A Phase II Study of Maintenance Vorolanib and Atezolizumab in Patients With Extensive-stage SCLC
Phase: PHASE2
Conditions: Extensive-stage Small Cell Lung Cancer
Sponsor: Washington University School of Medicine

 
 
 
A phase II study of maintenance vorolanib and atezolizumab in patients with extensive-
stage SCLC 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 202007036 
Version Date: 10 May 2022 
 
Principal Investigator: 
Daniel Morgensztern, M.D. 
Phone:  (314) 362-5817 
E-mail:  danielmorgensztern@wustl.edu  
 
Sub-Investigators 
 
 
 
Modality 
Maria Baggstrom, M.D.  
 
 
Medical Oncology 
Siddhartha Devarakonda, M.D.  
 
Medical Oncology 
Ramaswamy Govindan, M.D. 
 
 
Medical Oncology 
Peter Oppelt, M.D. 
 
 
 
Medical Oncology 
Kevin Palka, M.D. 
 
 
 
Medical Oncology 
Timothy Rearden, M.D.  
 
 
Medical Oncology 
Caron Rigden, M.D. 
 
 
 
Medical Oncology 
Saiama Waqar, M.D. 
 
 
 
Medical Oncology 
Jeff Ward, M.D., Ph.D.  
 
 
Medical Oncology 
Brett Herzog, M.D., Ph.D. 
 
 
Medical Oncology 
Feng Gao, M.D., Ph.D.  
 
 
Biostatistics 
Danielle Turlington, PharmD 
 
 
Pharmacy 
 
Study Drugs:  
 
Vorolanib 
Atezolizumab 
 
IND#: 
151151 
IND Sponsor: 
Daniel Morgensztern, M.D. 
NCT#: 
NCT04373369 
Funded by: 
Equinox Sciences LLC, a company of XCovery Holdings, Inc. 
  
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 

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A phase II study of maintenance vorolanib and atezolizumab in patients with extensive-
stage SCLC 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
19 June 2020 
Amendment #1 Version 
 
 
 
 
 
 
16 February 2021 
Amendment #2 Version 
 
 
 
 
 
 
05 November 2021 
Amendment #3 Version 
 
 
 
 
 
 
10 May 2022 
 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 

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Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
B-HCG 
Beta human chorionic gonadotropin  
BMT 
Bone marrow transplant 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CNS 
Central nervous system 
CR 
Complete response 
CRc 
Cytogenetic complete remission 
CRi 
Complete remission incomplete 
CRm 
Morphologic complete remission 
CRF 
Case report form 
CST 
Central standard time 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLT 
Dose limiting toxicity 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
DSMC 
Data Safety Monitoring Committee 
ECG (or EKG) 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization 
FWA 
Federal wide assurance 
GCP 
Good Clinical Practice 
HHS 
Department of Health and Human Services 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MDS 
Myelodysplastic syndrome 
MM 
Multiple myeloma 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCCN 
National Cancer Center Network 

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NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NSCLC 
Non-small cell lung cancer 
OHRP 
Office of Human Research Protections  
ORR 
Overall response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal investigator 
PR 
Partial response 
PSA 
Prostate-specific antigen 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RFS 
Relapse free survival 
RR 
Response rate 
SAE 
Serious adverse event 
SCLC 
Small cell lung cancer 
SCC 
Siteman Cancer Center 
SCT 
Stem cell transplant 
SD 
Stable disease 
TSH 
Thyroid stimulating hormone 
TTP 
Time to progression 
UPN 
Unique patient number 
US 
Ultrasound 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell (count) 
 
 

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TABLE OF CONTENTS 
PROTOCOL SUMMARY ..........................................................................................................8 
Synopsis ..................................................................................................................................8 
SCHEMA ................................................................................................................................. 10 
1.0 
SCHEDULE OF ACTIVITIES ....................................................................................... 11 
2.0 
INTRODUCTION .......................................................................................................... 12 
2.1 
Background ................................................................................................................. 12 
3.0 
OBJECTIVES AND ENDPOINTS ................................................................................. 14 
4.0 
STUDY POPULATION ................................................................................................. 15 
4.1 
Inclusion Criteria ........................................................................................................ 15 
4.2 
Exclusion Criteria ....................................................................................................... 16 
4.3 
Inclusion of Women and Minorities ............................................................................ 18 
5.0 
REGISTRATION PROCEDURES ................................................................................. 18 
5.1 
Confirmation of Patient Eligibility .............................................................................. 19 
5.2 
Patient Registration in the Siteman Cancer Center OnCore Database........................... 19 
5.3 
Assignment of UPN .................................................................................................... 19 
5.4 
Screen Failures............................................................................................................ 19 
6.0 
TREATMENT PLAN..................................................................................................... 19 
6.1 
Study Intervention Description .................................................................................... 19 
6.2 
Study Intervention Administration .............................................................................. 19 
6.3 
Definitions of Evaluability .......................................................................................... 20 
6.4 
Concomitant Therapy and Supportive Care Guidelines................................................ 20 
6.5 
Women of Childbearing Potential ............................................................................... 21 
6.6 
Duration of Therapy .................................................................................................... 22 
6.7 
Duration of Follow-up................................................................................................. 22 
6.8 
Lost to Follow-Up ....................................................................................................... 23 
7.0 
DOSE DELAYS/ DOSE MODIFICATIONS ................................................................. 23 
7.1 
Atezolizumab Dose Modifications .............................................................................. 23 
7.2 
Vorolanib Dose Modifications .................................................................................... 24 
8.0 
REGULATORY AND REPORTING REQUIREMENTS .............................................. 26 
8.1 
Washington University Sponsor-Investigator Reporting Requirements ........................ 26 
8.2 
Exceptions to Expedited Reporting ............................................................................. 28 
9.0 
PHARMACEUTICAL INFORMATION ....................................................................... 29 
9.1 
Atezolizumab .............................................................................................................. 29 
9.2 
Vorolanib .................................................................................................................... 30 
10.0 CORRELATIVE STUDIES ........................................................................................... 31 
10.1 Peripheral Research Blood .......................................................................................... 31 
10.2 Biopsy Sample Collection ........................................................................................... 32 
11.0 DATA SUBMISSION SCHEDULE ............................................................................... 32 
11.1 Adverse Event Collection in the Case Report Forms ................................................... 32 
12.0 MEASUREMENT OF EFFECT ..................................................................................... 33 
12.1 Antitumor Effect – Solid Tumors ................................................................................ 33 
12.2 Disease Parameters ..................................................................................................... 33 
12.3 Baseline tumor imaging .............................................................................................. 34 
12.4 Tumor imaging during the trial.................................................................................... 35 
12.5 Response Criteria ........................................................................................................ 35 

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13.0 DATA AND SAFETY MONITORING .......................................................................... 38 
14.0 STATISTICAL CONSIDERATIONS ............................................................................ 38 
14.1 Sample Size Estimates ................................................................................................ 38 
14.2 Accrual Rate ............................................................................................................... 39 
14.3 Populations of Analysis ............................................................................................... 39 
14.4 Statistical Analysis Plan .............................................................................................. 39 
15.0 REFERENCES ............................................................................................................... 41 
APPENDIX A: ECOG Performance Status Scale ...................................................................... 44 
APPENDIX B: Definitions for Adverse Event Reporting .......................................................... 45 
APPENDIX C: Reporting Timelines ......................................................................................... 47 
APPENDIX D: PATIENT’S MEDICATION DIARY ............................................................... 50 
 
 

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PROTOCOL SUMMARY 
 
Synopsis 
Title: 
A phase II study of maintenance vorolanib and atezolizumab in 
patients with extensive-stage SCLC 
 
Study Description: 
Our hypothesis is that the addition of vorolanib to atezolizumab 
during the maintenance phase of first-line therapy for extensive-
stage small cell lung cancer after at least 3 but not more than 4 cycles 
of induction therapy with platinum, etoposide, and atezolizumab will 
improve progression-free survival (PFS) compared to single agent 
atezolizumab or sunitinib used in historical controls. 
 
Consenting and eligible patients who have no evidence of tumor 
progression after 3 to 4 cycles of induction therapy will receive 
atezolizumab IV every 3 weeks and vorolanib by mouth daily. Note 
that the induction chemotherapy is standard of care; only the 
maintenance treatment with vorolanib and atezolizumab are 
considered investigational for purposes of this protocol. 
 
Objectives: 
Primary Objective: 
To determine PFS at 6 months for maintenance vorolanib with 
atezolizumab after treatment with platinum, etoposide, and 
atezolizumab in patients with extensive-stage SCLC. 
 
Secondary Objectives: 
1. To determine the PFS for maintenance vorolanib with 
atezolizumab after treatment with platinum, etoposide, and 
atezolizumab in patients with extensive-stage SCLC. 
2. To determine the overall survival (OS) for the combination 
of maintenance vorolanib and atezolizumab in patients with 
extensive-stage SCLC. 
3. To evaluate toxicity and tolerability for the combination of 
maintenance vorolanib and atezolizumab in patients with 
extensive-stage SCLC.  
 
Endpoints: 
1. Kaplan-Meier product limit estimator will be used to estimate 
the PFS at 6 months, with the inclusion of 90% confidence 
interval. 
2. Kaplan-Meier product limit estimator will be used to estimate 
the PFS. 
3. Kaplan-Meier product limit estimator will be used to estimate 
the OS. 
4. Toxicity will be assessed using NCI-CTCAE v 5.0. 
 

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Study Population: 
Thirty-three (33) adults with extensive stage small cell lung cancer 
will be enrolled to this study. 
 
Phase: 
II 
 
Description of Sites / 
Facilities Enrolling: 
This is a single center study enrolling at Siteman Cancer Center at 
Washington University School of Medicine in St. Louis, MO. 
 
Description 
of 
Study 
Intervention: 
Atezolizumab is administered intravenously at a dose of 1200 mg on 
Day 1 of each 21-day cycle.  Vorolanib is administered orally at a 
dose of 200 mg on Days 1 through 21 of each 21-day cycle. 
 
Study Duration: 
30 to 36 months 
 
Participant Duration: 
Participants may receive treatment until evidence of disease 
progression, severe toxicity, or other protocol-defined termination 
point. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SCHEMA 
 
 
 
 

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1.0 
SCHEDULE OF ACTIVITIES 
 
Screening can only start after confirmation of no tumor progression after at least 3 and not more than 4 
cycles of induction chemotherapy (as prescribed per standard of care treatment). Baseline imaging should 
be conducted within 21 days and laboratory tests within 7 days prior to start of study treatment. There is a 
5-day window for each cycle of treatment. Cycles are 21 days. The first cycle should begin no more than 
six weeks and no sooner than three weeks after last dose of induction treatment. This period may be 
extended to 8 weeks in patients requiring brain radiotherapy after completion of induction 
chemo/immunotherapy for brain metastases. 
 
 
Screening6 
C1D112 
C2D1 
D1 of 
every 
subsequent 
cycle 
Every 6 
Weeks 
through 
Week 249, 
10 
Every 12 
weeks10 
EOT 
F/U3 
Informed 
Consent 
X 
 
 
 
 
 
 
 
H&P, ECOG 
PS 
X 
X 
X 
X 
 
 
X 
 
CBC diff, plts 
X 
X 
X 
X 
 
 
 
 
CMP, lipase, 
amylase5 
X 
X 
X 
X 
 
 
 
 
LDH 
X 
X 
 
 
 
 
 
 
PTT/aPTT, 
INR 
X 
X 
X 
X 
 
 
 
 
TSH with 
reflex free T4 
X 
X 
 
X13 
 
 
 
 
Urinalysis 
X 
 
 
X 
 
 
 
 
Hepatitis B 
and C test 
X 
 
 
 
 
 
 
 
Pregnancy test 
X1 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
CT scan 
X 
 
 
 
X 
X9 
X 
 
Brain MRI 
X 
 
 
 
 
X 
 
 
Vorolanib 
 
     X-------------------------------(Daily)------------------------X 
 
Atezolizumab 
 
X 
X 
X 
 
 
 
 
Research 
blood11 
X7 
 
X 
 
 
 
X 
 
Tissue 
collection 
X4 
 
 
 
 
 
X4 
 
AE assessment 
X8 
     X-----------------------------------------------------------------X2 
Progression 
and survival 
 
 
 
 
 
 
 
X 
1. For women of childbearing potential only, pregnancy test must be obtained within 7 days prior to C1D1. 
2. For 90 days after end of treatment. 
3. Every 6 months for 3 years. Patient status will be reviewed through the medical record or phone contact. 
4. When available, archival tissue will be used. Baseline fresh biopsy will be optional. If a repeat biopsy is done at 
the time of disease progression, a research tissue sample will be taken at that time. 
5. CMP includes glucose, calcium, sodium, potassium, CO2, chloride, BUN, creatinine, alkaline phosphatase, 
alanine amino transferase (ALT), aspartate amino transferase (AST), bilirubin, albumin, and total protein. 

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6. Once consent is obtained, screening lab tests should be performed within 7 days prior to C1D1, with the exception 
of research blood sample.  
7. Research blood sample at screening should be obtained within 21 days prior to start of C1D1. Patient must be 
determined eligible for the study prior to research blood draw. 
8. AE assessment at baseline is intended to establish patient’s current medical condition. No regulatory reporting of 
AEs at baseline is required. 
9. CT should be performed every 6 weeks for the first 6 months. After the Week 24 scans, CT should be performed 
every 12 weeks thereafter (ie, Week 36, Week 48, etc). Imaging will follow calendar days without adjustments 
for delays in cycle starts. 
10. +/- 7 days 
11. Patients with hemoglobin below 9 mg/dL will not have blood collection.  
12. Baseline labs should be checked to verify eligibility. 
13. TSH should be checked at the end of every 2 cycles. 
 
 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
2.1.1 Small cell lung cancer 
 
Small cell lung cancer (SCLC), which accounts for approximately 13% of all cases 
of lung cancer in the United States, is an aggressive tumor characterized by rapid 
doubling time and early development of metastases.1 Despite the good response to 
initial therapy, essentially all patients with metastatic disease and the majority of 
those with earlier stages develop tumor progression.2 The standard therapy for 
SCLC has been a combination of platinum plus etoposide, with response rates, 
median progression-free survival (PFS) and median overall survival (OS) of 
approximately 60%, 5 months and 9 months respectively.3-5 In the phase II Cancer 
and Leukemia Group B trial 30504, patients with extensive stage SCLC who did 
not have tumor progression after four to six cycles of carboplatin plus etoposide 
were randomized to maintenance sunitinib or placebo.6 The median PFS from 
randomization was increased in the sunitinib arm (3.7 months vs 2.1 months). More 
recently, the addition of programmed death ligand 1 (PD-L1) atezolizumab to 
carboplatin plus etoposide was associated with increased PFS and OS when 
compared to chemotherapy alone, with the former increasing from 4.3 months to 
5.2 months and the latter from 10.3 months to 12.3 months respectively in the 
IMPower 133 trial.7 More recently, data from the CASPIAN trial demonstrated that 
the addition of durvalumab to platinum-etoposide doublet therapy improved OS 
from 10.3 months to 13 months.8Although CASPIAN and the IMPower 133 trials 
represent landmark trials in the treatment of SCLC, the added benefit from immune 
checkpoint blockers is still modest, with an absolute increase in the median OS of 
only 2.0 months and 2.7 months for atezolizumab and durvalumab, respectively. At 
the time of relapse, SCLC is usually resistant to additional therapy, with modest 
efficacy from topotecan,9,10 other chemotherapy drugs,11 or immune checkpoint 
blockers. 12,13  
 
2.1.2 Atezolizumab 

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Under normal physiologic conditions, the immune checkpoint molecules maintain 
self-tolerance preventing autoimmunity and limiting collateral damage to the 
normal tissues during response to infections.14,15 Cancer cells however, may co-opt 
these molecules to evade immune destruction. Programmed death 1 (PD-1), one of 
the key checkpoint molecules, may bind to two ligands, PD-L1/PD-L2. PD-L1 is 
an extracellular protein that downregulates immune responses primarily in 
peripheral tissues through binding to its two receptors PD-1 and B7.1. PD-1 is an 
inhibitory receptor expressed on T cells following T-cell activation, which is 
sustained in states of chronic stimulation such as in chronic infection or cancer.16,17 
Binding of PD-L1 to PD-1 inhibits T-cell proliferation, cytokine production, and 
cytolytic activity, leading to the functional inactivation or exhaustion of T cells.18 
Atezolizumab is a humanized IgG1 monoclonal antibody against PD-L1, which 
was approved in combination with carboplatin plus etoposide in patients with 
extensive stage SCLC.7  
 
2.1.3 Vorolanib (X-82) 
 
Vorolanib is an oral multi-kinase inhibitor of vascular endothelial growth factor 
receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), colony-
stimulating factor 1 receptor (CSF1R), stem cell factor (c-Kit), and FMS-like 
tyrosine kinase 3 (FLT3). Vorolanib inhibits angiogenesis by binding its target 
receptors (VEGFR and PDGFR). Vorolanib is structurally related to sunitinib and 
was been designed to improve upon the safety profile without compromising the 
efficacy of sunitinib. The combined effect on VEGFR and PDGFR allows these 
drugs to target endothelial cells and pericytes, respectively. In addition to the 
primary targets of VEGFR and PDGFR, CSF1R blockage reprograms tumor-
infiltrating macrophages and might improve responses to T-cell checkpoint 
inhibitor therapy.19  
 
2.1.4 Study Rationale 
 
Although the combination of platinum doublet with atezolizumab showed 
improved outcomes compared to chemotherapy alone and became the new standard 
of care in eligible patients, the benefit is modest and the survival for patients with 
extensive stage SCLC remains poor.  
 
Preclinical models and biospecimens collected from patients who have participated 
in checkpoint inhibitor clinical trials have shown that the paucity and dysfunction 
of T-cells in tumors along with malformation of T memory cells were found to be 
associated with resistance to checkpoint inhibitors.20 However, emerging evidence 
suggests that angiogenesis may play a key role in tumor-mediated immune 
regulation. VEGF may inhibit dendritic cell maturation21,22 and T lymphocyte 
infiltration into the tumor microenvironment,23 while anti-VEGF therapy can 
improve T-cell infiltration into tumors.24 The combination of the monoclonal 
antibody against VEGFR2, ramucirumab, with the anti-PD1 antibody 

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pembrolizumab showed promising efficacy in patients with non-small cell lung 
cancer, urothelial and upper gastrointestinal malignancies.25 Furthermore the 
combination of atezolizumab with the VEGF inhibitor bevacizumab was safe and 
improved PFS compared to sunitinib in patients with metastatic renal cell 
carcinoma expressing PD-L1.26 The combination of immune checkpoint blockers 
with anti-angiogenic tyrosine kinase inhibitors, including axitinib27 has also been 
shown to be feasible. In the phase I study with single agent vorolanib, the study 
ended prior to the determination of the maximum tolerated  dose due to the apparent 
saturation of absorption at doses of 400 to 800 mg per day, with 400 mg per day 
becoming the recommended dose.28 Nevertheless, in a phase I/II study evaluating 
the combination of nivolumab 240 mg every two weeks plus escalating doses of  
vorolanib from 200, 300 or 400 mg per day, the treatment was considered safe, 
although there was one dose-limiting toxicity of elevated liver enzymes in a patient 
enrolled into dose cohort 2 (300 mg).29 Therefore, we chose voloranib 200 mg per 
day as the dose for the combination with atezolizumab.  
 
Based on the data from maintenance sunitinib, which improved the median PFS 
from 2.1 to 3.7 months compared to placebo after induction chemotherapy,6 
estimated PFS from atezolizumab in the maintenance therapy of approximately 2.2 
months,7 and likely synergism between immune checkpoint blockers and anti-
angiogenesis drugs, we propose the addition of voloranib to atezolizumab during 
the maintenance phase of first-line therapy for extensive-stage SCLC after three to 
four cycles of induction therapy with platinum, etoposide, and atezolizumab. We 
hypothesize that the addition of vorolanib to atezolizumab during maintenance 
therapy will improve the PFS compared to single agent atezolizumab or sunitinib 
from historical controls.  
 
2.1.5 Correlative studies rationale 
 
Vorolanib is a multikinase inhibitor mainly targeting VEGFR and PDGFR. 
Emerging evidence suggests that angiogenesis may play a key role in tumor-
mediated immune regulation. In addition, high baseline angiopoietin-2 was found 
to be associated with poor survival in patients receiving CTLA-4 or PD-L1 
inhibitors, and levels of angiopoietin-2 increase in patients after receiving CTLA-
4 or PD-L1 inhibitors.30 Exploring the change of a panel of markers including 
angiopoietin-2 and VEGF in the study may shed light on treatment response and 
mechanisms of resistance. Additionally, we plan to assess the predictive and 
prognostic value of PD-L1 expression level and other immune-related biomarkers 
such as tumor immune infiltrates in patients enrolled in the study. 
 
 
3.0 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary 

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To determine the PFS at 6 months for maintenance 
vorolanib with atezolizumab after treatment with 
platinum, etoposide, and atezolizumab in patients 
with extensive stage SCLC. 
Kaplan-Meier product limit estimator 
will be used to estimate the PFS at 6 
months, with the inclusion of 90% 
confidence interval (CI). 
Secondary 
To determine the PFS for maintenance vorolanib with 
atezolizumab after treatment with platinum, 
etoposide, and atezolizumab in patients with 
extensive stage SCLC. 
Kaplan-Meier product limit estimator 
will be used to estimate the PFS. 
To determine the overall survival (OS) for the 
combination of maintenance vorolanib and 
atezolizumab in patients with extensive stage SCLC. 
Kaplan-Meier product limit estimator 
will be used to estimate the OS. 
To evaluate toxicity and tolerability for the 
combination of maintenance vorolanib and 
atezolizumab in patients with extensive stage SCLC. 
Toxicity by CTCAE v 5.0. 
Tertiary/Exploratory 
To evaluate the duration of benefit for the 
combination of vorolanib and atezolizumab in 
patients with extensive stage SCLC. 
 
To evaluate for blood and tissue (when available) 
biomarkers before and after (if available) the 
maintenance therapy. 
 
 
 
4.0 
STUDY POPULATION 
 
4.1 
Inclusion Criteria 
 
1. Histologically or cytologically confirmed extensive stage small cell lung cancer 
without prior specific systemic therapy aside from induction with platinum, etoposide, 
and atezolizumab. Measurable disease is not required for eligibility.  
 
2. Receipt of at least 3 cycles (and no more than 4 cycles) of platinum plus etoposide and 
atezolizumab during the induction phase, without tumor progression as determined by 
CT scan and brain MRI. Patients should be able to start the study treatment no more 
than 6 weeks from the last dose of induction chemo/immunotherapy. This period may 
be extended to 8 weeks in patients requiring brain radiotherapy after completion of 
induction chemo/immunotherapy for brain metastases.  
 
3. At least 18 years of age. 
 
4. ECOG performance status ≤ 1 (see Appendix A) 
 
5. Normal bone marrow and organ function as defined below: 
a. Absolute neutrophil count ≥ 1.5 K/cumm 
b. Platelets ≥ 100 K/cumm 

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c. Hemoglobin ≥ 9.0 g/dL 
d. Total bilirubin ≤ 1.5 x IULN 
e. AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN (≤ 5 x IULN for patients with liver 
metastases) 
f. Creatinine ≤ 1.5 x IULN OR measured or calculated creatinine clearance > 50 
mL/min for patients with creatinine levels > 1.5 x IULN 
g. Urine protein ≤ 1+ or urine protein to creatinine ratio ≤ 1; if UPC ratio is > 1 on 
urinalysis, then 24-hour urine collection for protein must be obtained and level must 
be < 1,000 mg for patient enrollment 
h. aPTT and either INR or PT ≤ 1.5 x IULN unless participant is receiving 
anticoagulant therapy as long as PT or a PTT is within therapeutic range of intended 
use of anticoagulants. 
 
6. Patients receiving therapeutic non-Coumadin anticoagulation are eligible, provided 
they are on a stable dose (per investigator judgment) of anticoagulant. 
 
7. The effects of atezolizumab and vorolanib on the developing human fetus are unknown.  
For this reason, women of childbearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control, abstinence) prior to study 
entry and for the duration of study participation.  Should a woman become pregnant or 
suspect she is pregnant while participating in this study, she must inform her treating 
physician immediately.  Men treated or enrolled on this protocol must also agree to use 
adequate contraception prior to the study, for the duration of the study, and 31 weeks 
after last dose of study treatment. Women must use birth control for at least 31 weeks 
after last dose of study treatment. Women must not be breastfeeding. 
 
8. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
4.2 
Exclusion Criteria 
 
1. A history of other malignancy with the exception of malignancies for which all 
treatment was completed at least 2 years before registration and the patient has no 
evidence of disease. 
 
2. Currently receiving any other investigational agents. 
 
3. Patients with untreated brain metastases are excluded. Patients with clinically evident 
CNS hemorrhage are excluded. Prophylactic cranial irradiation is not allowed. Patients 
with brain metastases treated with whole brain radiation therapy, radiosurgery, or 
surgery are eligible.  
 
4. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to vorolanib, atezolizumab, or other agents used in the study. 
 

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5. Use of chronic antiplatelet therapy, including aspirin, nonsteroidal anti-inflammatory 
drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or 
clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is 
permitted. 
 
6. Systemic glucocorticoids with prednisone dose higher than 10 mg/day or equivalent.  
 
7. Arterial or venous thromboembolic event, including but not limited to myocardial 
infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, 
within 6 months prior to enrollment. 
 
8. Uncontrolled or poorly controlled hypertension with systolic blood pressure (BP)> 160 
mmHg systolic or diastolic > 100 mmHg for > 3 weeks prior to C1D1), despite standard 
medical management. 
 
9. Gastrointestinal perforation, and/or fistula, or risk factors for perforation within 6 
months prior to enrollment.  
 
10. Grade 3 or 4 gastrointestinal bleeding within 3 months prior to enrollment. 
 
11. History of active autoimmune disease, including but not limited to systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis 
associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s 
syndrome, Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or 
glomerulonephritis. 
 
12. History of idiopathic pulmonary fibrosis, pneumonitis (including drug-induced), 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing 
pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan.  
 
13. Hemoptysis (defined as bright red blood or ≥ ½ teaspoon) within 28 days prior to Cycle 
1 Day 1 or with radiographic evidence of intratumor cavitation or radiologically 
documented evidence of major blood vessel invasion or encasement by cancer. 
 
14. Serious or non-healing wound, ulcer, or bone fracture within 28 days prior to Cycle 1 
Day 1. 
 
15. Undergone major surgery within 28 days prior to Cycle 1 Day 1, or minor 
surgery/subcutaneous venous access device placement within 7 days prior to Cycle 1 
Day 1, or has elective or planned major surgery to be performed during the course of 
the clinical trial. 
 
16. Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis, cirrhosis at a level of Child-Pugh B or worse, cirrhosis (any degree) with a 
history of hepatic encephalopathy or clinically meaningful ascites resulting from 

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cirrhosis (defined as ascites from cirrhosis requiring diuretics or paracentesis), fatty 
liver, and inherited liver disease.  
 
17. Active tuberculosis. 
 
18. Administration of a live, attenuated influenza vaccine within 4 weeks before Cycle 1 
Day 1 or at any time during the study. 
 
19. Severe infections within 2 weeks prior to Cycle 1 Day 1, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia.  
 
20. Received oral or intravenous (IV) antibiotics within 2 weeks prior to Cycle 1 Day 1. 
Note: Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or chronic obstructive pulmonary disease) are eligible.  
 
21. History of deep venous thrombosis, pulmonary embolism, or any other significant 
thromboembolism (venous port or catheter thrombosis or superficial venous 
thrombosis are not considered “significant”) during the 3 months prior to Cycle 1 Day 
1. 
 
22. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
serum pregnancy test within 7 days prior to C1D1. 
 
23. Active hepatitis B (chronic or acute) defined as having a positive hepatitis B surface 
antigen (HBsAg) test at screening.  Note: Patients with past or resolved hepatitis B 
infection (defined as having a negative HBsAg test and a positive total hepatitis B core 
antibody (HBcAb) test are eligible. 
 
24. Patients known to be HIV positive are ineligible. 
 
4.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.   
 
 
5.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 

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5.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below  
 
1. The registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
5.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
5.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study. All data 
will be recorded with this identification number on the appropriate CRFs. 
 
5.4 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but do not meet all eligibility criteria.  A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (if applicable).   
 
 
6.0 
TREATMENT PLAN 
 
6.1 
Study Intervention Description 
 
Atezolizumab is a PD-L1 blocking antibody indicated for the treatment of urothelial 
carcinoma, non-small cell lung cancer, triple-negative breast cancer, and extensive stage 
small cell lung cancer (in combination with carboplatin and etoposide). 
 
Vorolanib is an investigational agent not approved by the FDA. 
 
6.2 
Study Intervention Administration 
 
Atezolizumab will be given intravenously at a dose of 1200 mg over 60 minutes on Day 1 
of each 21-day cycle. If the first infusion is tolerated, all subsequent infusions may be 
delivered over 30 minutes. 
 

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Vorolanib is administered orally at a dose of 200 mg on Days 1 through 21 of each 21-day 
cycle.  
 
Vorolanib is an oral tablet intended to be taken whole with food at the same time (+/- 6 
hours) every day. If a patient misses a dose, the patient should take the missed dose as soon 
as possible, but within 12 hours from the time they usually take their dose  If more than 12 
hours have passed the patient should restart at the next dose. If vomiting occurs after taking 
the study medication, the patient should be instructed not to retake the dose, and should 
just take his/her next scheduled dose of vorolanib. Patients will be instructed to bring all 
unused drug and their medication diary (Appendix D) to each study visit for assessment of 
compliance.   
 
6.3 
Definitions of Evaluability 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 90-day follow up after the conclusion 
of treatment or death. 
 
All patients are evaluable for disease response unless they discontinue treatment prior to 
completion of Cycle 2 and have not had any disease assessment. 
 
6.4 
Concomitant Therapy and Supportive Care Guidelines 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy 
or vaccination may be required. The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the participant’s primary physician. 
 
6.4.1 Acceptable Concomitant Medications 
 
All treatments that the investigator considers necessary for a participant’s welfare 
may be administered at the discretion of the investigator in keeping with the 
community standards of medical care. 
 
6.4.2 Prohibited Concomitant Medications 
 
Participants are prohibited from receiving the following therapies while on the trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol  
• Chemotherapy not specified in this protocol  
• Investigational agents other than atezolizumab and vorolanib  
• Live vaccines within 30 days prior to the first dose of study treatment and 
while participating in the study. Examples of live vaccines include, but are 
not limited to, the following: measles, mumps, rubella, varicella/zoster, 
yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza 

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vaccines for injection are generally killed virus vaccines and are allowed; 
however, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines and are not allowed.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms 
from an event of clinical interest of suspected immunologic etiology. The 
use of physiologic doses of corticosteroids may be approved after 
consultation with the PI. 
• Chronic antiplatelet therapy, including aspirin, nonsteroidal anti-
inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), 
dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use 
(maximum dose 325 mg/day) is permitted. 
• Vorolanib is primarily metabolized by CYP3A4 based on in vitro studies 
using human liver microsome. Therefore, concurrent use of any medication, 
herbal supplement or food known to be a strong inhibitor or strong inducer 
of CYP3A4 is prohibited unless there are no therapeutic alternatives.  
 
Participants who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the 
study.  
 
However, the decision to continue the participant on study treatment requires the 
mutual agreement of the investigator and the participant. 
 
6.4.3 Rescue Medications and Supportive Care for Patients Receiving 
Atezolizumab 
 
Participants should receive appropriate supportive care measures as deemed 
necessary by the treating investigator. Suggested supportive care measures for the 
management of AEs with potential immunologic etiology include the use of oral or 
IV treatment with corticosteroids, as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids. Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. For each disorder, attempts should be made to rule out 
other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be 
applied when the Investigator determines the events to be related to atezolizumab.  
 
 
Note: If after the evaluation of the event, it is determined not to be related to 
atezolizumab, the Investigator does not need to follow the treatment guidance. 
 
6.5 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 

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have a negative serum pregnancy test within 7 days prior to the first dose of study 
treatment. Women must not be breastfeeding. 
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the study 
and for 31 weeks following the last dose of study treatment.  
 
If a patient is suspected to be pregnant, study treatment should be immediately 
discontinued.  A positive urine test must be confirmed by a serum pregnancy test.  If it is 
confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 31 weeks after the last dose of study treatment, the investigator must be notified in 
order to facilitate outcome follow-up. 
 
6.6 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
Treatment may continue for up to two-years or until one of the following criteria applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious noncompliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• Siteman Cancer Center or Xcovery Holdings decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will still be followed as 
indicated in the study calendar. 
 
6.7 
Duration of Follow-up 
 
Patients will be followed by review of the medical record or through direct contact for 
survival every 6 months for up to 3 years after discontinuation of study treatment. Patients 
removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.   

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6.8 
Lost to Follow-Up 
 
A participant will be considered lost to follow-up if he or she fails to return for 6 weeks 
and is unable to be contacted by the study team. 
 
The following actions must be taken if the participant fails to return to clinic for a required 
study visit: 
o The study team will attempt to contact the participant and reschedule the missed 
visit within 2 weeks and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain if the participant wishes to and/or should 
continue in the study. 
o Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address).  These contact attempts should be documented in the participant’s medical 
record or study file. 
o Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 
7.0 
DOSE DELAYS/ DOSE MODIFICATIONS 
 
Dosing for atezolizumab and vorolanib should be modified as described in the sections below. If 
dosing is suspended due to an adverse event that does not resolve within 6 weeks and is deemed 
related to one but not the other agent, the unrelated drug(s) may be restarted at the PI’s discretion 
depending on the toxicity profile. Other holds and modifications may be made at the discretion of 
the PI. 
 
7.1 
Atezolizumab Dose Modifications 
 
Atezolizumab dose modification is not allowed. However, study treatment may be 
temporarily suspended in patients experiencing toxicity considered to be related to study 
treatment for up to 60 days after the last dose if they experience toxicity that require a dose 
to be withheld. If atezolizumab is withheld because of toxicity for > 60 days after the last 
dose, then the patient will be discontinued from atezolizumab treatment and will be 
followed for safety and efficacy.  
 
Adverse Reaction 
Severity/Grade of 
Reaction 
Management 
Pneumonitis 
Grade 2 
Withhold dose until improved 
to < Grade 1 and corticosteroid 
dose is less than or equal to 
prednisone 10 mg per day (or 
equivalent 
Grade 3 or 4 
Permanently discontinue 

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Hepatitis 
AST or ALT >3-8 x 
ULN OR total bilirubin  
> 1.5-3 x ULN 
Withhold dose until improved 
to < Grade 1 and corticosteroid 
dose is less than or equal to 
prednisone 10 mg per day (or 
equivalent) 
AST or ALT > 8 x ULN 
OR total bilirubin > 3 x 
ULN 
Permanently discontinue 
Colitis or Diarrhea 
Grade 2 or 3 
Withhold dose until improved 
to < Grade 1and corticosteroid 
dose is less than or equal to 
prednisone 10 mg per day (or 
equivalent) 
Grade 4 
Permanently discontinue 
Endocrinopathies 
(including hypophysitis, 
adrenal insufficiency, 
hyperthyroidism, and 
type 1 diabetes) 
Grade 2, 3 or 4 
Withhold dose until improved 
to < Grade 1and clinically 
stable on hormone replacement 
therapy. 
Pancreatitis 
Amylase OR Lipase 
greater than 2 x ULN 
Withhold dose until improved 
to < Grade 1and clinically 
stable  
Other immune-mediated 
adverse reactions 
Grade 3 
Withhold dose until improved 
to < Grade 1and corticosteroid 
dose is less than or equal to 
prednisone 10 mg per day (or 
equivalent) 
Grade 4 
Permanently discontinue 
Infections 
Grade 3 or 4 
Withhold dose until improved 
to < Grade 1 
Infusion-Related 
Reactions 
Grade 1 or 2 
Interrupt or slow the rate of 
infusion 
Grade 3 or 4 
Permanently discontinue 
 
7.2 
Vorolanib Dose Modifications  
 
Patients will be initiated on 200 mg once daily of vorolanib. If toxicity occurs reduce dose 
according to the table below. Doses will not be re-escalated once reduced.  
 
Starting Dose 
200 mg 
Level -1 
100 mg 
 
 
7.2.1 Dose Modifications Due to Hematologic Toxicity 
 

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If hematologic toxicity occurs, treatment with vorolanib should be held, and re-
evaluated in at least 1 week. ANC and platelets should be monitored at least weekly 
until recovery. If ANC and/or platelets do not recover within 4 weeks, the patient 
will be discontinued from the trial unless the treating physician and PI agree that 
continued treatment at a reduced dose is in the best interest of the patient. 
 
Event 
Vorolanib Dose 
Neutropenia (ANC) 
Grade 3-4 
Hold dose until recovery to ≤ grade 2, then resume 
vorolanib at100 mg QD 
Recurrent grade 4 
Hold dose until recovery to ≤ grade 2, then resume 
vorolanib at 100 mg QD. 
Thrombocytopenia 
Grade 3 
Hold dose until improvement of platelets ≥ 75 x 109/L 
• If resolved in ≤ 5 days, then resume without a dose 
reduction. 
• If resolved in > 5 days, but < 4 weeks, then resume 
vorolanib at 100 mg QD. 
 
7.2.2 Dose Modifications Due to Non-Hematologic Toxicity 
 
Vorolanib can be held for one cycle due to toxicity. If vorolanib is held for longer 
than one cycle, discussion with the PI is required before restarting vorolanib. If a 
grade 3 non-hematologic toxicity that is possibly, probably, or definitely related to 
vorolanib occurs, that is expected to be manageable and reversible with dose 
reduction, treatment with vorolanib should be held until the toxicity resolves to ≤ 
grade 1 and resumed at 100 mg QD. Patients with grade 3 related non-hematologic 
toxicity that does not resolve to ≤ grade 1 within 2 weeks or any grade 4 related 
non-hematological toxicity on vorolanib at 100 mg QD should be removed from 
the trial. 
 
Specific Recommendations for Rash, Nausea, Vomiting and Diarrhea:  
For patients with grade 3 rash, nausea, vomiting, and/or diarrhea that is thought to 
be possibly, probably, or definitely related to vorolanib, then vorolanib should be 
held and supportive care initiated. If the grade 3 toxicity lasts ≤ 7 days, patients 
may restart vorolanib at 100 mg QD when toxicity returns to ≤ grade 1. If the patient 
has recurrent grade 3 toxicity despite supportive care, the patient will restart 
vorolanib 100 mg QD once toxicity has resolved to ≤ grade 1.  
 
Specific Recommendations for Liver Function Test Abnormalities:  
For patients with grade 3 liver enzyme elevations (AST/ALT) regardless of the 
cause, vorolanib should be held until the values recover to ≤ grade 1. Patients with 
a CTCAE v5 Grade 2 elevation of ALT in conjunction with a bilirubin ≥ 2 x ULN 
may remain in the study if a correctable, non-drug related cause of the liver test 
evaluations can be documented; otherwise, the patient must be discontinued from 
the trial.  

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Specific Recommendations for the Treatment of Hypertension:  
Medication recommendations for the treatment of hypertension should be applied 
based on the patient and clinical status. General recommendations on initial 
management of hypertension are:  
 
Patients should have optimally managed BP (≤160/90 mmHg) prior to starting 
study treatment. After starting treatment with vorolanib, BP should be monitored 
regularly. Patients with persistent HTN with readings above 140/90 mmHg, should 
initiate treatment with an ACE inhibitor (e.g. benazepril, lisonopril), angiotensin II 
receptor blocker (ARB) (e.g. losartan), thiazide diuretic (e.g. HCTZ), or 
dihydropyrimidine calcium channel blocker (e.g. amlodipine). Titrate to BP control 
with dose escalation of the chosen drug, or if additional agents are needed, choose 
a second agent from the recommended list.  
 
For patients whose HTN is ≥160/90, vorolanib should be held and initiation of 
combination therapy with an ACE inhibitor and dihydropyrimidine calcium 
channel blocker is recommended. Patients should check BP daily and return to 
clinic within 3 weeks.  
 
 
8.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below. Please refer to Appendix B for definitions and Appendix C for a grid of reporting 
timelines. 
 
Adverse events will be tracked from start of treatment through 90 days after end of treatment.  All 
adverse events must be recorded on the toxicity tracking case report form (CRF) with the exception 
of: 
• Baseline adverse events, which shall be recorded on the medical history CRF 
 
Refer to the data submission schedule in Section 11 for instructions on the collection of AEs in the 
electronic data capture system (EDC). 
 
8.1 
Washington University Sponsor-Investigator Reporting Requirements 
 
8.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change. 
 

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8.1.2 Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The Washington University Sponsor/Investigator  is required to notify the QASMC 
of any unanticipated problems involving risks to participants or others occurring at 
WU or any BJH or SLCH institution that has been reported to and acknowledged 
by HRPO.  (Unanticipated problems reported to HRPO and withdrawn during the 
review process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to qasmc@wustl.edu.  Submission to QASMC must include the myIRB form 
and any supporting documentation sent with the form. 
 
8.1.3 Reporting to Xcovery 
 
If a vorolanib event requires expedited safety reporting to the FDA, then Xcovery 
will need a copy of the final 7 or 15-day MedWatch report via email to 
safety@xcovery.com. Submit to Xcovery no later than calendar day 4 for a 7-day 
report and no later than calendar day 10 for a 15-day report, when possible, for 
submission to Competent Authorities, and any central/local ECs, and investigators 
as applicable per U.S. specific regulatory reporting requirements.  
 
The Xcovery Safety Reporting specialist will generate an Expedited Safety 
Report/Cross Report Investigator Letter Template and will distribute the Safety 
Cross-Report packet (Expedited Safety Cross Report Investigator Alert Letter and 
MedWatch) to participating Xcovery investigators no later than calendar day 7 for 
a 7-day report and no later than calendar day 15 for a 15-day report, as per country 
U.S. specific reporting requirements. 
 
8.1.4 Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA 
DIFFER FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It 
is the responsibility of the Washington University Sponsor-Investigator to report to 
the FDA as follows: 
 
• Report any unexpected fatal or life-threatening suspected adverse reaction 
(refer to Appendix B for definitions) no later than 7 calendar days after 
initial receipt of the information.   
• Report a suspected adverse reaction that is both serious and unexpected 
(SUSAR, refer to Appendix B) no later than 15 calendar days after it is 
determined that the information qualifies for reporting.  Report an adverse 
event (refer to Appendix B) as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the drug and the adverse 
event, such as: 

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o A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure 
o One or more occurrences of an event that is not commonly associated 
with drug exposure but is otherwise uncommon in the population 
exposed to the drug 
o An aggregate analysis of specific events observed in a clinical trial that 
indicates those events occur more frequently in the drug treatment 
group than in a concurrent or historical control group 
• Report any findings from epidemiological studies, pooled analysis of 
multiple studies, or clinical studies that suggest a significant risk in humans 
exposed to the drug no later than 15 calendar days after it is determined 
that the information qualifies for reporting. 
• Report any findings from animal or in vitro testing that suggest significant 
risk in humans exposed to the drug no later than 15 calendar days after it 
is determined that the information qualifies for reporting.  
• Report any clinically important increase in the rate of a serious suspected 
adverse reaction of that listed in the protocol or IB within 15 calendar days 
after it is determined that the information qualifies for reporting. 
 
Submit each report as an IND safety report in a narrative format or on FDA Form 
3500A or in an electronic format that FDA can process, review, and archive.  Study 
teams must notify the Siteman Cancer Center Protocol Development team of each 
potentially reportable event within 1 business day after initial receipt of the 
information, and must bring the signed 1571 and FDA Form 3500A to the Siteman 
Cancer Center Protocol Development team no later than 1 business day prior to the 
due date for reporting to the FDA. 
 
Each notification to FDA must bear prominent identification of its contents (“IND 
Safety Report”) and must be transmitted to the review division in the Center for 
Drug Evaluation and Research (CDER) or in the Center for Biologics Evaluation 
and Research (CBER) that has responsibility for review of the IND.  Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such (“Follow-up IND Safety 
Report”). 
 
8.2 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 8.1 include: 
• planned hospitalizations 
• hospitalizations < 24 hours 
• respite care 
• events related to disease progression 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
 

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9.0 
PHARMACEUTICAL INFORMATION 
 
9.1 
Atezolizumab 
 
Commercial supply of atezolizumab will be used. 
 
Other Names:  Tecentriq™, MPDL3280A 
Classification:  monoclonal antibody 
M.W.:  150 KD 
Mode of Action: anti-PD-L1 
 
9.1.1 Description 
 
Atezolizumab is a humanized IgG1 monoclonal antibody consisting of two heavy 
chains (448 amino acids) and two light chains (214 amino acids). Atezolizumab 
targets human PD-L1 and inhibits its interaction with its receptor PD-1. 
Atezolizumab also blocks the binding of PD-L1 to B7.1, an interaction that is 
reported to provide additional inhibitory signals to T cells (Butte et al. 2007).  
 
9.1.2 How Supplied 
 
Atezolizumab is supplied in a single-use, 20-mL glass vial as a colorless-to-
slightly-yellow, sterile, preservative-free clear liquid solution intended for IV 
administration. Atezolizumab is formulated as 60 mg/mL atezolizumab in 20 mM 
histidine acetate, 120 mM sucrose, 0.04% polysorbate 20, at a pH of 5.8. The vial 
is designed to deliver 20 mL (1200 mg) of atezolizumab solution but may contain 
more than the stated volume to enable delivery of the entire 20 mL volume. 
 
9.1.3 Preparation 
 
The prescribed dose of atezolizumab should be diluted in 250 mL 0.9% NaCl and 
infused through a 0.2 micrometer in-line filter. The IV bag may be constructed of 
PVC or PO; the IV infusion line may be constructed of PVC or PE; and the 0.2 
micrometer in-line filter may be constructed of PES. The prepared solution may be 
stored at 2°C-8°C or room temperature for up to 8 hours. 
 
9.1.4 Storage 
 
2°C-8°C (36°F-46°F) Vial contents should not be frozen or shaken and should be 
protected from direct sunlight. 
 
If a storage temperature excursion is identified, promptly return atezolizumab to 
2°C-8°C (36°F-46°F) and quarantine the supplies.  
 
9.1.5 Stability 
 

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Stability studies are ongoing. 
 
CAUTION: No preservative is used in atezolizumab; therefore, the vial is intended 
for single use only. Discard any unused portion of drug remaining in a vial.  
 
9.1.6 Route of Administration 
 
IV infusion. 
 
9.1.7 Method of Administration 
 
Atezolizumab is administered as an intravenous infusion over 60 minutes. If the 
first infusion is tolerated, all subsequent infusions may be delivered over 30 
minutes. Do not administer atezolizumab as an intravenous push or bolus.  No 
premedication is indicated for administration of Cycle 1 of atezolizumab. Patients 
who experience an infusion related reaction with Cycle 1 of atezolizumab may 
receive premedication with antihistamines or antipyretics/analgesics (e.g. 
acetaminophen) for subsequent infusions. 
 
9.1.8 Potential Drug Interactions 
 
Cytochrome P450 enzymes as well as conjugation/glucuronidation reactions are 
not involved in the metabolism of atezolizumab. No drug interaction studies for 
atezolizumab have been conducted or are planned. There are no known interactions 
with other medicinal products or other form of interactions. 
 
9.2 
Vorolanib 
 
9.2.1 Vorolanib Description 
 
Oral vorolanib drug product has been formulated as orange tablets with dosage 
strengths of 50 mg (oblong tablets) or 100 mg (oblong tablets) of vorolanib drug 
substance. The tablets are coated with a colored, nonfunctional, globally accepted 
film coating.  
 
Additional information may be found in the vorolanib investigator’s brochure.  
 
9.2.2 Clinical Pharmacology 
 
Clinical pharmacology studies have not been performed to date.  
 
 
9.2.3 Pharmacokinetics and Drug Metabolism 
 
Vorolanib is primarily metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 
and CYP2C9 based on in vitro studies using human liver microsomes. Thus, 

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coadministration of vorolanib with potent CYP3A4 inhibitors and inducers should 
be avoided. 
 
9.2.4 Supplier(s) 
 
Vorolanib will be provided free of charge by Xcovery Holdings, Inc.  
 
 
9.2.5 Dosage Form and Preparation 
 
Vorolanib will be supplied in 100 mg tablets.  
 
9.2.6 Storage and Stability 
 
Vorolanib tablets (100 mg) are stored in 60cc wide mouth round HDPE bottles with 
a pharmaceutical desiccant canister, closed with a white polypropylene child 
resistant cap and foil induction inner seal. Thirty tablets are included in each bottle.  
 
Vorolanib should be stored at room temperature (15ºC-30ºC/59ºF- 86ºF).  
 
9.2.7 Administration 
 
Vorolanib is an oral drug which will be administered daily on an outpatient basis at 
the assigned dose level.  Patients should take vorolanib at approximately the same 
time every day with food.  If a patient misses a dose, the patient should be instructed 
not to make up that dose and resume dosing with the next scheduled dose.  Patients 
will be instructed to bring all unused medication and their medication diary to each 
study visit for assessment of compliance. 
 
 
10.0 
CORRELATIVE STUDIES 
 
10.1 
Peripheral Research Blood 
 
10.1.1 Collection of Specimen(s) 
 
Patients will have 40 mL of blood collected in 3 green heparinized tubes and 1 red 
top tube at baseline (within 21 days prior to start of the therapeutic intervention), 
Day 1 of Cycle 2, and end of treatment. Patients with hemoglobin below 9 mg/dL 
will not have blood collection.  
 
The samples will be processed by standard operating procedures by centrifugation. 
All samples will be frozen in liquid nitrogen and stored under liquid nitrogen vapor 
in an inventoried storage unit at the Siteman Cancer Center Tissue Procurement 
Core Facility until analysis.  
 

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We will evaluate whether the combination of vorolanib and atezolizumab (a) alters 
populations of circulating monocytes and myeloid derived suppressor cells, (b) 
increases the number and affects the phenotype of circulating NK cells, effector 
CD8+ and effector CD4+ T-cell subsets, (c) results in the generation of durable 
populations of memory CD8+ and CD4+ T-cells and (d) alters the ratio of 
circulating regulatory T-cells to effector CD8+ cells.  We will utilize mass 
cytometry for these analyses, a high dimensional technique that allows the 
assessment of approximately 40 individual markers using metal labeled antibodies 
to enable deep profiling of selected phenotypic and functional makers on individual 
cells as well as unique statistical analyses to simplify the interpretation of complex 
relationships of large numbers of cells.  
 
10.2 
Biopsy Sample Collection 
 
 
 
10.2.1 Collection of Specimens 
 
 
 
When available, archival biopsy tissue will be used for a baseline biopsy. A 
baseline fresh biopsy will be optional.  
 
At progression, a repeat biopsy will be attempted when feasible aiming for up to 5 
cores if possible. 
 
 
11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Within 4 weeks prior to registration 
On-Study Form 
Medical History Form 
Prior to starting treatment 
Treatment Form 
Every cycle 
Patient Medication Diary 
Every cycle 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Research Specimen form 
At time of specimen collection 
Follow Up Form 
Every 6 months for 3 years 
Tumor Measurement Form 
Baseline, every 6 weeks for the 6 months, every 12 weeks 
thereafter, and end of treatment 
MedWatch Form 
See Section 8.0 for reporting requirements 
Progression Form 
Time of progression 
Death Form 
Time of death 
 
11.1 
Adverse Event Collection in the Case Report Forms 

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All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 8.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 6 weeks 
for the first 6 months and every 12 weeks thereafter using the same methods as the baseline 
imaging.  Brain MRIs will also be performed every 12 weeks for all patients.  In addition 
to a baseline scan, confirmatory scans should also be obtained not less than 4 weeks 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
12.2 
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 

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Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
12.3 
Baseline tumor imaging 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be within 21 days from starting the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 

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Conventional CT and MRI:  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
12.4 
Tumor imaging during the trial 
 
Study imaging will be performed, with the same imaging method used for baseline, every 
6 weeks (42 days +/- 7 days) for the first 6 months and every 12 weeks (84 days +/- 7 days) 
thereafter. Brain imaging will be performed every 12 weeks (84 days +/- 7 days).  Imaging 
will follow calendar days without adjustments for delays in cycle starts. Patient should 
continue to undergo imaging studies until tumor progression, withdrawal of consent, or 
death, whichever occurs first.   
 
12.5 
Response Criteria 
 
12.5.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 

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Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
12.5.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
12.5.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 

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SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported 
as “symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 
                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised 
 
12.5.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
12.5.5 Progression-Free Survival 
 

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PFS is defined as the duration of time from start of treatment to time of progression 
or death, whichever occurs first. 
 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least one patient has been enrolled) or one 
year after accrual has opened (if no patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Summary of toxicities 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Sample Size Estimates 
 
This single institution study will be designed using Simon’s two-stage MiniMax design. 
We plan to enroll thirty-three (33) SCLC patients with extensive stage disease. 

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Given historic rates of PFS at 6 months of approximately 20% for maintenance sunitinib 6 
or atezolizumab,7 we determined that a 6 month PFS of 40% with the combination 
vorolanib and atezolizumab would warrant further evaluation of this strategy. Based on 
Simon’s Minimax two-stage design, a total number of 33 patients allows 80% power at 1-
sided alpha of 0.05 to detect the expected difference. Eighteen (18) evaluable patients will 
be enrolled in stage I. Patient enrollment will continue while waiting for the data from stage 
I to mature for an interim futility analysis. If 5 or more patients from stage I exhibit 
progression-free survival of >6 months, then 15 additional patients will be enrolled in stage 
II. If 11 or more patients exhibit progression-free survival at 6 month out of all 33 evaluable 
patients, we would conclude that preliminary evidence for efficacy exists and that further 
investigation is warranted.  With this design, we will have 5% chance to erroneously stop 
the trial in stage 1 if the true 6-month PFS is ≥ 40%. However, there is a 72% chance of 
ending the trial during stage I, given a true 6-month PFS of 20% or less. 
 
Since the probability of disease-free survival at 3 months with standard therapy is 
approximately 40%, an additional analysis will also be performed based on the outcomes 
for the 18 patients at 3 months. If 10 or more patients develop tumor progression or death 
by the third month of maintenance treatment, the study accrual will be held until the 6 
month PFS becomes available for the decision to proceed to stage II of the trial.  
 
14.2 
Accrual Rate 
 
The rate of accrual for this study is expected to be 1-2 patients per month. The study is 
expected to complete within two to two and a half years. 
 
14.3 
Populations of Analysis 
 
Evaluable patients for safety will include those patients who receive at least 1 dose 
maintenance treatment of vorolanib with atezolizumab. 
 
Evaluable patients for efficacy will include those patients who receive at least 1 dose 
maintenance treatment of vorolanib with atezolizumab, and have a post-baseline disease 
assessment.  
 
14.4 
Statistical Analysis Plan 
 
Demographic and clinical characteristics of the sample, as well as response to treatment, 
toxicity by grade and loss to follow up will be summarized using descriptive statistics.  
 
An interim futility analysis will be performed at the time when 18 efficacy-evaluable 
patients are available. The patient enrollment will continue while the interim data is 
analyzed. However, if 10 or more patients develop tumor progression or death by the third 
month of maintenance treatment, the study accrual will be held until the 6 month PFS 
becomes available for the decision to proceed to stage II of the trial. If 4 or less patients 
exhibit progression-free survival of >6 months, the trial will be recommended for an early 

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termination due to futility. If 5 or more patients exhibit progression-free survival of >6 
months, then an additional 15 patients will be enrolled in the stage II.   
 
At the end of study, if 11 or more patients achieve progression-free survival at 6 month out 
of all 33 evaluable patients, we would conclude that preliminary evidence for efficacy 
exists and that further investigation is warranted. Kaplan-Meier product limit estimator will 
be used to describe the distribution of progression free survival (PFS) and overall survival 
(OS). The PFS at 6 month and its 90% confidence interval (CI) will also be calculated.   
 
 

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15.0 
REFERENCES 
 
1. 
Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung 
cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and 
end results database. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 2006;24:4539-44. 
2. 
Pietanza MC, Byers LA, Minna JD, Rudin CM. Small cell lung cancer: will recent progress 
lead to improved outcomes? Clinical cancer research : an official journal of the American 
Association for Cancer Research 2015;21:2244-55. 
3. 
Lara PN, Jr., Chansky K, Shibata T, et al. Common arm comparative outcomes analysis of 
phase 3 trials of cisplatin + irinotecan versus cisplatin + etoposide in extensive stage small cell 
lung cancer: final patient-level results from Japan Clinical Oncology Group 9511 and Southwest 
Oncology Group 0124. Cancer 2010;116:5710-5. 
4. 
Lara PN, Jr., Natale R, Crowley J, et al. Phase III trial of irinotecan/cisplatin compared 
with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic 
results from SWOG S0124. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology 2009;27:2530-5. 
5. 
Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with 
etoposide plus cisplatin for extensive small-cell lung cancer. The New England journal of medicine 
2002;346:85-91. 
6. 
Ready NE, Pang HH, Gu L, et al. Chemotherapy With or Without Maintenance Sunitinib 
for Untreated Extensive-Stage Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-
Controlled Phase II Study-CALGB 30504 (Alliance). Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology 2015;33:1660-5. 
7. 
Horn L, Gettinger SN, Gordon MS, et al. Safety and clinical activity of atezolizumab 
monotherapy in metastatic non-small-cell lung cancer: final results from a phase I study. Eur J 
Cancer 2018;101:201-9. 
8. 
Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus 
platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a 
randomised, controlled, open-label, phase 3 trial. Lancet 2019. 
9. 
von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, 
doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 1999;17:658-67. 
10. 
Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with intravenous 
topotecan as second-line therapy in small-cell lung cancer. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 2007;25:2086-92. 
11. 
Levy B, Saxena A, Schneider BJ. Systemic therapy for small cell lung cancer. J Natl Compr 
Canc Netw 2013;11:780-7. 
12. 
Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus 
ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 
1/2 trial. The lancet oncology 2016;17:883-95. 
13. 
Ott PA, Elez E, Hiret S, et al. Pembrolizumab in Patients With Extensive-Stage Small-Cell 
Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 2017;35:3823-9. 
14. 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature 
reviews Cancer 2012;12:252-64. 

Protocol Version: 05/10/2022 
 
Page 42 of 50 
15. 
Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of 
advanced human cancer. Clinical cancer research : an official journal of the American Association 
for Cancer Research 2013;19:1021-34. 
16. 
Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on 
tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. 
Cancer Immunol Immunother 2005;54:307-14. 
17. 
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and 
immunity. Annu Rev Immunol 2008;26:677-704. 
18. 
Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 
1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 
2007;27:111-22. 
19. 
Zhu Y, Knolhoff BL, Meyer MA, et al. CSF1/CSF1R blockade reprograms tumor-
infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic 
cancer models. Cancer Res 2014;74:5057-69. 
20. 
Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint 
inhibitors. Br J Cancer 2018;118:9-16. 
21. 
Ohm JE, Carbone DP. VEGF as a mediator of tumor-associated immunodeficiency. 
Immunol Res 2001;23:263-72. 
22. 
Oyama T, Ran S, Ishida T, et al. Vascular endothelial growth factor affects dendritic cell 
maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor 
cells. J Immunol 1998;160:1224-32. 
23. 
Huang H, Langenkamp E, Georganaki M, et al. VEGF suppresses T-lymphocyte 
infiltration in the tumor microenvironment through inhibition of NF-kappaB-induced endothelial 
activation. FASEB J 2015;29:227-38. 
24. 
Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA. 
Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the 
effectiveness of adoptive immunotherapy of cancer. Cancer Res 2010;70:6171-80. 
25. 
Herbst RS, Arkenau HT, Santana-Davila R, et al. Ramucirumab plus pembrolizumab in 
patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, 
or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial. The 
lancet oncology 2019;20:1109-23. 
26. 
Rini BI, Powles T, Atkins MB, et al. Atezolizumab plus bevacizumab versus sunitinib in 
patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, 
open-label, phase 3, randomised controlled trial. Lancet 2019;393:2404-15. 
27. 
Rini BI, Powles T. Immune Checkpoint Blockade plus Axitinib for Renal-Cell Carcinoma. 
The New England journal of medicine 2019;380:2582. 
 
28.         Bendell JC, Patel MR, Moore KN, et al. Phase I, first-in-human, dose-escalation study to 
evaluate the safety, tolerability and pharmacokinetics of vorolanib in patients with advanced solid 
tumors. Oncologist 2019; 24: 455-e121. 
29.     Whisenant J, Beckermann K, Borhaei H. Phase I/II study to evaluate the safety and 
preliminary activity of nivolumab in combination with vorolanib in patients with refractory thoraci 
tumors. Proceedings of the American Association for Cancer Research 2019; 79: 13 pp CT171. 
30. 
Wu X, Giobbie-Hurder A, Liao X, et al. Angiopoietin-2 as a Biomarker and Target for 
Immune Checkpoint Therapy. Cancer Immunol Res 2017;5:17-28. 
 
 

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Acknowledgements 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials Core 
which provided protocol development services. The Siteman Cancer Center is supported in part 
by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 

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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 

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APPENDIX B: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 

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o A life-threatening adverse event 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 

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APPENDIX C: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Xcovery 
Serious AND 
unexpected suspected 
adverse reaction 
 
 
Report no later than 15 
calendar days after it is 
determined that the 
information qualifies 
for reporting 
If a vorolanib-related event requires 
expedited safety reporting to the FDA, 
then Xcovery will need a copy of the 
final 7 or 15-day MedWatch report via 
email to safety@xcovery.com. 
Submitno later than calendar day 4 for a 
7-day report and no later than calendar 
day 10 for a 15-day report. 
Unexpected fatal or 
life-threatening 
suspected adverse 
reaction 
 
 
Report no later than 7 
calendar days after 
initial receipt of the 
information 
 
Unanticipated 
problem involving risk 
to participants or 
others 
Report within 10 working days.  If the event 
results in the death of a participant enrolled 
at WU/BJH/SLCH, report within 1 working 
day. 
Report via email after 
IRB acknowledgment 
 
 
Major deviation 
Report within 10 working days.  If the event 
results in the death of a participant enrolled 
at WU/BJH/SLCH, report within 1 working 
day. 
 
 
 
A series of minor 
deviations that are 
being reported as a 
continuing 
noncompliance 
Report within 10 working days.   
 
 
 
Protocol exception 
Approval must be obtained prior to 
implementing the change 
 
 
 
Clinically important 
increase in the rate of 
a serious suspected 
adverse reaction of 
 
 
Report no later than 15 
calendar days after it is 
determined that the 
information qualifies 
for reporting 
If a vorolanib-related event requires 
expedited safety reporting to the FDA, 
then Xcovery will need a copy of the 
final 7 or 15-day MedWatch report via 

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Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Xcovery 
that list in the protocol 
or IB 
email to safety@xcovery.com. 
Submitno later than calendar day 4 for a 
7-day report and no later than calendar 
day 10 for a 15-day report. 
Complaints 
If the complaint reveals an unanticipated 
problem involving risks to participants or 
others OR noncompliance, report within 10 
working days.  If the event results in the 
death of a participant enrolled at 
WU/BJH/SLCH, report within 1 working 
day.  Otherwise, report at the time of 
continuing review. 
 
 
 
Breach of 
confidentiality 
Within 10 working days. 
 
 
 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not 
represent a safety issue and the patient will 
be withdrawn, report at continuing review. 
 
 
 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Xcovery 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be 
reported in the toxicity 
table in the DSM report 
which is typically due 
every 6 months. 
The most current 
toxicity table from the 
DSM report is provided 
to the FDA with the 
IND’s annual report. 
 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
 
 
 

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enrolled at WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at the time of 
continuing review. 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, 
report at continuing review. 
 
 
 
 
 
 

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APPENDIX D: PATIENT’S MEDICATION DIARY 
 
Today’s Date:    
 
 
 
 
Agent:  vorolanib 
Cycle:    
 
 
Patient Name:    
 
 
 
 
 
 
Study ID#:   
 
 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month.  Take _____mg ( ___tablets) of vorolanib daily at approximately the same 
time each day with food.  Take it with a glass of water and drink the glass of water in as little time as possible.  Do 
not chew. 
2. Record the date, the number of capsules taken, and when you took them. 
3. If you forget to take your vorolanib, the dose should be taken as soon as possible, but not more than 12 hours 
from the time you usually take your dose. If more than 12 hours has passed since the usual time you take your 
dose, then do not take a dose that day.  Restart taking it the next day.  
4. If you have any questions or notice any side effects, please record them in the comments section.  Record the 
time if you should vomit and do not retake the medicine until the next scheduled treatment. 
5. Please return the forms to your physician or your study coordinator when you go to your next appointment.  
Please bring your unused study medications and/or empty bottles with you to each study visit. 
 
Day 
Date 
What time was 
dose taken? 
# of tablets 
taken 
Comments 
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