Conditions: Cancer of Pancreas
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

Brief summary:
Determine the overall response rate (ORR) of bemcentinib plus chemotherapy (nab-paclitaxel/gemcitabine) in patients with metastatic pancreatic adenocarcinoma.

Detailed description:
Bemcentinib inhibits pancreatic cancer proliferation as monotherapy and in combination with gemcitabine through inhibition of the Axl pathway. The combination of nab-paclitaxel/gemcitabine has encouraging signs of clinical activity in patients with metastatic pancreatic cancer38. We would like to build on this combination in a biomarker driven phase 1b/2 clinical trial of bemcentinib in nab-paclitaxel/gemcitabine for patients with metastatic pancreatic cancer.

Arms:
arm 1: bemcentinib 200 mg oral daily every 21 days. Nab-paclitaxel 100 mg/m\^2 Day 1 /8 every 21 days. Gemcitabine 800 mg/m\^2 Day 1 /8 every 21 days. Cisplatin 25 mg/m\^2 Day 1 /8 every 21 days. arm 2: bemcentinib 200 mg oral daily every 28 days. Nab-paclitaxel 125 mg/m\^2 Day 1 /8 /15 every 28 days. Gemcitabine 1000 mg/m\^2 Day 1 /8 /15 every 28 days.

Interventions: intervention 1: Bemcentinib intervention 2: Nab-paclitaxel intervention 3: Gemcitabine intervention 4: Cisplatin
Intervention descriptions: intervention 1: 200mg orally starting Cycle 1 day 2 every 21 days or 28 days. intervention 2: 25 mg/m\^2 Day 1 /8 every 21 days or 28 days. intervention 3: Gemcitabine 1000 mg/m\^2 Day 1 /8 every 21 days or 28 days intervention 4: Cisplatin 25 mg/m\^2 Day 1 /8 every 21 days

Protocol document:
Prot_SAP_000.pdf: 
 
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CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016; 12/2018; 07/2020 
 
Title: A phase1b/2 Clinical Trial of Chemotherapy and the AXL-inhibitor 
Bemcentinib for Patients With Metastatic Pancreatic Cancer  
 Principal Investigator(s): Syed Kazmi, M.D.  
 
 Version 6: October 1, 2020  
NCT Number: NCT03649321  
 
 
 
 


 
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CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016; 12/2018; 07/2020 
 
PROTOCOL NUMBER SCCC-08218 
A phase1b/2 clinical trial of chemotherapy and the AXL-inhibitor bemcentinib for patients with metastatic 
pancreatic cancer 
 
Principal Investigator:  
Muhammad S. Beg, M.D. 
University of Texas Southwestern Medical Center 
Harold C. Simmons Cancer Center 
Division of Hematology-Oncology 
5323 Harry Hines Blvd., MC 8852 
Dallas, TX 75390-8852 
Phone 214-648-4180 
Fax 214-648-1955 
 
 
 
 
Muhammad.beg@utsouthwestern.edu 
 
 
 
 
 
Biostatistician: 
 
Chul Ahn PhD 
 
 
 
 
Professor of Biostatistics and Director 
 
 
 
 
Harold C. Simmons Cancer Center 
 
 
 
 
Biostatistics Core 
 
 
 
 
5323 Harry Hines Blvd 
 
 
 
 
Dallas, TX 75390-8551 
 
 
 
 
Phone 214-648-4017 
 
 
 
 
Chul.Ahn@utsouthwestern.edu 
 
 
 
 
 
Study Drug/Treatment: 
Bemcentinib 
 
 
 
 
Nab-paclitaxel (ABRAXANE®) 
 
 
 
 
Gemcitabine (GEMZAR®) 
 
 
 
 
Cisplatin (Phase 1b) 
 
IND/IDE Number: 
 
141513  
 
IND/IDE Holder Name:  
Muhammad S. Beg, M.D. 
 
Funding Source:  
BerGenBio  
 
NCT Number: 
NCT03649321 
 
Initial version: 
Version 1: Feb 2018  
 
Amended: 
Version 2: October 30, 2018 
 
Version 3: January 07, 2019 
 
Version 4: June 28, 2019 
 
Version 5: March 25, 2020 
 
 
Version 6: October 1, 2020  
 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Comprehensive Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 
 


 
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CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016; 12/2018; 07/2020 
 
 
Coordinating Site 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Comprehensive Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 
 
Data Safety and Monitoring Committee: 
 
UTSW SCCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-7084 or deliver to NB2.300 
 
Pharmacovigilance: 
Covance Clinical and Periapproval Services Ltd 
Osprey House 
Maidenhead Office Park 
Westacott Way 
Maidenhead 
BERKS 
SL6 3QH 
SAE Reporting: 
GlobalSAEInbox@covance.com 
IMP Provider 
BerGenBio ASA 
Jonas Lies vei 91 
5009 Bergen 
Norway 
 
Laboratory details and contact information are provided in the laboratory manual. 
 
 


 
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This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016; 12/2018; 07/2020 
 
 
Signature Page 
 
Title:  A phase1b/2 clinical trial of chemotherapy and the AXL-inhibitor bemcentinib for patients with 
metastatic pancreatic cancer 
PROTOCOL NUMBER: SCCC-08218 
 
Amendment/Version #6: October 1, 2020 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...........................................................................................1 
STUDY SCHEMA .............................................................................................................3 
 
STUDY SUMMARY ..........................................................................................................3 
1.0.......................................................................... BACKGROUND AND RATIONALE
..............................................................................................................................................6 
1.1 
Disease Background........................................................................................................ 6 
1.2 
Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities ................. 7 
1.3 
Other Agents .................................................................... Error! Bookmark not defined. 
1.4 
Rationale ........................................................................................................................ 15 
1.5 
Correlative Studies ........................................................................................................ 16 
2.0................................................................................................... STUDY OBJECTIVES
............................................................................................................................................16 
2.1 
Primary Objectives ......................................................................................................... 16 
2.2 
Secondary Objectives .................................................................................................... 16 
2.3 
Exploratory Objectives ................................................................................................... 16 
2.4 
Endpoints ....................................................................................................................... 16 
3.0.............................................................................................. PATIENT ELIGIBILITY
............................................................................................................................................18 
3.1 
Inclusion Criteria ............................................................................................................ 17 
3.2 
Exclusion Criteria ........................................................................................................... 18 
4.0..................................................................................................... TREATMENT PLAN
............................................................................................................................................20 
4.1 
Phase 1b Treatment Dosage and Administration .......................................................... 20 
4.2 
Phase 2 Treatment Dosage and Administration ............................................................ 20 
4.3 
Administration of bemcentinib ....................................................................................... 21 


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4.4 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 21 
4.5 
Concomitant Medications/Treatments ........................................................................... 28 
4.6 
Other Modalities and Procedures .................................................................................. 28 
4.7 
Duration of Therapy ....................................................................................................... 29 
4.8 
Duration of Follow Up .................................................................................................... 29 
4.9 
Removal of Subjects from Protocol Therapy ................................................................. 29 
4.10 
Subject Replacement..................................................................................................... 29 
5.0................................................................................................ STUDY PROCEDURES
............................................................................................................................................30 
5.1 
Screening/Baseline Procedures .................................................................................... 30 
5.2 
Procedures During Treatment ....................................................................................... 30 
5.3 
Follow-up Procedures .................................................................................................... 33 
5.4 
Time and Events Table .................................................................................................. 34 
5.5 
Removal of Subjects from Study ................................................................................... 35 
6.0................................................................................................... Measurement of Effect
............................................................................................................................................35 
6.1 
Antitumor Effect- Solid Tumors ...................................................................................... 35 
6.2 
Safety/Tolerability .......................................................................................................... 40 
7.0...................................................................................................... ADVERSE EVENTS
............................................................................................................................................40 
7.1 
Experimental Therapy.................................................................................................... 40 
7.2 
Adverse Event Monitoring ............................................................................................. 41 
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting ...................... 42 
7.4 
Stopping Rules .............................................................................................................. 45 
8.0..................................................................... DRUG/TREATMENT INFORMATION
............................................................................................................................................45 
8.1 
Agent/Treatment - Bemcentinib ..................................................................................... 45 


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9.0...................................................................... CORRELATIVES/SPECIAL STUDIES
............................................................................................................................................46 
9.1 
Sample Collection Guidelines ........................................................................................ 46 
9.2 
Assay Methodology ....................................................................................................... 47 
9.3 
Specimen Banking ......................................................................................................... 47 
10.0........................................................................ STATISTICAL CONSIDERATIONS
............................................................................................................................................47 
10.1 
Study Design/Study Endpoints ...................................................................................... 47 
10.2 
Sample Size and Accrual .............................................................................................. 48 
10.3 
Data Analyses Plans...................................................................................................... 49 
11.0............................................................................................ STUDY MANAGEMENT
............................................................................................................................................49 
11.1 
Conflict of Interest .......................................................................................................... 49 
11.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 49 
11.3 
Required Documentation ............................................................................................... 50 
11.4 
Registration Procedures ................................................................................................ 50 
11.5 
Data Management and Monitoring/Auditing .................................................................. 51 
11.6 
Adherence to the Protocol ............................................................................................. 51 
11.7 
Amendments to the Protocol ......................................................................................... 53 
11.8 
Record Retention ........................................................................................................... 53 
11.9 
Obligations of Investigators ........................................................................................... 53 
12.0.............................................................................................................. REFERENCES
............................................................................................................................................54 
13.0............................................................................................................... APPENDICES
............................................................................................................................................55 


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LIST OF ABBREVIATIONS (EXAMPLES) 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
Bid 
Twice a Day 
BP 
Blood Pressure 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
COI 
Conflict of Interest 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DOT 
Disease Oriented Team 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
EMT 
Epithelial to Mesenchymal Transition 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard Ratio 
HR 
Heart Rate 
HRPP 
Human Research Protections Program 
IB 
Investigator’s Brochure 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
KPS 
Karnofsky Performance Status 
LD 
Longest Diameter 
LDH 
Lactate Dehydrogenase 
MDS 
Myelodysplastic Syndrome 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NS 
Normal Saline 
NSCLC 
Non-Small Cell Lung Cancer 
NYHA 
New York Heart Association 


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OR 
Objective Response 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death Receptor 
PD-L1 
Programmed Death Ligand 1 
PDA 
Pancreatic Ductal Adenocarcinoma 
PDAC 
Pancreatic Ductal Adenocarcinoma Cancer 
PI 
Principal Investigator 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
QOL 
Quality of Life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
RR 
Respiratory Rate 
RTR 
Receptor Tyrosine Kinase 
SAE 
Serious Adverse Event 
SCCC 
Simmons Comprehensive Cancer Center 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGPT 
Serum Glutamic Pyruvic Transaminase 
SMC 
Safety Monitoring Committee 
TNBC 
Triple Negative Breast Cancer 
ULN 
Upper Limit of Normal 
UPIRSO 
Unanticipated Problems Involving Risks to Subjects or Others 
WBC 
White Blood Cells 
 
 
 
 
 


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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
Metastatic Pancreatic 
Cancer
-ECOG 0-1
-No prior treatment for 
metastatic disease
-Adequate hepatic, 
renal, and hematologic 
BGB324 + Chemotherapy 
BGB324 200 mg oral daily
Nab-Paclitaxel 125 mg/m2 Day 1/8 every 21 days 
Gemcitabine 1000 mg/m2 Day 1/8 every 21 days
Cisplatin 25 mg/m2 Day 1/8 every 21 days 
Metastatic Pancreatic 
Cancer
- ECOG 0-1
- No prior treatment for 
metastatic disease
-Adequate hepatic, 
renal, and hematologic 
BGB + Chemotherapy 
BGB324 200 mg oral daily
Nab-Paclitaxel 125 mg/m2 Day 1, 8, 15 every 28 
days
Gemcitabine 1000 mg/m2 Day 1, 8, 15 every 28 
days
 
Phase 1b (completed) 
Phase 2 


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STUDY SUMMARY 
Title 
A phase1b/2 clinical trial of chemotherapy and the AXL-inhibitor 
bemcentinib for patients with metastatic pancreatic cancer  
Short Title 
Clinical trial of chemotherapy and  bemcentinib for metastatic pancreatic 
cancer  
Protocol Number 
BGB324 
BerGenBio protocol 
number 
BGBIL010 
Phase 
Phase 1b/2 
Methodology 
Safety run-in followed by a phase 2 study  
Study Duration 
30 months  
Study Center(s) 
2 US sites  
Objectives 
Determine the overall response rate (ORR) of bemcentinib plus 
chemotherapy (nab-paclitaxel/gemcitabine) in patients with metastatic 
pancreatic adenocarcinoma. 
Number of Subjects 
3-44 
Phase 1b/2 Diagnosis and 
Main Inclusion Criteria 
1. Ability to understand and the willingness to sign a written informed 
consent. 
2. Patients must have a histologically or cytologically confirmed 
pancreatic adenocarcinoma that is metastatic or recurrent.  
3. No prior systemic therapy for metastatic disease.  
a. Prior adjuvant therapy, if completed more than 6 months prior 
to date of enrollment, is acceptable. 
b. Radiosensitizing chemotherapy, if completed at least 4 
weeks prior to date of enrollment, is acceptable.  
4. Measurable disease per RECIST 1.1 criteria. 
5. Age 18-70 years  
6. ECOG performance status 0 or 1 
7. Adequate hematologic, hepatic and renal function as defined in  
Table 2 
8. Adequate contraception as defined in protocol section 3.1. 
9. Have resolution of toxic effect(s) of the most recent prior chemotherapy 
to Grade 1 or less (except alopecia). If the patient received major 
surgery or radiation therapy of >30 Gy, they must have recovered from 
the toxicity and/or complications from the intervention. 
Phase 1b Study 
Product(s), Dose, Route, 
Regimen 
Bemcentinib orally starting Cycle 1 day 2 
nab-Paclitaxel intravenously, Day 1 and 8 every 21 days 
Gemcitabine intravenously, Day 1 and 8 every 21 days 
Cisplatin intravenously, Day 1 and 8 every 21 days 
Phase 2 Study Products, 
Route, Regimen 
Bemcentinib orally starting Cycle 1 day 2 
nab-Paclitaxel intravenously, Day 1, 8 and 15 every 28 days 
Gemcitabine intravenously, Day 1, 8 and 15 every 28 days 
Phase 1b/2 Duration of 
administration 
 
Until progression or intolerable side effects.   
 


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Statistical Methodology 
To establish safety of the proposed combination, 3 -12 patients will be 
recruited in Phase1b (safety run in) based on modified 3+3 dose 
escalation rules. (completed 9/2020) 
 
In Phase 2 of the study, 35 patients will be enrolled The proposed 
scheme is based on Simon's minimax two-stage design for a phase 2 trial 
using 10% type I error rate and 80% power. 
For comparisons of 23% (null hypothesis) vs. 40% (alternative 
hypothesis), 21 patients will be accrued in the first stage. 
If there are 4 or fewer responses out of 21 patients, the trial will be 
stopped early for futility.  
Otherwise, 14 additional patients will be accrued for a total of 35 
patients.  
The null hypothesis will be rejected if 12 or more responses are observed 
out of 35 patients. 
 
 
 
 


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background and 
Introduction 
There is a desperate need to develop 
agents 
that 
specifically 
and 
efficaciously 
treat 
patients 
with 
pancreatic ductal adenocarcinoma 
cancer (PDAC) that have extremely 
recalcitrant 
cancers, 
and 
5-year 
survival rates of 8%. Unfortunately, 
PDACs 
have 
an 
ever-increasing 
incidence and are expected to be the 
second leading cancer by 20201,2. 
Current therapies against PDAC lack 
rationale that exploit cancer-specific 
targets, 
are 
subject 
to 
inherent 
resistance 
mechanisms, and are 
ineffective against non-cycling cancer 
cells. Efficacious treatments for these 
cancers will require use of agents that 
cause 
tumor-specific 
cell 
death 
independent of p53 or oncogenic 
driver 
mutations, 
or 
apoptotic 
processes 
(e.g., 
caspase-
independent), since a majority of 
these cancers lack functional p53, 
have activated or mutant tumor driver 
mutations, and/or have defects in 
apoptotic pathways that confer growth 
advantages and drug resistance3,4.   
 
AXL along with TYRO3 and MER 
belong to the TAM family of receptor 
tyrosine kinases (RTKs)5. AXL is 
activated by Growth Arrest-Specific factor 6 (GAS6), binding of which results in AXL dimerization, 
autophosphorylation and subsequent activation of signaling pathways, such as the PI3K/AKT, 
Mitogen-Activated Protein Kinase (MAPK), STAT and NF-κB cascades 5. GAS6-induced AXL 
signaling promotes adhesion, migration, invasion, pro-inflammatory cytokine production, anti-
apoptosis, proliferation and survival of cancer cells6. AXL is expressed highly in multiple cancers 5, 
is linked to metastasis 7,8 poor survival 9,10, and drug resistance11.   
 
 
 
Figure 1. BGB324 inhibits Axl activity in pancreatic cancer cells in vitro. 


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The AXL pathway is relevant in 
pancreatic cancer as systemic 
AXL inhibition may enhance the 
efficacy 
of 
cancer 
therapy 
through multiple mechanisms. 
AXL is expressed highly in 70% 
of resected pancreatic tumors 
(n=54). AXL expressing tumors 
were associated with poorer 
recurrence 
free 
and 
overall 
survival12. 
Selective 
AXL 
pathway inhibition potently block 
metastasis in several preclinical 
models of pancreatic cancer. Our 
group recently demonstrated that 
pharmacologic inhibition of Gas6 
activity 
impaired 
pancreatic 
tumor growth and metastatic 
spread in an AXL-dependent 
manner 13. This is associated with 
a loss of mesenchymal protein 
expression, EMT transcription 
factor 
expression, 
decreased 
tumor proliferation and increased 
apoptosis13. 
 
Bemcentinib is a first in class, oral 
tyrosine kinase inhibitor of the 
AXL pathway. We investigated 
the anti-proliferative effect of AXL 
inhibition by bemcentinib in 6 
human and 3 mouse PDAC cell 
lines in vitro by MTS assay (Fig. 
1G). Bemcentinib inhibited cell 
proliferation in a dose-dependent 
manner with IC50 values ranging 
from 
1-4.0 
µM. 
Notably, 
bemcentinib reduced the in vitro IC50 value of gemcitabine 3-fold in all cell lines (Fig. 1H).  In 
contrast to the relatively modest sensitization of gemcitabine by bemcentinib in vitro, we observed 
a dramatic effect of this therapeutic combination on overall survival in vivo in mice bearing large 
advanced PDAC tumors. A genetically engineered mouse model of PDAC (KIC) that received 
saline had a median survival of 61.5 days, while treatment with bemcentinib or gemcitabine only 
modestly extended the median survival to 65 and 69 days, respectively (P value of 0.03 and <0.001 
vs. controls). However, combination therapy significantly improved survival to a median of 83.5 
days (P value < 0.0001 vs. control; P value < 0.05 vs. gemcitabine alone) (Fig. 2A).14 
AXL is also expressed by innate immune cells, including natural killer (NK) cells 15 and tumor-
associated macrophages 16, and has been implicated in immune suppression17. AXL pathway 
drives proliferation of myc activated pancreatic cancers in preclinical models. Additionally, inhibition 
of AXL results in antiproliferative activity and suppression of neutrophil infiltration. 
 
1.2 
Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
Bemcentinib is a small molecule, orally bioavailable, highly specific inhibitor of AXL kinase. AXL is 
a member of the Tyro3, Axl, Mer (TAM) family of receptor tyrosine kinases. AXL receptor 
overexpression has been detected in a wide range of solid tumours and myeloid leukaemias18,19. 
Figure 2. AXL inhibition in mice with advanced PDA 
improves survival.  
Figure 2. AXL inhibition in mice with advanced PDA 
improves survival.  


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AXL receptor expression correlates with malignant progression and is an independent predictor of 
poor patient overall survival in several malignancies including pancreatic20, prostate21, lung22,23, 
breast24, colon25  and AML26. 
 
Aberrant activation of AXL in tumour cells promotes tumourigenicity, invasiveness, survival and 
metastasis in a range of cancer types19 and is a recognised mechanism of acquired resistance to 
targeted therapeutics in vitro and in vivo23,27. Inhibition of AXL blocks tumor formation, metastasis 
and reverses drug resistance (e.g. erlotinib) in several experimental cancer models, including 
TNBC, hormone resistant prostate cancer and adenocarcinoma of the lung28,24,21,23. This key role 
for AXL signaling in malignancy is associated with the Epithelial to Mesenchymal Transition (EMT), 
a gene regulatory programme governing hundreds of genes, that engenders invasive and stem cell 
activities during development, wound healing and tissue homeostasis29,30. In tumours, EMT 
produces malignant features that drive drug resistance and metastasis31,24,27. Tumour EMT is 
activated by hypoxia, inflammatory cytokines and chemotherapy and is strongly associated with 
the development of drug resistance31,30. AXL is activated by EMT in tumour cells and AXL signaling 
is required to maintain EMT-associated metastatic, stem cell and drug resistance traits32,24,33,23,27. 
EMT in tumour cells is linked to immunosuppression via enhanced expression of the 
PD1/programmed death ligand 1 (PD-L1) axis34,35. The importance of AXL signaling in mediating 
this transformation is becoming increasingly understood. 
1.2.1 Summary of Pre-Clinical Activity 
Bemcentinib demonstrates potent inhibition of AXL in biochemical and cell-based 
kinase inhibition assays. The selectivity of bemcentinib for AXL is illustrated in 
Table 1. 
 
Table 1 Bemcentinib Kinase Selectivity Profile 
 
 
Kinase 
Kinome Scan 
binding assay 
(Kd) 
KinaseProfiler 
kinase activity 
assay 
(IC50) 
BaF3 cell-based 
kinase activity 
assay 
(IC50) 
nM 
fold 
nM 
fold 
nM 
fold 
Axl 
0.4 
1 
4.6 
1 
63 
1 
Tie2 
270 
680 
30 
6.4 
355 
5.5 
Ret 
73 
180 
38 
8.1 
>31
6 
>5 
Flt1 
400 
>10
00 
40 
8.7 
>10
00 
>15 
Flt4 
460 
>10
00 
41 
8.8 
>10
00 
>15 
Yes 
810 
>10
00 
43 
9.2 
n/a 
n/a 
 n/a = not applicable 
 
 Bemcentinib inhibits the growth and survival of tumor cell lines derived from a 
range of solid and leukemic tumors.  
 
A modest substrate and time-dependent inhibition of CYP3A4/5 activity by 
bemcentinib was observed in an in vitro study with human liver microsomes.  
A comprehensive summary of the pre-clinical activity of bemcentinib is presented 
in the current version of the Investigator’s Brochure (IB). 
 
 


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1.2.2 
Non-clinical toxicology of bemcentinib 
To support clinical studies with bemcentinib a series of animal toxicology and 
safety studies, including 28-day repeat dosing studies in rodents and monkeys and 
a single dose telemetered cardiovascular (CV) safety study in monkeys, have been 
conducted. Comparisons of the data reported in the rodent and monkey studies 
indicate that primates are more sensitive to bemcentinib on a per body weight 
basis. 
 
The results of the repeat dose 28-day study in monkeys identified the liver, 
reticuloendothelial system and hematopoietic system as target organs. These 
events were largely thought to be due to macrophage accumulation and were only 
partially reversible across the planned 16-day recovery period, although this was 
anticipated to be due to the slow elimination of the compound. Similar findings 
were identified in mice treated across a range of dose levels with partial recovery 
noted 16 days later. 
 
In the CV safety study, single oral administration of bemcentinib (7.5 mg/kg – 60 
mg/kg) was associated with recoverable, non-adverse decreases in heart rate and 
corresponding increases in the RR interval durations. Dose-dependent increase in 
QTc interval was noted at all dose levels; the magnitude of the QTc effect at the 
highest dose level was 17%, whilst at 7.5 mg/kg and 15 mg/kg, the change 
generally fell below 10% compared to vehicle control and pre-dose values. These 
observations were consistent with the previously identified IC50 for human ether-à-
go-go related gene (hERG) channel inhibition of 0.53 M bemcentinib. 
 
Bemcentinib was negative in the Ames bacterial mutation assay, suggesting that 
bemcentinib is not mutagenic. Bemcentinib was also negative in an in vitro 
mammalian cell cytogenetic study in human lymphocytes suggesting that 
bemcentinib is not clastogenic. 
 
1.2.3 
High Dose Steroids and Mouse Model 
In an academic model of osteoporosis, bemcentinib was administered in 
combination with high dose corticosteroids (12.5 mg/kg per day of prednisolone). 
In this research study, 6 out of 7 mice experienced severe toxicity after five 
continuous days of combination therapy.  Four out of 7 animals died and the other 
2 were euthanized for humane reasons. The exact mechanism of this effect is 
currently under investigation. The mice received very high levels of corticosteroids 
to induce rapid onset of osteoporosis – on a mg/kg basis, the corticosteroid dose 
was 20-fold higher than a typical high dose commonly used in clinical practice. 
Additionally, the dose of bemcentinib used in this model was 50mg/kg which is 6-
fold higher than the maximum exposure observed in human clinical studies. 
Following further investigational toxicology studies, it has been established that 
effects of steroids are not exacerbated by coadministration of bemcentinib.   
However, investigators are encouraged to follow their local guidelines for 
monitoring if a patient requires treatment with high dose steroids. 
 
1.2.4. 
Pharmacokinetics and Metabolism of bemcentinib 
Bemcentinib had moderate to high plasma clearance (33.7, 18.7 and 43.3 
mL/min/kg in rats, dogs and monkeys, respectively) i.e. plasma clearance 
approached hepatic blood flow in these species. Since bemcentinib is sequestered 
into blood cells, blood clearance will be lower than plasma clearance at least in 
monkeys (monkeys are currently the only species tested). However, bemcentinib 
was metabolically stable in vitro suggesting that liver metabolism was unlikely to 
contribute significantly to the elimination of bemcentinib in vivo. 


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There was an inhibitory effect of bemcentinib on cytochrome P450 (CYP) 3A4 IC50 
1 to 5 micromolar; therefore, there is at least a moderate risk of interactions with 
co-administered drugs that are CYP3A4 substrates. 
1.3 
Clinical Studies with bemcentinib 
Please refer to the current version of the bemcentinib Investigator’s Brochure for further details of 
the clinical studies with bemcentinib. 
 
At the cut off date of 30th July 2020, one Phase I (Study BGBC001) study has been completed in 
healthy volunteers and one Phase II study (Study BGBC007) evaluating bemcentinib in 
combination with pembrolizumab in patients with triple negative breast cancer (TNBC) has been 
terminated due to pre-defined futility. Four oncology clinical studies are currently active with 
BerGenBio as the sponsor, with a further 6 Investigator-led clinical studies enrolling patients with 
advanced cancers. Bemcentinib is being administered as monotherapy and with cytarabine and 
decitabine in Study BGBC003, with erlotinib in Study BGBC004, and with pembrolizumab in Study 
BGBC008. Two new studies have also been set up to investigate the use of bemcentinib in the 
treatment of hospitalized patients with COVID-19 (BGBCIL019 and BGBC020), with one patient 
enrolled to date in study BGBCIL019. 
 
In addition, seven investigator-led studies are ongoing: BGBIL005 in patients with advanced 
NSCLC using bemcentinib in combination with docetaxel, BGBIL006 conducted in patients with 
advanced non-resectable or metastatic melanoma using bemcentinib in combination with 
pembrolizumab or dabrafenib and trametinib, BGBIL009 in patients with AML or MDS using 
bemcentinib alone, BGBIL010 in patients with metastatic pancreatic cancer using bemcentinib in 
combination with nab-paclitaxel, gemcitabine and cisplatin, BGBIL013 in patients with recurrent 
glioblastoma, BGBIL011, the mesothelioma stratified therapy (MiST) study in patients with 
relapsed mesothelioma patients in combination with pembrolizumab and BGBIL019, in 
hospitalized patients with Covid-19. 
 
 
1.3.1. 
Safety Summary and reference safety information 
The reference safety information below is based on a data cut of active trials on 30 July 
2020 as presented in the IB V14.0 dated 14 October 2020. At the time of cut-off, 241 have 
been treated with bemcentinib in four BerGenBio sponsored clinical studies, enrolling 
patients with AML, MDS, NSCLC, TNBC,TNIBC and Covid-19 Please refer to the latest 
edition of the IB for the most up-to-date safety information during the conduct of this clinical 
study. 
 
In this IB update, acute kidney injury has been added as a new event for the expectedness 
assessment following treatment with bemcentinib in the Reference Safety Information 
(RSI). Although acute kidney injury has been added to the RSI on the basis of 2 reported 
SAEs, there are a number of factors in each clinical presentation that confound and make 
it unlikely that bemcentinib is associated with the development of acute kidney injury. In all 
ongoing clinical studies, there are a number of inclusion/exclusion criteria that ensure 
patients with renal impairment are not enrolled into clinical studies of bemcentinib. Patients 
enrolled in clinical studies are also monitored closely so early renal impairment can be 
detected, with these measures including measuring blood creatinine levels, as well as other 
renal function parameters, clinical chemistry, and urinalysis at each study visit. 
 
Most commonly reported TEAEs in company sponsored studies were diarrhea (49%), 
nausea (32%) and ECG QT prolongation and fatigue (both 27%).  In most cases these 
events responded well to symptomatic treatment and did not lead to treatment 
discontinuation or dose reduction. As expected the incidence of infections was higher in 


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the relapsed/refractory AML/MDS patient group whilst reversible increases in serum 
creatinine were more frequent in patients with NSCLC. 
 
At the data cut-off date of 30 July 2020, a total of 342 SAEs reports in 147 patients across 
the four BerGenBio sponsored clinical studies. SAEs in 73 patients being considered 
related to study treatment. In the Investigator-led studies, 128 SAEs were reported in 71 
patients. 
  
 
Study BGBC003 
At the data cut-off date, a total of 72 SAEs were reported in 30 out of 36 patients enrolled 
in Part A and 101 SAEs were reported in 46 out of 63 patients enrolled in Part B. 
Twenty-two SAEs in 15 patients in Part A and 33 SAEs in 23 patients in Part B were study 
treatment-related. The most commonly reported SAEs were febrile neutropenia, 
pneumonia, sepsis, pyrexia and anaemia.  
 
 
 
Study BGBC004 
At the data cut-off date, a total of nine patients out of 40 patients enrolled experienced 16 
SAEs: two events in one patient in the run-in phase, four events in three patients in Arm A 
(600 mg/200 mg monotherapy dose), three events in two patients in Arm B, and seven 
events in three patients in Arm C. Three patients experienced SAEs which were suspected 
to be related to bemcentinib: one patient in Arm A (one event of transient ischemic attack 
[Grade 2] and one event of a transient neurologic event [Grade 2]), one patient in Arm B 
(increased creatine phosphokinase [Grade 3]), and one patient in Arm C (diarrhea [Grade 
3]). None of the related SAEs led to discontinuation from the study. 
 
 
Study BGBC007 
At the data cut-off date, a total of 22 patients out of 29 patients enrolled experienced 63 
SAEs, with 34 SAEs in 15 patients assessed as related to treatment with bemcentinib. 
Nineteen SAEs led to dose interruption, four to dose reduction whilst 13 patients withdrew 
from treatment due to SAEs. Most commonly reported SAEs were pyrexia, dyspnea, liver 
toxicity/ elevated liver function tests (LFTs), pleural effusion, maculo-papular rash, and 
febrile neutropenia.  
 
 
Study BGBC008 
At the data cut-off date, a total of 39 patients out of 73 patients enrolled experienced 74 
SAEs. A total of 20 SAEs in 12 patients were assessed as related to treatment with 
bemcentinib and pembrolizumab and 23 SAEs in 15 patients were assessed as related to 
bemcentinib alone. Most commonly reported SAEs were pneumonia, AST increased, ALT 
increased, dyspnoea, autoimmune hepatitis, and pyrexia. 
 
1.3.2 
Rationale for bemcentinib dose 
Daily dosing with 200 mg bemcentinib has been performed in patients with NSCLC and 
relapsed/refractory AML. Serial specimens of myeloid blasts have been collected from 
patients with AML. In myeloid blasts samples collected from patients who have completed 
21-days of therapy exhibit reduced levels of phospho-Axl, phospho-Akt and phospho-ERK. 
All of these changes are consistent with inhibition of intracellular signaling pathways which 
are driven by signaling through Axl. Further evidence of Axl modulation in patients treated 
at this dose level is evident in the accompanying increase in soluble Axl which is closely 
related to the average concentration achieved. Increased levels of soluble Axl occurs 
downsteam of increased sheddase activity following inhibition of intracellular MAPK 
signalling. These observations suggest that a daily dose of 200 mg bemcentinib has 
significant impact on inhibiting Axl signalling in patients. 
 
1.3.3 
Rationale for chemotherapy selection 


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Molecular targeted therapies and immune checkpoint inhibitors have revolutionized the 
treatment of many other solid tumors, such as lung cancer, renal cell carcinoma and 
melanoma. Chemotherapy remains the standard of care for patients with metastatic 
pancreatic cancer.36,37 The combination of gemcitabine, nab-paclitaxel and cisplatin has 
been shown to have activity in pancreatic cancer in a single arm, pilot clinical trial of 25 
patients38. By RECIST 1.1 criteria, two patients had complete response (8.3%), 15 partial 
response (62.5%), 4 stable disease (16.7%), and 3 progressive disease (12.5%). Median 
time on therapy was 5.5 months, range (1 – 9.5). Most updated median OS was 16.5 
months.  
 
Treatment related grade 3 - 4 adverse events included thrombocytopenia 76% (gr 3 = 36%, 
gr 4 = 40%) with no serious bleeding events, anemia 32% (gr 3 = 32%, gr 4 = 0%), 
neutropenia 24% (gr 3 = 20%, gr 4 = 4%), infection 20% (gr 3 = 16%, gr 4 = 4%), and 
diarrhea 16% (gr 3 = 16%, gr 4 = 0%). Peripheral neuropathy ≥ gr 3 was seen in only 1 pt 
(gr 3 = 4%). Grade 5 AEs were infection (1), cardiac arrest (1), and stroke (1).  
 
Although this was a small study, the high response rates are encouraging and warrant 
further investigation in pancreatic cancer. Our preclinical data demonstrates synergy with 
gemcitabine and we would like to build on the triple chemotherapy combination in this 
clinical trial. Of note, additional clinical trials with this combination are underway for other 
cancers (cholangiocarcinoma NCT02392637). The adverse events from triple agent 
chemotherapy are summarized in the Figures 1 and 2. 
 
1.3.4 
Rationale for safety run in (Phase 1b)  
As highlighted previously, the combination 
of 
triple 
agent 
chemotherapy 
with 
gemcitabine, nab-paclitaxel and cisplatin 
led to unprecedented tumor response 
rates in a pilot clinical trial in pancreatic 
cancer patients38. Toxicity in the form of 
cytopenia was observed. In this clinical 
trial we propose to add the AXL pathway 
inhibitor 
bemcentinib 
with 
systemic 
chemotherapy. Bemcentinib is in clinical 
trials as monotherapy, in combination with 
checkpoint 
inhibitor 
pembrolizumab, 
chemotherapy (docetaxel) and the oral 
tyrosine kinase inhibitor erlotinib. The main 
toxicity observed with bemcentinib 
was 
gastrointestinal 
disturbance. 
There were no DLTs and all adverse 
events were grade 1, except for 
nausea and vomiting, which were 
grade 
2 
(See 
IB 
for 
details). 
Bemcentinib related cytopenias were 
not frequently observed. Given the 
non 
overlapping 
toxicities, 
we 
anticipate bemcentinib will combine 
with 
triple 
agent 
chemotherapy 
(gemcitabine/nab-paclitaxel/cisplatin) 
without significant additional toxicity. 
 
 
 
 
 
 


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Adverse events have been reviewed by the study Safety Monitoring Committee (SMC) and the 
SCCC DSMC before enrollment into phase 2 can commence. The SMC is comprised of a 
representative from each investigational site and a representative of the Sponsor study team. Once 
safety of combination treatment has been demonstrated, enrollment on the phase 2 2 portion, of 
the trial will begin. 
 
Treatment will begin at Dose level 1 (Section 4.0) and additional dose levels can be explored based 
on input from the SMC. 
 
The criteria used to determine if the study will advance to Phase 2 can be referenced in section 
10.1 of the protocol. 
1.4 
Other Agents 
1.4.1 
Nab-Paclitaxel 
NAB-PACLITAXEL for Injectable Suspension (also known as ABI-007, nab-
paclitaxel, paclitaxel protein-bound particles for injectable suspension) is an 
albumin-bound form of paclitaxel with a mean particle size of approximately 130 
nanometers. Paclitaxel exists in the particles in a non-crystalline, amorphous state. 
NAB-PACLITAXEL is supplied as a white to yellow, sterile, lyophilized powder for 
reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to 
intravenous infusion. Each single-use vial contains 100 mg of paclitaxel and 
approximately 900 mg of human albumin. Each milliliter (mL) of reconstituted 
suspension contains 5 mg paclitaxel. NAB-PACLITAXEL is free of solvents.   The 
active agent in NAB-PACLITAXEL is paclitaxel.  
 
 
 
Indication 
 
In the United States, NAB-PACLITAXEL for Injectable Suspension (paclitaxel 
protein-bound particles for injectable suspension) is indicated for the treatment of 
metastatic PDAC as first-line treatment, in combination with gemcitabine. 
 
 
 
Introduction 
NAB-PACLITAXEL is a biologically interactive albumin-bound paclitaxel combining 
a protein with a chemotherapeutic agent in the particle form. This composition 
provides a novel approach of increasing intra-tumoral concentrations of the drug 
by a receptor-mediated transport process allowing transcytosis across the 
endothelial cell. This albumin-specific receptor mediated process involves the 
binding of albumin to a specific receptor (gp60) on the intraluminal endothelial cell 
membrane, resulting in activation of a protein (caveolin-1), which initiates an 
internalization process in the endothelial cell through the formation of caveolae, 
with transport of the intact albumin-bound chemotherapeutic complex via these 
caveolae to the underlying tumor interstitium39.  Other postulated mechanisms of 
action for the combination of gemcitabine with nab-paclitaxel include 
downregulation of cytidine deaminase by paclitaxel resulting in higher/sustained 
concentrations of gemcitabine, macropinocytosis of proteins such as albumin by 
Ras-transformed cells which would allow for enhanced uptake of paclitaxel loaded 
albumin nanoparticles into pancreatic cancer tumor cells40,41. 
 
 
Preclinical Studies with NAB-PACLITAXEL  
Preclinical 
studies 
comparing 
NAB-PACLITAXEL 
to 
Taxol® 
(paclitaxel 
Cremophor® EL solvent-based, BMS) demonstrated lower toxicities, with an MTD 
approximately 50% higher for NAB-PACLITAXEL compared to Taxol.  At equal 
doses there was less myelosuppression and improved efficacy in a xenograft 
tumor model of human mammary adenocarcinoma.  At equitoxic doses of 
paclitaxel, NAB-PACLITAXEL treated groups showed more complete regressions, 
longer time to recurrence, longer doubling time, and prolonged survival. At equal 
dose, tumor paclitaxel area under the curve was 33% higher for NAB-


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PACLITAXEL versus solvent based paclitaxel, indicating more effective 
intratumoral accumulation of NAB-PACLITAXEL42.  
 
 Clinical Studies with NAB-PACLITAXEL 
A multicenter, multinational, randomized, open-label study was conducted in 861 
patients comparing NAB-PACLITAXEL plus gemcitabine versus gemcitabine 
monotherapy as first-line treatment of metastatic adenocarcinoma of the pancreas. 
Key eligibility criteria were Karnofsky Performance Status (KPS) ≥70, normal 
bilirubin level, transaminase levels ≤ 2.5 times the upper limit of normal (ULN) or ≤ 
5 times the ULN for patients with liver metastasis, no prior cytotoxic chemotherapy 
in the adjuvant setting or for metastatic disease, no ongoing active infection 
requiring systemic therapy, and no history of interstitial lung disease. Patients with 
rapid decline in KPS (≥10%) or serum albumin (≥20%) during the 14 day screening 
period prior to study randomization were ineligible. 
 
A 
total 
of 
861 
patients 
were 
randomized 
(1:1) 
to 
the 
NAB-
PACLITAXEL/gemcitabine arm (N=431) or to the gemcitabine arm (N=430). 
Randomization was stratified by geographic region (Australia, Western Europe, 
Eastern Europe, or North America), KPS (70 to 80 versus 90 to 100), and presence 
of 
liver 
metastasis 
(yes 
versus 
no). 
Patients 
randomized 
to 
NAB-
PACLITAXEL/gemcitabine received NAB-PACLITAXEL 125 mg/m2 as an 
intravenous infusion over 30-40 minutes followed by gemcitabine 1000 mg/m2as 
an intravenous infusion over 30-40 minutes on Days 1, 8, and 15 of each 28-day 
cycle. Patients randomized to gemcitabine received 1000 mg/m2 as an intravenous 
infusion over 30-40 minutes weekly for 7 weeks followed by a 1-week rest period 
in Cycle 1 then as 1000 mg/m2 on Days 1, 8 and 15 of each subsequent 28-day 
cycle. Patients in both arms received treatment until disease progression or 
unacceptable toxicity. The major efficacy outcome measure was overall survival 
(OS). Additional outcome measures were progression-free survival (PFS) and 
overall response rate (ORR), both assessed by independent, central, blinded 
radiological review using RECIST (version 1.0). 
 
In the intent to treat (all randomized) population, the median age was 63 years 
(range 27-88 years) with 42% ≥ 65 years of age; 58% were men; 93% were white 
and KPS was 90-100 in 60%. Disease characteristics included 46% of patients 
with 3 or more metastatic sites; 84% of patients had liver metastasis; and the 
location of the primary pancreatic lesion was in the head of pancreas (43%), body 
(31%), or tail (25%). 
 
The median overall survival of the NAB-PACLITAXEL/gemcitabine group was 8.5 
months compared to 6.7 months in the gemcitabine alone group (HR 0.72, 
p<0.0001). PFS was similarly improved in the combination arm (5.5 vs. 3.7 months, 
HR 0.69, p<0.0001). Overall response rate by central review was 23% with NAB-
PACLITAXEL/gemcitabine and 7% with gemcitabine alone (p<0.0001). 
 
 
Potential Risks of NAB-PACLITAXEL Toxicities  
The most common toxicities reported with NAB-PACLITAXEL when given with 
gemcitabine in the pancreatic cancer studies include myelosuppression 
(neutropenia: 73%, thrombocytopenia: 38%), fatigue (59%), peripheral edema 
(46%), pyrexia (41%), nausea (54%) vomiting (36%), diarrhea (44%), sensory 
neuropathy (54%), alopecia (50%), arthralgia (11%), myalgia (10%). During post 
marketing surveillance, rare cases of severe hypersensitivity reactions have 
occurred.  
 


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Further Information See Appendix 2 Nab paclitaxel (Nab-PaclitaxelTM) 
Prescribing Information (Updated 1/2012) – Accessed via Nab-Paclitaxel 
Website: http://www.Nab-Paclitaxel.com/docs/Nab-
Paclitaxel_PrescribingInformation.pdf 
 
1.4.2 
Gemcitabine 
The most common toxicities reported for gemcitabine include myelosuppression, 
transient elevations in serum transaminases (approximately 70%), nausea and 
vomiting (69%), fever (41%), rash (30%), diarrhea (19%), flu syndrome, (19%), 
infection (16%), alopecia (15%), edema (13%), stomatitis (11%),) neurotoxicity 
(mild 10%, severe <1%), mild proteinuria and hematuria; Hemolytic Uremia 
Syndrome (HUS) reported rarely (0.25%), dyspnea (0.2%) and serious pulmonary 
toxicity (0.06%). Also reported include constipation and pruritus. 
 
Gemcitabine (GemzarTM) Prescribing Information (Updated 09/2017) – 
Accessed via Gemzar Website: http://pi.lilly.com/us/gemzar.pdf 
 
1.4.3 Cisplatin – Phase 1b 
The most common toxicities of cisplatin include nephrotoxicity (28-36%; acute 
renal failure and chronic renal insufficiency), peripheral neuropathy (dose and 
duration dependent), nausea and vomiting (76% to 100%), myelosuppression 
(25% to 30%; nadir: day 18-23; recovery: by day 39; mild with moderate doses, 
mild-to-moderate with high-dose therapy), liver enzymes increased (especially 
SGOT and bilirubin), ototoxicity (10% to 30%; manifested as high frequency 
hearing loss; ototoxicity is especially pronounced in children), tissue irritation 
(extravasation). 
 
Other toxicities (<1%) include alopecia (mild), anaphylactic reaction, arrhythmias, 
arterial vasospasm (acute), blurred vision, bradycardia, diarrhea, heart block, 
heart failure, hemolytic anemia (acute), hemolytic uremic syndrome, 
hypercholesterolemia, hypocalcemia, hypokalemia, hypomagnesemia, 
hyponatremia, hypophosphatemia, limb ischemia (acute), mesenteric ischemia 
(acute), myocardial infarction, myocardial ischemia, mouth sores, neutropenic 
typhlitis, optic neuritis, orthostatic hypotension, pancreatitis, papilledema, 
phlebitis, reversible posterior leukoencephalopathy syndrome (RPLS), SIADH, 
stroke, thrombophlebitis, thrombotic thrombocytopenic purpura. 
 
Cisplatin Prescribing Information (updated 2012) – Accessed via Daily Med 
(National Library of Medicine) 
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a440f077-46f6-4688-
a209- 65bce38d1c92 
 
1.5 
Rationale for clinical trial 
Bemcentinib inhibits pancreatic cancer proliferation as monotherapy and in combination 
with gemcitabine through inhibition of the AXL pathway. The combination of nab-
paclitaxel/gemcitabine has encouraging signs of clinical activity in patients with metastatic 
PDAC38. We would like to build on this combination in a biomarker driven phase 1b/2 
clinical trial of bemcentinib plus chemotherapy for patients with metastatic PDAC.  
 
The chemotherapy regimen for phase 2 will be gemcitabine and nab-paclitaxel combined 
with bemcentinib. The trial design has been modified from a randomized study of 
gemcitabine/nab-paclitaxel/cisplatin +/- bemcentinib to a single arm study of 
gemcitabine/nab-paclitaxel + bemcentinib. This decision was made after discussion with 
the study investigators and industry collaborator based on the observed clinical activity 
and tolerance of gemcitabine/nab-paclitaxel/cisplatin with bemcentinib in phase 1b. The 


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modified, single arm phase 2, design will allow the investigators to assess the addition of 
bemcentinib to standard of care chemotherapy based on historical control of 
chemotherapy alone. Single arm phase 2 trials with a response rate end point will allow a 
preliminary measure of activity which can then be confirmed in a future confirmatory 
randomized trial. Therefore, the treatment in Phase 2 of the trial will involve nab-
paclitaxel/gemcitabine/bemcentinib. 
 
Rationale for Phase 2: 
Phase 2 of the trial will allow further assessment of clinical activity and tolerance of therapy 
1.6 
Correlative Studies 
Tissue and blood biomarker assays are proposed with the goal to assess the effect of 
chemotherapy and bemcentinib on 1) AXL pathway activity in tumor tissue, 2) changes in 
immune landscape including upregulation of immune cytokines, and immune cell infiltration 
into the tumor, 3) apoptosis and decreased proliferation of tumor, and 4) to identify 
predictive biomarkers of response.  
Investigators will follow methods previously described13,14. 
Baseline and on treatment blood and tissue collection will be obtained as described in 
section 5. 
 
Details on sample collection are summarized in the laboratory manual.  
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 
Determine the clinical activity as defined by overall response rate (ORR) of 
bemcentinib plus chemotherapy (nab-paclitaxel/gemcitabine) in patients with 
metastatic pancreatic adenocarcinoma. 
2.2 
Secondary Objectives 
2.2.1 
Determine clinical activity of bemcentinib plus chemotherapy as defined by 
complete response rate (CRR), partial response, stable disease, duration of 
response – overall response/stable disease, median progression free survival 
(PFS), 1-year and 2-year overall survival (OS) rate. 
 
 
 
2.2.2 
Determine clinical benefit rate as defined by CR, PR, and SD response rates.  
 
 
2.2.3 
Assess safety and tolerability of bemcentinib plus chemotherapy in patients with 
metastatic pancreatic adenocarcinoma. 
2.3 
Exploratory Objectives 
2.3.1 
Compare the effect of treatment, with chemotherapy alone vs chemotherapy + Axl 
inhibitor bemcentinib on changes in tissue and blood biomarkers. 
 
2.3.2 
Correlate changes in tissue and blood biomarkers with clinical outcomes (ORR). 
2.4 
Endpoints 
 
Primary End point:  
 
 
Overall response rate (ORR)  
 
2.4.1 
Complete response rate (CRR), partial response, stable disease, duration of 
response - overall response/stable disease 
2.4.2 
Clinical benefit response – percent of CR, PR, and SD 


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2.4.3 
Median PFS, 1 year and 2 year overall survival (OS) rate 
2.4.4 
Safety and tolerability of the combination 
2.4.5 
Correlate changes in circulating and tissue biomarkers with clinical outcome 
(ORR) 
 
3.0 
SUBJECT ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all inclusion and no exclusion criteria to 
be registered into the study. Study treatment may not begin until a subject is registered.  
3.1 
Inclusion Criteria 
1. Ability to understand and the willingness to sign a written informed consent. 
2. Patients must have histologically or cytologically confirmed recurrent or metastatic 
pancreatic adenocarcinoma.  
3. No prior systemic therapy for metastatic or recurrent disease.  
-Prior adjuvant therapy, if completed more than 6 months prior to date of 
enrollment, is acceptable.  
-Radiosensitizing chemotherapy, if completed at least 4 weeks from date of 
enrollment, is acceptable.  
4.  
Measurable disease per RECIST1.1 criteria 
5.  
Age 18-70 years at the time of enrollment 
6.  
ECOG performance status 0 or 1  
7.  
Have resolution of toxic effect(s) or intervention complication to Grade 1 or less 
(except alopecia) from any prior chemotherapy, major surgery, or radiation therapy 
of >30 Gy. 
8.  
Adequate hematologic, hepatic, and renal function as defined per Table 2. All 
screening labs should be performed within 14 days of date of enrollment.  
 
Table 2 
 
 
Hemoglobin 
≥ 10 g/dL 
ANC 
≥ 1,500/µL 
Platelets 
≥ 100,000/µL 
Total bilirubin 
< 1.5 x institutional ULN 
AST (SGOT) & 
ALT(SGPT) 
≤ 2.5 x institutional ULN in patients without known liver metastasis; ≤ 5 x 
institutional ULN in patients with known liver metastasis 
Serum creatinine 
≤ 1.5 times ULN, and calculated creatinine clearance ≥ 60 mL/min using the 
Cockcroft-Gault equation) 
INR or PT 
International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 times 
the ULN  
Albumin 
≥  3.0 g/dL 
 
9.  
Female patients of childbearing potential must have a negative pregnancy test (either 
urine or serum pregnancy test). If the urine pregnancy test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required. A female of child-
bearing potential is any woman (regardless of sexual orientation, having undergone 
a tubal ligation, or remaining celibate by choice) who meets the following criteria: 
• 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
• 
Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 
consecutive months). 
 
10.  Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry, for the 


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duration of study participation, and for 120 days following completion of therapy. 
Should a woman become pregnant or suspect she is pregnant while participating in 
this study, she should inform her treating physician, or study team member, 
immediately. 
 
3.2 
Exclusion Criteria 
 
1. 
Is currently participating and receiving study therapy in a first line setting for metastatic 
or recurrent pancreatic adenocarcinoma. 
2. 
Participated in a study of an investigational agent or used an investigational device 
within 4 weeks of the first dose of study treatment.  
3. 
Patients with known untreated brain metastases. Patients without known or suspected 
brain metastases do not require radiologic imaging prior to enrollment.  
4. 
Has a known additional malignancy that is progressing or requires active treatment. 
Note: Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma 
of the skin that has undergone potentially curative therapy or in situ cervical cancer. 
5. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, significant pulmonary disease (shortness of breath at rest or mild exertion), 
or uncontrolled infection or psychiatric illness/social situations that would limit 
compliance with study requirements. 
6. 
History of the following cardiac conditions: 
7. 
Congestive cardiac failure of >Grade II severity according to the NYHA (defined as 
symptomatic at less than ordinary levels of activity); 
8. 
Ischemic cardiac event including myocardial infarction within 3 months prior to date 
of enrollment  
9. 
Uncontrolled cardiac disease, including unstable angina pectoris, uncontrolled 
hypertension (i.e. sustained systolic BP >160 mmHg or diastolic BP >90 mmHg), 
cardiac arrhythmia, or need to change medication due to lack of disease control within 
6 weeks prior to date of enrollment; 
10. History or presence of sustained bradycardia (≤55 BPM), left bundle branch block, 
cardiac pacemaker or ventricular arrhythmia. Note: Patients with a supraventricular 
arrhythmia requiring medical treatment, but with a normal ventricular rate are eligible; 
11. Known family history or personal history of long QTc syndrome or previous drug-
induced QTc prolongation of at least Grade 3 (QTc >500 ms). 
12. Abnormal left ventricular ejection fraction (LVEF) on ECHO or MUGA less than  <45%. 
13. Current treatment with any agent known to cause Torsades de Pointes which cannot 
be discontinued at least five half-lives or two weeks prior to the first dose of study 
treatment. 
14. Screening 12-lead ECG, in triplicate, with a measurable QTc interval according to 
Fridericia’s correction >450 ms. 
15. Known active infection with human immunodeficiency virus (HIV), hepatitis B or C 
viruses (screening not required, follow institutional practice):  
16. Patients who have a history of hepatitis B infection are eligible provided they are 
hepatitis B surface antigen negative.  
17. Patients who have a history of hepatitis C infection are eligible provided they have no 
evidence of hepatitis C ribonucleic acid using a quantitative polymerase chain 
reaction assay at least 6 months after completing treatment for hepatitis C infection. 
18. Active, clinically significant serious infection requiring treatment with antibiotics, anti-
virals or anti-fungals. 
19. Treatment with any medication which is predominantly metabolized by CYP3A4 and 
has a narrow therapeutic index 
20. Major surgery within 4 weeks prior to date of enrollment; excluding skin biopsies and 
procedures for insertion of central venous access devices. 
21. Inability to tolerate oral medication 


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22. Existing gastrointestinal disease affecting drug absorption such as celiac disease or 
Crohn’s disease, or previous bowel resection which is considered to be clinically 
significant or could interfere with absorption. 
23. Known lactose intolerance 
24. Is pregnant or breastfeeding 
25. Any significant medical condition lab abnormality, or psychiatric illness, in the opinion 
of the investigator, that might interfere with the patient's participation in the study or 
in the evaluation of the study results. 
26. Unwillingness or inability to comply with study procedures. 
 
4.0 
TREATMENT PLAN 
4.1 
Phase 1b Treatment Dosage and Administration 
REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Starting 
Dose 
 
Route 
 
Schedule 
Cycle Length 
bemcentinib 
Do not eat for at least two hours 
before and one hour following 
bemcentinib dose.  Take at same 
time each day. 
200 mg 
orally 
Daily starting on 
Cycle 1 day 2 
3 weeks (21 days) 
 
nab-
paclitaxel 
Infusion time – 30 min (+/- 5 min) 
100 
mg/m2 
intravenously 
Day 1 and 8 
gemcitabine 
Infusion time – 30 min (+/- 5 min) 
800 
mg/m2 
intravenously 
Day 1 and 8 
cisplatin 
Infusion time – 60 min (+/- 5 min) 
25 mg/m2 
intravenously 
Day 1 and 8 
 
4.2 
Phase 2 Treatment Dosage and Administration 
REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Starting Dose 
 
Route 
 
Schedule 
Cycle 
Length  
bemcentinib 
Do not eat for at least two hours 
before and one hour following 
bemcentinib dose.  Take at same 
time each day. 
200 mg  
orally 
Daily starting on 
Cycle 1 day 2 
4 weeks (28 
days) 
 
nab-paclitaxel 
Infusion time – 30 min (+/- 5 min) 
125 mg/m2 
intravenously 
Day 1, 8, and 15 
gemcitabine 
Infusion time – 30 min (+/- 5 min) 
1000 mg/m2 
intravenously  
Day 1, 8, and 15 
 
The study drugs will be stored according to package inserts.  
Drugs will be administered in the following order with the specified pre-medications and hydration:  
 
Pre-medication: 
*Phase 1b only* Pre cisplatin hydration: 0.9% Sodium Chloride Injection 1000 mL with Mannitol 
18.5 grams and Magnesium Sulfate 2 grams IV infusion over 2 hours on days 1 and 8 repeated 
every 21 days. 
 
*Phase 2* Aloxi (palonosetron) 0.25 mg IV, Emend (fosaprepitant) 150 mg IV and 
dexamethasone 12 mg IV within 30 minutes prior to treatment on days 1, 8, 15 repeated every 28 
days. Patients will continue oral antiemetic prophylaxis at home with dexamethasone 4 mg bid for 
2 days after chemotherapy.  
 


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Phase 1b - Chemotherapy administration: 
Nab-paclitaxel 100 mg/m2 in NS dilute to a total concentration of 5 mg/mL (DO NOT FILTER) 
over 30 minute IV infusion on days 1 and 8 repeated every 21 days, followed by:  
Cisplatin 25mg/m2 in 500 mL of NS over 60 minute IV infusion on days 1 and 8 repeated every 21 
days, followed by:  
Gemcitabine 800 mg/m2 in 500ml over 30 minute IV infusion on days 1 and 8 repeated every 21 
days  
 
Phase 2 – Chemotherapy Administration: 
Nab-paclitaxel 125mg/m2 in NS dilute to a total concentration of 5 mg/mL (DO NOT FILTER) over 
30 minute IV infusion on days 1, 8, 15 repeated every 28 days, followed by:  
Gemcitabine 1000 mg/m2 in 500ml over 30 minute IV infusion on days 1, 8, 15 repeated every 28 
days  
 
Post-hydration 
*Phase 1b only* Post-cisplatin hydration: 0.9% Sodium Chloride Injection 1000 mL IV infusion 
over 3 hours on days 1 and 8 repeated every 21 days. May start at the same time as the 
gemcitabine infusion. 
 
(Premedication and drug concentration may be changed to match institutional standard of 
care)  
4.3 Administration of bemcentinib 
• 
Bemcentinib is provided in bottles containing a specified number of capsules per bottle to 
dispense to patients. Patients will be asked to take the specified number of capsules for their 
prescribed dose on an empty stomach at a similar time each morning when they wake or more 
than 2 hours after a light meal, with water. To maintain a fasted state, patients should be told 
not to eat or drink anything other than water for at least 1 hour after taking the drug.   
 
• 
At all clinic visits, patients will be asked not to take their bemcentinib dose before coming into 
the clinic. All samples will be collected pre-dose (for both chemotherapy and bemcentinib) 
prior to bemcentinib and chemotherapy administration.  
 
4.4 Toxicities and Dosing Delays/Dose Modifications 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each patient 
will be assessed for the development of toxicity according to the Time and Events table (Section 
5.5).  
Dose adjustments should be made according to the system showing the greatest degree of 
toxicity.  
 
Toxicity will be graded according to the NCI CTCAE, Version 5 (which is available at:  
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_8.5x11.pdf). For any event which is apparent at baseline, the dose modification will 
apply according to the corresponding shift in toxicity grade if the investigator feels this is 
appropriate, (e.g. if a patient has grade 1 asthenia at baseline which increases to grade 2 
during treatment, this will be considered as a shift of 1 grade and treated as a grade 1 toxicity 
for dose modification purposes).   
 
A cycle of therapy may be delayed up to 21 days to allow for weather events, patient’s personal 
emergencies, observation of holidays, or other unforeseen delays that the Investigator deems 
to be in the best interest of the patient. 
 
For any dose interruptions, re-initiation of therapy may be delayed for a maximum of 21 days 
to allow recovery from any toxicity. In exceptional cases where subjects are responding or 


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receiving clinical benefit, re-initiation of therapy after missing > 21 consecutive days of 
treatment may be done on a case-by-case basis after confirmation with the Principal 
Investigator and/or Medical Monitor 
 
Treatment related toxicities will be attributed by investigators as:  
1) Bemcentinib related,  
2) Chemotherapy related or 
3) Related to combination of bemcentinib+chemotherapy.    
 
Dose modifications and treatment delays based on observed drug-related toxicity will be 
performed as described below. 
 
 
 
4.4.1 
Bemcentinib Dose modifications 
If a patient experiences toxicity deemed related to bemcentinib, as defined by 
probably or definitely related, please follow guidance in Table 3. Tolerability is 
determined by the PI/ treating Sub-Investigator.  
 
 
Table 2: Dose modification of bemcentinib for toxicity 
 
If after a 21 day delay, bemcentinib-related toxicity has not resolved to Grade ≤ I the patient 
should be withdrawn from the study, unless the request is made due to rationale mentioned in 
section 4.3.  Once a patient has undergone a dose reduction subsequent escalation is not 
possible. 
 
In order to reduce the risk of QTc prolongation, all efforts should be made to maintain the patient’s 
serum potassium levels at > 4 mmol/L during treatment with bemcentinib and for 2 weeks following 
Grade (CTCAE) 
Recommended Dose Modification 
Grade 1  
Any occurrence 
Maintain dose at 200mg (no modification) 
Grade 2 
Any occurrence 
Interrupt treatment until toxicity returns to baseline or 
Grade 1, then resume bemcentinib at 200mg daily. If the 
patient develops the same toxicity at Grade 2, please 
discuss with medical monitor 
Grade 3 
Any occurrence 
Interrupt treatment until toxicity returns to baseline or 
Grade 1 
Resume bemcentinib at 100 mg daily on Day 1 of 
subsequent cycle, then titrate up to 200 mg daily . If 200 
mg daily dose is not tolerated, reduce the dose to 100 mg 
daily. If the patient develops the same toxicity at Grade 3, 
please discuss with medical monitor /PI 
Grade 4  
1st occurrence 
Discontinue permanently or discuss with medical 
monitor/PI 
Notes: 
• Dose reduction below 100 mg daily is not possible (a single capsule contains 100 mg 
bemcentinib) 
• Patients being considered for dose reduction or permanent discontinuation of bemcentinib may 
be discussed with the Medical Monitor/PI 
• Patients are eligible for a 12 week dose delay with bemcentinib. For delays longer than 12 
weeks, Medical Monitor/ PI approval is needed 


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completion of therapy. Patients with a QTc of ≥ 480 ms should be closely monitored on the clinical 
trial unit until their QTc falls below 480 ms and their electrolytes should be measured and corrected 
as necessary.  
 
If a patient experiences QTc prolongation despite normal serum potassium and magnesium levels, 
bemcentinib dosing should be modified as outlined in Table 4. If a patient experiences ventricular 
arrhythmia at any time they should be withdrawn from the study. 
 
 
Table 4: Dose Modification of bemcentinib for QTc Prolongation 
 
QTcF 
Recommended bemcentinib Dose Modification 
Grade 1 (451-480 ms) 
Any occurrence 
No dose modification required 
Grade 2 (481-500 ms)  
1st occurrence and 2nd 
occurrence 
  
Continue dosing and conduct weekly ECGs; 
i)    if QTcF reduces to ≤Grade 1 by 14 days from initial recording, no dose 
modification is required 
ii)   if QTcF does not reduce to ≤Grade 1 by 14 days from initial recording, 
dose reduce to 100 mg daily and titrate it to 200mg if possible 
3rd and subsequent 
occurrence  
At 3rd occurrence, interrupt bemcentinib dosing for ≤ 14 days and conduct 
weekly ECGs; 
 i) if QTcF reduces to ≤Grade 1 within 14 days, restart bemcentinib at 100 
mg dose and maintain at 100 mg for the remainder of the study 
ii) if QTcF does not reduce to ≤Grade 1 within 14 days, discontinue 
treatment permanently or discuss with medical monitor.  At any subsequent 
occurrence, discontinue treatment permanently or discuss with medical 
monitor. 
 
≥Grade 3 (>501 ms)  
Any occurrence 
For 1st occurrence, interrupt treatment for ≤14 days; 
- if QTcF reduces to ≤Grade 1, reduce dose by 100 mg daily, 
discontinue treatment if dose reduction is not possible or discuss with 
medical monitor 
- if QTcF does not reduce to ≤Grade 1, discontinue treatment or 
discuss with medical monitor 
For 2nd occurrence, discontinue treatment or discuss with medical 
monitor 
Ventricular arrhythmia 
 
Any occurrence 
Discontinue permanently 
Notes: 
• Serum calcium, magnesium and potassium should be measured per schedule of events while as defined in 
study procedure whilst receiving bemcentinib;  
• Treatment interruption for bemcentinib-related QTcF prolongation is only allowed for 14 days 
• Dose reduction below 100 mg daily is not possible (a single capsule contains 100 mg bemcentinib) 
• Patients being considered for dose reduction or permanent discontinuation of bemcentinib may be discussed 
with the Medical Monitor 
 
4.4.2 Chemotherapy dose modifications 
Any toxicity associated or possibly associated with gemcitabine and Nab-Paclitaxel 
treatment may be managed according to standard medical practice. 
 


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• 
A maximum of 21 day treatment delay, from date of intended dose, is permitted to allow 
recovery of toxicities.  
• 
In the event that patients must have treatment delayed within a cycle, those doses held 
during a cycle will be skipped and not made up – treatment schedule will not be altered 
from Q4W design due to skipped dose. 
• 
If chemotherapy is on hold due to treatment related toxicity the treating investigator will 
determine whether to concurrently hold or continue bemcentinib.  
• 
Dose modifications/delay/cessation of individual drugs (bemcentinib, gemcitabine, Nab-
Paclitaxel, or cisplatin) can be done based on the specific toxicity.  
• 
Once a dose of any study drug has been reduced, it should not be increased at a later 
time.   
• 
Growth factors may be used to treat hematologic toxicity, per institutional standard, and 
will not constitute a dose reduction.  
 
Table 5: Phase 1b Dose Levels 
 
Dose Level 
Nab-Paclitaxel (mg/m2) 
Cisplatin 
(mg/m2) 
Gemcitabine 
(mg/m2) 
Bemcentinib 
Baseline 
100 
25 
800 
200 mg 
- 
1 
75 
25 
600 
200 mg 
- 
2 
50 
25 
600 
100 mg 
 
Table 6: Phase 2 Dose Levels 
 
Dose Level 
Nab-Paclitaxel (mg/m2) 
Gemcitabine 
(mg/m2) 
Bemcentinib 
1 - Baseline 
125 D1, 8, 15 
1000 D1, 8, 15 
200 mg 
- 
1 
125 D1, 15 
1000 D1, 15 
200 mg 
- 
2 
100 D1, 15 
800 D1, 15 
200 mg 
- 
3 
75 D1, 15 
600 D1, 15 
100 mg  
 
Hematologic Toxicity 
In the event dose modifications are required at the beginning of a cycle or within a cycle due to 
hematologic toxicities, doses of nab-paclitaxel and gemcitabine may be adjusted as detailed 
below.  
 
Table 7: Dose Modifications for Day 1 of Each Cycle (Hematologic Toxicity) 
 
ANC 
 
Platelets 
Timing 
≥ 1,500 cells/mm3 
AND 
≥ 100,000/uL 
Treat on time 
< 1,500 cells/mm3 
OR 
< 100,000/uL 
Delay by 1 week intervals until recovery 
 
 
 
Table 8: Phase 1b/2 Dose Modifications for Day 8, 15 of Each Cycle (Hematologic Toxicity)* 
 


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Day 8 Laboratory 
Results 
Nab-Paclitaxel 
Cisplatin 
(Phase 1b only) 
Gemcitabine 
ANC > 1000 and 
Platelets ≥ 100,000 
100% 
100% 
100% 
ANC 500-1000a or 
Platelets 50,000-
99,000 
Decrease dose by 1 level 
(treat on time) 
100% 
Decrease dose by 1 
level (treat on time) 
ANC < 500 or 
Platelets < 50,000 
HOLD 
HOLD 
HOLD 
Febrile Neutropenia 
(Grade 3 or 4)b 
HOLD. Upon resuming 
dosing, decrease to next 
lower dose level and do not 
re-escalate throughout the 
rest of treatment. 
HOLD 
HOLD. Upon resuming 
dosing, decrease to 
next lower dose level 
and do not re-escalate 
throughout the rest of 
treatment. 
Recurrent 
Febrile Neutropenia 
(Grade 3 or 4) 
Decrease 2 dose levels from 
prior and do not re-escalate 
throughout the rest of 
treatment. 
HOLD 
Decrease 2 dose levels 
from prior  and do not 
re-escalate throughout 
the rest of treatment. 
*  See Table 4 for dose reductions guidelines. 
a  If patients do not experience resolution of neutropenia within 21 days, despite 
optimal G-CSF treatment, study treatment will be discontinued.  
b  Febrile neutropenic patients should have their chemotherapy treatment interrupted and the following 
work up and treatment is recommended:  A full sepsis diagnostic work-up should be performed while 
continuing broad spectrum antibiotics. If cultures are positive, the antibiotic may or may not be changed, 
depending on the sensitivity profile of the isolated organism. Patients with persisting fever after 3 weeks, 
despite uninterrupted antibiotic treatment, will discontinue study treatment. Patients can also receive G-
CSF, in addition to antibiotic treatment, to hasten the resolution of their febrile neutropenia (following 
current institutional guidelines). In all cases, blood counts must have returned to non-neutropenic levels 
before resuming chemotherapy treatment. 
 
Special Instructions Regarding Treatment of Chemotherapy-related Toxicity 
Dose modification or delay may occur in the setting of lower Grade toxicity if the treating physician believes 
that it is in the interest of a subject’s safety.  Alopecia and nausea and/or vomiting that can be controlled by 
antiemetics do not require dose modification or interruption.  No dose reduction or interruption will be 
required for anemia as it can be satisfactorily managed by transfusions. Suggested guidance for dose 
reductions for non-hematologic toxicity are listed below. Nab-Paclitaxel and Gemcitabine and specific 
exceptions are listed separately below Tables 8 and 9. 
 
Table 9: Guidance for Phase 1b/2 Dose Modifications on Day 1 of Each Cycle (Non-Hematologic 
Toxicity)* 
 
Toxicity 
Nab-Paclitaxel /Gemcitabine dose this cycle 
Grade 0-2 toxicity 
Same as Day 1 previous cycle (except for Grade 2 cutaneous toxicity where 
doses of nab-paclitaxel/gemcitabine can be reduced to next lower dose level – 
see below) 
Grade 3 toxicitya,c 
Decrease nab-paclitaxel/gemcitabine to next lower dose levela 
Grade 4 toxicityb 
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Dose held in 2 previous 
consecutive cycles 
Decrease nab-paclitaxel/gemcitabine to next lower dose level and continue 
throughout the rest of treatment 
*  
Except peripheral neuropathy and nephrotoxicity (see section 4.3.2.4) 
a  If the toxicity only affects neuropathy, then only nab-paclitaxel should be reduced (see below). 
b  Pulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or asymptomatic, will be exempt 
from this requirement (see below).  
c 
Excluding > Grade 3 electrolyte abnormality that lasts <24 hours to 72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical interventions.  
 
 
Table 10: Guidance for Phase 1b/2 Dose Modifications on Day 8 & 15 of Each Cycle (Non-
Hematologic Toxicity) 
 
CTC Grade 
% of Day 1 Nab-Paclitaxel/Gemcitabine Dose 
0-2 
100%a 
3+ 
Hold treatment until resolution to ≤ Grade 1b,c 
a 
Except for cutaneous toxicity (see below).  
b  Pulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or asymptomatic, will be exempt 
from this requirement. 
c  Excluding electrolyte abnormalities per judgment of the physician/investigator.  
 
4.4.2.1 G-CSF Administration 
The exact dosage amount and schedule for G-CSF support will be left to the treating 
physician’s discretion.  A recommended approach would be to administer G-CSF 5 
mcg/kg/day (rounded to the nearest vial size per investigator’s standard of care) 24 hours 
after chemotherapy until recovery to the predetermined neutrophil count. 
 
 
4.4.2.2 Sensory Neuropathy 
nab-paclitaxel treatment should be withheld in patients who experience ≥ Grade 3 peripheral 
neuropathy. Gemcitabine administration can continue during this period. Patients 
experiencing peripheral neuropathy that requires a delay in scheduled nab-paclitaxel dosing 
for ≥ 21 days will discontinue study treatment. The time to resolution to Grade ≤ 2 should 
be the adverse event duration used for adverse event reporting. In those patients who 
experience Grade 4 sensory neuropathy, both drugs should be withheld, and treatment 
resumed at a reduction of 2 dose levels (Dose Level -2) in subsequent cycles after the 
sensory neuropathy improves to  Grade 2.  Note: the investigator may elect to dose modify 
for Grade 2 sensory neuropathy. 
 
4.4.2.3 Cutaneous Toxicity 
Patients who develop Grade 2 or 3 cutaneous toxicity should have their dose reduced to 
the next lower dose level as per Table 5. If the patient continues to experience these 
reactions, despite dose reduction, treatment should be discontinued. Patients who develop 
Grade 4 cutaneous toxicity should have treatment discontinued. 
 
 
4.4.2.4 Gastrointestinal Toxicity 
If Grade 3 mucositis or diarrhea occurs, all 3 study drugs should be withheld until resolution 
to ≤ Grade 1, then reinstituted at the next lower dose level as per Table 4. Patients who 
develop Grade 4 mucositis or diarrhea should have treatment discontinued. 
 


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4.4.2.5 Pulmonary Embolism  
Asymptomatic or clinically mild pulmonary embolism can be treated with low-molecular 
weight heparin without interruption of therapy. Moderate to severe pulmonary embolism will 
require permanent discontinuation of treatment. 
 
 
4.4.2.6 Interstitial Pneumonitis 
Pulmonary toxicity has been reported for both gemcitabine and paclitaxel. Epidemiology 
reports show that gemcitabine monotherapy is weakly associated with lung toxicity. A 
retrospective review of pooled clinical trial data of 4,448 patients with mixed cancer 
indications reported an incidence of dyspnea of 0.2% and serious pulmonary toxicity of 
0.06%.  
During study participation, patients should be carefully monitored for signs and symptoms 
of pneumonitis (i.e. episodes of transient or repeated dyspnea with unproductive persistent 
cough or fever) and, if observed, immediate clinical evaluation and timely institution of 
appropriate management (emphasizing the need for corticosteroids if an infectious process 
has been ruled out as well as appropriate ventilation and oxygen support when required). 
Administration of study drugs will be permanently discontinued upon making a diagnosis of 
interstitial pneumonitis. 
 
Prevention, Surveillance and Management of Interstitial Pneumonitis 
During study treatment, episodes of transient or repeated dyspnea with unproductive 
persistent cough or fever should be paid attention to. Radiographic evaluation with chest X-
rays and CT scans (normal or high resolution) may be indicated to look for infiltrates, ground-
glass opacities, or honeycombing patterns. Pulse oximetry and pulmonary function tests 
can show respiratory and ventilation compromise. 
Infections should be ruled out with routine immunological/ microbiological methods. 
Transbronchial lung biopsy is not recommended, given its limited value and risk of 
pneumothorax and hemorrhage, and should be reserved for cases with unclear etiology.  
Study drug administration should be interrupted upon diagnosis of interstitial pneumonitis 
and patients permanently discontinued from further study drug treatment. After ruling out an 
infectious etiology, intravenous high-dose corticosteroid therapy and secondary pathogen 
coverage should be instituted without delay. Patients with an added immunological 
component may also require immune modulation with azathioprine or cyclophosphamide. 
Appropriate ventilation and oxygen support should be used when required.  
 
 
4.4.2.7 Sepsis 
Sepsis has been reported in less than 1% patients during Nab-Paclitaxel monotherapy and 
fatalities attributed to these events have been rare. However, the risk was appreciably 
higher in patients with advanced or metastatic pancreatic cancer receiving Nab-Paclitaxel 
in combination with gemcitabine with a rate of 5% in patients with or without neutropenia 
receiving Nab-Paclitaxel/gemcitabine. Complications due to the underlying pancreatic 
cancer, especially biliary obstruction, or presence of biliary stent, were identified as 
significant contributing factors. The increased risk of sepsis in the setting of advanced or 
metastatic cancer in combination with gemcitabine could be managed with prophylactic 
antibiotic treatment in febrile patients (regardless of neutrophil count) and dose reduction, 
and with G-CSF treatment in neutropenic patients. If a patient becomes febrile (regardless 
of neutrophil count), initiate treatment with broad spectrum antibiotics. For febrile 
neutropenia, withhold Nab-Paclitaxel and gemcitabine until fever resolves and ANC ≥ 1500, 
then resume treatment at reduced dose levels. 
Prophylaxis Against Sepsis 
Due to the incidences of non-neutropenic sepsis, at the first occurrence of fever ≥ 38.5°C 
(regardless of neutrophil count), institution of ciprofloxacin (500 mg orally, twice daily) or 
amoxicillin/clavulanate (500 mg orally, 2-3 times daily) in patients with allergy to 


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fluoroquinolones should be initiated. On their first visit, patients should be provided with 
enough ciprofloxacin (or the alternative antibiotic) for use at home, and they should be 
instructed to begin taking it when they first record a temperature of ≥ 38.5 °C (or if they feel 
they are developing a fever and a thermometer is not available). They should also 
immediately contact their physician for guidance on where to go for blood counts and to be 
evaluated for sepsis as soon as possible. Hospitalization or evaluation in the emergency 
room may be required depending on the clinical presentation. If hospitalization is required, 
this should be reported as a Serious Adverse Event (SAE). 
 
 
4.4.2.8 Hypersensitivity Reactions 
Hypersensitivity reactions rarely occur.  If they do occur, minor symptoms such as flushing, 
skin reactions, dyspnea, lower back pain, hypotension, or tachycardia may require 
temporary interruption of the infusion.  However, severe reactions, such as hypotension 
requiring treatment, dyspnea requiring bronchodilators, angioedema or generalized urticaria 
require immediate discontinuation of study drug administration and aggressive symptomatic 
therapy.  Patients who experience severe hypersensitivity reactions to Nab-Paclitaxel 
should not be re-challenged.  It is not recommended to administer Nab-Paclitaxel to patients 
with prior hypersensitivity to a taxane.  
 
Nab-Paclitaxel Premedication 
Patients do not require premedication prior to Nab-Paclitaxel administration, as 
hypersensitivity reactions are rare. Although the solubilizing agents Cremophor® EL and 
Tween® 80 have long been implicated in adverse events including hypersensitivity 
reactions due to their detergent-like nature and known ability to induce histamine release43, 
the administration of solvent-based taxanes (Taxol and Taxotere) requires 
premedication with corticosteroids and histamine receptor blocking agents to prevent the 
occurrence of hypersensitivity reactions. However, the hypersensitizing role of the taxane 
molecules themselves cannot be ruled out.   
 
In the unlikely event of a mild hypersensitivity reaction, premedication may be administered 
using the premedication regimen the institution typically uses for solvent based paclitaxel.  
In the rare event of a severe hypersensitivity reaction, discontinue Nab-Paclitaxel. 
 
Concomitant Medications 
Supportive care, including but not limited to anti-emetic medications, may be administered 
at the discretion of the Investigator.  Erythropoietin and G-CSF may be administered at the 
discretion of the investigator, consistent with institutional guidelines. 
4.5 
Concomitant Medications/Treatments 
Supportive care, including but not limited to anti-emetic medications, may be administered 
at the discretion of the Investigator.   
Erythropoietin and G-CSF may be administered at the discretion of the investigator, 
consistent with institutional guidelines.  
Concurrent treatment with any agent known to cause Torsade de Points is an exclusion 
criterion for the study. 
 
4.6 
Other Modalities or Procedures 
Blood and tissue specimens will be collected, for analysis of pharmacodynamic endpoints 
of therapy.  
Detailed procedures for the collection, processing, storage, and shipment of the samples 
will be provided in the Study Laboratory Manual.  
 
Tissue collection:  
 


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Baseline tissue collection: Baseline tissue specimen should be requested/collected as 
specified in the lab manual(tissue block is preferred). Repeat biopsy is not required at 
baseline, archival tissue is sufficient.  
 
On treatment tissue: The on-treatment tissue collection should be performed, if feasible, 
during Cycle 2 or Cycle 3 in patients who consent to tissue collection. 
- 
The most accessible tumor disease site (preferably not a target lesion), as 
determined by investigator, will be biopsied. 
- 
Up to 3 X Core needle biopsy will be preferred when clinically possible. 
 
Blood 
Refer to lab manual for details 
 
 
Baseline sample Cycle 1 Day 1: Baseline sample should be collected prior to treatment.  
 
On treatment samples: On treatment blood samples will be collected pre-dose on the 
following days: 
1. Cycle 1 Day 2  
2. Cycle 1 Day 4 
3. Cycle 1 Day 8 
4. Cycle 1 Day 11 
5. Cycle 1 Day 15 
6. Cycle 2 Day 1 
7. Cycle 2 Day 8 
8. Cycle 2 Day 15 
9. Day 1 of each subsequent cycle 
10. At the time of disease progression or End of Study visit, whichever comes first.  
 
4.7 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Subject decides to withdraw from the study, OR 
• 
General or specific changes in the patient’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator 
4.8 
Duration of Follow Up 
After completion of treatment, for any reason, subjects will be followed until death, lost to 
follow-up, or withdraw of consent for long term follow-up. 
4.9 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in Section 5.6 apply. 
Notify the UTSW Principal Investigator and document the reason for study removal and 
the date the subject was removed in the Case Report Form.  The subject should be 
followed-up per protocol.  
4.10 
Subject Replacement 
Phase 1b: Patients in safety run-in phase should be followed for at least 3 weeks (Cycle 
1). Patients who are withdrawn prior to the 3 week monitoring in the run-in phase will be 
replaced to allow the stated number of patients to be observed for safety. 
 


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Phase 2: Patients in safety run-in phase should be followed for at least 4 weeks (Cycle 1). 
Patients who are withdrawn prior to the 4 week monitoring in the run-in phase for any 
reason other than DLT will be replaced to allow the stated number of patients to be 
observed for safety.  
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed solely for the purpose of this research study will be done only 
after obtaining informed consent. However, assessments performed for routine care of 
the patient may be used for baseline values even if  completed before informed consent 
was obtained. 
 
All screening procedures must be performed within 21 days prior to date of enrollment, 
with the exception of laboratory assessments. The screening procedures include: 
• 
Informed Consent 
• 
Medical history 
• 
ECOG Performance Status 
• 
Inclusion / exclusion criteria 
• 
Vital Signs 
• 
Physical examination 
• 
Concomitant medication notation 
• 
Tumor Measurements per RECIST 1.1 
• 
Hematology: CBC with differential and platelet count  
• 
Serum chemistries: glucose, creatinine, BUN, total bilirubin, AST, ALT, alkaline 
phosphatase albumin, LDH, total protein, and electrolytes (sodium, potassium, 
phosphorus, chloride, C02, magnesium, calcium).   In patients with known Gilbert’s 
syndrome, it is recommended to perform a direct bilirubin and indirect bilirubin. 
Calculate creatinine clearance.  
• 
CA 19-9 
• 
CPK 
• 
Pregnancy test (either urine or serum pregnancy test) within 72 hours prior to the first 
dose of study treatment.  If the urine pregnancy test is positive or cannot be confirmed 
as negative, a serum pregnancy test will be required. 
• 
EKG - triplicate 12-lead EKGs must be taken less than 5 minutes apart with the patient 
having rested for at least 10 minutes in the supine position prior to assessment 
• 
ECHO or MUGA 
• 
Archival Tissue for correlative analysis. Baseline tissue specimen should be 
requested/collected as specified in the lab manual (tissue block is preferred). Repeat 
biopsy is not required at baseline, archival tissue is sufficient. Confirmation or presence 
of archival tumor tissue is not mandatory for eligibility. 
 
5.2 
Procedures During Treatment (Cycle is 28 days) 
Day 1 


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• 
Inclusion/exclusion review (Cycle 1 only)  
• 
Physical exam  
• 
Vital Signs  
• 
Measurement of weight (kg) and BSA calculation prior to dosing   
• 
ECOG Performance Status   
• 
Hematology  
• 
Serum chemistries  
• 
Blood for correlative analysis 
• 
CA 19-9 (C3 and every subsequent odd cycle Day 1) 
• 
CPK (C3 and every subsequent odd cycle Day 1 
• 
EKG (not Cycle 1) 
• 
Pregnancy Test  
• 
Adverse Events (AEs) using the NCI CTCAE 5.0 
• 
Concomitant medication notation  
• 
Chemotherapy administration 
• 
PK testing (5ml at cycles 2, 3 and 4 only) – 1st 15 patients only. 
• 
Tumor measurements per RECIST 1.1 (before C3 and prior to every odd cycle) 
• 
Optional Tissue biopsy for correlative analysis. The on-treatment tissue collection 
should be performed during Cycle 2 or Cycle 3 in patients who consent to tissue 
collection 
 
 
Day 2 (Only cycle 1 for patients receiving bemcentinib 
• 
Vital Signs  
• 
Hematology 
• 
EKG 
• 
Blood for correlative analysis  
• 
AEs using the NCI CTCAE 5.0 
• 
Concomitant medication notation  
• 
Start bemcentinib dosing  
 
 
 
Day 4 (Only cycle 1 for patients receiving bemcentinib) 
• 
Vital Signs 
• 
EKG 
• 
Hematology 
• 
Blood for correlative analysis 
• 
AEs using the NCI CTCAE 5.0 
• 
PK testing 1st 15 patients only 
• 
Concomitant medication notation 
• 
Bemcentinib dosing 
 
 
Day 8 of each cycle 
• 
 Vital Signs 
• 
Hematology 


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• 
Serum chemistries 
• 
Blood for correlative analysis (Cycle 1 and 2 only) 
• 
AEs using the NCI CTCAE 5.0 
• 
PK testing (Cycle 1 only)  1st 15 patients only 
• 
EKG bemcentinib patients only 
• 
Concomitant medication notation 
• 
Chemotherapy administration 
• 
Bemcentinib dosing 
 
 
 
Day 11 (Only cycle 1 for patients receiving bemcentinib) 
• 
Vital Signs 
• 
EKG 
• 
AEs using NCI CTCAE 5.0 
• 
PK testing 1st 15 patients only 
• 
Concomitant medication notation 
• 
Bemcentinib dosing 
 
Day 15 of each cycle   
• 
Vital Signs 
• 
Hematology 
• 
Serum chemistries 
• 
Blood for correlative analysis (Cycle 1 and 2 only) 
• 
AEs using the NCI CTCAE 5.0 
• 
PK testing (Cycle 1 only) 1st 15 patients only                                      
• 
EKG bemcentinib patients only 
• 
Concomitant medication notation 
• 
Chemotherapy administration 
• 
Bemcentinib dosing 
Day 18 (Only cycle 1 for patients receiving bemcentinib) 
• 
Vital Signs 
• 
EKG 
• 
AEs using the NCI CTCAE 5.0 
• 
Concomitant medication notation 
• 
Bemcentinib dosing 
 
 
Off Treatment Visit (30 days after last dose – any drug) 
• 
Physical Exam 
• 
Measurement of weight (kg) and BSA calculation 
• 
Vital signs 
• 
ECOG Performance status 
• 
Hematology 
• 
Serum chemistries 
• 
CA 19-9 
• 
CPK 


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• 
EKG (only for patients that received bemcentinib) 
• 
Blood for correlative analysis 
• 
AEs using the NCI CTCAE 5.0 
• 
Concomitant medication notation 
 
5.3 
Follow-up Procedures 
- 
If treatment related toxicities occur, the subject will be followed every month (+/- 7 days), 
from off treatment visit date, after completion of (or early withdrawal from) study 
treatment until resolution  
- 
If no treatment related toxicities occur, the subject will be followed for survival end points 
every 3 months (+/-7 days), from off treatment visit date. This may be done through 
medical record review or phone call.   
 
 


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Schedule of Events 
Screening 
C1D1 
C1D2 
& 
C1D4 
C1
D8 
C1 
D11 
C1 
D15  
C1 
D18  
C2+ 
D1i 
C2+ 
D8i 
C2+ 
D15i 
Off
-Tx 
Long 
Term 
FU 
Informed Consent 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Performance 
Status 
X 
X 
 
 
 
 
X 
 
 
X 
 
Inclusion / 
exclusion criteria 
X 
X 
review 
 
 
 
 
Vital Signsa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight and BSA 
Calculation 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
Physical 
examinationb 
X 
X 
 
 
 
X 
 
 
X 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Tumor 
Measurements 
X 
 
 
 
 
X 
before 
C3, 
etc. 
 
 
 
Hematologyc 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Serum Chemistryc 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
Tumor Marker 
CA19-9 
X 
 
 
 
 
 
X C3, 
etc. 
 
 
X 
 
CPK 
X 
 
 
 
 
 
X C3, 
etc. 
 
 
X 
 
Pregnancy testd 
X 
X 
 
 
 
 
X 
PK testinge 
 
X 
X 
X 
X 
X 
X C2, 
3 & 4 
only 
EKGf 
X 
 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
ECHO or MUGA 
X 
 
 
 
 
Xg 
 
Xg 
 
Blood for 
Correlative 
analysisj 
 
X 
X 
X 
 
X 
Xj 
Xh 
X 
X 
Archived Tissue 
for Correlative 
analysis 
X 
 
 
 
 
 
 
 
 
Optional: Tissue 
biopsy 
 
 
 
 
 
 
X 
(once) 
Cycle 
2 or 3 
 
 
Chemotherapy 
dosing 
 
X 
 
X 
 
X 
X 
X 
X 
Bemcentinib 
dosingj 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Survival Status 
 
 
 
 
 
 
 
 
 
 
 
X 
 
a  Vital signs include BP, HR, RR, temperature. Height is only required at screening.  
b  Full physical examination includes neuropathy assessment at screening, C1D1, and end of study.  
c  See sections 5.1 for full listing of required labs 
d  Only for women of childbearing potential 
e  PK samples will be taken for the first 15 patients.  
f 
For the screening, triplicate 12-lead EKGs must be taken less than 5 minutes apart with the patient 
having rested for at least 10 minutes in the supine position prior to assessment.  All subsequent 
assessments are single ECGs unless QTc prologation is observed, then triplicate ECGs will be required.  
If a patient has bemcentinib interrupted for 14 days or more for toxicity, an ECG will be conducted twice 
weekly for the following 2 weeks once a patient restarts daily dosing. If patient is permanently 
discontinued from bemcentinib, with no residual cardiovascular related toxicities, ECGs can be 
discontinued until off treatment visit.  
g  ECHO or MUGA as clinically indicated  
h  Collect only at Cycle 2  
i  +/- 3 day window for subsequent cycles to account for holidays. Patient may be treated before a test is 
resulted provided the following is met: 1) test is drawn and pending, 2) investigator deems safety of the 
patient will not be effected, and 3) all protocol specified treatment parameters are met. 
j  Please refer to lab manual for additional collection details. No longer required if bemecentinib is 
permanently discontinued.  
 
 
  
5.5 
Removal of Subjects from Study 
Subjects can be taken off the study treatment and/or study at any time at their own request, 
or they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may 
include: 
• Subject voluntarily withdraws from treatment (follow-up permitted); 
• Subject withdraws consent (termination of treatment and follow-up); 
• Subject is unable to comply with protocol requirements; 
• Subject demonstrates disease progression (unless continued treatment with study 
drug/treatment is deemed appropriate at the discretion of the investigator and approval 
by PI); 
• Subject experiences toxicity that makes continuation in the protocol unsafe; 
• Treating physician judges continuation on the study would not be in the subject’s best 
interest; 
• Subject becomes pregnant (pregnancy to be reported along same timelines as a serious 
adverse event); 
• Lost to follow-up, only after 3 documented attempts, he or she can be deemed lost to 
follow-up.   
 
6.0 
MEASUREMENT OF EFFECT 
6.1 
Antitumor Effect-Solid Tumors 
Response and progression will be evaluated in this study using the new international 
RECIST criteria (version 1.1, 2009) proposed by the RECIST committee44.  All patients 
who have measurable disease according to the RECIST criteria and who have their 
disease re-evaluated will be evaluable for response.  For the purposes of this study, 
patients should be reevaluated for response approximately every 3 cycles.  Note:  Lesions 
are either measurable or non-measurable using the criteria provided below. The term 


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“evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
6.1.1 
Definitions 
Evaluable for toxicity. All subjects will be evaluable for toxicity from the time of 
their first treatment with study therapy. 
 
Evaluable for objective response.  Only those subjects who have measurable 
disease present at baseline, have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for response. 
These subjects will have their response classified according to the definitions 
stated below. (Note: Subjects who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
 
6.1.2 
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 with 
conventional techniques (CT or MRI) or as >10 mm with spiral CT scan. All tumor 
measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Non-measurable disease.  
All other lesions (or sites of disease), including small lesions (longest diameter <10 
mm or pathological lymph nodes with ≥10 to <15mm short axis), as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI).  For bone and cystic lesions please refer to the RECIST criteria 
(version 1.1, 2009). 
 
Note: Previously irradiated lesions are non-measurable except in cases of 
documented progression of the lesion since the completion of radiation therapy. 
 
Target lesions.  
A maximum of 2 lesions per organ and 5 lesions in total 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) and their 
suitability for accurate repeated measurements (either by imaging techniques or 
clinically). A sum of the diameters for all target lesions (longest for non-nodal 
lesions, short axis for nodal lesions) will be calculated and reported as the baseline 
sum diameters (LD). The baseline sum diameters will be used as reference by 
which to characterize the objective tumor response. 
 
Non-target lesions.  
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline.  Non-target lesions include measurable 
lesions that exceed the maximum numbers per organ or total of all involved organs 
as well as non-measurable lesions. It is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. 
“multiple enlarged pelvic lymph nodes” or “multiple liver metastases”).   
Measurements of these lesions are not required, but the presence or absence of 
each should be noted throughout follow-up.  
 
 
6.1.3 
Methods for Evaluation of Measurable Disease 


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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 when 
both methods have been used to assess the antitumor effect of a treatment. 
 
Clinical lesions.  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes).  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.  
 
Conventional CT and Magnetic Resonance Imaging.  Conventional CT and MRI 
should be performed to obtain images of 5 mm or less slice thickness. 
 
Tumor markers.  Tumor markers alone cannot be used to assess response.  If 
markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response. 
 
Cytology, Histology.  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions 
in tumor types, such as germ cell tumors, where known residual benign tumors 
can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the treatment) and progressive 
disease. 
 
6.1.4 
Response Criteria 
6.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target and non-target 
lesions including normalization of elevated tumor marker level.  Any 
pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm. All non-target lymph nodes must be 
non-pathological in size (< 10 mm short axis). Complete response must 
be confirmed at a second tumor assessment not less than 4 weeks apart 
from the assessment at which CR was observed. 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions, taking as reference the baseline sum LD. 
Partial response must be confirmed at a second tumor assessment not 
less than 4 weeks apart from the assessment at which PR was observed. 
 
Progressive Disease (PD):   
At least a 20% increase (and an absolute increase of at least 5 mm) in the 
sum of LD of measured lesions taking as references the smallest sum LD 
recorded since the treatment started. Appearance of new lesions will also 
constitute PD. In exceptional circumstances, unequivocal progression of 
non-target lesions may be accepted as evidence of disease progression. 
 


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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 
LD since the treatment started.  
 
Non-CR/Non-PD:  Persistence of 1 or more non-target lesions and/or 
maintenance of tumor marker level above the normal limits. 
 
6.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level.  
 
(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. 
 
Although a clear progression of “non-target” lesions only is exceptional, in 
such circumstances, the opinion of the treating physician should prevail, 
and the progression status should be confirmed at a later time by the study 
chair. 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
 
6.1.5 
Time point evaluation 
At each protocol specified time point, a response assessment occurs. Table 9 provides a summary 
of this for patients who have measurable disease at baseline. Table 10 provides a summary of this 
for patients with non-measurable (therefore non-target) disease. 
 
Table 11: Response for Measurable Disease 
Target 
Lesions 
Non-target Lesions  
New 
Lesions  
Overall 
Response  
Best Response for this 
Category Also Requires  
CR 
CR 
No 
CR 
≥ 4 weeks Confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
≥ 4 weeks Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Documented at least once ≥ 6 
weeks from baseline 
Not All 
Evaluated 
Non-PD 
No 
NE 
NE 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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Table 12: Response for Non-measurable Disease 
 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
NE = inevaluable a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised.  
 
 
6.1.6 
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 subject’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
Table 13: Response Assignment 
 
Overall Response First 
Time Point 
Overall Response 
Subsequent Time Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
NE 
NE 
NE 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. NE = inevaluable 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.  


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NE = inevaluable.  If a CR is truly met at first time point, then any disease seen at a subsequent 
time point, even disease meeting PR criteria relative to baseline, makes the disease PD at that 
point (since disease must have reappeared after CR).  Best response would depend on whether 
minimum duration for SD was met. However, sometimes ‘CR’ may be claimed when subsequent 
scans suggest small lesions were likely still present and in fact, the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR.  
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration.”  Every effort should be made to document the objective progression, even after 
discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  When 
the evaluation of complete response depends on this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before confirming the complete 
response status. 
 
6.1.7 
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 recurrent 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.  
6.1.8 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression. 
6.2 
Safety/tolerability 
 
Analyses will be performed for all subjects having received at least one dose of study therapy. The study 
will use the CTCAE version 5.0 for reporting of non-hematologic adverse events 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_40) and modified 
criteria for hematologic adverse events (Appendix #/letter). 
 
7.0 
ADVERSE EVENTS 
7.1 
Experimental Therapy 
For the most recent safety update (in drug studies), please refer to the current Investigator’s Brochure or 
Study Agent Prescribing Information. 
 


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7.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical trial, will begin 
after the 1st dose of study drug and are done to ensure the safety of subjects enrolled in the studies as 
well as those who will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of subject safety and care.  
 
All subjects experiencing an adverse event while on study or until 30 days post last dose, regardless of its 
relationship to study therapy, will be monitored until:  
➢ the adverse event resolves or the symptoms or signs that constitute the adverse event return 
to baseline;  
➢ there is a satisfactory explanation other than the study therapy for the changes observed; or 
➢ death. 
 
 
7.2.1 
Definitions  
Adverse Events will be reported as indicated by the appropriate following table (see below).    
 
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam, imaging finding or clinically significant laboratory finding), symptom, clinical 
event, or disease, temporally associated with the subject’s participation in the research, 
whether or not it is considered related to the subject’s participation in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they 
can occur in the context of social and behavioral research. Adverse events may be 
expected or unexpected. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Adverse events not 
specifically defined in the NCI CTCAE will be scored on the Adverse Event log according 
to the general guidelines provided by the NCI CTCAE and as outlined below.   
• 
Grade 1: Mild  
• 
Grade 2: Moderate 
• 
Grade 3: Severe or medically significant but not immediately life threatening 
• 
Grade 4: Life threatening consequences 
• 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
OHRP and UTSW HRPP define serious adverse events as those events, occurring at 
any dose, which meets any of the following criteria:  
• 
results in death; 
• 
is life-threatening (places the subject at immediate risk of death from the event as 
it occurred); 
• 
results in inpatient hospitalization1,2 or prolongation of existing hospitalization; 
• 
results in a persistent or significant disability/incapacity; 
• 
results in a congenital anomaly/birth defect; or 


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• 
based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
Note: A “Serious adverse event” is, by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and events 
that are expected in the context of the condition under study may be serious adverse 
events, independent of relatedness to the study itself. As examples, a car accident 
requiring >24 hour inpatient admission to the hospital would be a serious adverse event 
for any research participant; likewise, in a study investigating end-stage cancer care, any 
hospitalization or death which occurs during the protocol-specified period of monitoring for 
adverse and serious adverse events would be a serious adverse event, even if the event 
observed is a primary clinical endpoint of the study. 
1Pre-planned hospitalizations or elective surgeries are not considered SAEs. Note: If 
events occur during a pre-planned hospitalization or surgery, that prolong the existing 
hospitalization, those events should be evaluated and/or reported as SAEs.   
2 NCI defines hospitalization for expedited AE reporting purposes as an inpatient hospital 
stay equal to or greater than 24 hours. Hospitalization is used as an indicator of the 
seriousness of the adverse event and should only be used for situations where the AE 
truly fits this definition and NOT for hospitalizations associated with less serious events. 
For example: a hospital visit where a patient is admitted for observation or minor 
treatment (e.g. hydration) and released in less than 24 hours. Furthermore, 
hospitalization for pharmacokinetic sampling is not an AE and therefore is not to be 
reported either as a routine AE or in an expedited report.  
7.2.2 Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The phrase “unanticipated problems involving risks to subjects or others” is found, but not 
defined in the HHS regulations at 45 CFR 46, and the FDA regulations at 21 CFR 
56.108(b)(1) and 21 CFR 312.66. For device studies, part 812 uses the term unanticipated 
adverse device effect, which is defined in 21 CFR 812.3(s). Guidance from the regulatory 
agencies considers unanticipated problems to include any incident, experience, or 
outcome that meets ALL three (3) of the following criteria: 
• 
Unexpected in terms of nature, severity or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied;  
 
 
 
 
AND 
• 
Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research); 
 
AND  
• 
Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. Note: According to OHRP, if the adverse event is serious, it would always 
suggest a greater risk of harm. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  


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7.2.3 Steps to Determine If a Serious Adverse Event Requires Expedited Reporting to 
the SCCC DSMC 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v5).  
 
Step 2: Grade the adverse event using the NCI CTCAE v5. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE may NOT be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and is 
attributed (possibly, probably, or definitely) to the agent(s) must also be reported as 
indicated in the sections below. 
 
Step 4: Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the treatment. An 
adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in: 
• 
the current known adverse events listed in the Agent Information Section of this 
protocol (if applicable); 
• 
the drug package insert (if applicable); 
• 
the current Investigator’s Brochure (if applicable) 
• 
the Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
section of this protocol 
 
7.2.4 Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer Center 
(SCCC) Data Safety Monitoring Committee (DSMC) 
 
SAEs and UPIRSOs at all sites, which occur in research subjects on protocols for which 
the SCCC is the DSMC of record require reporting to the DSMC regardless of whether IRB 
reporting is required. All SAEs occurring during the protocol-specified monitoring period 
and all UPIRSOs should be submitted to the SCCC DSMC within 5 business days of the 
study team members awareness of the event(s). In addition, for participating centers other 
than UTSW, local IRB guidance should be followed for local reporting of serious adverse 
events or unanticipated problems. 
 
The UTSW study PI is responsible for ensuring SAEs/UPIRSOs are submitted to the SCCC 
DSMC Coordinator. This may be facilitated by the IIT project manager, study team, sub-
site or other designee. Hardcopies or electronic versions of the eIRB Reportable Event 
report; FDA Form #3500A forms, or other sponsor forms, if applicable; and/or any other 
supporting documentation available should be submitted to the DSMC Coordinator.  The 
DSMC Coordinator forwards the information onto the DSMC Chairman who determines if 
immediate action is required.  Follow-up eIRB reports, and all subsequent SAE or UPIRSO 
documentation that is available are also submitted to the DSMC Chair who determines if 


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further action is required. (See Appendix III of the SCCC DSMC Plan for a template Serious 
Adverse Event Form which may be utilized). 
  
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW Simmons 
Comprehensive Cancer Center, the IIT Project Manager or designee ensures that all 
participating sites are notified of the event and resulting action, according to FDA guidance 
for expedited reporting. DSMC Chairperson reviews all SAEs and UPIRSOs upon receipt 
from the DSMC Coordinator.  The DSMC Chairperson determines whether action is 
required and either takes action immediately, convenes a special DSMC session (physical 
or electronic), or defers the action until a regularly scheduled DSMC meeting.  
 
 
Telephone reports to: 
Muhammad Beg, MD  
214-648-7029 
 
Ellen Siglinsky-Clinical Research Manager  
214-648-7031 
 
Written reports to: 
Muhammad Beg, MD 
c/o GI Clinical Research Manager 
5323 Harry Hines Blvd, NB2.418 
Dallas, Texas 75390 
Fax: 214-648-1906  
 
UTSW SCCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-7084 or deliver to NB2.300 
 
Email: GlobalSAEInbox@Chiltern.com 
 
UTSW Investigator Initiated Trial (IIT) Team Email:  SCCC-IIT@UTSouthwestern.edu 
 
UTSW Institutional Review Board (IRB) 
Submit a Reportable Event via eIRB with a copy of the final sponsor report as attached 
supporting documentation 
 
Reporting Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRSOs) to the UTSW HRPP 
 
UTSW reportable event guidance applies to all research conducted by or on behalf of UT 
Southwestern, its affiliates, and investigators, sites, or institutions relying on the UT 
Southwestern IRB. Additional reporting requirements apply for research relying on a non-
UT Southwestern IRB. 
 
According to UTSW HRPP policy, UPIRSOs are incidents, experiences, outcomes, etc. 
that meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected in a subject’s 
underlying condition or not expected as a risk of the study; therefore, not included in 
the investigator’s brochure, protocol, or informed consent document),AND 
2. Probably or definitely related to participation in the research, AND 
3. Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
 


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recognized.  Note: According to OHRP, if the adverse event is serious, it would always 
suggest a greater risk of harm. 
 
For purposes of this policy, UPIRSOs include unanticipated adverse device effects 
(UADEs) and death or serious injury related to a humanitarian use device (HUD).  
 
UPIRSOs must be promptly reported to the UTSW HRPP within 5 working days of 
study team awareness. 
 
For research relying on a non-UT Southwestern IRB (external, central, or single IRB): 
 
Investigators relying on an external IRB who are conducting research on behalf of UT 
Southwestern or its affiliates are responsible for submitting LOCAL UPIRSOs to the UT 
Southwestern IRB within 5 working days of study team awareness. Investigators must 
report to their relying IRB according to the relying IRB’s policy. In addition, the external 
IRB’s responses or determinations on these local events must be submitted to the UT 
Southwestern IRB within 10 working days of receipt. 
 
Events NOT meeting UPIRSO criteria: 
 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, summarized, 
and submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/hrpp/quality-assurance/ 
7.4 
Stopping Rules 
The study can be stopped early based on the following critiera: 
• 
Per PI or sponsor discretion 
• 
DSMC recommendation  
• 
Futility analysis as detailed in section 10.2. 
 
8.0 
DRUG/TREATMENT INFORMATION 
Gemcitabine: See standard prescribing information 
Nab-paclitaxel: See standard prescribing information 
Cisplatin (Phase 1b): See standard prescribing information 
8.1 
Agent bemcentinib  
• 
Other names for the drug(s): BGB324, R428 
 
• 
Classification - type of agent: Kinase inhibitor 
 
• 
Mode of action: Inhibitor of Axl kinase 
 
• 
Storage and stability: bemcentinib capsules should be stored at or below 25oC in 
white round polyethylene bottles 
 
• 
Protocol dose: 200mg daily  
 
• 
Preparation: Capsules of 100mg bemcentinib 
 
• 
Route of administration for this study: Oral 
 


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• 
Incompatibilities: Concurrent treatment with any agent known to cause Torsade de 
Points is an exclusion criterion for the study. 
 
• 
Continuous treatment with more than 40mg prednisolone (or equivalent dose of 
systemic corticosteroid) is prohibited throughout the trial. 
 
• 
Treatment with any medication which is predominantly metabolized by CYP3A4 and 
has a narrow therapeutic index is an exclusion criterion for the study. 
 
• 
Availability: Provided by BerGenBio free of charge  
 
• 
Side effects: Adverse Drug Reactions occurring in ≥10% of patients are diarrhea, 
nausea, vomiting and electrocardiogram QT prolongation.  Please refer to the current 
Investigator’s Brochure for further details. 
 
• 
Nursing implications: EKG monitoring 
8.1.1 
Return and Retention of Study Drug 
Institutional pharmacy standard operating procedures will be followed for 
retention, storage, and destruction of study drug.  
 
8.1.2 
IP Compliance 
IP will be dispensed with a paper pill diary and instructions on how to complete 
and record each dosage.  
 
9.0 
CORRELATIVES/SPECIAL STUDIES 
Tissue and blood biomarker assays are proposed with the goal to assess the effect of combination 
chemotherapy and bemcentinib on 1) AXL pathway activity in tumor tissue, 2) changes in immune 
landscape including upregulation of immune cytokines, and immune cell infiltration into the tumor, 
3) apoptosis and decreased proliferation of tumor, and 4) to identify predictive biomarkers of 
response. 
 
Please see Laboratory Manual for details on blood and tissue collection guidelines. All shipments 
and questions should be directed to the following: 
 
Attn: Dr. Farjana Fattah 
Biomarker Research Core (BRC) Laboratory 
Simmons Comprehensive Cancer Center 
6001 Forest Park Rd, ND2.136 
Dallas, TX 75390 
Phone: (214) 645‐6430  
Back-Up Phone: (214) 648-4673 
Fax: (214) 645‐6347 
 
9.1 
Sample Collection Guidelines 
Samples will be collected at the time points listed in section 5 of this protocol.  
For details on sample collection and processing please refer to Laboratory Manual.  


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9.2 
Assay Methodology 
Samples will be stored at each investigators’ facility until requested by UTSW 
Coordinating Center. Batched analysis will be performed on study samples. A committee 
comprised of study investigators will determine the final correlative analysis plan.  
9.3 
Specimen Banking 
Subject samples collected for this study will be retained at UT Southwestern. Specimens 
will be stored indefinitely or until they are used up. If future use is denied or withdrawn by 
the subject, best efforts will be made to stop any additional studies and to destroy the 
specimens. 
 
Muhammad Shaalan Beg, MD will be responsible for reviewing and approving requests for 
clinical specimen from potential research collaborators outside of the University of Texas 
Southwestern Medical Center. Collaborators will be required to complete an agreement (a 
Material Transfer Agreement or recharge agreement) that states specimens will only be 
released for use in disclosed research. Any data obtained from the use of clinical specimen 
will be the property of the University of Texas Southwestern Medical Center for publication 
and any licensing agreement will be strictly adhered to.  
 
10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Study Design/Study Endpoints 
Phase 1b of the clinical trial is a safety run-in to establish safety of the combination of 
bemcentinib and chemotherapy (gemcitabine/nab-paclitaxel/cisplatin) (Enrollment 
Completed 9/2020) 
 
Phase 2 is a open label, clinical trial of chemotherapy (gemcitabine/nab-paclitaxel) with 
bemcentinib. 
  
The primary end point is overall response rate. 
 
Phase 1b: Safety run in (enrollment completed 9/2020) 
A modified 3+3 design will be used to determine the dose of bemcentinib for the 
randomized, Phase 2, of the study. 
 
In the safety run in, three patients will be enrolled to Dose level 1.  
•  If none of the first 3 evaluable patients in a dose cohort experiences a DLT within 
the DLT evaluation interval, then the randomized portion (Phase 2 of the trial will 
begin.  
•  If at least 1 of the first 3 evaluable patients in a cohort experiences a DLT within the 
DLT evaluation interval, then 3 additional patients will be treated at that dose level. 
−  If no more than 1 of the first 6 evaluable patients experiences a DLT 
during the DLT evaluation interval, then the  Phase 2 of trial will begin. 
−  If 2 or more of the first 6 evaluable patients in a cohort experience a DLT, 
that dose level has exceeded the MTD and a lower dose level will be 
explored. 
 
PI may investigate additional starting dose levels as defined in table 5 in the protocol. If 
additional doses outside of the protocol are needed, then a modification to the protocol 
may be considered. The study safety committee (comprising co-investigators and other 
site PIs) and the DSMC chair may be consulted as needed.  
 


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Dose limiting toxicity (DLT)  
Any patient who receives treatment on this protocol will be evaluable for toxicity. DLT will 
be defined by the occurrence of any of the following toxicities in patients of the trial which 
are possibly or probably related to study treatment, during cycle 1 only, as defined by 
CTCAE version 5.0  
• Any nonhematologic grade 3 or 4 toxicity except alopecia 
• Grade ≥ 3 diarrhea, vomiting, or nausea that persists for > 3 days despite optimal 
supportive care  
• Any Grade 4 or 5 treatment related toxicity that is at least possibly related to treatment 
 
Grade 4 neutropenia lasting more than 5 days or febrile neutropenia  
• Platelets <25,000 uL with significant bleeding 
• Grade ≥ 3 Anemia lasting for more than 5 days 
• Any drug-related liver function test (LFT) abnormality that meets the following criteria:  
 
If a subject has a baseline AST or ALT within normal limits:  
1. AST or ALT > 5-8x ULN for > 2 weeks  
2. AST or ALT > 8x ULN, irrespective of duration  
3. Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN  
 
If a subject has a baseline AST or ALT within Grade 1 or 2 toxicity range:  
1. AST or ALT > 10x ULN for > 2 weeks   
2. AST or ALT > 15x ULN, irrespective of duration   
3. Total bilirubin > 5x ULN  
4. Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN 
 
10.2 
Sample Size and Accrual 
Sample size: The total sample size of this study (Phase 1b and Phase 2) will be between 
3 and 44 patients. 
 
Phase 1b (enrollment completed 9/2020): will comprise a safety run-in for the first 3-12 
patients treated with bemcentinib plus nab-paclitaxel/gemcitabine/cisplatin.  
 
Sample size of Phase 1b will be determined by safety criteria as detailed above. Adverse 
event (safety) data will be reviewed by the Safety Monitoring Committee (SMC) before 
enrolment into Phase 2 can commence. The SMC will be comprised of a representative 
from each actively-recruiting investigational site and a representative of the Sponsor study 
team. Once safety of combination treatment has been demonstrated, enrollment on Phase 
2 portion, of the trial will begin. 
 
Phase 2: Patients will be treated with bemcentinib plus nab-paclitaxel/gemcitabine. Only 
patients that successfully complete the 1st imaging assessment will be considered 
evaluable for efficacy. Non-evaluable patients will be replaced.  
In Phase 2 of the study, 32 patients will be enrolled. The proposed scheme is based on 
Simon's minimax two-stage design for a phase 2 trial using 10% type I error rate and 80% 
power. 
For comparisons of 23% (null hypothesis) vs. 40% (alternative hypothesis), 21 patients will 
be accrued in the first stage. 
 
If there are 4 or fewer responses out of 21 patients, the trial will be stopped early for 
futility.  
Otherwise, 11 additional patients will be accrued for a total of 32 patients.  
The null hypothesis will be rejected if 10 or more responses are observed out of 32 
patients. 
 


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Interim Safety analysis: A preplanned interim safety analysis has been perfomed after 6 
patients have completed the DLT period in the revised Phase 1b. For additional paitnets 
the study team will analyze the presence of grade 3 or higher treatment-related toxicity. If 
3 or more of the first 6 patients treated in Phase 2 have grade 3 of higher treatment toxicity 
a lower starting dose of therapy (as detailed in Table 5) will be considered. 
 
 
10.3 
Data Analyses 
Statistical analysis: The overall response rate (ORR) and complete response (CR) rate are 
defined as the proportions of subjects with CR and objective response (OR), respectively. 
The efficacy endpoints CR and OR will be analyzed by estimating the CR and ORR and its 
95% CI with the exact binomial method. The analyses of ORR will be performed on the 
Response Evaluable Population. ORR is defined as the proportion of patients with 
CR+partial response as their best clinical response.   
The generalized estimating equation approach will be performed to see if there is an 
association between biomarker expression including, tissue axl expression, circulating 
multiplex assay (sAXL, gas 6), myc amplification status at baseline and clinical activity. If 
such an association exists, secondary analyses for efficacy endpoints will be conducted in 
“biomarker positive” and “biomarker negative” subpopulation determined by the cutoff 
points.  
Progression-free survival and overall survival will be estimated using Kaplan-Meier method 
and the corresponding 95% confidence interval will be estimated using Greenwood’s 
formula.  
Clinical Benefit rate (CBR) will be calculated as a sum of the proportion of patients with 
CR+PR +  Stable disease at week 8, week 12, week 24 and week 52. 
All patients will be evaluable for toxicity assessment. The number and percentage of 
subjects reporting treatment-emergent AEs will be summarized overall and by the worst 
CTCAE grade, system organ class, and preferred term. Similarly, the number and 
percentage of subjects reporting treatment-emergent SAEs and treatment-emergent 
AE/SAEs considered related to investigational product will be summarized. 
 
11.0 
STUDY MANAGEMENT 
11.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy on 
Conflicts of Interest.  All investigators will follow the University conflict of interest policy. 
 
11.2 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB must approve the consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s) and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 


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Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. Each 
consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject and by the person who conducted the informed 
consent discussion. 
11.3 
Required Documentation (for multi-site studies) 
Before the study can be initiated at any sub-site, the following documentation must be 
provided to the UTSW Research Manager. 
 
• 
A copy of the official IRB approval letter for the protocol and informed consent 
• 
IRB membership list or Federal-wide Assurance letter 
• 
CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study 
• 
Form FDA 1572 appropriately filled out and signed with appropriate documentation 
(NOTE: This is required if UT Southwestern holds the IND. Otherwise, the affiliate 
Investigator’s signature on the protocol is sufficient to ensure compliance) 
• 
A copy of the IRB-approved consent form 
• 
Protocol Signature Page 
• 
Acknowledgement for bemcentinib Investigator’s Brochure (IB) 
• 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
• 
Signed site-specific monitoring plan 
• 
Executed clinical research contract 
11.4 
Registration Procedures 
 
All subjects must be registered with the multi-site IIT team at UTSW before enrollment to 
study. Prior to registration, eligibility criteria must be confirmed with the multi-site IIT team 
at UTSW. To register a subject, email SCCC-IIT@UTSouthwestern.edu and Kelly Kyle at 
Kelly.Kyle@UTSouthwestern.edu Monday through Friday, 9:00AM-5:00PM.  
 
Each site will be given a number beginning with 01. New subjects at each site will receive 
a number upon study consent such that the first subject consented is numbered 001, the 
second subject consented receives the number 002, etc. In practice, the first subject at the 
first site will be numbered 01-001, the first subject at the second site will be 02-001, This 
number will not change upon confirmation of eligibility and enrollment or screen failure. 
 
Each newly consented subject should be numbered using the schema provided above. 
Upon registration, the registrar will assign the additional registration/randomization code 
according to the numbering schema outlined above, which should then be entered as the 
patient study id in Velos upon updating the status to enrolled. 
 
 
11.5 
Data Management and Monitoring/Auditing 
REDCap is the UTSW SCCC institutional choice for the electronic data capture of case 
report forms for SCCC Investigator Initiated Trials. REDCap will be used for electronic case 


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report forms in accordance with Simmons Comprehensive Cancer Center requirements, 
as appropriate for the project 
 
In order to facilitate remote source to case report form verification, the Simmons 
Comprehensive Cancer Center study team will require other institutions participating in this 
trial as sub-sites to enter data into the selected EDC system and upload selected de-
identified source materials when instructed.  
 
Trial monitoring will be conducted according to the study specific monitoring plan. For 
guidance on creating a monitoring plan, refer to the UTSW SCCC IIT Management Manual.   
 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
UTSW SCCC clinical trials.  As part of that responsibility, the DSMC reviews all serious 
adverse events and UPIRSOs in real time as they are reported and reviews adverse events 
on a quarterly basis.  The quality assurance activity for the Clinical Research Office 
provides for periodic auditing of clinical research documents to ensure data integrity and 
regulatory compliance.  A copy of the DSMC plan is available upon request. 
 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. The Quality Assurance 
Coordinator (QAC) works as part of the DSMC to conduct regular audits based on the level 
of risk. Audit findings are reviewed at the next available DSMC meeting.  In this way, 
frequency of DSMC monitoring is dependent upon the level of risk.  Risk level is determined 
by the DSMC Chairman and a number of factors such as the phase of the study; the type 
of investigational agent, device or intervention being studied; and monitoring required to 
ensure the safety of study subjects based on the associated risks of the study. Protocol-
specific DSMC plans must be consistent with these principles.  
11.6 
Adherence to the Protocol 
Except for an emergency situation, in which proper care for the protection, safety, and well-
being of the study subject requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol.  
11.6.1 Exceptions (also called single-subject exceptions or single-subject waivers): 
include any departure from IRB-approved research that is not due to an 
emergency and is: 
• intentional on part of the investigator; or 
• in the investigator’s control; or 
• not intended as a systemic change (e.g., single-subject exceptions to eligibility 
[inclusion/exclusion] criteria) 
➢ Reporting requirement*: Exceptions are non-emergency deviations that 
require prospective IRB approval before being implemented. Call the IRB if 
your request is urgent. If IRB approval is not obtained beforehand, this 
constitutes a major deviation. For eligibility waivers, studies which utilize the 
SCCC-DSMC as the DSMC of record must also obtain approval from the 
DSMC prior to submitting to IRB for approval.  
11.6.2 Emergency Deviations: include any departure from IRB-approved research that 
is necessary to:  
• avoid immediate apparent harm, or 
• protect the life or physical well-being of subjects or others 
➢ Reporting requirement*: Emergency deviations must be promptly 


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reported to the IRB within 5 working days of occurrence. 
  
11.6.3 Serious Noncompliance (formerly called major deviations or violations): 
include any departure from IRB-approved research that: 
• Increase risk of harm to subjects; and/or 
adversely affects the rights, safety, or welfare of subjects (any of which may 
also be an unanticipated problem); and/or  
• adversely affects the integrity of the data and research (i.e., substantially 
compromises the integrity, reliability, or validity of the research) 
➢ Reporting requirement*: Serious Noncompliance must be promptly 
reported to the IRB within 5 working days of discovery. 
 
11.6.4 Continuing Noncompliance: includes a pattern of repeated noncompliance (in  
or more protocols simultaneously, or over a period of time) which continues after 
initial discovery, including inadequate efforts to take or implement corrective or 
preventive action within a reasonable time frame. 
➢ Reporting requirement*: Continuing Noncompliance must be promptly 
reported to the IRB within 5 working days of discovery. 
11.6.5  Noncompliance (that is neither serious nor continuing; formerly called 
minor deviations) any departure from IRB-approved research that: 
• Does not meet the definition of serious noncompliance or continuing 
noncompliance 
➢ Reporting requirement*: Noncompliance that is neither serious nor 
continuing should be tracked and summarized the next IRB continuing review, 
or the notice of study closure- whichever comes first.. 
 
*Reporting Requirements reflect UTSW HRPP/IRB guidelines; participating sites should follow 
the reporting guidelines for their IRB of record 
11.7 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended.  When an amendment to the protocol substantially alters the study design 
or the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
11.8 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, 
signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator retain all 
study documentation pertaining to the conduct of a clinical trial. In the case of a study with 


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a drug seeking regulatory approval and marketing, these documents shall be retained for 
at least two years after the last approval of marketing application in an International 
Conference on Harmonization (ICH) region. In all other cases, study documents should be 
kept on file until three years after the completion and final study report of this investigational 
study. 
11.9 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits may be conducted, and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will require 
his/her final signature to verify the accuracy of the data. 
 
12.0 
REFERENCES 
 
 
1. American Cancer Society sp. 2013;www.cancer.org. 
2. Matrisian L, Aizenberg R, Rosenzweig A. Pancreatic Cancer Action Network Special Report:  The 
alarming rise of pancreatic cancer deaths in the United States:  Why we need to stem the tide today. 
http://wwwpancanorg/section_research/reports/pdf/incidence_report_2012pdf 2012. 
3. Gessner C, Liebers U, Kuhn H, et al. BAX and p16INK4A are independent positive prognostic 
markers for advanced tumour stage of nonsmall cell lung cancer. The European respiratory journal 
2002;19:134-40. 
4. Gu CD, Osaki T, Oyama T, et al. Detection of micrometastatic tumor cells in pN0 lymph nodes of 
patients with completely resected nonsmall cell lung cancer: impact on recurrence and Survival. 
Annals of surgery 2002;235:133-9. 
5. Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, 
signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res 2008;100:35-83. 
6. Verma A, Warner SL, Vankayalapati H, Bearss DJ, Sharma S. Targeting Axl and Mer kinases in 
cancer. Mol Cancer Ther 2011;10:1763-73. 
7. Li Y, Ye X, Tan C, et al. Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, 
metastasis and angiogenesis. Oncogene 2009;28:3442-55. 
8. Rankin EB, Fuh KC, Taylor TE, et al. AXL is an essential factor and therapeutic target for metastatic 
ovarian cancer. Cancer Res 2010;70:7570-9. 
9. Vajkoczy P, Knyazev P, Kunkel A, et al. Dominant-negative inhibition of the Axl receptor tyrosine 
kinase suppresses brain tumor cell growth and invasion and prolongs survival. Proc Natl Acad Sci U 
S A 2006;103:5799-804. 
10. Chen PX, Li QY, Yang Z. Axl and prostasin are biomarkers for prognosis of ovarian adenocarcinoma. 
Ann Diagn Pathol 2013;17:425-9. 
11. Zhang Z, Lee JC, Lin L, et al. Activation of the AXL kinase causes resistance to EGFR-targeted 
therapy in lung cancer. Nat Genet 2012;44:852-60. 
12. Song X, Wang H, Logsdon CD, et al. Overexpression of receptor tyrosine kinase Axl promotes tumor 
cell invasion and survival in pancreatic ductal adenocarcinoma. Cancer 2011;117:734-43. 
13. Kirane A, Ludwig KF, Sorrelle N, et al. Warfarin Blocks Gas6-Mediated Axl Activation Required for 
Pancreatic Cancer Epithelial Plasticity and Metastasis. Cancer Res 2015;75:3699-705. 


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14. Ludwig KF, Du W, Sorrelle NB, et al. Small-Molecule Inhibition of Axl Targets Tumor Immune 
Suppression and Enhances Chemotherapy in Pancreatic Cancer. Cancer Res 2018;78:246-55. 
15. Paolino M, Choidas A, Wallner S, et al. The E3 ligase Cbl-b and TAM receptors regulate cancer 
metastasis via natural killer cells. Nature 2014;507:508-12. 
16. Ye X, Li Y, Stawicki S, et al. An anti-Axl monoclonal antibody attenuates xenograft tumor growth and 
enhances the effect of multiple anticancer therapies. Oncogene 2010;29:5254-64. 
17. Akalu YT, Rothlin CV, Ghosh S. TAM receptor tyrosine kinases as emerging targets of innate immune 
checkpoint blockade for cancer therapy. Immunol Rev 2017;276:165-77. 
18. Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, 
signalling and potential therapeutic targeting in human cancer. Adv Cancer Res 2008 100:35–83. 
19. Linger RM, Keating AK, Earp HS, Graham DK. Taking aim at Mer and Axl receptor tyrosine kinases 
as novel therapeutic targets in solid tumors. Expert Opin Ther Targets 2010 14(10):1073-1090. 
20.  Song X, Wang H, Logsdon CD, et al. Overexpression of receptor tyrosine kinase Axl promotes tumor 
cell invasion and survival in pancreatic ductal adenocarcinoma. Cancer 2011 117(4):734-43. 
21. Paccez JD, Vasques GJ, Correa RG, et al. The receptor tyrosine kinase Axl is an essential regulator 
of prostate cancer proliferation and tumor growth and represents a new therapeutic target. Oncogene 
2013 32:689–698. 
22.  Ishikawa M, Sonobe M, Nakayama E, et al. Higher Expression of Receptor Tyrosine Kinase Axl and 
Differential Expression of its Ligand, Gas6, Predict Poor Survival in Lung Adenocarcinoma Patients. 
Ann Surg Oncol 2013 Dec;20 Suppl 3:S467-476. 
23.  Zhang Z, Lee JC, Lin L, et al. Activation of the AXL kinase causes resistance to EGFR-targeted 
therapy in lung cancer. Nat. Genet. 2012 44:852-60. 
24. Gjerdrum C, Tiron C, Hoiby T, et al. Axl is an essential epithelial-to-mesenchymal transition-induced 
regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci USA 2010 
107(3):1124-1129. 
25.  Yuen H-F, McCrudden CM, Huang Y-H, et al. TAZ Expression as a Prognostic Indicator in Colorectal 
Cancer. PLOS ONE 2013 8(1):e54211. 
26.  Ben-Batalla I, Schultze A, Wroblewski M, et al. Axl, a prognostic and therapeutic target in acute 
myeloid leukemia mediates paracrine cross-talk of leukemia cells with bone marrow stroma. Blood. 
2013 Oct 3;122(14):2443-2452. 
27.  Byers LA, Diao L, Wang J, et al. An epithelial-mesenchymal transition gene signature predicts 
resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming 
EGFR inhibitor resistance. Clin. Cancer Res. 2013 19:279-90. 
28.  Holland SJ, Pan A, Franci C, et al. R428, a selective small molecule inhibitor of Axl kinase, blocks 
tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res. 2010 
70(4):1544-1554. 
29.  Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of 
malignant and stem cell traits. Nat Rev Cancer 2009 9: 265–273. 
30.  Nieto MA. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu 
Rev Cell Dev Biol 2011 27:347-376. 
31. Thomson S, Petti F, Sujka-Kwok I, et al. A systems view of epithelial-mesenchymal transition 
signaling states. Clin Exp Metastasis 2011 28(2):137-55. 
32.  Blick T, Hugo H, Widodo E, et al. Epithelial mesenchymal transition traits in human breast cancer cell 
lines parallel the CD44hi/CD24lo/- stem cell phenotype in human breast cancer. J Mammary Gland Biol 
Neoplasia. 2010 15(2):235-252. 
33. Vuoriluoto K, H Haugen H, Kiviluoto S, et al. Vimentin regulates EMT induction by Slug and 
oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene 2011 
30(12):1436-1448. 
34. Lou Y, Diao l, Byers LA et al. Association of epithelial-mesenchymal transition status with PD1/PDL1 
expression and a distinct immunophenotype in non-small cell lung cancer: Implications for 
immunotherapy biomarkers. J Clin Oncol 32:5s, 2014 (suppl; abstr 3018). 
35. Chen L, Gibbons DL, Goswami S, et al. Metastasis is regulated via microRNA-200/ZEB1 axis control 
of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun. 2014 28 
(5):5241. doi: 10.1038/ncomms6241. 
36. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel 
plus gemcitabine. N Engl J Med 2013;369:1691-703. 


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37. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic 
cancer. N Engl J Med 2011;364:1817-25. 
38. Jameson GS BE, Babiker HM, Poplin E, et al. A phase Ib/II pilot trial with nab-paclitaxel plus 
gemcitabine plus cisplatin in patients (pts) with stage IV pancreatic cancer. Journal of Clinical 
Oncology 2017;35, no. 4_suppl 341-. 
39. Desai N, et al. Increased endothelial transcytosis of nanoparticle albumin-bound paclitaxel (ABI-007) 
by gp60-receptors: a pathway inhibited by taxol. . Proceedings of San Antonio Breast Cancer 
Symposium2004. 
40. Commisso C, Davidson SM, Soydaner-Azeloglu RG, et al. Macropinocytosis of protein is an amino 
acid supply route in Ras-transformed cells. Nature 2013;497:633-7. 
41. Frese KK, Neesse A, Cook N, et al. nab-Paclitaxel potentiates gemcitabine activity by reducing 
cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer discovery 2012;2:260-9. 
42. Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and 
endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with 
cremophor-based paclitaxel. Clinical cancer research : an official journal of the American Association 
for Cancer Research 2006;12:1317-24. 
43. ten Tije A, Verweij J, Loos W et al. Pharmacological effects of formulation vehicles - Implications for 
cancer chemotherapy. Clin Pharmacokinet 2003; 42(7):665-685. 
44. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. 
45. Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials 1989;10:1-10. 
 
 
 


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13.0 
APPENDICES 
 
Appendix 1 
Examples of CYP3A4 substrates are provided below. A further source of information on CYP3A4 
substrates can be found at The University of Washington Metabolism and Transport Drug 
Interaction Database (see www.druginteractioninfo.org). 
 
University of Indiana CYP3A4, 5, 7 P450 Drug Interactions Abbreviated "Clinically 
Relevant" Table of Substrates 
 
Macrolide antibiotics: 
HIV Antivirals: 
HMG CoA Reductase 
Inhibitors: 
clarithromycin 
indinavir 
atorvastatin 
erythromycin (not 3A5) 
ritonavir 
lovastatin 
NOT azithromycin 
saquinavir 
NOT pravastatin 
telithromycin 
nevirapine 
NOT rosuvastatin 
  
 
simvastatin 
Anti-arrhythmics: 
Prokinetics: 
 
quinidine→3-OH 
cisapride 
Others: 
  
 
alfentanyl 
Benzodiazepines: 
Antihistamines: 
aripiprazole 
alprazolam 
astemizole 
boceprevir 
diazepam→3OH 
chlorpheniramine 
buspirone 
midazolam 
 
carbamazepine 
triazolam 
Calcium Channel 
Blockers: 
gleevec 
 
amlodipine 
haloperidol 
Immune Modulators: 
diltiazem 
pimozide 
cyclosporine 
felodipine 
quinine 
tacrolimus (FK506) 
nifedipine 
tamoxifen 
sirolimus 
nisoldipine 
telaprevir 
 
nitrendipine 
trazodone 
PDE-5 Inhibitors: 
verapamil 
vincristine 
sildenafil 
 
 
tadalafil 
 
 
vardenafil 
 
 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University 
School of Medicine (2007). "/clinpharm/ddis/clinical-table/" Accessed 20 October 2016. 
 
 
Pharmacy Times published List of CYP3A4 Substrates 
Alfentanil (Alfenta) 
Docetaxel 
(Taxotere) 
Ketoconazole 
(Nizoral) 
Quinine 
Alfuzosin 
(Uroxatral) 
Donepezil 
(Aricept) 
Lapatinib (Tykerb) 
Ranolazine 
(Ranexa) 


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Almotriptan (Axert) 
Doxorubicin 
(Adriamycin) 
Levomethadyl 
(Orlaam) 
Repaglinide 
(Prandin) 
Alprazolam 
(Xanax) 
Droperidol 
Loperamide 
(Imodium) 
Rifabutin 
(Rimactane) 
Amiodarone 
(Cordarone) 
Dutasteride 
(Avodart) 
Lopinavir (Kaletra) 
Ritonavir 
(Norvir) 
Amlodipine 
(Norvasc) 
Ebastine 
(Kestine) 
Loratadine 
(Claritin) 
Saquinavir 
(Invirase) 
Aprepitant 
(Emend) 
Efavirenz 
(Sustiva) 
Lovastatin 
(Mevacor) 
Sibutramine 
(Meridia) 
Atazanavir 
(Reyataz) 
Eletriptan 
(Relpax) 
Maraviroc 
(Selzentry) 
Sildenafil 
(Viagra) 
Atorvastatin 
(Lipitor) 
Eplerenone 
(Inspra) 
Mefloquine 
(Lariam) 
Simvastatin 
(Zocor) 
Bepridil (Vascor) 
Ergotamine 
(Ergomar) 
Methylprednisolone 
Sirolimus 
(Rapamune) 
Bexarotene 
(Targretin) 
Erlotinib 
(Tarceva) 
Midazolam 
(Versed) 
Solifenacin 
(Vesicare) 
Bosentan 
(Tracleer) 
Erythromycin 
Mifepristone 
(Mifeprex) 
Sufentanil 
(Sufenta) 
Bromocriptine 
(Parlodel) 
Estazolam 
(ProSom) 
Modafinil (Provigil) 
Sunitinib 
(Sutent) 
Budesonide 
(Entocort) 
Eszopiclone 
(Lunesta) 
Nefazodone 
Tacrolimus 
(Prograf) 
Buprenorphine 
(Subutex) 
Ethinyl Estradiol 
Nevirapine 
(Viramune) 
Tadalafil 
(Cialis) 
Bupropion (Zyban, 
Wellbutrin, Voxra) 
Ethosuximide 
(Zarontin) 
Nicardipine 
(Cardene) 
Tamoxifen 
(Nolvadex) 
Carbamazepine 
(eg, Tegretol) 
Etoposide 
(Vepesid) 
Nifedipine (Adalat) 
Tamsulosin 
(Flomax) 
Cevimeline 
(Evoxac) 
Exemestane 
(Aromasin) 
Nimodipine 
(Nimotop) 
Teniposide 
(Vumon) 
Cilostazol (Pletal) 
Felodipine 
(Plendil) 
Nisoldipine (Sular) 
Testosterone 
Cisapride 
(Propulsid) 
Fentanyl 
(Sublimaze) 
Nitrendipine 
(Baypress) 
Tiagabine 
(Gabitril) 
Clarithromycin 
(Biaxin) 
Finasteride 
(Proscar) 
Oxybutynin 
(Ditropan) 
Tinidazole 
(Tindamax) 
Clonazepam 
(Klonopin) 
Flurazepam 
(Dalmane) 
Oxycodone 
(Percodan) 
Tipranavir 
(Aptivus) 
Clopidogrel 
(Plavix) 
Fosamprenavir 
(Lexiva) 
Paclitaxel (Taxol) 
Topiramate 
(Topamax) 
Colchicine 
Galantamine 
(Reminyl) 
Paricalcitol 
(Zemplar) 
Triazolam 
(Halcion) 
Cyclophosphamide 
(Cytoxan) 
Gefitinib (Iressa) 
Pimozide (Orap) 
Vardenafil 
(Levitra) 
Cyclosporine 
(Neoral) 
Granisetron 
(Kytril) 
Pioglitazone 
Verapamil 
(Calan) 
Dapsone 
(Avlosulfon) 
Halofantrine 
(Halfan) 
Praziquantel 
(Biltricide) 
Vinblastine 
(Velbane) 
Darunavir 
(Prezista) 
Ifosfamide (Ifex) 
Prednisolone 
Vincristine 
(Oncovin) 
Dasatinib (Sprycel) 
Imatinib 
(Gleevec) 
Prednisone 
Ziprasidone 
(Geodon) 
Delavirdine 
(Rescriptor) 
Indinavir 
(Crixivan) 
Propoxyphene 
(Darvon) 
Zolpidem 
(Ambien) 
Dexamethasone 
(Decadron) 
Irinotecan 
(Camptosar) 
Quazepam (Doral) 
Zonisamide 
(Zonegran) 
Dihydroergotamine 
Isradipine 
(DynaCirc) 
Quetiapine 
(Seroquel) 
Zopiclone 
(Imovane) 


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Diltiazem (Cardizem) 
Itraconazole 
(Sporanox) 
Quinacrine 
 
Disopyramide 
(Norpace) 
Ixabepilone 
(Ixempra) 
Quinidine 
 
 
CYP3A4 Substrates obtained from: Pharmacy Times ‘Get to Know an Enzyme: CYP3A4’.  John R. Horn, 
PharmD, FCCP, and Philip D. Hansten, PharmD.  Published Online: Monday, September 1, 2008 
 
 


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Appendix 2 
 2C8 SUBSTRATES:  
AMODIAQUINE 
 
CERIVASTATIN 
 
PACLITAXEL 
 
REPAGLINIDE 
 
SORAFENIB 
 
TORSEMIDE 
 2C8 INHIBITORS:  
GEMFIBROZIL 
 
GLITAZONES (thiazolidinediones) 
 
MONTELUKAST 
 
QUERCETIN 
 
TRIMETHOPRIM 
 2C8 INDUCERS:  
RIFAMPICIN 
 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of 
Medicine (2007). "https://drug-interactions.medicine.iu.edu" Accessed 29 October 2018. 
 

ICF_001.pdf: 
STU062018-024, Beg, FormE-ConsentPhase1b, Mod_10, 08-09-21 
 
Page 1 of 20 
 
Phase 1b, v22Mar2021 
 The University of Texas Southwestern Medical Center  
Parkland Health & Hospital System 
 
Phase 1b Research Consent 
CONSENT TO PARTICIPATE IN RESEARCH 
 
 
Title of Research: 
A phase1b/2 clinical trial of chemotherapy and the AXL-
inhibitor bemcentinib for patients with metastatic 
pancreatic cancer 
Funding Agency/Sponsor: 
UT Southwestern Medical Center 
 
Study Doctor: 
Muhammad Beg, MD  
 
 
You may call the study doctor or research personnel during regular office hours at 214-
648-7097.  At other times, you may call them at 214-645-4673. 
 
Instructions: 
Please read this consent form carefully and take your time making a decision about 
whether to participate.  As the researchers discuss this consent form with you, please ask 
him/her to explain any words or information that you do not clearly understand.  The 
purpose of the study, risks, inconveniences, discomforts, and other important information 
about the study are listed below.  If you decide to participate, you will be given a copy of 
this form to keep. 
 
Why is this study being done? 
The purpose of this study is to test the effectiveness (how well the drug works), safety, 
and tolerability of the investigational drug combination of bemcentinib plus 
chemotherapy (nab-paclitaxel/gemcitabine/cisplatin) in patients with metastatic 
pancreatic adenocarcinoma.  
 
Bemcentinib (also known as BGB324 or R428) is an experimental oral drug that has not 
yet been approved by the FDA.  Bemcentinib inhibits (blocks) Axl, a surface membrane 
protein kinase receptor that is overexpressed in many human cancers including lung, 
breast, and pancreatic cancer.  By inhibiting Axl, bemcentinib inhibits the growth of 
tumor cells and also makes cancer cells more sensitive to chemotherapy. Bemcentinib 
is currently being tested across various types of solid tumor and hematologic cancers in 
combination with chemotherapy and immunologic treatments.  
Why is this considered research?  
This is a research study because we would like to determine the disappearance of 
tumor(s) identified and measured prior to starting bemcentinib plus chemotherapy (nab-
paclitaxel/gemcitabine/cisplatin) in patients with metastatic pancreatic cancer. 
 
 Nab-paclitaxel, gemcitabine and cisplatin combination is an option for treatment 
for metastatic pancreatic adenocarcinoma. However, due to the addition of 
IRB Approved Date: 8/9/2021


STU062018-024, Beg, FormE-ConsentPhase1b, Mod_10, 08-09-21 
 
Page 2 of 20 
 
Phase 1b, v22Mar2021 
bemcentinib to Nab-paclitaxel/gemcitabine/cisplatin, it is also considered 
investigational and is not approved by the U.S. Food and Drug Administration 
(FDA). 
 
The following definitions may help you understand this study:  
 .   
 Standard medical care means the regular care you would receive from your 
personal doctor if you choose not to participate in this research. 
 Researchers means the study doctor and research personnel at the University of 
Texas Southwestern Medical Center at Dallas and its affiliated hospitals. 
 
Why am I being asked to take part in this research study? 
You are being asked to take part in this study because you have pancreatic 
adenocarcinoma that is metastatic or recurrent.  
 
Conflict of Interest 
A member of the research team, Muhammad Beg, MD is a paid consultant of Bristol-
Myers Squibb. Bristol-Myers Squibb is the company who manufactures the drug 
Cisplatin, which will be considered standard of care for this study and will be billed to 
your insurance. 
   
Do I have to take part in this research study? 
No.  You have the right to choose whether you want to take part in this research study.  
If you decide to participate and later change your mind, you are free to stop participation 
at any time. 
 
If you decide not to take part in this research study it will not change your legal rights or 
the quality of health care that you receive at this center. 
 
How many people will take part in this study? 
About 44 people will take part in this study at UT Southwestern and Parkland Health & 
Hospital System and a number of other medical facilities around the country.  There will 
be a total of up to 44 people participating in this research study throughout the United 
States and/or other countries. 
 
What is involved in the study? 
If you volunteer to take part in this research study, you will be asked to sign this consent 
form and will have the following tests and procedures completed.  Some of the 
procedures may be part of your standard medical care, but others are being done solely 
for the purposes of this study. 
 
Screening Procedures 
To help decide if you qualify to be in this study, the researchers will ask you 
questions about your health, including any medications (including vitamins and 
nutritional supplements) you take and any surgical procedures that you have had. 
 
IRB Approved Date: 8/9/2021


STU062018-024, Beg, FormE-ConsentPhase1b, Mod_10, 08-09-21 
 
Page 3 of 20 
 
Phase 1b, v22Mar2021 
You may also have to fill out certain forms or have the following exams, tests or 
procedures: 
 
 
Medical History  
 
Assess your overall functioning using a specific scale for cancer patients 
(ECOG) 
 
Vital Signs  
 
Physical examination 
 
Blood draw (approx. 5 teaspoons) for the following:  
o Routine safety tests to evaluate blood count, liver, and 
kidney function.  
o CA 19-9 a test that measures the level of tumor-associated 
antigens (substances causing an immune response) found in 
the blood. 
o CPK – an enzyme found in your muscles  
 
Pregnancy test (either urine or serum (blood) pregnancy test). 
o If the urine pregnancy test is positive or cannot be confirmed 
as negative, a serum pregnancy test will be required. 
 
Electrocardiogram (ECG): an electrical tracing of your heart rhythm, done 
in triplicate.  
o Wires or “leads” will be attached to your chest with an adhesive 
and you will be asked to lie still while the machine prints out an 
electrical “record” of your heart’s activity 
 
Echocardiogram or MUGA: sonogram of the heart to determine how well 
the heart is pumping blood. 
 
Optional tumor tissue collection to assess the effect of chemotherapy and 
bemcentinib.  
 
Group Assignment 
This study is being conducted in two phases, Phase 1b and Phase 2.  Phase 1b is a 
safety run in to check the safety in using the combination of bemcentinib and 
chemotherapy (gemcitabine/nab-paclitaxel/cisplatin).  Based on the observed activity 
and tolerance of gemcitabine, nab-paclitaxel and cisplatin with bemcentinib in Phase 
1b, cisplatin is being removed from the treatment regimen in Phase 2. Phase 2 is a 
single arm phase 2 clinical trial of chemotherapy (gemcitabine and nab-paclitaxel) 
with bemcentinib. A revised safety run in will be completed in Phase 2 to verify the 
safety of the combination. You are currently participating in Phase 1b. 
 
Phase 1b: Safety run in (bemcentinib/gemcitabine/nab-paclitaxel/cisplatin) 
 Three patients will be enrolled for the safety run in to determine the starting dose 
of bemcentinib. 
o -If none of the first 3 patients experience a side effect from the combination 
of bemcentinib and chemotherapy (gemcitabine/nab-paclitaxel/cisplatin), 
then the randomized portion (part 2) of the trial will begin.  
o If at least 1 of the first 3 patients experiences a side effect of the combination 
IRB Approved Date: 8/9/2021


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Phase 1b, v22Mar2021 
of bemcentinib and chemotherapy (gemcitabine/nab- paclitaxel/cisplatin), 
then 3 additional patients will be treated at that dose level. 
o If no more than 1 of the first 6 patients experiences a side effect of the 
combination of bemcentinib 
and 
chemotherapy 
(gemcitabine/nab-
paclitaxel/cisplatin), then the randomized portion of the trial will begin. 
o If 2 or more of the first 6 patient’s experiences a side effect of the 
combination of bemcentinib 
and 
chemotherapy 
(gemcitabine/nab-
paclitaxel/cisplatin) and the dosage is more than the maximum tolerated 
dose, a lower dose level will be explored. 
 
Phase 2: Single Arm (bemcentinib/nab-paclitaxel/gemcitabine) 
 Subjects in this phase will be assigned to receive the combination of 
bemcentinib and chemotherapy (gemcitabine/nab-paclitaxel). The first 6 
patients in this phase will participate in a revised safety run in to ensure the 
safety of this combination. 
 
Study Medication/Intervention 
Subjects participating in phase 1 of the study you will take: 
 
o Bemcentinib daily, orally (by mouth) starting on Cycle 1 day 2 
o You will be asked, not to eat for at least two hours before and one hour 
following the bemcentinib dose.  You will take bemcentib at the same time 
each day. 
o Nab-Paclitaxel given intravenously on Day 1 and 8 every 21 days 
o Gemcitabine given intravenously on Day 1 and 8 every 21 days 
o Cisplatin given intravenously on Day 1 and 8 every 21 days 
 
Procedures for storing of extra or left over samples 
Subject samples collected for this study will be retained at University of Texas 
Southwestern Medical Center. Specimens will be stored indefinitely or until they 
have been completely used. If future use is denied or withdrawn by you, best efforts 
will be made to stop any additional studies and to destroy the specimens. 
 
Muhammad Beg, MD, will be responsible for reviewing and approving requests for 
clinical specimen from potential research collaborators outside of University of Texas 
Southwestern Medical Center.  
 
Collaborators will be required to complete an agreement that states specimens will 
only be released for use in disclosed research. Any data obtained from the use of 
clinical specimen will be the property of University of Texas Southwestern Medical 
Center for publication and any licensing agreement will be strictly adhered to. 
 
 
Do you agree to take part in the Optional Tissue for correlative analysis?  
Please indicate your choice by completing your initials on the line next to your choice. 
 
___________ Yes, I agree to take part in the optional tissue biopsy. 
IRB Approved Date: 8/9/2021


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Phase 1b, v22Mar2021 
 
___________ No, I do not agree to take part in the optional tissue biopsy 
 
Procedures and Evaluations during the Research 
 
Please note each cycle of treatment is 21 days in length 
 
Day 1 
 
Inclusion/exclusion review (Cycle 1 only)  
 
Physical exam  
 
Vital Signs  
 
Measurement of weight and Body Surface Area (BSA) calculation prior to 
dosing   
 
Assess your overall functioning using a specific scale for cancer patients 
(ECOG) 
 
Blood draw (approx. 4 teaspoons) for the following:  
o Routine safety tests to evaluate blood count, liver, and 
kidney function. 
o Blood for correlative analysis to assess the effect of 
chemotherapy and bemcentinib 
o CA 19-9 (C3 and every subsequent odd cycle Day 1) 
o CPK (C3 and every subsequent odd cycle Day 1) 
 
EKG (Cycle 2 and beyond ) 
 
Pregnancy test 
 
Evaluation of your baseline sign/symptoms  
 
Review all medications that you are currently taking  
 
Administration of chemotherapy  
 
Blood draw for pharmacokinetic (PK) testing (approximately 1 teaspoons 
at cycles 2, 3 and 4 only). PK testing is testing that show how the body 
processes the drug.  (1st 15 patients only) 
 
Tumor imaging will be completed to measure your tumor before C3 and 
prior to every odd cycle 
 
Optional Tissue biopsy for correlative analysis. The on-treatment tissue 
collection will be performed during Cycle 2 or Cycle 3 in patients who have 
consented to tissue collection. 
 
Day 2 (Only cycle 1 for patients receiving bemcentinib) 
 
Vital Signs  
 
EKG 
 
Blood draw (approximately 4 teaspoons) for the following: 
o Routine safety tests to evaluate blood count, liver, and kidney 
function. 
o Blood for correlative analysis to assess the effect of chemotherapy 
and bemcentinib 
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Phase 1b, v22Mar2021 
 
Adverse events or side effects will be evaluated 
 
Review all medications that you are currently taking  
 
Start bemcentinib- you will take this first dose in clinic.  
 
Day 4 (Only cycle 1 for patients receiving bemcentinib) 
 
Vital Signs  
 
EKG 
 
Adverse events or side effects will be evaluated 
 
Blood draw to evaluate blood counts 
 
Blood draw for PK testing (approximately 1 teaspoon) (1st 15 patients only) 
 
Review all medications that you are currently taking  
 
Bemcentinib – you will be asked to take this in the clinic 
 
Day 8 of each cycle   
 
Vital Signs 
 
Assess your overall functioning using a specific scale for cancer patients 
(ECOG) (Cycle 1 only). 
 
Blood draw (approximately 5 teaspoons) for the following: 
o Routine safety tests to evaluate blood count, liver, and kidney 
function. 
o Blood for correlative analysis (pre-bemcentinib treatment) to assess 
the effect of chemotherapy and bemcentinib (Cycle 1 and 2 only) 
 
Adverse events or side effects will be evaluated 
 
Blood draw for PK testing (Cycle 1 only)  approximately 1.5 teaspoons (1st 
15 patients only)                                      
 
EKG (to be completed on bemcentinib patients only) 
 
Administration of chemotherapy  
 
Bemcentinib -you will be asked to take this in the morning prior to coming 
to clinic. 
 
Day 11 (Only cycle 1 for patients receiving bemcentinib) 
 
Vital Signs  
 
EKG 
 
Adverse events or side effects will be evaluated 
 
Blood draw for PK testing - approximately 1 teaspoon (1st 15 patients only) 
 
Review of all medications that you are currently taking  
 
 Bemcentinib - you will be asked to take this in the clinic  
 
 
Day 15 of each cycle 
 
Vital Signs  
 
Blood draw (approximately 5 teaspoons) for the following: 
o Routine safety tests to evaluate blood count, liver, and kidney 
function. 
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Phase 1b, v22Mar2021 
o Blood for correlative analysis (pre-bemcentinib treatment) to assess 
the effect of chemotherapy and bemcentinib (Cycle 1 and 2 only) 
 
Blood draw for PK testing - approximately 1 teaspoon (1st 15 patients only) 
 
EKG for bemcentinib patients only 
 
Administration of chemotherapy 
 
Bemcentinib dosing – you will be asked to take this in the clinic 
 
 
 
Day 18 (Only cycle 1 for patients receiving bemcentinib) 
 
Vital Signs  
 
EKG 
 
Adverse events or side effects will be evaluated 
 
Review of all medications that you are currently taking  
 
Bemcentinib dosing - you will be asked to take this at home 
 
 
Off Treatment Visit (30 days after last dose) 
 
Physical exam 
 
Measurement of weight (kg) and BSA calculation 
 
Vital signs 
 
Assess your overall functioning using a specific scale for cancer patients 
(ECOG) 
 
CA 19-9 a test that measures the level of tumor-associated antigens 
(substances causing an immune response) found in the blood. 
 
CPK 
 
EKG (only for patients that received bemcentinib) 
 
Blood draw  (approximately 5 teaspoons) for the following: 
o Routine safety tests to evaluate blood count, liver, and 
kidney function. 
o Blood for correlative analysis to assess the effect of 
chemotherapy and bemcentinib 
o Blood for RNA sequencing  
 
Adverse events or side effects will be evaluated 
 
Any medication that you are currently taking will be discussed 
Follow-up Procedures 
- 
You will be followed every month after completion of (or early withdrawal 
from) study treatment until resolution of treatment related side effects.  
- 
You will be followed for long term status every 3 months (this may be done 
through either a medical record review or follow up phone calls), from your 
off treatment visit date, until death or you withdraw consent from follow-up.   
 
How long can I expect to be in this study? 
The estimated time you might be in the study is about 30 months. However, the Study Doctor 
IRB Approved Date: 8/9/2021


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Phase 1b, v22Mar2021 
may discontinue study treatment at any time if it is determined your disease has worsened, 
you experience intolerable or unacceptable side effects, your doctor determines that your 
safety is at risk, you become pregnant, you have a disappearance of tumor(s) identified 
before starting  the study medication, or the study ends.  
 
You can choose to stop participating for any reason at any time.  However, if you decide 
to stop participating in the study, we encourage you to tell the researchers.  You may be 
asked if you are willing to complete some study termination tests. 
 
What are the risks of the study? 
As with all research studies, the study medication and study procedures may involve 
unknown risks. Any medication can have temporary and permanent side effects and 
can cause unforeseen adverse reactions. 
 
Study Procedure/Intervention 
Because of your participation in this study, you are at risk for the following side effects. 
You should discuss these with the researchers and your regular health care provider.  
 
What are the risks that can be anticipated with bemcentinib:  
The following side effects have been reported in other patients who have received 
bemcentinib alone or in combination with other cancer treatments. 
 
Very common side effects (occurring in 20 of 100 people or more): 
 Diarrhea 
 Feeling sick 
 Changes in liver enzymes which may indicate inflammation in the liver 
(particularly in combination with other drugs) 
 Changes in the electrical activity of the heart, known as QT prolongation – more 
details are provided below 
 
Common side effects (occurring in at least 5 but less than 20 of 100 people) 
 Fatigue 
 Vomiting 
 Decreased red blood cells (anemia) 
 Decreased appetite 
 Changes in blood tests that may indicate altered kidney function 
 Rash (particularly in combination with other drugs) 
 
QT prolongation is when the heart muscle takes longer than normal to recharge its 
electrical impulses between beats. These electrical impulses are needed to help the 
heart to beat regularly. Most patients who experience QT prolongation do not 
experience any symptoms and only show signs on an ECG. If patients do have 
symptoms with QT prolongation, which are uncommon and due to erratic heart beats, 
these may include light headedness, heart palpitations, irregular heartbeat, weakness or 
blurred vision – such symptoms may precede fainting. Occasionally heart irregularities 
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Phase 1b, v22Mar2021 
can lead to fainting without warning. If heart rate abnormalities continue this may also 
result in epileptic-type seizures. 
 
If you are considered to have any risk factors for the development of an abnormal heart 
rhythm, caused by a QTc prolongation, you will not be able to take part in this study. If 
you do participate in this study your heart function will be closely monitored through 
ECGs. 
 
Side effects involving the digestive system experienced by patients in clinical trials with 
bemcentinib included nausea, vomiting and diarrhea. In almost all cases these side 
effects were controlled by medication, but occasionally treatment breaks were also 
required. 
 
Many of the patients with leukemia who were treated with bemcentinib experienced 
infections or fever when their white blood cells were low, although in the majority of 
these cases, the cause of the infection was thought to be due to their leukemia rather 
than bemcentinib. 
 
In some of the patients who were treated with bemcentinib in combination with other 
cancer treatments, increase in liver enzymes was noted on blood tests. This may 
indicate inflammation in the liver, however in almost all of the cases this was temporary, 
and the liver enzymes returned back to normal after few days either spontaneously or 
with treatment. 
  
 
Below listed are the risks associated with the chemotherapy medications that will be 
given in this study. It should be noted that the potential occurrence of adverse effects for 
each of the products stated may be increased when the three medications are used in 
combination. 
 
What are the risks that can be anticipated with Nab-paclitaxel: 
Very common side effects (occurring in > 1/10 of patients): 
 Low white blood cell count - which may temporarily place you at risk for infections, 
including oral thrush, respiratory infection, and pneumonia. 
 Low red blood cell count – which may cause you to feel tired, look pale, and have 
shortness of breath) 
 Low platelet count - which may lead to bruising or bleeding) 
 Changes in ECG tracings of the heart rhythm, or increased or decreased or 
irregular heart rate 
 Increase in liver function tests (AST and ALT) 
 Increase in kidney function tests (creatinine)  
 Shortness of breath 
 Pneumonitis or inflammation of the walls of the lungs 
 
Common side effects (occurring in > 1/100 to 1/10 of patients) 
 Fatigue 
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Phase 1b, v22Mar2021 
 Numbness, tingling or burning of hands and feet 
 Fluid retention in the hands and feet  
 Fever 
 Nausea 
 Vomiting 
 Diarrhea 
 Hair loss (reversible) 
 Appetite loss 
 Rash 
 Dehydration 
 Pneumonia 
 Cardiac ischemia/infarction (heart attack) 
 Chest pain, cardiac arrest, fast heart beat 
 Blockage of a blood vessel 
 Blockage of a vessel in the lung leading to shortness of breath, pain and potentially 
coughing up blood 
 Hypertension 
 Strokes or temporary blockages of vessels in the brain 
 Cough 
 Visual disorders including keratitis (inflammation of part of the eye), cystoid 
macular edema (painless edema in part of the eye) 
 Muscle or joint pain 
 Urinary tract infections 
 Nail changes 
 Nosebleeds 
 
Uncommon side effects (occurring in > 1/1000 to 1/100 of patients): 
 Serious allergic reaction  that may include symptoms such as shortness of breath, 
flushing, low blood pressure, chest pain, irregular or slow heart beats, trouble 
breathing.  
 
Rare side effects (occurring in > 1/10,000 to <1/1,000 patients) 
 
Nab- paclitaxel contains human albumin, a derivative of human blood.  Based on effective 
donor screening and product manufacturing processes, it carries a remote risk from 
transmission of viral diseases.  A theoretical risk for transmission of Creutzfeldt-Jakob 
Disease (CJD) also is considered extremely remote. No cases of transmission of viral 
diseases or CJD have ever been identified for albumin. 
 
What are the risks that can be anticipated with Cisplatin 
Very common side effects (occurring in > 1/10 of patients), some may be serious i.e. 
causing hospitalization, life-threatening or where noted, may cause death: 
 
 Kidney (abnormal function or failure) 
 Low platelet count - which may lead to bruising or bleeding 
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Phase 1b, v22Mar2021 
 Low white blood cell count - which may temporarily place you at risk for infection 
 Low red blood cell count – which may cause you to feel tired, look pale, and have 
shortness of breath 
 Fever associated with low white blood count 
 Nausea 
 Vomiting 
 Diarrhea 
 Loss of taste  
 Loss of appetite 
 Dry skin 
 Dehydration 
 Hair loss (reversible) 
 
Common side effects (occurring in > 1/100 to 1/10 of patients): 
 Low magnesium, low calcium and low potassium levels which may lead to muscle 
cramps 
 Liver function test abnormal( increase in liver enzymes and bilirubin) 
 Numbness, tingling, pain, or burning of hands and feet 
 Sepsis (life threatening condition when body’s response to infection causes organ 
damage) 
 Irregular heartbeat 
 Inflammation of a vein at injection site 
 Difficulty breathing, inflammation of the lungs, and respiratory failure 
 Tinnitus (ringing in ears)  
 
Uncommon side effects (occurring in > 1/1000 to < 1/100 of patients): 
 Myocardial infarction (heart attack) 
 Heart block 
 Heart failure 
 Arterial vasospasm (constriction of the blood vessels) 
 Low blood pressure 
 Stroke 
 Blockage in the kidney capillaries that may cause kidney failure 
 Visual disturbances (temporary), Flashing light or blurry vision, altered color 
perception 
 
 
Rare side effects (occurring in > 1/10,000 to <1/1,000 patients) 
 
 Serious allergic reaction that may include symptoms such as: swelling of the 
face, tongue, throat, itching, wheezing, trouble breathing, dizziness, increased 
heart rate and low blood pressure. 
 Toxicity of the eyes sometime severe but usually reversible (such as 
inflammation of the optic nerve, swelling of the optic disc and possible cerebral 
blindness).   
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Phase 1b, v22Mar2021 
 Soft tissue damage at the site of injection leading to irreversible tissue damage. 
 Loss of certain types of brain function characterized by spasms and reduced 
levels of consciousness. 
 Hearing loss 
 Reduced albumin levels in blood 
 Inflammation of the mucous membranes of the mouth 
 Increased risk of leukemia 
 
What are the risks that can be anticipated Gemcitabine   
Very common side effects (occurring in > 1/10 of patients): 
 
 Low red blood cell count – which may cause you to feel tired, look pale, and have 
shortness of breath) 
 Low platelet count (which can lead to bruising or bleeding) 
 Low white blood cell count (which may temporarily place you at risk for infection) 
 Constipation 
 Lack of appetite 
 Fever 
 Flu-like symptoms (fever, feeling tired, loss of appetite, chills and cough) 
 Hair loss (reversible) 
 Liver function tests abnormal 
 Protein in urine 
 Blood in urine 
 Fluid retention in the hands and feet 
 Muscle or joint pain 
 Nausea 
 Vomiting 
 Rash 
 Numbness, tingling, pain, or burning of hands and feet 
 Inflammation of the mucous membranes of the mouth 
 
Common side effects (occurring in > 1/100 to 1/10 of patients): 
 Fever associated with low white blood cells 
 
Uncommon side effects (occurring in > 1/1000 to < 1/100 of patients): 
 Abnormal kidney function or failure 
 Build up of urea in the kidneys  
 Sepsis (life threatening condition when body’s response to infection causes organ 
damage) 
 Irritation or bruising at the site of the infusion 
 Serious allergic reaction that may include symptoms such as: swelling of the face, 
tongue, throat, itching, wheezing, trouble breathing, dizziness, increased heart rate 
and low blood pressure 
 Serious lung toxicity including inflammation of the lungs, spasm of the lungs, 
swelling of the lungs and adults respiratory distress syndrome (ARDS) 
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Phase 1b, v22Mar2021 
 
Rare side effects (occurring in > 1/10,000 to <1/1,000 patients) 
 Increase of toxicities with radiation therapy 
 Capillary leak syndrome a condition in which fluid and proteins leak out of tiny 
blood vessels into surrounding tissue.  This can result in dangerously low blood 
pressure, low albumin and a decrease in plasma volume. 
 Swelling of the brain that may lead to headache, confusion, seizures, and loss of 
vision. 
 
Risks of Radiation – Diagnostic Test 
The radiation dose that you will get from diagnostic tests is medically indicated for your 
condition and it is the same that you would get if you were not involved in this research 
study. 
CT Scan: CT scans are used to create images of internal bones and organs using 
radiation. The contrast solution that may be given for a CT scan may cause an allergic 
reaction (rare). Severe allergic reactions can be life threatening. CT contrast solution 
can cause kidney damage, especially if you are diabetic, dehydrated (lost body water) 
or elderly. 
 
Magnetic Resonance Imaging (MRI): There are no known risks from exposure to 
magnetic fields. You may experience nervousness and/or anxiety due to the loud 
banging made by the machine while it is taking pictures and from confinement in a tight 
space (claustrophobia). If you become anxious, you can stop the procedure at any time. 
You may also experience some discomfort and fatigue from lying still during 
imaging. 
 
If you have any metal clips or plates in your body, you should tell the investigator. 
MRI may not be appropriate if you are pregnant or are trying to become 
pregnant. MRI may not be appropriate if you have permanent eyeliner or 
eyebrows or any pieces of metal in your body, such as the following: 
 heart pacemaker, heart valve replacement, or aortic clips 
 metal fragments in your eyes, skin, or elsewhere in your body 
 brain clips or pieces of metal used in aneurysm surgery or intercranial bypass 
 venous umbrella 
 pieces of metal in the body resulting from work as a sheet-metal worker or welder 
 clips placed in an internal organ 
 prosthetic devices, such as middle ear, eye, joint, or penile implants 
 joint replacement. 
 hearing aid that cannot be removed 
 neurostimulator 
 insulin pump 
 intrauterine device (IUD) 
 shunts or stents 
 metal mesh or coil implants 
 metal plate, pin, screws, or wires, or any other metal implants 
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If you have a history of an implanted device or clips in your pelvis (involving your uterus 
or fallopian tubes) or under your skin, acting as a contraceptive to prevent pregnancy, 
the MRI technologist will obtain specific information about the make and model of your 
 
Psychological Stress 
Some of the questions we will ask you as part of this study may make you feel 
uncomfortable.  You may refuse to answer any of the questions, take a break or stop 
your participation in this study at any time. 
 
Loss of Confidentiality 
Any time information is collected; there is a potential risk for loss of confidentiality.  
Every effort will be made to keep your information confidential; however, this cannot be 
guaranteed.  
 
Risks to Sperm, Embryo, Fetus or Breast-fed Infant 
Males: Being in this research may damage your sperm, which could cause harm to a 
child that you may father while on this study. If you take part in this study and are 
sexually active, you must agree to use a medically-acceptable form of birth control 
through 120 days following your last dose of study drug. Medically-acceptable forms of 
birth control include: 
(1) surgical sterilization (vasectomy), or 
(2) a condom used with a spermicide (a substance that kills sperm). 
 
Females: If you are part of this study while pregnant or breast-feeding an infant, it is 
possible that you may expose the unborn child or infant to risks.  For that reason, 
pregnant and breast-feeding females cannot participate in the study.  If you can become 
pregnant, a pregnancy test will be done, and it must be negative before you participate 
in this study. If you take part in this study and you are sexually active, you and any 
person that you have sex with must use a medically-acceptable birth control 
(contraceptives) through 120 days your last dose of study drug.  Medically-acceptable 
birth control (contraceptives) includes: 
(1) surgical sterilization (such as hysterectomy or “tubes tied”), 
(2) approved hormonal contraceptives ( such as birth control pills, patch or ring; 
Depo-Provera, Implanon), 
(3) barrier methods (such as condom or diaphragm) used with a spermicide (a 
substance that kills sperm), or  
(4) an intrauterine device (IUD). 
If you do become pregnant during this study, you must tell the researchers immediately. 
 
Radiation exposure to a woman’s reproductive organs may harm an embryo or fetus.  
Also, if radioactive materials are used for certain types of scans, harm may come to an 
embryo, fetus, or an infant who is breast feeding.   
 
Pregnancy tests performed during the early stages of pregnancy do not always reveal 
pregnancy.  Therefore, radiation exposure that includes the reproductive organs will be 
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Phase 1b, v22Mar2021 
limited to the first ten days after a woman who can become pregnant has begun her 
most recent menstrual period.  This is standard policy in clinics and hospitals within UT 
Southwestern.  This policy applies unless there is an important medical reason requiring 
radiation outside this time frame 
 
Risks of Blood Drawing 
Risks associated with drawing blood from your arm include minimal discomfort and/or 
bruising.  Infection, excess bleeding, clotting, and/or fainting also are possible, although 
unlikely. 
 
You will have approximately 10 tablespoons of blood collected because you are in this 
research study. 
 
Risk of Optional Tumor Samples (collected by biopsy) 
The biopsy may cause some pain and discomfort and may result in some bleeding and 
bruising. It is possible, but not likely, that you could get an infection. In very rare cases, 
people might have an allergic reaction to the numbing medicine. The allergic reaction 
could include rash/hive, flushing of the face, itching, wheezing and tightness in the throat. 
There will be a small scar from the biopsy.   
Other Risks 
There may possibly be other side effects that are unknown at this time. If you are 
concerned about other, unknown side effects, please discuss this with the researchers. 
 
How will risks be minimized or prevented?   
Study risks will be minimized or prevented by several measures at the beginning of the 
study and throughout your participation in the study.  
 
 
You will be screened prior to enrollment to ensure that you meet the safety 
requirements of the study.  All treatments will be modified within the study parameters to 
match your treatment needs. These modifications will include the timing and technical 
details of your operation. Throughout your participation in the study you will be 
evaluated by personnel trained to recognize, minimize, and treat side effects of your 
treatment. You will be withdrawn from the study if you experience an adverse event 
which causes unacceptable risk as determined by the investigators.  You will continue 
to receive standard medical care if you are no longer participating in the study.  
 
What will my responsibilities be during the study?   
While you are part of this study, the researchers will follow you closely to determine 
whether there are problems that need medical care.  It is your responsibility to do the 
following: 
 Ask questions about anything you do not understand. 
 Keep your appointments. 
 Follow the researchers’ instructions. 
 Let the researchers know if your telephone number or address changes. 
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 Tell the researchers before you take any new medication, even if it is prescribed 
by another doctor for a different medical problem or something purchased over 
the counter. 
 Tell the study doctor or study staff about any changes in your health. 
 Tell your regular doctor about your participation in this study. 
 Report to the researchers any injury or illnesses while you are on study even if 
you do not think it is related.  
 
If I agree to take part in this research study, will I be told of any new risks that 
may be found during the course of the study? 
Yes.  You will be told if any new information becomes available during the study that 
could cause you to change your mind about continuing to participate or that is important 
to your health or safety. 
 
What should I do if I think I am having problems? 
If you have unusual symptoms, pain, or any other problems while you are in the study, 
you should report them to the researchers right away.  Telephone numbers where they 
can be reached are listed on the first page of this consent form. 
 
If you have a sudden, serious problem, like difficulty breathing or severe pain, go to the 
nearest hospital emergency room, or call 911 (or the correct emergency telephone 
number in your area).  Tell emergency personnel about any medications you are taking, 
including any medications you are taking for this study.   
 
What are the possible benefits of this study? 
If you agree to take part in this study, there may or may not be direct benefits to you.  
The researchers cannot guarantee that you will benefit from participation in this 
research. 
 
We hope the information learned from this study will benefit others with pancreatic 
cancer in the future.  Information gained from this research could lead to better 
treatment.   
 
What options are available if I decide not to take part in this research study? 
You do not have to participate in this research to receive care for your pancreatic cancer. 
Instead of being in this study, you have the following options: 
 Evaluation by a medical oncologist for chemotherapy regimens such as Nab-
Paclitaxel/ gemcitabine and FOLFIRINOX for metastatic/ recurrent pancreatic 
cancer 
 Evaluation by a radiation oncologist for standard radiation treatment 
 Observation and supportive care 
 Participation in another research study 
 
By participation in this research, you may be forgoing other standard options with known 
clinical benefit.  
 
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Will I be paid if I take part in this research study? 
No. You will not be paid to take part in this research study.  There are no funds 
available to pay for parking expenses, transportation to and from the research center, 
lost time away from work and other activities, lost wages, or child care expenses. 
 
Costs – Will taking part in this study cost anything? 
You or your health insurance company will be responsible for the cost of treatments and 
procedures that would be done whether or not you took part in this study, such as 
standard of care procedures described in the procedures section above. It is important 
to understand that some insurance companies do not cover some costs (for example, 
approved drugs used in a way different from the package instructions). If your insurance 
company does not cover these treatments or procedures, you will be required to pay for 
them. 
 
Ask the researchers if you have any questions about what it will cost you to take part in 
this study (for example bills, fees, or other costs related to the research). 
 
The sponsor will provide the study drug, bemcentinib, free of charge during this study. 
At the end of your participation you must return all unused study drug to the researcher. 
 
What will happen if I am harmed as a result of taking part in this study? 
Compensation for an injury resulting from your participation in this research is not 
available from the University of Texas Southwestern Medical Center at Dallas or 
Parkland Health & Hospital System. 
 
The sponsor, UT Southwestern, has expressed a willingness to help pay the medical 
expenses necessary to treat such an injury. 
 
You retain your legal rights during your participation in this research. 
 
If you have any questions concerning the availability of medical care or if you think you 
have experienced a research-related illness, injury or emergency, contact the research 
team listed at the top of this form immediately. 
 
Can I stop taking part in this research study? 
Yes.  If you decide to participate and later change your mind, you are free to stop taking 
part in the research study at any time. 
 
If you decide to stop taking part in this research study, it will not affect your relationship 
with the UT Southwestern staff or doctors.  Whether you participate or not will have no 
effect on your legal rights or the quality of your health care you receive. 
 
If you are a medical student, fellow, faculty, or staff at the Medical Center, your status 
will not be affected in any way. 
 
Your doctor is a research investigator in this study.  He is interested in both your 
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medical care and the conduct of this research study.  At any time, you may discuss your 
care with another doctor who is not part of this research study.  You do not have to take 
part in any research study offered by your doctor. 
 
If I agree to take part in this research study, can I be removed from the study 
without my consent? 
Yes.  The researchers may decide to take you off this study if: 
 Your medical problem remains unchanged or becomes worse. 
 The researchers believe that participation in the research is no longer safe for 
you. 
 The researchers believe that other treatment may be more helpful. 
 The sponsor or the FDA stops the research for the safety of the participants. 
 The sponsor cancels the research. 
 If you become pregnant. 
 You are unable to keep appointments or to follow the researcher’s instructions. 
 
Will my information be kept confidential? 
Medical information collected during this study and the results of any test or procedure 
that may affect your medical care may be included in your medical record. The 
information included in your medical record will be available to health care providers 
and authorized persons including your insurance company. 
 
You should know that certain organizations that may look at and/or copy your medical 
records for research, quality assurance, and data analysis include: 
• 
UT Southwestern Medical Center  
 
BerGenBio ASA, collaborator and provider of bemcentinib. 
• 
Representatives of government agencies, like the U.S. Food and Drug 
Administration (FDA), involved in keeping research safe for people; and 
• 
The UT Southwestern Institutional Review Board.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results.  You can search this Web 
site at any time. 
 
In addition to this consent form, you will be asked to sign an "Authorization for Use and 
Disclosure of Protected Health Information."  This authorization will give more details 
about how your information will be used for this research study, and who may see 
and/or get copies of your information. 
 
Are there procedures I should follow after stopping participation in this research? 
 Let the researchers know immediately that you wish to withdraw from the 
research. 
 Return to the research center for any tests that may be needed for your safety. 
 Return any unused study materials, including empty containers. 
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 Discuss your future medical care, if any, with the researchers and/or your 
personal doctor. 
 
Whom do I call if I have questions or problems? 
For questions about the study, contact Muhammad Beg, MD at (214) 648.7097 during 
regular business hours and at (214) 645.4673 after hours and on weekends and 
holidays.   
 
For questions about your rights as a research participant, contact the UT Southwestern 
Institutional Review Board (IRB) Office at 214-648-3060. 
 
 
 
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Phase 1b, v22Mar2021 
SIGNATURES: 
 
YOU WILL BE GIVEN A COPY OF THIS CONSENT FORM TO KEEP. 
 
Your signature below certifies the following: 
 
 You have read (or been read) the information provided above. 
 You have received answers to all of your questions and have been told who to 
call if you have any more questions. 
 You have freely decided to participate in this research. 
 You understand that you are not giving up any of your legal rights. 
 
 
____________________________________________ 
 
 
Name of Participant (Printed) 
 
 
____________________________________________ 
________ 
_______ AM / PM 
Signature of Participant 
Date 
Time 
 
____________________________________________ 
 
 
Name of Person Obtaining Consent (Printed) 
 
 
____________________________________________ 
________ 
_______ AM / PM 
Signature of Person Obtaining Consent 
Date 
Time 
 
Witness  
I attest that the information in the consent form was accurately explained to, and 
apparently understood by the subject or the subject's legal authorized representative, 
and that informed consent was freely given by the subject or the subject’s legal 
authorized representative. 
____________________________ 
 
 
     ________     _______AM / PM 
Name of Witness (Printed)  
 
 
 
 
Date  
Time 
__________________________                                       ________     _______AM / PM 
Signature of Witness                                                                Date                Time 
 
IRB Approved Date: 8/9/2021