Phase 1 Trial of Dose Escalated BGB324 in Combination With Docetaxel for Previously Treated Advanced Non-small Cell Lung Cancer (NSCLC)
Phase: PHASE1
Conditions: Non-Small Cell Lung Carcinoma
Sponsor: University of Texas Southwestern Medical Center

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Official title: SPOC-2015-01: Phase 1 trial of dose escalated 
BGB324 in combination with docetaxel for previously treated 
advanced non-small cell lung cancer (NSCLC) 
NCT number: NCT02922777 
IRB approved date: 07/22/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL NUMBERS: 
SPOC-2015-01  
 
TITLE: 
Phase 1 trial of dose escalated Bemcentinib BGB324 in combination 
with docetaxel for previously treated advanced non-small cell lung 
cancer (NSCLC) 
 
 
ORIGINAL VERSION NUMBER:             1.0 
ORIGINAL VERSION DATE: 
 
05/22/15 
REVISIONS 
 
  
1.0 dated 23 February 2016 
2.0 dated 25 August 2016 
3.0 dated 29 March 2017 
4.0 dated 02 June 2018 
5.0 dated 22 July 2020 
 
SITE:  
 
 
Non-small cell lung cancer (NSCLC) 
HISTOLOGY: 
 
 
STAGE: 
 
 
Advanced (Stage IV—AJCC 7th edition)  
MODALITY:  
 
Intravenous 
TYPE:  
 
 
Chemotherapy 
ARMS: 
 
 
Single 
 
SPOC PROTOCOL CHAIRPERSON: 
 
            David E. Gerber, MD 
 
 
PARTICIPANTS: 
UT Southwestern Medical Center 
 
David E. Gerber, M.D. 
 
Harold C. Simmons Cancer Center 
 
Division of Hematology/Oncology 
 
5323 Harry Hines Blvd., Mail Code 8852 
 
Dallas, TX  75390-8852 
 
Telephone: 214-648-4180 
 
Fax:  214-648-1955 
 
Email: david.gerber@utsouthwestern.edu 
 
Texas Tech University Health Sciences Center, 
School of Medicine Cancer Center (SPOC 
Operations Office) 
3601 4th Street, Stop 9440 
Lubbock, TX 79430-9440 
Telephone : 806-743-2507 
Fax:  806-743-2691 

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Email : sponc@ttuhsc.edu 
 
C. Patrick Reynolds, M.D., PhD.  
(not a treating physician) 
Texas Tech University Health Sciences Center 
3601 4th Street STOP 9445 
Lubbock, TX  79430-6450 
Ph:  806-743-1558 
Email: patrick.reynolds@ ttuhsc.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
****************************************************************************** 
THE SOUTH PLAINS ONCOLOGY CONSORTIUM ASSUMES NO RESPONSIBILITY FOR THE 
USE OF THIS EXPERIMENTAL PROTOCOL OUTSIDE THE PARTICIPATING INSTITUTIONS 
****************************************************************************** 

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TABLE OF CONTENTS 
 
TREATMENT SCHEMA………………………………………………………………………………5 
1.0 
OBJECTIVES ………………………………………………………………………………….7 
2.0 
BACKGROUND AND HYPOTHESES ……………………………………………………...7 
 
 
2.1  Lung Cancer  …………………………………………………………………….....7 
 
 
2.2  Second-Line Chemotherapy for advanced NSCLC …………………………….. .. 8 
 
 
2.3  Axl ……………………………………………………………………………….....8 
 
 
2.4  Bemcentinib (BGB324) ……...……………………………………………………..8 
 
 
2.5  Rationale for Current Study……………………………………………………… 11 
3.0 
DRUG INFORMATION……………………………………………………………………....15 
 
 
3.1  Bemcentinib (BGB324)...…………………………………………………………15 
 
 
3.2  Docetaxel…………………………………………………………………………..16 
 
 
 
4.0 
ELIGIBILITY CRITERIA……………………………………………………………………18 
 
 
4.1  Inclusion Criteria…………………………………………………………………..18 
 
 
4.2  Exclusion Criteria………………………………………………………………….19 
5.0 
PATIENT REGISTRATION………………………………………………………………… 20 
 
 
5.1  Informed Consent…………………………………………………………………. 20 
 
 
5.2  Patient Registration……………………………………………………………….. 20 
 
 
5.3  Protocol Waivers and Treatment Deviations………………………………………20 
6.0 
STUDY DESIGN AND RULES FOR DOSE ESCALATION……....................................... 20 
 
 
6.1  Dose Limiting Toxicity (DLT)…………………………………………………….21 
 
 
6.2  Maximum Tolerated Dose (MTD)…………………………………………………22 
 
 
6.3  Dose Escalation Schedule………………………………………………………….22 
7.0 
STUDY PROCEDURES………………………………………………………………………24 
 
 
7.1  Assessment Schedule during Screening Visit ……………………………………. 29 
 
 
7.2  Screening Assessments…………………………………………………………….29 
 
 
7.3  Assessments During the Treatment Period………………………………………...30 
 
 
7.4  Patient Withdrawal Criteria ……………………………………………………… 35 
8.0 
DOSE DELAYS/DOSE MODICATIONS …………………………………………………...36 
 
 
8.1  Bemcentinib (BGB324)….………………………………………………………...36 
 
 
8.2  Docetaxel ………………………………………………………………………….39 
9.0 
TOXICITY REPORTING AND ASSESSMENT …………………………………………...41 
 
 
9.1  Reporting Toxicities……………………………………………………………….41 
 
 
9.2  Additional Adverse Event Experience Reporting…………………………………41 
 
 
9.3  Adverse Events …………………………………………………………………....44 
10.0 
DEFINITION OF RESPONSE ………………………………………………………………46 
 
 
10.1  Key Definitions ………………………………………………………………….46 
 
 
10.2  Other Considerations …………………………………………………………… 48 
 
 
10.3  Response Criteria ………………………………………………………………  48 
 
 
10.4  Response Definitions…………………………………………………………… 49 
11.0 
PHARMACOKINETIC AND CORRELATIVE STUDIES……..………………………… 51 
 
 
11.1  Pharmacokinetic Analyses…………………………..……………….…………...51 
 
 
11.2  Blood Biomarker Studies ……………………………..………………………… 52 
12.0 
STATISTICAL CONSIDERATIONS ………………………………………………………..52 
 
 
12.1  General Considerations…………………………………………………………... 52 
 
 
12.2  Analysis of Clinical Endpoints …………………………………………………...52 
 
 
12.3  Analysis of Pharmacokinetic and Laboratory Studies …………………………... 53 

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12.4  Estimated Accrual Time…………………………………………………………. 53 
 
 
12.5  Results ……………………………………………………………………………53 
 
 
12.6 Sample Size Justification …………………………………………………………53 
13.0 
REGISTRATION GUIDELINES …………………………………………………………… 54 
 
 
13.1  Procedures for On-Study and Treatment Deviations ………………………….…54 
14.0     RECORDS TO BE KEPT AND DATA SUBMISSION SCHEDULE ……………………...54 
 
 
14.1  Confidentiality of Records ……………………………………………………….54 
 
 
14.2  Patient Consent Form …………………………………………………………….54 
 
 
14.3  Registration Eligibility Worksheet ………………………………………………54 
15.0 
MINORITIES AND WOMEN STATEMENT ……………………………………………   55 
16.0      ETHICAL AND REGULATORY CONSIDERATIONS…………………………………   55 
17.0 
REFERENCES ………………………………………………………………………………  56 
18.0  
APPENDICES………………………………………………………………………………….58 
 
Appendix A:   Registrations Procedures for Phase I Trials……………………………………58 
 
Appendix B: 
Common Terminology for Adverse Events v3.0 ……………………………   60 
 
Appendix C:    Adverse Events Reporting Material …………………………………………   61 
 
Appendix D: 
Performance Scale Criteria ………………………………………………….62 
  
Appendix E: 
Specimen Collection Form for Pharmacokinetic Studies……….. ……………63 
Appendix F:     Specimen Collection Form for Multiple Cytokine  
 
 
and Angiogenic Factor Assay Performance ……………..................................65 
 
Appendix G: 
Specimen Collection Form Tissue collection for PD …………………………66 
 
Appendix H: 
Specimen Collection Form for Whole blood collection for mRNA and PBMC 
isolation………………………………………………………………………  67 
 
Appendix I: 
Drugs With Risk of Causing Torsades de Pointes…………………………… 68 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TREATMENT SCHEMA 
 
NOTE: PK samples will be drawn only for the first 15 enrolled subjects. 
 
 
 
 
 
 
 

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Bemcentinib and Docetaxel Dose Cohorts 
 
 
 
Bemcentinib dose (mg) 
Docetaxel dose 
(mg/m2 IV on 
Day 1 of each 
cycle) 
 
Cycle 1 
Days -7, -6, and -5 
Cycle 1 
Days -4 to 21 
Cycles ≥ 2 
All days 
Cohort -1a, b 
 
200* daily 
100 daily 
100 daily 
60 
Cohort 1 
 
200* daily 
100 daily 
100 daily 
75 
Cohort 2 
 
400* daily 
200 daily 
200 daily 
75 
Cohort 2Aa 
 
400* daily 
200 daily 
200 daily 
60 
 
 
 
NOTE:  Cohort -1 will be enrolled only if Cohort 1 or Cohort 2 dosing exceeds the  maximum tolerated 
dose.  
a. If Cohort -1 is enrolled without exceeding the MTD, bemcentinib may be dose escalated to 400 mg 
daily on Days -7, -6, and -5, then 200 mg daily on subsequent days (Cohort 2A). 
 
b. If Cohort -1 or Cohort 2A is enrolled without exceeding the MTD, a subsequent cohort with 
docetaxel dose re-escalated to 75 mg/m2 every 21 days with concurrent myeloid growth factor 
support every cycle will be enrolled. 
 
If dose-limiting toxicity (DLT) is experienced during or attributed to (ie, occurs shortly after) the 3-day 
loading period, dose de-escalation will occur as follows without adjustment of daily maintenance dose: 
 
Loading Cohort 1:  loading dose x 3 days 
Loading Cohort -1:  loading dose x 2 days 
Loading Cohort -2:  loading dose x 1 day 
Loading Cohort -3:  no loading dose; initiate treatment with standard daily dose 
 
 
This is a single-arm phase 1 clinical trial. Dose escalation will be according to a standard 3+3 schema with 
a planned expansion cohort at the recommended phase 2 dose (RP2D).  At least 3 weeks must elapse 
between initiation of study therapy for the first patient on a new dose level after the treatment of the last 
patient on the previous dose level.  
 
 
To permit assessment of pharmacodynamic and pharmacokinetic effects of  bemcentinib alone and in 
combination, the trial will employ a staggered initiation during Cycle 1.  Specifically,  bemcentinib will 
be administered alone on Days -7 to -1 prior to docetaxel administration.  

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Docetaxel will be administered on Day 1 of each 21-day cycle.  Bemcentinib will be self-administered daily 
every day of each 21-day cycle.  On Docetaxel administration days,  bemcentinib will be administered first. 
 A loading dose of  bemcentinib will be given during the first three days of the run-in period prior to Cycle 
1 (Day -7 , Day -6 and Day -5), followed by a lower daily maintenance dose during the remainder of the 
run-in period and throughout continuous 21-day treatment cycles.   Bemcentinib dosing can be interrupted, 
per protocol, for a maximum of 14 days to manage adverse events. If dosing is interrupted for >7 days 
dosing will re-commence at the loading dose for the first three days.  Treatment will continue with both 
agents until disease progression or unacceptable toxicity. 
Correlative and pharmacodynamic studies, including tissue and blood analyses, will be performed on all 
patients.   
1.0  OBJECTIVES 
1.1 Primary Objective 
• 
To determine the safety and tolerability and recommended Phase 2 dose (RP2D) of  bemcentinib 
administered with the standard dose of docetaxel in patients with NSCLC. 
1.2 Secondary Objectives 
• 
To determine the response rate, progression-free survival and overall survival of bemcentinib 
therapy in combination with docetaxel in patients with NSCLC. 
• 
To determine pharmacokinetics and pharmacodynamics of  bemcentinib alone and in combination 
with docetaxel. 
• 
To assess the PK of docetaxel in combination with bemcentinib. 
2.0 BACKGROUND AND HYPOTHESES 
2.1  Lung Cancer 
Lung cancer remains the leading cause of cancer-related deaths worldwide with an estimated incidence of 
1.6 million cases resulting in 1.4 million deaths in annually.1  Non-small-cell lung cancer (NSCLC) 
represents 80-85% of cases, and adenocarcinoma is the most common histology.2  The majority of NSCLC 
patients present with advanced or metastatic disease that is not amenable to surgical resection.  Platinum-
based combination chemotherapy has reached a therapeutic plateau with a median overall survival (OS) of 
7.4 to 9.9 months.   
2.2  Second-Line Chemotherapy for Advanced NSCLC 
There exists a critical need to improve second-line therapy for advanced non-small cell lung cancer 
(NSCLC). Currently, three drugs are FDA approved for this indication: docetaxel, pemetrexed, and 
erlotinib. In unselected lung cancer populations, these agents have radiographic response rates less than 
10%, median progression-free survival ranging 2.2-2.9 months, and median overall survival ranging 6.7-
8.3 months.1-3 In 2014, clinical practice has evolved to the point that use of pemetrexed is restricted to 
nonsquamous histology (based on differential efficacy according to histology that has been attributed to 
differential levels and activity of thymidylate synthase) and is commonly used as a first-line and/or 
maintenance agent rather than a second-line agent. Regarding erlotinib, its current clinical use is largely 

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restricted to patients with activating epidermal growth factor receptor (EGFR) gene mutations, where it is 
commonly employed as first-line therapy. As a result, both on protocol and in standard practice, docetaxel 
has emerged as the predominant second-line therapy for this challenging disease.  Recently, the addition of 
the vascular endothelial growth factor receptor (VEGFR) monoclonal antibody ramucirumab to docetaxel 
chemotherapy has been shown to improve clinical outcomes slightly.3 
2.3  Axl  
Axl is a member of the TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases (RTKs) that regulate 
multiple cellular processes.  These include cell survival, proliferation, and migration.  Mer and Axl share 
the natural ligand Gas6, which binds Axl with 3-10 fold greater intensity than Mer.4  The role of these RTKs 
in normal physiology appears related to clearance of apoptotic cells, cytokine secretion, platelet 
aggregation, erythropoiesis, and natural killer cell differentiation and maturation.5-8   
 
The oncogenic potential of Axl has been attributed to autocrine and paracrine functions.  In addition to 
signaling through canonical PI3K/Akt and MAPK/Erk pathways, Axl may also mediate tumor-stromal cell 
interactions, resulting in modification of the inflammatory response and angiogenesis.9,10  Recently, Axl 
has also been implicated in epithelial-to-mesenchymal transition (EMT), which promotes metastasis and 
giving cells the ability to migrate through extracellular matrix and intravasate into blood vessels.11   
In non-small cell lung cancer (NSCLC), Axl expression is associated with poor clinical outcomes, lymph 
node involvement, and higher disease stage.12  Axl and Gas6 ligand have been detected at high levels in 
more than 50% of NSCLC cell lines.13  Further suggesting a major role in NSCLC biology, Axl is also 
among the most highly phosphorylated (ie, activated) RTKs in NSCLC cell lines and tumors.14,15   
It has been reported that Axl mediates chemoresistance in a variety of cancer types, including NSCLC,16 
breast cancer,17 and esophageal adenocarcinoma.18 Epithelial to mesenchymal transition (EMT) is a 
common mechanism of resistance to chemotherapy, including resistance to docetaxel. Axl activation causes 
EMT19, while inhibition of Axl can reverse mesenchymal phenotype, thereby restoring drug sensitivity. 
2.4   Bemcentinib (BGB324) 
 
Bemcentinib (BGB324) is a potent selective small molecule inhibitor of Axl, a surface membrane protein 
kinase receptor that is over-expressed in many metastatic solid tumors and has been identified as a marker 
of a poor prognosis in patients with non-small cell lung cancer (NSCLC). 
 
Please refer to the current version of the bemcentinib Investigator’s Brochure for more information of the 
non-clinical and clinical data available on bemcentinib. 
2.4.1  Nonclinical Studies with bemcentinib 
2.4.1.1  Specificity of Inhibition of Axl Kinase 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 

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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 
>316 
>5 
Flt1 
400 
>1000 
40 
8.7 
>1000 
>15 
Flt4 
460 
>1000 
41 
8.8 
>1000 
>15 
Yes 
810 
>1000 
43 
9.2 
n/a 
n/a 
n/a = not applicable 
2.4.1.2  Inhibition of Proliferation of Non-Small Cell Lung Cancer Cells 
The anti-proliferative activity of bemcentinib was demonstrated in a panel of human NSCLC cell lines by 
either resazurin cell viability assay or colony formation assay.  As summarized in Table 2, bemcentinib 
inhibited proliferation of several human lung cancer cell lines with IC50 values of 0.4 - 0.8 μM; the anti-
proliferative effect was dose-responsive (not shown).   
Table 2.  Effect of Bemcentinib on Proliferation of Human NSCLC Cell Lines 
 
Tumor Type 
Cell Line 
IC50 (µM) 
NSCLC 
A549 
0.56 
NCI-H1299 
0.67 
HCC827 
0.76 
H358 
0.43 
 
The ability of bemcentinib to inhibit cell proliferation was investigated in a panel of 654 human tumor cell 
lines.  When administered at a concentration of 1µM, bemcentinib inhibited proliferation by >50% in 48 of 
the cell lines tested, including 10/101 NSCLC.  
2.4.1.3  Bemcentinib and corticosteroids 
 
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. 
 
However, following the investigational toxicology studies conducted during the last year, it has 
been established that effects of steroids are not exacerbated by co-administration of bemcentinib. 

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However investigators are encouraged to follow their local guidelines for monitoring if a patient 
requires treatment with high dose steroids. If required, additional advice on the concomitant use 
of steroids with bemcentinib should be obtained from the appointed study Medical Monitor. (See 
Sections 6.5.1 and 4.3.3.1 of IB, version 12.) 
2.4.2  Clinical Studies with Bemcentinib 
There has been one previous clinical study conducted with bemcentinib (Protocol BGBC001).  This study 
explored the effect of a single administration of  bemcentinib in healthy male volunteers.  Eight dose levels 
(50 mg, 100 mg, 150 mg, 200 mg, 400 mg, 600 mg, 1000 mg and 1500 mg) were evaluated under fasted 
conditions in cohorts of four subjects (32 subjects in total).  Seven of these subjects went on to receive a 
single administration of the same dose of bemcentinib under fed conditions. 
In general, exposure to bemcentinib was well tolerated with all toxicities being spontaneously reversible 
and predominantly gastrointestinal in nature.  No serious adverse events were reported.  Adverse events 
judged as related to bemcentinib are summarized in Table 3.  
Table 3.  Bemcentinib-Related Adverse Events Reported Following a Single Oral 
Administration of Bemcentinib to Healthy Male Subjects  
Bemcentinib 
Dose (mg) 
Number of 
Subjects 
Treated 
Adverse Event 
Maximum Grade 
50 
4 fasted; 1 fed 
Non-cardiac chest pain 
1 
100 
4 fasted; 2 fed 
Orthostatic hypotension 
1 
150 
4 fasted; 1 fed 
Abdominal distension (2 
pts) 
1 
400 
4 fasted; 2 fed 
Diarrhea 
1 
600 
4 fasted 
Diarrhea 
Flatulence 
Nausea (2 pts) 
1 
1 
1 
1000 
4 fasted 
Nausea 
1 
1500 
4 fasted 
Diarrhea 
Nausea 
Vomiting 
Headache 
Dizziness 
1 
2 
2 
1 
1 
 
2.4.2.1  ECG Findings 
In light of the recoverable, non-adverse decreases in heart rate and corresponding increases in the RR 
interval durations observed in the cardiovascular study in monkeys, each subject in Study BGBC001 
underwent serial ECG assessment after administration of bemcentinib.  The overall pattern indicated that  

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bemcentinib administration was accompanied by a variable increase in QTcF, the magnitude of which was 
related to systemic exposure.  The maximum QTcF recorded was Grade 1 in severity.  
2.4.2.2  Bemcentinib Pharmacokinetics 
 
In Clinical Study BGBC004 (A Multi-Center Open-Label Phase I/2 Study of bemcentinib in Combination 
with Erlotinib in Patients with Stage IIIb or Stage IV Non-Small Cell Lung Cancer), plasma concentration 
profiles of bemcentinib have been modelled (first-order absorption, one-compartment disposition) from 
seven patients administered 600 mg/200 mg bemcentinib as monotherapy. In general, the PK model 
adequately fitted the individual plasma profile, with generally good precision of estimated parameters.  
PK parameters, at steady state, for seven patients administered 200 mg bemcentinib daily are summarized 
in Table 4. 
Table 4.  Pharmacokinetic Parameters of Bemcentinib, at Steady State, Following a Loading Dose of 
600 mg and Daily Oral Administration of 200 mg Bemcentinib (BGBC004) 
 
Patient # 
AUC0-24h 
Cav 
Cmax 
t½ 
(ng.h/mL) 
CV (%)* 
(ng/mL) 
CV (%)* 
(ng/mL) 
CV (%)* 
(h) 
CV (%)~ 
312-101 
5011 
222 
209 
222 
228 
769 
51.4 
44.1 
312-102 
10208 
2364 
425 
2364 
443 
18723 
117 
23.4 
311-103 
12249 
12.7 
510 
12.7 
525 
49.7 
76.2 
19.8 
310-105 
4334 
9.82 
181 
9.82 
191 
35.7 
93.3 
27.9 
311-106 
6313 
11.6 
263 
11.6 
267 
18.0 
28.7 
3338 
310-107 
14127 
5.22 
589 
5.22 
595 
20.2 
293 
11.6 
310-108† 
935 
966 
40.0 
966 
42.0 
879 
87.5 
26.3 
Geometric mean 
7895 
 
329 
 
342 
 
84.3 
 
CV (%) ~ 
52.4 
 
52.4 
 
50.2 
 
92.4 
 
Abbreviations: AUC0-∞=area under plasma concentration versus time curve extrapolated to infinity; Cav=average concentration at 
steady state; Cmax=maximum plasma concentration; CV=coefficient of variation; t1/2= half-life 
CV* represents precision of PK parameter; CV~ represents between-patient variability; † Anomalously low exposure, excluded 
from summary statistics 
 
2.5 Rationale for this study 
2.5.1  Axl inhibition sensitizes chemoresistant mesenchymal NSCLC cells to docetaxel 
In vitro studies indicate that signaling through Axl stimulates a number of pro-survival pathways, some of 
which are mediated by AKT phosphorylation and up-regulation of the epithelial receptor kinase pathway.  
Recent non-clinical data indicate that Axl inhibition selectively sensitizes cancer cell to antimitotic agents. 
This study is designed primarily to evaluate the safety of the Axl inhibitor bemcentinib when administered 
in combination with docetaxel, and to establish the maximum tolerated dose and recommended Phase II 
dose of the combination of bemcentinib and docetaxel in patients with Stage IIIb or Stage IV NSCLC.   
Wilson et al screened 643 NSCLC and breast cancer cell lines and found a strong correlation between Axl 
expression and mesenchymal phenotype.20 Mesenchymal phenotype was associated with increased drug 
resistance, especially increased resistance to docetaxel. They also confirmed that induction of EMT with 

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exposure of epithelial cells to TGF-b increases Axl expression and docetaxel resistance. Furthermore, 
inhibition of Axl with R428, Axl tyrosine kinase inhibitor, increased docetaxel sensitivity 1000-fold and 
caused synergistic increase in cell death. This synergy was confirmed in multiple cell lines and is not 
specific to R428. In fact, Axl inhibition with siRNA or by sequestering Axl ligand, GAS6, with Axl-Fc 
chimera causes synergistic cell death in cell lines exposed to docetaxel. Similarly, Axl inhibition with R428 
increases cell susceptibility to other antimitotic agents, such as inhibitors of Aurora kinase and polo kinase. 
The anti-tumor activity of R428 in combination with docetaxel was evaluated in the human MDA-MB231 
xenograft model.  Treatment was initiated when tumors reached 100-200 mm3.  Mice were treated with 
vehicle control, R428 alone at 125 mg/kg orally 5 times a week, docetaxel at 10 mg/kg once a week 
intravenously or combination of the two. While neither treatment alone had significant effect on tumor 
growth in this docetaxel-resistant tumors, combination of R428 and docetaxel resulted in significant 
(p<0.005) anti-tumor activity.20  
 
Figure 1.  Anti-Tumor Effect of R428 and docetaxel in the MDA-MB231 Xenograft Model 
 
 
Potentiation of docetaxel effect with Axl inhibition is believed to be in part mediated by inhibition of PI3K 
signaling. PI3K inhibitors, PWT-458 and GDC-0941, enhance efficacy of taxane-based therapy in NSCLC 
and breast cancer, respectively.21,22 Axl is known to cause activation of PI3K/Akt pathway. This process is 
inhibited by R428. 
Given excellent synergistic effect of docetaxel and Axl inhibition in NSCLC and a good tolerance of Axl 
inhibitor, bemcentinib, the current phase I trial of the combination of docetaxel and bemcentinib was 
designed. 
2.5.2 Rationale for Bemcentinib Starting Dose 
 
In BGBC004 eight patients with previously treated NSCLC were treated with a loading dose of 600 mg on 
days one and two followed by 200 mg daily. Treatment was well tolerated and no patients withdrew from 
the study as a result of toxicity. Two patients remain on treatment for more than six months with a best 
response of stable disease. The most common treatment affected System Organ Class was gastrointestinal 
disorders. A further four patients received an identical dose regimen of bemcentinib in combination with 
erlotinib at a dose of 150 mg BD. In patients receiving the combination gastrointestinal disorders were more 

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marked during the period of the loading dose but returned to baseline once patients became established on 
the 200 mg daily dose of bemcentinib.  
In healthy subjects who received a single oral dose of bemcentinib, the elimination of bemcentinib was 
slow, with t1/2 > 24 hours.  The administration schedule and starting dose of bemcentinib proposed for this 
study is based on fitting a one-compartment model, incorporating a lag time and no weighting, to the 
available clinical PK data.  It is anticipated that administration of a loading dose of bemcentinib on the first 
3 days (Day -7, Day -6 and Day -5) prior to Cycle 1 followed by daily dosing at a lower level will deliver 
the optimum exposure of bemcentinib.  The application of a loading dose will facilitate achievement of 
therapeutic levels, while daily dosing will prevent wide changes in systemic concentration during therapy.  
The simulated mean plasma concentration-time profile of bemcentinib, based on the PK model, following 
dosing of bemcentinib at 600 mg on Day 1 and 600 mg on Day 2 and 200 mg daily thereafter is presented 
in Figure 2A.   
 
Figure 2A. 
Predicted (fasted in healthy subjects) and observed (fasted) plasma profile of   
Bemcentinib in patients after daily oral administration of 200 mg Bemcentinib 
(Study BGBC004) 
 
 
 
 
0
100
200
300
400
500
600
700
0
72
144
216
288
360
432
504
576
648
720
792
864
936
1008
Concentration (ng/mL)
Time (h)
Predicted (healthy subjects)
312-101
312-102
311-103
310-105
311-106
310-107
310-108
311-209
311-209
311-210

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Figure 2B. Predicted plasma profile of bemcentinib after oral administration of 200 mg daily, 
467 mg thrice weekly or 600 mg thrice weekly 
 
Administration of bemcentinib three times per week is expected to achieve a similar weekly steady state as 
a 7 days per week daily dosing. As shown in Figure 2B, administration of 467 mg bemcentinib three times 
per week (a total of 1400 mg a week) should achieve a similar steady as 200 mg bemcentinib daily 
administration (a total of 1400 mg a week). Therefore, administration of 100 mg bemcentinib thrice weekly 
(300 mg a week) is expected to achieve a similar steady state as administration of 43 mg bemcentinib daily 
(300 mg a week). 
 
2.5.3  Study Design 
This is a multi-center, open-label Phase I study on bemcentinib in combination with docetaxel in advanced 
NSCLC. The study will be conducted at up to 2 clinical sites in the US.   
The study is designed to determine the maximum dose of bemcentinib that can be safely administered in 
combination with docetaxel.   It is anticipated that a minimum of two bemcentinib dose levels will be 
evaluated, with up to approximately 12 patients enrolled (6 per cohort if expansion required) in the dose-
escalation phase.  Including an expansion cohort, a maximum of 30 patients will be enrolled on this trial.  
In the absence of unacceptable toxicity, patients will be allowed to continue receiving bemcentinib in 
combination with docetaxel until disease progression.   
The starting dose of docetaxel will be 75 mg/m2 given IV every 21 days, with dose de-escalation to 60 
mg/m2 IV q21 days if the starting dose exceeds the MTD. The dose of bemcentinib will be escalated in a 
standard 3+3 fashion until an MTD or the RP2D is reached.  At the recommended phase 2 dose (RP2D), 
an additional 18-24 patients will be enrolled in an expansion cohort, for a total accrual of 30 patients. 
3.0 
Due to the occurrence of high-grade neutropenia during early cycles of combination 
docetaxel + bemcentinib, this protocol was modified to require myeloid growth factor 
0
50
100
150
200
250
300
0
48
96
144
192
240
288
336
384
432
480
528
576
624
672
Concentration (ng/mL)
Time (h)
600 mg LD 200 mg daily
600 mg LD 467 mg thrice weekly
300 mg LD 600 mg thrice weekly

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administration starting with Cycle 1. Specifically, treatment-emergent neutropenia during 
Cycle 1 led to myeloid growth factor use starting in Cycle 2 for nine of 19 patients. 
Although the degree of observed neutropenia did not necessarily constitue a dose limiting 
toxicity, it became apparent that serial administration of this regimen would not be 
practical. In modifying the protocol, it was also recognized that some patients may not 
tolerate or require ongoing myeloid growth factors over time, either because they are less 
susceptible to cytopenias or undergo treatment dose reductions for non-hematologic 
reasons. Accordingly, allowance has been made for discontinuation of growth factors with 
subsequent treatment cycles.   DRUG INFORMATION 
After registration, all eligible patients will receive the combination regimen of bemcentinib and docetaxel 
as described in the study design.  
3.1  Bemcentinib 
3.1.1 
Shipping, Storage, and Handling of Pharmaceutical Form 
Accountability for study treatment bemcentinib is the responsibility of the Investigator.  The 
Investigator/designee must ensure that bemcentinib will be dispensed to patients in accordance with the 
protocol and that any unused bemcentinib will be disposed of or returned in accordance with written 
instructions from the IMP supplier.  
Study staff should refer to the Directions for Handling and Administration document for specific 
instructions regarding the handling, storage, dispensing and destruction, if applicable, of bemcentinib. 
Bemcentinib has been manufactured in accordance with appropriate Good Manufacturing Practice (GMP) 
standards.  Bemcentinib will be labeled in compliance with GMP Annex 13 requirements, FDA 
requirements and local regulatory guidelines. 
Bemcentinib will be supplied in size zero Swedish orange hydroxypropyl methylcellulose (HPMC) 
capsules at a dose strength of 100 mg for oral dosing.  Please refer to Section 4 of the current version of the 
Investigator’s Brochure for additional information on the physical, chemical and pharmaceutical properties 
of bemcentinib. 
Bemcentinib will be shipped to the site and must be stored at the site in a secure location under ambient 
temperature conditions.   
3.1.2 
Bemcentinib administration 
Bemcentinib will be administered on an empty stomach first thing in the morning with water and at least 1 
hour before or 2 hours after food at approximately the same time on each dosing day, other than on the 
morning of study visit days when bemcentinib should be administered during the visit. Patients should 
record dosing in the dosing diary provided. Bemcentinib should be administered before docetaxel 
administration (where applicable).  In dose de-escalation cohort -2 or certain dose reductions, bemcentinib 
will be administered three times weekly. 
3.1.3 
 Bemcentinib Accountability 
The investigator/designee must maintain complete and accurate accountability records for  bemcentinib, 
showing the date of receipt and quantity of all supplies of investigational product.  These records must 
include accurate patient-specific dispensing information, including quantity of capsules and/or bottles 
dispensed, date dispensed and quantity and date returned (or disposed of). 

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At the end of the study, reconciliation must be made between the amount of  bemcentinib supplied, 
dispensed and subsequently returned to the sponsor or destroyed at site, with reconciliation of any 
discrepancies. 
Destruction of  bemcentinib at site may be performed only by authorized personnel following written 
receipt of approval from the sponsor.  The procedure should be fully documented as outlined in the 
Directions for Handling and Administration document. 
3.2 Docetaxel 
Commercially available docetaxel will be used for this study.  It will be supplied in accordance with 
applicable local laws and regulations. 
Docetaxel 75 mg/m2 will be administered as a 1-hour IV infusion. In dose de-escalation cohorts, docetaxel 
60 mg/m2 will be administered as a 1-hour IV infusion. The amount of docetaxel administered will be 
determined on Day 1 of each cycle, or per institutional guidelines, by calculating the patient’s BSA. When 
calculating the dose of docetaxel, rounding the BSA according to institutional practice is permitted.  The 
dose of docetaxel may be capped at the dose corresponding to a BSA of 2 m2 if necessary to comply with 
institutional practices.  Premedication for docetaxel will follow the local institutional standard of care 
guidelines. 
3.2.1 
Storage and Handling of Docetaxel 
See product information for complete information including storage and handling precautions. 
3.2.2 
Docetaxel Administration Information 
See product information for complete information including preparation and administration 
instructions.3.4 
Concomitant Medications 
All prescription, non-prescription, or over-the-counter medications, including herbal remedies, taken by the 
patient at entry and during the study must be clearly documented in the CRF.   
The patients must be instructed that no additional medication will be allowed without the prior consent of 
the Investigator.  
Concurrent treatment with any medication which is predominantly metabolized by CYP3A4 and has a 
narrow therapeutic index is an exclusion criterion for the study. 
Concurrent treatment with any agent known to cause Torsade de Points is an exclusion criterion for the 
study and is prohibited while receiving study therapy.  A comprehensive list of these prohibited medications 
is provided in Appendix J. 
In general, concomitant medications to control side effects of therapy may be given during treatment, with 
specific guidelines described in the sections below.   
3.2.3 
Prior Treatment 
All prior treatments received within 14 days prior to enrollment will be recorded on the eCRF, including 
the name of the drug, route, indication, start date, and stop date (if applicable).  Prior therapy for the 
treatment of NSCLC will also be recorded on the eCRF. 

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3.2.4 
Birth Control  
The effects of bemcentinib on conception, and the unborn fetus, are not known.  Female patients having 
any chance of becoming pregnant must either abstain from sexual intercourse or use 2 methods of birth 
control. This must include at least 1 highly active method such as the intrauterine device (IUD), hormonal 
birth control pills/injections/implants, tubal ligation or partner’s vasectomy, and one additional effective 
method such as latex condoms, diaphragm, or cervical cap, prior to, during, and for 3 months after, 
completion of study drug treatment. Men must use a latex condom every time they have sexual intercourse 
during therapy and for 4 weeks after discontinuing bemcentinib, even if they had a successful vasectomy. 
3.2.5 
Supportive Care 
Supportive care can be prescribed as medically appropriate, including but not limited to:   
• 
Erythropoietin or other specific RBC growth factors; RBC transfusions. 
• 
Bone marrow colony stimulating factors. NOTE:  due to the occurrence of neutropenia considered dose-
limiting or complicating the feasibility of long-term treatment administration in earlier cohorts, starting 
with subjects enrolled on protocol Version 5.0 or later, patients receiving docetaxel 75 mg/m2 and/or 
bemcentinib maintenance dose of 200 mg daily must receive myeloid growth factors (eg, G-CSF, 
preferably pegylated G-CSF) starting with cycle 1. In certain cases, myeloid growth factors may be 
omitted from subsequent treatment cycles. Examples include intolerance of myeloid growth factors, 
dose-reduction of docetaxel, or suspicion [based on available laboratory and clinical data] that patient 
would tolerate treatment and not develop severe neutropenia if myeloid growth factors were omitted.  
• 
Platelet transfusions 
• 
Steroids (inhaled, topical, or for physiologic replacement, or for short term treatment of conditions such 
as allergic reactions and asthma flares, or for appetite stimulation).  A standard 3-5 day course of 
dexamethasone following the institutions standard of care for the prevention of chemotherapy-induced 
nausea and vomiting is allowed.      
• 
Bone-modifying agents, eg, bisphosphonates or denosumab, to reduce the number and frequency of 
skeletal-related complications of bone metastases,. 
• 
Other concomitant medications may be given as clinically indicated.  Please consult with the medical 
monitor. 
▪ 
Appropriate analgesics, antibiotics, blood products, anti-emetics (see ondansetron contraindication in 
Appendix J), fluids, electrolytes and general supportive care are to be used as necessary  
▪ 
Palliative radiation therapy is permitted on study. bemcentinib should be withheld the day before, during, 
and day after radiation. Docetaxel should not be administered during palliative radiation therapy. 
3.2.6 
Treatment Beyond Progression 
In some instances, a patient may be deemed to be receiving benefit from study therapy despite 
RECIST progressive disease. In these cases, study treatment may be continued if the following 
criteria are met: 
• No ongoing intolerable treatment-related AEs 
• Patient informed of available treatment options  

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• Case discussed with and decision to treat beyond progression approved by Study Chair  
 
4.0 
ELIGIBILITY CRITERIA 
4.1 Inclusion criteria 
A patient is eligible for the study if the following criteria are met: 
1. 
Provision of written informed consent to participate in this investigational study 
2. 
Histologically or cytologically confirmed advanced (stage 4, according to the American Joint 
Committee on Cancer [AJCC] Staging manual) NSCLC  
3. 
Up to three previous lines of therapy for advanced NSCLC, of which one must have been a 
platinum-based doublet therapy and no more than two were cytotoxic chemotherapy. 
4. 
Radiographic disease recurrence or progression during or after the last line of chemotherapy 
5. 
Patients with known activating EGFR mutations or ALK rearrangements should have progressed 
after appropriate targeted treatment in addition to progressing during or after platinum-based 
doublet chemotherapy 
6. 
European Cooperative Oncology Group (ECOG) performance status 0 or 1  
7. 
Age 18 years or older 
8. 
Measurable or evaluable disease according to RECIST v1.1 
9. 
Previously treated brain metastases (surgery and/or radiation therapy) are eligible, provided that 
patients are asymptomatic and not requiring corticosteroids 
10. 
The following minimum intervals are required between prior treatment and initiation of study 
therapy: 
Cytotoxic chemotherapy:  3 weeks 
Molecularly targeted therapy or immunotherapy:  2 weeks 
Conventional fractionated radiation therapy:  2 weeks 
Stereotactic radiation therapy:  1 week 
Major surgery:  3 weeks 
11. 
Adequate hematologic function (absolute neutrophil count [ANC] ≥ 1500 cells/µL; hemoglobin ≥ 
9 g/dL; platelets ≥ 100,000/µL 
12. 
Adequate renal function (serum creatinine ≤ 1.5 mg/dL or calculated creatinine clearance ≥ 50 
mL/min using the Cockcroft-Gault equation) 
13. 
Adequate hepatic function:  total bilirubin ≤ upper limit of normal [ULN], alanine aminotransferase 
[ALT] ≤ 1.5 x ULN, aspartate aminotransferase [AST] ≤ 1.5 x ULN).  ALT and AST ≤ 5x ULN if 
documented liver metastases 
14. 
Previous treatment-associated toxicities resolved to CTCAE grade ≤2 (except alopecia) or to their 
baseline. NOTE: Prior immunotherapy-related endocrinopathy controlled with ongoing medical 
management (eg, hypothyroidism, adrenal insufficiency, diabetes) is permitted. 

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15. 
Adequate archival tissue (10-15 slides, or 5 slides with 3 sections per slide) for biomarker analysis. 
If an otherwise eligible candidate does not have adequate archival tissue, enrollment will be 
considered on a case-by-case after discussion with Study Chair. 
16. 
Female patients of childbearing potential must have a negative serum pregnancy test within 7 days 
prior to taking their first dose of bemcentinib.  Male patients and female patients of reproductive 
potential must agree to practice highly effective methods of contraception (such as hormonal 
implants, combined oral contraceptives, injectable contraceptives, intrauterine device with 
hormone spirals, total sexual abstinence, vasectomy) throughout the study and for ≥3 months after 
the last dose of bemcentinib. Female patients are considered NOT of childbearing potential if they 
have a history of surgical sterility, including tubal ligation, or evidence of post-menopausal status 
defined as any of the following: 
• 
Natural menopause with last menses >1 year ago 
• 
Radiation induced oophorectomy with last menses >1 year ago 
• 
Chemotherapy induced menopause with last menses >1 year ago 
4.2 Exclusion Criteria   
A patient is excluded from the study if any of the following criteria are met: 
1. 
Pregnant or lactating 
2. 
Abnormal left ventricular ejection fraction on echocardiography (less than the lower limit of normal 
for a patient of that age at the treating institution or <45%) 
3. 
History of an ischemic cardiac event including myocardial infarction within 3 months of study 
entry 
4. 
Peripheral neuropathy NCI CTCAE ≥Grade 2 at baseline 
5. 
Pulmonary hemorrhage or hemoptysis > 2.5 mL blood within 6 weeks (or within 2 weeks if source 
definitively treated [eg, radiation therapy or bronchoscopic procedure])  
6. 
Congestive cardiac failure of >Grade 2 severity according to the NYHA defined as symptomatic at 
less than ordinary levels of activity 
7. 
Unstable cardiac disease, including unstable angina or unstable hypertension, as defined by the 
need for change in medication for lack of disease control within the last three months 
8. 
History or presence of sustained bradycardia (less than or equal to 60 BPM) or history of 
symptomatic bradycardia, left bundle branch block, cardiac pacemaker or significant atrial 
tachyarrythmias, as defined by the need for treatment 
9. 
Previous treatment with docetaxel or an Axl inhibitor 
10. 
Current treatment with agents that may prolong QT interval and may cause Torsade de Points which 
cannot be discontinued at least five half-lives prior to treatment.  Please see Appendix J for list of 
relevant medications 
11. 
Known family or personal history of long QTc syndrome or ventricular arrhythmias including 
ventricular bigeminy 
12. 
Previous history of Grade 3 or worse drug-induced QTc prolongation requiring treatment 
withdrawal  
13. 
Screening 12-lead ECG with a measurable QTc interval according to Fridericia’s correction >450 
ms  

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14. 
Ongoing infection requiring systemic treatment 
15. 
Inability to tolerate oral medication 
16. 
Impaired coagulation as evidenced by: 
• 
INR >1.5 times ULN, or 
• 
aPTT > 1.5 times ULN 
NOTE: a therapeutic PT and/or INR is acceptable if the patient is on a relevant anticoagulant 
such as warfarin 
17. 
Clinically active existing gastrointestinal disease affecting drug absorption, such as celiac disease 
or Crohn’s disease 
18. 
Previous bowel resection anticipated to affect drug absorption 
19. 
Any evidence of severe or uncontrolled systemic conditions (e.g., severe hepatic impairment) or 
current unstable or uncompensated respiratory or cardiac conditions which makes it undesirable for 
the patient to participate in the study or which could jeopardize compliance with the protocol  
20. 
Treatment with any medication which is predominantly metabolized by CYP3A4 and has a narrow 
therapeutic index 
21. 
Active, uncontrolled central nervous system (CNS) disease  
22. 
Known active infection with human immunodeficiency virus (HIV), hepatitis B or C viruses  
(screening not required)  
23. 
Major surgery within 28 days prior to the start of bemcentinib, excluding skin biopsies and 
procedures for insertion of central venous access devices 
5.0 
PATIENT REGISTRATION 
This is a study of the South Plains Oncology Consortium (SPOC).  Registration and assignment to the dose 
level will be done centrally at data coordinating center (DCC) at Texas Tech University Health Sciences 
Center, Lubbock (see Appendix A). 
5.1 Informed Consent   
Informed Consent must be obtained before the patient is registered.  The FDA requires that both the 
signature and the date be in the handwriting of the subject or the subject’s legally authorized representative, 
that the date be the actual date on which the form is signed, and that the informed consent process be 
documented in the physician’s progress notes or the nurse’s notes. 
 
5.2 Patient Registration 
Registration will be done centrally at the South Plains Oncology Consortium (SPOC).  To register a patient, 
the research nurse or data manager (at the treating institution) must complete the eligibility form and the 
registration form and give (or FAX) copies to the SPOC Consortium Manager at 806-743-2691.  The 
research nurse or data manager will call the SPOC Consortium Manager at 806-743-2690 and after 
verifying the eligibility, the SPOC Consortium Manager will assign a study number, assign a dose, and 
register the patient onto the study (see Appendix A: Registration Procedures for Phase I Trials). 
5.3 Protocol Waivers and Treatment Deviations   
Protocol waivers and/or treatment deviations are generally not allowed.  However, should the need arise to 
amend the protocol in order for the protocol document to more accurately reflect the initial intent of the 
investigator(s), then the treating physician must contact the PI who originated the protocol for the 
Consortium to obtain approval.  If approved, the Consortium protocol PI must immediately submit an 

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amendment to the protocol.  A backup for the originating PI has been designated and is specified in the 
registration worksheet. 
6.0 
STUDY DESIGN AND RULES FOR DOSE ESCALATION/DE-ESCALATION 
Rules for dose escalation, de-escalation, dose expansion, and termination of escalation are given below. 
Patient enrollment, adverse events relevant to dose escalation, and toxicity follow-up will be recorded in a 
Phase 1 tracking log in addition to case report forms.  This log will be consulted prior to enrolling each 
cohort of new patients, to verify that the criteria for dose escalation have been met.  The Phase 1 Tracking 
log is maintained at the Data Coordinating Center (DCC), and is kept current on a weekly basis. 
Toxicity will be assessed and reported on all patients who begin to receive treatment.  Patients who do not 
complete the first cycle (for any reason other than toxicity or tolerability of the regimen) and who do not 
experience toxicity will not be counted as having successfully completed one cycle and will be considered 
unevaluable for toxicity.  All patients who are not evaluable for toxicity will be replaced. 
A standard 3 + 3 design will be used; the usual rules for dose escalation, expansion, and de-escalation will 
apply based on patients who are “evaluable for toxicity.”  Dose escalation decisions will be based on 
toxicities observed during cycle 1 (7-day lead-in plus 21-day combination period) of treatment.     
For all patients receiving more than one cycle of therapy, toxicities will continue to be monitored and 
recorded; for all patients who are classified as not “evaluable for toxicity,” all toxicities will be monitored 
and recorded. 
6.1  Dose Limiting Toxicity (DLT)  
DLT will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events [NCI CTCAE] version 4.03 (See Appendix B) during the first cycle of treatment (7-day lead-in plus 
21 days of combination therapy) for the purposes of establishing the MTD and RP2D of bemcentinib in 
combination with the standard dose of docetaxel.  DLTs will include:   
• 
Grade 3 or 4 nausea, vomiting, or diarrhea that persists despite maximum prophylactic and supportive 
care 
• 
Any other Grade 3 or 4 non-hematological toxicity that is considered to be clinically significant and 
causally related to bemcentinib or the combination of docetaxel + bemcentinib 
• 
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding 
• 
Grade 4 neutropenia persisting for seven days or more (despite myeloid growth factors) 
• 
Treatment discontinuation or dose reduction for more than 72 hours during the first cycle as a result of 
treatment-related toxicity 
To be evaluable for dose limiting toxicity, a patient must have received at least one dose of bemcentinib.  
To be considered not to have experienced DLT, a patient must complete one 21-day cycle of treatment 
before a dose-escalation evaluation is made.  To be considered as informative to support dose escalation of 
the loading dose (Days -7, -6, and -5), a patient must receive three loading doses.  To be considered as 
informative to support dose escalation of the daily dose, a patient must miss no more than 3 daily doses 
(including the lead-in period).  Patients who are not evaluable for toxicity will be replaced.   

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Although all toxicities at each course will be recorded, only DLTs thought possibly, probably, or definitely 
attributable to bemcentinib and docetaxel during the first treatment cycle will be used in the decision to 
dose escalate, expand, or de-escalate. 
Treatment will be discontinued if a patient experiences a DLT which does not resolve to ≤ Grade 1 or 
baseline (if higher) prior to the next cycle, or which, in the opinion of the physician, is likely to recur on 
subsequent treatment. 
6.2 Maximum Tolerated Dose (MTD) 
The maximum tolerated dose (MTD) is defined as the highest dose tested in which none or only one patient 
experienced DLT attributable to the study protocol, when at least six patients were treated at that dose level 
and are evaluable for toxicity.  The MTD is one dose level below the lowest dose tested in which 2 or more 
patients experienced DLT attributable to the study protocol.  At least 6 patients will be treated at the MTD.   
Once the MTD has been established (and presumably this will be the dose selected for further phase 2 
testing—ie, recommended phase 2 dose [RP2D]), up to an additional 12 patients will be treated at that dose 
level.  The experience of patients treated in this expansion cohort will be used to (a) better estimate the true 
proportion of patients who cannot complete the first cycle of therapy at the MTD, (b) obtain additional 
preliminary activity data (c) obtain additional pharmacokinetic data, and (d) obtain additional 
pharmacodynamic data. 
6.3 Dose Escalation/De-Escalation Schedule 
The docetaxel dose will be fixed at the standard intravenous dose of 75 mg/m2 every 21 days, or 60 mg/m2 
every 21 days if de-escalation or dose reduction occurs.  
The dose levels of bemcentinib are presented in Table 5; in each dose level, a loading dose of  bemcentinib 
will be administered during the first three days of the run-in period prior to Cycle 1 (Days -7, -6, and -5), 
followed by a lower daily maintenance dose during the remainder of the run-in period and throughout 
continuous 21-day treatment cycles.  At least three evaluable patients will be entered per cohort in a standard 
3+3 study design as described below.  A minimum of 6 patients will be treated at the MTD or RP2D. 
 
Table 5.   
Bemcentinib-Docetaxel Dose Cohorts 
 
 
Bemcentinib dose (mg) 
Docetaxel dose 
(mg/m2 IV on 
Day 1 of each 
cycle) 
 
Cycle 1 
Days -7, -6, and -5 
Cycle 1 
Days -4 to 21 
Cycles ≥ 2 
All days 
Cohort -1a, b 
 
200* daily 
100 daily 
100 daily 
60 
Cohort 1 
 
200* daily 
100 daily 
100 daily 
75 
Cohort 2 
 
400* daily 
200 daily 
200 daily 
75 

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Cohort 2Aa 
 
400* daily 
200 daily 
200 daily 
60 
 
 
NOTE:  Cohort -1 (and potentially Cohort -2) will be enrolled only if Cohort 1 dosing exceeds the 
maximum tolerated dose.   
 
a. If Cohort -1 is enrolled without exceeding the MTD, bemcentinib may be dose escalated to 400 mg 
daily on Days -7, -6, and -5, then 200 mg daily on subsequent days (Cohort 2A). 
 
b. If Cohort -1 or Cohort 2A is enrolled without exceeding the MTD, a subsequent cohort with 
docetaxel dose re-escalated to 75 mg/m2 every 21 days with concurrent myeloid growth factor 
support every cycle will be enrolled. 
 
*If dose-limiting toxicity (DLT) is experienced during or attributed to (ie, occurs shortly after) the 3-day 
loading period, dose de-escalation will occur as follows without adjustment of daily maintenance dose: 
 
Level 1:  loading dose x 3 days 
Level -1:  loading dose x 2 days 
Level -2:  loading dose x 1 day 
Level -3:  no loading dose; initiate treatment with standard daily dose 
 
This is a single-arm phase 1 clinical trial. Dose escalation will be according to a standard 3+3 schema with 
a planned expansion cohort of up to 12 additional patients at the recommended phase 2 dose (RP2D).  At 
least 1 week must elapse between initiation of study therapy for patients within a dose cohort.  At least 3 
weeks must elapse after the treatment of the last patient on the previous dose level before initiation of study 
therapy for the first patient on a new dose level.  
Initially three patients will be recruited into Cohort 1 and must complete one 21-day cycle of treatment 
before a dose-escalation evaluation is made.  A patient must receive all three days of the loading dose and 
miss no more than 3 daily doses in Cycle 1 in order to be considered as informative to support dose 
escalation. 
The decision to dose escalate (or not) will be made by the SPOC Safety Monitoring Committee (SMC).  
Minutes of the SMC meeting will be recorded and circulated for final approval before being placed in the 
Trial Master File (TMF).  The decision to dose escalate will be based on the safety and tolerability of  
bemcentinib observed in the first cycle of treatment.   
Three patients will be treated at each dose level unless DLT criteria are exceeded.  If 0/3 patients experience 
DLT attributable to the study protocol, 3 patients will be treated at the next higher dose cohort. 
If one patient in a cohort experiences a DLT during Cycle 1, the cohort will be expanded to six patients.  If 
two of three or two of six patients in a cohort experience DLT, no further dose-escalation will take place 
and the next lower dose cohort will be explored, according to the Table 6. The maximum dose at which no 
more than one out of three or one out of six patient experienced DLT, will be nominated as the MTD.  A 
recommended dose for Phase II (RP2D) will be established; the RP2D may be lower than the MTD but will 
not be higher than the MTD.  A minimum of 6 patients will be treated at the RP2D.  

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NOTE: DLTs experienced during or attributed to (ie, occurs shortly after) the 3-day loading period will be 
interpreted and responded to independently of DLTs occurring during daily maintenance dosing.  Separate 
dose de-escalation levels will be applied (see Table 8A).   
If a patient withdraws or is withdrawn for reasons other than DLT prior to completing Cycle 1, the patient 
will be replaced for the purposes of evaluation of MTD.  The operating characteristics of the 3+3 dose 
escalation process are summarized in Figure 3. 
 
 

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Figure 3.  Operating Characteristics of the 3+3 Dose Escalation Process 
 
7.0 
STUDY PROCEDURES 
Eligible patients will visit the study site to receive study treatment and protocol-specified procedures 
according to the relevant Schedule of Events table in Table 6.  The treatment period will consist of 
continuous 21-day treatment cycles.   
Patients will attend the clinic once per week during Cycle 1 and then once per cycle thereafter.  All patients 
will continue to receive docetaxel and bemcentinib for as long as, in the opinion of the Investigator, they 
continue to derive clinical benefit or until unacceptable toxicity, clinically significant disease progression, 
death or withdrawal of consent. NOTE: treatment beyond formal progression may be considered for patients 
if (1) the treating investigator feels they are deriving clinical benefit; (2) the patient is not experiencing 
substantial treatment-related toxicity; (3) the case is reviewed with and approved by the Study Chair. 
0 DLT 
Escalate to 
next dose level 
1 DLT 
>1 DLT 
Enter 3 eligible patients 
Enter 3 more 
patients at 
same dose level 
STOP 
MTD = Previous dose 
level or de-escalation 
1 DLT in 6 
patients 
>1 DLT in 6 
patients 

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Table 6. Schedule of Events 
 
 
 
Cycle 
1 
≥2 
End-of-
Studyr 
 
Week -1 
Week 1 
Week 2 
Week 3 
≥ 4 Weeks  
28 days 
after last 
dose 
Cycle Day 
-28 to -
8 
-7 
-6 
 
-5 
-4 
1 
2-7 
8 
9-14 
15 
16  -  
21 
1 
2    
-  
20 
21 
 
Visit window days 
 
0 
0 
 
0 
 
0 
+2 
 
±
2 
0 
±2 
0 
+2 
0 
-5/+2 
+7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance status 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Physical examinationa 
Xa 
X 
 
 
 
X 
 
X  
X 
 
X 
 
 
Xa 
Vital signsb 
X 
X 
X 
X 
 
X 
 
X  
X 
 
X 
 
 
X 
12-Lead ECGc 
X 
 
X 
X 
X 
X 
 
X  
X 
 
X 
 
 
X 
Serum pregnancy testd 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical chemistryf 
X 
Xe 
X 
 
 
X 
 
X  
X 
 
X 
 
 
X 

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Cycle 
1 
≥2 
End-of-
Studyr 
 
Week -1 
Week 1 
Week 2 
Week 3 
≥ 4 Weeks  
28 days 
after last 
dose 
Cycle Day 
-28 to -
8 
-7 
-6 
 
-5 
-4 
1 
2-7 
8 
9-14 
15 
16  -  
21 
1 
2    
-  
20 
21 
 
Hematologyg 
X 
Xe 
X 
 
 
X 
 
X  
X 
 
X 
 
 
X 
Coagulationh 
X 
Xe 
 
 
 
 
 
X  
X 
 
X 
 
 
X 
Urinalysisi 
X 
Xe 
 
 
 
 
 
X  
X 
 
X 
 
 
X 
Echocardiogram or 
MUGA scan 
X 
 
 
 
 
 
 
 
 
 
 
Xj 
 
 
 
PK blood sampling k 
 
 
X 
X 
 
X 
X 
 
 
 
 
X 
 
 
 
Tissue collection for 
PDl 
X 
 
 
 
 
X 
 
 
 
Xl 
 
 
Xq 
Xq 
Blood collection for 
mRNA isolation, PBMC 
isolation and PDm 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Xq 
Xq 
Disease assessmentn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xo 
Bemcentinib 
administrationp 
 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
 
Docetaxel 
administration 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Drug accountability 
 
 
 
 
 
X 
 
X  
X 
 
X 
 
 
X 

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Cycle 
1 
≥2 
End-of-
Studyr 
 
Week -1 
Week 1 
Week 2 
Week 3 
≥ 4 Weeks  
28 days 
after last 
dose 
Cycle Day 
-28 to -
8 
-7 
-6 
 
-5 
-4 
1 
2-7 
8 
9-14 
15 
16  -  
21 
1 
2    
-  
20 
21 
 
Adverse events 
X 
X ------------------------------------------------------------------------------------------------------------------------- X 
Concomitant 
medications 
 
X-------------------------------------------------------------------------------------------------------------------------- X 
a. 
Physical examination conducted at the Screening and End-of-Study visits.  A symptom-directed examination will be conducted at other visits 
b. Blood pressure, pulse, respiratory rate, temperature 
c. 
Triplicate 12-lead ECG, 5 minutes apart, after resting for ≥10 minutes in supine position during screening  and during each visit (pre-dose). On Cycle 1 an additional triplicate 
ECG will be conducted pre-dose on  Day-5 and Day -4.  Patients who re-start bemcentinib following interruption for QTc prolongation should also have ECGs performed 
according to this schedule , QT interval correction will be performed using the Friderica formula 
d. For women of child-bearing potential only 
e. 
Unless conducted as part of the screening procedures within 3 days prior to Day -7 
f. 
Clinical chemistry laboratory parameters uric acid, electrolytes, blood urea nitrogen (BUN), total protein, total bilirubin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), serum creatinine, creatinine phosphokinase, alkaline phosphatase, albumin, calcium, phosphorus, glucose,  magnesium and amylase and lipase (during 
Screening ONLY) 
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 completion of therapy.  
Serum calcium and magnesium should be measured and reasonable efforts made to maintain at normal levels throughout treatment. 
g. Hematology laboratory parameters (full blood count including differential white cell count, haemoglobin, hematocrit and platelets) 
h. Coagulation parameters: prothrombin time (PT) and/or INR, activated partial thromboplastin time (aPPT) 
i. 
Dipstick measurement of blood, nitrite, glucose, ketones, leukocytes, protein, and pH.  (Microscopic analysis is not required unless clinically indicated)  
j. 
Cycle 4 Day 1 ONLY 

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k. PK samples will be collected only on the first 15 enrolled subjects. Blood sampling for the determination of bemcentinib and/or docetaxel in plasma will be conducted at the 
following time-points. Detailed procedures for the collection, processing, storage and shipment of samples will be provided in the Study Laboratory Manual.  
Bemcentinib = All time points are pre-dose (C1D-6, C1D-5, C1D1, C1D2, C2D1, C4D1) 
Docetaxel = C1D1 (0.5, 1, 2, 4, 6, 8 hrs, +/- 20 minutes.), C1D2 (pre-dose), C1D3 (Pre-dose). See Appendix E 
l. 
After consenting patients, optional tissue specimens may be collected for analysis of pharmacodynamic endpoints of bemcentinib. The baseline tissue specimen should be 
collected after enrollment within 28 days prior to first dose of study drug. The on-treatment tissue collection should be performed during Cycle 1 or Cycle 2 (any time after 14 
days of continuous exposure to bemcentinib and initiation of docetaxel). The tissue collection and blood collection should be performed on the same day. Detailed procedures 
for the collection, processing, storage and shipment of the samples will be provided in the Study Laboratory Manual 
m. 
Blood samples will be collected for isolation of PBMC, isolation of mRNA from whole blood sample and for the investigation of other pharmacodynamic effects of  bemcentinib. 
The baseline sample should be collected on Cycle 1, Day -7 prior to administration of the first dose of bemcentinib, then again on Day 1 of Cycles 1 and 2 prior to infusion of 
docetaxel and finally at the time of disease progression or End of Study visit, whichever comes first. Detailed procedures for the collection, processing, storage and shipment 
of the samples will be provided in the Study Laboratory Manual 
n. 
Disease assessment via RECIST v1.1 will be performed at the end of even-numbered cycles beginning with Cycle 2 (Day 21);  the assessment may be performed up to 5 days 
before Day 21 (Day 17 - Day 21) but attempts should be made to conduct the assessment as close to Day 21 as possible.  Disease assessment may be performed prior to initiation 
of the next cycle, but results must be available prior to initiation of treatment and must confirm continued eligibility for next cycle) 
o. 
If not performed within previous 28 days 
p. 
Bemcentinib will be administered on an empty stomach first thing in the morning with water and at least 1 hour before or 2 hours after food at approximately the same time on 
each dosing day, other than on the morning of study visit days when bemcentinib should be administered during the visit. Patients should record dosing in the dosing diary 
provided.  Bemcentinib should be administered before docetaxel administration (where applicable).  In dose de-escalation cohort -2 or certain dose reductions, bemcentinib will 
be administered three times weekly. 
q. 
The Time of progression tissue collection for PD (in consenting patients only), blood collection for PD should be performed any time after documentation of clinical/radiographic 
disease progression and no later than the  End-of-Study visit (the tissue specimen should be derived from a lesion exhibiting clinical/radiographic progression). 
r. 
Survival information will be collected by phone, follow-up visit, or medical records approximately every 4 months from date of final tumor assessment until patient’s death, 
until patient is lost to follow up, or until study closure.  
 
 
 
 

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7.1 Assessment Schedule During Screening Visit 
All patients must sign and date an IRB-approved informed consent document prior to completing any 
screening assessments.  However, evaluations performed before the consent as standard of care for NSCLC 
can be used for screening assessments as long as they meet the protocol timelines. 
Eligibility criteria are evaluated within 28 days prior to enrollment, with confirmation that the patient 
continues to meet eligibility criteria pre-dose on Cycle 1 Day -7. 
All screening evaluations must be completed prior to initiating treatment with the study medication.  A 
maximum of 4 weeks will be allowed to complete screening assessments. 
7.2 Screening Assessments to be Completed Within 28 days Prior to Enrollment: 
 
During screening, the following procedures will be performed: 
 
• 
Written informed consent 
• 
Demographics 
• 
Medical history 
• 
Review of inclusion/exclusion criteria 
• 
Performance status assessment 
• 
Physical examination 
• 
Vital signs 
• 
Serial 12-lead ECGs, in triplicate (≤5 minutes apart), performed after the patient has been supine 
for ≥10 minutes) 
• 
Serum pregnancy test, if applicable 
• 
Clinical chemistry (including amylase and lipase), hematology, urinalysis, coagulation 
• 
Echocardiogram or MUGA scan  
• 
Tissue collection for PD (consenting patients only) 
• 
Disease assessment, including radiologic assessment as below 
Male patients and female patients of reproductive potential must agree to practice highly effective methods 
of contraception throughout the study and for ≥3 months after the last dose of bemcentinib.  Highly effective 
methods of contraception are defined as: 
• 
Hormonal implants, combined oral contraceptives, injectable contraceptives 
• 
An intrauterine device with hormone spirals 
• 
Tubal ligation 
• 
True total sexual abstinence 
• 
Vasectomy 
If it is not possible to use one of these highly effective methods of contraception, two barrier methods used 
simultaneously are acceptable. 

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7.2.1 
Radiologic Assessments at screening 
The following radiologic assessment will be performed within 4 weeks prior to randomization: 
• 
CT/MRI scans of the chest and upper abdomen.   
• 
Brain imaging will be performed only if clinically indicated (headache, focal neurological findings) or 
if known history of treated brain metastases.  
• 
For patients with baseline abnormalities on brain MRI, these studies will be repeated every 4 cycles (ie, 
every 12 weeks) 
7.3  Study Assessments 
7.3.1 Assessments Before Initiation of Treatment on Cycle 1 Day -7 
The following laboratory assessments will be performed: 
• 
Hematology and clinical chemistry.  If any laboratory values no longer meet eligibility criteria, 
initiation of Cycle 1 Day -7 treatment should be delayed for 2 to 3 days and laboratory tests should be 
repeated.     
• 
Serum pregnancy test prior to treatment on Cycle 1 Day -7 for patients of childbearing potential.  A 
negative test is required before the patient may receive study drug. 
• 
Serial 12-lead ECGs, in triplicate per screening procedures 
NOTE: Screening lab tests and procedures may substitute for those on Cycle 1 Day -7 if performed 
within 3 days of Cycle 1 Day -7.   
7.3.2 
Safety Assessments During the Treatment Period 
NOTE:  In dose de-escalation cohort -2 (and after dose reduction in other cohorts), bemcentinib will be 
administered three times weekly, so administration may not fall precisely on the days indicated below. 
 
NOTE: PK samples will be collected only from the first 15 enrolled subjects.  
Cycle 1 (bemcentinib lead-in) 
 
Day -7  
• 
Symptom-directed physical examination 
• 
Vital signs 
• 
Serum pregnancy test (unless conducted as part of Screening procedures within 3 days prior to Day 
-7) (Day -7 only) 
• 
Clinical chemistry (does not have to be repeated if conducted as part of Screening procedures within 
3 days prior to Day -7) 
• 
Hematology, coagulation, urinalysis (unless conducted as part of Screening procedures within 3 
days prior to Day -7) 
• 
Blood collection for PD  
• 
Blood collection for mRNA isolation from whole blood 
• 
Blood collection for PBMC isolation from whole blood 
• 
Bemcentinib administration  

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• 
Adverse events assessment 
• 
Concomitant medications assessment 
 
 
Day -6  
• 
Vital signs 
• 
Clinical chemistry  
• 
Hematology 
 
• 
Blood sampling for PK for bemcentinib (pre-dose) 
• 
Bemcentinib administration  
 
Day -5 
• 
Vital signs 
• 
Pre-dose serial 12-lead ECGs, in triplicate per screening procedures 
• 
Blood sampling for PK for bemcentinib (pre-dose) 
• 
Bemcentinib administration  
Day -4 
• 
Pre-dose serial 12-lead ECGs, in triplicate per screening procedures 
• 
Bemcentinib administration  
Cycle 1 
 
Day 1 
• 
Symptom-directed physical examination 
• 
Vital signs 
• 
Serial 12-lead ECGs, in triplicate per screening procedures 
• 
Clinical chemistry  
• 
Hematology,  
Blood sampling for PK for bemcentinib (pre-dose); for docetaxel 0.5, 1, 2, 4, 6, 8 hrs ( ± 20 minutes) 
 
• 
Blood collection for PD before docetaxel administration 
• 
Blood collection for mRNA isolation from whole blood 
• 
Blood collection for PBMC isolation from whole blood 
 
• 
Docetaxel administration 
 
• 
Bemcentinib administration 

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• 
Drug accountability 
• 
Adverse events assessment 
• 
Concomitant medications assessment 
 
Day 2 (only if PK sampling planned) 
• 
Blood sampling for PK for bemcentinib and docetaxel pre-dose  
• 
Bemcentinib administration 
Day 3 (only if PK sampling planned) 
• 
Blood sampling for PK for docetaxel pre-dose (optional) 
• 
Bemcentinib administration 
 
Days 8 and 15 
• 
Symptom-directed physical examination 
• 
Vital signs 
• 
Serial 12-lead ECGs, in triplicate per screening procedures 
• 
Clinical chemistry  
• 
Hematology, coagulation, urinalysis  
• 
Bemcentinib administration 
• 
Drug accountability 
• 
Adverse events assessment 
• 
Tissue collection for PD (in consenting patients, may be any time after 14 consecutive days of 
bemcentinib administration in Cycle 1 or 2) 
• 
Concomitant medications assessment 
 
Cycle ≥2 
 
Day 1 
• 
Performance status assessment  
• 
Symptom-directed physical examination 
• 
Vital signs 
• 
Serial 12-lead ECGs, in triplicate per screening procedures 
• 
Clinical chemistry, hematology, urinalysis, coagulation 
• 
Blood sampling for PK for bemcentinib (pre-dose) 
• 
Tissue collection for PD (in consenting patients if not performed in Cycle 1) 
• 
Blood collection for PD before docetaxel administration 
• 
Blood collection for mRNA isolation from whole blood 
• 
Blood collection for PBMC isolation from whole blood 
• 
Docetaxel administration 

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• 
Bemcentinib administration 
• 
Drug accountability 
• 
Adverse events assessment 
• 
Concomitant medications assessment 
• 
Disease assessment (by RECIST 1.1; may be performed at any point Days 16-21; even-numbered 
cycles only 
• 
Echocardiogram or MUGA scan (Cycle 4 only) 
 
 
 
Disease progression 
• 
Tissue collection for PD from a lesion demonstrating progression (in consenting patients, any time 
after the documentation of disease progression and no later than the End-of-Study visit) 
• 
Blood collection for PD (any time after the documentation of disease progression and no later than 
the End-of-Study visit, and at the same time as PD tissue collection in consenting patients) 
 
End-of-Study Visit 
The following assessments will be carried out for every patient enrolled into the study 28 days after the last 
dose of study medication or at study withdrawal. 
• 
Performance status assessment 
• 
Physical examination 
• 
Vital signs 
• 
Serial 12-lead ECGs, in triplicate per screening procedures 
• 
Clinical chemistry, hematology, coagulation, urinalysis 
• 
Tissue collection for PD from a lesion demonstrating progression (in consenting patients, if not 
already collected) 
• 
Blood collection for PD (if not already collected at the time of disease progression) 
• 
Blood collection for mRNA isolation from whole blood 
• 
Blood collection for PBMC isolation from whole blood 
• 
Drug accountability 
• 
Adverse events assessment 
• 
Concomitant medications assessment 
 
7.3.3 
Off-Therapy Evaluations  
Survival information will be collected by phone, follow-up visit, or medical records approximately every 4 
months from date of final tumor assessment until patient’s death, until patient is lost to follow up, or until 
study closure.  
 
7.3.4 
Efficacy Assessments 
 

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7.3.4.1 Radiologic Assessments 
• 
CT/MRI scans of the chest and upper abdomen will be performed every 2 cycles.  The same imaging 
technique must be utilized throughout the study.  Patients who stop study treatment for reasons other 
than disease progression should undergo imaging every 9 weeks until disease progression, death, or 
initiation of subsequent cancer therapy. 
• 
Brain imaging will be repeated only when clinically indicated.  If, during baseline brain MRI, it was 
determined that there were clinically significant abnormalities, brain MRI will be repeated every 4 
cycles (ie, every 12 weeks) 
7.3.4.2 Pharmacokinetic and Biomarker Assessments: Pharmacokinetic assessments will be performed in 
the first 15 enrolled patients*  
 
• 
Bemcentinib PK time points (see Appendix E): 
• 
Cycle 1 Day -6: pre-dose 
• 
Cycle 1 Day-5: pre-dose 
• 
Cycle 1 Day 1: pre-dose 
• 
Cycle 1 Day 2: pre-dose 
• 
Cycle 2 Day 1: pre-dose 
• 
Cycle 4 Day 1: pre-dose 
• 
Docetaxel PK time points: 
• 
Cycle 1 Day 1: post-dose 0.5, 1, 2, 4, 6, 8 hours (+/-20 minutes). Suggested draw time: 
− 
0.5 (24-36 minutes post dose) 
− 
1hr (48 - 1h 12 minutes post dose) 
− 
2 hrs (1h 36 - 2h 24minutes post dose) 
− 
4 hrs (3h 12 - 4h 48 minutes post dose) 
− 
6 hrs (4hrs 48 - 7h 12 minutes post dose) 
− 
8 hrs (6hrs 24 - 9h 36 post dose) 
 
• 
Cycle 1 Day 2:  bemcentinib pre-dose 
• Cycle 1 Day 3:  bemcentinib pre-dose (optional) 
 
 
Plasma samples (one 3 ml ACD tube) will be taken at baseline (Cycle 1 Day -7), pre-infusion on Cycle 
1 Day 1 and Cycle 2 Day 1, and at disease progression or End-of-Treatment visit, whichever is first. 
2.5 ml of whole blood samples will be collected in PAXgene tubes for mRNA isolation and subsequent 
analysis of cytokines and cell surface markers by qPCR analysis, consistent with a change in immune 

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activation before and after drug treatment. Two tubes of 8.5 ml whole blood will be collected in ACD 
tubes for PBMC isolation to monitor immune cells. 
Plasma samples will be used for biomarker analysis of potentially relevant biomarkers utilizing 
proteomic, transcriptomic, somatic mutation profiling, and assays for angiogenic and immunological 
markers. 
 
7.4 Patient Withdrawal Criteria 
 
7.4.1 
Withdrawal from treatment 
A patient may be withdrawn from treatment for any of the following reasons: 
• 
Objective disease progression following radiological assessment as determined by the Investigator (per 
modified RECIST 1.1 criteria). NOTE: treatment beyond formal progression may be considered for 
patients if (1) the treating investigator feels they are deriving clinical benefit; (2) the patient is not 
experiencing substantial treatment-related toxicity; (3) the case is reviewed with and approved by the 
Study Chair. 
• 
Clinical progression 
• 
Adverse event (including intercurrent illness or unacceptable toxicity) 
• 
Death 
• 
Patient’s request/to withdrawal consent from treatment 
NOTE:  Because secondary endpoints of this study include overall and progression-free survival, 
patients should be encouraged to permit follow up for disease and survival status. 
• 
Lost to follow up 
• 
Other Investigator decision (with documentation of reason) 
• 
Study termination or termination of treatment by Sponsor 
 
7.4.2 
Withdrawal from study 
A patient may be withdrawn from the study for the following reasons:   
• 
Patient’s request/withdrawal of consent 
NOTE:  Because secondary endpoints of this study include overall and progression-free survival, 
patients should be encouraged to permit follow up for disease and survival status. 
• 
Lost to follow up 
• 
Death 
• 
Study termination by Sponsor 
 
 

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8.0 
DOSING DELAYS/DOSE MODIFICATIONS 
 
All toxicities should be graded according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03.  
 
In general, dose reductions and interruptions should be performed for the suspected 
causative agent.  In instances where treatment-related toxicity cannot reasonably be assigned 
to a single agent, both BEMCENTINIB and docetaxel doses should be reduced. If one of the 
therapeutic agents is withheld or discontinued for toxicity, the other agent may be continued. 
8.1  Bemcentinib  
 
If a patient experiences drug-related toxicity which requires treatment with bemcentinib to be interrupted, 
a delay of up to 14 days is permitted to allow for resolution of toxicity.  Toxicities must have resolved to ≤ 
Grade 1 or to baseline for treatment to recommence.  For Grade 1 or Grade 2 (tolerable) toxicity, the patient 
may resume dosing at the same dose level.  For ≥ Grade 2 (intolerable) toxicity, the patient may resume 
dosing at a dose level defined by the grade of the toxicity and the number of occurrence(s) of prior toxicity 
as outlined in Tables 7 and 8.  
 
 
 
 

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Table 7.  Dose Modification of Maintenance Bemcentinib for Toxicity 
 
Grade (CTCAE) 
Recommended Dose Modification 
Grade 1 and Grade 2 (tolerable) 
Any occurrence 
Maintain dose if toxicity is tolerated by the patient and at the 
discretion of the investigator 
Grade 2 (intolerable) 
1st or 2nd occurrence  
of same adverse event  
Interrupt treatment until toxicity returns to baseline, Grade 1 or 
tolerable Grade 2. Resume dosing at same dose 
3rd occurrence  
of same adverse event  
 
Interrupt treatment until toxicity returns to baseline, Grade 1 or 
tolerable Grade 2 
Dose reduce by 100 mg 
4th occurrence  
of same adverse event  
Discontinue permanently 
Grade 3 
1st occurrence 
Interrupt treatment until toxicity returns to baseline, Grade 1 or 
tolerable Grade 2 
Dose reduce by 100 mg or 
Discontinue permanently if dose has already been reduced  
2nd occurrence  
of same adverse event at G3 
Discontinue permanently 
Grade 4  
1st occurrence 
Discontinue permanently 
 
NOTES: 
 
• 
If treatment-related toxicity has not resolved to Grade ≤1 or to baseline (with the exception of 
alopecia) within 14 days, discussion with and approval by Study Chair is required prior to restarting 
therapy. 
• 
Dose reduction below 100 mg daily is not possible (a single capsule contains 100 mg bemcentinib). 
• 
If bemcentinib dose has been decreased to 100 mg daily, it may be reescalated to starting dose of 
200 mg daily following adequate recovery from toxicity per investigator discretion.   
 
If one week or more elapses without administration of bemcentinib, the loading doses for the cohort to 
which the patient is assigned should be repeated when treatment is re-initiated.  
 
 

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In clinical study BGBC001, evidence of bemcentinib exposure-related QTcF prolongation was observed.  
In order to reduce the risk of QTcF prolongation, 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 
completion of therapy.  Serum calcium and magnesium should be measured and reasonable efforts 
made to maintain at normal levels throughout treatment.  Patients with a QTcF of >480 ms should be 
closely monitored until the QTcF falls below 480 ms; electrolytes should be measured and corrected as 
necessary. 
 
Triplicate 12-lead ECG, 5 minutes apart, after resting for ≥10 minutes in supine position during screening  
and during each visit (pre-dose). On Cycle 1 an additional triplicate ECG will be conducted pre-dose on 
Day-5 and Day -4.  Patients who re-start bemcentinib following interruption for QTc prolongation should 
also have ECGs performed according to this schedule. 
  
If a patient experiences QTcF prolongation despite normal serum potassium and magnesium levels,  
bemcentinib dosing should be modified as outlined in Table 8.  
 
QT interval will be corrected using Friderica’s calculation 
 
 

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Table 8.  Dose Modification of Bemcentinib for QTcF Prolongation 
 
QTcF 
Recommended Bemcentinib Dose Modification 
Grade 1 (451-480 ms) 
Any occurrence 
No dose modification required 
Grade 2 (481-500 ms)  
1st 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, interrupt 
treatment for ≤14 days 
- if QTcF reduces to ≤Grade 1, no dose modification is required, and dosing can 
recommence at the allocated dose 
- if QTcF does not reduce to ≤Grade 1, dose reduce by 100 mg 
≥2nd occurrence  
(without dose modification) 
Repeat procedure for “1st occurrence” 
- if treatment interruption is required on more than 2 occasions, dose reduction 
by 100 mg is recommended 
≥2nd occurrence  
(at reduced dose) 
  
Continue dosing and conduct weekly ECGs; 
 i) if QTcF reduces to ≤Grade 1 by 14 days from initial recording, no further dose 
modification is required 
ii) if QTcF does not reduce to ≤Grade 1 by 14 days from initial recording, interrupt 
treatment for ≤14 days 
- if QTcF reduces to ≤Grade 1, no dose modification is required and dosing can 
recommence; if treatment interruption is required on more than 2 occasions at 
reduced dose, dose reduce by another 100 mg or discontinue treatment if dose 
reduction is not possible 
- if QTcF does not reduce to ≤Grade 1, dose reduce by another 100 mg or 
discontinue treatment if dose reduction is not possible 
≥Grade 3 (>501 ms)  
1st occurrence 
Interrupt treatment for ≤14 days; 
- if QTcF reduces to ≤Grade 1, dose reduce by 100 mg or discontinue treatment 
if dose reduction is not possible 
- if QTcF does not reduce to ≤Grade 1, discontinue treatment 
2nd occurrence  
Discontinue permanently 
Ventricular arrhythmia 
1st occurrence 
Discontinue permanently 
Notes: 
• Electrolytes should be measured at the time of reporting QTc prolongation, and regularly until the QTc has returned to 
baseline.  Any clinically significant electrolytes should be corrected.The mean QTcF value from triplicate ECG readings 
should be used when considering dose modification 
• Treatment interruption for bemcentinib-related toxicity should be limited to 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 
 
8.2 Docetaxel 
 

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Each cycle of chemotherapy may be delayed until the ANC is ≥ 1500 cells/μL and the platelet count is ≥ 
100,000 cells/μL and hepatic function is acceptable. Institutional standard practices may be used to adjust 
doses for toxicity. However, in the absence of such standard practices, suggested dose adjustments for 
docetaxel-related hematologic and non-hematologic toxicities are provided in Table 9 and Table 10, 
respectively. 
 
Table 9. Dose Adjustments for Docetaxel-related Hematologic Toxicities* 
 
Situation 
Recommended 
Docetaxel Dose 
First episode of febrile neutropenia 
reduce 1 dose level 
Second episode of febrile neutropenia 
reduce additional dose 
level 
 
ANC <500/mm3 
reduce one dose level 
Grade 4 thrombocytopenia or bleeding associated 
with thrombocytopenia 
reduce one dose level. 
ANC= absolute neutrophil count 
 
NOTE:  due to the occurrence of neutropenia considered dose-limiting or neutropenia complicating the 
feasibility of long-term treatment administration in earlier cohorts, starting with patients enrolled on 
protocol Version 5.0 or later, patients receiving docetaxel 75 mg/m2 and/or bemcentinib maintenance 
dose of 200 mg daily must receive myeloid growth factors (eg, G-CSF, preferably pegylated G-CSF). In 
certain cases, myeloid growth factors may be omitted from subsequent treatment cycles. Examples 
include intolerance of myeloid growth factors, dose-reduction of docetaxel, or suspicion [based on 
available laboratory and clinical data] that patient would tolerate treatment and not develop severe 
neutropenia if myeloid growth factors were omitted. 
 
Table 10. Dose Adjustments for Docetaxel-related Non-hematologic Non-neuropathic 
Toxicities* 
 
NCI CTCAE Grade 
Recommended Docetaxel Dose 
0 to 2 
Continue current dose 
3 (except alopecia) 
Reduce one dose level 
4 
Reduce two dose levels 
NCI-CTCAE= National Cancer Institute (United States Common Terminology Criteria for Adverse events 
(Version 4.03). *treatment may be withheld until the toxicity has been reduced to grade ≤ 2.  
 
In addition to the dose adjustments, patients may receive supportive care as necessary.23,24  Patients 
experiencing febrile neutropenia secondary to docetaxel chemotherapy may receive granulocyte colony 
stimulating factor therapy in association with subsequent chemotherapy doses. Erythropoietin may also be 
used as clinically indicated, along with other supportive care.  
 
If Cohort -1 or Cohort -2 is enrolled without exceeding the MTD, a subsequent cohort with docetaxel 
dose re-escalated to 75 mg/m2 every 21 days with concurrent myeloid growth factor support every cycle 
will be enrolled. 
 
Dose re-escalation may be considered on a case-by-case basis. 

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*NOTE:  For starting docetaxel dose of 60 mg/m2, dose reduction is displayed in the table below and 
compared to the 75 mg/m2 starting dose 
 
Dose Level 
Docetaxel dose 
Starting dose 
60 mg/m2 
75 mg/m2 
-1 
35 mg/m2 
60 mg/m2 
-2 
N/A 
35 mg/m2 
 
In cases where docetaxel or bemcentinib is permanently discontinued for toxicity reasons, the other 
agent(s) may be continued provided that (a) the patient is tolerating their ongoing administration, and (b) 
there is evidence of ongoing clinical benefit. 
9.0 
TOXICITY REPORTING AND ASSESSMENT 
It is the responsibility of each treating institution to report all adverse events to the clinical monitor of this 
IND and the IND sponsor. Copies of adverse events reports will be sent by the IND Sponsor to the FDA 
(see Section 9.3). 
 
In accordance with good clinical practices, all adverse events and all dose escalations will be reviewed by 
the South Plains Oncology Consortium (SPOC) Data Safety and Monitoring Committee (DSMC).  The 
SPOC DSMC will record these discussions and decisions in the SPOC Phase I tracking log.  This 
information will be made available as needed. 
9.1 Reporting Toxicities 
Using the Notification of Toxicity form in Appendix C, report to the SPOC Consortium Manager (office 
phone: 806-743-2690, cell phone:  806-773-4836 FAX: 806-743-2691, e-mail: amanda.knight@ttuhsc.edu) 
within 24 hours of knowledge of the event: 
• 
All serious adverse events (SAEs) 
• 
All dose-limiting toxicities (DLTs) 
• 
All unexpected adverse events deemed possibly, probably, or definitely related to 
study drugs or procedures 
The SPOC DSMC will review all serious adverse events and unexpected adverse events in real time with 
other members of the DSMC by phone conference.  This Phase I trial will be monitored by the SPOC 
DSMC after the first patient, before any dose escalation, with each new event, or at least annually.  Meeting 
minutes will document these reviews and will be made available as needed.  A description of the SPOC 
DSMC is contained in the SPOC “Standard Operating Procedure for the SPOC DSMC. 
 
All toxicities should be reported, whether or not they are attributable to the study drugs.  All life-
threatening toxicities mandate a telephone contact within 24 hours of the event between the reporting 
institution’s principal investigator (PI) and the PI’s or their designates of the other participating 
institutions.   
 
Any supporting documentation (i.e., laboratory, pathology, progress notes, discharge summary, autopsy, 
etc.) explaining the AE should accompany the submitted report. 

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9.2 Additional Adverse Event Experience Reporting 
Adverse Experience (AE) reports of a serious nature are to be reported by phone to the SPOC Consortium 
Manager at 806-743-2690, and to the Study Protocol Chair and IND Sponsor (David E. Gerber, MD) at 
office 214-648-4180, within 24 hours of knowledge of the event:  
 
• 
All life-threatening events (Grade 4) which might be due to study drugs or 
procedures 
• 
All fatal events 
• 
Serious events requiring or extending hospitalization which may be due to study 
drugs or procedures 
 
A written report should be sent within the time specified to all relevant IRB’s following the event.  
 
Written reports will be sent to the SPOC Consortium Manager (phone: 806-743-2690, FAX: 806-743-2691, 
e-mail: amanda.knight@ttuhsc.edu).  The Consortium Manager will submit the report to BerGenBio AS, 
who will be the point-of-contact for IND-related matters.  The IND sponsor will review the report and if 
required submit to the Food and Drug Administration submitted within 10 working days to: 
 
 
Food and Drug Administration 
 
P.O. Box 3001 
 
Bethesda, MD 20824 
 
A copy of any written reports submitted to the FDA will be provided to: 
 
David Gerber, M.D. 
Division of Hematology-Oncology 
Harold C. Simmons Cancer Center 
University of Texas Southwestern Medical Center 
5323 Harry Hines Blvd., Mail Code 8852 
Dallas, TX  75390-8852 
Ph:  214-648-4180 
E-mail:  david.gerber@utsouthwestern.edu 
  
 
All adverse experiences are to be recorded in the patient’s medical record, and will be transcribed to the 
patient’s case report form (CRF). 
 
The SPOC Consortium Manager will distribute the report to participating institutions to be filed with each 
collaborating site’s IRB as follows: 
 
TTUHSC:  within 5 days 
UT Southwestern:  within 10 working days 
Covenant Health Systems:  within 10 working days  
 
9.2.1. Reporting of Serious Adverse Events 
Any SAE experienced by a patient between the time of the first administration of BEMCENTINIB and 28 
days after the last administration is to be recorded on an SAE Report Form within 24 hours of knowledge 
by the investigator of its occurrence, regardless of the severity and causality of the event. Related SAEs 

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should continue to be reported indefinitely. The SAE Report Form should be faxed or e-mailed to the 
Chiltern International (US fax numbers: 1 888 726 8416; GlobalSAEInbox@chiltern.com ) 
.  A telephone report may only be made in exceptional circumstances and must be followed by completion 
of the SAE Report Form within 1 working day.  Where applicable, information from relevant hospital case 
records and post-mortem reports should be obtained.  
 
All SAEs that have not resolved by the end of the study, or that have not resolved upon the patient’s 
discontinuation from the study, must be followed until any of the following occur: 
• 
The event resolves 
• 
The event stabilizes 
• 
The event returns to baseline status 
• 
The event can be attributed to agents other than study treatment or to factors unrelated to study 
conduct  
• 
It becomes unlikely that any additional information can be obtained  
 
9.2.2  Immediate Reporting of Serious Adverse Events  
Expedited safety reporting within this clinical study complies with the ICH Guideline for Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting (E2A), investigational new drug 
(IND) application safety reporting (under 21CFR312.32), and with applicable local regulatory 
requirements. 
The sponsor of the IND assumes responsibility for appropriate reporting of AEs to the Regulatory 
Authorities and Institutional Review Boards (IRB).  Although this responsibility can be delegated, the 
sponsor of the IND retains ultimate responsibility for safety reporting.   
 
All SAEs that are unexpected and associated with the use of the investigational product are classified as 
suspected unexpected serious adverse reactions (SUSARs) and must be reported to the IRBs and Regulatory 
Authorities within 7 calendar days if fatal or life threatening, or within 15 calendar days if non-life 
threatening and non-fatal.  The Sponsor/designee must also report SUSARs to all investigational sites. 
 
Any safety information from other observations that could change the risk-benefit evaluation of 
bemcentinib should be promptly communicated to the Regulatory Authorities and IRBs.  Any other 
SUSARs associated with bemcentinib should be reported as soon as the Sponsor becomes aware of them, 
including SUSARs which occur in another clinical study conducted by the same Sponsor or which are 
identified by spontaneous reports, a publication, or which are transmitted to the sponsor by another 
Regulatory Authority.  
 

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Other safety issues that also qualify for expedited reporting where they might materially alter the current 
benefit-risk assessment of the bemcentinib (sufficient to consider changes in the administration or in the 
overall conduct of the trial), include: 
• 
An increase in the rate of occurrence of an expected serious adverse reaction, which is judged to 
be clinically important 
• 
Post-study SUSARs that occur after the patient has completed a clinical trial and are reported by 
the Investigator to the Sponsor 
• 
New events relating to the conduct of the trial or the development of bemcentinib likely to affect 
the safety of the patients, such as: 
o An SAE which could be associated with study procedures and which could modify the 
conduct of the study 
o A major safety finding which differs from the underlying disease 
 
Expedited reporting is not usually required for reactions which are serious but expected, and it is 
inappropriate to report events that are considered unrelated to the investigational product. 
 
The cause of death of a patient in a clinical study, unless it is associated with disease progression, is 
considered a SAE whether the event is expected or associated with the investigational agent. 
 
9.2.3  Pregnancy 
In the event of a pregnancy occurring in female patients, or in the partners of male patients during the study, 
the pregnancy must be reported to the Chiltern International (US fax numbers: 1 888 726 8416; 
GlobalSAEInbox@chiltern.com )  by the investigational staff within one working day of their knowledge 
of the event using a Pregnancy Notification Form. 
 
The reporting period for pregnancies will start with the first study-related procedure and end 28 days after 
the final administration of bemcentinib. 
 
Any female patients who become pregnant while taking part in the study will be withdrawn; a male patient 
whose partner becomes pregnant can remain in the study.  A patient who completes or withdraws from the 
trial before the full term of the pregnancy will be asked to consent to provision of follow-up information 
about the pregnancy and its outcome. 
9.3 Adverse Events  
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal relationship 
with its treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporally associated with the use of the study drug, 
whether or not considered related to the study drug. 

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NOTE: Abnormal vital signs that are considered clinically relevant by the Investigator must be reported as 
AEs. 
9.3.1 
Serious Adverse Events 
A serious adverse event (SAE) is any AE occurring at any dose that meets 1 or more of the following 
criteria as assessed by either the Sponsor or Investigator: 
• 
Results in death. 
• 
Is life-threatening event- an AE is considered to be life-threatening if either the Investigator or the 
Sponsor determines the occurrence of the event places the patient at immediate risk of death.  It does 
not refer to an AE that, if it occurred in a more severe form, may have resulted in death.  
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization - Hospitalization is 
defined as an admission to hospital ≥24 hours.  Any pre-planned hospitalization for an elective 
procedure that is unrelated to participation in the study will not be considered an SAE.  
• 
Results in a significant incapacity or disruption of the ability to conduct normal life activities.  
• 
Results in a congenital anomaly or birth defect. 
• 
Important medical event - any event that does not meet the above criteria, but that when based upon 
medical judgment jeopardizes the patient and may require medical or surgical intervention to prevent 
1 of the outcomes listed in the definition of “SAE.” 
NOTE: If standard of care or institutional practice requires hospitalization of patients for the sole purpose 
of delivering chemotherapy including study therapy then such hospital admissions will not be considered 
or reported as SAEs.  However, should an SAE develop during such hospitalization, it will be considered 
and reported as such. 
NOTE: All pregnancies occurring during this study are reported in the same timeframe as SAEs.  If a 
pregnancy is confirmed during the study, the continued use of the study drug must be immediately 
evaluated.  When possible, all reports of pregnancy must be followed for information regarding the course 
of the pregnancy and delivery, as well as the condition of the newborn or other outcome.  Follow-up 
information concerning the outcome of the pregnancy will be provided by the Investigator to the study 
medical monitor in a timely manner and regardless of whether the patient has discontinued participation in 
the study.  If the newborn is healthy, additional follow up is not needed.     
9.3.2 
Relationship to Study Drug 
 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated, Unlikely, Possibly, Probably or Definitely Related).  The 
Investigator should decide whether, in his or her medical judgment, there is a reasonable possibility that the 
event may have been caused by the investigational product.  If no valid reason exists for suggesting a 
relationship, then the AE should be classified as “unrelated.”  If there is any valid reason, even if 
undetermined, for suspecting a possible cause-and-effect relationship between the investigational product 
and the occurrence of the AE, then the AE should be considered “related.”  Definitions of the relationship 
of an AE to the use of the study medication are as follows: 
• 
Unrelated- The AE is clearly not related to study treatment.  An AE for which sufficient information 
exists to indicate that the etiology is unrelated to the study drug.  The etiology must be specified. 

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• 
Unlikely - The AE is doubtfully related to study treatment.  The event is most likely produced by other 
factors such as the patient’s clinical condition, therapeutic interventions or concomitant drugs 
administered to the patient and it does not follow a known response pattern to the study drug. 
• 
Possibly - The AE may be related to study treatment.  The event follows a reasonable temporal 
sequence from the time of drug administration, and/or follows a known response pattern to the study 
drug, but could have been produced by other factors such as the patient’s clinical condition, therapeutic 
interventions, or concomitant drugs administered to the patient. 
• 
Probably - The AE is likely related to study treatment.  The event follows a reasonable temporal 
sequence from the time of drug administration, and follows a known response pattern to the study drug, 
and cannot be reasonably explained by other factors such as the patient’s clinical condition, therapeutic 
interventions, or concomitant drugs administered to the patient. 
• 
Definitely - The AE is clearly related to study treatment.  An AE that follows a reasonable temporal 
sequence from administration of the study drug; follows a known response pattern to the drug; and, 
when appropriate to the protocol, is confirmed by improvement on stopping the drug (de-challenge) 
and reappearance of the reaction after repeat exposure (re-challenge); and cannot be reasonably 
explained by the known characteristics of the patient’s clinical state or by other therapies. 
10.0 
DEFINITION OF RESPONSE 
 
This is a Phase I study for which the primary endpoints are determination of treatment tolerability, toxicities, 
and pharmacokinetics of combined docetaxel plus bemcentinib.  In addition, we will record all antitumor 
responses.  To be evaluable for response, patient must have evaluable disease at study entry and must have 
completed at least one course of therapy, or have discontinued therapy for reasons of toxicity or progression 
of disease. 
  
Dose-escalation rules and toxicity summaries will include those patients who complete any therapy and 
who are followed a minimum of 4 weeks after the start of the first cycle, or who experience dose limiting 
toxicity.  Patients who complete one cycle of treatment will be included in the analysis of tumor response.   
The outcome status (in terms of toxicity, response, reason off study, progression, and survival) of all eligible 
patients will be reported.  Patients who begin treatment will be accounted for in the summaries of toxicity.  
All patients who complete the first course of treatment will be included in the analysis of survival and time-
to-failure.   
10.1 Key Definitions 
10.1.1 Measurable Disease 
• 
Measurable non-nodal lesions: those that can be accurately measured in at least 1 dimension (LD) to 
be recorded as ≥10 mm by CT scan (CT scan slice thickness no greater than 5 mm).  
• 
Malignant lymph nodes:  to be considered pathologically enlarged and measurable, a lymph node must 
measure ≥15 mm in the short axis (SA) when assessed by CT scan (CT slice thickness recommended 
to be no greater than 5 mm). 
• 
It is recommended that slice gaps not be utilized for the image acquisition procedures. 
• 
Superficial lesions (eg, skin lesions) on physical exam will not be considered radiographically 
measurable unless they are measurable on CT or MRI.  

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• 
All radiographic measurements should be taken and recorded in millimeters utilizing an electronic 
measurement method based on lesion boundary definition. 
• 
Lesions on chest X-ray will not be considered measurable.  
10.1.2 Non-Measurable Disease 
All other lesions (or sites of disease), including small lesions (LD<10 mm or pathological lymph nodes ≥10 
mm to <15 mm in the SA) as well as truly non-measurable lesions are considered non-measurable disease.  
Lesions considered truly non-measurable include:  leptomeningeal disease, ascites, pleural or pericardial 
effusions, inflammatory breast disease, lymphangitic involvement of skin or lung, masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible imaging techniques.  
10.1.3 Target Lesions 
• 
Target lesions must be measurable lesions. 
• 
All lesions up to a maximum of two lesions per organ and five lesions in total, representative of all 
involved organs, will be identified as target lesions, recorded and measured at baseline, and followed 
consistently throughout the study.  
• 
Target lesions should be selected on the basis of their size (based on LD for non-nodal lesions or SA 
for lymph nodes), their suitability for accurate repeated measurements, and on their being most 
representative of the patient’s tumor burden. 
• 
A sum of the diameters for all target lesions will be calculated and reported for each time point.  The 
baseline sum of diameters will be used as a reference by which the objective tumor response will be 
characterized. 
• 
Brain lesions that were previously irradiated cannot be recorded as target lesions.  Stable brain 
lesions post radiotherapy should be documented as non-target lesions.  At post-baseline evaluations, 
the brain lesions should be marked as “Not done” if a brain scan was not done, as follow-up brain 
scans are only required when clinically indicated. 
• 
Bone lesions should be recorded as non-target lesions regardless of irradiation treatment status.   
10.1.4 Non-Target Lesions 
• 
All other lesions (or sites of disease, including any measurable lesions that were not selected as target 
lesions) will be identified as non-target lesions and indicated as present at baseline. 
• 
It is possible to record multiple non-target lesions involving the same organ as a single item (eg, 
multiple enlarged pelvic lymph nodes or multiple liver metastases). 
• 
Measurements of these non-target lesions will not be performed, but the presence, absence, or 
unequivocal progression of these lesions should be noted throughout follow-up assessments. 
10.1.5 New Lesions 
• 
The finding of a new lesion should be unequivocal (ie, not attributable to differences in scanning 
technique, change in imaging modality, etc.). 
• 
If a new lesion is equivocal (ie, because of its small size), and follow-up imaging confirms that it is 
definitely a new lesion, the progression of that new lesion is from the time it was seen on the initial 
scan.   

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• 
A lesion identified on a follow-up scan in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. 
• 
A lesion that reappears at follow up after a PR or SD is not considered new.  The lesion’s LD (or SA 
for lymph nodes) is added back into the sum of diameters.   
• 
A lesion that reappears at follow up after a complete response (CR) is automatically considered PD. 
10.1.6 Lymph Nodes 
• 
At baseline, lymph nodes with tumor burden will be considered as target lesions if the SA is ≥ 15 mm.   
• 
At baseline, lymph nodes will be considered as non-target lesions if the SA is ≥10 mm and < 15 mm. 
• 
At baseline, lymph nodes will be considered as normal if the SA is <10 mm. 
• 
At follow up, a lymph node must measure ≥10 mm in the SA to be considered a new lesion.   
o A lymph node that was identified as target disease at baseline that falls below the measurable 
threshold at follow up, and then gets larger is not considered new if it follows a PR or SD.  The 
lymph node SA measurement is added back into the sum of diameters. 
o A lymph node that was identified as target disease at baseline that falls below the measurable 
threshold at follow up, and then gets larger following a CR is automatically PD. 
10.2 
Other Considerations 
10.2.1 Irradiated Lesions   
Previously irradiated lesions cannot be selected as target unless there is a documented disease progression, 
defined as increase of at least 1 cm in LD compared to nadir scan.   
10.2.2 Handling of Lesions that Split 
When non-nodal and nodal lesions split or fragment, the individual lesion diameters of the fragmented 
portions should be added together to calculate the target lesion sum. 
10.2.3 Handling of Lesions that Merge 
As lesions merge, a boundary between the lesions should be drawn so the LD or SA of each individual 
lesion can continued to be measured.  If the lesions have merged in a way that they can no longer be 
separated by this boundary, the LD or SA of the merged lesion should be measured. 
10.2.4 Measurement of Small Lesions on Follow-up Scans 
Non-Nodal 
A non-nodal target lesion that is present but too small to measure (TSTM) accurately at evaluations after 
baseline (< 5 mm but greater than 0 mm in unilateral dimension) will be classified as TSTM and will be 
assigned a value of 5 mm for the purposes of determining the sum of diameters.  All other lesions will have 
actual size recorded (ie, ≥ 5 mm). 
Lymph Nodes 
A target lymph node should always have the actual SA measurement recorded, even if the lymph node 
regresses to <10 mm on study.  This means that when lymph nodes are included as target lesions, the sum 

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of diameters may not be zero even if CR criteria are met, since a normal lymph node is defined as having 
an SA of <10 mm. 
10.3 
Response Criteria  
10.3.1 Target Lesion Response Criteria 
• 
Complete Response (CR): Disappearance (or normalization) of all target lesions.  
o Any pathological lymph nodes (whether target or non-target) must have reduction in SA to <10 
mm.  
• 
Partial Response (PR): At least 30% decrease in the sum of diameters of target lesions taking as 
reference the baseline sum of diameters.  
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum of diameters while on study.   
• 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum of diameters on study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  
• 
Non-evaluable (NE): Patient time points that have inadequate or missing images, including the 
inability to visualize >25% of target disease. 
10.3.2 Non-Target Lesion Response Criteria   
• 
CR: Disappearance (or normalization) of all non-target lesions.  All lymph nodes must be non-
pathological in size (< 10 mm SA). 
• 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s). 
• 
PD: Unequivocal progression of existing non-target lesions.   
• 
NE: Patient time points that have inadequate or missing images, including the inability to visualize > 
50% of non-target disease. 
• 
No Disease (ND): No non-target disease noted.  The absence of non-target lesions at follow-up time 
points is designated as ND and not SD when there is no non-target disease noted at baseline. 
10.3.3 New Lesion Response Criteria 
If at least 1 new lesion is present, the patient is considered to have PD overall. 
10.3.4 Response Assessment in Case of Missing or Technically Inadequate Scans 
If no lesions were identified at baseline in a specific body region (eg, chest, abdomen) and the scan of that 
body region is unavailable or technically inadequate at follow up, then the response assessment will be 
based on the scans of the other regions. 
10.4 
Response Definitions 
10.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
 
Disappearance of all target lesions 
 

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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 
 
Progressive Disease (PD):  
 
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD 
recorded since the treatment started or the appearance 
of one or more new lesions 
 
Stable Disease (SD): 
 
 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum LD since the treatment 
started 
 
10.4.2 Evaluation of Non-target Lesions 
 
Complete Response (CR):  
 
Disappearance of all non-target lesions and 
normalization of tumor marker level 
 
 
Incomplete Response/  
  
 
Stable Disease (SD): 
 
 
 
Persistence of one or more non-target lesion(s) 
or/and 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 review panel (or 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. 
 
10.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded 
since the treatment started).  The patient’s best response assignment will depend on the achievement of both 
measurement and confirmation criteria (see Section 10.4.4 ). 
 
 
  
Target Lesions 
Non-target 
Lesions 
New Lesions 
Overall Response 
 
CR 
 
CR 
 
No 
 
CR 
 
CR 
 
 
No 
 
PR 

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Incomplete 
response/SD 
 
PR 
 
Non-PD 
 
No 
 
PR 
SD 
 
Non-PD 
 
No 
 
SD 
 
PD 
 
Any 
 
Yes or No 
 
PD 
 
Any 
 
PD 
 
Yes or No 
 
PD 
 
Any 
 
Any 
 
Yes 
 
PD 
 
 
Note: 
• 
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. 
 
10.4.4 
Confirmatory Measurement/Duration of Response  
 
Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed at least 4 weeks after the criteria for 
response are first met.  In the case of SD, follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 4 weeks. 
 
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.  
 

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11.0 
PHARMACOKINETIC AND CORRELATIVE STUDIES 
Pharmacokinetic studies will be performed on all patients.  Blood and serum biomarker studies 
will be performed on all patients.  Imaging biomarker studies will be performed on a subset of 
patients treated at UT Southwestern Medical Center 
 
11.1 
Pharmacokinetic Analyses 
Full details of analysis of the possible effects of bemcentinib on docetaxel will be provided in a 
Pharmacokinetics Analysis Plan.  In brief, the Pharmacokinetics Analysis Population will include those 
patients who receive ≥1 cycle of bemcentinib and ≥1 dose of docetaxel and have PK data available. PK 
parameters of docetaxel that will be measured are summarized in Table 11. 
 
Table 11.  Docetaxel PK Parameters to be Evaluated 
Cmax 
The observed maximum plasma concentration after single dose administration 
tmax 
The time to reach Cmax  
AUC0-tau 
The area under the curve within a dosing interval, calculated by the linear 
up-log down trapezoidal method. 
z 
The apparent terminal rate constant estimated from individual linear 
regression of the terminal part of the log concentration vs. time curve 
t½ 
The apparent terminal half-life, calculated by 0.693/z  
 
Where possible, individual, mean and median docetaxel plasma concentration-time data will be presented 
in tabular and/or graphical form. 
11.2 
Correlative studies 
11.2.1 Blood biomarkers 
Blood will be collected at the following time-points for biomarker analysis.  (Multiplex cytokine and 
angiogenic factor assay, qPCR for cytokine and immune markers): 
• 
Cycle 1 Day -7,prior to administration of bemcentinib 
• 
Cycle 1 Day 1, pre-infusion 
• 
Cycle 2 Day 1, pre-infusion 
• 
At disease progression/end of treatment 
 
11.2.2 Tissue biomarkers 
 
11.2.2.1 
Archival tumor tissue is required and can be collected at: 
• 
Pre-study baseline (optional) or 
• 
Archival material from diagnostic or subsequent biopsies  

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12.0 
STATISTICAL CONSIDERATIONS 
12.1 
General considerations 
This is a Phase I and pharmacologic study.  The South Plains Oncology Consortium (SPOC) will be the 
coordinating center for this study; SPOC will be responsible for registering patients (Section 5.2 and 
Appendix A) and for maintaining a complete database of the study information (Section 14.0). 
12.2 
Analysis of Clinical Endpoints 
The design of this Phase I trial is described in Section 6.0; the definition of MTD is given in Section 6.2 
and the rules for dose escalation are given in Sections 6.3.  
The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory 
determination such as absolute neutrophil count), severity (by NCI CTCAE v4.0 and nadir or maximum 
values for the laboratory measures), time of onset (i.e., cycle number), duration, and reversibility or 
outcome.   
Tables will be created to summarize these toxicities and side effects by dose and by cycle. Toxicities will 
be reported for all patients receiving study drug. Baseline information (e.g., the extent of prior therapy) and 
demographic information will be presented to describe the patients treated in this Phase I study.  All 
responses will be reported.  Response rate with its 95% confidence interval will be estimated using the 
exact Binomial method. The response rate in this study population will be compared with that of the 
historical control using the one-sample Binomial test. Progression-free survival and the overall survival 
will be summarized with Kaplan-Meier plots to describe the outcome of patients treated on this protocol. 
12.3 Analysis of Pharmacokinetic and Laboratory Studies 
Pharmacokinetic data (i.e. plasma concentrations of bemcentinib) will be analyzed using compartmental 
and non-compartmental models using PCNONLIN™ version 4.2 or equivalent software.  The 
pharmacokinetic parameters will be estimated for each patient and will be summarized by dose level with 
standard descriptive statistics (means and standard deviations – possibly after transformation, if necessary 
- or medians and ranges). If appropriate, summary statistics will also be provided for the entire group of 
patients. The relative plasma levels of bemcentinib will also be tabulated and summarized. These levels 
will be compared with observed toxicities and clinical response in an exploratory manner. However, the 
heterogeneity of the patient population and the small number of patients treated at each dose make formal 
statistical inference of these molecular studies unlikely.  
12.4 
Estimated accrual time 
Review of patient accrual onto recent phase 1 studies suggests that the study should be completed in less 
than 30 months. 
12.5 
Results 
All patients who receive at least one cycle of bemcentinib will be accounted for in the analysis; the reasons 
for going off study will be documented for each patient.  Baseline and demographic information will be 
documented for each patient.  Observed toxicities will be summarized in terms of type, severity, time of 
onset, duration, reversibility, and outcome. 
Intention to treat analysis will be used to allow for drop-outs and withdrawals, so that data from all study 
participants will be analyzed.  This method will estimate without bias the effect of the treatment policy on 

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end-points to be analyzed, but may underestimate the magnitude of the treatment effect in patients who 
complete therapy. 
Depending on cohort expansion requirements, a total of 6-12 patients will be accrued to the dose-escalation 
phase 1 pilot trial, with another 18-24 patients accrued at the MTD for a total of 30 patients.  Since the trial 
population will be drawn from a multi-institution base, it is anticipated that accrual will be completed over 
18 to 30 months. 
12.6 
Sample Size justification  
Enrolling 30 patients in the total study population will provide more than 80% power to detect an increase 
in response rate from 10% (historical control with docetaxel monotherapy) to 25%, using the one-sample 
Binomial test with a one-sided alpha of 0.1.  If only those patients treated at the MTD are included 
(projected N=18-24), we will have approximately 67% power to detect a similar increase in response rate, 
with a one-sided alpha of 0.1.  The projected 15% absolute increase in response rate is based on marked 
potentiation of taxane effects in in vitro models and a 50% improvement in tumor growth inhibition in 
preclinical xenograft studies.20  
Biomarker Analyses 
Exploratory biomarker analyses will examine potential predictive biomarkers for correlation with 
bemcentinib activity and safety.  A separate SAP will be prepared for the biomarker analyses. 
13.0 
REGISTRATION GUIDELINES 
To register a patient, the research nurse or data manager must complete the eligibility form and the 
registration form and give (or FAX) copies to the SPOC Consortium Coordinator (at 806-743-2691).  The 
research nurse or data manager will call the SPOC Consortium Coordinator (at 806-743-2690), and after 
verifying the eligibility, the SPOC Consortium Coordinator will assign a study number, assign a dose, and 
register the patient onto the study.  See Appendix A (“Registration Procedures for Phase I Trials”). 
Informed Consent must be obtained before the patient is registered.  The FDA requires that both the 
signature and the date be in the handwriting of the subject or the subject’s legally authorized representative, 
that the date be the actual date on which the form is signed, and that the informed consent process be 
documented in the physician’s progress notes or the nurse’s notes. 
13.1 
Procedures for On-Study and Treatment Deviations.   
Any on-study or treatment deviations need to be discussed with and reported to SPOC and the Study Chair.  
14.0 
RECORDS TO BE KEPT AND DATA SUBMISSION SCHEDULE 
14.1 
Confidentiality of Records 
The original data collection forms will be stored at the originating institution.  A copy of all data forms will 
be maintained in secure files or electronically at the SPOC Operations Center.  
14.2 
Patient Consent Form 
At the time of registration, will fax a copy of the signed and dated informed consent and HIPAA documents 
to SPOC (see registration procedures in Appendix A). 

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14.3 
Registration Eligibility Worksheet 
At the time of registration, the information requested on the On-Study/Eligibility Form will be submitted 
to the Consortium Coordinator at SPOC as described in the Appendix A (“Registration Procedures for 
Phase I Trials”). 
This study will be monitored by SPOC.  All centers will submit data collected at their institution to the 
South Plains Oncology Consortium Operations Center (SPOC).  A complete database will reside at SPOC. 
All data will be collected using SPOC data collection forms via the electronic database.  The original source 
data collection forms will reside at the originating institution in secure location. 
The data manager will complete the Registration Worksheet /Eligibility Form (a SPOC form which includes 
the eligibility checklist). 
Within two weeks of completion of the first cycle, the data manager must complete the Phase I, Cycle I 
Toxicity form online. 
Within two weeks of registration, the data manager will complete and submit the On-Study Form in the 
database. 
Within two weeks of registration, the data manager will have electronically submitted to SPOC the 
following information: 
 
Treatment   
 
Supplemental Data (if applicable) 
 
Adverse Events  
 
Response/Off-Study/Follow-Up  
Within two weeks of going off study, data manager will complete and submit to SPOC, the “Off-Study 
Summary” information. 
SPOC may conduct on-site audits to verify submitted data against primary medical records and will provide 
periodic data summaries to the Protocol Chairman. 
15.0 
MINORITIES AND WOMEN STATEMENT 
Patients of both genders and all racial/ethnic groups are eligible for this study if they meet the eligibility 
criteria outlined in Section 5.0.  To date, there is no information that suggests that differences in drug 
metabolism or disease response would be expected in one group compared to another.  Efforts will be made 
to accrue a representative sample.  However, since this is a Phase I trial, considerations for patient safety 
and a reluctance to expose patients either to a potentially toxic and/or ineffective treatment, will limit the 
total number of patients entered.  If differences in outcome appear to be associated with gender or ethnic 
identity, then a follow-up study will be designed to investigate those differences more fully.   
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
All Institutional, NCI, Federal, and State of Texas regulations concerning the Informed Consent form will 
be fulfilled.  Bemcentinib will be administered under an IND for each drug, which is approved by and 
subject to the regulations of the FDA. 
When results of this study are reported in medical journals or at meetings, identification of those taking part 
will be withheld.  Medical records of patients will be maintained in strictest confidence, according to current 

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legal requirements.  However, they will be made available for review, as required by the FDA or other 
authorized investigators such as the NCI or the IND sponsors (or their delegates), under the guidelines 
established by the Federal Privacy Act. 
 
 

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17.0 
REFERENCES 
 
 
1. 
Jemal A, Bray F, Center MM, et al: Global cancer statistics. CA Cancer J Clin 61:69-90, 
2011 
 
2. 
Ettinger DS, Akerley W, Bepler G, et al: Non-small cell lung cancer. J Natl Compr Canc 
Netw 8:740-801, 2010 
 
3. 
Garon EB, Ciuleanu TE, Arrieta O, et al: Ramucirumab plus docetaxel versus placebo plus 
docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on 
platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 384:665-
73, 2014 
 
4. 
Nagata K, Ohashi K, Nakano T, et al: Identification of the product of growth arrest-specific 
gene 6 as a common ligand for Axl, Sky, and Mer receptor tyrosine kinases. J Biol Chem 271:30022-7, 
1996 
 
5. 
Linger RM, Keating AK, Earp HS, et al: TAM receptor tyrosine kinases: biologic 
functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res 100:35-83, 2008 
 
6. 
Angelillo-Scherrer A, Burnier L, Lambrechts D, et al: Role of Gas6 in erythropoiesis and 
anemia in mice. J Clin Invest 118:583-96, 2008 
 
7. 
Behrens EM, Gadue P, Gong SY, et al: The mer receptor tyrosine kinase: expression and 
function suggest a role in innate immunity. Eur J Immunol 33:2160-7, 2003 
 
8. 
Caraux A, Lu Q, Fernandez N, et al: Natural killer cell differentiation driven by Tyro3 
receptor tyrosine kinases. Nat Immunol 7:747-54, 2006 
 
9. 
Wu YM, Robinson DR, Kung HJ: Signal pathways in up-regulation of chemokines by 
tyrosine kinase MER/NYK in prostate cancer cells. Cancer Res 64:7311-20, 2004 
 
10. 
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 70:1544-54, 
2010 
 
11. 
Mudduluru G, Vajkoczy P, Allgayer H: Myeloid zinc finger 1 induces migration, invasion, 
and in vivo metastasis through Axl gene expression in solid cancer. Mol Cancer Res 8:159-69, 2010 
 
12. 
Shieh YS, Lai CY, Kao YR, et al: Expression of axl in lung adenocarcinoma and correlation 
with tumor progression. Neoplasia 7:1058-64, 2005 
 
13. 
Wimmel A, Glitz D, Kraus A, et al: Axl receptor tyrosine kinase expression in human lung 
cancer cell lines correlates with cellular adhesion. Eur J Cancer 37:2264-74, 2001 
 
14. 
Rikova K, Guo A, Zeng Q, et al: Global survey of phosphotyrosine signaling identifies 
oncogenic kinases in lung cancer. Cell 131:1190-203, 2007 
 
15. 
Stommel JM, Kimmelman AC, Ying H, et al: Coactivation of receptor tyrosine kinases 
affects the response of tumor cells to targeted therapies. Science 318:287-90, 2007 
 
16. 
Zhang Z, Lee JC, Lin L, et al: Activation of the AXL kinase causes resistance to EGFR-
targeted therapy in lung cancer. Nat Genet 44:852-60, 2012 
 
17. 
Liu L, Greger J, Shi H, et al: Novel mechanism of lapatinib resistance in HER2-positive 
breast tumor cells: activation of AXL. Cancer Res 69:6871-8, 2009 
 
18. 
Hector A, Montgomery EA, Karikari C, et al: The Axl receptor tyrosine kinase is an 
adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma. Cancer Biol Ther 
10:1009-18, 2010 
 
19. 
Asiedu MK, Beauchamp-Perez FD, Ingle JN, et al: AXL induces epithelial-to-
mesenchymal transition and regulates the function of breast cancer stem cells. Oncogene 33:1316-24, 2014 
 
20. 
Wilson C, Ye X, Pham T, et al: AXL inhibition sensitizes mesenchymal cancer cells to 
antimitotic drugs. Cancer Res 74:5878-90, 2014 
 
21. 
Wallin JJ, Guan J, Prior WW, et al: GDC-0941, a novel class I selective PI3K inhibitor, 
enhances the efficacy of docetaxel in human breast cancer models by increasing cell death in vitro and in 
vivo. Clin Cancer Res 18:3901-11, 2012 

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22. 
Yu K, Lucas J, Zhu T, et al: PWT-458, a novel pegylated-17-hydroxywortmannin, inhibits 
phosphatidylinositol 3-kinase signaling and suppresses growth of solid tumors. Cancer Biol Ther 4:538-45, 
2005 
 
23. 
Rizzo JD, Brouwers M, Hurley P, et al: American Society of Clinical Oncology/American 
Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult 
patients with cancer. J Clin Oncol 28:4996-5010, 2010 
 
24. 
Smith TJ, Khatcheressian J, Lyman GH, et al: 2006 update of recommendations for the use 
of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 24:3187-
205, 2006 
 
 
 
 
 

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18.0 
APPENDICES  
 
APPENDIX A - REGISTRATION PROCEDURES FOR PHASE I TRIALS 
 
I. REGISTRATION POLICIES 
 
 
A. 
Registrations for Phase I protocols within this co-operative agreement must be made 
through the Operations Office of the South Plains Oncology Consortium (SPOC) between 
the hours of 8:30 a.m. and 4:30 p.m. Central Time Zone, Monday through Friday (except 
holidays).  Documentation of current IRB approval of this protocol must be on file prior to 
registration of patients at these institutions. 
 
 
B. 
Patients must begin protocol therapy within 72 hours of registration. 
 
 
C. 
Pre-study laboratory tests, scans, and x-rays, must be completed prior to registration, within 
the time frame specified in the protocol.  The eligibility checklist in the On-
Study/Eligibility Form must be completed.  Patients must sign an informed consent prior 
to registration. 
 
 
D. 
A patient failing to meet all protocol requirements may not be registered.  If you have any 
questions regarding eligibility, contact the SPOC Consortium Coordinator at 806-743-
2690. 
 
II.  "HOLDING A SLOT" FOR A POTENTIAL PATIENT 
 
 
A. 
If a potential patient has been identified for a Phase I trial, the data manager or research) 
must contact the Consortium Coordinator (806-743-2690) to verify that a dose-level is 
open. 
 
 
 
1. 
If the current dose-level is open, then the Consortium Coordinator will reserve the 
"slot" for that patient for 14 days to allow sufficient time to complete the required 
tests and obtain the informed consent.  Only one reserved slot will be allowed per 
consortium institution at a new dose level (given all sites have simultaneous IRB 
approval).  If an institution has several potential patients, the Phase I Consortium 
Coordinator must contact each of the other institutions to see if there are pending 
patient(s).  The other Consortium institutions have 7 days to fill an available slot 
and then 14 days to evaluate a patient.  If no patient is available in that time, the 
institution which has additional patients for the study will then be given another 
slot at that dose level. 
 
 
 
 
a. 
The research nurse or data manager must call back within 14 days to 
complete the registration or cancel the patient. 
 
 
 
2. 
If no dose-level is open (based on the criteria for dose expansion or escalation - as 
described in the protocol), then the Consortium Coordinator can indicate the 
anticipated date of reopening and the slot may be reserved for that patient.  
 

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a. 
The research nurse or data manager must stay in touch with the 
Consortium Coordinator and must cancel the slot reservation immediately 
if the patient for whom a slot has been reserved is no longer available or 
eligible for enrollment. 
 
 
 
3. 
No more than 3 patients may be held on the waiting list for a single  
 
 
 
protocol.   
 
a. 
If a patient on the waiting list becomes ineligible, then the research nurse 
or data manager must call to remove the patient from the list. 
 
 
 
4. 
No slot reservation at a given dose level will be made prior to escalation or 
expansion until such time as the 3rd patient at that level has been evaluated for 
toxicity. 
 
III. 
REGISTRATION PROCEDURES 
 
 
A. 
Once a patient is eligible, all the pre-study requirements have been fulfilled, and informed 
consent obtained, then the data manager or research nurse will inform the Consortium 
Coordinator (806-743-2690) and FAX him/her a copy of the signed Informed Consent, 
HIPAA documents and the completed On-Study/Eligibility Form (FAX Number: 806-743-
2691). 
 
 
 
1. 
SPOC will provide copies of the On-Study/Eligibility Form for each Phase I trial 
under this co-operative agreement. 
 
 
B. 
The Consortium Coordinator will verify that the patient is eligible, that pre-study tests have 
been completed, and that the forms are complete.  He/She will then register the patient, 
confirm the dose-level and provide a Consortium patient ID number.  The Consortium 
Coordinator will call the research nurse or data manager and verbally confirm the 
registration.  
 
The Consortium Coordinator will send paper confirmation within 24 hours to the site’s research nurse or 
data manager and the Study Chair (Dr. David Gerber).  

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APPENDIX B - Common Terminology Criteria for Adverse Events v3.0 
 
 
NCI Common Toxicity Criteria ver4.0 can be found at the CTEP website: 
 
http://ctep.cancer.gov/forms/CTCAEv4.pdf 
 
 

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APPENDIX C   - Adverse Events Reporting Material 
 
SOUTH PLAINS ONCOLOGY CONSORTIUM 
 
NOTIFICATION OF TOXICITY 
 
THIS FORM OR A COPY OF A SUBMITTED AdEERS REPORT MUST BE FAX'D (806-743-2691) 
TO THE CONSORTIUM COORDINATOR WITHIN 24 HOURS OF ONSET OF ADVERSE EVENT.  
 
PROTOCOL INFORMATION 
 
Consortium Protocol Number:  SPOC- 2015-01 
 
NCI # (if applicable):  _____________ 
 
Protocol Title: Phase 1 trial of dose escalated BGB324 in combination with docetaxel for previously 
treated advanced non-small cell lung cancer (NSCLC) 
 
Treating Institution:  ________________________________________________________________ 
 
Reporter Name:  ______________________________________ 
Phone #:_______________________ 
 
Email:   __________________________________________________ 
PATIENT INFORMATION 
 
Patient Name________________________________________ 
Pt Study ID:  _____________________ 
 
 
ADVERSE EVENT INFORMATION 
 
Adverse Event:  _______________________________ 
 
Start Date of AE: ____/____/____ 
 
 
If Phase I trial, is the adverse event considered dose-limiting?   
 __ No    __ Yes 
Is toxicity reportable as defined by NCI Guidelines? 
 __ No    __ Yes 
 
Has the event been reported to the following: 
 
Institutional IRB  
__ No    __ Yes  
 
Date: __ __ / __ __  / __ __ 
 
FDA  
 
__ No    __ Yes  
 
Date: __ __ / __ __  / __ __ 
 
AdEERS/MedWatch __ No    __ Yes  
 
Date: __ __ / __ __  / __ __ 
 
 
 
 
Report sent to SPOC?  __ No    __ Yes  
Date: __ __ / __ __  / __ __ 
 
 
 

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APPENDIX D:  PERFORMANCE SCALE CRITERIA  
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percen
t 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
 
0 
Dead. 
 
 
 
 

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APPENDIX E 
 
Specimen Collection Form for Pharmacokinetics Analysis 
 
SPOC-2015-1 Phase 1 trial of dose escalated BGB324 in combination with docetaxel for previously 
treated advanced non-small cell lung cancer (NSCLC). 
 
Patient's Name_______________  _____________     Patient Accession #  __________  
                                          (first) 
                        (last) 
 
Study Site  ___________  Height _____cm Weight:  _____kg  BSA ____. ___m2 
 
Bemcentinib Dose =  __________ mg   Docetaxel Dose= _________ mg/m2 
 
Start Date/time   __________________  End Date/time ___________________  
 
 
 
 
 Bemcentinib PK collection time-points 
Sample 
 Name 
Matrix 
Description 
Sample  
Date 
(mm:dd:yy) 
Expected  
Time 
(hh:mm) 
Actual  
Time 
(hh:mm) 
Drawn By 
(initials) 
Comments 
Cycle 1 
Day -6, 0hr 
Plasm
Pre-dose 
 
 
 
 
 
 
Cycle 1 
Day -5, 0hr 
Plasm
Pre-dose 
 
 
 
 
 
 
Cycle 1 
Day 1, 0hr 
Plasm
Pre-dose 
 
 
 
 
 
Cycle 1 
Day 2, 0hr 
Plasm
Pre-dose 
 
 
 
 
 
Cycle 2 
Day 1, 0hr 
Plasm
 Pre-dose 
 
 
 
 
 
 
Cycle 4 
Day 1, 0 hr 
Plasm
Pre-dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Docetaxel PK collection time-points 
 
Sample 
 Name 
Matrix 
Description Sample  
Date 
(mm:dd:yy) 
Expected  
Time 
(hh:mm) 
Actual  
Time 
(hh:mm) 
Drawn By 
(initials) 
Comments 
Cycle 1 
Day 1, 0.5hr 
Plasma 
post-dose 
 
 
 
 
 
 
Cycle 1 
Day 1, 1 hr 
Plasma 
 1 hrs 
 
 
 
 
 
 
Cycle 1 
Day 1, 2hr 
Plasma 
2 hrs 
 
 
 
 
 
Cycle 1 
Day 1, 4hr 
Plasma 
4 hrs 
 
 
 
 
 
Cycle 1 
Day 1, 6hr 
Plasma 
6 hrs  
 
 
 
 
 
Cycle 1 
Day 1, 8hr 
Plasma 
8 hrs 
 
 
 
 
 
Cycle 1 
Day 2, 0 hr 
Plasma 
Pre-dose 
(BGB324 
predose) 
 
 
 
 
 
 
Cycle 1 
Day 3, 0 hr 
Plasma 
Pre-dose 
(BGB324  
predose) 
 
 
 
 
 
 
 
Draw Blood (4.5ml) into a sodium or lithium heparin (green top) tube for bemcentinib and K2-EDTA tube 
(purple top) for docetaxel.  CLAMP INFUSION LINES AND FLUSH LINES OR PORT BEFORE 
DRAWING DISCARD AND SAMPLE to prevent entrainment of drug into the sample.  IMMEDIATELY 
WRAP TUBE IN FOIL to protect from light AND CHILL ON ICE.  PLASMA to be stored in FOIL 
WRAPPED TUBES and FROZEN at -80 C.  RECORDING THE EXACT TIME OF DRAW IS MORE 
IMPORTANT THAN DRAWING EXACTLY ON SCHEDULE. 
 
 
. See lab manual for detailed procedure. 
 
 

STU052015-077, Gerber, FormA-ResearchProtocol-V5.0-07.23.20, Mod_23, 08-17-20 (1) 
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APPENDIX F 
 
Specimen Collection Form for Multiplex Cytokine and Angiogenic Factor Assay Performance 
 
SPOC-2015-01 Phase 1 trial of dose escalated BGB324 in combination with docetaxel for previously 
treated advanced non-small cell lung cancer (NSCLC). 
 
Patient's Name_______________  _____________     Patient Accession #  __________  
                                          (first) 
                        (last) 
 
Study Site  ___________  Height _____cm Weight:  _____kg  BSA ____. ___m2 
 
 Bemcentinib Dose =  __________ mg   Docetaxel Dose= _________ mg/m2 
 
Start Date/time   __________________  End Date/time ___________________  
 
 
 
PD Collection Time-points  
Sample 
 Name 
Matrix 
Description 
Sample  
Date 
(mm:dd:yy) 
Expected  
Time 
(hh:mm) 
Actual  
Time 
(hh:mm) 
Drawn By 
(initials) 
Comments 
Cycle 1 
Day -7 
Plasma 
Pre-BGB324 
 
 
 
 
 
 
Cycle 1 
Day 1 
Plasma 
Pre-docetaxel 
 
 
 
 
 
 
Cycle 2 
Day 1 
Plasma 
Pre-docetaxel  
 
 
 
 
 
 
EOT/ 
Disease
Progr 
Plasma 
 
 
 
 
 
 
 
 
Blood will be drawn into a 3ml ACD (yellow top) tube and immediately chilled in an ice-water bath. 
 
ALL SAMPLES MUST BE PROTECTED FROM LIGHT AT ALL TIMES BY WRAPPING IN 
FOIL IMMEDIATELY.    
 
BLOOD AND PLASMA MUST BE PROTECTED FROM LIGHT AS MUCH AS POSSIBLE 
DURING HANDLING, AND PLASMA TO BE STORED IN FOIL WRAPPED TUBES. 
 
See lab manual for detailed procedure. 
. 
 
. 
 

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. 
APPENDIX G 
Specimen Collection Form Tissue collection for PD 
 
SPOC-2015-01 -  Phase 1 trial of dose escalated BGB324 in combination with docetaxel for 
previously treated advanced non-small cell lung cancer (NSCLC). 
 
Patient's Name_______________  _____________     Patient Accession #  __________  
                                          (first) 
                        (last) 
 
Study Site  ___________  Height _____cm Weight:  _____kg  BSA ____. ___m2 
 
 Bemcentinib Dose =  __________ mg   Docetaxel Dose= _________ mg/m2 
 
Start Date/time   __________________  End Date/time ___________________  
 
 
 
Tissue Collection for PD 
Sample 
 Name 
Matrix 
Sample  
Date 
(mm:dd:yy) 
Expected  
Time 
(hh:mm) 
Actual  
Time 
(hh:mm) 
Collected  
By 
(initials) 
Comments 
Baseline 
biopsy 
 
 
 
 
 
Pre first  
line  
treatment 
biopsy 
 
 
 
 
 
EOT 
biopsy 
 
 
 
 
 
 
 
See lab manual for detailed procedure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX H 
 
Specimen Collection Form for Whole blood collection for mRNA and PBMC isolation 
 
SPOC-2015-01 -  Phase 1 trial of dose escalated BGB324 in combination with docetaxel for 
previously treated advanced non-small cell lung cancer (NSCLC). 
 
Patient's Name_______________  _____________     Patient Accession #  __________  
                                          (first) 
                        (last) 
 
Study Site  ___________  Height _____cm Weight:  _____kg  BSA ____. ___m2 
 
 Bemcentinib Dose =  __________ mg   Docetaxel Dose= _________ mg/m2 
 
Start Date/time   __________________  End Date/time ___________________  
 
 
Whole blood Collection for mRNA and PBMC isolation 
Sample 
 Name 
Matrix 
Description 
Sample  
Date 
(mm:dd:yy) 
Expected  
Time 
(hh:mm) 
Actual  
Time 
(hh:mm) 
Collected  
by 
(initials) 
Comments 
Cycle 1 
Day -7 
Whole blood 
Pre-BGB324 
 
 
 
 
 
 
Cycle 1 
Day 1 
Whole blood 
Pre-docetaxel 
 
 
 
 
 
 
Cycle 2 
Day 1 
 Whole blood 
Pre-docetaxel 
 
 
 
 
 
 
EOT 
Disease 
Progression 
Whole blood  
 
 
 
 
 
 
 
 
 
Collect 2.5ml whole blood in PAXgene tubes and 8.5 ml blood in two ACD tubes. 
See lab manual for detailed procedure. 
 
 
 

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APPENDIX I 
Drugs that are Generally Accepted to Have a Risk of Causing Torsades de Pointes 
 
Generic Name 
Brand Name 
Amiodarone 
Coradone/Pacerone 
Anagrelide 
Agrylin®, Xagrid® 
Aresenic trioxide 
Trisenox 
Astemizole 
Hismanal 
Azithromycin 
Zithromax®, Zmax® 
Bepridil 
Vascor 
Chlorquine 
Arelan 
Chlorpromazine 
Thorazine 
Cisapride 
Propulsid 
Citalopram 
Celexa®, Cipramil® 
Clarithromycin 
Biaxin 
Cocaine 
Cocaine 
Disopyramide 
Norpace 
Dofetilide 
Tikosyn 
Domperidone 
Motilium 
Dronedarone 
Multaq® 
Droperidol 
Inapsine 
Erythromycin 
Erythrocin/E.E.S. 
Escitalopram 
Cipralex®, Lexapro® 
Flecainide 
Tambocor®, Almarytm® 
Halofantrine 
Halfan 
Haloperidol 
Haldol 
Ibutilide 
Covert 
Levomethadyl 
Orlaam 
Mesoridazine 
Serentil 
Methadone 
Methadose/Dolophine 
Moxifloxacin 
Avelox 
Ondansetron 
Zofran®, Anset® 
Petamidine 
NebuPent/Pentam 
Pimozide 
Orap 
Probucol 
Lorelco 
Procainamide 
Pronestyl/Procan 
Quinidine 
Cardioquin/Quinaglute 
Sevoflurane 
Ulane®, Sojourn® 
Sotalol 
Betapace 
Sparfloxacin 
Zagam 
Sulpiride 
Dogmatil®, Dolmatil® 
Terfenadine 
Seldane 
Thioridazine 
Mellaril 

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Vandetanib 
Zactima 
Adapted from “The University of Arizona Center for Education and Research on Therapeutics.”  See the 
following website for an updated list of drugs that cause Torsades de Pointes:  www.AZCERT.org