National Taiwan University Hospital  
 
Hung-Yang Kuo,  
M.D. 
郭弘揚 醫師 
 
Jhe-Cyuan Guo,  
M.D. 
郭哲銓 醫師 
 
Ta-Chen Huang,  
M.D. 
黃大成 醫師 
 
Tsung-Hao Liu,  
M.D. 
劉宗灝 醫師 
 
Chia-Chi Lin,  
M.D., Ph.D. 
林家齊 醫師 
 
Kun-Huei Yeh,  
M.D., Ph.D. 
葉坤輝 醫師  
                   
Division of Chest Surgery: 
Jang-Ming Lee 
M.D., Ph.D. 
李章銘 醫師 
Pei-Ming Huang 
M.D., Ph.D. 
黃培銘 醫師 
 
 
 
 
 
 
 
 

Protocol of Cabozantinib-Atezolizumab  
for ESCC, 27-Nov-2020, Version 1.0 
 
 
PROTOCOL SYNOPSIS 
STUDY TITLE:  
A PHASE II STUDY OF CABOZANTINIB AND ATEZOLIZUMAB IN PATIENTS 
WITH RECURRENT OR METASTATIC ESOPHAGEAL SQUAMOUS CELL 
CARCINOMA (ESCC) WHO FAILED PLATINUM-BASED THERAPY 
 
STUDY SCIENTIFIC 
OBJECTIVE 
To demonstrate that combination of cabozantinib and 
atezolizumab is safe and efficacious in patients with 
recurrent/metastatic esophageal squamous cell carcinoma 
(ESCC) 
STUDY DESIGN 
 
 
A single-arm, single-institute, phase II study. 
 
The combination of cabozantinib and atezolizumab:  
• Cabozantinib 40 mg, PO, QD;  
• Atezolizumab 1200 mg, IV, Q3W;  
• Treatment will be continued until intolerable toxicities occur 
and/or patients no longer derive clinical benefits from the 
treatment.  
Evaluation and follow-up: 
• Clinical evaluation including blood sampling: every 3 weeks  
• Tumor response evaluation: every 9 weeks  
• Follow-up of potential treatment-related AEs will be 
continued until 30 days after discontinuing protocol 
treatment of start of next salvage treatment, whichever 
comes first.  
• The planned enrollment number of study subjects is 37. 
• The ORR of anti-PD-1 mAbs for R/M ESCC patients has 
been around 15% according to previous studies.  
• We hypothesize that combination of cabozantinib plus 
atezolizumab will improve the ORR from 15% to 30%. With 
one-sided, 0.1 type I error (α), 0.2 type II error (β, 
corresponding power: 0.8), the sample size will be 37. 
 
STUDY POPULATION 
 
 
The target population is recurrent/metastatic ESCC patients who 
failed first-line platinum-based chemotherapy. 
 
<Inclusion criteria> 
1. Histologically proven squamous cell carcinoma of esophagus. 
2. Progression from first-line platinum-based chemotherapy for 
recurrent or metastatic ESCC, or progression within 6 months 
after neoadjuvant, definitive, or adjuvant chemo(radio) -therapy 
for loco-regional ESCC. 
3. Measurable disease per RECIST 1.1  
4. Recovery to baseline or ≤ Grade 1 per Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0 from toxicities 
related to any prior treatments, unless AE(s) are clinically 

Protocol of Cabozantinib-Atezolizumab  
for ESCC, 27-Nov-2020, Version 1.0 
STUDY TITLE:  
A PHASE II STUDY OF CABOZANTINIB AND ATEZOLIZUMAB IN PATIENTS 
WITH RECURRENT OR METASTATIC ESOPHAGEAL SQUAMOUS CELL 
CARCINOMA (ESCC) WHO FAILED PLATINUM-BASED THERAPY 
 
nonsignificant and/or stable on supportive therapy as 
determined by the Investigator.   
5. Age twenty years or older 
6. Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1.    
7. The subject is receiving antiviral therapy per local standard of 
care if the subject has active HBV infection (defined by HBsAg 
positive); the subject must have HBV DNA < 500 IU/mL. 
- 
Patients with HBV infection are required to continue antiviral 
therapy throughout the Treatment Period, and till at least 3 
months after discontinuing Trial treatment.    
8. Adequate organ and marrow function, based upon meeting all of 
the following laboratory criteria within 14 days prior to 
treatment:  
- 
Absolute neutrophil count (ANC) ≥ 1500/µL without 
granulocyte colony-stimulating factor support within 2 weeks 
before screening laboratory sample collection.    
- 
White blood cell (WBC) count ≥ 2500/µL.  
- 
Platelets ≥ 100,000/µL without transfusion within 2 weeks 
before screening laboratory sample collection.   
- 
Hemoglobin ≥ 9 g/dL without transfusion within 2 weeks before 
screening laboratory sample collection.   
- 
Alanine aminotransferase (ALT), AST, and alkaline phosphatase 
(ALP) ≤ 3 × upper limit of normal (ULN).   
- 
Total bilirubin ≤ 1.5 mg/dL.  
- 
Serum albumin ≥ 2.8 g/dL.  
- 
Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance 
≥ 40 mL/min (≥ 0.67 mL/sec) using the Cockcroft-Gault 
equation: 
Males: (140 – age) x weight (kg)/(serum creatinine [mg/dL] × 
72) 
Females: [(140 – age) x weight (kg)/(serum creatinine [mg/dL] 
× 72)] × 0.85 
- 
Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 
mg/mmol), or 24-h protein ≤ 1 g.  
9. Capable of understanding and complying with the protocol 
requirements and must have signed the informed consent 
document prior to any screening assessment except those 
procedures performed as standard of care within the screening 
window.  
10. Sexually active fertile subjects and their partners must agree to 
use highly effective methods of contraception that alone or in 
combination result in a failure rate of less than 1% per year 
when used consistently and correctly (see Appendix G) during 
the course of the study and for 5 months after the last dose of 
study treatment. An additional contraceptive method, such as a 
barrier method (eg, condom), is recommended.  
11. Female subjects of childbearing potential must not be pregnant 
at screening. Females of childbearing potential are defined as 

Protocol of Cabozantinib-Atezolizumab  
for ESCC, 27-Nov-2020, Version 1.0 
STUDY TITLE:  
A PHASE II STUDY OF CABOZANTINIB AND ATEZOLIZUMAB IN PATIENTS 
WITH RECURRENT OR METASTATIC ESOPHAGEAL SQUAMOUS CELL 
CARCINOMA (ESCC) WHO FAILED PLATINUM-BASED THERAPY 
 
premenopausal females capable of becoming pregnant (ie, 
females who have had any evidence of menses in the past 12 
months, with the exception of those who had prior 
hysterectomy). However, 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.   
<Exclusion criteria>  
1. Previously treated with PD-1/PD-L1 blockade or any type of 
small molecule kinase inhibitor (including investigational kinase 
inhibitor)  
2. Receipt of any type of cytotoxic, biologic or other systemic 
anticancer therapy (including investigational) within 4 weeks 
before first dose of study treatment. 
3. Prior radiotherapy regimen exceeding 70 Gy for a single site, 
including ESCC or other metastatic sites:  
- 
For radiotherapy to treat ESCC:  
If the radiation is combined with chemotherapy, a minimum of 
4 months must elapse between the end of radiotherapy and 
registration. If the radiation is given alone, a minimum of 8 
weeks must elapse between the end of radiotherapy and 
registration.  
- 
For radiotherapy to treat metastatic site:  
A minimum of 3 weeks must elapse between prior radiation and 
registration.  
- 
All treatment areas should be fully healed with no sequelae from 
RT that would predispose to fistula formation. Unhealed or with 
sequelae from RT that would predispose to fistula formation. 
4. Known brain metastases or cranial epidural disease unless 
adequately treated with radiotherapy and/or surgery (including 
radiosurgery) and stable for at least 4 weeks before first dose of 
study treatment. Eligible subjects must be neurologically 
asymptomatic and without corticosteroid treatment at the time 
of first dose of study treatment.  
5. Concomitant anticoagulation with oral anticoagulants (eg, 
warfarin, direct thrombin and Factor Xa inhibitors) or platelet 
inhibitors (eg, clopidogrel), except for the following allowed 
anticoagulants:   
a. Low-dose aspirin for cardioprotection (per local applicable 
guidelines) is permitted. 
b. Low-dose low molecular weight heparins (LMWH) are 
permitted.  
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 6 weeks before first dose of study 
treatment, and who have had no clinically significant 
hemorrhagic complications from the anticoagulation regimen or 
the tumor.   

Protocol of Cabozantinib-Atezolizumab  
for ESCC, 27-Nov-2020, Version 1.0 
STUDY TITLE:  
A PHASE II STUDY OF CABOZANTINIB AND ATEZOLIZUMAB IN PATIENTS 
WITH RECURRENT OR METASTATIC ESOPHAGEAL SQUAMOUS CELL 
CARCINOMA (ESCC) WHO FAILED PLATINUM-BASED THERAPY 
 
6. Administration of a live, attenuated vaccine within 30 days prior 
to treatment.  
7. Any subject who cannot be evaluated by computed tomography 
(CT) because of allergy or other contraindication to both CT and 
MRI contrast agents.  
8. The subject has uncontrolled, significant intercurrent or recent 
(within the last 3 months before treatment [unless otherwise 
specified below]) illness including, but not limited to, the 
following conditions:  
- 
Cardiovascular disorders:  
a. 
Congestive heart failure (CHF) class III or IV as defined 
by the New York Heart Association, unstable angina 
pectoris, serious cardiac arrhythmias.  
b. 
Uncontrolled hypertension defined as sustained blood 
pressure (BP) > 140 mm Hg systolic or > 90 mm Hg 
diastolic despite optimal antihypertensive treatment.  
c. 
Stroke (including transient ischemic attack [TIA]), 
myocardial infarction (MI), or other ischemic event or 
thromboembolic event (eg, DVT, pulmonary embolism) 
within 6 months before treatment.   
- 
Gastrointestinal (GI) disorders including those associated with a 
high risk of perforation or fistula formation:  
a. 
Tumors invading the GI-tract, active peptic ulcer disease, 
inflammatory bowel disease, diverticulitis, cholecystitis, 
symptomatic cholangitis or appendicitis, acute pancreatitis 
or acute obstruction of the pancreatic or biliary duct, or 
gastric outlet obstruction.   
b. Abdominal fistula, GI perforation, bowel obstruction, or 
intra-abdominal abscess within 6 months prior to treatment. 
Complete healing of an intra-abdominal abscess must be 
confirmed prior to treatment.  
c. 
Any episodes of GI bleeding requiring transfusion or 
hospitalization for at least 6 months before treatment.  
- 
Clinically significant hematuria, hematemesis, or hemoptysis of 
> 0.5 teaspoon (2.5 ml) of red blood, or other history of 
significant bleeding (eg, pulmonary hemorrhage) within 3 
months before treatment.    
- 
Cavitating pulmonary lesion(s) or known endobronchial 
invasion.  
- 
Lesions invading major blood vessel, including, but not limited 
to: inferior vena cava, pulmonary artery, or aorta.  
- 
Other clinically significant disorders such as:  
a.      Active or history of autoimmune disease or immune  
deficiency, including, but not limited to, myasthenia gravis,  
myositis, autoimmune hepatitis, systemic lupus  
erythematosus, rheumatoid arthritis, psoriatic arthritis,  
inflammatory bowel disease, antiphospholipid antibody  
syndrome, Wegener granulomatosis, Sjögren’s syndrome,  
Guillain-Barré syndrome, or multiple sclerosis (see  

Protocol of Cabozantinib-Atezolizumab  
for ESCC, 27-Nov-2020, Version 1.0 
STUDY TITLE:  
A PHASE II STUDY OF CABOZANTINIB AND ATEZOLIZUMAB IN PATIENTS 
WITH RECURRENT OR METASTATIC ESOPHAGEAL SQUAMOUS CELL 
CARCINOMA (ESCC) WHO FAILED PLATINUM-BASED THERAPY 
 
Appendix C for a more comprehensive list of autoimmune  
diseases and immune deficiencies). Subjects with the  
following conditions are eligible for the study:  
i.   A history of autoimmune-related hypothyroidism and on     
thyroid replacement hormone   
ii.  Controlled Type 1 diabetes mellitus and on an insulin  
regimen  
iii. Asthma that requires intermittent use of bronchodilators  
iv. Eczema, psoriasis, lichen simplex chronicus, or vitiligo  
with dermatologic manifestations only provided all of  
following are true:  
- Rash covers < 10% of body surface area  
- Disease is well controlled at baseline and requires only  
low-potency topical corticosteroids  
- No occurrence of acute exacerbations of the underlying  
condition requiring psoralen plus ultraviolet A radiation,  
methotrexate, retinoids, biologic agents, oral calcineurin  
inhibitors, or high potency or oral corticosteroids within  
the previous 12 months   
b.     Any condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalent) or 
other immunosuppressive medications within 14 days 
before treatment.   
Note: Inhaled, intranasal, intra-articular, and topical 
corticosteroids and mineralocorticoids are permitted.   
Transient use of systemic corticosteroids for allergic 
conditions such as contrast allergy is allowed.  
c.   Active infection requiring systemic treatment, known 
history of infection with human immunodeficiency virus 
(HIV) or acquired immunodeficiency syndrome  
d.   (AIDS)-related illness, or a known positive test for 
tuberculosis due to tuberculosis infection. Subjects with 
active hepatitis B virus infection controlled with antiviral 
therapy are eligible (see Inclusion Criterion 7). Subjects 
with active, uncontrolled hepatitis C virus infection are 
eligible provided liver function meets eligibility criteria and 
are receiving management of the disease per local 
institutional practice (note: antiviral treatment for HCV is 
allowed).   
e.   History of idiopathic pulmonary fibrosis, organizing 
pneumonia, drug-induced pneumonitis, idiopathic 
pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan   
f.   Serious non-healing wound/ulcer/bone fracture. 
g.   Malabsorption syndrome.  
h.   Free thyroxine (FT4) outside the laboratory normal 
reference range. Asymptomatic subjects with FT4 
abnormalities can be eligible. 
i.    Requirement for hemodialysis or peritoneal dialysis.  

Protocol of Cabozantinib-Atezolizumab  
for ESCC, 27-Nov-2020, Version 1.0 
STUDY TITLE:  
A PHASE II STUDY OF CABOZANTINIB AND ATEZOLIZUMAB IN PATIENTS 
WITH RECURRENT OR METASTATIC ESOPHAGEAL SQUAMOUS CELL 
CARCINOMA (ESCC) WHO FAILED PLATINUM-BASED THERAPY 
 
j.    History of solid organ transplant including allogeneic stem 
cell transplant.  
9. Major surgery (eg, GI surgery, removal or biopsy of brain 
metastasis) within 8 weeks before treatment. Minor surgeries 
within 10 days before treatment. Subjects must have complete 
wound healing from major surgery or minor surgery before 
treatment. Subjects with clinically relevant ongoing 
complications from prior surgery are not eligible.  
10. Corrected QT interval calculated by the Fridericia formula 
(QTcF) > 500 ms per electrocardiogram (ECG) within 14 days 
before treatment.   
Note: If a single ECG shows a QTcF with an absolute value 
> 500 ms, two additional ECGs at intervals of 
approximately 3 min must be performed within 30 min after 
the initial ECG, and the average of these three consecutive 
results for QTcF will be used to determine eligibility   
11. History of psychiatric illness likely to interfere with ability to 
comply with protocol requirements or give informed consent.  
12. Pregnant or breastfeeding females.  
13. Inability to swallow tablets.  
14. Previously identified allergy or hypersensitivity to components 
of the study treatment formulations or history of severe 
hypersensitivity to monoclonal antibodies.  
15. Any other active malignancy at time of treatment or diagnosis of 
another malignancy within 2 years before treatment that requires 
active treatment, except for superficial skin cancer. 
 
PRIMARY ENDPOINT 
 
 
Primary endpoints include:  
• 
The efficacy, evaluated as objective tumor response rate (ORR) 
of patients with ESCC who receive the combination of 
cabozantinib plus atezolizumab. 
 
Secondary endpoints include:  
• 
Efficacy-wise: duration of response (DOR), progression-free 
survival (PFS), and overall survival (OS)  
• 
Safety-wise: toxicities per CTCAE 5.0 
 
Exploratory biomarker studies to search for biomarkers 
predictive of the efficacy of cabozantinib combined with 
atezolizumab and associated with outcomes of the patients will 
include:  
• 
Tissue-based biomarkers: PD-L1 expression by combined 
positive score [CPS], expression of AXL and cMET by 
immunohistochemistry (IHC) and gene expression profiling, 
immune gene expression profiles, and tumor mutational burden 
[TMB]);  
• 
Blood-based markers: profiling of cytokines/chemokines, and 
phenotyping of immune cells;  
• Imaging-based biomarkers: FDG-PET imaging. 

Protocol of Cabozantinib-Atezolizumab  
for ESCC, 27-Nov-2020, Version 1.0 
STUDY TITLE:  
A PHASE II STUDY OF CABOZANTINIB AND ATEZOLIZUMAB IN PATIENTS 
WITH RECURRENT OR METASTATIC ESOPHAGEAL SQUAMOUS CELL 
CARCINOMA (ESCC) WHO FAILED PLATINUM-BASED THERAPY 
 
STUDY TREATMENT 
Cabozantinib 40 mg, PO, QD plus 
Atezolizumab 1200 mg, IV, Q3W;  
 
Treatment will be continued until intolerable toxicities occur and/or 
patients no longer derive clinical benefits from the treatment. 
FOLLOW-UP 
• 
Clinical evaluation including blood testing: every 3 weeks 
• 
Tumor response evaluation: every 9 weeks  
• 
Follow-up of potential treatment-related AEs will be continued 
until 30 days after discontinuing protocol treatment of start of 
next salvage treatment, whichever comes first. 
STATISTICAL 
CONSIDERATION 
• 
The planned enrollment number of study subjects is 37. 
• 
The ORR of anti-PD-1 mAbs for R/M ESCC patients has been 
around 15% according to previous studies.  
• 
We hypothesize that combination of cabozantinib plus 
atezolizumab will improve the ORR from 15% to 30%. With one-
sided, 0.1 type I error (α), 0.2 type II error (β, corresponding power: 
0.8), the sample size will be 37. 
 
 
 
 
 
 
 
 
 
 

Protocol of Cabozantinib-Atezolizumab  
for ESCC, 27-Nov-2020, Version 1.0 
9  
STATISTICAL CONSIDERATIONS  
9.1 Statistical Analysis Plan Summary 
An overview of the endpoints and operating characteristics is shown in Table 9-1. 
 
Table 9-1  
Summary of Endpoint Operating Characteristics  
Accrual per month  
2 subjects  
Endpoint:  
ORR (Primary 
endpoint) 
  Power  
82%  
  Alpha allocated (1-sided)  
0.1 
  
Assumed median, history 
15% 
  
Assumed median, experimental 
30%  
 Estimated patient number 
37 
  Time to enroll (months)  
19 
    Time for follow-up (months)  
6 
 
9.2 
 Statistical Analysis Plan 
9.2.1 Sample Size Determination 
The target sample size of this prospective, single-arm, phase 2 study is 37 patients. A sample size 
of 37 achieves 82% power to detect a difference (P1-P0) of 0.15 using a one-sided binomial exact 
test. The target significance level is 0.1. These results assume that the population proportion under 
the null hypothesis is 0.15 and the alternative hypothesis is 0.3. The sample size was calculated by 
PASS. The average number of newly diagnosed ESCC patients at our center is around 180 patients 
per year.  Among them, 30% patients present with metastatic disease and 60% patients present 
with locally advanced disease. Around 50% of locally advanced ESCC will have recurrent diseases 
indicated for this study.  We plan to enroll 2 patients per month into this trial.  Therefore, the 
estimated duration of total enrollment will be 19 months. With additional follow-up of 6 months 
after the last enrollment, the whole study period of the trial will be 25 months. 
The primary objective of the study is to improve overall response rate for recurrent or metastatic 
ESCC patients who have failed a platinum-based chemotherapy. The secondary objectives of the 
study included the median progression-free survival, overall survival, and safety and toxicity. 
According to the two phase III global clinical trials (KEYNOTE-181 and ATTRACTION-3), the 
ORR for second-line immune checkpoint inhibitors is around 15%. We estimated the ORR could 
improve to 30% in the combination of atezolizumab and cabozantinib. 

Protocol of Cabozantinib-Atezolizumab  
for ESCC, 27-Nov-2020, Version 1.0 
9.2.2   
Definition of Variables 
Overall response rate (ORR) is the proportion of patients whose tumor is significantly reduced. 
ORR is generally defined as the sum of complete responses (CRs) – patients with no detectable 
evidence of a tumor over a specified time period – and partial responses (PRs) – patients with a 
decrease in tumor size over a specified time period. The response will be recorded after each 
response evaluation by an imaging study (CT scan), and the updated best of response will be 
adopted for final analysis of the primary endpoint. Progression-free survival (PFS) is the time from 
enrollment to the first occurrence of disease progression or death from any cause (whichever 
occurs first) and will be conducted in the whole study population. It is designed to include 
progression events as determined by the investigators per RECIST 1.1 or death. Patients who have 
neither progressed nor died or who are lost to follow-up are censored at the date of the last tumor 
assessment or last follow up for progression of disease. Patients for whom no post-baseline tumor 
assessments are available are censored at day 1. 
Overall survival (OS) is the time from enrollment to death of any cause or the last follow-up 
(censored). 
Evaluation of Toxicity: The incidence and severity of toxicity will be summarized according to 
the NCI Common Toxicity Criteria Version 4.0.  
 
9.2.3  
General Statistical Consideration 
Statistical analysis for ORR and safety will be performed for subjects given at least one dose of 
the investigational product. Statistical analyses for PFS, OS will be performed for intention-to-
treat population. 
Our hypothesis is that combinational treatment with ORR as 30% is superior to historical ORR of 
a single agent atezolizumab as 15%. To control type I error under one-sided 10%, with power of 
80%, we’ll use the exact method of one-sample inference for a binomial proportion. For the 
percentages of CR, PR and SD, the corresponding 95% CI will be estimated using the Clopper-
Pearson method for each treatment group.  
Final analysis will be done when the last patient enrolled has been treated for 6 months. 
The survival estimates will be derived from Kaplan and Meier curves.