Clinical trial NCT04820023
Conditions: NSCLC
Sponsor: Bridge Biotherapeutics, Inc.
Start date: 2021-04-02; Completion date: 2023-11-29
Enrollment: 45 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This clinical trial is the first-in-human study of BBT-176. The purpose of this trial is to investigate the safety and tolerability of BBT-176 (Part 1) and to evaluate the anti-tumor activity of BBT-176 (Part 2).

Detailed description:

Arms: arm 1: BBT-176: 20mg, Orally, Once daily (QD) arm 2: BBT-176: 80mg, Orally, QD arm 3: BBT-176: 160mg, Orally, QD arm 4: BBT-176: 320mg, Orally, QD arm 5: BBT-176: 480mg, Orally, QD arm 6: BBT-176: 600mg, Orally, QD arm 7: BBT-176: 160mg, Orally, Twice daily (BID) arm 8: BBT-176: 200mg, Orally, BID arm 9: BBT-176: 240mg, Orally, BID
Interventions: intervention 1: BBT-176, QD intervention 2: BBT-176, BID
Intervention descriptions: intervention 1: BBT-176 given orally alone, QD intervention 2: BBT-176 given orally alone, BID

Protocol documents:
Prot_002.pdf: 
Phase 1/2 Study of BBT-176 in Advanced NSCLC with Progression After EGFR TKI Treatment  
Version 5.0 
Protocol BBT176-ONC-001 
26 Jul 2022 
 
This document is confidential. 
 
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1 
Clinical Study Protocol 
 
 
Protocol Title:  
A Phase 1/2, Open-Label Study to Assess the Safety, 
Tolerability, Pharmacokinetics, and Anti-tumor Activity of 
BBT-176 in Patients with Advanced Non-Small Cell Lung 
Cancer (NSCLC) who Progressed Following Prior Therapy 
with an Epidermal Growth Factor Receptor Tyrosine 
Kinase Inhibitor (EGFR TKI) Agent 
 
Short Title: 
Phase 1/2 Study of BBT-176 in Advanced NSCLC with 
Progression After EGFR TKI Treatment 
 
Protocol Number: 
BBT176-ONC-001 
 
Version Number and Date:  
V5.0/ 26 Jul 2022 
Drug Product: 
BBT-176 
 
IND No.: 
146802 
 
Study Phase: 
1/2 
 
Sponsor: 
                                              
 
Good Clinical Practices (GCP) Statement 
This study is to be performed in full compliance with the protocol, GCP, and applicable regulatory 
requirements. All required study documentation will be archived as required by regulatory authorities. 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Bridge Biotherapeutics, Inc. meant 
solely for the purpose of reviewing or performing this study. Any viewing or disclosure of such 
information that is not authorized in writing by Bridge Biotherapeutics, Inc. is strictly prohibited.  
 
 


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2 
TABLE OF CONTENTS 
1 
Clinical Study Protocol .................................................................................................. 1 
2 
TABLE OF CONTENTS ............................................................................................... 2 
3 
PROTOCOL SUMMARY ............................................................................................. 7 
3.1 
Synopsis ...................................................................................................................... 7 
3.2 
Schema of Part 1 and Part 2 ...................................................................................... 12 
3.3 
Schedule of Activities (SoA) .................................................................................... 12 
4 
INTRODUCTION ........................................................................................................ 17 
4.1 
Study Rationale ......................................................................................................... 17 
4.2 
Background ............................................................................................................... 17 
4.3 
Risk/Benefit Assessment .......................................................................................... 19 
4.3.1 
Known Potential Risks ...................................................................................... 19 
4.3.2 
Known Potential Benefits ................................................................................. 19 
4.3.3 
Assessment of Potential Risks and Benefits ..................................................... 19 
4.3.4 
Needs to Explore Alternative Dosing Schedule ................................................ 20 
5 
OBJECTIVES AND ENDPOINTS ............................................................................. 21 
5.1 
Part 1 ......................................................................................................................... 21 
5.2 
Part 2 ......................................................................................................................... 21 
5.3 
Endpoints .................................................................................................................. 22 
5.3.1 
Part 1 ................................................................................................................. 22 
5.3.2 
Part 2 ................................................................................................................. 22 
6 
STUDY DESIGN .......................................................................................................... 23 
6.1 
Overall Design .......................................................................................................... 23 
6.1.1 
Part 1 ................................................................................................................. 23 
6.1.2 
Part 2 ................................................................................................................. 24 
6.2 
Justification for Dose ................................................................................................ 24 
6.3 
Treatment Duration and End of Study Definition ..................................................... 25 
6.3.1 
Treatment Duration ........................................................................................... 25 
6.3.2 
End of Study ...................................................................................................... 25 
7 
STUDY POPULATION ............................................................................................... 26 
7.1 
Inclusion Criteria ...................................................................................................... 26 
7.2 
Exclusion Criteria ..................................................................................................... 28 


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7.3 
 ...................................................... 30 
7.4 
 .......................................................................................................... 30 
7.5 
 .................... 31 
8 
STUDY TREATMENT AND DOSE MODIFICATIONS ........................................ 32 
8.1 
Study Treatment(s) Administration .......................................................................... 32 
8.1.1 
Study Treatment Description ............................................................................ 32 
8.1.2 
Method of Assigning Patients to Treatment Groups ......................................... 32 
8.1.3 
Dosing and Administration ............................................................................... 32 
8.2 
Preparation, Handling, Storage, and Accountability ................................................ 39 
8.2.1 
Acquisition and Accountability ........................................................................ 39 
8.2.2 
Formulation, Appearance, Packaging, and Labeling ........................................ 39 
8.2.3 
Product Storage and Stability ............................................................................ 39 
8.2.4 
Preparation ........................................................................................................ 39 
8.3 
Measures to Minimize Bias: Randomization and Blinding ...................................... 40 
8.4 
Study Treatment Compliance ................................................................................... 40 
8.5 
Prior and Concomitant Therapy ................................................................................ 40 
8.5.1 
Emergency Procedures ...................................................................................... 41 
8.5.2 
Restrictions ........................................................................................................ 41 
9 
STUDY TREATMENT DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................... 42 
9.1 
Discontinuation of Trial ............................................................................................ 42 
9.2 
Participant Discontinuation/Withdrawal from the Study .......................................... 42 
9.3 
Lost to Follow-Up ..................................................................................................... 43 
10 
STUDY ASSESSMENTS AND PROCEDURES ....................................................... 44 
10.1 
Efficacy Assessments ................................................................................................ 44 
10.1.1 
 .................................................................. 44 
10.1.2 
 ............................................................... 44 
10.1.3 
 ................................................................................................... 45 
10.2 
Safety Assessments ................................................................................................... 45 
10.2.1 
 ................................................................................ 45 
10.2.2 
 ..................................................................................... 45 
10.2.3 
 ................................................ 46 


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10.3 
Pharmacokinetics ...................................................................................................... 48 
10.4 
Volume of Blood ....................................................................................................... 48 
10.5 
Study Procedures ...................................................................................................... 49 
10.5.1 
 ................... 49 
10.5.2 
 ............................................................................. 53 
10.6 
Adverse Events and Serious Adverse Events ........................................................... 56 
10.6.1 
Definition of Adverse Events (AE) ................................................................... 56 
10.6.2 
Definition of Serious Adverse Events (SAE) ................................................... 56 
10.6.3 
Classification of an Adverse Event ................................................................... 57 
10.6.4 
Time Period and Frequency for Event Assessment and Follow-up .................. 57 
10.6.5 
Adverse Event Reporting .................................................................................. 57 
10.6.6 
Serious Adverse Event Reporting ..................................................................... 58 
10.6.7 
Reporting Events to Participants ....................................................................... 58 
10.6.8 
Adverse Events of Special Interest ................................................................... 58 
10.6.9 
Overdose ........................................................................................................... 59 
10.6.10 Reporting of Pregnancy .................................................................................... 59 
11 
STATISTICAL CONSIDERATIONS ........................................................................ 60 
11.1 
Sample Size Determination ....................................................................................... 60 
11.1.1 
 ................................................................................................................. 60 
11.1.2 
 ................................................................................................................. 60 
11.2 
Populations for Analysis ........................................................................................... 60 
11.3 
Procedures for Handling Missing, Unused, and Spurious Data ................................ 61 
11.4 
General Methodology ............................................................................................... 61 
11.5 
Baseline Comparison ................................................................................................ 61 
11.6 
Efficacy Analysis ...................................................................................................... 61 
11.6.1 
 .................................................................................. 61 
11.6.2 
 ................................................................................. 62 
11.6.3 
 ........................................................................................ 62 
11.7 
Safety Analysis ......................................................................................................... 62 
11.8 
Pharmacokinetic Analysis ......................................................................................... 63 
11.9 
Pharmacodynamic Analysis ...................................................................................... 63 
11.10 Interim Analysis ........................................................................................................ 63 


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12 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 64 
12.1 
Informed Consent Process ........................................................................................ 64 
12.2 
Consent and Other Informational Documents Provided to Participants ................... 64 
12.3 
Consent Procedures and Documentation .................................................................. 64 
12.4 
Confidentiality and Privacy ...................................................................................... 64 
12.5 
Data Handling ........................................................................................................... 65 
12.6 
Source Documents .................................................................................................... 66 
12.7 
Record Retention ...................................................................................................... 66 
12.8 
Safety Monitoring Committee .................................................................................. 66 
12.9 
Clinical Monitoring ................................................................................................... 67 
12.10 Quality Assurance and Quality Control .................................................................... 68 
12.11 Protocol Deviations and GCP Non-Compliance ....................................................... 68 
12.12 Publication and Data Sharing Policy ........................................................................ 69 
12.13 Conflict of Interest Policy ......................................................................................... 69 
12.14 Abbreviations ............................................................................................................ 69 
12.15 Protocol Amendment History ................................................................................... 72 
13 
REFERENCES ............................................................................................................. 96 
14 
APPENDICES ............................................................................................................... 98 
Appendix 1. 
Signature of Investigator .......................................................................... 99 
Appendix 2. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 100 
Appendix 3. 
 ... 101 
Appendix 4. 
 
 ........................................................................ 110 
Appendix 5. 
 
 .................................................................. 111 
 
 
 


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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference for Harmonisation 
(ICH) GCP and the following United States (US) Code of Federal Regulations (CFR) applicable 
to clinical studies: 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312. 
The Principal Investigator will assure that no deviation from or changes to the protocol will take 
place without prior agreement from the Investigational New Drug (IND), Sponsor, and 
documented approval from the Institutional Review Board (IRB), except where necessary to 
eliminate an immediate hazard(s) to the trial participants.  
Investigators and clinical trial staff who are responsible for the conduct, management, or 
oversight of clinical trials have completed Human Patients Protection and ICH GCP Training. 
The protocol, informed consent form (ICF)(s), recruitment materials, and all participant materials 
will be submitted to the IRB for review and approval.  Approval of both the protocol and the 
consent form must be obtained before any participant is enrolled.  Any amendment to the 
protocol will require review and approval by the IRB before the changes are implemented to the 
study.  All changes to the consent form will be IRB approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, 
using a previously approved consent form. 
 
 


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3 
PROTOCOL SUMMARY 
3.1 Synopsis 
Name of Study Drug: 
BBT-176 
Protocol Number:  
BBT176-ONC-001 
Title of Study: 
A Phase 1/2, Open-Label Study to Assess the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity 
of BBT-176 in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) who Progressed Following Prior 
Therapy with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) Agent 
Study Description: 
This Phase 1/2 study will be conducted in 2 parts: 
 
Study Objective(s): 
Part 1. 
Primary Objectives: 
• 
To investigate the safety and tolerability of BBT-176 when given orally to patients with locally 
advanced or metastatic NSCLC with EGFR mutation 
• 
To determine the MTD and/or RP2D of BBT-176 (RP2D may be different for selected mutant types) 
Secondary Objectives: 
• 
To characterize the pharmacokinetics (PK) of BBT-176 after a single oral dose and at steady state after 
multiple oral doses  
• 
To evaluate the anti-tumor activity of BBT-176 in selected mutant types by evaluation of the Objective 
Response Rate (ORR) using RECIST version 1.1 
Exploratory Objectives: 
• 
To investigate the Duration of Response (DoR) and the Progression-Free Survival (PFS) using 
RECIST version 1.1 
• 
To investigate the relationship between the anti-tumor activity and blood-borne biomarkers (i.e., 
circulating tumor DNA [ctDNA]) 
Part 2. 
Primary Objective: 
• 
To evaluate the anti-tumor activity of BBT-176 in selected mutant types by evaluation of ORR using 
RECIST version 1.1 
Secondary Objectives: 
• 
To evaluate the anti-tumor activity of BBT-176 in selected mutant types by evaluation of DoR and PFS 
using RECIST version 1.1 
• 
To evaluate the safety and tolerability of BBT-176 at the RP2D 
• 
To characterize the PK of BBT-176 after a single oral dose and at steady state after multiple oral doses 
Exploratory Objective: 
• 
To investigate the relationship between the anti-tumor activity and blood-borne biomarkers (i.e., 
ctDNA) 
Endpoints for Evaluation:  


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Part 1: 
Primary: 
• 
Safety and tolerability (Incidence of adverse events and clinical laboratory abnormalities defined as 
dose-limiting toxicities (DLTs)) 
Secondary: 
• 
PK parameters (half-life [T1/2], peak concentration [Cmax], time to peak concentration [Tmax], area 
under the concentration-time curve [AUC]) 
• 
ORR per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) 
Exploratory: 
• 
DoR and PFS per RECIST version 1.1 
• 
Pharmacodynamic biomarker (ctDNA) 
 
Part 2: 
Primary: 
• 
ORR per RECIST version 1.1 
Secondary: 
• 
DoR and PFS per RECIST version 1.1 
• 
Safety and tolerability (Incidence of adverse events) 
• 
Plasma BBT-176 concentrations at steady state  
Exploratory: 
• 
Pharmacodynamic biomarker (ctDNA) 
Number of Patients to be Enrolled: 
 
Part 1. 
• 
• 
Part 2. 
• 
   
Study Design: 
This is a Phase 1/2, open-label, multi-center, multiple-dose, dose-escalation and enrichment study of BBT-176 
designed in 2 parts. 
Part 1. Dose Escalation Phase 1 Study 
 
At the discretion of the
 
Part 2.  Enrichment Phase 2 Study 


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Safety Monitoring: 
The study will be monitored by a Safety Monitoring Committee (SMC), comprised of the Principal Investigator 
for each site, the CRO Medical Monitor, and a Sponsor representative(s) or designee. During the trial, all 
serious AEs (SAEs) and potential DLTs, as well as any PK results, will be sent to the SMC on a continual basis. 
The SMC may choose more conservative dosing decisions or stopping rules for the dose-escalation or dose-
expansion cohorts. 
I
 
 
I
  
 then SMC will convene and 
review; will recommend the Sponsor to continue or discontinue each of these cohorts.  
 then SMC will convene 
and review; will recommend to the Sponsor, RP2D for further evaluation in Part 2.  
 
In Part 2
, the SMC will continually review the safety of
 
 
Study Periods:  
• 
Screening:
• 
Treatment duration: Patients should continue on treatment with BBT-176 until RECIST v1.1 defined 
progression, unacceptable toxicities, or until treatment discontinuation criteria (Section 9) are met. 
• 
Safety follow-up:
after the last administration of study drug or immediately before 
initiation of any other cancer therapies. 
Inclusion/Exclusion Criteria: 
Key Inclusion Criteria: 
• 
Provision of signed and dated, written informed consent before any study specific procedures, 
sampling and analyses 
• 
Histological or cytological confirmation of advanced and/or metastatic stage IIIB/IV NSCLC 
• 
Radiological documentation of disease progression while on a previous continuous (at least 30 days) 
treatment with an EGFR TKI monotherapy (including, but not limited to, osimertinib, afatinib, 
dacomitinib, gefitinib, or erlotinib) 
• 
Patients must fulfill all of the following: 
o 
 


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• 
For
:
 
 
Key Exclusion Criteria: 
Patients must not enter the study if any of the following exclusion criteria are fulfilled: 
• 
Treatment with any of the following: 
o 
An EGFR TKI, including but not limited to osimertinib, afatinib, dacomitinib, gefitinib, or 
erlotinib within 8 days of the first dose of study treatment. 
o 
Small molecule targeted inhibitor other than EGFR inhibitor class, or cytotoxic 
chemotherapy within 14 days; biologic anti-cancer medicine (cytokines or antibodies, etc.) 
within 28 days (before the initiation of BBT-176 treatment) for the systemic treatment of 
advanced NSCLC 
o 
Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of 
study treatment 
o 
Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of 
study treatment   
o 
Patients receiving radiation to more than 30% of the bone marrow or with a wide field of 
radiation within 6 weeks of the first dose of study treatment 
• 
Any unresolved toxicities from prior therapy greater than NCI Common Terminology Criteria for 
Adverse Events (CTCAE v5.0) Grade 1 at the time of starting study treatment, with the exception of 
alopecia and Grade 2 neuropathy related to prior platinum-therapy  
• 
Investigational Product: 
BBT-176 (20 mg, 40 mg, 100 mg) oral capsules 
Mode of Administration: 
BBT-176 will be administered
  
Comparative Drug(s): 
None 
Statistical Methods: 
Number of Patients 
Part 1 –
 
Part 1 of the study will include approximately up to
with locally advanced or metastatic NSCLC 
with EGFR mutation. Additional patients may be required, depending on the number of cohorts and the number 
of evaluable patients needed. 
Part 2 –
 
An enrichment phase
selected mutant types will be enrolled and dosed at the RP2D. 
Given no clinical efficacy had been studied and reported in this patient group, there will be no statistical 
hypothesis assumed in regard to efficacy. Descriptive statistics will be applied to summarize efficacy.  


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Statistical Considerations 
 
Efficacy: 
 
according to the founder mutation, i.e., exon 19 deletion or L858R, will be analyzed as 
subgroups.  
Pharmacokinetics: 
Pharmacodynamics: 
Descriptive statistics will be provided for pharmacodynamic parameters whenever applicable. Exploratory 
analysis of the relationship between pharmacodynamic measurements and PK, efficacy (including biomarker), 
and safety profiles in patients may be performed. 
Safety: 
The number and percentage of patients with AEs by system organ class and preferred term will be summarized 
for each dose level and overall in Part 1, and by cohort and overall in Part 2. Summary statistics will also be 
provided for laboratory parameters, vital signs, and other safety parameters. 
 
 
 
 
 
 


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3.2 Schema of Part 1 and Part 2 
Figure 1. Schema of Part 1 
 
 
Figure 2. Schema of Part 2 
 
 
 
 
3.3 Schedule of Activities (SoA) 
Part 1 (Dose-Escalation and RP2D Exploratory Cohorts, Phase 1) 
 
Treatment Phase 
EOT a 
Safety F/U b 


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Screeni
ng 
Phase 
Cycle 1 
 
 
 
 
a. 
End of Treatment (EOT) visit: the last day of study treatment administration. 
b. 
Safety F/U visit: 30 days (± 3 days) after the last dose of study treatment or prior to initiation of another systemic anti-
cancer therapy, whichever occurs first. 
c. 
The first dose of each cycle is considered Day 1 of each cycle, and cycles will repeat every 21 days unless there is a 
treatment delay.  
d. 
On Cycle 1, Day 1 before taking dose: confirmation of inclusion/exclusion criteria. 
e. 
Complete physical exams, to include auscultation of the heart for new development of murmur, at Screening, Day 1 of 
each Cycle, EOT, and Safety F/U visit. If physical or lab findings suggest cardiac damage, echocardiogram or MUGA 
should be done. 


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Part 2 (Enrichment, Phase 2) 
 
 
Treatment Phase 
EOT a 


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Screening 
Phase 
Cycle 1 
Cycle 2 and 
Beyond 
Safety 
F/U b 
 


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4 
INTRODUCTION 
4.1 Study Rationale 
Lung cancer is one of the most common types of cancer and a leading cause of cancer mortality. 
In the United States, the majority of lung cancer cases are expected to be non-small cell lung 
cancer (NSCLC).  As a potent molecular driver, the aberration of epidermal growth factor 
receptor (EGFR) is highly correlated with advanced NSCLC. Activating EGFR mutations 
account for 7% to 15% of NSCLC in Caucasian patients and 30% to 50% in East Asian patients 
(Liu et al 2017, Rotow and Bivona 2017). 
The advent of tyrosine kinase inhibitor (TKI) therapy greatly improved outcomes for patients 
with EGFR-mutated NSCLC. However, drug resistance due to T790M mutation severely limits 
the use of first-generation TKIs, and the most recently approved, third-generation, irreversible 
TKI osimertinib is rapidly compromised by acquired mutation of C797S. Treatment options for 
patients whose NSCLC progresses following TKI therapy are limited, contributing to poorer 
prognosis and high mortality risk. Thus, there is an urgent need for novel EGFR TKIs, 
particularly ones with efficacy against C797S-triple mutation. 
BBT-176 is a competitive TKI that targets selected drug-resistant EGFR mutants, including 
C797S-triple mutation. In preclinical models, the combination of BBT-176 and cetuximab also 
showed beneficial synergistic effects on relative tumor volume and survival, as well as on 
activity of the EGFR signaling pathway. 
This is a Phase 1/2 trial to be conducted in 2 parts, the Phase 1 dose-escalation study (Part 1) and 
the Phase 2 enrichment study (Part 2), to evaluate the maximum tolerated dose (MTD) and to 
observe tumor response in patients with locally advanced or metastatic NSCLC with EGFR 
mutation. 
4.2 Background 
Targeted therapy, including EGFR TKIs, developed in the past 2 decades has significantly 
improved response rates compared with cytotoxic chemotherapy. Activating mutations in the 
EGFR gene cause NSCLC that has been effectively treated by the first-generation EGFR 
inhibitors, gefitinib and erlotinib (Mok et al 2009, Rosell et al 2012).  In EGFR-mutation-
positive patients, the response rate was significantly higher with gefitinib treatment (71.2%) than 
with chemotherapy (47.3%), and progression-free survival (PFS) was significantly longer with 
gefitinib treatment (9.5 months) than with chemotherapy (6.3 months) (Fukuoka et al 2011).  
Also, patients in the erlotinib-treated group achieved a higher response rate (58%) compared 
with the 15% response rate in the chemotherapy group, and PFS of the erlotinib-treated group 
was significantly longer than that of the chemotherapy-treated group (9.7 months versus 
5.2 months, respectively). Molecular analysis showed that the most responder-harboring 
mutations are the deletion mutation of exon 19 (del19), accounting for 45% of mutations, and the 


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L858R substitution mutation in exon 21, accounting for 40% to 45% of mutations. These first-
generation EGFR TKIs seemed to efficiently control the EGFR activating mutation-harboring 
tumors. However, the toxicity associated with erlotinib or gefitinib was worse than that of 
chemotherapy, particularly due to the inhibition effect of these TKIs on wild-type EGFR in skin 
and intestine. More importantly, there was acquired resistance after 9 to 14 months of treatment 
with the most common resistance mechanism being a point mutation in exon 20 called T790M in 
EGFR kinase domain (Sequist et al 2015). The secondary mutation, T790M, increases the 
affinity of Adenosine Triphosphate (ATP) for the binding site, thereby reducing the binding 
affinity of reversible EGFR TKIs. Third-generation EGFR inhibitors have been developed to 
overcome T790M resistance through the covalent inhibition of EGFR by binding a cysteine side 
chain (Cys797). Osimertinib (AZD9291) is the irreversible EGFR TKI approved by the US Food 
and Drug Administration (FDA) for the treatment of tumors with EGFR-activating mutations in 
the presence of T790M post-TKI resistance and has been significantly effective (Janne et al 
2015). Osimertinib is more effective on mutant forms of EGFR (both the activating mutations 
and T790M) than wild-type EGFR, suggesting the role as a first-line EGFR inhibitor as well. 
However, despite its critical efficacy, a tertiary mutation (EGFR C797S) often appeared in the 
osimertinib-treated patients, causing acquired resistance and accumulating evidence suggest that 
both first- and second-line treatment with osimertinib will eventually and ultimately cause 
C797S triple mutation (Thress et al 2015, Wang et al 2017, and Rangachari et al 2019). Because 
C797 is the critical covalent binding site of osimertinib, the mutation results in loss of the drug’s 
irreversible inhibition mechanism and, consequently, drug resistance. As such, C797S mutation 
could be an ideal mechanism to evade the third-generation inhibitor, and a new EGFR inhibitor 
would be needed to effectively inhibit EGFR triple mutants such as del19/T790M/C797S or 
L858R/T790M/C797S. 
BBT-176 is a competitive TKI that targets selected drug-resistant EGFR mutants, 
 
 
 
 
 
 
 
 
 
 
 
In vitro pharmacokinetic (PK) studies of BBT-176 have been conducted in the mouse, rat, dog, 
and monkey. 
 
 
 


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4.3 Risk/Benefit Assessment 
4.3.1 
Known Potential Risks 
In preclinical toxicity studies conducted to date, BBT-176 was negative for in vitro toxicity as 
assessed by hERG patch clamp, AMES, and micronucleus testing. The animals receiving BBT-
176 showed similar class effects as other EGFR TKIs and dose-related toxicological findings 
including clinical signs, body weights, food consumption, clinical pathology parameters, organ 
weights, gross pathology, and histopathological examination, with similar toxicity overall 
compared with brigatinib (for details, refer to the Investigator’s Brochure). Therefore, potential 
risks based on its mechanism of action may be similar to those reported for other EGFR TKIs. 
For example, brigatinib can cause severe, life-threatening and fatal pulmonary adverse reactions 
consistent with interstitial lung disease (ILD)/pneumonitis, hypertension, bradycardia, elevated 
creatine phosphokinase and pancreatic enzymes, hyperglycemia, and embryo-fetal toxicity based 
on animal reproduction studies, as reported in its Prescribing Information [Prescribing 
Information of Alunbrig (brigitinib)]. Osimertinib, a kinase inhibitor indicated for the treatment 
of patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed on or 
after EGFR TKI therapy, can cause ILD/pneumonitis, prolongation of the corrected QT (QTc) 
interval, cardiomyopathy, and embryo-fetal toxicity based on animal reproduction studies, as 
reported in its Prescribing Information [Prescribing Information of Tagrisso (osimertinib)]. 
4.3.2 
Known Potential Benefits 
BBT-176 is a competitive TKI that has demonstrated in vitro activity and in vivo efficacy against 
EGFR mutants, including those with C797S-triple mutation. BBT-176 in combination with 
cetuximab demonstrated beneficial synergistic effects that may translate to clinical efficacy. 
BBT-176 alone or in combination with cetuximab may potentially be of benefit in the treatment 
of NSCLC with mutations that render other EGFR TKIs ineffective. 
4.3.3 
Assessment of Potential Risks and Benefits 
Overall, the potential benefits of this study are considered to outweigh the potential risks. TKI 
therapy can be a highly effective treatment for EGFR-mutated NSCLC; however, drug resistance 
greatly limits its utility. Patients whose NSCLC progresses following TKI therapy have limited 
treatment options and poor prognosis. Evaluation and development of novel EGFR TKIs are 
needed, particularly ones with efficacy against C797S-triple mutation. 


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Even if the patient has progressed after TKI therapy, if there is a treatment proven to be 
effective, it is beneficial for the patient to receive the proven treatment. In particular, if patients 
with T790M mutation have not yet received osimertinib treatment, it is beneficial for patients to 
receive osimertinib treatment before participation in this trial. In this case, the Investigator 
should provide information to the patient so that the patient can receive treatment that has proven 
effective. 
 
4.3.4 
Needs to Explore Alternative Dosing Schedule  
 
 
 
 
 
 
 
  
 
 


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5 
OBJECTIVES AND ENDPOINTS 
5.1 
Part 1 
Primary Objectives: 
• To investigate the safety and tolerability of BBT-176 when given orally to patients with 
locally advanced or metastatic NSCLC with EGFR mutation 
• To determine the MTD and/or recommended Phase 2 dose (RP2D) of BBT-176 (RP2D 
may be different for selected mutant types) 
MTD and RP2D: 
 
 
 
 
 
 
Secondary Objectives: 
• To characterize the PK of BBT-176 after a single oral dose and at steady state after 
multiple oral doses when given orally  
• To evaluate the anti-tumor activity of BBT-176 in selected mutant types by evaluation of 
the Objective Response Rate (ORR) using Response Evaluation Criteria In Solid Tumors 
(RECIST) version 1.1 
Exploratory Objectives: 
• To investigate the Duration of Response (DoR) and the Progression-Free Survival (PFS) 
using RECIST version 1.1 
• To investigate the relationship between the anti-tumor activity and blood-borne 
biomarkers (i.e., circulating-tumor DNA [ctDNA]) 
5.2 
Part 2 
Primary Objective: 
• To evaluate the anti-tumor activity of BBT-176 in selected mutant types by evaluation of 
ORR using RECIST version 1.1 
Secondary Objectives: 
• To evaluate the anti-tumor activity of BBT-176 in selected mutant types by evaluation of 
Duration of Response (DoR) and PFS using RECIST version 1.1 
• To evaluate the safety and tolerability of BBT-176 at the RP2D 
• To characterize the snapshot PK of BBT-176 at steady state after multiple oral doses 


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Exploratory Objective: 
• To investigate the relationship between the anti-tumor activity and blood-borne 
biomarkers (i.e., ctDNA) 
5.3 
Endpoints 
5.3.1 
Part 1 
5.3.1.1 
Primary Endpoint 
• Safety and tolerability (incidence of adverse events [AEs] and clinical laboratory 
abnormalities defined as DLTs) 
5.3.1.2 
Secondary Endpoints 
• PK parameters (half-life [T1/2], peak concentration [Cmax], time to peak concentration 
[Tmax], area under the concentration-time curve [AUC]) 
• ORR per RECIST version 1.1 
5.3.1.3 
Exploratory Endpoints 
• DoR and PFS per RECIST version 1.1 
• Pharmacodynamic biomarker (ctDNA) 
5.3.2 
Part 2 
5.3.2.1 
Primary Endpoint 
• ORR per RECIST version 1.1 
5.3.2.2 
Secondary Endpoints 
• DoR and PFS per RECIST version 1.1 
• Safety and tolerability (incidence of AEs) 
• Plasma BBT-176 concentrations at steady state 
5.3.2.3 
Exploratory Endpoint 
• 
Pharmacodynamic biomarker (ctDNA) 
 
 


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6 
STUDY DESIGN 
6.1 
Overall Design 
 
 
 
 
6.1.1 
Part 1 
The primary endpoint in Part 1 is t
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intra-patient Dose Escalation: 
Intra-patient dose escalation is allowed when the next higher dose level is open to enrollment; A 
patient has the option to be escalated to the next higher dose level if the patient meets following 
conditions 
1) 
 


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2) 
 
 
 
onger-term treatment  
The Investigator and the Sponsor will continue to monitor safety of BBT-176 for potential 
cumulative toxicity.    
 
 
 
 
 
 
6.1.2 
Part 2 
In Part 2, the primary endpoint is tumor response 
 
 
 
 
 In Part 2, patients with confirmed EGFR mutation types as confirmed in Part 1 will be 
enrolled to receive BBT-176 to further assess the efficacy, tolerability, and PK of BBT-176.  
There are no specific stopping criteria for this part of the study and emerging data will be 
monitored regularly by the SMC. 
6.2 
Justification for Dose 
BBT-176 
 will be the starting dose tested in Part 1 (dose-escalation study). 
 
 
 
 
 
 
 
 
 
 
 


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• 
Acute gastrointestinal toxicities like nausea, vomiting and diarrhea may be less with BID 
dosing schedule.  
• 
 
 
  
• 
 
 
  
 
 
 
  
6.3 
Treatment Duration and End of Study Definition 
6.3.1 
Treatment Duration 
Patients should continue on treatment with BBT-176 until RECIST v1.1 defined progression, 
unacceptable toxicities, symptomatic progression or until the criteria for treatment 
discontinuation criteria (Section 9) are met. 
A patient is considered to have completed the study when all phases of the study, including the 
last visit or the last scheduled procedure shown in the Schedule of Activities (SoA; Section 3.3), 
have been completed. 
6.3.2 
End of Study 
The trial will be completed when all enrolled patients have discontinued treatment and 
completed the end-of-study visit and safety follow-up. 


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7 
STUDY POPULATION 
7.1 
Inclusion Criteria 
For inclusion in the study, patients must fulfill all of the following criteria: 
1. Provision of signed and dated, written informed consent before any study specific 
procedures, sampling and analyses 
2. Aged at least 18 years 
3. Histological or cytological confirmation of advanced and/or metastatic stage IIIB/IV 
NSCLC 
4. Radiological documentation of disease progression while on a previous continuous (at 
least 30 days) treatment with an EGFR TKI monotherapy (including, but not limited to, 
osimertinib, afatinib, dacomitinib, gefitinib, or erlotinib). All patients must have 
documented radiological progression on the last treatment administered prior to enrolling 
in the study 
5. 
 
 
 
 
 World Health Organization 
(WHO) criteria, after treatment of an EGFR TKI 
6. Adequate bone marrow reserve or organ function as demonstrated by all of the following 
laboratory values: 
• Absolute neutrophil count (ANC) > 1.5 × 109 cells/L (without growth factor 
support for 2 weeks prior to testing) 
• Platelet count > 75 × 109 cells/L (without transfusion or growth factor support for 
1 week prior to testing) 
• Hemoglobin > 9.0 g/dL (without transfusion or growth factor support for 2 weeks 
prior to testing) 
• Alanine aminotransferase ≤2.5 times the upper limit of normal (ULN) 
• Aspartate aminotransferase ≤2.5 times the ULN 
• Total bilirubin ≤1.5 times the ULN  


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• Creatinine ≤1.5 times the ULN, creatinine clearance ≥50 mL/min (measured or 
calculated by Cockcroft-Gault equation). Confirmation of creatinine clearance is 
required when creatinine is > 1.5 times the ULN 
7. 
 
 
 
 
 
 
  
 
 
8. Patients must have measurable disease per RECIST v1.1 presented  
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 
10. Females, if of child-bearing potential, should be using adequate contraceptive measures, 
should not be breastfeeding, and must have a negative pregnancy test result prior to start 
of dosing, or must have evidence of non-child-bearing potential by fulfilling one of the 
following criteria at Screening: 
• Post-menopausal defined as aged more than 50 years and amenorrhoeic for at 
least 12 months following cessation of all exogenous hormonal treatments 
• Women aged fewer than 50 years will be considered postmenopausal if they have 
been amenorrhoeic for 12 months or more following cessation of exogenous 
hormonal treatments and with Luteinizing Hormone (LH) and Follicle 
Stimulating Hormone (FSH) levels in the post-menopausal range as defined by 
the institution 
• Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy but not tubal ligation 
11. Male patients should be willing to use barrier contraception (i.e., condoms) 


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7.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Treatment with any of the following: 
• An EGFR TKI, including but not limited to osimertinib, afatinib, dacomitinib, 
gefitinib, or erlotinib within 8 days of the first dose of study treatment.  
• Small molecule targeted inhibitor other than EGFR inhibitor class, or cytotoxic 
chemotherapy within 14 days; biologic anticancer medicine (cytokines or 
antibodies, etc.) within 28 days (before the initiation of BBT-176 treatment) for 
the systemic treatment of advanced NSCLC  
• Major surgery (excluding placement of vascular access) within 4 weeks of the 
first dose of study treatment 
• Radiotherapy with a limited field of radiation for palliation within 1 week of the 
first dose of study treatment 
• Patients receiving radiation to more than 30% of the bone marrow or with a wide 
field of radiation within 6 weeks of the first dose of study treatment 
• Patients receiving CYP2C8 or P-gp strong inhibitor (see Appendix 4) 
2. Any unresolved toxicities from prior therapy greater than NCI Common Terminology 
Criteria for Adverse Events (CTCAE v5.0) Grade 1 at the time of starting study 
treatment, with the exception of alopecia and Grade 2 neuropathy related to prior 
platinum-therapy 
3. Spinal cord compression or brain metastases, unless asymptomatic and stable fulfilling 
one of following: 
• Not requiring active treatments prior to start of study treatment  
• Requiring stable dosing regimens of low-dose oral corticosteroid (up to 20 mg 
prednisone/day or equivalent) for at least 4 weeks prior to the first dose of study 
treatment  
4. Even if the patient has progressed after EGFR TKI therapy, if there is a treatment proven 
to be effective, the patient should receive the treatment first. This includes cases where 
documented evidence of MET amplification, HER2 mutation, or SCLC transformation 
exists and treatments or clinical trials that have been proven for the corresponding 
mutations are available. 
5. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled 
hypertension and active bleeding diatheses that in the Investigator’s opinion makes it 


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undesirable for the patient to participate in the trial or would jeopardize compliance with 
the protocol, or active infection including hepatitis B, hepatitis C, and human 
immunodeficiency virus (HIV). Screening for chronic conditions is not required 
6. Any of the following cardiac criteria: 
• Mean resting QTc interval (corrected by Fridericia’s formula [QTcF]) > 470 msec 
obtained from average value of 3 electrocardiograms (ECGs), using the screening 
clinic ECG machine derived QTc value 
• Any clinically important abnormalities in rhythm, conduction or morphology of 
resting ECG (e.g., complete left bundle branch block, third degree heart block, 
second degree heart block, or PR interval of >250 msec) 
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic 
events, such as heart failure (ejection fraction < 50%; for details refer to 
Section 10.2.3.3), hypokalemia, congenital long QT syndrome, family history of 
long QT syndrome or unexplained sudden death before the age of 40 years in 
first-degree relatives, or any concomitant medication known to prolong the QT 
interval 
7. Past medical history of ILD, drug-induced ILD, radiation pneumonitis that required 
steroid treatment, or any evidence of clinically active ILD 
8. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow 
the study treatment, or previous significant bowel resection that would preclude adequate 
absorption of BBT-176 
9. Involvement in the planning and conduct of the study 
10. Judgment by the Investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions, and requirements 
11. Previous or concomitant malignancies at other sites, except effectively treated non-
melanoma skin cancers, carcinoma in situ of cervix, ductal carcinoma in situ or 
effectively treated malignancy that has been in remission for more than 3 years and is 
considered to be cured 
12. History or presence of hypersensitivity or idiosyncratic reaction to the study drug(s) or 
related compounds 
13. History or presence of alcoholism or drug abuse within the past 2 years prior to the first 
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7.3 
Tumor and Mutation Assessment for Eligibility 
The RECIST assessment by the Investigator/local radiologist will be the basis for eligibility, 
continuation, or discontinuation of the trial in an individual patient. The independent central 
RECIST v1.1 review will be conducted. 
EGFR mutational status for eligibility will be assessed in medical history, ctDNA, and/or tumor 
tissue from each patient. 
For Part 1, 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
7.4 
Screen Failures 
Screen failures are defined as participants who consent to participate but are not subsequently 
enrolled in the study. Minimal screening failure information includes demography, screen failure 
details, eligibility criteria, and any serious adverse event (SAE). Potential study participants may 
have inclusionary laboratory one single time repeated during the screening period for inclusion. 
Patients recorded as a screen failure may be rescreened once per investigator’s discretion. 
 


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7.5 
Definition of Evaluable Patient (For Part 1 Dose Escalation Cohorts) 
An evaluable patient is defined as a patient who has completed minimum safety evaluation 
requirements during the first 21 days or has experienced a DLT during the first 21 days. 
 
 
 
 
 
 
During Part 1 dose escalation cohorts, in the case that patients in the cohort are not evaluable, 
additional patients will be enrolled in the cohort.  
Patients who are not evaluable might continue trial treatment upon agreement between 
Investigator and Sponsor, however the patient will not be considered for the evaluation of MTD. 
 
 


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8 
STUDY TREATMENT AND DOSE MODIFICATIONS 
8.1 
Study Treatment(s) Administration 
8.1.1 
Study Treatment Description 
BBT-176 is a competitive TKI that targets selected drug-resistant EGFR mutants, including 
C797S-triple mutation. 
8.1.2 
Method of Assigning Patients to Treatment Groups 
For Part 1, the eligible patients will be assigned to the dose escalation cohorts first, and to 
exploratory cohorts if there are no available dose escalation cohorts.  
An Interactive Web Response System (IWRS) system will be deployed to manage the supply of   
BBT-176 capsules to sites and to manage the dispensing of BBT-176 to patients. 
The treatment medication assignment will be managed through an IWRS system. In addition, 
patient’s screening, dose assignment, all drug dispensation visits, and EOT visit will be 
documented in the IWRS system. 
Screening and treatment slots are assigned according to the cohort management plan. After the 
Sponsor (or designated CRO) has been notified by a site about a potential patient, the slot will be 
reserved to this site for a maximum of 7 calendar days. If the informed consent form (ICF) has 
not been signed by the potential patient within this time window, the slot will be opened up again 
for all recruiting sites. 
Patients who meet the eligibility criteria and who have given their written informed consent will 
be entered into the study. 
Before entering patients at the next dose level, it will be ensured that all patients at an ongoing 
cohort have completed the first cycle. Prior to inclusion of a new patient, the Investigator should 
confirm the respective dose with the Sponsor (or designated CRO). 
8.1.3 
Dosing and Administration 
8.1.3.1 
Dosing and Meal Timing 
There is no meal restriction on BBT-176 dosing. Patients will take BBT-176 at home at about the 
same time every day, except on days with scheduled study visits including pre-dose PK 
sampling, patients should not take their dose of study medication at home in order to complete 
pre-dose PK plasma collection. 
8.1.3.2 
Starting Dose and Dose Levels 
BBT-176 will be administered orally once daily at a starting dose of 20 mg in Cohort 1. The 
starting dose justification is described in Section 6.2. 


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The dose-escalation scheme proposes 
 as 
shown in Table 1.  
 
  
 
 
 
In case 160 mg BID is assessed to be intolerable by the Safety Monitoring Committee, then 120 
mg BID may be explored further. Dosage and frequency for Dose level ≥2 may be altered based 
on the PK, pharmacodynamics, and safety data obtained from previous dose level. 
 
8.1.3.3 
Dose Escalation 
Bayesian Model-based Method for dose escalation: 
Bayesian model-based method will be used for the next dose recommendation for dose 
escalation. Dose-escalation of BBT-176 to determine the MTD will be guided by the mCRM 
using a BLRM following dose 
 
 
 
 
 
 


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Prior Distribution Specification 
The prior distribution will be calculated based on: 
1. Probability of DLT at 
 mg (starting dose): 0.05 
2. Estimate of MTD: 
 
In the 28-days GLP toxicology study, t
 
 
herefore, patients 
 are not expected to show DLT. 
Based on these, 
 
 
The 
 
 
 
 on these, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The acceptable dose range is on a continuous scale between the minimum and maximum doses. 
The upper limit of the acceptable range is the largest dose whose probability of overdosing is less 
than the EWOC threshold. The lower limit of the acceptable range is the dose whose DLT rate is 
equal to the lower limit of the targeted toxicity interval. 
 


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When the acceptable dose range of the next cohort is recommended by the BLRM, the SMC will 
decide the next dose within the acceptable dose range or a lower dose than the lower limit. The 
SMC will consider the following for the dose decision: 
• 
  
Intermediate or lower dose levels, as long as they fulfil the EWOC criterion, may be 
recommended by the SMC and investigated if agreed upon between Investigator and Sponsor. 
 
 
 will be applied 
to guide 
 
  The 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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8.1.3.4 
RP2D Exploration 
At the discretion of the Sponsor, once the RP2D has been provisionally established, 
   
additional patients with molecularly defined biomarker may be enrolled and treated at that dose 
in order to further characterize safety, tolerability, PK, and efficacy, and to confirm its selection 
as the optimal dose to evaluate in Phase 2. RP2D exploration may be conducted in more than one 
cohort according to mutant types. 
The 
 
 
  
 
8.1.3.5 
 
 
 
 
 
8.1.3.6 
Dose Reduction Criteria 
In Part 1, no dose reduction is permitted in Cycle 1 without the Sponsor approval. If a patient in 
Part 1 is confirmed to have experienced a DLT in Cycle 1, then the Investigator, with the 
Sponsor approval, may do either of the following: 
• Continue treating the patient at the next lower dose level evaluated, if the Investigator 
expects clinical benefit from further treatment, the toxicity is manageable, and the 
Investigator and the Sponsor’s medical monitor (or designee) agree. A patient who 
receives a modified dose will be evaluated for safety at that dose level, but will not be 
counted towards the number of patients with DLTs at that dose level. 
• Discontinue the patient from the treatment and the study. 
Treatment with BBT-176 should be held until the toxicity resolves to ≤Grade 2. Dosing may then 
be resumed at either the same dose or the next lower dose level evaluated, per Investigator 
discretion. If treatment is resumed at the same dose, and the patient experiences the same 


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toxicity, the dose should be reduced following treatment hold and resolution of the event. If the 
patient continues to experience toxicity, a second dose reduction to a previously evaluated lower 
dose is permitted. Only two dose-reduction steps are allowed. If a patient continues to experience 
toxicity after two dose-reduction steps, or if dosing with BBT-176 is interrupted for 
>14 consecutive days due to toxicity, treatment should be discontinued, unless otherwise agreed 
upon between the Investigator and the Sponsor. 
During Part 1, after Cycle 1, up to two dose reduction steps are allowed for each patient, if 
CTCAE Grade 3 or 4 toxicities are observed. The dose may be held or continued at the next 
lower dose level as described below. 
For the RP2D exploratory cohort, the Investigators will have discretion to adjust dose in 
individual patients according to tolerability and safety from Cycle 1. Two dose reductions steps 
are allowed. If a patient continues to experience toxicity after two dose reduction steps, or if 
dosing with BBT-176 is interrupted for >14 consecutive days due to toxicity, treatment should be 
discontinued, unless otherwise agreed upon between the Investigator and the Sponsor. The dose 
may be increased, if the sponsor agrees, not exceeding MTD, when such concerns are resolved or 
mitigated. The Investigator may consult to the Sponsor about dose adjustment. Below table is an 
example. In case of not-specified adverse events, the Investigator and the Sponsor will discuss 
further and determined the adjusted dose according to available scientific literatures.  
 
Table 2. Recommended Dose Adjustment Scheme  


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If a patient at the RP2D was required to reduce their dose level due to a non-drug-related 
toxicity, and the toxicity subsequently resolved, then the dose may be re-escalated back to the 
recommended dose, if tolerated. 
8.2 
Preparation, Handling, Storage, and Accountability 
8.2.1 
Acquisition and Accountability 
The Investigator will maintain accurate records of the receipt of all study medications. In 
addition, accurate records will be kept regarding when and how much study medication is 
dispensed and used by each patient in the study. Reasons for deviation from the expected 
dispensing regimen must also be recorded. Study medication will be reconciled by the site. The 
Investigator agrees to provide sufficient access to study medication as required for the 
reconciliation process to be completed in a timely fashion. 
8.2.2 
Formulation, Appearance, Packaging, and Labeling 
BBT-176 is 
 The 
formulated BBT-176 contains citric acid and pharmaceutically acceptable excipients. For 
 
 
 
 
 
 
 
8.2.3 
Product Storage and Stability 
Bottles containing BBT-176 should be stored at temperatures of 15°C to 30°C (59°F to 86°F), 
protected from high humidity and direct sunlight. The cap on the bottle should be tightly closed 
after each use and out of the reach of children. 
8.2.4 
Preparation 
No preparation is required for BBT-176.  


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8.3 
Measures to Minimize Bias: Randomization and Blinding 
Randomization and blinding are not applicable to this non-randomized, open-label trial. 
8.4 
Study Treatment Compliance 
Adherence to administration of study treatment will be assessed by the amount of study 
treatment distributed versus the amount returned.  
The appropriate number of capsules for 3 weeks treatment will be provided to patients to be self-
administered at home. Patients will be asked to bring the remaining trial medication at the end of 
each cycle to the Investigator site for a compliance check. Remaining capsules will be counted 
by Investigator/site staff and recorded. Discrepancies between the number of capsules remaining 
and the calculated number of capsules the patients should have taken must be documented and 
explained. If the patient is eligible for further treatment, a new bottle of study drug will be 
dispensed. 
In case a patient feels uncomfortable from the number of capsules, divided oral intake within 20 
minutes is allowed.  
Patient diary will also be assessed as a supplementary method for treatment compliance check. 
In case a patient is unable to comply to the protocol-defined procedures due to public health 
policy, e.g., COVID-19 pandemic quarantine measures, the Investigator may delay physical 
examinations and laboratory examinations if the sponsor agrees. The Investigator should try 
every effort to communicate directly with the patient for safety follow-up, e.g., by telephone call 
or video conference. Such communications must be documented in eCRF.     
8.5 
Prior and Concomitant Therapy 
Prior medication will be recorded as part of the past medical history.  
Concomitant therapy is defined as any medicinal product, prescribed or over-the-counter, taken 
by a patient other than the study drug. Use of concomitant medications will be recorded and 
reported. The Investigator will have discretion to prescribe medications which are recommended 
by public treatment guidelines to prevent or mitigate adverse events in cancer patients, e.g., 
nausea, vomiting, or diarrhea.  
The Investigator will be responsible for preventive vaccination of the subjects according to the 
available public health policy of the jurisdiction where this clinical trial is being conducted. The 
Investigator may discuss with the Sponsor on individual decisions.  
 


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8.5.1 
Emergency Procedures 
Careful assessment of all patients with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnea, cough, fever) should be performed to exclude drug-induced 
ILD. Study drugs should be interrupted pending investigation of these symptoms. If drug-
induced ILD is diagnosed, appropriate treatment should be instituted as necessary. 
8.5.2 
Restrictions 
• Concomitant medications, or therapy to provide adequate supportive care, may be given 
as clinically necessary. 
• Palliative radiotherapy may be given as described above. 
• Additional experimental anti-cancer treatment and/or standard chemo-, immunotherapy, 
hormone treatment (with the exception of megestrol acetate for decreased appetite), or 
radiotherapy (other than palliative radiotherapy for symptom control) is not allowed 
concomitantly with the administration of study treatment. 
• 
 
 
 
 
) 
 
 


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9 
STUDY TREATMENT DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
9.1 
Discontinuation of Trial 
This study may be temporarily suspended or prematurely terminated by the Sponsor if there is 
sufficient reasonable cause. Written notification documenting the reason for study suspension or 
termination by the Sponsor will be provided to investigators or the Sponsor, respectively; study 
participants; the Institutional Review Board (IRB); and regulatory authorities. Study participants 
will be contacted, as applicable, and be informed of any changes to the study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
• Failure to meet enrollment goals overall or at a particular trial site 
The study may resume once concerns are addressed to the satisfaction of the Sponsor, IRB, 
and/or regulatory authorities. 
9.2 
Participant Discontinuation/Withdrawal from the Study 
Patients are free to withdraw from participation in the study at any time upon request. A patient 
may be withdrawn from the study by the Investigator or designee and not be allowed to continue 
the study if any of the following occur: 
• Withdrawal of consent by the patient 
• Withdrawal of patient at the discretion of the Investigator or designee if concurrent 
illnesses occur that may invalidate the study data or are considered to increase the risk 
from the study participation 
• Discovery that the patient has entered the study in violation of the inclusion/exclusion 
criteria stated in the protocol 
• Significant critical protocol violation occurs during the study 
• Pregnancy 
The reason for discontinuation or withdrawal from the study will be recorded. Patients who sign 
the ICF and are discontinued or withdrawn from the study should visit the clinic for EOT 
procedures shown in the SoA (Section 3.3). Samples and data collected from patients up to the 
point of discontinuation/withdrawal may still be included in the analyses. 
 


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9.3 
Lost to Follow-Up 
A patient will be considered lost to follow-up if he or she fails to return for scheduled visits and 
is unable to be contacted by the study site staff. If a patient fails to return to the clinic for a 
required study visit, the site will attempt to contact the patient and reschedule the missed visit 
and ascertain if the participant wishes to and/or should continue in the study. 
Before a participant is deemed lost to follow-up, the Investigator or designee will make every 
effort to regain contact. These contact attempts should be documented in the participant’s 
medical record or study file. 
 
 
 
 
 


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10 
STUDY ASSESSMENTS AND PROCEDURES 
10.1 
Efficacy Assessments 
The following efficacy parameters will be measured: 
• Tumor response according to RECIST, version 1.1: ORR, DoR, PFS (at Screening and 
every 6 weeks from Cycle 1 Day 1 until progression 
• Biomarker analysis: ctDNA (at Screening and every 2 cycles until progression) 
10.1.1 
Tumor Assessment (RECIST v1.1) 
Tumor assessment (RECIST version 1.1) will be performed at Screening and every 6 weeks from 
Cycle 1 Day 1 until progression of disease, EOT, or until the patient commences further anti-
cancer treatment, whichever comes first. 
• Imaging may be performed within 7 days before the scheduled visit.  
• 
In the event of a delay or discontinuation of study drug, tumor assessment should 
continue to follow the original schedule. 
The Investigator will choose the anatomical extent and the modality of imaging study, while 
brain MRI is mandatory at screening. The assessment by the Investigator/local radiologist will be 
the basis for eligibility, continuation, or discontinuation of the trial in an individual patient.  
 
 
 
 
 
 
 
10.1.2 
Circulating Tumor DNA Assessment 
 
 
 
 
 
 
 
 


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10.1.3 
Tumor Biopsy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.1.3.1 
Archival Tumor Blocks Taken Before the Study 
 
 
 
 
  
 
 
10.2 
Safety Assessments 
10.2.1 
Maximum Tolerated Dose 
 
 
 
 
10.2.2 
Dose Limiting Toxicity 
A 
 
 


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last day of Cycle 1 (21 days after start of multiple dosing) in dose-escalation cohorts and that 
 
 
 
 
 
 
 
 
 
 
 
 
 
A DLT excludes:  
1. 
 
 
 
 
 
 
The incidence and type of AE fulfilling the above DLT criteria from Cycle 2 within each 
cohort/dose level and beyond will be taken into account by the SMC in determining dose-
escalation steps and will be considered when selecting the RP2D by the Sponsor. 
Any DLT must be immediately (within 24 hours of first knowledge) reported to the Sponsor. 
10.2.3 
Adverse Events and Other Safety Assessments 
For details of AE assessment refer to Section 10.6. 
 
  
  
  
 
10.2.3.1 
Laboratory Tests 
Laboratory tests includes: 


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Complete blood count with differential, platelet count and ANC 
Plasma: total protein, albumin, creatinine, blood urea nitrogen (BUN), uric acid, bilirubin (total 
and direct), alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), gamma glutamyltransferase (GGT), glucose, calcium, phosphorus, chloride, sodium, 
potassium, magnesium, serum amylase, serum lipase, and coagulation tests (prothrombin time 
[PT] or international normalized ratio [INR], activated partial thromboplastin time [aPTT]). 
Serology (at Screening): hepatitis B surface antigen (HBsAg), Anti-hepatitis C virus (HCV), 
HIV test 
Urine: glucose, protein, blood 
10.2.3.2 
Electrocardiogram 
Twelve-lead ECG will be performed at the visit indicated in the SoA (Section 3.3). The timing 
and number of ECGs may be altered depending on the emerging PK and safety profile. 
Twelve-lead ECGs will be obtained after the patient has been resting supine or semi-supine for at 
least 10 minutes prior to times indicated. All ECGs should be recorded with the patient in the 
same physical position. Screening, Day 1 of each Cycle, EOT, and Safety F/U visit. Serial ECGs 
will be conducted on Cycle 1, Day 1 pre-dose and at 2 (±10 min), 4 (±15 min), and 6 (±15 min) h 
post-dose, on Day 2 prior to discharge. When ECGs are scheduled at the same time as blood 
draws, the ECGs will be obtained prior to and as close to the scheduled blood draw as possible. 
For screening and each time point of Cycle 1, ECG recording should be repeated 3 times with an 
interval of about 5minutes. Single ECG recording will be taken from Cycle 2. A standardized 
ECG machine should be used, and the patient should be examined using the same machine 
throughout the study if possible. 
From version 5.0. ECG on Day 2 is not applicable.  
After ECGs have been recorded, the Investigator or designated physician will review each of the 
ECGs and may refer to a local cardiologist if appropriate. A copy should be filed in the patient’s 
medical records. If an abnormal ECG finding at Screening or baseline is considered to be 
clinically significant by the Investigator, it should be reported as a concurrent condition. For all 
ECGs, details of rhythm, ECG intervals, and an overall evaluation will be recorded. 
10.2.3.3 
Echocardiogram/Multiple-gated Acquisition (MUGA) Scan 
At Screening: only patients with suspect cardiac disease with negative effect on ejection fraction 
(EF) will be measured during Screening according to local standards at the Investigator’s 
discretion (e.g., echocardiogram or MUGA). Echocardiogram or MUGA scan within 6 months is 
accepted for screening assessment.  
During the study and safety follow-up visit, if physical or lab findings suggest cardiac damage, 
echocardiogram or MUGA should be done. 


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10.3 
Pharmacokinetics 
Venous blood samples will be collected to measure the BBT-176 concentrations in plasma as 
well as the following PK parameters: 
• T1/2 (Part 1 only) 
• Cmax 
• Tmax 
• AUC (Part 1 only) 
• Ctrough (Part 1 only) 
 
  
 
   
 
 
 
 
   
 
 
 
  
The timing of the PK samples may be adjusted during the study, dependent on emerging data, in 
order to ensure appropriate characterization of the plasma concentration-time profiles. 
A 10-minute window will be allowed for samples taken at 1 hour; a 20-minute window for 
samples taken at 2 to 8 hours; and a 1-hour window for samples taken at 12 and 24 hours.  In 
case of divided dosing, blood collection time must be measured from the time of the first divided 
intake.  
Details about blood sample collection, preparation of sample, storage/shipment, and disposal will 
be provided in the laboratory manual. 
10.4 
Volume of Blood 
The number of samples taken, as well as the volume required for each analysis, may be changed 
during the study as new data become available. The estimated total volume of blood that will be 


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drawn from each patient in this study for mandatory samples up to the end of Cycle 2 is 
approximately 
 
 
Safety laboratory assessments will be performed locally at each site’s laboratory by means of 
their established methods. The number of samples/blood volumes is therefore subject to site-
specific change. 
10.5 
Study Procedures 
 The first dose of each cycle is considered Day 1 of each cycle, and cycles will repeat every 21 
days unless there is a treatment delay. Please refer to 3.3 Schedule of Activities (SoA) for each 
visit window. 
10.5.1 
Part 1 (Dose-Escalation and RP2D Exploratory Cohort, Phase 1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 


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• 
 
  
  
  
 
 
 
 
 
 
  
 
 
 
  
  
 
  
 
    
   
 
  
 
Safety Follow-up 
Safety follow-up should be performed 3
 after the last administration of study 
drug or immediately before initiation of any other cancer therapies. 
• Complete physical examination, including measurement of weight, auscultation of the 
heart for new development of murmur (if physical or lab findings suggest cardiac 
damage, echocardiogram or MUGA should be done) 
• ECOG performance status  
• Vital signs 
• Laboratory tests 
• Serum pregnancy test in female patients of childbearing potential 
• 12-lead ECG  
• Concomitant medications  


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• AE assessments 
10.5.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  


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• Complete physical examination, including measurement of weight, auscultation of the 
heart for new development of murmur (if physical or lab findings suggest cardiac 
damage, echocardiogram or MUGA should be done) 
• ECOG performance status 
• Vital signs (including blood pressure, heart rate, respiratory rate, and temperature)  
• Laboratory tests: pre-dose 
• Serum pregnancy test in female patients of childbearing potential 
• 12-lead ECG: pre-dose 
• Return BBT-176 and diary review 
• BBT-176 and diary distribution 
• Whole blood sampling for ctDNA (every 6 weeks from Cycle 1 Day 1, within 7 days 
from Day 1 of odd number of cycles [Cycles 3, 5, 7, and so on]) 
• RECIST version 1.1 tumor assessment (every 6 weeks from Cycle 1 Day 1, within 7 days 
from Day 1 of odd number of cycles [Cycles 3, 5, 7, and so on])  
• Concomitant medications  
• AE assessments 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
  
 
 
  
 
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Safety follow-up should be performed 
 after the last administration of study 
drug or immediately before initiation of any other cancer therapies. 
• Complete physical examination, including measurement of weight, auscultation of the 
heart for new development of murmur (if physical or lab findings suggest cardiac 
damage, echocardiogram or MUGA should be done) 
• ECOG performance status  
• Vital signs 
• Laboratory tests 
• Serum pregnancy test in female patients of childbearing potential 
• 12-lead ECG  
• Concomitant medications  
• AE assessments 
10.6 
Adverse Events and Serious Adverse Events 
10.6.1 
Definition of Adverse Events (AE) 
The descriptions found in the revised NCI CTCAE version 5.0 will be utilized for AE reporting.  
In case of AE(s), investigators may perform unscheduled clinical examination(s), intervention(s), 
etc. for AE management. 
10.6.2 
Definition of Serious Adverse Events (SAE) 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: death, a life-threatening AE, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the participant and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. 
10.6.2.1 
Exceptional Events of SAE 
Following cases will not be considered as SAEs. These cases will be reported to Sponsor or 
Syneos Health same as Aes. 
• A routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
• An elective surgery or preplanned procedure to treat a pre-existing condition that is 
unrelated to the indication under study and has not worsened since signing the ICF. 
• A treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE and not resulting in hospital admission. 


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• Any social reasons and respite care, in the absence of any deterioration in the subject’s 
general condition. 
• Hospitalization for an event solely related to disease progression is not considered an 
SAE. 
• If progressive disease occurs and is associated with symptoms the meet the definition of 
SAE, the term “PD” should not be reported as SAE, however signs and symptoms of PD 
will be reported as an SAE. 
10.6.3 
Classification of an Adverse Event 
10.6.3.1 
Severity of Event 
The grading scales found in the revised NCI CTCAE version 5.0 will be utilized for AE scoring.   
10.6.3.2 
Relationship to Study Treatment 
All Aes will have their relationship to study treatment assessed as follows: 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment. 
• Unlikely – The AE is doubtfully related to the study treatment. 
• Unrelated – The AE is clearly NOT related to the study treatment. 
10.6.3.3 
Expectedness 
An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study treatment. 
10.6.4 
Time Period and Frequency for Event Assessment and Follow-up 
Assessments for Aes will be conducted on all study visits indicated in the SoA (Section 3.3). The 
PI will record all reportable events with start dates occurring any time after informed consent is 
obtained until 30 days (for non-serious Aes) after the last day of study participation or until 
resolution or stabilization (for SAEs). At each study visit, the Investigator will inquire about the 
occurrence of AE/ SAEs since the last visit. 
10.6.5 
Adverse Event Reporting 
All Aes occurring while on study must be documented appropriately regardless of relationship. 
Information to be collected includes event description, time of onset, clinician’s assessment of 
severity, relationship to study product, and time of resolution/stabilization of the event. Any 
medical condition that is present at the time of screening and is highly likely to have been 
present from before obtaining ICF will not be reported as an AE, but will be reported as part of 
medical history. However, if the study participant’s condition deteriorates at any time during the 
study, it will be recorded as an AE (worsening of the underlying disease or of other pre-existing 


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conditions will be recorded as an AE in the eCRF).  Changes in vital signs, ECG, physical 
examination, and lab test result deemed clinically significant by the Investigator will be recorded 
as AE in the eCRF. 
 
Collection and Reporting of PD: 
If progressive disease occurs and is associated with symptoms, the term “PD” should not be 
reported as an AE, however signs and symptoms of PD will be reported as an AE. 
10.6.6 
Serious Adverse Event Reporting 
Any SAE must be reported to the Sponsor or Syneos Health Safety and Pharmacovigilance 
within 24 hours of awareness of the event, whether or not considered study treatment-related, 
and must include an assessment of whether there is a reasonable possibility that the study 
treatment caused the event. 
Email Address: safetyreporting@syneoshealth.com 
Fax:  +1 877 464-7787 
The Investigator must complete, sign and date the SAE report form, verify the accuracy of the 
information recorded on the SAE report form with the corresponding source documents. 
All SAEs will be followed until satisfactory resolution or until the site Investigator deems the 
event to be chronic or the patient is stable. Other supporting documentation of the event may be 
requested by the Sponsor or Sponsor’s representative and should be provided as soon as possible. 
The Sponsor will be responsible for notifying the Regulatory agencies and all participating Pis of 
potential serious risks as soon as possible, but in no case later than 15 calendar days after the 
Sponsor/Investigator determines that the information qualifies for reporting (21 CFR 312.32I(1)). 
The Sponsor and Sponsor’s representative must notify the FDA and all participating PIs of any 
suspected unexpected fatal or life-threatening adverse reactions as soon as possible, but in no 
case later than 7 calendar days after the Sponsor’s initial receipt of the information (21 CFR 
312.32(c)(2)). 
10.6.7 
Reporting Events to Participants 
Not applicable. 
10.6.8 
Adverse Events of Special Interest 
DLT evaluation will occur in Part 1. Please refer to Section 10.2.2 for definition of DLTs. 
AEs of special interest (AESI) for the purposes of this study, based on the known safety profiles 
of EGFR inhibitors, include gastrointestinal (>Grade 2), skin (>Grade 2), pulmonary (≥Grade 2), 
and/or serious events requiring reporting to the Sponsor as an SAE.  


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Any laboratory hepatic toxicity meeting Hy’s law criteria for suspected severe drug induced 
liver injury, defined as a rise in serum aminotransferases (AST or ALT) of >3 × ULN and total 
bilirubin ≥2 × ULN, in the absence of any alternative reason (e.g., liver metastasis, liver disease, 
or concomitant medication), will also be considered an AESI. 
Protocol-specified AESI are to be reported in an expedited manner, similar to an SAE, even if 
they are not an SAE (within 24 hours). 
10.6.9 
Overdose 
Special situations including overdose are not in themselves AEs, but may result in AEs. 
An overdose in which signs, symptoms, or abnormalities meet the definition of an AE or SAE 
must be fully documented and reported consistent with AE and SAE reporting guidelines. 
10.6.10 
 Reporting of Pregnancy 
Although not an AE in and of itself, pregnancy as well as its outcome must be documented, as at 
least one of the study medications in this study is known to have risk of embryo-fetal toxicity. 
All female patients who are capable of becoming pregnant will be asked to provide consent to 
use a highly effective contraception to avoid pregnancy (for female patients a double-barrier 
method of contraception, for male patients a condom with spermicide) or total abstinence from 
the time of providing informed consent until 30 days after the last dose of study drug. Use of oral 
contraceptives is not allowed as a method of birth control. 
Reports of pregnancy of a patient or female partner must be reported and recorded on the 
Sponsor’s or Sponsor approved pregnancy form and must be submitted to Syneos Health Safety 
& Pharmacovigilance within 24 hours of awareness:  
Email Address: safetyreporting@syneoshealth.com  
Fax:  +1 877 464-7787 
 
 


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11 
STATISTICAL CONSIDERATIONS 
11.1 
Sample Size Determination 
11.1.1 
Part 1 
Dose-Escalation: up to 48 patients with locally advanced or metastatic NSCLC with EGFR 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
11.2 
Populations for Analysis 
 
 
 
 
 
 
 
  
  
 
  
 
 
  


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11.3 
Procedures for Handling Missing, Unused, and Spurious Data 
All available efficacy and safety data will be included in the data listings and tabulations. No 
imputation of values for missing data will be performed. 
11.4 
General Methodology 
 
 
  
 
 
 
 
11.5 
Baseline Comparison 
Demographic and baseline characteristics will be summarized by cohort. 
11.6 
Efficacy Analysis 
 
 
 
 
 
 
 
 
11.6.1 
Objective Response Rate 
 
 


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or-evaluable population by cohort, additionally. 80% 
confidence intervals will be provided. 
11.6.2 
Progression-Free Survival 
 
 
 
11.6.3 
Duration of Response 
 
 
 
 
 
11.7 
Safety Analysis 
Safety variables to be assessed will include AEs, laboratory test results (hematology, clinical 
chemistry, and urinalysis), ECG, weight, and vital signs. 
Adverse event terms recorded ion the eCRFs will be mapped to preferred terms using the 
Medical Dictionary for Drug Regulatory Activities (MedDRA®) version 23.0 or later. The 
number and percentage of patients with AEs will be summarized for each dose level and overall 
according to the system organ class and preferred term. Adverse events (including AESI) will be 
summarized for overall frequency (number and percentage of patients), worst reported severity, 
and relationship to study treatment for each preferred term per patient. Serious adverse events 
will be similarly summarized. Listings of deaths, SAEs, and AEs leading to early termination of 
study treatment or premature withdrawal from study will also be provided. 
Laboratory variables will be summarized using actual values and changes from baseline to 
scheduled time points. Laboratory values will also be categorized according to their CTCAE 
(v5.0) toxicity grade and tabulated by worst on-study toxicity grade. The baseline value of a 
variable is defined as the last value obtained on or before the date and time of the first BBT-176 
dose.  
ECG, weight, and vital signs will also be summarized by actual values and changes from 
baseline to scheduled time points using descriptive statistics. Changes in QTcF will also be 
evaluated for the proportion of patients with absolute values > 500 msec and change from 
baseline > 60 msec. 


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11.8 
Pharmacokinetic Analysis 
The PK profile of BBT-176 will be analyzed by measurement of area under the plasma 
concentration-time curve [(AUClast, AUCinf, AUCτ)], Cmax, Tmax, and T1/2. Ctrough will also be 
presented. Individual and mean concentration-time curves on linear and semi-logarithmic scales 
will be provided. 
11.9 
Pharmacodynamic Analysis 
All pharmacodynamics biomarker analyses will be based on the pharmacodynamics population. 
No formal statistical analysis of pharmacodynamics endpoints will be performed. 
Pharmacodynamics data from each assay will be listed by cohort and patient. Summary tables of 
values (n, mean, median, standard error of the mean, standard deviation) will be created for each 
pharmacodynamics biomarker. Exploratory analysis of the relationship between 
pharmacodynamic measurements and PK, efficacy, and safety profiles in patients may be 
performed. 
11.10 
Interim Analysis 
Interim analysis will be performed, if necessary. 
 
 
 
 


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12 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
12.1 
Informed Consent Process 
In obtaining and documenting informed consent, the Investigator must comply with applicable 
regulatory requirements (e.g., 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56) and should 
adhere to ICH Good Clinical Practice (GCP). Prior to the beginning of the trial, the Investigator 
should have the IRB’s written approval for the protocol and the written ICF(s) and any other 
written information to be provided to the participants. 
12.2 
Consent and Other Informational Documents Provided to Participants 
The IRB-approved ICF describing in detail the study treatment, study procedures, potential 
benefits and risks is to be given to the participant, and written documentation of informed 
consent is required prior to administering the study treatment.  
The ICF contains a statement that consent is freely given, that the patient is aware of the risks of 
entering the study, and that the patient is free to withdraw from the study at any time. Informed 
consent must be given by the patient and/or legal representative after the receipt of detailed 
information on the study. 
12.3 
Consent Procedures and Documentation 
The informed consent process will be initiated prior to the patient’s agreeing to participate in the 
study and continues throughout the patient’s study participation. Extensive discussion of risks 
and possible benefits of participation will be provided to the patients and their families.  
ICFs will be IRB-approved, and the patient will be asked to read and review the document. The 
Investigator will explain the research study to the patient and answer any questions that may 
arise. All patients will receive a verbal explanation in terms suited to their comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants. 
Patients will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The patients will have the opportunity to discuss the study with their family 
members or think about it prior to agreeing to participate. The patient will sign the ICF prior to 
any procedures being done specifically for the study.  
The patients may withdraw consent at any time throughout the course of the trial. A copy of the 
ICF will be given to the patients for their records. The rights and welfare of the patients will be 
protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
12.4 
Confidentiality and Privacy 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, the 
Sponsor, and their agents. This confidentiality is extended to cover testing of biological samples 


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and genetic tests in addition to the clinical information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study, or the data will be released to any 
unauthorized third party without prior written approval of the Sponsor. 
The study monitor, other authorized representatives of the Sponsor, representatives of the IRB or 
pharmaceutical company supplying study product may inspect all documents and records 
required to be maintained by the Investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records. 
Study participant contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by local IRB and Institutional regulations. 
12.5 
Data Handling 
Any data to be recorded directly on the eCRFs (to be considered as source data) will be 
identified at the start of the study. Data reported on the eCRF that are derived from source 
documents should be consistent with the source documents, or the discrepancies must be 
explained. See also Section 12.6.  
Clinical data will be entered by site personnel on eCRFs for transmission to the Sponsor. Data on 
eCRFs transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site, unless the study site makes direct data entry to the 
databases for which no other original or source documentation is maintained. In such cases, the 
study site should document which eCRFs are subject to direct data entry and should have in 
place procedures to obtain and retain copies of the information submitted by direct data entry. 
All study forms and records transmitted to the Sponsor must only include coded identifiers such 
that directly identifying personal information is not transmitted. The primary method of data 
transmittal is via the secure, internet-based electronic data capture (EDC) system maintained by 
Syneos Health. Access to the EDC system is available to only authorized users via the study’s 
internet web site, where a user unique assigned username and password are required for access. 
Any changes made to data after collection will be made through the use of the EDC system. 
Electronic CRFs will be considered complete when all missing and/or incorrect data have been 
resolved. 
As part of understanding the PK of the study drug, plasma samples may be used for metabolite 
identification and profiling evaluation. As part of understanding the efficacy and safety of the 
study drug, biopsy samples may be used for gene expression and profiling evaluation. Residual 
plasma and biopsy samples may be stored up to 5 years from study completion. If the residual 
samples are used, the results will be reported to the regulatory agencies. 


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12.6 
Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. The Investigator will provide direct 
access to source documents and/or source data in the facilitation of trial-related monitoring, 
audits, review by IECs/IRBs, and regulatory inspections. 
The Investigator/institution should maintain adequate and accurate source documents and trial 
records that include all pertinent observations on each of the site’s trial patients. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, not obscure the original entry, and be explained if necessary. 
12.7 
Record Retention 
Study records and source documents must be preserved for at least 2 years after the last 
marketing application approval in an ICH region or after at least 2 years have elapsed since 
formal discontinuation of clinical development of the investigational drug, and in accordance 
with the applicable local privacy laws, whichever is the longer time period. 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited to, the 
Standards for Individually Identifiable Health Information, 45 CFR, Parts 160 and 164 (the 
Health Insurance Portability Accountability Act of 1996 [HIPAA] Privacy Regulation). The 
Investigator shall ensure that study patients authorize the use and disclosure of protected health 
information in accordance with HIPAA Privacy Regulation and in a form satisfactory to the 
Sponsor. 
12.8 
Safety Monitoring Committee 
The study will be monitored by an SMC comprised of the PI for each site, the CRO Medical 
Monitor, and a Sponsor representative(s) or designee. During the trial, all SAEs and potential 
DLTs, as well as any PK results, will be sent to the SMC on a continual basis. The SMC may 
choose more conservative dosing decisions or stopping rules for the dose-escalation cohorts. The 
patients who exercised the option of intra-patient dose escalation will be monitored by the SMC 
as well. Ad hoc SMC meeting may be convened to discuss potential DLT cases more in depth.  
In Part 1 of the trial (dose-escalation cohorts), the SMC will decide the dose of BBT-176 for the 
next cohort, as well as define the MTD, based on available PK, statistical assistance tool (BLRM 
or mTPI-2), safety findings. The RP2D may be set lower than the MTD if there are concerns 
about tolerability or if the analysis of biomarker and pharmacodynamic data suggests a lower 
dose would be appropriate.  
In RP2D exploratory cohort, SMC will make balanced evaluation and recommendation about 
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When clinical data of at least six patients are available from each of two subgroups of this 
cohort, then SMC will convene and review; will recommend the Sponsor to continue or 
discontinue each of these cohorts.  
When clinical data of at least twelve patients are available from each of two subgroups , then 
SMC will convene and review; will recommend to the Sponsor, RP2D for further evaluation in 
Part 2.  
Even after RP2D is determined, the Sponsor may continue to enroll patients into RP2D 
exploratory cohort up to 30 patients in each cohort. 
In Part 2 of the trial (enrichment), the SMC will continually review the safety of BBT-176.  
The SMC will assess safety data and operate under the rules of an approved charter that will be 
written and reviewed at the inception of the SMC. At that time, each data element that the SMC 
needs to assess will be clearly defined. The SMC will provide its input to the Sponsor and CRO 
as needed. 
Further information describing the SMC scope and procedures will be provided in the SMC 
Charter. 
12.9 
Clinical Monitoring 
The Sponsor has engaged the services of a CRO, to perform all monitoring functions within this 
clinical study. CRO monitors will work in accordance with CRO Standard Operating Procedures 
(SOPs) and have the same rights and responsibilities as monitors from the Sponsor organization. 
Monitors will establish and maintain regular contact between the Investigator and the Sponsor. 
Monitors will evaluate the competence of each study center, informing the Sponsor about any 
problems relating to facilities, technical equipment or medical staff. During the study, monitors 
will check that written informed consent has been obtained from all patients correctly and that 
data are recorded correctly and completely. Monitors are also entitled to compare entries in 
eCRFs with corresponding source data and to inform the Investigator of any errors or omissions. 
Monitors will also ensure adherence to the protocol at the study center. They will arrange for the 
supply of study treatment and ensure appropriate storage conditions are maintained. 
Monitoring visits will be conducted according to all applicable regulatory requirements and 
standards. Regular monitoring visits will be made to each center while patients are enrolled in 
the study. The monitor will make written reports to the Sponsor on each occasion contact with 
the Investigator is made, regardless of whether it is by phone or in person. 
During monitoring visits, entries in the eCRFs will be compared with the original source 
documents (source data verification) including, but not limited to:  
a. Patient identification number 
b. Patient consent obtained 


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c. Patient eligibility criteria (inclusion and exclusion criteria) 
d. Efficacy variables 
e. Medical record of AE 
12.10 
Quality Assurance and Quality Control 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation, and completion. An individualized quality management 
plan will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
at each stage of data handling. Any missing data or data anomalies will be communicated to the 
site(s) for clarification/resolution.  
The Sponsor (or designated CRO) is responsible for implementing and maintaining quality 
assurance (QA) and QC systems with written SOPs. In accordance with the written SOPs, 
monitors will verify that the clinical trial is conducted, data are generated, and biological 
specimens are collected, recorded, and reported in compliance with the protocol, ICH GCP, and 
applicable regulatory requirements (e.g., GLP, Good Manufacturing Practice [GMP]). The 
Sponsor and monitor will determine the frequency of monitoring visits. 
During the study, the Sponsor may conduct audits separately from routine monitoring. The 
investigational site will provide direct access to all trial-related sites, source data/documents, and 
reports for routine monitoring and/or auditing by the Sponsor, and inspection by local and 
regulatory authorities. 
12.11 
Protocol Deviations and GCP Non-Compliance 
A protocol deviation is any noncompliance to the clinical trial protocol and non-compliance with 
ICH/GCP; both will be monitored and reported as per local regulations. The non-compliance 
may be on the part of the patient, the Investigator, or the study site/CRO staff. Protocol 
deviations must be documented, and corrective actions have to be developed and implemented 
promptly.  
It is the responsibility of the site Investigator to use continuous vigilance to identify and report 
deviations timely. All deviations must be addressed in study source documents and reported to 
the monitor and/or Sponsor. Protocol deviations must be sent to the reviewing IRB per their 
policies. The site Investigator is responsible for knowing and adhering to the reviewing IRB 
requirements.  
For protocol deviations deemed to have no influence on the interpretation of study results, the 
level and reason of deviation or delay will be accurately described and comprehensively 
considered by the Investigator, Sponsor, monitor, or statistician. 


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Protocol waivers are not permitted. Neither CRO nor Sponsor approves of protocol waivers, as 
per GCP and regulatory guidelines. All major protocol deviations should be listed in the Clinical 
Study Report. 
 
12.12 
Publication and Data Sharing Policy 
The data generated by this study are the proprietary information of the Sponsor. Public 
disclosure of study data may include publication in a peer-reviewed journal.  
 
12.13 
Conflict of Interest Policy 
Actual or perceived conflict of interest of persons who have a role in the design, conduct, 
analysis, publication, or any aspect of this trial will be disclosed and managed. 
 
12.14 
Abbreviations 
ADSP 
Adaptive Study Design Plan 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANC 
Absolute Neutrophil Count 
ATP 
Adenosine Triphosphate 
AUC 
Area Under the Concentration-Time Curve 
 
 
 
y  
CFR 
Code Of Federal Regulations 
CI 
Confidence Interval 
Cmax 
Peak Concentration 
CR 
Complete Response 
CRO 
Contract Research Organization 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
 
 
DLT 
Dose Limiting Toxicity 
DoR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EF 
Ejection Fraction 
EGFR 
Epidermal Growth Factor Receptor 
EOT 
End of Treatment 
EWOC 
Escalation with Overdose Control 


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FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HED 
Human Equivalent Dose 
HIV 
Human Immunodeficiency Virus 
HNSTD 
Highest Non-Severely Toxic Dose  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
ILD 
Interstitial Lung Disease 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
IWRS 
Interactive Web Response System 
 
LH 
Luteinizing Hormone 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
MTPI-2 
Modified Toxicity Probability Interval-2 
MUGA 
Multi-gated Acquisition  
NOAEL 
No Observed Adverse Effect Level 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
PBPK 
Physiologically Based PK 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PR 
Partial Response 
PSA  
Prostate Specific Antigen 
QA 
Quality Assurance 
QC 
Quality Control 
QD 
Once daily 
QTc 
corrected QT Interval 
QTcF 
QT Interval Corrected Using Fridericia’s Formula 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SMC 
Safety Monitoring Committee 
SoA 
Schedule of Activities 


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SOP 
Standard Operating Procedure 
STD 
Severely Toxic Dose 
T1/2 
Half-life 
TKI 
Tyrosine Kinase Inhibitor 
Tmax 
Time to Peak Concentration 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
 


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12.15 
Protocol Amendment History 
Version 
Date 
Description of Change 
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Version 
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Brief Rationale 
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Date 
Description of Change 
Brief Rationale 
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Description of Change 
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Version 
Date 
Description of Change 
Brief Rationale 
and appropriate treatment should be instituted as 
n
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Brief Rationale 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Brief Rationale 
Screening and every 2 cycles (same with 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Brief Rationale 
 
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13 
REFERENCES 
AstraZeneca Pharmaceuticals. Tagrisso (osimertinib) Prescribing Information. November 2015 
Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results 
from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel 
in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin 
Oncol. 2011 Jul 20;29(21):2866-2874 
Gettinger, Scott N., et al. Activity and safety of brigatinib in ALK-rearranged non-small-cell lung 
cancer and other malignancies: a single-arm, open-label, phase 1/2 trial. The Lancet Oncology 
2016; 17.12: 1683-1696 
Janne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung 
cancer. N Engl J Med. 2015 Apr 30;372(18):1689-1699 
Liu L, Liu J, Shao D, et al. Comprehensive genomic profiling of lung cancer using a validated 
panel to explore therapeutic targets in East Asian patients. Cancer Sci. 2017 Dec;108(12):2487-
2494 
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin paclitaxel in pulmonary 
adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-957 
Neuenschwander, Beat, Michael Branson, and Thomas Gsponer. Critical aspects of the Bayesian 
approach to phase I cancer trials. Statistics in medicine. 2008;27.13: 2420-2439 
O'Quigley J, Pepe M, and Fisher L. Continual reassessment method: a practical design for phase 
1 clinical trials in cancer. Biometrics. 1990 Mar;46(1):33-48 
Piantadosi S, Fisher JD, and Grossman S. Practical implementation of a modified continual 
reassessment method for dose-finding trials. Cancer Chemother Pharmacol. 1998;41(6):429-36 
Rangachari D, To C, Shpilsky JE, et al. EGFR-mutated lung cancers resistant to osimertinib 
through EGFR-C797S respond to first-generation reversible EGFR inhibitors but eventually 
acquire EGFR-T790M/C797S in preclinical models and clinical samples. J Thorac Oncol. 2019; 
Nov:14(11):1995-2002 
Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line 
treatment for European patients with advanced EGFR mutation-positive non-small-cell lung 
cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 
Mar;13(3):239-246 
Rotow J and Bivona TG. Understanding and targeting resistance mechanisms in NSCLC. Nat Rev 
Cancer. 2017 Oct 25;17(11):637–658 
Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR -mutated non–small-cell lung 
cancer. N Engl J Med. 2015 Apr 30;372(18):1700-1709 


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Takeda Pharmaceutical Company Limited. Alunbrig (brigatinib) Prescribing Information. 
December 2018 
Thress KS, Paweletz CP, Felip E, et al. Acqired EGFR C797S mediates resistance to AZD9291 in 
advanced non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015 Jun;21(6):560-562 
Wang Z, Yang JJ, Huang J, et al. Lung adenocarcinoma harboring EGFR T790M and in trans 
C797S responds to combination therapy of first and third generation EGFR-TKIs and shifts allelic 
configuration at resistance. J Thorac Oncol. 2017 Nov;12(11):1723−1727 
Guo W, Wang SJ, Yang S, et al. A Bayesian interval dose-finding design addressing Ockham’s 
razor: mTPI-2. Contemp Clin Trials. 2017;58:23-33 
Razelle K, Chia-Chi L, et al. Moving Beyond 3+3: The Future of Clinical Trial Design 2021 
ASCO EDUCATIONAL BOOK  May 2021; https:// doi.org/10.1200/ EDBK_319783 
 
 
 
 
 
 
 
 


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14 
APPENDICES 
Appendix 1. Signature of Investigator 
Appendix 2. Eastern Cooperative Oncology Group (ECOG) Performance Status 
Appendix 3. Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) 
Appendix 4. List of CYP3A4 Substrates With Narrow Therapeutic Index, CYP2C8 Strong 
Inhibitor, and P-gp Inhibitor 
Appendix 5. Decision rules for dose escalation derived from the modified toxicity 
probability interval-2 (mTPI-2) method 
 
 


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Appendix 1. Signature of Investigator 
Protocol Title:  A Phase 1/2, Open-Label Study to Assess the Safety, Tolerability, Pharmacokinetics, 
and Anti-tumor Activity of BBT-176 in Patients with Advanced Non-Small Cell Lung Cancer 
(NSCLC) who Progressed Following Prior Therapy with an Epidermal Growth Factor Receptor 
Tyrosine Kinase Inhibitor (EGFR TKI) Agent 
 
Protocol Number:  
BBT176-ONC-001 
 
This protocol is a confidential communication of Bridge Biotherapeutics, Inc. I confirm that I have 
read this protocol, I understand it, and I will work according to this protocol. I will also work 
consistently with the ethical principles that have their origin in the Declaration of Helsinki and that 
are consistent with Good Clinical Practice and the applicable laws and regulations. Acceptance of 
this document constitutes my agreement that no unpublished information contained herein will be 
published or disclosed without prior written approval from the Sponsor. 
 
Instructions to the Investigator:  Please SIGN and DATE this signature page. PRINT your name, 
title, and the name of the center in which the study will be conducted. Return the signed copy to the 
CRO. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
 
 
Signature of Investigator: 
________________________________ 
Date: _____________ 
 
 
Printed Name:  
 
________________________________ 
 
 
Name of Center: 
 
________________________________ 
 
 
 


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Appendix 2. Eastern Cooperative Oncology Group (ECOG) Performance Status 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.1982;5:649-55.


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Appendix 3. Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) 
The text below was obtained from the following reference:  
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). European Journal of Cancer.2009;45:228-247. 
DEFINITIONS 
Response and progression will be evaluated in this trial using the international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1). Changes in only the 
largest diameter (uni-dimensional measurement) of the tumor lesions are used in the RECIST criteria. 
Note: Lesions are either measurable or non-measurable using the criteria provided below. The term 
“evaluable” in reference to measurability will not be used because it does not provide additional meaning 
or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
• 
10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice thickness 
and a minimum of 10 mm). 
• 
20 mm by chest X ray (if clearly defined and surrounded by aerated lung). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be 
≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow up, only the short axis will be measured and followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter ≥ 10 to < 15 mm with 
conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable disease. 
Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical examination that is not measurable by reproducible imaging techniques are all non-measurable. 
Bone lesions: 
• 
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance of 
bone lesions 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can 
be evaluated by cross sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
• 
Blastic bone lesions are non-measurable. 
Cystic lesions: 


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• 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non measurable) since they are, by definition, 
simple cysts. 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
locoregional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Trial protocols should detail the conditions under which such lesions 
would be considered measurable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be identified 
as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organ, but in addition 
should be those that lend themselves to reproducible repeated measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be visible by 
imaging even if not involved by tumor. Pathological nodes which are defined as measurable and may be 
identified as target lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. Only the short 
axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported as 2 
dimensions in the plane in which the image is obtained (for CT scan this is almost always the axial plane; 
for MRI the plane of acquisition may be axial, sagittal, or coronal). The smaller of these measures is the 
short axis. For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis 
of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as 
the node measurement. All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should 
be considered non target lesions. Nodes that have a short axis < 10 mm are considered non pathological 
and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then as noted above, only the short axis is added into the sum. The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
Non-target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-
target lesions and should also be recorded at baseline. Measurements are not required and these lesions 
should be followed as “present”, “absent”, or in rare cases “unequivocal progression” (more details to 
follow). In addition, it is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g., “multiple enlarged pelvic lymph node” or “multiple liver 
metastases”). 


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GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 4 weeks 
before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging based evaluation should always be done 
rather than clinical examination unless the lesion(s) being followed cannot be imaged but are assessable 
by clinical examination. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. As is described in Appendix II of the original source 
article cited above, when CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g., 
for body scans). 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not advised. 
However, they can be useful to confirm complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete response or surgical resection is an 
endpoint. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare cases if 
required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where known 
residual benign tumors can remain). When effusions are known to be a potential adverse effect of 
treatment (e.g., with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation 
of the neoplastic origin of any effusion that appears or worsens during treatment can be considered if the 
measurable tumor has met criteria for response or stable disease in order to differentiate between response 
(or stable disease) and progressive disease. 
RESPONSE CRITERIA 
 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to < 10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of one or more new lesions is also considered progression). 
 


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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even if the 
nodes regress to below 10 mm on study. This means that when lymph nodes are included as target 
lesions, the “sum” of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and PD, the 
actual short axis measurement of the nodes is to be included in the sum of target lesions. 
 
Target lesions that become “too small to measure”. While on study, all lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, even 
when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes which are recorded as target 
lesions at baseline become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being “too small to measure”. When this occurs it is important that 
a value be recorded in the eCRF. If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned (Note: It is less likely 
that this rule will be used for lymph nodes since they usually have a definable size when normal and are 
frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness (but should not be 
changed with varying CT slice thickness). The measurement of these lesions is potentially non-
reproducible, therefore providing this default value will prevent false responses or progressions based 
upon measurement error. To reiterate, however, if the radiologist is able to provide an actual measure, that 
should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions “fragment”, the longest diameters of 
the fragmented portions should be added together to calculate the target lesion sum. Similarly, as lesions 
coalesce, a plane between them may be maintained that would aid in obtaining maximal diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal longest diameter for 
the “coalesced lesion”. 
 
Evaluation of Non-target Lesions 
 
While some non-target lesions may actually be measurable, they need not be measured and instead should 
be assessed only qualitatively at the time points specified in the protocol. 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
 


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Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered progression). 
 
When the patient also has measurable disease. In this setting, to achieve “unequivocal progression” on the 
basis of the non-target disease, there must be an overall level of substantial worsening in non-target 
disease such that, even in presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest “increase” in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of target disease 
will therefore be extremely rare. 
 
When the patient has only non-measurable disease. This circumstance arises in some phase 3 trials when 
it is not a criterion of trial entry to have measurable disease. The same general concept apply here as 
noted above, however, in this instance there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden. Because worsening in non-target disease 
cannot be easily quantified (by definition: if all lesions are truly non-measurable) a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in magnitude to the increase 
that would be required to declare PD for measurable disease: i.e., an increase in tumor burden 
representing an additional 73% increase in “volume” (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from “trace” to “large”, an 
increase in lymphangitic disease from localized to widespread, or may be described in protocols as 
“sufficient to require a change in therapy”. If “unequivocal progression” is seen, the patient should be 
considered to have had overall PD at that point. While it would be ideal to have objective criteria to apply 
to non-measurable disease, the very nature of that disease makes it impossible to do so, therefore the 
increase must be substantial. 
 
New Lesions 
 
The appearance of new malignant lesions denotes disease progression; therefore, some comments on 
detection of new lesions are important. There are no specific criteria for the identification of new 
radiographic lesions; however, the finding of a new lesion should be unequivocal: i.e., not attributable to 
differences in scanning technique, change in imaging modality or findings thought to represent something 
other than tumor (for example, some “new” bone lesions may be simply healing or flare of pre-existing 
lesions). This is particularly important when the patient’s baseline lesions show partial or complete 
response. For example, necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic 
lesion, which it is not. 
 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. An example of this is the patient who has 


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visceral disease at baseline and while on trial has a CT or MRI brain ordered which reveals metastases. 
The patient’s brain metastases are considered to be evidence of PD even if he/she did not have brain 
imaging at baseline. 
 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. 
 
While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate 
the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible “new” disease). New lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm: 
• 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. 
• 
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-
PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans 
are needed to determine if there is truly progression occurring at that site (if so, the date of PD 
will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the study drug treatment until the 
end of treatment taking into account any requirement for confirmation. On occasion a response may not 
be documented until after the end of therapy so protocols should be clear if post-treatment assessments 
are to be considered in determination of best overall response. Protocols must specify how any new 
therapy introduced before progression will affect best response designation. The patient’s best overall 
response assignment will depend on the findings of both target and non-target disease and will also take 
into consideration the appearance of new lesions. Furthermore, depending on the nature of the trial and 
the protocol requirements, it may also require confirmatory measurement. Specifically, in non-
randomized trials where response is the primary endpoint, confirmation of PR or CR is needed to deem 
either one the “best overall response”. 
 
The best overall response is determined once all the data for the patient are known. Best response 
determination in trials where confirmation of complete or partial response IS NOT required: Best 
response in these trials is defined as the best response across all time points (for example, a patient who 
has SD at first assessment, PR at second assessment, and PD on last assessment has a best overall 
response of PR). When SD is believed to be best response, it must also meet the protocol specified 
minimum time from baseline. If the minimum time is not met when SD is otherwise the best time point 
response, the patient’s best response depends on the subsequent assessments. For example, a patient who 
has SD at first assessment, PD at second and does not meet minimum duration for SD, will have a best 


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response of PD. The same patient lost to follow-up after the first SD assessment would be considered 
inevaluable. 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR* 
CR 
CR 
PR 
 
SD 
 
Not all evaluated 
PD 
Any 
Any 
CR 
Non-CR/non-PD 
Not evaluated 
Non-PD or not all 
evaluated 
Non-PD or not all 
evaluated 
Non-PD 
Any 
PD 
Any 
No 
No 
No 
No 
 
No 
 
No 
Yes or No 
Yes or No 
Yes 
CR 
PR 
PR 
PR 
 
SD 
 
NE 
PD 
PD 
PD 
* CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; and NE 
= invaluable. See text for more details. 
Note:  When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based on 
increase in size of the nodes. As noted earlier, this means that patients with CR may not have a total sum 
of “zero” in the eCRF. 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in most 
trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a confirmed 
response. 
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic deterioration”. 
Every effort should be made to document objective progression even after discontinuation of treatment. 
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for stopping trial 
therapy. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of complete response. FDG-
PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual 
radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and supported by disease-specific medical 
literature for the indication. However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 


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For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes, or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next 
scheduled assessment, progression is confirmed, the date of progression should be the earlier date when 
progression was suspected. 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
 
Confirmation 
 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is required 
to ensure that the identified responses are not the result of measurement error. This will also permit 
appropriate interpretation of results in the context of historical data where response has traditionally 
required confirmation in such trials. However, in all other circumstances, i.e., in randomized trials (phase 
2 or 3) or trials where stable disease or progression are the primary endpoints, confirmation of response is 
not required since it will not add value to the interpretation of trial results. However, elimination of the 
requirement for response confirmation may increase the importance of central review to protect against 
bias, in particular in trials which are not blinded. 
 
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a minimum 
interval (in general not less than 6 to 8 weeks) that is defined in the trial protocol. 
 
Duration of Overall Response 
 
The duration of overall response is measured from the time that measurement criteria are first met for 
CR/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 on study). 
 
The duration of overall complete response is measured from the time measurement criteria that 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 (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on study (if 
the baseline sum is the smallest, this is the reference for calculation of PD). 
 
The clinical relevance of the duration of stable disease varies in different studies and diseases. If the 
proportion of patients achieving stable disease for a minimum period of time is an endpoint of importance 
in a particular trial, the protocol should specify the minimal time interval required between two 
measurements for determination of stable disease. 
 
Note: The DoR and stable disease as well as the PFS are influenced by the frequency of follow-up after 
baseline evaluation. It is not in the scope of this guideline to define a standard follow-up frequency. The 
frequency should take into account many parameters including disease types and stages, treatment 


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periodicity, and standard practice. However, these limitations of the precision of the measured endpoint 
should be taken into account if comparisons between trials are to be made.


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SAP_003.pdf: 
 
1
 
 
 
Statistical Analysis Plan 
 
 
 
 
 
A Phase 1/2, Open-Labeled Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Anti-tumor Activity of BBT-176 in Patients with Advanced 
Non-Small Cell Lung Cancer (NSCLC) who Progressed Following Prior Therapy 
with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor  
(EGFR TKI) Agent  
 
 
 
 
 
 
 
 
 
 
Bridge Biotherapeutics, Inc 
 
 
 
 
  Protocol BBT176-ONC-001 
 
 
 
 
 
 
Protocol Version 
 
 
  
 
Statistical Analysis PlanVersion 1.0 
28 JAN  2021 
 
 


STATISTICAL ANALYSIS PLAN
BBT176-ONC-001 
 
2
 
Contents 
 
Signature Page .................................................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................. 5 
1. INTRODUCTION .......................................................................................................................... 7 
2. SUMMARY OF KEY PROTOCOL INFORMATION .............................................................. 7 
2.1   Study Objectives and Endpoints ........................................................................................................ 7 
2.1.1   Primary Objectives ......................................................................................................................... 7 
2.1.2   Secondary Objectives ..................................................................................................................... 7 
2.1.3   Exploratory Objectives ................................................................................................................... 8 
2.2   Study Design ......................................................................................................................................... 8 
2.2.1   Part 1 Study Design: Dose-Escalation Study ................................................................................. 9 
2.2.2   Part 1 Study Design: RP2D Exploration study............................................................................. 11 
2.2.3  
............................................................................... 11 
2.3   Schedule of Activities (SOA) ............................................................................................................. 11 
3. DETERmination of sample size .................................................................................................. 15 
3.1   Part 1 ................................................................................................................................................... 15 
3.2  
................................................................................................................................................... 15 
4. GENERAL ANALYSIS CONSIDERATION............................................................................ 16 
4.1   Data Summaries ................................................................................................................................. 16 
4.2   Data Handling .................................................................................................................................... 16 
4.2.1   Baseline Value .............................................................................................................................. 16 
4.2.2   Conventions .................................................................................................................................. 17 
4.2.3   Standard Calculations ................................................................................................................... 17 
5. ANALYSIS POPULATION ........................................................................................................ 18 
6. STUDY POPULATION............................................................................................................... 18 
6.1   Patient Disposition ............................................................................................................................. 18 
6.2   Demographic and Baseline Characteristics ..................................................................................... 19 
6.3   Medical History .................................................................................................................................. 19 
6.4   Prior and Concomitant Medication ................................................................................................. 19 
7. Efficacy Analyses .......................................................................................................................... 19 
7.1   Tumor Response ................................................................................................................................ 20 
7.1.1   Overall Time Point Response ....................................................................................................... 20 
7.1.2   Best Response ............................................................................................................................... 21 
7.1.3   Best Overall Response .................................................................................................................. 23 
7.2   Objective Response Rate (ORR) ...................................................................................................... 23 
7.3   Duration of Response (DoR) ............................................................................................................. 23 
7.4   Progression-Free Survival (PFS) ...................................................................................................... 23 
7.5   Handling Missing, Unused, and Spurious Data .............................................................................. 24 
7.6  
................................................................................................................................. 24 
7.7   Methods of Efficacy Analysis ............................................................................................................ 24 
8. Pharmacokinetic (PK) Analyses ................................................................................................. 24 
8.1   PK Sampling Schedule ...................................................................................................................... 25 
8.2   Handling of the Below the Lower Limit of Quantification (BLQ) and the No Reportable 
Concentration Values ................................................................................................................................ 25 


STATISTICAL ANALYSIS PLAN V1.0 
BBT176-ONC-001 
 
3
8.3   Handling of the Difference between the Scheduled and the Actual Sampling Times ................. 25 
8.4   Plasma PK Endpoints ........................................................................................................................ 25 
8.5   Statistical Analyses ............................................................................................................................ 27 
9. Pharmacodynamic (PD) Analyses .............................................................................................. 29 
10. Safety Analyses ........................................................................................................................... 30 
10.1   Extent of Exposure........................................................................................................................... 30 
10.2   Adverse Events (AEs) ...................................................................................................................... 30 
10.3   Clinical Laboratory Evaluations .................................................................................................... 31 
10.4   Vital Signs ......................................................................................................................................... 31 
10.5   Physical Examination ...................................................................................................................... 31 
10.7   Eastern Cooperative Oncology Group (ECOG) ........................................................................... 32 
REFERENCES ................................................................................................................................. 33 
Appendix 1. Partial Date Conventions ........................................................................................... 34 
Appendix 2. Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) ................ 36 
Appendix 3. Eastern Cooperative Oncology Group (ECOG) Performance Status ................... 44 
 
 
 


STATISTICAL ANALYSIS PLAN
BBT176-ONC-001 
 
4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN
BBT176-ONC-001 
 
5
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation Definition 
AE 
 
Adverse Event 
ANC  
Absolute Neutrophil Count 
ATC  
Anatomical Therapeutic Chemical 
AUC  
Area Under the Concentration-Time Curve 
 
BMI 
 
Body Mass Index 
CI 
 
Confidence Interval 
Cmax  
Peak Concentration 
CR 
 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Event 
ctDNA  
Circulating Tumor DNA 
DLT 
 
Dose Limiting Toxicity 
DoR 
 
Duration of Response 
ECG  
Electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
eCRF  
Electronic Case Report Form 
EGFR  
Epidermal Growth Factor Receptor 
EOT 
 
End of Treatment 
 
HCV  
Hepatitis C Virus 
HED  
Human Equivalent Dose 
HIV 
 
Human Immunodeficiency Virus 
ICH 
 
International Conference on Harmonisation 
IV 
 
Intravenous(ly) 
 
 
MTD  
Maximum Tolerated Dose 
MUGA 
Multi-gated Acquisition 
NCI 
 
National Cancer Institute 
NE 
 
Not Evaluable 
NSCLC 
Non-Small Cell Lung Cancer 
ORR  
Objective Response Rate 
PD 
 
Progressive Disease 
PFS 
 
Progression-Free Survival 
PK 
 
Pharmacokinetics 
PD 
 
Pharmacodynamics 
PP 
 
Per Protocol 
PR 
 
Partial Response 
PS 
 
Performance Status 
QTc 
 
corrected QT (interval) 
QTcF  
QT Interval Corrected Using Fridericia9s Formula 
RECIST 
Response Evaluation Criteria In Solid Tumors 


STATISTICAL ANALYSIS PLAN 
BBT176-ONC-001 
 
6
RP2D  
Recommended Phase 2 Dose 
SAE 
 
Serious Adverse Event 
SD 
 
Stable Disease 
SMC  
Safety Monitoring Committee 
SoA 
 
Schedule of Activities 
T1/2 
 
Half-life 
 
AESI  
Adverse Event of Special Interest 
TKI 
 
Tyrosine Kinase Inhibitor 
Tmax  
Time to Peak Concentration 
WHO  
World Health Organization 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
BBT176-ONC-001 
 
7
1. INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of Bridge Biotherapeutics Protocol Number BBT176-ONC-001 entitled 
<A Phase 1 / 2, Open-Label Study to Assess the Safety, Tolerability, Pharmacokinetics, and Anti-
tumor Activity of BBT-176 in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) 
who Progressed Following Prior Therapy with an Epidermal Growth Factor Receptor Tyrosine 
Kinase Inhibitor (EGFR TKI) Agent.=  The statistical methods described herein are based on the 
analyses proposed in the Protocol version
This study is designed in 2 parts 
designated Part 1 (dose-escalation study) and Part 2
 
 
 
2. SUMMARY OF KEY PROTOCOL INFORMATION  
 
2.1   Study Objectives and Endpoints 
 
2.1.1   Primary Objectives 
 
Table 1 shows the primary objectives and endpoints of Part 1 (dose-escalation study). 
 
Table 1. Part 1 Primary Objectives and Endpoints 
Part 1 Primary Objectives 
Endpoints 
• 
To investigate the safety and tolerability of BBT-
176 when given orally alone or in combination 
with cetuximab to patients with locally advanced 
or metastatic NSCLC with EGFR mutation 
• 
To determine the MTD and/or RP2D of BBT-176 
 
Incidence of adverse events [AEs] and clinical 
laboratory abnormalities defined as DLTs 
 
Table 2 shows the primary objectives and endpoints of Part 2
 
 
Table 2. Part 2 Primary Objectives and Endpoints 
Part 2 Primary Objectives 
Endpoints 
To evaluate the anti-tumor activity of BBT-176 in 
selected mutant types by evaluation of ORR using 
RECIST version 1.1  
Objective Response Rate [ORR] per RECIST version 
1.1 
 
 
2.1.2   Secondary Objectives 
 
Table 3 shows the secondary objectives and endpoints of Part 1
. 
 
Table 3. Secondary Objectives and Endpoints 
Part 1 Secondary Objectives 
Endpoints 
• 
To characterize the PK profile of BBT-176 after a 
single oral dose and steady state after multiple 
doses when given orally alone and in combination 
with cetuximab  
• 
Plasma concentrations of BBT-176 
• 
PK parameters (t1/2, Cmax, tmax, AUC, Ctrough) 


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• 
To evaluate the anti-tumor activity of BBT-176 in 
selected mutant types by evaluation of the ORR 
using RECIST version 1.1 
• 
ORR per RECIST version 1.1 
 
 
Table 4 shows the secondary objectives and endpoints of Part 2
 
 
Table 4. Secondary Objectives and Endpoints 
Part 2 Secondary Objectives 
Endpoints 
• 
To evaluate the anti-tumor activity of BBT-176 in 
selected mutant types by evaluation of the Duration 
of Response (DoR) and the Progression-Free 
Survival (PFS) using RECIST version 1.1  
• 
DoR per RECIST version 1.1 
• 
PFS per RECIST version 1.1 
• 
To evaluate the safety and tolerability of BBT-176 
at the PR2D 
• 
Incidence of adverse events [AEs] and clinical 
laboratory abnormalities defined as DLTs 
• 
To characterize the snapshot PK of BBT-176 at 
steady sate after multiple oral doses 
• 
Plasma BBT-176 concentrations at steady state 
• 
PK parameters (Cmax, tmax) 
 
 
2.1.3   Exploratory Objectives 
 
Table 5 shows the exploratory objectives and endpoints of Part 1 (dose-escalation study). 
 
Table 5. Exploratory Objectives and Endpoints 
Part 1 Exploratory Objectives 
Endpoints 
• 
To investigate the DoR and PFS using RECIST 
version 1.1 
• 
DoR per RECIST version 1.1 
• 
PFS per RECIST version 1.1 
• 
To investigate the relationship between the anti-
tumor activity and blood-borne biomarkers (i.e., 
circulating-tumor DNA [ctDNA]) 
• 
Pharmacodynamic biomarker (ctDNA) 
 
 
Table 6 shows the exploratory objectives and endpoints of Part 2
 
 
Table 6. Exploratory Objectives and Endpoints 
Part 2 Exploratory Objectives 
Endpoints 
• 
To investigate the relationship between the anti-
tumor activity and blood-borne biomarkers (i.e., 
circulating-tumor DNA [ctDNA]) 
• 
Pharmacodynamic biomarker (ctDNA) 
 
 
 
2.2   Study Design  
 
 
 


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2.2.1   Part 1 Study Design: Dose-Escalation Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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o 
 
 
 
 
 
 
 
 
 
2.2.2   Part 1 Study Design: RP2D Exploration study 
 
 
 
 
 
 
 
 
 
 
2.2.3   Part 2 Study Design:
 
 
 
 
 
 
 
 
 
 
 
 
   
 
2.3   Schedule of Activities (SOA) 
 
 
 
 
yond 


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3. DETERMINATION OF SAMPLE SIZE 
 
3.1   Part 1 
 
Dose-Escalation: up to
patients with locally advanced or metastatic NSCLS with EGFR 
mutation are planned for enrollment.
 
 
 
 
3.2   Part 2 
 
 
 
 
 
 
 
 
 
 
 
 


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4. GENERAL ANALYSIS CONSIDERATION 
 
4.1   Data Summaries 
The statistical analyses will be reported using summary tables, figures, and data listings. The 
International Conference on Harmonization (ICH) numbering convention will be used for all 
tables, listings, and figures. Unless otherwise specified, all statistical testing will be two-sided 
and will be performed at the 0.05 significance level. Unless otherwise specified, all confidence 
intervals (CIs) will be constructed at the 95% confidence level.  
 
The results of the statistical analyses will be reported using summary tables, figures, and data 
listings. The International Conference on Harmonization (ICH) numbering convention will be 
used for all tables, listings, and figures. 
 For other estimates, unless otherwise 
specified, 95% CIs will be provided. 
 
Continuous variables will be summarized with means, standard deviations, medians, minimums, 
and maximums. Categorical variables will be summarized by counts and by percentages of 
patients in corresponding categories. Time-to-event variables will be summarized using the 
Kaplan-Meier estimates. All summary tables will be presented by part and cohort. Baseline 
summaries will also include a total summary column.  
 
Individual subject data obtained from the electronic case report forms (eCRFs), and any derived 
data will be presented by subject in data listings. Data from all assessments, whether scheduled 
or unscheduled, will be included in the listings. Summary tables will be presented for scheduled 
assessments only. 
All analyses and tabulations will be performed using SAS v9.4 on a SAS server platform. 
Tables and listings will be presented in rich text format. Upon completion, all SAS programs will 
be validated by an independent programmer. In addition, all program output will undergo a 
senior level statistical review. The validation process will be used to confirm that statistically 
valid methods have been implemented and that all data manipulations and calculations are 
accurate. Checks will be made to ensure accuracy, consistency with this plan, consistency within 
tables, and consistency between tables and corresponding data listings. Upon completion of 
validation and quality review procedures, all documentation will be collected and filed by the 
project statistician or designee. 
 
4.2   Data Handling 
 
4.2.1   Baseline Value 
Unless otherwise specified, the baseline value is defined as the last value obtained before the 
date and time of the first BBT-176 dose. Post-baseline values are defined as value obtained after 
the first dose of BBT-176. Change from baseline is defined as a post-baseline value minus the 
baseline value.  
 


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4.2.2   Conventions  
 
Percentages are showed as a rate relative to the total number of subjects with a percent sign (%).  
For frequency counts of categorical variables, categories whose counts are zero will be displayed 
for the sake of completeness. For categories with zero counts no percentage will be displayed. 
 
For continuous variables, the precision of the original measurements will be maintained in 
summaries and listings, when possible. Generally, means, medians and standard deviations will 
be presented with an increased level of precision; means and medians will be presented to one 
more decimal place than the raw data, and the standard deviations will be presented to two more 
decimal places than the raw data. 
 
Summaries of continuous variables that have some values recorded using approximate values 
(e.g. < or >) will use imputed values. That is, approximate values will be imputed using the 
closest exact value for that measurement. Listing will present the data in the original format. 
For tables where rounding is required, rounding will be done to the nearest round-off unit. For 
example, if the round-off unit is the ones place (i.e., integers), values  XX.5 will be rounded up 
to XX+1 while values < XX.5 will be rounded down to XX. 
 
Listings will present the data in the original format. Durations of AEs and concomitant 
medications will not be derived using imputed dates but, rather, be set to missing when an event 
has a partially or completely missing start date or end date. 
 
 
4.2.3   Standard Calculations 
 
Variables requiring calculation will be derived using the following formula. 
• Study Day 3 Study Day 1 is defined as the date of the first treatment. For a given event 
date, Study Day is calculated relative to the date of first dose of study drug. 
Study Day = [Event Date 3 First Dose Date] + 1 (in days),  
 
where the event date is on or after the first treatment date. 
 
 
 = [Event Date 3 First Dose Date] (in days),  
 
where the event date is before the first treatment date. 
• Duration (Days) 3 A duration in days is calculated as the number of days between one 
date (Date1) and another later date (Date2), including both the start and end days. 
Duration (days) = [Date2 3 Date1] + 1 (in days) 
• Duration (Months) 3 A duration in months is calculated as the duration in days divided 
by 30.4375 (~365.25/12), rounded to one decimal place. 
• Duration (Years) 3 A duration in years is calculated as the duration in days divided by 
365.25, rounded to one decimal place. 
• Age (Years) 3 Age is calculated as the number of years from the date of birth to the date 
of informed consent using the following formula. 
Age (years) = [Date informed consent signed 3 Date of birth (in days)] / 365.25,  
rounded down to the closest year. 


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• Height 3 Height entries made in inches (in) are converted to centimeters using the 
following formula: 
Height (cm) = Height (in) * 2.54, rounded to the one decimal place. 
• Weight 3 Weight entries made in pounds (lbs) are converted to kilograms (kgs) using the 
following formula: 
Weight (kg) = Weight (lb) / 2.2046, rounded to the one decimal place. 
• Body Mass Index (BMI) 3 BMI is derived using following formula. 
BMI (kg/m2) = Weight (kg) / [(Height (cm) / 100]2, rounded to one decimal place. 
• Temperature 3 Temperature entries in degrees Centigrade are converted to degrees 
Fahrenheit using the following formula: 
Temperature (degrees Fahrenheit) = 1.8 * Temperature (degrees Centigrade) + 32, 
rounded to one decimal place. 
 
 
5. ANALYSIS POPULATION 
 
  
 
 
 
 
 
 
6. STUDY POPULATION  
 
6.1   Patient Disposition 
 
Patient disposition information will be summarized by each dose escalation cohort, overall 
patients in Part 1 and each expansion cohort, overall patients in Part 2. Summaries will include 
the number of enrolled patients, the number of patients in each analysis population, and the 
number of patients completing the study, and the primary reason for discontinuation. 


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6.2   Demographic and Baseline Characteristics 
Demographic variables include: age, sex, ethnicity, and race. Age will be calculated in years 
relative to the informed consent date. Other baseline characteristics include: medical history, 
previous cancer treatment, previous tumor tissues collection, weight, height, and BMI. 
Descriptive statistics will be presented for medical history, age, weight height, BMI. Frequency 
counts and percentages will be presented for sex, ethnicity and race. Demographic and baseline 
characteristics will be summarized by each dose escalation cohort, over all patients in Part 1 and 
each expansion cohort, overall patients in Part 2.  All demographic and baseline characteristics 
will be presented in a data listing.  
 
6.3   Medical History 
The number and percentage of subjects will be summarized by cohort and overall for each body 
system. 
 
6.4   Prior and Concomitant Medication 
Verbatim terms on eCRFs will be mapped to Anatomical Therapeutic Chemical (ATC) class and 
Generic Drug Names using
 
All medications taken within 28 days prior to the administration of study drug and during the 
course of the study (includes over-the-counter and prescription drugs) and any non-drug 
treatment/procedures must be recorded on the eCRF, including the reason for treatment, generic 
name of the drug, dosage, route, and date of administration. 
Prior medications are those that start taken prior to the administration of study drug, even if they 
continue after dosing. Concomitant medications are those that start on or after the date of the first 
dose of study medication. See Appendix 1 for handling of partial dates for medications; in cases 
where it is not possible to define a medication as prior or concomitant, the medication will be 
classified by the worst case4ie, concomitant. 
Prior and concomitant medications will be summarized by WHO ATC class include the 
therapeutic (i.e., the second level of Anatomical Therapeutic Chemical [ATC] classification 
system code, that is, corresponding to the first 3 figures), preferred name (the fourth level of the 
ATC code, that is, corresponding to the first 5 figures) and verbatim text and generic drug name 
for the Safety population. Summaries will be presented by each dose escalation cohort, over all 
patients in Part 1 and each dose expansion cohort, over all patients in Part 2. The number and 
percentage of patients using each medication will be presented. Patients may have more than one 
medication per ATC class and generic drug name. At each level of patient summarization, a 
patient is counted once if he/she reported one or more medications at that level. Each summary 
will be ordered in descending order of incidence of ATC class and generic drug name within 
each ATC class. 
 
 
7. EFFICACY ANALYSES 
 
All efficacy analysis will be based on the PP population. This study will utilize the definitions of 
tumor response as described in Response Evaluation Criteria in Solid Tumors (RECIST) version 
1.1 (Appendix 2). 


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7.1   Tumor Response 
 
Tumor assessment (RECIST version 1.1) will be performed at Screening and every 6 weeks from 
Cycle 1 Day1 until progression of disease, EOT, or until the patient commences further anti-cancer 
treatment, whichever comes first. All efficacy data will be summarized 
 
Baseline as well as change from baseline and percentage change from 
baseline measurements of the sum of the longest diameters for the target lesions will be 
summarized at each scheduled evaluation using descriptive statistics including mean, standard 
deviation, median, minimum and maximum values.  
 
7.1.1   Overall Time Point Response 
 
The investigator9s assessment of a patient9s target lesion response, non-target lesion response, and 
appearance of new lesions (collected from the eCRF) will be used to determine the overall tumor 
response at each time point as shown
 
 
 
The possible overall tumor responses at a time point, from best to worst, are as follows. 
• Complete Response (CR) 
• Partial Response (PR) 
• Stable Disease (SD) 
• Progressive Disease (PD) 
 
If no assessment is done or a response cannot be determined, it is designated as Not Evaluable 
(NE). 
 


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7.1.2   Best Response 
 
The best responses for pairs of time point responses (when confirmation of CR and PR are required) 
are determined as shown 
 
 
 
 
 
 
 
 
 
 
 


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• 
 
 
7.1.3   Best Overall Response 
 
A Best Response is determined for each sequential pair of post-treatment time points (and in some 
cases, triplets of sequential time points). Then, the Best Overall Response for a patient (when 
confirmation of CR and PR are required) is the best of these Best Responses.  
 
 
7.2   Objective Response Rate (ORR) 
 
The ORR will be estimated by the number of patients with a best overall response of CR or PR 
divided by the total number of patients who are evaluable for efficacy. The best overall response 
is the best response recorded from the start of the treatment until progression of disease, EOT, or 
until the patient commences further anti-cancer treatment, whichever comes first.  
 
 
7.3   Duration of Response (DoR) 
 
DoR is calculated for every patient with a response to therapy (PR and CR) and is defined as the 
number of days from the date of initial response to the date of the first documented disease 
progression/relapse (including clinical progression) or death, whichever occurs first. The exact 
date of a response is based on the tumor response assessment dates as defined in Section 7.1.1. If 
disease progression/relapse does not occur, DoR is censored as of the date of their last imaging 
exam of target or non-target lesions. Patients without an assessment of disease progression/relapse 
who discontinue the study and indicate progressive disease or clinical progression as the primary 
reason for ending treatment will be counted as having progressed on their last dose date of BBT-
1764whichever date is earlier.  
 
7.4   Progression-Free Survival (PFS) 
 
PFS will be calculated for each patient as the number of days from the first day of treatment to 
the date of the first documented disease progression/relapse or date of death, whichever occurs 
first. The exact date of disease progression is based on the tumor response assessment dates as 
indicated in Section 7.1.1. If disease progression/relapse does not occur, PFS is censored as of 
the date of their last imaging exam of target or non-target lesions. However, for patients without 
an assessment of disease progression/relapse who escalate to a higher dose, PFS is censored as of 
the date of their first dose of study medication in the later dose cohort. Patients without an 
assessment of disease progression/relapse who discontinue the study and indicate progressive 
disease or clinical progression as the primary reason for ending treatment will be counted as 
having progressed on their last dose date of BBT-1764whichever date is earlier.  
 


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7.5   Handling Missing, Unused, and Spurious Data 
 
All available efficacy data will be included in the data listings and tabulations. No imputation of 
values for missing data will be performed.  
 
7.6  
 
 
 
7.7   Methods of Efficacy Analysis 
The extent of disease will be assessed using the sum of the longest diameter from the target 
lesions. Change from baseline and percent change from baseline measurements will be 
summarized at each scheduled evaluation using descriptive statistics.  
The investigators9 assessments of patients9 target lesion response, non-target lesion response, and 
appearance of new lesions (collected from the eCRF) are used to determine the overall [tumor] 
response at each time point as shown in Section 7.1.1. The investigators9 assessments will be 
shown in listings.  
 
Next, as indicated in Section 7.1.2, the best [tumor] response for sequential pairs (or triplets) of 
time point responses (recorded from the start of study treatment until the end of treatment) are 
determined as shown in Table 14 and in the subsequent discussion. Finally, as indicated in 
Section 7.1.3, the Best Overall Response for a patient4when confirmation of CR and PR are 
required4is the best of these Best Responses. The number and percent of patients in each 
category of Best Overall Response (CR, PR, SD, and PD) will be summarized by cohort.  
 
The ORR will be presented with frequencies and percentages with 80% confidence interval.  
The frequency and percentages of patients with a best overall response of CR, PR, with stable 
disease (SD), or with PD will be summarized by cohort, additionally. 80% confidence intervals 
will be provided. 
 
DoR will be summarized using the Kaplan-Meier estimate including median estimate, first 
quartile, 3rd quartile.  
 
Progression-free survival in days will be summarized using the Kaplan-Meier to estimate the 
median PFS. The quartiles, including the median time-to-event and its two-sided 95% CI will be 
presented for each endpoint. Summaries will be presented for each cohort and overall. 
 
 
8. PHARMACOKINETIC (PK) ANALYSES 
 
All pharmacokinetic analyses will be based on the PK populations. This SAP describes the method 
of deriving PK using non-compartmental analysis applying  appropriate software, i.e., Phoenix™ 


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WinNonlin® (Version 8.0 or higher, Certara Corporation), and all other analyses and summaries 
using SAS® (Version 9.4 or higher, SAS Institute Inc.). 
 
The PK analyses will be conducted for BBT-176 in plasma, will include a listing, summary, and 
figure of concentrations, and derived PK parameters as described below. 
 
 
8.1   PK Sampling Schedule 
Plasma samplings for PK analyses will be done according to
  
 
8.2   Handling of the Below the Lower Limit of Quantification (BLQ) and the No 
Reportable Concentration Values 
. 
Subjects for whom there are insufficient data to calculate the PK parameters will be included in 
the concentration tables only and will be excluded from the PK and statistical analysis. 
 
8.3   Handling of the Difference between the Scheduled and the Actual Sampling Times 
The actual clock time for dosing and each collection time for the PK samples will be recorded. For 
all sampling times, the actual sampling times relative to dosing will be calculated as the difference 
between the actual clock time of sampling and the actual clock time of dosing. The actual post-
dose sampling times relative to dosing expressed in hours and rounded off to three decimal digits 
will be used to calculate the PK parameters, except for pre-dose samples occurring prior to dosing, 
which will always be reported as zero (0.000), regardless of the time difference. Scheduled 
sampling times will be presented in concentration tables and mean graphs, while actual sampling 
times will be presented in the individual graphs. 
 
8.4   Plasma PK Endpoints 
 
  
 


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Additional PK parameters may be computed if deemed appropriate. 
 
8.5   Statistical Analyses 
 
 
 
 
 
 


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9. PHARMACODYNAMIC (PD) ANALYSES 
 
 


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No formal statistical analysis of pharmacodynamics endpoints will be performed. 
Data listings will be created for each pharmacodynamics biomarker by cohort and patient.  
 
Summary tables of values (number of observations, mean, median, standard error of the mean, 
standard deviation) will be created for each pharmacodynamics biomarker.  
 
 
10. SAFETY ANALYSES 
All safety analyses will be based on the Safety population. Safety variables to be assessed will 
include AEs, laboratory test results (hematology, clinical chemistry, and urinalysis), ECGs, 
weight, vital signs.  
 
10.1   Extent of Exposure 
Study drug exposure will be summarized for each dose escalation cohort and all patients in the 
dose escalation phase. Duration of treatment is defined as the last dose date minus the first dose 
date plus 1. Drug adjustments and interruptions are listed and summarized for each cohort. 
 
10.2   Adverse Events (AEs) 
An AE is any untoward, undesired, or unplanned event in the form of signs, symptoms, disease, 
or laboratory or physiologic observations occurring in a person given a test article (study drug) in 
a clinical study. The description found in the revised NCI CTCAE version 5.0 will be utilized for 
AE reporting.  
 
All AEs will have their relationship to study treatment assessed as follows: 
• Definite 3 The AE is clearly related to the study treatment 
• Probable 3 The AE is likely related to the study treatment 
• Possible 3 The AE may be related to the study treatment 
• Unlikely 3 The AE is doubtfully related to the study treatment 
• Unrelated 3 The AE is clearly NOT related to the study treatment 
 
A serious AE (SAE) is an AE that: 
• Results in death. 
• Is life-threatening.  
• Requires inpatient hospitalization or prolongation of an existing hospitalization. 
• Results in a persistent or significant disability or incapacity. 
• Results in a congenital anomaly or birth defect. 
• Additionally, important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  
 
A Treatment-emergent AE (TEAE) is an AE with an onset day on or after the day of the initial 
dose of study drug.   
 
AEs of special interest (AESI) is an AE that: 


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• Gastrointestinal, skin (>Grade 2), pulmonary (≥Grade 2), and/or serious events requiring 
reporting to the Sponsor as an SAE.  
• Any laboratory hepatic toxicity meeting Hy9s law criteria for suspected severe drug 
induced liver injury, defined as a rise in serum aminotransferase (AST or ALT) 
of >3xUNL and total bilirubin ≥2 x ULN, in the absence of any alternative reason (e.g., 
liver metastasis, liver disease, or concomitant medication) 
 
AE terms recorded on the eCRF will be mapped to preferred terms using
An overall summary will be 
provided of the number and percentage of patients reporting AEs, TEAEs, treatment-related 
TEAEs, serious TEAEs, treatment-related serious TEAEs, AEs of special interest (AESIs), 
TEAEs leading to study drug withdrawal and TEAEs leading to death. In the overall summary, 
additionally, the number and percentage of patients with at least one severe TEAE, with at least 
one moderate TEAE but no severe TEAE and with only mild TEAEs will be provided.   
 
The number and percentage of patients with AEs will be summarized for each dose level and 
overall in Part 1, and by cohort and overall in Part 2 according to the system organ class and 
preferred term. AEs (including AESI) will be summarized for overall frequency (number and 
percentage of patients), worst reported severity, and relationship to study treatment for each 
preferred term per patient. SAEs will be similarly summarized. Listings of death, SAEs, and AEs 
leading to early termination of study treatment or premature withdrawal from study will be also 
provided.  
 
 
10.3   Clinical Laboratory Evaluations 
 
Laboratory parameters (serum chemistry, hematology, coagulation, urinalysis, and serology test) 
will be presented in data listings. Abnormal values will be flagged as high or low relative to the 
local lab normal ranges, where applicable. Values that are deemed as abnormal, clinically 
significant (as collected on the eCRF) will also be flagged in the data listing.  
Laboratory variables will be summarized using actual values and changes from baseline to 
scheduled time points. Laboratory values will also be categorized according to their NCI-
CTCAE version 5.0 toxicity grade and tabulated by worst on-study toxicity grade. The baseline 
value of a variable is defined as the last value obtained on or before the date and time of the first 
BBT-176 dose.  
 
 
10.4   Vital Signs 
 
Vital signs (pulse, respiration, blood pressure, oral temperature, and weight) will be summarized 
by dose cohort for the dose escalation phase and for each expansion cohort using descriptive 
statistics at baseline and at each post-baseline time point. Actual values and changes from 
baseline to scheduled time points will also be summarized.  
 
10.5   Physical Examination 
 


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Physical examination results will be summarized by shift tables from baseline compared to 
scheduled post-baseline time-points presenting the number and percentage of patients with 
normal /abnormal NCS / abnormal CS and not evaluable results.  
 
10.6   Electrocardiogram (ECG) 
 
The ECG data analysis will be conducted based on methodology recommended in the ICH E14 
guidance, The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential 
for Non-antiarrhymic Drugs. Descriptive statistics at baseline and at each scheduled post-
baseline time point as well as changes from baseline will be summarized for each ECG 
parameter (heart rate, RR interval, PR interval, QRS interval, QT interval, QT interval corrected 
using Frederica9s formula (QTcF)) by dose escalation cohort, overall patients in Part 1 and each 
expansion cohort and overall patients in Part 2. The number and percentage of patients with 
normal, abnormal and abnormal clinically significant categories will be provided for the overall 
ECG evaluation for each visit by dose escalation cohort. 
 
The RR interval will be calculated from heart rate using the following formula: 
• RR (milliseconds) = 60*1000 / [heart rate in beats per minute] 
 
Frederica9s formula, which corrects the QT interval for the effect of heart rate, is 
• QTcF (milliseconds) =  QT / [(RR/1000)0.33] or, equivalently, QT / [(60/heart rate) 0.33] 
 
The RR value derived from heart rate will be used in any derivations (eg, QTcF) rather than the 
value collected on the eCRF. Further, the derived QTcF values rather than the QTcF collected in 
the eCRF will be used for all analyses. Both the collected and derived RR and QTcF values will 
be shown in the listings. 
All ECG information as well as change from baseline will be listed by dose escalation cohort and 
over all patients in Part 1 and each expansion cohort and overall patients in Part 2.  
In addition, a categorical summary of abnormal QTcF values will be presented for each dose 
escalation cohort and overall patients in Part 1 and each expansion cohort and overall patients in 
Part 2. Additionally, a frequency table with number and  percentage of patients with noteworthy 
QTcF values (> 450, > 480 and > 500 ms) during the study and of patients  noteworthy QTcF 
changes from baseline (≥ 30 but <60; ≥ 60 ms) will be provided for each dose escalation 
cohort,  
 
 
10.7   Eastern Cooperative Oncology Group (ECOG)  
 
Eastern Cooperative Oncology Group (ECOG) performance status scores will be included in a 
data listing; shift tables assessing the worst post-baseline value will be presented (see Appendix 
3). 
 
 
 
 


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REFERENCES 
1. Gettinger, Scott N., et al. Activity and safety of brigatinib in ALK-rearranged non-small-cell 
lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial. The Lancet 
Oncology 2016; 17.12: 1683-1696 
 
2. Guidance for Industry E14 The Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-antiarrhythmic Drugs, U.S. Department of Health and Human 
Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 
October 2005. 
 
3. Gough K, Hutchinson M, Keene O, Byrom B, Ellis S, Lacey L, McKellar J. Assessment of Dose 
Proportionality: Report from the Statisticians in The Pharmaceutical Industry/Pharmacokinetics UK 
joint working party. Drug Inf J. 1995; 29:1039-1048.  
 
4. Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, Forgue ST. CI 
criteria for assessment of dose proportionality, Pharmaceut. Res. 2000; 17: 1278-1283. 
 
5. Hummel J, McKendrick S, Brindley C and French, R. Exploratory assessment of dose 
proportionality: review of current approaches and proposal for a practical criterion. Pharmaceut. 
Statist. 2009; 8: 38-49. 
 
 
 


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APPENDIX 1. PARTIAL DATE CONVENTIONS 
 
 
 


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APPENDIX 2. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST 
VERSION 1.1) 
The text below was obtained from the following reference:  
 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). European Journal of Cancer.2009;45:228-247. 
 
DEFINITIONS 
 
Response and progression will be evaluated in this trial using the international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1). Changes in only the 
largest diameter (uni-dimensional measurement) of the tumor lesions are used in the RECIST criteria. 
Note: Lesions are either measurable or non-measurable using the criteria provided below. The term 
<evaluable= in reference to measurability will not be used because it does not provide additional meaning 
or accuracy. 
 
Measurable Disease 
 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
• 
10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice thickness 
and a minimum of 10 mm). 
• 
20 mm by chest X ray (if clearly defined and surrounded by aerated lung). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be 
≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow up, only the short axis will be measured and followed. 
 
Non-measurable Disease 
 
All other lesions (or sites of disease), including small lesions (longest diameter ≥ 10 to < 15 mm with 
conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable disease. 
Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical examination that is not measurable by reproducible imaging techniques are all non-measurable. 
 
Bone lesions: 
 
• 
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance of 
bone lesions 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can 
be evaluated by cross sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
• 
Blastic bone lesions are non-measurable. 
Cystic lesions: 


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• 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non measurable) since they are, by definition, 
simple cysts. 
• 
8Cystic lesions9 thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
locoregional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Trial protocols should detail the conditions under which such lesions 
would be considered measurable. 
Target Lesions 
 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be identified 
as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organ, but in addition 
should be those that lend themselves to reproducible repeated measurements. 
 
Lymph nodes merit special mention since they are normal anatomical structures which may be visible by 
imaging even if not involved by tumor. Pathological nodes which are defined as measurable and may be 
identified as target lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. Only the short 
axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported as 2 
dimensions in the plane in which the image is obtained (for CT scan this is almost always the axial plane; 
for MRI the plane of acquisition may be axial, sagittal, or coronal). The smaller of these measures is the 
short axis. For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis 
of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as 
the node measurement. All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) 
should be considered non target lesions. Nodes that have a short axis < 10 mm are considered non 
pathological and should not be recorded or followed. 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then as noted above, only the short axis is added into the sum. The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
 
Non-target Lesions 
 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-
target lesions and should also be recorded at baseline. Measurements are not required and these lesions 
should be followed as <present=, <absent=, or in rare cases <unequivocal progression= (more details to 
follow). In addition, it is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g., <multiple enlarged pelvic lymph node= or <multiple liver 
metastases=). 
 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 


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All measurements should be recorded in metric notation, using calipers if clinically assessed. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 4 weeks 
before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging based evaluation should always be done 
rather than clinical examination unless the lesion(s) being followed cannot be imaged but are assessable 
by clinical examination. 
 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. As is described in Appendix II of the original source 
article cited above, when CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g., 
for body scans). 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not advised. 
However, they can be useful to confirm complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete response or surgical resection is an 
endpoint. 
 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare cases if 
required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where known 
residual benign tumors can remain). When effusions are known to be a potential adverse effect of 
treatment (e.g., with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation 
of the neoplastic origin of any effusion that appears or worsens during treatment can be considered if the 
measurable tumor has met criteria for response or stable disease in order to differentiate between response 
(or stable disease) and progressive disease. 
 
RESPONSE CRITERIA 
 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to < 10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of one or more new lesions is also considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 


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Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even if the 
nodes regress to below 10 mm on study. This means that when lymph nodes are included as target 
lesions, the <sum= of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and PD, the 
actual short axis measurement of the nodes is to be included in the sum of target lesions. 
 
Target lesions that become <too small to measure=. While on study, all lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, even 
when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes which are recorded as target 
lesions at baseline become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being <too small to measure=. When this occurs it is important that 
a value be recorded in the eCRF. If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned (Note: It is less likely 
that this rule will be used for lymph nodes since they usually have a definable size when normal and are 
frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness (but should not be 
changed with varying CT slice thickness). The measurement of these lesions is potentially non-
reproducible, therefore providing this default value will prevent false responses or progressions based 
upon measurement error. To reiterate, however, if the radiologist is able to provide an actual measure, that 
should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions <fragment=, the longest diameters of 
the fragmented portions should be added together to calculate the target lesion sum. Similarly, as lesions 
coalesce, a plane between them may be maintained that would aid in obtaining maximal diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal longest diameter for 
the <coalesced lesion=. 
 
Evaluation of Non-target Lesions 
 
While some non-target lesions may actually be measurable, they need not be measured and instead should 
be assessed only qualitatively at the time points specified in the protocol. 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
 


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Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered progression). 
 
When the patient also has measurable disease. In this setting, to achieve <unequivocal progression= on the 
basis of the non-target disease, there must be an overall level of substantial worsening in non-target 
disease such that, even in presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest <increase= in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of target disease 
will therefore be extremely rare. 
 
When the patient has only non-measurable disease. This circumstance arises in some phase 3 trials when 
it is not a criterion of trial entry to have measurable disease. The same general concept apply here as 
noted above, however, in this instance there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden. Because worsening in non-target disease 
cannot be easily quantified (by definition: if all lesions are truly non-measurable) a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in magnitude to the increase 
that would be required to declare PD for measurable disease: i.e., an increase in tumor burden 
representing an additional 73% increase in <volume= (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from <trace= to <large=, an 
increase in lymphangitic disease from localized to widespread, or may be described in protocols as 
<sufficient to require a change in therapy=. If <unequivocal progression= is seen, the patient should be 
considered to have had overall PD at that point. While it would be ideal to have objective criteria to apply 
to non-measurable disease, the very nature of that disease makes it impossible to do so, therefore the 
increase must be substantial. 
 
New Lesions 
 
The appearance of new malignant lesions denotes disease progression; therefore, some comments on 
detection of new lesions are important. There are no specific criteria for the identification of new 
radiographic lesions; however, the finding of a new lesion should be unequivocal: i.e., not attributable to 
differences in scanning technique, change in imaging modality or findings thought to represent something 
other than tumor (for example, some <new= bone lesions may be simply healing or flare of pre-existing 
lesions). This is particularly important when the patient9s baseline lesions show partial or complete 
response. For example, necrosis of a liver lesion may be reported on a CT scan report as a <new= cystic 
lesion, which it is not. 
 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. An example of this is the patient who has 
visceral disease at baseline and while on trial has a CT or MRI brain ordered which reveals metastases. 
The patient9s brain metastases are considered to be evidence of PD even if he/she did not have brain 
imaging at baseline. 
 


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If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. 
 
While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate 
the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible <new= disease). New lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm: 
• 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. 
• 
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-
PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans 
are needed to determine if there is truly progression occurring at that site (if so, the date of PD 
will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the study drug treatment until the 
end of treatment taking into account any requirement for confirmation. On occasion a response may not 
be documented until after the end of therapy so protocols should be clear if post-treatment assessments 
are to be considered in determination of best overall response. Protocols must specify how any new 
therapy introduced before progression will affect best response designation. The patient9s best overall 
response assignment will depend on the findings of both target and non-target disease and will also take 
into consideration the appearance of new lesions. Furthermore, depending on the nature of the trial and 
the protocol requirements, it may also require confirmatory measurement. Specifically, in non-
randomized trials where response is the primary endpoint, confirmation of PR or CR is needed to deem 
either one the <best overall response=. 
 
The best overall response is determined once all the data for the patient are known. Best response 
determination in trials where confirmation of complete or partial response IS NOT required: Best 
response in these trials is defined as the best response across all time points (for example, a patient who 
has SD at first assessment, PR at second assessment, and PD on last assessment has a best overall 
response of PR). When SD is believed to be best response, it must also meet the protocol specified 
minimum time from baseline. If the minimum time is not met when SD is otherwise the best time point 
response, the patient9s best response depends on the subsequent assessments. For example, a patient who 
has SD at first assessment, PD at second and does not meet minimum duration for SD, will have a best 
response of PD. The same patient lost to follow-up after the first SD assessment would be considered 
inevaluable. 
 
 


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Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR* 
CR 
CR 
PR 
 
SD 
 
Not all evaluated 
PD 
Any 
Any 
CR 
Non-CR/non-PD 
Not evaluated 
Non-PD or not all 
evaluated 
Non-PD or not all 
evaluated 
Non-PD 
Any 
PD 
Any 
No 
No 
No 
No 
 
No 
 
No 
Yes or No 
Yes or No 
Yes 
CR 
PR 
PR 
PR 
 
SD 
 
NE 
PD 
PD 
PD 
* CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; and NE 
= invaluable. See text for more details. 
Note:  When nodal disease is included in the sum of target lesions and the nodes decrease to <normal= 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based on 
increase in size of the nodes. As noted earlier, this means that patients with CR may not have a total sum 
of <zero= in the eCRF. 
In trials where confirmation of response is required, repeated 8NE9 time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in most 
trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a confirmed 
response. 
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as <symptomatic deterioration=. 
Every effort should be made to document objective progression even after discontinuation of treatment. 
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for stopping trial 
therapy. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of complete response. FDG-
PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual 
radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and supported by disease-specific medical 
literature for the indication. However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes, or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next 
scheduled assessment, progression is confirmed, the date of progression should be the earlier date when 
progression was suspected. 


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CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
 
Confirmation 
 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is required 
to ensure that the identified responses are not the result of measurement error. This will also permit 
appropriate interpretation of results in the context of historical data where response has traditionally 
required confirmation in such trials. However, in all other circumstances, i.e., in randomized trials (phase 
2 or 3) or trials where stable disease or progression are the primary endpoints, confirmation of response is 
not required since it will not add value to the interpretation of trial results. However, elimination of the 
requirement for response confirmation may increase the importance of central review to protect against 
bias, in particular in trials which are not blinded. 
 
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a minimum 
interval (in general not less than 6 to 8 weeks) that is defined in the trial protocol. 
 
Duration of Overall Response 
 
The duration of overall response is measured from the time that measurement criteria are first met for 
CR/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 on study). 
 
The duration of overall complete response is measured from the time measurement criteria that 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 (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on study (if 
the baseline sum is the smallest, this is the reference for calculation of PD). 
 
The clinical relevance of the duration of stable disease varies in different studies and diseases. If the 
proportion of patients achieving stable disease for a minimum period of time is an endpoint of importance 
in a particular trial, the protocol should specify the minimal time interval required between two 
measurements for determination of stable disease. 
 
Note: The DoR and stable disease as well as the PFS are influenced by the frequency of follow-up after 
baseline evaluation. It is not in the scope of this guideline to define a standard follow-up frequency. The 
frequency should take into account many parameters including disease types and stages, treatment 
periodicity, and standard practice. However, these limitations of the precision of the measured endpoint 
should be taken into account if comparisons between trials are to be made. 
 
 


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APPENDIX 3. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS  
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.1982;5:649-5