Clinical trial NCT03455829
Conditions: Carcinoma, Non-Small-Cell Lung Lung Cancer Non-small Cell Lung Cancer
Keywords: Lung Cancer Non-small Cell Lung Cancer CDK 4/6 Inhibitor EGFR-Positive EGFR Mutation- Positive T790M EGFR Mutant lerociclib
Sponsor: G1 Therapeutics, Inc.
Start date: 2018-03-29; Completion date: 2022-02-14
Enrollment: 30 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a study to investigate the potential clinical benefit of G1T38 as an oral therapy in combination with osimertinib in patients with EGFR mutation-positive metastatic non-small cell lung cancer.

The study was an open-label design, planned to consist of 2 parts: a safety, pharmacokinetic, and dose-finding portion (Part 1), and a randomized portion (Part 2). Both parts were to include 3 study phases: Screening Phase, Treatment Phase, and Survival Follow-up Phase. The Treatment Phase began on the day of first dose with study treatment and completes at the Post-Treatment Visit. Approximately, 144 patients were planned to be enrolled in the study.

Detailed description:
Part 2, the Phase 2 part of the study, was not conducted due to changes in corporate strategy. There were no safety signals identified in Phase 1/Part 1 that would have precluded the conduct of Part 2. As a result, 30 out of the planned 144 patients were enrolled.

All tumor assessments were conducted by the Investigators or site radiologist. In order to reduce the burden to the patients, data of overall survival (OS) were no longer required (since 29 January 2020). No OS analysis was conducted for Part 1 due to limited data in Part 1.

PK data for Cohorts 4 (150 BID) and 5 (200 BID) were not analyzed as they were deemed unnecessary, as the PK data from Cohorts 1-3 were sufficient to achieve the secondary study objective of assessing the effect of osimertinib on PK parameters of G1T38.

Arms: arm 1: Patients will receive a single oral dose of G1T38 on Cycle 1 Day -16 and on Cycle 1 Day -2. Patients will receive oral osimertinib 80 mg beginning Cycle 1 Days -14. Patients will begin G1T38 once-daily dosing on Cycle 1 Day 1 (in combination with osimertinib 80 mg). arm 2: Patients will receive a single oral dose of G1T38 on Cycle 1 Day -16 and on Cycle 1 Day -2. Patients will receive oral osimertinib 80 mg beginning Cycle 1 Days -14. Patients will begin G1T38 once-daily dosing on Cycle 1 Day 1 (in combination with osimertinib 80 mg). arm 3: Patients will receive a single oral dose of G1T38 on Cycle 1 Day -16 and on Cycle 1 Day -2. Patients will receive oral osimertinib 80 mg beginning Cycle 1 Days -14. Patients will begin G1T38 once-daily dosing on Cycle 1 Day 1 (in combination with osimertinib 80 mg). arm 4: Patients will receive a single oral dose of G1T38 on Cycle 1 Day -16 and on Cycle 1 Day -2. Patients will receive oral osimertinib 80 mg beginning Cycle 1 Days -14. Patients will begin G1T38 once-daily dosing on Cycle 1 Day 1 (in combination with osimertinib 80 mg). arm 5: Patients will receive a single oral dose of G1T38 on Cycle 1 Day -16 and on Cycle 1 Day -2. Patients will receive oral osimertinib 80 mg beginning Cycle 1 Days -14. Patients will begin G1T38 once-daily dosing on Cycle 1 Day 1 (in combination with osimertinib 80 mg).
Interventions: intervention 1: G1T38 intervention 2: Osimertinib
Intervention descriptions: intervention 1: CDK 4/6 inhibitor intervention 2: EGFR TKI; 80 mg

Protocol documents:
Prot_000.pdf: 
G1 Therapeutics CONFIDENTIAL 
 
 
  
 
 
 
 
Phase 1b/2 Safety, Pharmacokinetic, and Efficacy Study of G1T38 in Combination with 
Osimertinib in Patients with EGFR Mutation-Positive Metastatic Non-Small Cell Lung 
Cancer (NSCLC) 
 
 
Clinical Study Protocol G1T38-03  
 
 
EudraCT #: 2017-004315-39 
 
 
Version 4.0 Issue Date: 02September 2019 
 
Investigational Phase: 1b/2 
 
Sponsored by: 
G1 Therapeutics 
700 Park Offices Drive, Suite 200 
Research Triangle Park, NC 27709 
 
 
 
 
 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND/OR TRADE SECRET 
INFORMATION THAT IS DISCLOSED ONLY IN CONNECTION WITH THE 
LICENSING AND/OR REGISTRATION OF PRODUCTS FOR G1 THERAPEUTICS.  
THIS DOCUMENT SHOULD NOT BE DISCLOSED OR USED, IN WHOLE OR IN 
PART, FOR ANY OTHER PURPOSE WITHOUT THE PRIOR WRITTEN CONSENT OF 
G1 THERAPEUTICS. 




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PROTOCOL SIGNATURE PAGE 
Clinical Study Protocol G1T38-03: Phase 1b/2 Safety, Pharmacokinetic, and Efficacy 
Study of G1T38 in Combination with Osimertinib in Patients with EGFR Mutation-Positive 
Metastatic Non-Small Cell Lung Cancer (NSCLC)  
Protocol Version 4.0 Issue Date: 02 September 2019 
By signing below, the investigator agrees to adhere to the protocol as outlined. 
Principal Investigator: 
 
 
Principal Investigator Signature 
Date 
Principal Investigator Name 
Institution 
 




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8.3. 
Dose, Dosing Regimen, and Route ................................................................................................. 42 
8.3.1. 
G1T38 ........................................................................................................................... 42 
8.3.2. 
Osimertinib .................................................................................................................... 42 
8.3.3. 
 ...................................................................................................................................... 43 
8.3.3.1. 
G1T38 ...................................................................................................... 43 
8.3.3.2. 
Osimertinib .............................................................................................. 44 
8.4. 
Randomization and Blinding ........................................................................................................... 47 
8.5. 
Prior and Concomitant Medications and Procedures ...................................................................... 47 
8.5.1. 
CYP3A4 Substrates ....................................................................................................... 47 
8.5.2. 
CYP3A4 Inhibitors and Inducers .................................................................................. 48 
8.5.3. 
BCRP Inhibitors ............................................................................................................ 49 
8.5.4. 
BCRP substrates ............................................................................................................ 49 
8.5.5. 
Gastric pH Elevating Agents ......................................................................................... 49 
8.5.6. 
CYP2C8 Inhibitors and Inducers .................................................................................. 49 
8.6. 
Systemic Corticosteroid Use ........................................................................................................... 50 
8.7. 
Supportive Care for Gastrointestinal Adverse Events ..................................................................... 50 
8.8. 
Additional Cautions ........................................................................................................................ 50 
8.9. 
Concomitant Radiotherapy or Surgery ............................................................................................ 50 
8.10. 
Contraception .................................................................................................................................. 51 
8.11. 
Treatment Compliance .................................................................................................................... 52 
9. 
STUDY SCHEDULE .................................................................................................................................. 53 
9.1. 
Screening Phase .............................................................................................................................. 59 
9.2. 
Treatment Phase .............................................................................................................................. 59 
9.3. 
Post-Treatment Visit/Early Termination ......................................................................................... 60 
9.4. 
Survival Follow-up Phase ............................................................................................................... 60 
9.5. 
Unscheduled Visits ......................................................................................................................... 60 
10. STUDY PROCEDURES AND ASSESSMENTS ....................................................................................... 61 
10.1. 
Efficacy Assessments ...................................................................................................................... 61 
10.1.1. 
Tumor Lesions: Identification and Follow-up ............................................................... 62 
10.1.1.1. 
Measurable Lesions ................................................................................. 62 
10.1.1.2. 
Nonmeasurable Lesions ........................................................................... 63 
10.1.1.3. 
New Lesions ............................................................................................ 63 
10.1.2. 
Definitions of Tumor Response and Disease Progression ............................................. 63 
10.1.2.1. 
Evaluation of Target Lesion Response .................................................... 63 
10.1.2.2. 
Evaluation of Nontarget Lesions .............................................................. 64 
10.1.2.3. 
Evaluation of Overall Response at Each Time Point ............................... 64 
10.2. 
Cell-Free DNA ................................................................................................................................ 65 
10.3. 
Archival Tumor Tissue ................................................................................................................... 65 
10.4. 
Optional Tumor Biopsy at Time of Disease Progression ................................................................ 65 
10.5. 
Pharmacokinetic Assessments ........................................................................................................ 66 
10.5.1. 
Pharmacokinetic Sampling ............................................................................................ 66 
10.5.2. 
Pharmacokinetic Parameters ......................................................................................... 67 
10.6. 
Safety Assessments ......................................................................................................................... 68 
10.6.1. 
Adverse Events and Serious Adverse Events ................................................................ 68 
10.6.1.1. 
Definition of Adverse Event .................................................................... 69 
10.6.1.2. 
Definition of Serious Adverse Event ....................................................... 70 
10.6.1.3. 
Assessment of the Severity of Adverse Events ........................................ 72 
10.6.1.4. 
Assessment of the Causal Relationship of Adverse 
Events to Study Drug ............................................................................... 72 
10.6.1.5. 
Assessment of the Outcome of Adverse Events ....................................... 72 
10.6.1.6. 
Method, Frequency, and Time Period for Detecting 
Adverse Events and Serious Adverse Events ........................................... 73 
10.6.1.7. 
Documentation of Adverse Events and Serious Adverse 
Events ...................................................................................................... 73 


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10.6.1.8. 
Adverse Event Coding ............................................................................. 73 
10.6.1.9. 
Reporting of Serious Adverse Events ...................................................... 73 
10.6.1.10. 
Follow-up of Adverse Events .................................................................. 74 
10.6.1.11. 
Regulatory Aspects of Adverse Event Reporting .................................... 74 
10.6.1.12. 
Handling of Overdose .............................................................................. 75 
10.6.1.13. 
Reporting of Pregnancies ......................................................................... 75 
10.6.2. 
Clinical Laboratory Assessments .................................................................................. 76 
10.6.3. 
Demographics and Vital Signs ...................................................................................... 78 
10.6.4. 
Physical Examination .................................................................................................... 78 
10.6.5. 
Electrocardiogram Assessments .................................................................................... 78 
10.6.6. 
Ophthalmic Examination............................................................................................... 79 
10.6.7. 
Echocardiogram/MUGA ............................................................................................... 79 
10.7. 
Biomarker Analysis......................................................................................................................... 80 
10.8. 
Appropriateness of Measurements .................................................................................................. 80 
11. STUDY TERMINATION OR STUDY DRUG DISCONTINUATION ..................................................... 81 
11.1. 
Study Termination........................................................................................................................... 81 
11.2. 
Site Termination .............................................................................................................................. 81 
11.3. 
Discontinuation of Study Drug ....................................................................................................... 81 
11.4. 
Withdrawal of Patients from the Study ........................................................................................... 82 
12. STATISTICS ............................................................................................................................................... 83 
12.1. 
Sample Size and Power ................................................................................................................... 83 
12.2. 
General Considerations ................................................................................................................... 83 
12.2.1. 
Analysis Populations ..................................................................................................... 83 
12.2.2. 
Timing of Analyses ....................................................................................................... 84 
12.2.2.1. 
Interim Safety Reviews ............................................................................ 84 
12.2.2.2. 
Independent Data Monitoring Committee ............................................... 84 
12.2.2.3. 
Final Analysis .......................................................................................... 84 
12.2.2.4. 
End of Study Analysis ............................................................................. 84 
12.2.3. 
General Considerations for Data Analysis .................................................................... 84 
12.3. 
Part 1 (Phase 1b) Statistical Analyses ............................................................................. 85 
12.3.1. 
Other Safety Endpoints ................................................................................................. 85 
12.3.2. 
Efficacy Endpoints ................................................................................................... 86 
12.4. 
Part 2 Statistical Analyses ............................................................................................................... 87 
12.4.1. 
Safety evaluation ........................................................................................................... 89 
12.5. 
Pharmacokinetic Analysis ............................................................................................................... 90 
 
 
13. QUALITY CONTROL AND QUALITY ASSURANCE ........................................................................... 92 
14. ETHICS AND PROTECTION OF HUMAN PATIENTS .......................................................................... 93 
14.1. 
Ethical Conduct Statement .............................................................................................................. 93 
14.2. 
Independent Ethics Committee/Institutional Review Board ........................................................... 93 
14.3. 
Informed Consent ............................................................................................................................ 93 
14.4. 
Patient Confidentiality .................................................................................................................... 93 
14.5. 
Adherence to the Protocol ............................................................................................................... 93 
14.6. 
Protocol Amendments ..................................................................................................................... 94 
14.7. 
Patient Compliance ......................................................................................................................... 94 
15. DATA HANDLING AND RECORD KEEPING ........................................................................................ 95 
15.1. 
Data Collection and Retrieval ......................................................................................................... 95 
15.2. 
Investigator Reporting Requirements.............................................................................................. 95 
15.3. 
Records Retention ........................................................................................................................... 95 
15.4. 
Study Monitoring ............................................................................................................................ 96 
15.5. 
Audits and Inspections .................................................................................................................... 96 


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16. PUBLICATION POLICY ........................................................................................................................... 97 
17. REFERENCES ............................................................................................................................................ 98 
18. APPENDICES ........................................................................................................................................... 100 
 


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1.1. 
List of In-Text Tables 
Table 4-1 
Summary of G1T38-Related Adverse Events by Preferred Term 
and CTCAE Grade Occurring in Study G1T38-02 (as of 
25 August 2017) ............................................................................................................ 25 
Table 4-2 
Osimertinib and G1T38: Potential Risks for Drug-Drug 
Interactions and Mitigating Data ................................................................................... 28 
Table 5-1 
Study Objectives ........................................................................................................... 31 
Table 6-1 
Projected G1T38 Dose Levels, Part 1 ........................................................................... 33 
Table 8-1 
G1T38 Dose Level Adjustments Based on G1T38-related 
Hematologic Toxicities ................................................................................................. 43 
Table 8-2 
Recommended Dose Modifications for Osimertinib-Related 
Adverse Reactions ......................................................................................................... 45 
Table 9-1 
Schedule of Assessments for Part 1 .............................................................................. 54 
Table 9-2 
Schedule of Assessments for Part 2 .............................................................................. 57 
Table 10-1 
Evaluation of Overall Response at Each Time Point for Patients 
with Target Lesions ....................................................................................................... 65 
Table 10-2 
Part 1: Cycle 1 Day -16 and Cycle 1 Day -2 Blood Sampling 
Scheme .......................................................................................................................... 66 
Table 10-3 
Part 2 Blood Sampling Scheme for G1T38 Population PK 
Analysis ......................................................................................................................... 67 
Table 10-4 
Pharmacokinetic Parameters for G1T38 
 .................................................... 68 
Table 10-5 
Clinical Laboratory Tests .............................................................................................. 77 
Table 18-1 
Drugs Known to Prolong the QT Interval ................................................................... 100 
Table 18-2 
Drugs that May Prolong QT Interval .......................................................................... 101 
 
1.2. 
List of In-Text Figures 
Figure 8-1 
Study Schema: Part 1 .................................................................................................... 40 
Figure 8-2 
Study Schema: Part 2 .................................................................................................... 41 
Figure 12-1 
Categories of Source Data for Patients .......................................................................... 88 
 
 


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2. 
LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BCRP 
breast cancer resistance protein  
β-hCG 
beta human chorionic gonadotropin  
BOR 
best overall response 
CBC 
complete blood count 
CBR 
clinical benefit rate 
CDK4/6 
cyclin-dependent kinase 4/6 
cfDNA 
cell-free DNA 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL/F 
apparent oral clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum concentration 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DLT 
dose-limiting toxicity 
EC50 
50% effective concentration 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
ER 
estrogen receptor 
FDA 
Food and Drug Administration 


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Abbreviation 
Definition 
FDG-PET 
positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose 
FGFR 
fibroblast growth factor receptor 
FIH 
first-in-human 
G1 
gap 1 phase of the cell cycle 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GEMM 
genetically engineered mouse model  
HDPE 
high-density polyethylene  
HED 
human equivalent dose 
HER2 
human epidermal growth factor receptor 2 
hERG 
human ether-à-go-go related gene 
HR 
hormone receptor 
HRCT 
high-resolution computed tomography  
IB 
Investigator’s Brochure 
IC50 
50% inhibitory concentration 
ICH 
International Council for Harmonisation 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IGF1R 
insulin-like growth factor 1 receptor 
ILD 
interstitial lung disease 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IWRS 
interactive web-response system 
LD 
longest diameter 
LVEF 
left ventricular ejection fraction 
MATE1 or 2-K 
multidrug and toxin extrusion 1 or 2-K  
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition 
NCI 
National Cancer Institute 
NE 
not evaluable 
NSCLC 
non-small cell lung cancer 
NTL 
nontarget lesion 
NYHA 
New York Heart Association 
OCT1 or 2  
organic cation transporter 1 or 2 


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Abbreviation 
Definition 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PR 
partial response 
PTV 
Post-Treatment visit 
QTc 
QT interval corrected for heart rate 
Rb 
retinoblastoma protein 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors  
RP2D 
recommended Phase 2 dose 
S 
synthesis phase of cell cycle in which DNA is replicated 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SMC 
safety monitoring committee 
SOC 
system organ class 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 
TKI 
tyrosine kinase inhibitor 
Tmax 
time to reach Cmax 
ULN 
upper limit of normal 
US 
United States 
Vz/F 
apparent volume of distribution during the terminal phase 
WHO 
World Health Organization 
 
 


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3. 
SYNOPSIS 
Title 
Phase 1b/2 Safety, Pharmacokinetic, and Efficacy Study of G1T38 in 
Combination with Osimertinib in Patients with EGFR 
Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC) 
Study Rationale 
Non-small cell lung cancers (NSCLCs) represent the vast majority of 
lung cancers around the world, and epidermal growth factor receptor 
(EGFR) mutations occur in approximately 15% of NSCLCs in the 
United States and up to 62% of NSCLCs in Asia. Osimertinib 
(Tagrisso®) has been established as the second-line standard of care in 
EGFR-positive NSCLC with a T790M mutation after failure of a 
first-line EGFR tyrosine kinase inhibitor (TKI), and has also recently 
demonstrated benefit in first-line EGFR-positive NSCLC regardless of 
T790M status. Historical median progression-free survival (PFS) with 
second-line osimertinib monotherapy is approximately 10 months, and 
the overall response rate (ORR) is approximately 70%. Nearly all 
patients eventually develop resistance to osimertinib and experience 
disease progression. 
The putative resistance mechanisms to osimertinib include activating 
mutations in PIK3CA, MEK1, and KRAS; amplifications in MET, 
HER2, and FGFR1; activation of the IGF1R pathway; and EGFR 
C797S mutation. Many of these are upstream of cyclin-dependent 
kinase 4/6 (CDK4/6), suggesting that combining G1T38 with 
osimertinib has the potential to block these resistance pathways, delay 
the time to resistance, prolong PFS, and thus delay the need for 
cytotoxic chemotherapy. 
In a well-established, erlotinib-resistant, T790M-positive NSCLC 
murine model, adding G1T38 to erlotinib treatment resulted in a 
77% delay in tumor growth compared with erlotinib alone; whereas, 
erlotinib alone showed no statistically significant change compared 
with vehicle control. Furthermore, the addition of G1T38 to afatinib 
treatment nearly doubled the time to resistance when compared with 
treatment with afatinib only. Finally, in murine tumors that became 
resistant to afatinib, the addition of G1T38 caused stable disease (SD). 
These results suggest that the addition of G1T38 to an EGFR inhibitor 
could potentially extend PFS in patients with NSCLC. 
Clinical Phase 
1b/2 
Indication 
Treatment of EGFR T790M mutation-positive metastatic (Stage IV) 
NSCLC after first-line EGFR TKI failure 




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Study Design 
This is a Phase 1b/2, multicenter, open-label study of the safety, 
tolerability, pharmacokinetics (PK), and efficacy of G1T38 in 
combination with osimertinib for patients with EGFR mutation-positive 
metastatic NSCLC. This open-label study consists of 2 parts: Part 1 will 
evaluate the effect of osimertinib on the PK parameters of G1T38 and 
the safety and tolerability (including dose-limiting toxicities [DLTs]) of 
escalating doses of G1T38 in combination with osimertinib to 
determine the recommended Phase 2 dose (RP2D); and Part 2 will be a 
randomized portion to further evaluate the safety, tolerability, and 
efficacy of the RP2D. Both parts of the study include 3 study phases: 
Screening Phase, Treatment Phase, and Survival Follow-up Phase. The 
Treatment Phase begins on the day of the first dose of study drug and 
completes at the Post-Treatment visit.  
Part 1 
Part 1 Pharmacokinetic Interaction and Dose-Escalation Cohorts 
Cohort 1: Six patients will be enrolled in the first cohort in Part 1 to 
assess the potential effect of osimertinib on the PK parameters of 
G1T38. G1T38 is a substrate of the breast cancer resistance protein 
(BCRP) transporter protein and osimertinib has been shown to increase 
the area under the concentration-time curve (AUC) and maximum 
concentration (Cmax) of concurrently administered rosuvastatin, a BCRP 
substrate, by 35% and 72%, respectively. Patients will receive a single 
oral dose of G1T38 200 mg on Cycle 1 Day -16 and blood samples for 
G1T38 PK evaluation will be collected over the subsequent 48-hour 
period. Patients will then receive oral osimertinib 80 mg once daily 
without G1T38 on Cycle 1 Days -14 to -3, and then both G1T38 and 
osimertinib on Cycle 1 Day -2, after which blood samples for G1T38 
PK evaluation will be collected over the subsequent 48-hour period. 
Osimertinib once-daily dosing will continue on Cycle 1 Day -1 and 
through the end of the Treatment Phase. On Cycle 1 Day 1, patients will 
begin G1T38 once-daily dosing, which will continue through the end of 
the Treatment Phase (note: there is no Day 0 in the study). DLTs will be 
evaluated from Cycle 1 Day -16 through Cycle 1 Day 28 (the DLT 
period). A safety monitoring committee (SMC) will evaluate all safety 
and available PK data through the DLT period for Cohort 1 prior to the 
enrollment of additional cohorts. 
Cohorts 2 and beyond: Following completion of Cohort 1, additional 
sequential dose-escalation cohorts may be enrolled using a standard 
3 + 3 design and will follow the same schedule as described for the first 
cohort. All dose escalation/de-escalation recommendations made by the 
SMC will be based on review of safety and available PK data from the 
DLT period of the current cohort, as well as the cumulative safety data 
from all patients enrolled. 
Definition of Dose-Limiting Toxicities 
Dose-limiting toxicities are drug-related adverse events (AEs) defined 
as follows: 
• 
Grade 4 neutropenia 
• 
≥ Grade 3 neutropenic infection/febrile neutropenia 
• 
Grade 4 thrombocytopenia 


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• 
≥ Grade 3 thrombocytopenia with bleeding 
• 
≥ Grade 3 nonhematologic toxicity (additional criterion for nausea, 
vomiting, diarrhea, or fatigue: lasting > 5 days with maximal 
medical management) 
• 
Liver function test abnormalities meeting Hy’s Law criteria 
(aspartate aminotransferase [AST] or alanine aminotransferase 
[ALT] ≥ 3 × upper limit of normal [ULN] and total bilirubin 
≥ 2 × ULN).   All study drugs must be permanently discontinued in 
any patient meeting Hy’s Law criteria. 
Part 2 
In Part 2, eligible patients will be enrolled into a randomized portion of 
the study. Patients will be randomized (1:1) to receive osimertinib or 
G1T38 (at the RP2D) + osimertinib, with stratification by presence of 
central nervous system (CNS) metastases (yes versus no) and ethnicity 
(Asian versus non-Asian). Following screening, patients will begin 
osimertinib or G1T38 + osimertinib once-daily oral dosing on Cycle 1 
Day 1. 
Patients who are initially randomized to receive osimertinib alone may 
crossover to the G1T38 + osimertinib group at the time of disease 
progression as determined by blinded independent central review 
(BICR). 
An independent data monitoring committee (IDMC) shall review all 
cumulative safety and efficacy data, as well as all available PK data, 
approximately every 4 months during the Treatment Phase. 
Treatment Duration  
Study drug administration will continue for each patient until disease 
progression per RECIST, Version 1.1, unacceptable toxicity, 
withdrawal of consent, or discontinuation by investigator, whichever 
occurs first. Patients in Part 2 who are initially randomized to receive 
osimertinib alone may crossover to the osimertinib + G1T38 arm at the 
time of disease progression.  
Study Duration 
Part 1: The duration of Part 1 will be approximately 9 months. 
Part 2: The ORR is expected to read out approximately 1 year after 
Part 2 enrollment begins. PFS is expected to read out approximately 
2.5 years after Part 2 enrollment begins. 
The Survival Follow-up Phase will continue until at least 50% of the 
patients in Part 2 have died. 
Approximate Number of 
Patients 
Overall, up to 144 patients will be enrolled in the study. In Part 1, up to 
36 patients may be enrolled. In Part 2, 108 patients will be enrolled. 
Number of Study Centers 
Approximately 50 centers globally may participate.   
Diagnosis and Key Criteria 
for Inclusion 
For a patient to be eligible for participation in this study, all of the 
following criteria must apply. A full list of inclusion criteria are 
provided in Section 7.1.1.  
• 
Women or men, 18 years or older 
• 
Histologic or cytologic confirmed diagnosis of NSCLC 
• 
Stage IV NSCLC 


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• 
Documented EGFR mutation (at any time since the initial diagnosis 
of NSCLC) known to be associated with EGFR TKI sensitivity 
(including G719X, exon 19 deletion, L858R, L861Q) 
o Part 2 Only: Tumor T790M mutation-positive status 
based on an appropriate test (tumor biopsy or cell-free 
DNA [cfDNA]) taken after documented disease 
progression on first-line treatment with a first or second 
generation EGFR TKI 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 
of 0 or 1, with no deterioration over the previous 2 weeks and a 
minimum life expectancy of 12 weeks 
• 
Evaluable (Part 1 only) or measurable disease  
• 
Left ventricular ejection fraction (LVEF) ≥ institution’s lower limit 
of the reference range 
• 
Adequate bone marrow reserve and organ function as demonstrated 
by the following laboratory values: 
o Hemoglobin ≥ 90 g/L 
o ANC ≥ 1.5 × 109/L 
o Platelet count ≥ 100 × 109/L 
o Calculated creatinine clearance ≥ 50 mL/minute 
o Total bilirubin ≤ 1.5 × ULN; < 3 × ULN if the patient has 
documented Gilbert’s disease or liver metastases 
o ALT < 2.5 × ULN if no demonstrable liver metastases or 
< 5 × ULN in the presence of liver metastases 
o AST < 2.5 × ULN if no demonstrable liver metastases or 
< 5 × ULN in the presence of liver metastases  
Additional criteria that apply to Part 2 only: 
• 
Measurable disease as defined in RECIST, Version 1.1, as 
determined by the investigator 
Key Criteria for Exclusion 
A patient will not be eligible for participation in this study if any of the 
following criteria apply. A full list of exclusion criteria are provided in 
Section 7.1.2. 
o Treatment with any of the following: 
o EGFR TKIs (erlotinib, gefitinib, afatinib, osimertinib) within 
9 days of the first dose of study drug; other approved EGFR 
TKIs within 5 half-lives of the first dose of study drug 
o Investigational agents within 28 days, or 5 half-lives, 
whichever is longer, of the first dose of study drug; antibody 
based therapy within 6 weeks of the first dose of study drug 
o Part 1 only: More than 2 prior lines of cytotoxic chemotherapy 
for advanced NSCLC 
o Part 2 only: Any prior cytotoxic chemotherapy for advanced 
NSCLC 
 
Part 2 only: Previous treatment with osimertinib or other 
T790M active EGFR TKI 
o Blood transfusions or hematopoietic growth factor therapy 
within 14 days of first screening visit 
o Prior radiotherapy treatment to > 25% of the bone marrow or 
radiotherapy with a wide field of radiation within 28 days of the 


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first dose of study drug 
o Patients receiving medications, herbal supplements, or foods 
known to be potent inhibitors of cytochrome P450 (CYP)3A4 
or orally administered sensitive substrates of CYP3A4 within 
14 days prior to first dose of study drug (see Sections 8.5.1 and 
8.5.2) 
o Patients receiving medications, herbal supplements, or foods 
known to be potent inducers of CYP3A4 within 21 days prior 
to first dose of study drug (see Section 8.5.2) 
o Patients receiving medications, herbal supplements, or foods 
known to be potent inhibitors of BCRP within 14 days prior to 
first dose of study drug (see Section 8.5.2) 
o Part 1 only: Patients receiving medications that raise gastric pH 
within 7 days prior to first dose of study drug (see Section 
8.5.5).  
o Any unresolved toxicities from prior surgeries or therapy 
> Grade 1 (Common Terminology Criteria for Adverse Events 
[CTCAE] Version 4.03) at the time of starting study drug with 
the exception of alopecia (any grade) and platinum therapy-
related peripheral neuropathy (> Grade 2) 
o Known active uncontrolled or symptomatic central nervous 
system (CNS) metastases, carcinomatous meningitis, or 
leptomeningeal disease as indicated by clinical symptoms, 
cerebral edema, and/or progressive growth. Patients with a 
history of CNS metastases or cord compression are eligible if 
they are currently asymptomatic and clinically stable off 
anticonvulsants and steroids for at least 28 days prior to first 
dose of G1T38. 
o Any evidence of severe or uncontrolled systemic diseases, 
including uncontrolled hypertension and active bleeding 
diatheses, which in the investigator’s opinion makes it 
undesirable for the patient to participate in the study or which 
would jeopardize compliance with the protocol  
o Known chronic, active infection  
o Cardiac criteria as outlined in Section 7.1.2 
o Past medical history of interstitial lung disease, drug-induced 
interstitial lung disease (ILD), radiation pneumonitis which 
required steroid treatment, or any evidence of clinically active 
interstitial lung disease 
o Prior hematopoietic stem cell or bone marrow transplantation 
Other Medicinal Products 
Osimertinib 80 mg orally once daily, with or without food. 
Investigational Medicinal 
Product Dosage and 
Administration 
G1T38 will be administered orally once daily. The starting dose for 
Part 1 will be a G1T38 dose of 200 mg once daily and subsequent dose 
levels will be determined by the SMC. All patients in Part 2, will 
receive the RP2D selected by the SMC. All doses of G1T38 shall be 
administered with food. 




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2 treatment groups. The odds ratio and its associated 80% CI will be 
presented.   
In addition, potential influences of baseline patient characteristics such 
as age, ECOG performance status, and selected biomarkers on the 
endpoints may be evaluated to compare the 2 treatment groups.  
For Part 2 of the study, because crossover to G1T38 + osimertinib is 
allowed for patients following progression on osimertinib alone, the 
treatment effect on OS may be confounded and may not be estimated 
properly by the above defined methods. Therefore, an exploratory 
analysis will be performed using the rank-preserving structural failure 
time (RPSFT) method and Cox model with inverse probability of 
censoring weighting (IPCW) to correct for confounding introduced by 
the crossover. 
Safety Analysis 
The safety analysis will include all treated patients. Descriptive 
statistics of safety will be presented. All treatment-emergent AEs, 
drug-related AEs, serious adverse events (SAEs), and drug-related 
SAEs will be tabulated using worst grade per National Cancer Institute 
(NCI) CTCAE, Version 4.03 criteria by system organ class and 
preferred term. On-study laboratory parameters including hematology, 
chemistry, and liver function tests will also be summarized using worst 
grade per NCI CTCAE, Version 4.03 criteria. 
Rationale for Number of 
Patients 
It is estimated that up to 36 patients will be enrolled in the 
dose-escalation part of the study (Part 1). The actual number of patients 
will depend on the number of dose levels/cohorts that are tested.   
For the randomized part of the study (Part 2), it is assumed that the 
overall 1-sided type I error rate is 0.1 and the type II error rate used to 
compute sample size is 0.20 (corresponding to 80% power). Patients 
will be randomized using a 1:1 treatment allocation ratio between the 
2 treatment groups (osimertinib versus G1T38 + osimertinib).  
Assuming a 10.1 month median PFS for the osimertinib group based on 
historical data, and an HR of 0.6, the required number of PFS events is 
70. Assuming an accrual period of 12 months and an additional 
follow-up period of 18 months after the last patient is enrolled, the 
calculated total sample size is 98 patients. Allowing for a 
dropout/lost-to-follow-up rate of approximately 10%, gives an adjusted 
total sample size of 108 patients for Part 2. 


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4. 
INTRODUCTION 
4.1. 
Background 
The cyclin D/cyclin-dependent kinase 4/6 (CDK4/6)/p16INK4a/retinoblastoma protein (Rb) 
pathway is frequently disrupted in cancer. A majority of human neoplasms maintain 
functional Rb, but have aberrations that increase the activity of CDK4/6, which inhibits Rb 
function and allows cell proliferation (Ortega et al 2002; Shapiro 2006). As such, CDK4/6 
appears to be a key enzyme necessary for the proliferation of human cancers that have 
functional Rb. G1 Therapeutics, Inc. is developing G1T38 as a potent and selective small 
molecule inhibitor of the CDK4/6-cyclin D complex for oral treatment of patients with 
CDK4/6-dependent tumors, such as non-small cell lung cancer (NSCLC). 
NSCLC represent the vast majority of lung cancers around the world, and epidermal growth 
factor receptor (EGFR) mutations occur in approximately 15% of NSCLC in the United 
States and up to 62% of cases in Asia. Osimertinib (Tagrisso®), a third generation EGFR 
tyrosine kinase inhibitor (TKI), has been established as the second-line standard of care in 
patients with metastatic EGFR T790M mutation positive NSCLC whose disease has 
progressed on or after a first-line EGFR TKI, and has also recently demonstrated benefit in 
first-line EGFR-positive NSCLC regardless of T790M status (Sequist and Neal, 2017; 
Ramalingam et al 2017). Standard of care treatment following disease progression with 
osimertinib remains parenteral cytotoxic chemotherapy as no oral treatment options currently 
exist in this setting. 
Historical median progression-free survival (PFS) with osimertinib monotherapy is 
approximately 10 months, and the overall response rate (ORR) is approximately 70% 
(Tagrisso Prescribing Information 2017). Nearly all patients eventually develop resistance to 
osimertinib and experience disease progression. The putative resistance mechanisms to 
osimertinib include activating mutations in PIK3CA, MEK1, and KRAS, and/or 
amplifications in MET, human epidermal growth factor receptor 2 (HER2), fibroblast growth 
factor receptor 1 (FGFR1), and activation of the insulin-like growth factor 1 receptor 
(IGF1R) pathway; many of these are upstream of CDK4/6 (Ramalingam et al 2017; 
Minari et al 2016; Ko et al 2017). G1T38 has the potential to block these resistance 
pathways, delay the time to resistance, and prolong PFS when added to osimertinib, and thus 
has the potential to delay the need for cytotoxic chemotherapy. Nonclinical 
osimertinib-resistant tumor models are not currently available. Therefore, the addition of 
G1T38 to either erlotinib or afatinib, which are first and second generation EGFR inhibitors, 
respectively, has been evaluated in the H1975 mouse model (EGFRL858R/T790M) to assess 
proof of principle. Tumor growth delay was compared in mice treated with an EGFR 
inhibitor (erlotinib or afatinib) alone or EGFR inhibitor and G1T38. As the EGFRT790M 
mutation is known to accelerate time to resistance to afatinib and erlotinib, it was anticipated 
that erlotinib alone would be ineffective and the time to afatinib resistance would be short. 
As expected, mice treated with erlotinib showed no statistically significant difference in 
tumor growth when compared to the vehicle only cohort. However, when G1T38 was added 
to erlotinib treatment, there was a 77% tumor growth delay when compared to controls, 
suggesting the addition of G1T38 reversed erlotinib resistance. Furthermore, the addition of 
G1T38 to afatinib treatment extended time to resistance from 18 days (afatinib alone) to 








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In Study G1T38-01, single or twice daily (total daily dose split into 2 equal doses, taken 
every 12 hours) oral doses of G1T38 in the dose range of 3 to 600 mg/day appeared to be 
well to moderately tolerated in a group of healthy male and female subjects. In most subjects 
with moderate tolerability, gastrointestinal AEs were the most common moderate intensity 
treatment-emergent AEs (TEAEs). Dosing under fed conditions appeared to improve 
gastrointestinal tolerability. Effects on hematologic parameters were not observed due to the 
limited duration of dosing. 
There were no deaths, other serious adverse events (SAEs), or AEs that led to withdrawal 
from the study and no subjects experienced severe or life-threatening TEAEs. For subjects 
treated with G1T38 in Study G1T38-01, 37 (65%) subjects reported a total of 
121 treatment-related TEAEs. The most frequently (≥ 20% of subjects) reported 
treatment-related TEAEs by Medical Dictionary for Regulatory Activities (MedDRA) system 
organ class (SOC) were gastrointestinal disorders (reported by 60% of pooled G1T38-dosed 
subjects versus 17% of pooled placebo-dosed subjects) and nervous system disorders (33% 
for both pooled G1T38-dosed subjects and placebo-dosed subjects). The most frequently 
(≥ 10% of all subjects) reported treatment-related TEAEs by preferred term were diarrhea 
(reported by 46% of pooled G1T38-dosed subjects versus 6% of pooled placebo-dosed 
subjects), nausea (33% versus 6%, respectively), headache (18% versus 22%, respectively), 
and fatigue (12% versus 6%, respectively). Note: Six subjects reported ‘loose stool(s)’ that 
did not meet the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 
definition of diarrhea that requires an increase in stool frequency; however, the MedDRA 
codes ‘loose stool(s)’ to diarrhea. Exclusion of these 6 subjects with loose stool(s), resulted 
in 20 out of 57 (35%) of pooled G1T38-dosed subjects reporting diarrhea. The intensity of 
loose stool(s) in all 6 subjects was reported as mild.  
Sixteen (28%) of 57 G1T38-dosed subjects experienced at least 1 treatment-related TEAE of 
moderate (Grade 2) intensity. The most common treatment-related TEAEs of moderate 
intensity were diarrhea in 6 (11%) subjects, nausea in 5 (9%) subjects, headache in 
5 (9%) subjects, and somnolence in 2 (4%) subjects. In the placebo group, 
1 treatment-related headache of moderate severity was reported in 1 (6%) placebo-dosed 
subject. 
Gastrointestinal tolerability of G1T38 was improved by dosing concurrently with a high-fat 
meal. Four (50%) of 8 subjects in the fed state versus 8 (100%) of 8 subjects in the fasted 
state experienced a gastrointestinal TEAE. 
In ongoing Study G1T38-02, as of the data cut date of 25 August 2017, 18 patients have 
received at least 1 dose of G1T38. Dose levels administered included 200 mg once daily 
(n = 6); 100 mg twice daily (n = 6); 300 mg once daily (n = 3); and 150 mg twice daily 
(n = 3). G1T38 is administered on a continuous daily dosing schedule and the longest 
duration of therapy was 197 days as of 25 August 2017. One DLT of Grade 4 neutropenia 
has been observed in 1 patient administered 200 mg G1T38 once daily. This patient’s 
neutropenia recovered with dose interruption for 20 days and treatment was restarted at 
150 mg once daily with no further episodes of Grade 4 neutropenia. No deaths or SAEs have 
been reported to date. 
Fifteen of 18 patients (83.3%) had at least 1 G1T38-related AE (Table 4-1). The most 
common G1T38-related AEs occurring in ≥ 5 subjects were neutrophil count decreased 
(9 subjects [50%]), white cell count decreased (7 subjects [38.9%]), anemia (6 subjects 


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[33.3%]), neutropenia (5 subjects [27.8%]), diarrhea (5 subjects [27.8%]), and nausea 
(5 subjects [27.8%]). 
 
Table 4-1 
Summary of G1T38-Related Adverse Events by Preferred Term and 
CTCAE Grade Occurring in Study G1T38-02 (as of 25 August 2017) 
Preferred Term 
G1T38-02 
 (N = 18)a 
Grade 1-2 
n (%) 
Grade 3 
n (%) 
Grade 4 
n (%) 
Grade 5 
n (%) 
Overall 
n (%) 
Number (%) of patients with any 
G1T38-related TEAEs 
11 (61.1) 
3 (16.7) 
1 (5.6) 
0 
15 (83.3) 
Neutrophil count decreased 
7 (38.9) 
2 (11.1) 
0 
0 
9 (50.0) 
White blood cell count decreased 
7 (38.9) 
0 
0 
0 
7 (38.9) 
Anaemia 
6 (33.3) 
0 
0 
0 
6 (33.3) 
Diarrhoea 
5 (27.8) 
0 
0 
0 
5 (27.8) 
Nausea 
5 (27.8) 
0 
0 
0 
5 (27.8) 
Neutropenia 
3 (16.7) 
1 (5.6) 
1 (5.6) 
0 
5 (27.8) 
Haematuria 
3 (16.7) 
0 
0 
0 
3 (16.7) 
Vomiting 
3 (16.7) 
0 
0 
0 
3 (16.7) 
Blood creatinine increased 
2 (11.1) 
0 
0 
0 
2 (11.1) 
Platelet count decreased 
2 (11.1) 
0 
0 
0 
2 (11.1) 
Alopecia 
1 (5.6) 
0 
0 
0 
1 (5.6) 
Blood bilirubin increased 
1 (5.6) 
0 
0 
0 
1 (5.6) 
Blood lactate dehydrogenase increased 
1 (5.6) 
0 
0 
0 
1 (5.6) 
Blood urea increased 
1 (5.6) 
0 
0 
0 
1 (5.6) 
Dry eye 
1 (5.6) 
0 
0 
0 
1 (5.6) 
Dry mouth 
1 (5.6) 
0 
0 
0 
1 (5.6) 
Lacrimation increased 
1 (5.6) 
0 
0 
0 
1 (5.6) 
Leukopenia 
1 (5.6) 
0 
0 
0 
1 (5.6) 
Monocyte count decreased 
1 (5.6) 
0 
0 
0 
1 (5.6) 
Stomatitis 
1 (5.6) 
0 
0 
0 
1 (5.6) 






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Based on the DDI information available for osimertinib and the nonclinical evaluation of 
G1T38, it is highly unlikely that G1T38 will alter the PK of osimertinib. This conclusion is 
based on the mitigating data in Table 4-2. 
Table 4-2 
Osimertinib and G1T38: Potential Risks for Drug-Drug Interactions and 
Mitigating Data  
Potential Risk 
Mitigating Data 
G1T38 inhibits CYP3A4 (IC50 = 78 µM) and 
osimertinib is CYP3A4 substrate 
The strong CYP3A4 inhibitor itraconazole had no 
clinically meaningful effect on the PK of osimertinib 
 
Osimertinib is a CYP3A4 substrate 
G1T38 does not induce CYP3A4 
G1T38 inhibits BCRP (IC50 = 7.21 µM) and 
osimertinib is a BCRP substrate 
Does not meet FDA thresholda as clinically relevant 
using the following FDA formula: [I]/IC50 ≥ 0.1, 
where [I] represents the mean anticipated steady-state 
G1T38 total Cmax for a 600 mg G1T38 dose 
(0.338 µM) 
[I]/IC50 = 0.338 µM/7.21 µM = 0.0468 
a 
FDA Guidance for Industry: Drug Interaction Studies - Study Design, Data Analysis, Implications for Dosing, and 
Labeling Recommendations. February 2012. 
 
4.4.2. 
Dose Rationale 
Part 1 
Single doses of up to 600 mg of G1T38 were safely administered in the FIH study 
 with no ≥ Grade 3 study G1T38-related AEs observed. The ongoing Phase 1/2 
patient study (G1T38-02) utilizing continuous daily doses of G1T38 in combination with 
fulvestrant has examined G1T38 doses of 200 mg once daily, 300 mg once daily, 400 mg 
once daily, 100 mg twice daily, and 150 mg twice daily with no observed SAEs to date and 
only one G1T38-related DLT of Grade 4 neutropenia in a patient receiving 200 mg once 
daily, who had a baseline absolute neutrophil count (ANC) of 1500 cells/mL. The 
neutropenia recovered following a 20-day interruption of G1T38 dosing and re-initiation of 
G1T38 at 150 mg once daily thereafter. The patient remains on study at this reduced dose for 
> 100 days without the occurrence of Grade 4 neutropenia. Subsequent to the G1T38-02 data 
cut date of 25 August 2017, the 400 mg once-daily dose has been determined to be tolerable 
(no DLTs in the 3 patient cohort) by the safety monitoring committee (SMC) and the study is 
currently enrolling patients at a G1T38 dose of 500 mg once daily. 
Osimertinib is classified as a weak inhibitor of BCRP according to the FDA Guidance for 
Industry: Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, 
and Labeling Recommendations (2012). AUC is considered the most relevant parameter in 
terms of G1T38 safety as the chronic administration of CDK4/6 inhibitors such as G1T38 
appears to be the primary factor leading to clinically significant neutropenia, whereas brief 
relatively higher concentrations (ie, Cmax) appear to have little effect on neutropenia as was 
observed in Study G1T38-01. 
The starting dose of G1T38 will be 200 mg once daily in combination with 80 mg once daily 
osimertinib. This G1T38 dose allows a safety coverage of 100% relative to the G1T38 dose 
of 400 mg once daily that was well tolerated in the ongoing Phase 1b/2 study (dose escalation 


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ongoing; dose level as of 04 October 2017 was 500 mg once daily). It is anticipated that the 
potential effect of osimertinib on the PK parameters of G1T38 will not exceed that observed 
with rosuvastatin (a model BCRP substrate). 
Following assessment of the safety, tolerability and PK data for the first cohort in this study, 
subsequent cohorts will be enrolled utilizing a 3+3 design as described in Section 6.1.1. 
Part 2 
The doses of G1T38 and osimertinib to be used in Part 2 of the study will be determined 
during Part 1 as described in Section 6.1.1.  
4.5. 
Risk/Benefit Assessment 
The safety profile of G1T38 observed to date in the ongoing Phase 1/2 study is similar to 
other CDK4/6 inhibitors such as palbociclib, with neutropenia being the most common 
drug-related AE and with Grade 1 and 2 gastrointestinal effects (nausea, vomiting, and 
diarrhea) also being observed. There have been no observed G1T38-related pulmonary, 
cardiac, skin, or clinically significant ophthalmic AEs to date (see Section 4.3.1).   
The most common osimertinib-related AEs (≥ 20%) are diarrhea (41%), rash (34%), dry skin 
(23%), nail toxicity (22%), and fatigue (22%) (Tagrisso Prescribing Information 2017). 
Significantly less frequent, but potentially more severe osimertinib-related AEs include 
pneumonitis/interstitial lung disease, QTc prolongation, cardiomyopathy, and keratitis. Based 
on extensive nonclinical data and clinical data to date with G1T38, none of these more severe 
osimertinib-related AEs have been observed with G1T38 to date. This study includes 
appropriate exclusion criteria, baseline examinations, and on-study monitoring to carefully 
exclude at-risk patients and to evaluate patients for the development of these more severe 
osimertinib-related AEs during the course of the study. Management of osimertinib related 
toxicities shall follow the prescribing information for osimertinib (Tagrisso Prescribing 
Information 2017; see Appendix 2). 
Neutropenia, the vast majority Grade 1 or 2, has also been observed with osimertinib therapy, 
with up to 2.2% of patients experiencing Grade 3 neutropenia. Absolute neutrophil counts 
will be monitored weekly for the first 8 weeks (2 cycles) then every other week for the next 
2 cycles. Beginning with Cycle 5 Day 1, patients with stable ≤ Grade 2 hematologic 
parameters may have hematology monitored monthly (Day 1 of each cycle); patients that do 
not meet this criteria will continue to have every other week assessment of hematologic 
parameters. The neutropenia induced by CDK4/6 inhibitors, including G1T38, is reversible 
with interruption of therapy and dose reduction if necessary. Specific guidelines for 
managing neutropenia are included in Section 8.3.3. 
Patients will be carefully monitored for potential gastrointestinal AEs and managed 
symptomatically with appropriate therapies. G1T38 will also be dosed with food as this was 
shown to improve gastrointestinal tolerability in the FIH study. 
In summary, the potential benefits of extending PFS with osimertinib plus G1T38 and 
delaying the need for cytotoxic chemotherapy outweigh the potential risks of gastrointestinal 
AEs and neutropenia, both of which are easily monitored and treatable. Furthermore, febrile 


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neutropenia with the CDK4/6 inhibitor palbociclib in combination with fulvestrant has been 
reported in only 0.9% of patients, indicating a low risk to the patient, and neutropenia in 
general with CDK4/6 inhibitors recovers in the vast majority of patients with treatment 
interruption and/or dose reduction (Palbociclib Prescribing Information 2017). 
 




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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design and Plan 
This open-label study consists of 2 parts: Part 1 will evaluate the effect of osimertinib on the 
PK parameters of G1T38 and the safety and tolerability of escalating doses of G1T38 in 
combination with osimertinib to determine the recommended Phase 2 dose (RP2D); and 
Part 2 will be a randomized portion to further evaluate the safety, tolerability, and efficacy of 
the RP2D. Both parts of the study include 3 study phases: Screening Phase, Treatment Phase, 
and Survival Follow-up Phase. The Treatment Phase begins on the day of the first dose of 
study drug and completes at the Post-Treatment Visit. 
6.1.1. 
Part 1 
The goals of Part 1 are to determine the effect of osimertinib on the PK parameters of G1T38 
and to determine the RP2D of G1T38 in combination with osimertinib by assessing the safety 
(including DLTs), tolerability, PK, and efficacy of escalating doses of G1T38 administered 
with osimertinib.  
During Part 1, an SMC will provide oversight and guidance regarding safety concerns, as 
outlined in the SMC Charter. All dose escalation/de-escalation decisions will made by the 
SMC, which will be comprised of the sponsor, medical monitor, independent medical doctor, 
and the principal investigator(s). The SMC will make the final dose determination for each 
subsequent cohort. Therefore the actual dose may differ from the projected dose levels in 
Table 6-1 as the SMC may determine that intermediate dose levels warrant exploration. 
Part 1 Pharmacokinetic Interaction and Dose-Escalation Cohorts 
Cohort 1: Six patients will be enrolled in the first cohort in Part 1 to assess the potential 
effect of osimertinib on the PK parameters of G1T38. Projected dose levels are presented in 
Table 6-1. Patients will receive a single oral dose of G1T38 200 mg on Cycle 1 Day -16 and 
blood samples for G1T38 PK evaluation will be collected over the subsequent 48-hour 
period. Patients will then receive oral osimertinib 80 mg once daily without G1T38 on 
Cycle 1 Days -14 to -3, and then both G1T38 and osimertinib on Cycle 1 Day -2, after which 
blood samples for G1T38 PK evaluation will be collected over the subsequent 48-hour 
period. Osimertinib once-daily dosing will continue on Cycle 1 Day -1 and through the end 
of the Treatment Phase. On Cycle 1 Day 1, patients will begin G1T38 once-daily dosing, 
which will continue through the end of the Treatment Phase (note: there is no Day 0 in the 
study). DLTs will be evaluated from Cycle 1 Day -16 through Cycle 1 Day 28 (the DLT 
period). An SMC will evaluate all safety and available PK data through the DLT period for 
Cohort 1 prior to the enrollment of additional cohorts.  
Thereafter, additional sequential dose-escalation cohorts may be enrolled using a standard 
3 + 3 design and will follow the same schedule as described for the first cohort. All dose 
escalation/de-escalation recommendations made by the SMC will be based on review of 
safety and available PK from the DLT period of the current cohort, as well as the cumulative 
safety data from all patients enrolled. Further details with respect to decision making will be 
described in the SMC Charter. If a patient is withdrawn prior to completing all of the 


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assessments during the DLT period for reasons other than toxicity in any cohort in Part 1, the 
patient will be replaced. 
Table 6-1 
Projected G1T38 Dose Levels, Part 1 
Cohort 
G1T38 Dosea (mg) 
Level 2 dose reduction  
100 
Level 1 dose reduction 
150 
1 
200 
2 
300 
3 
400 
4 
500 
5 
650 
a 
Intermediate dose levels may be explored at the discretion of the SMC 
 
The maximum G1T38 dose in this study will not exceed 650 mg/day. 
6.1.1.1. 
G1T38 Dose Evaluation Criteria 
In the first Cohort of 6 patients, a relatively low dose of G1T38 will be administered to allow 
for a sufficient safety window. This low dose of G1T38 is anticipated to be below the 
maximum tolerated dose (MTD), even if osimertinib increases the systemic exposure of 
G1T38 (see Section 4.4.2). However, if ≥ 2 of 6 patients experience a DLT, then the MTD 
will have been exceeded and a lower G1T38 dose level may be explored. If 1 or fewer 
patient(s) in the first cohort of 6 experience a DLT, then 3 patients may be enrolled at the 
next SMC recommended G1T38 dose level. 
The G1T38 dose evaluation criteria for Cohorts 2 and beyond are listed below. 
• If there is no DLT in a given dose level cohort, then 3 patients may be enrolled at the 
next SMC recommended G1T38 dose level.  
• If there is 1 DLT in a given dose level cohort of 3 patients, an additional 3 patients 
will be enrolled at this G1T38 dose level. If no additional DLTs are observed (ie, 
≤ 1 out of 6 with DLT), escalation may proceed to the next SMC recommended 
G1T38 dose level.  
• If there are ≥ 2 DLTs in a given dose level cohort, then the MTD will have been 
exceeded and a lower G1T38 dose level may be explored as determined by the SMC. 
6.1.1.2. 
Definition of Dose-Limiting Toxicities (Applicable to Cycle 1 Day -16 
through Cycle 1 Day 28 in Part 1) 
Dose-limiting toxicities are drug-related AEs defined as follows: 
• Grade 4 neutropenia 
• ≥ Grade 3 neutropenic infection/febrile neutropenia 
• Grade 4 thrombocytopenia  
• ≥ Grade 3 thrombocytopenia with bleeding 
• ≥ Grade 3 nonhematologic toxicity (additional criteria for nausea, vomiting, diarrhea, 
or fatigue: lasting > 5 days with maximal medical management) 


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• Liver function test abnormalities meeting Hy’s Law criteria (aspartate 
aminotransferase [AST] or alanine aminotransferase [ALT] ≥ 3 × upper limit of 
normal [ULN] and total bilirubin ≥ 2 × ULN). All study drugs must be permanently 
discontinued in any patient meeting Hy’s Law criteria. 
Each patient will be evaluated for toxicity during the Treatment Phase. The toxicity of 
G1T38 administered with osimertinib will be assessed by the investigators using National 
Cancer Institute (NCI) CTCAE, Version 4.03. 
6.1.2. 
Part 2 
In Part 2, eligible patients will be enrolled into a randomized portion of the study. Patients 
will be randomized (1:1) to receive osimertinib or G1T38 (at the RP2D) + osimertinib. 
Following screening, patients will begin once daily oral dosing with osimertinib or 
G1T38 + osimertinib on Cycle 1 Day 1.  
Patients who are initially randomized to receive osimertinib alone may crossover to 
G1T38 + osimertinib at the time of disease progression as determined by blinded 
independent central review (BICR). Patients should continue osimertinib monotherapy 
uninterrupted prior to crossover. The date of crossover is defined as the first date the patient 
receives G1T38 + osimertinib. 
An independent data monitoring committee (IDMC) shall review all cumulative safety and 
efficacy data, as well as all available PK data, approximately every 4 months during the 
Treatment Phase of Part 2 of the study. The IDMC shall make recommendations regarding 
continuation of the study, suggested modification of the study, or cessation of the study based 
on cumulative safety and efficacy data, including cessation for futility. Further details with 
respect to decision making will be described in the IDMC Charter. 


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7. 
STUDY POPULATION  
7.1. 
Selection of Patients 
Overall, up to 144 patients may be enrolled in the study.  
In Part 1, up to 36 patients may be enrolled.  
In Part 2, up to 108 patients will be enrolled. 
7.1.1. 
Inclusion Criteria 
Patient eligibility shall be reviewed and documented by an appropriately qualified member of 
the investigator’s study team before patients are included in the study. Patients must meet all 
of the following inclusion criteria to be eligible for enrollment into the study: 
1. Provision of signed and dated written informed consent prior to any study specific 
procedures, sampling, and analysis 
2. Women or men, 18 years or older 
3. Histologic or cytologic confirmed diagnosis of NSCLC 
4. Stage IV NSCLC 
5. Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known 
to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, 
L861Q). Patients in Part 1 that are EGFR TKI treatment naive will be enrolled based on a 
locally available EGFR mutation test result that has been FDA-approved and performed 
in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (US 
sites) or based on a locally available EGFR mutation test result that has been performed 
in an accredited laboratory (sites outside of the US). 
a. Part 2 Only: Tumor EGFR T790M mutation-positive status after documented 
disease progression on first-line treatment with a first or second generation 
EGFR TKI. Patients will be enrolled based on a locally available T790M 
mutation test result (tumor biopsy or cell-free DNA [cfDNA]) that has been 
FDA-approved (eg, cobas® EGFR Mutation Test v2, FoundationOne CDx™) 
and performed in a CLIA-certified laboratory (US sites) or a locally available 
T790M mutation test result (tumor biopsy or cfDNA) that has been performed 
in an accredited laboratory (sites outside of the US). Testing for the presence 
of the T790M mutation in plasma specimens (cfDNA) is recommended only 
in patients for whom a tumor biopsy cannot be obtained. 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with no 
deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks 


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7. Evaluable disease (Part 1 only) or measurable disease as defined in Response Evaluation 
Criteria in Solid Tumors (RECIST), Version 1.1, as determined by the investigator 
• Measurable disease is defined as having at least 1 lesion, not previously 
irradiated, that can be accurately measured at baseline as ≥ 10 mm in the 
longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) 
with computerized tomography (CT) or magnetic resonance imaging (MRI), 
which is suitable for accurate repeated measurements. 
8. Left ventricular ejection fraction (LVEF) ≥ institution’s lower limit of the reference range 
9. Adequate bone marrow reserve or organ function as demonstrated by the following 
laboratory values: 
a. Hemoglobin ≥ 90 g/L 
b. ANC ≥ 1.5 × 109/L 
c. Platelet count ≥ 100 × 109/L 
d. Calculated creatinine clearance ≥ 50 mL/min (by Cockcroft-Gault formula 
[Cockcroft and Gault 1976] or 51Cr-EDTA)  
e. Total bilirubin ≤ 1.5 × ULN; < 3 × ULN if the patient has documented 
Gilbert’s disease or liver metastases 
f. ALT < 2.5 × ULN if no demonstrable liver metastases or < 5 × ULN in the 
presence of liver metastases 
g. AST < 2.5 × ULN if no demonstrable liver metastases or < 5 × ULN in the 
presence of liver metastases  
10. Contraception: Patients must be willing to comply with the requirements for 
contraception as described in Section 8.10 
Additional criteria that apply to Part 2 only: 
11. Measurable disease as defined in RECIST, Version 1.1, as determined by the investigator 
7.1.2. 
Exclusion Criteria 
A patient will not be eligible for participation in this study if any of the following criteria 
apply. 
1. Treatment with any of the following: 
a.  EGFR TKIs (erlotinib, gefitinib, afatinib, osimertinib) within 9 days of the 
first dose of study drug; other approved EGFR TKIs within 5 half-lives of the 
first dose of study drug 


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b. Investigational agents within 28 days, or 5 half-lives, whichever is longer, of 
the first dose of study drug; antibody based therapy within 6 weeks of the first 
dose of study drug 
c. Part 1: More than 2 prior lines of cytotoxic chemotherapy for advanced 
NSCLC 
d. Part 2: Previous treatment with osimertinib or other T790M active EGFR TKI 
e. Part 2:Any prior cytotoxic chemotherapy for advanced NSCLC 
2. Major surgery within 14 days of the first screening visit 
3. Blood transfusions or hematopoietic growth factor therapy within 14 days prior of first 
screening visit 
4. Prior radiotherapy treatment to > 25% of the bone marrow or radiotherapy with a wide 
field of radiation within 28 days of the first dose of study drug 
5. Patients receiving medications, herbal supplements, or foods known to be potent 
inhibitors of CYP3A4 or orally administered sensitive substrates of CYP3A4 within 14 
days prior to first dose of study drug, including but not limited to the following: 
a. Inhibitors, for example: clarithromycin, diltiazem, erythromycin, grapefruit 
juice, itraconazole, ketoconazole, nefazodone, ritonavir, telithromycin, and 
verapamil 
b. Substrates, for example: astemizole, cisapride, cyclosporine, 
dihydroergotamine, ergotamine, everolimus, pimozide, quinidine, sirolimus, 
and tacrolimus 
6. Patients receiving medications, herbal supplements, or foods known to be potent inducers 
of CYP3A4 within 21 days prior to the first dose of study drug, including but not limited 
to the following: 
a. Inducers, for example: carbamazepine, Hypericum perforatum (St. John’s 
wort), phenobarbital, phenytoin, rifampin 
7. Patients receiving medications, herbal supplements, or foods known to be potent 
inhibitors of BCRP within 14 days prior to first dose of study drug, including but not 
limited to the following: 
a. Inhibitors, for example: sulfasalazine, curcumin, turmeric supplements, 
cyclosporine, eltrombopag 
8. Part 1: Patients receiving medications that raise gastric pH within 7 days prior to first 
dose of study drug such as proton pump inhibitors (eg, omeprazole, pantoprazole, 
lansoprazole, esomeprazole, rabeprazole, dexlansoprazole), H2 blockers (eg, nizatidine, 


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famotidine, cimetidine, ranitidine), and antacids (eg, sodium bicarbonate, calcium 
carbonate, aluminum-based antacids, magnesium compounds, alginic acid).  
9. Any unresolved toxicities from prior surgeries or therapy of > Grade 1 (CTCAE, 
Version 4.03) at the time of starting study drug with the exception of alopecia (any grade) 
and platinum therapy-related peripheral neuropathy (> Grade 2) 
10. Known active uncontrolled or symptomatic central nervous system (CNS) metastases, 
carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, 
cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or 
cord compression are eligible if they are currently asymptomatic and clinically stable off 
anticonvulsants and steroids for at least 28 days prior to first dose of G1T38. 
11. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled 
hypertension and active bleeding diatheses, which in the investigator’s opinion makes it 
undesirable for the patient to participate in the study or which would jeopardize 
compliance with the protocol 
12. Known chronic, active infection including but not limited to hepatitis B virus, hepatitis C 
virus, tuberculosis, and human immunodeficiency virus (HIV); screening for chronic 
conditions is not required 
13. Any of the following cardiac criteria: 
a. Mean resting corrected QT interval (QTc) > 470 msec obtained from 
3 electrocardiograms (ECGs), using the screening clinic ECG machine 
derived QTc value 
b. Any clinically important abnormalities in rhythm, conduction, or morphology 
or resting ECG, eg, complete left bundle branch block, third degree heart 
block, second degree heart block, PR interval > 250 msec 
c. Any factors that increase the risk of QTc prolongation (see Appendix 3 for list 
of drugs) or risk of arrhythmic events such as heart failure, hypokalemia, 
congenital long QT syndrome, family history of long QT syndrome or 
unexplained sudden death under 40 years of age in first degree relatives, or 
any concomitant medication known to prolong the QT interval 
d. Uncontrolled ischemic heart disease or uncontrolled symptomatic congestive 
heart failure (Class III or IV as defined by the New York Heart Association 
[NYHA] functional classification system) 
e. Known history of stroke, cerebrovascular accident, or myocardial infarction 
within 6 months prior to first dose of study drug 
14. Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation 
pneumonitis which required steroid treatment, or any evidence of clinically active 
interstitial lung disease 


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15. Refractory nausea and vomiting, chronic gastrointestinal disease, gastrointestinal ulcer, 
gastrointestinal bleeding, inability to swallow the formulated product, or previous 
significant bowel resection that would preclude adequate absorption of study drug 
16. History of other malignancies, except for the following: (1) adequately treated basal or 
squamous cell carcinoma of the skin; (2) curatively treated a) in situ carcinoma of the 
uterine cervix, b) prostate cancer, or c) superficial bladder cancer; or (3) other curatively 
treated solid tumor with no evidence of disease for ≥ 3 years 
17. History of hypersensitivity to active or inactive excipients of study drug or drugs with a 
similar chemical structure or class to study drug 
18. Women who are pregnant or breastfeeding 
19. Psychiatric illness/social situations that would limit study compliance 
20. Legal incapacity or limited legal capacity 
21. Judgement 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 
22. Prior hematopoietic stem cell or bone marrow transplantation 


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8. 
TREATMENTS 
8.1. 
Treatments Administered 
Study drugs will be administered as follows for each cohort in Part 1 of the study: 
• Cycle 1 Day -16: single oral dose of G1T38 
• Cycle 1 Day -15: no study drug administered 
• Cycle 1 Days -14 to -3: oral once-daily doses of osimertinib  
• Cycle 1 Day -2: single oral dose of osimertinib and G1T38 
• Cycle 1 Day -1: single oral dose of osimertinib  
Beginning with Cycle 1 Day 1, oral once-daily doses of G1T38 and osimertinib will 
commence (Figure 8-1). 
Figure 8-1 
Study Schema: Part 1 
 
 
PTV = Post-Treatment visit 
There is no Day 0 in the study. A treatment cycle is defined as 28 days. 
In Part 2, eligible patients will be randomized (1:1) to receive osimertinib or G1T38 (at the 
RP2D) + osimertinib. Randomized patients will begin once-daily oral dosing of osimertinib 
or G1T38 + osimertinib on Cycle 1 Day 1 (Figure 8-2). 


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Figure 8-2 
Study Schema: Part 2 
 
PTV = Post-Treatment visit 
 
8.1.1. 
Investigational Medicinal Product (IMP) 
G1T38 will be initially supplied initially as oral capsules containing 25 or 100 mg 
equivalents of G1T38 free base. Excipients used in the formulation include microcrystalline 
cellulose, hypromellose, mannitol, croscarmellose sodium, and magnesium stearate.  
Once available, G1T38 supply will be transitioned to oral tablets containing 50 or 200 mg of 
G1T38 free base.  Excipients used in the tablet formulation include microcrystalline 
cellulose, hypromellose, croscarmellose sodium, and magnesium stearate. The film coating 
contains polyethylene glycol:  polyvinyl alcohol graft copolymer, talc, titanium dioxide, 
mono-and di-glycerides, and partially hydrolyzed polyvinyl alcohol. 
Alternate strengths may be utilized in the event that they become available.   
Packaging and Labeling  
G1T38 is packaged in high-density polyethylene (HDPE) bottles and sealed with 
child-resistant closures. Bottles of G1T38 capsules contain 30 capsules; whereas, bottles of 
G1T38 tablets contain 35 tablets.  Bottles of G1T38 will be labeled and supplied to the 
investigator or pharmacist/designee who will inventory the contents and document them 
according to the drug accountability requirements (Section 8.1.4). 
Storage  
The G1T38 shall be stored at 15°C to 30°C. 
Study drugs will be stored in a locked cabinet/secure area under applicable storage conditions 
at the site and only the pharmacist/designee and designated personnel will have access to the 
study drugs. 


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8.1.2. 
Other Investigational Medicinal Products  
8.1.2.1. 
Osimertinib 
A description of the formulation, packaging and labeling for osimertinib can be found in the 
respective current prescribing information (see Appendix 2).  
Store osimertinib bottles at 25°C (77°F). Excursions are permitted to 15°C to 30°C (59°F to 
86°F). 
8.1.3. 
Procedure for Dispensing  
Dispensing instructions will be provided in the Pharmacy Manual and will be maintained in 
the pharmacy records.  
8.1.4. 
Investigational Product Accountability 
The pharmacist/designee will verify the integrity of the clinical study supplies (storage 
conditions, correct amount received, condition of shipment, bottle numbers, etc.) according 
to the investigative site’s standard operating procedures (SOPs). Additional requirements 
may be found in the Pharmacy Manual. 
8.2. 
Method of Assigning Patients to Treatment Groups 
A unique patient identification number and allocation to a cohort/treatment group will be 
assigned by an interactive web-response system (IWRS).  
8.3. 
Dose, Dosing Regimen, and Route 
8.3.1. 
G1T38  
The starting dose of G1T38 is 200 mg orally (see Section 4.4.2). Dose escalation/ 
de-escalation is described in Section 6.1.1.1. The maximum G1T38 dose level explored shall 
not exceed 650 mg per day.  
In Part 1, all patients will receive single doses of G1T38 on Cycle 1 Day -16 and Cycle 1 
Day -2 and begin continuous G1T38 once-daily dosing on Cycle 1 Day 1 (note: there is no 
Day 0 in the study). In Part 2, patients randomized to osimertinib with G1T38 will begin 
G1T38 once-daily continuous oral dosing on Cycle 1 Day 1. 
G1T38 should be taken with food. G1T38 should be taken at approximately the same time 
each day.  
8.3.2. 
Osimertinib    
All patients will receive continuous oral osimertinib 80 mg once daily (starting on Cycle 1 
Day -14 in Part 1 and on Cycle 1 Day 1 in Part 2). 
Osimertinib may be taken with or without food, and should be taken at approximately the 
same time each day. 


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8.3.3. 
Dose Modification 
8.3.3.1. 
G1T38 
Dose adjustments of G1T38 for toxicities are to be made according to the organ system 
showing the greatest degree of drug-related toxicity. Toxicities will be graded using NCI 
CTCAE, Version 4.03. No more than 2 G1T38 dose level reductions in total are allowed for 
any patient. Toxicity that requires dose level reduction more than twice will lead to 
permanent discontinuation of G1T38 dosing for the individual patient.  
Since fatigue can be a symptom of cancer progression, dose reduction will only be performed 
if the fatigue is deemed to be drug related in the opinion of the investigator. 
An off-drug period of up to 21 consecutive days is permitted to allow recovery from any 
toxicity. Off-drug periods of greater than 21 days may be allowed if the investigator believes 
the potential benefits of continued treatment outweigh the potential risks, but such cases must 
be discussed with the medical monitor.  
Dose Modifications for G1T38-Related Hematologic Toxicity 
The G1T38 dose level adjustments in Table 8-1 are based on hematologic adverse reactions, 
except lymphopenia (unless associated with clinical events, eg, opportunistic infections). 
Table 8-1 
G1T38 Dose Level Adjustments Based on G1T38-related Hematologic 
Toxicities 
CTCAE Grade of 
Hematologic Toxicity 
 
G1T38 Dose Adjustment 
Grade 3  
Continue G1T38 and repeat CBC at next scheduled visit. 
≥ Grade 3 neutropenia  
associated with a documented 
infection or fever ≥ 38.5°C  
Withhold G1T38 and monitor counts weekly until ANC > 1 x 109/L. 
Resume therapy at the next lower dose.  
≥ Grade 3 thrombocytopenia 
associated with bleeding 
Withhold G1T38 and monitor counts weekly until platelet count ≥ 75 x 109/L.  
Resume therapy at the next lower dose. 
Grade 4  
Withhold G1T38 and monitor counts weekly until ANC > 1 x 109/L and 
platelet count > 75 x 109/L.  
Resume therapy at the next lower dose. 
ANC = absolute neutrophil count; CBC = complete blood count; CTCAE = Common Terminology Criteria for Adverse 
Events 
 
Granulocyte-colony stimulating factor  
The optimal treatment for G1T38-induced neutropenia is to withhold G1T38. 
Granulocyte-colony stimulating factor (G-CSF) will not work in this setting because G1T38 
induces a G1 cell cycle arrest in myeloid precursors that cannot be overcome by G-CSF. 
Withholding G1T38 treatment will allow neutrophil counts to recover naturally as the study 
drug concentrations in the body decline and the myeloid precursors are released from 
G1 arrest and mature to produce neutrophils. If the patient experiences neutropenia lasting 


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more than 10 days after the cessation of G1T38 and the investigator believes that G-CSF use 
is clinically indicated, then the investigator must contact the medical monitor to discuss the 
use of G-CSF. 
In the event that the patient experiences a drug-related hematologic toxicity warranting dose 
reduction, which may be related to G1T38 or osimertinib (ie, the investigator is unable to 
determine whether the toxicity is related to G1T38 or osimertinib), the investigator shall 
dose-reduce G1T38 first. If the toxicity does not resolve following the first dose reduction of 
G1T38, then the investigator shall use clinical judgement to determine if a second G1T38 
dose reduction is warranted or if osimertinib dose reduction is warranted. In this situation, 
discussion with the medical monitor is recommended. 
Dose Modifications for G1T38-Related Nonhematologic Toxicity 
For any ≥ Grade 3 G1T38-related nonhematologic toxicity (excluding alopecia) persisting 
despite optimal medical treatment, withhold treatment with G1T38 until symptoms resolve to 
Grade ≤ 2 (if not considered a safety risk for the patient). Treatment should be resumed at the 
next lower dose level of G1T38.  
Any patient with liver function test abnormalities meeting Hy’s Law criteria (AST or ALT 
≥ 3 × ULN and total bilirubin ≥ 2 × ULN) must have all study drugs permanently 
discontinued. 
Patients with gastrointestinal AEs (eg, nausea, vomiting, diarrhea) may have the total daily 
dose split, as close to 50:50 as possible, to a morning dose and an evening dose as a means to 
potentially improved gastrointestinal tolerability. Dose-splitting is not permitted during the 
DLT evaluation period or the PK evaluation period. In this situation, discussion with the 
medical monitor is suggested.  
8.3.3.2. 
Osimertinib 
Dose modifications for osimertinib for adverse reactions are to be made according to 
Table 8-2. 
 
If a patient experiences a Grade 3 (CTCAE) or higher and/or unacceptable toxicity (any 
grade), where the investigator considers the AE of concern to be specifically associated with 
osimertinib (and not attributable to the disease or disease-related processes for which the 
patient is being treated), dosing will be interrupted and supportive therapy administered as 
required in accordance with local practice/guidelines. 
If a toxicity resolves or reverts to ≤ Grade 2 (CTCAE) within 3 weeks of onset, treatment 
with osimertinib may be restarted at the same dose or a lower dose using the rules below for 
dose modifications (Table 8-2) and with discussion and agreement with the sponsor’s study 
team physician as needed. There will be no individual modifications to dosing schedule in 
response to toxicity, only potential dose reduction or dose interruption.  
 


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If the toxicity does not resolve to ≤ Grade 2 (CTCAE) after 3 weeks, then osimertinib 
therapy shall be permanently discontinued and the patient shall be observed until resolution 
or stabilization of the toxicity. 
Patients experiencing any of the following AEs will not be permitted to restart osimertinib 
treatment: 
• Corneal ulceration 
• Interstitial lung disease (ILD) 
• QTc interval prolongation with signs/symptoms of serious arrhythmia 
• Symptomatic congestive heart failure or asymptomatic left ventricular dysfunction 
that persists ≥ 4 weeks 
• Liver function test abnormalities meeting Hy’s Law criteria (AST or ALT ≥ 3 × ULN 
and total bilirubin ≥ 2 × ULN). All study drugs must be permanently discontinued in 
any patient meeting Hy’s Law criteria.   
Table 8-2 
Recommended Dose Modifications for Osimertinib-Related Adverse 
Reactions 
Target Organ 
Adverse Reactiona 
Dose Modification 
Pulmonary  
Interstitial lung disease/ pneumonitis 
Permanently discontinue osimertinib 
Cardiac 
QTc interval > 500 msec on at least 
2 separate ECGs 
Withhold osimertinib until QTc interval is 
< 481 msec or recovery to baseline, then resume 
at 40 mg dose 
QTc interval prolongation with 
signs/symptoms of life-threatening 
arrhythmia 
Permanently discontinue osimertinib 
Symptomatic congestive heart failure 
or asymptomatic left ventricular 
dysfunction that persists ≥ 4 weeks 
Permanently discontinue osimertinib 
Other 
≥ Grade 3 adverse reaction 
Withhold osimertinib for up to 3 weeks 
If improvement to Grade 0 to 2 within 
3 weeks 
Resume at 80 or 40 mg daily (investigator’s 
discretion) 
If no improvement within 3 weeks 
Permanently discontinue osimertinib 
ECG = electrocardiogram; QTc = QT interval corrected for heart rate 
 
a 
Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4.03.  
Source: Table copied from Table 1 of the osimertinib package insert (see Appendix 2) 
 
In the event that the patient experiences a drug-related hematologic toxicity, which may be 
related to G1T38 or osimertinib, the investigator shall dose-reduce G1T38 first (refer to 
Section 8.3.3.1). 
In the event that the patient receiving G1T38 + osimertinib experiences an 
osimertinib-related toxicity requiring permanent discontinuation of osimertinib, the patient 
may continue G1T38 monotherapy at the discretion of the investigator. 


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Details regarding the management of specific AEs related to osimertinib are discussed in 
Sections 8.3.3.2.1 to 8.3.3.2.6. 
8.3.3.2.1. 
Interstitial Lung Disease/Pneumonitis-like Toxicity 
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormality 
suggestive of ILD is observed, an interruption in osimertinib dosing is recommended, and the 
sponsor study team shall be informed. It is strongly recommended to perform a full 
diagnostic workup (including high-resolution computed tomography [HRCT], blood and 
sputum culture, hematological parameters) to exclude alternative causes such as 
lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary 
hemorrhage. In the presence of confirmatory HRCT scans where other causes of respiratory 
symptoms have been excluded, a diagnosis of ILD shall be considered and osimertinib 
treatment permanently discontinued.  
In the absence of a diagnosis of ILD, osimertinib may be restarted following consultation 
with the sponsor’s study team physician.  
8.3.3.2.2. 
QTc Prolongation 
Patients with QTcF prolongation to > 500 msec shall have study treatment interrupted and 
regular ECGs performed until resolution to < 481 msec, and then restarted at a reduced dose 
of osimertinib 40 mg. If the toxicity does not resolve to < 481 msec within 21 days, the 
patient will be permanently withdrawn from osimertinib treatment.  
8.3.3.2.3. 
Keratitis 
Keratitis was reported in 0.7% (n = 6) of the 833 patients treated with osimertinib in the 
AURA studies. Patients presenting with signs and symptoms suggestive of keratitis such as 
acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, 
and/or red eye shall be referred promptly to an ophthalmology specialist.  
8.3.3.2.4. 
Changes in Cardiac Contractility 
Across clinical trials, LVEF decreases of ≥ 10% and a drop to < 50% occurred in 4.0% 
(26/655) of patients treated with osimertinib who had baseline and at least 1 follow-up LVEF 
assessment. Based on the available clinical trial data, a causal relationship between effects on 
changes in cardiac contractility and osimertinib has not been established. In patients with 
symptomatic congestive heart failure or asymptomatic left ventricular dysfunction that 
persists ≥ 4 weeks, permanently discontinue osimertinib therapy (Table 8-2).  
Permanent Discontinuation Due to Toxicity  
Patients experiencing corneal ulceration, ILD, symptomatic congestive heart failure or 
asymptomatic left ventricular dysfunction that persists ≥ 4 weeks, or QTc prolongation with 
signs/symptoms of serious arrhythmia will not be permitted to restart osimertinib treatment.  
Any patient with liver function test abnormalities meeting Hy’s Law criteria (AST or ALT 
≥ 3 × ULN and total bilirubin ≥ 2 × ULN) must have all study drugs permanently 
discontinued. 


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8.3.3.2.5. 
Skin Reactions 
Changes in the CTCAE grade of skin reactions will be collected in the AE eCRF.  
Photographs of skin reactions may be collected and these photographs shall be available for 
central review by the sponsor or designee and for external expert dermatological review if 
required, if patient consent is obtained.  
Skin biopsies may be taken of skin reactions.  
8.3.3.2.6. 
Diarrhea 
In the event that the patient experiences drug-related diarrhea, which may be related to 
G1T38 or osimertinib, the investigator shall dose-reduce G1T38 first (refer to 
Section 8.3.3.1). 
Changes in CTCAE grade of diarrhea will be captured in the AE eCRF.  
8.4. 
Randomization and Blinding 
Parts 1 and 2 are open label. In Part 1, no treatment randomization will be required. In Part 2, 
patients will be randomized (1:1) to receive osimertinib or G1T38 (at the RP2D) + 
osimertinib. Study drug administration shall begin no more than 96 hours after 
randomization. Randomization will be stratified according to 2 factors: the presence or 
absence of CNS metastases at screening and Asian versus non-Asian ethnicity. 
8.5. 
Prior and Concomitant Medications and Procedures 
All concomitant medications including prescription medications, over-the-counter 
preparations, herbal remedies, traditional remedies, growth factors, blood products, and 
parenteral nutrition taken during the 14 days prior to signing the ICF, during the study 
treatment, and through the Post-Treatment visit shall be documented in the eCRF.    
Administration of concomitant, nonprotocol anticancer therapies prior to disease progression 
is not permitted during the treatment phase of this study. Concomitant radiotherapy and 
surgeries may be permitted as described in Section 8.8. 
Administration of other concomitant investigational agents for any indication is not permitted 
during the treatment phase of this study. 
Medications will be coded by the sponsor or designee using the most recent World Health 
Organization (WHO) Drug Dictionary version. 
If medically feasible, patients taking regular medication(s), with the exception of prohibited 
medications (see below), should be maintained on those medications throughout the study 
period.  
Refer to Appendix 4 for additional details regarding concomitant medications. 
8.5.1. 
CYP3A4 Substrates 
G1T38 has the potential to inhibit CYP3A4/5 in both a competitive and time-dependent 
manner based on in vitro studies. Using the FDA recommended model-based predictions in 


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the guidance for drug interaction studies (US Department of Health and Human Services, 
Food and Drug Administration, Center for Drug Evaluation and Research, 2012), G1T38 
has the potential to significantly inhibit CYP3A4 in the gut and thus may have a clinically 
significant effect on orally administered CYP3A4 substrates with a narrow therapeutic index 
and such drugs are prohibited during participation in this study (beginning 14 days prior to 
first dose of study drug until 14 days after last dose of study drug).   
• Prohibited, orally administered CYP3A substrates with a narrow therapeutic 
index, including but not limited to the following: 
o Astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, 
everolimus, pimozide, quinidine, sirolimus, and tacrolimus 
• Caution should be used with concurrent use of other orally administered CYP3A 
substrate drugs with consideration of dose reduction of the substrate if clinical 
signs and symptoms of toxicity emerge (eg, muscle aches with 3-hydroxy-
3-methylglutaryl coenzyme A reductase inhibitors). 
 
The model-based calculation for inhibition of CYP3A4 in the liver predicts a marginal 
inhibitory effect by G1T38 and therefore the likelihood of a clinically significant drug 
interaction for CYP3A substrates administered via routes other than oral (eg, intravenous, 
transdermal, inhalation, etc.) is low.  
• Caution should be used with concurrent use of non-orally administered CYP3A 
substrates with a narrow therapeutic index with consideration of dose reduction of the 
substrate if clinical signs and symptoms of toxicity emerge (eg, increased somnolence 
with transdermal fentanyl or intravenous midazolam). 
8.5.2. 
CYP3A4 Inhibitors and Inducers 
G1T38 is a substrate for CYP3A4, although the extent of metabolism by CYP3A4 is 
expected to be low in humans since the in vitro clearance of G1T38 in human liver 
microsomes and hepatocytes was low. G1T38 exposure may be altered by concomitant use of 
drugs, herbal supplements, or foods that are strong CYP3A inhibitors or inducers and such 
drugs are prohibited during participation in this study (beginning 14 days prior to first dose 
of study drug until 14 days after last dose of study drug).  
• Prohibited, strong inhibitors of CYP3A4, including but not limited to the 
following: clarithromycin, itraconazole, ketoconazole, nefazodone, erythromycin, 
grapefruit juice, telithromycin, diltiazem, verapamil, and ritonavir 
  
• Prohibited, strong or moderate CYP3A inducers, including but not limited to the 
following: phenytoin, rifampin, carbamazepine, St John’s Wort, phenobarbital, 
bosentan, modafinil, and nafcillin  
In addition, coadministration of osimertinib with a strong CYP3A4 inducer decreased the 
exposure of osimertinib compared to administration of osimertinib alone. Decreased 
osimertinib exposure may lead to reduced efficacy (Tagrisso Prescribing Information 2017). 


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Once enrolled, all patients must try to avoid concomitant use of medications, herbal 
supplements, and/or ingestion of foods that are known to be potent inducers of CYP3A4 
whenever feasible, but patients may receive any medication that is clinically indicated for 
treatment of AEs. Such drugs must have been discontinued for an appropriate period before a 
patient enters screening and for a period of 3 months after the last dose of osimertinib. All 
concomitant medications should be captured on the eCRF. Guidance on medicines to avoid, 
medications that require close monitoring, and on washout periods is provided in 
Appendix 4. 
8.5.3. 
BCRP Inhibitors 
A primary objective of this study is to assess the effect of osimertinib on the PK of G1T38 
via the mechanism of BCRP inhibition by osimertinib. Therefore, patients are prohibited 
from taking drugs, herbal supplements, or foods that are strong BCRP inhibitors during 
participation in this study (beginning 14 days prior to the first dose of study drug until 
14 days after last dose of study drug). 
 
• Prohibited, strong inhibitors of BCRP, including but not limited to the following: 
sulfasalazine, curcumin, turmeric supplements, cyclosporine, eltrombopag 
 
8.5.4. 
BCRP substrates 
Patients taking concomitant medications whose disposition is dependent upon BCRP and 
which have a narrow therapeutic index should be closely monitored for signs of changed 
tolerability as a result of increased exposure of the concomitant medication while receiving 
osimertinib. Guidance on medications to avoid, medications that require close monitoring, 
and on washout periods is provided in the appendices. 
Patients taking rosuvastatin should have creatine phosphokinase levels monitored (due to 
BCRP-mediated increase in exposure). If the patient experiences any potentially relevant 
AEs suggestive of muscle toxicity including unexplained muscle pain, tenderness, or 
weakness, particularly if accompanied by malaise or fever, rosuvastatin must be stopped and 
any appropriate further management should be taken. 
8.5.5. 
Gastric pH Elevating Agents 
The solubility of G1T38 is pH dependent. Drugs that raise gastric pH may alter the 
bioavailability of G1T38 and confound the interpretation of PK data. During Part 1 of the 
study, concurrent use of medications that raise gastric pH is prohibited from 7 days prior to 
first dose of study drug until after the final PK sample is collected on Cycle 1 Day 1. Such 
medications include proton pump inhibitors (eg, omeprazole, pantoprazole, lansoprazole, 
esomeprazole, rabeprazole, dexlansoprazole), H2 blockers (eg, nizatidine, famotidine, 
cimetidine, ranitidine), and antacids (eg, sodium bicarbonate, calcium carbonate, 
aluminum-based antacids, magnesium compounds, alginic acid).  
 
8.5.6. 
CYP2C8 Inhibitors and Inducers 
G1T38 is a substrate for CYP2C8, although the extent of metabolism by CYP2C8 is 
expected to be low in humans since the in vitro clearance of G1T38 in human liver 


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microsomes and hepatocytes was low. G1T38 exposure may be altered by concomitant use of 
drugs, herbal supplements, or foods that are strong CYP2C8 inhibitors or inducers. 
• Caution should be exercised with concomitant use of drugs that are strong inhibitors 
of CYP2C8 (eg, gemfibrozil, quercetin, sulfinpyrazone, trimethoprim, and 
nicardipine). 
• Caution should be exercised with concomitant use of drugs that are strong or 
moderate inducers of CYP2C8 (eg, rifampin, phenobarbital, and carbamazepine). 
8.6. 
Systemic Corticosteroid Use 
Steroids given for physiological replacement (up to 10 mg per day of prednisone or 
equivalent), as anti-emetics, or by inhalation, ophthalmic, or topical route are allowed. Short 
courses (up to 21 days) of steroids are allowed to treat acute conditions if medically 
necessary.   
8.7. 
Supportive Care for Gastrointestinal Adverse Events 
Medications to treat gastrointestinal AEs are allowed at any time during the study, as 
indicated (eg, loperamide for diarrhea, 5-HT3 antagonists for nausea/vomiting, etc.). Such 
medications shall not be used as primary prophylaxis prior the onset of any gastrointestinal 
AEs. After a patient has experienced a gastrointestinal AE, supportive treatments may be 
used as secondary prophylaxis if the patient continues to experience the AE. 
 
8.8. 
Additional Cautions 
G1T38 inhibited P-gp, BCRP, MATE1, MATE2-K, and OCT1 and 2 membrane transporters 
and therefore caution should be exercised with concomitant use of drugs that are substrates 
for these transporters (Section 4.2.2; Appendix 4). MATE2-K is involved with tubular 
secretion of creatinine and inhibition of MATE2-K by G1T38 may cause an increase in 
serum creatinine levels unrelated to true changes in renal function. 
G1T38 is a substrate and inhibitor of P-gp and BCRP efflux transporters. G1T38 exposure 
may be altered by concomitant use of drugs that are strong inhibitors or inducers of P-gp or 
BCRP. Caution should be exercised with concomitant use of drugs that are strong inhibitors 
or inducers of P-gp. Use of strong inhibitors of BCRP during participation in this study is 
prohibited. 
The use of herbal medicine or traditional remedies is not recommended during the active 
treatment phase. 
8.9. 
Concomitant Radiotherapy or Surgery 
Palliative radiotherapy is not allowed within the DLT period. In Part 1 (after the DLT period) 
and in Part 2, palliative radiotherapy may be permitted to control symptoms (eg, treatment of 
painful bony lesions or brain or thoracic lesions) provided that the lesions were known to be 
present at the time of study entry and the investigator clearly documents that the need for 
palliative radiotherapy is not indicative of disease progression. Refer to Appendix 6 for 
additional guidelines on radiotherapy. 


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Any diagnostic, therapeutic, or surgical procedures performed during the study period shall 
be documented.  
8.10. 
Contraception 
Females 
All females of childbearing potential must have a negative serum beta human chorionic 
gonadotropin (β-hCG) test result at screening and not be breastfeeding prior to start of 
dosing.  
Females must be either postmenopausal, surgically sterile, or agree to use 2 forms of highly 
effective contraception from the start of the study until 4 months after discontinuation of 
study drug. 
Highly effective methods of contraception are those that result in a low failure rate (ie, less 
than 1% per year) when used consistently and correctly. These include the following: 
• Established use of oral, injected, or implanted hormonal methods of contraception 
(stable dose at least 3 months prior to dosing)  
• Placement of an intrauterine device or intrauterine system  
• Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. Barrier 
methods alone (without spermicide) are not acceptable methods. Likewise, 
spermicide alone is not an acceptable method.  
• Male sterilization (with the appropriate post vasectomy documentation of the absence 
of sperm in the ejaculate). For female patients on the study, the vasectomized male 
partner should be the sole partner for that patient.  
True abstinence, when this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and 
withdrawal are not acceptable methods of contraception. 
Postmenopausal is defined as meeting 1, 2, or 3 below: 
1. At least 60 years of age and amenorrheic for at least 12 months following 
cessation of all exogenous hormonal treatments OR  
2. Medically confirmed ovarian failure OR 
3. Younger than 60 years of age and have had cessation of regular menses for at 
least 12 consecutive months with no alternative pathological or physiological 
cause and have serum levels of estradiol and follicle stimulating hormone within 
the laboratory’s reference range for postmenopausal females 
Acceptable surgical sterilization techniques are complete or partial hysterectomy or bilateral 
tubal ligation with surgery at least 6 months prior to dosing, and bilateral oophorectomy with 
surgery at least 2 months prior to dosing.  


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Males 
If male and sexually active, a condom, with spermicide, must be used with all partners from 
the start of the study until 4 months after discontinuation of study drug, or must be 
vasectomized. Patients should refrain from donating sperm from the start of dosing until 
4 months after discontinuation of study treatment. 
8.11. 
Treatment Compliance 
The investigator or designee will dispense the study drug only for use by patients enrolled in 
the study as described in this protocol. The study drug is not to be used for reasons other than 
those described in this protocol. Compliance will be assessed via return of pill bottles and pill 
counts. The clinical study site will maintain records of G1T38 and osimertinib receipt, 
dispensing, including the applicable lot numbers, bottle numbers, and pill counts upon return 
of study drug bottles at clinic visits.  


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9. 
STUDY SCHEDULE 
The procedures and assessments to be performed during the study are outlined in Table 9-1 
(Part 1) and Table 9-2 (Part 2). 


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Table 9-1 
Schedule of Assessments for Part 1 
Assessment 
Screen
-ing 
Treatment Phase 
Details 
Provided in 
Section 
Cycle 1 
 Cycles 1 and 2 
Cycle 3 and Every 
Cycle Thereafter 
Discon-
tinuation 
Post-
Treat-
ment 
Visit 
(+10) 
Day -16 
Day -14 
(+ 1) 
Day -2 
(± 1) 
Day 1 
(+ 2) 
Day 8 
(± 2) 
Day 15 
(± 2) 
Day 22 
(± 2) 
Day 1 
(± 3) 
Day 15 (± 3) 
[as required 
in Cycle 5 
and beyond] 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
9.1 
EGFR mutation 
status 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Archival tumor 
sample (if 
available) 
X 
 
 
 
 
 
 
 
 
 
 
 
10.3 
Demographics and 
baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
10.6.3 
Vital signs 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
10.6.3 
Inclusion/ exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
7.1 
Physical 
examination, 
including weight 
X 
 
 
 
 
 
 
 
 
 
 
X 
10.6.4 
Symptom-directed 
physical 
examination 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
10.6.3 
Full ophthalmic 
examination 
X 
Perform if the patient experiences any visual symptoms 
10.6.6 
ECOG performance 
status 
X 
X 
 
 
X 
 
 
 
X 
 
X 
X 
7.1.1 
Blood sample for 
cell-free DNA  
 
X 
 
 
X 
(Cycle 
2 only)  
 
X 
(Cycle 
1 only) 
 
 
X  
(odd 
Cycles 
only) 
 
 
X 
10.2 


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Assessment 
Screen
-ing 
Treatment Phase 
Details 
Provided in 
Section 
Cycle 1 
 Cycles 1 and 2 
Cycle 3 and Every 
Cycle Thereafter 
Discon-
tinuation 
Post-
Treat-
ment 
Visit 
(+10) 
Day -16 
Day -14 
(+ 1) 
Day -2 
(± 1) 
Day 1 
(+ 2) 
Day 8 
(± 2) 
Day 15 
(± 2) 
Day 22 
(± 2) 
Day 1 
(± 3) 
Day 15 (± 3) 
[as required 
in Cycle 5 
and beyond] 
Pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Table 10-5 
and 10.6.2; 
(includes 
Cycle 5 and 
beyond 
decrease in 
monitoring 
frequency) 
Clinical chemistry 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
Hematology 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
 
X 
 
 
 
X 
 
X 
X 
Cystatin C 
 
X 
Only if serum creatinine > ULN 
ECG 
X 
X 
 
X 
X 
(Cycle 
2 only) 
 
 
 
X 
 
X 
X 
10.6.5 
Echocardiogram/ 
MUGA scan 
X 
 
 
 
 
 
 
 
C3D1 and every third 
cycle (12 weeks ± 7 
days) thereafter 
 
 
10.6.7 
Tumor assessments 
(RECIST v1.1) 
X 
 
 
 
After every even cycle (± 7 days) relative to C1D1; after 
18 months, every third cycle (± 7 days) relative to C1D1 
X 
 
10.1 
CT/MRI brain  
X 
 
 
 
After every even cycle (± 7 days) relative to C1D1 if indicated; 
after 18 months, every third cycle (± 7 days) relative to C1D1 
X 
 
Optional tumor 
biopsy at time of 
progression 
 
 
 
 
 
 
 
 
 
 
X 
 
10.4 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
9.1 
Dispense study 
drug 
 
X 
 
 
X 
 
 
 
X 
 
 
 
8.1.3 
Dose with G1T38 
(Part 1 only) 
 
X 
 
X 
Daily dosing with G1T38 beginning on Cycle 1 Day 1 
 
 
8.1 
Dose with 
osimertinib  
(Part 1 only) 
 
 
Daily dosing with osimertinib beginning on Cycle 1 Day -14 
 
 
Plasma samples for 
PK analysis (Part 1) 
 
X 
 
X 
 
 
 
 
 
 
 
 
10.5.1 


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Assessment 
Screen
-ing 
Treatment Phase 
Details 
Provided in 
Section 
Cycle 1 
 Cycles 1 and 2 
Cycle 3 and Every 
Cycle Thereafter 
Discon-
tinuation 
Post-
Treat-
ment 
Visit 
(+10) 
Day -16 
Day -14 
(+ 1) 
Day -2 
(± 1) 
Day 1 
(+ 2) 
Day 8 
(± 2) 
Day 15 
(± 2) 
Day 22 
(± 2) 
Day 1 
(± 3) 
Day 15 (± 3) 
[as required 
in Cycle 5 
and beyond] 
Concomitant 
medications and 
procedures 
 
At every visit 
8.5 
Adverse events 
 
At every visit 
10.6.1 
C = Cycle; CT = computed tomography; D = Day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; MRI = magnetic resonance imaging; MUGA = multigated 
acquisition; PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid Tumors; ULN = upper limit of normal 


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Table 9-2 
Schedule of Assessments for Part 2 
Assessment 
Screening 
Treatment Phase 
Details Provided 
in Section 
 Cycles 1 and 2 
Cycle 3 and Every Cycle 
Thereafter 
Discon-
tinuation 
Post-Treatment Visit 
(+10) 
Day 1 
(± 2) 
Day 8 
(± 2) 
Day 15 
(± 2) 
Day 22 
(± 2) 
Day 1 
(± 3) 
Day 15 (± 3)  
[as required 
in Cycle 5 
and beyond] 
Informed consent 
X 
 
 
 
 
 
 
 
 
9.1 
EGFR mutation 
status, must be 
T790M positive 
X 
 
 
 
 
 
 
 
 
Medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
Archival tumor 
sample (if available) 
X 
 
 
 
 
 
 
 
 
10.3 
Demographics and 
baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
10.6.3 
Vital signs 
X 
X 
 
X 
 
X 
 
X 
X 
10.6.3 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
7.1 
Physical examination, 
including weight 
X 
 
 
 
 
 
 
 
X 
10.6.4 
Symptom-directed 
physical examination 
 
X 
 
X 
 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
10.6.3 
Full ophthalmic 
examination 
X 
Perform if the patient experiences any visual symptoms 
10.6.6 
ECOG performance 
status 
X 
X 
 
 
 
X 
 
X 
X 
7.1.1  
Blood sample for 
cell-free DNA  
 
X  
 
X (Cycle 
1 only) 
 
X (odd 
Cycles 
only) 
 
 
X 
10.2 


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Assessment 
Screening 
Treatment Phase 
Details Provided 
in Section 
 Cycles 1 and 2 
Cycle 3 and Every Cycle 
Thereafter 
Discon-
tinuation 
Post-Treatment Visit 
(+10) 
Day 1 
(± 2) 
Day 8 
(± 2) 
Day 15 
(± 2) 
Day 22 
(± 2) 
Day 1 
(± 3) 
Day 15 (± 3)  
[as required 
in Cycle 5 
and beyond] 
Pregnancy test 
X 
X 
(C1 only) 
 
 
 
 
 
 
X 
Table 10-5 and 
10.6.2 
(includes Cycle 5 
and beyond 
decrease in 
monitoring 
frequency) 
Clinical chemistry 
X 
X 
 
X 
 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
X 
 
X 
X 
Cystatin C 
 
X 
Only if serum creatinine > ULN 
Electrocardiogram 
X 
X 
 
 
 
X 
 
X 
X 
10.6.5 
Echocardiogram/ 
MUGA scan 
X 
 
 
 
 
C3D1 and every third cycle  
(12 weeks ± 7 days) 
thereafter  
X 
 
10.6.7 
Tumor assessments 
(RECIST v1.1) 
X 
After every even cycle (± 7 days) relative to C1D1; after 18 months, every 
third cycle (± 7 days) relative to C1D1 
X 
 
10.1 
CT/MRI brain  
X 
After every even cycle (± 7 days) relative to C1D1 if indicated; after 18 
months, every third cycle (± 7 days) relative to C1D1 
X 
 
Optional tumor biopsy 
at time of progression 
 
 
 
 
 
 
 
X 
 
10.4 
Randomization  
 
X 
 
 
 
 
 
 
 
8.4 
Dispense study drug 
 
X 
 
 
 
X 
 
 
 
8.1.3 
Dose osimertinib ± 
G1T38 
 
Daily dosing with osimertinib ± G1T38 
 
 
8.19.2 
Blood samples for 
G1T38 PK 
 
X (C2 
only) 
 
X (C1 
only) 
X (C1 
only) 
 
 
 
 
10.5.1 
Concomitant 
medications and 
procedures 
 
At every visit 
8.5 
Adverse events 
 
At every visit 
10.6.1 
C = Cycle; CT = computed tomography; D = Day; ECOG = Eastern Cooperative Oncology Group; MRI = magnetic resonance imaging; MUGA = multigated acquisition; 
PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid Tumors; ULN = upper limit of normal 
 


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9.1. 
Screening Phase 
Patients shall be screened no more than 21 days before the first dose of study drug is 
administered (ie, 21 days prior to Cycle 1 Day -16 in Part 1 or 21 days prior to Cycle 1 Day 1 
in Part 2). Written informed consent must be obtained from each patient before the initiation 
of any screening procedures. After a patient has given informed consent, eligibility will be 
determined by a review of the inclusion/exclusion criteria (see Section 7.1) and completion 
of all screening procedures outlined in Table 9-1 (Part 1) and Table 9-2 (Part 2).  
Patients that are EGFR TKI treatment naive in Part 1, will be enrolled based on a locally 
available EGFR mutation test result that has been FDA-approved and performed in a 
CLIA-certified laboratory (US sites) or based on a locally available EGFR mutation test 
result that has been performed in an accredited laboratory (sites outside of the US). 
For Part 2, tumor EGFR T790M mutation-positive status after documented disease 
progression on first-line treatment with a first or second generation EGFR TKI is required.  
Patients in Part 2 will be enrolled based on a locally available T790M mutation test result 
(tumor biopsy or cfDNA) that has been FDA-approved (eg, cobas® EGFR Mutation Test v2 
and FoundationOne CDx™) and performed in a CLIA-certified laboratory (US sites) or a 
locally available T790M mutation test result (tumor biopsy or cfDNA) that has been 
performed in an accredited laboratory (sites outside of the US). Testing for the presence of 
the T790M mutation in plasma specimens (cfDNA) is recommended only in patients for 
whom a tumor biopsy cannot be obtained. 
Available, most recent archival tumor tissue (eg, block or slides) will be collected and 
banked for assessment of relevant DNA, RNA, and protein markers, such as those involved 
in the CDK4/6 pathway (see Section 10.3). For additional guidance, please refer to the 
Laboratory Manual. 
Concomitant medications will be monitored continuously from the time of informed consent 
through the Post-Treatment Visit. Adverse events are captured after the first dose of study 
drug. Medical events that occur prior to first dose of study drug (G1T38 and/or osimertinib) 
shall be captured on the Medical History page of the electronic case report form (eCRF).   
Eligibility will be determined prior to enrollment (Part 1) or randomization (Part 2) and the 
start of study drug dosing. Eligible patients will be instructed on all protocol requirements, 
including any restrictions on concomitant medication usage (see Section 8.5). 
9.2. 
Treatment Phase 
Adverse events and concomitant medications will be monitored throughout the study.  
Study drugs will be administered as described in Section 8.1. 
 
The timing for assessments and procedures to be performed during the treatment period is 
outlined in Table 9-1 (Part 1) and Table 9-2 (Part 2). 
Patients that crossover from the osimertinib group to the G1T38 + osimertinib group 
following confirmation of radiographic disease progression by BICR shall follow the timing 


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for assessments and procedures as outlined in Table 9-2 beginning with Cycle 1 Day 1, 
including tumor assessments, until disease progression on G1T38 + osimertinib.  
9.3. 
Post-Treatment Visit/Early Termination 
Patients will return to the study center for a Post-Treatment visit 30 days from the last dose 
(+ 10 days). The procedures and assessments to be performed at this visit are outlined in 
Table 9-1 (Part 1) and Table 9-2 (Part 2). 
After completing the Post-Treatment visit, patients will enter the long-term Survival 
Follow-up Phase. 
9.4. 
Survival Follow-up Phase 
Follow-up shall be attempted and documented for each patient that is in the long-term 
Survival Follow-up Phase at least once every 3 months. Follow-up can be via telephone, 
clinic visits, or by receiving information from a family member or another provider who is 
administering care. Patients will be followed for survival until at least 50% of the patients 
enrolled to Part 2 of the study have died. This will be considered the end of study.  However, 
patients who are still receiving treatment at this time shall continue to receive study treatment 
until the criteria for study drug discontinuation are met. 
 
The following information will be collected for all patients: 
 
• Survival status 
• Details of any anticancer treatment  
 
For patients who have not had disease progression at the time of study drug discontinuation, 
tumor assessments should be performed every 8 weeks until the occurrence of progressive 
disease or study completion.  
 
9.5. 
Unscheduled Visits 
Additional visits can be performed at the discretion of the investigator. 


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10. 
STUDY PROCEDURES AND ASSESSMENTS  
10.1. 
Efficacy Assessments 
Clinical sites will perform all radiology assessments according to RECIST version 1.1. 
Day-to-day patient care decisions will be based upon investigator assessments. Blinded 
independent central review-determined response according to RECIST version 1.1 will be the 
primary outcome measure used to determine progression-free survival (PFS) and best overall 
response (BOR) in Part 2 of this study. All imaging assessments including unscheduled visit 
scans shall be collected on an ongoing basis and sent to a sponsor-appointed imaging vendor. 
The methods used at baseline for assessment of tumor burden [CT or MRI scans of chest and 
abdomen (including liver and adrenal glands)] must be used at each subsequent follow-up 
assessment. Any other areas of disease involvement shall be additionally investigated based 
on the signs and symptoms of individual patients. The baseline assessment shall be 
performed within 21 days of treatment start. CT or MRI scans obtained prior to informed 
consent will not need to be repeated if performed within 21 days prior to the first dose of 
study drug. Subsequent assessments are to be performed after every even cycle (every 8 
weeks relative to Cycle 1 Day 1) until objective disease progression. After 18 months of 
treatment, subsequent tumor assessments shall be performed every third cycle (every 12 
weeks ± 1 week) relative to Cycle 1 Day 1. If a patient has a radiological response (CR or 
PR), a confirmatory radiological assessment shall be performed at least 4 weeks after the 
response was first noted.  It is important to follow the assessment schedule as closely as 
possible. If scans are performed outside of the scheduled visit (± 1 week) and the patient has 
not progressed, every attempt shall be made to perform the subsequent scans at their 
scheduled time points. Any other sites at which new disease is suspected shall also be 
appropriately imaged. In Part 2, patients that crossover from the osimertinib group to the 
G1T38 + osimertinib group following BICR confirmation of radiographic disease 
progression shall continue tumor assessments after every even cycle (every 8 weeks relative 
to the crossover date) until objective disease progression. After 18 months of treatment 
following crossover, subsequent tumor assessments shall be performed every third cycle (12 
weeks ± 1 week) until disease progression.  
Patients with known or suspected brain metastases at screening shall have a CT/MRI of the 
brain prior to starting study drug. These patients shall be followed up on study with repeated 
CT/MRI assessment, using the same frequency as RECIST assessments. The same modality 
for CT/MRI shall be used for a patient throughout the study. Brain metastases will be 
assessed as nontarget lesions (NTLs).  
If the investigator is in doubt as to whether progression has occurred, particularly with 
response to NTLs or the appearance of a new lesion, it is advisable to continue treatment 
until the next scheduled assessment or sooner if clinically indicated and reassess the patient’s 
status. If repeat scans confirm progression, then the date of the initial scan shall be declared 
as the date of progression. 
For those patients who have not progressed at the time of study drug discontinuation, tumor 
assessments should continue every 8 weeks from the previous, regularly scheduled scan until 


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disease progression or study completion.  If the patient does not plan to return for subsequent 
post-treatment scans and has not had a scan within the prior 4 weeks, perform tumor 
assessment at the Discontinuation visit. 
The same method of assessment (CT or MRI) shall be used to characterize tumors at 
screening and at all follow-up assessments. If positron emission tomography (PET) is used, it 
shall also be accompanied by spiral CT or MRI. 
RECIST Version 1.1 - Blinded Independent Central Review Assessment 
The BICR of radiological imagining data will be carried out using RECIST version 1.1. All 
radiological scans for all subjects (including those at unscheduled visits, or outside visit 
windows) will be provided to the BICR. Prior radiotherapy reports for subjects (at baseline) 
and information on biopsied lesions will also be provided to the BICR as appropriate.  
Further details of the BICR will be documented in the Blinded Independent Review Charter. 
10.1.1. 
Tumor Lesions: Identification and Follow-up 
10.1.1.1. 
Measurable Lesions 
Measurable tumor lesions are defined as tumor lesions with a longest diameter (measured in 
at least 1 dimension) with a minimum size as follows (Eisenhauer 2009):  
• 10 mm by CT or MRI (with a scan slice thickness of no greater than 5 mm) 
Measurable lymph nodes must be ≥ 15 mm on the short axis by CT or MRI (with a scan slice 
thickness of no greater than 5 mm); only the short axis is to be measured at baseline and 
follow-up. 
Lytic bone lesions or mixed lytic-blastic lesions with a soft tissue component meeting the 
definition of measurability above can be considered measurable lesions. Cystic lesions 
representing cystic metastases that meet the definition of measurability described above can 
be considered measurable lesions. If present, noncystic lesions should be selected as target 
lesions for this study. 
A tumor lesion that has been previously irradiated may be considered measurable if 
unequivocal growth of the lesion has been demonstrated.  
Target lesions: At baseline, up to 5 measurable tumor lesions/lymph nodes (with a 
maximum of 2 lesions per organ) should be identified as target lesions that will be followed 
to quantitate the status of disease during the study. Lesions with the longest diameter, that are 
representative of all involved organs, and for which reproducible repeated measurements can 
be obtained should be selected as the target lesions.  
At baseline and each follow-up time point (see Table 9-1), each target lesion should be 
measured and the overall tumor burden will be calculated as the sum of the diameters of the 
target lesions (longest diameter [LD] for tumor lesions and short axis for lymph nodes) and 
documented in the eCRF. If a target lesion fragments into multiple smaller lesions, the LDs 
of all fragmented portions are added to the sum of the diameters. If multiple lesions coalesce, 
the LD of the coalesced lesion will be included in the sum of the diameters. 


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10.1.1.2. 
Nonmeasurable Lesions 
Nonmeasurable lesions include tumor lesions with a longest diameter < 10 mm, lymph nodes 
with ≥ 10 to < 15 mm short axis, or nonmeasurable lesions such as leptomeningeal disease, 
ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, or abdominal masses/abdominal organomegaly identified by 
physical exam that is not measurable by CT scan or MRI (Eisenhauer 2009).  
Nontarget lesions: All other lesions (or sites of disease) identified at baseline should be 
identified as NTLs and recorded in the eCRF. Measurements of these lesions are not 
required, but the presence, absence, or unequivocal progression of each NTL should be 
recorded in the eCRF at each follow-up time point. Multiple NTLs in the same organ may be 
noted as a single item on the eCRF.  
10.1.1.3. 
New Lesions 
Any new lesions should be identified and recorded at each follow-up assessment, as these are 
markers of disease progression. As defined in the RECIST, Version 1.1 guidelines 
(Eisenhauer 2009), new lesions include the following: 
• A lesion in an anatomical location that was not scanned at baseline 
• Equivocal new lesion of small size that with continued therapy and follow-up is 
found to progress and represent new disease (progression should be considered as of 
the date of the initial scan) 
• Negative positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-
glucose (FDG-PET) at baseline, but has a positive FDG-PET at follow-up 
• No FDG-PET at baseline and a positive FDG-PET at follow-up that corresponds to a 
new site of disease as confirmed by CT (date of disease progression should be the 
date of the initial abnormal FDG-PET scan) 
Note: Findings attributable to differences in scanning technique or a change in type of 
imaging (CT versus MRI) and findings representing something other than tumor (eg, healing 
or flare of existing bone lesions, necrosis of a liver lesion) should not be considered new 
lesions. 
10.1.2. 
Definitions of Tumor Response and Disease Progression 
The determination of tumor response and progression will be based on the 
RECIST, Version 1.1 criteria (Eisenhauer 2009). The definitions for tumor response per the 
RECIST, Version 1.1 criteria are as follows: 
10.1.2.1. 
Evaluation of Target Lesion Response 
• Complete response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or nontarget) 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 of diameters.  


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• 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. The appearance of 1 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 of diameters while on 
study. 
A response category of not evaluable (NE) is to be used when there is inadequate information 
to otherwise categorize the response status.  If a patient has a radiological response (CR or 
PR), a confirmatory radiological assessment shall be performed at least 4 weeks after the 
response was first noted. 
10.1.2.2. 
 Evaluation of Nontarget Lesions 
• Complete response (CR): Disappearance of all NTLs and normalization of tumor 
marker level. All lymph nodes must be < 10 mm short axis. 
• Non-CR/Non-PD: Persistence of 1 or more NTLs and/or maintenance of tumor 
marker level above the normal limits. 
• Progressive Disease (PD): Unequivocal progression of existing NTLs or the 
appearance of at least 1 new lesion.  
• To achieve “unequivocal progression” on the basis of nontarget disease, there 
must be an overall substantial worsening in nontarget disease, such that, even in 
the presence of SD or PR in target lesions, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest “increase” in size of 1 
or more nontarget lesions is usually not sufficient to qualify for unequivocal 
progression status. 
 
If a patient has a CR, a confirmatory radiological assessment shall be performed at least 4 
weeks after the response was first noted. 
10.1.2.3. 
Evaluation of Overall Response at Each Time Point 
Patients who have at least 1 postdose tumor assessment (CT scan or MRI) will be considered 
evaluable for tumor response.  
Categorization of objective tumor response assessment at each visit will be based on 
RECIST Version 1.1: CR, PR, SD and PD. Target lesion progression will be calculated in 
comparison to when the tumor burden was at a minimum (ie, smallest sum of diameters 
previously recorded on study). In the absence of progression, target lesion tumor response 
(CR, PR, SD) will be calculated in comparison to the baseline tumor measurements obtained 
before starting treatment. 
Table 10-1 describes the evaluation of overall response at each time point based on target and 
NTL responses at each time point, as well as the appearance of new lesions. Evaluation of 
overall response at each time point for patients with NTLs only may be found in Appendix 5. 


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The BOR is the best response recorded from randomization until disease progression. 
Confirmation of CR and PR is required as described in Sections 10.1.2.1 and 10.1.2.2.  
Table 10-1 
Evaluation of Overall Response at Each Time Point for Patients with 
Target Lesions 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/not evaluated 
No 
PR 
SD 
Non-PD/not evaluated 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR= partial response, SD = stable disease, PD = progressive disease, NE = not evaluable 
Source: (Eisenhauer 2009) 
 
10.2. 
Cell-Free DNA 
Blood samples for cfDNA analysis will be drawn at the time points outlined in Table 9-1 and 
Table 9-2. Beginning with Cycle 3 Day 1, cfDNA samples shall be collected on Day 1 of odd 
numbered Cycles (ie, Cycles 3, 5, 7, etc.). After 18 months of treatment, subsequent cfDNA 
sample collection shall be performed every 12 weeks until disease progression.   
Part 2 patients that crossover are not required to have blood samples collected for cfDNA at 
the crossover date. 
The samples will be used for analysis related to the effects of G1T38 on the tumor, including 
correlation with clinical efficacy endpoints. The processed samples may be stored up to 
15 years; handling and storage are to be found in the Laboratory Manual. 
10.3. 
Archival Tumor Tissue 
If available, archival tumor tissue (eg, block or slides) will be collected and banked for 
assessment of relevant DNA, RNA, and protein markers, such as those involved in the 
CDK4/6 pathway. For additional guidance, please refer to the Laboratory Manual. 
10.4. 
Optional Tumor Biopsy at Time of Disease Progression 
Optional fresh tumor biopsies at the time of disease progression may be collected and banked 
for analysis of relevant DNA, RNA, and protein markers, such as those involved in resistance 
pathways. For additional guidance, please refer to the Laboratory Manual. 
 


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10.5. 
Pharmacokinetic Assessments  
10.5.1. 
Pharmacokinetic Sampling 
Blood samples for measurement of G1T38 and osimertinib concentrations will be collected 
as described below and outlined in Table 9-1 (Part 1) and Table 9-2 (Part 2). Information on 
blood sample collection, handling and storage can be found in the Laboratory Manual.  
Part 1  
Serial PK blood samples for the measurement of G1T38 concentration in plasma will be 
collected from all patients in Part 1 on Cycle 1 Day -16 and Cycle 1 Day -2 as outlined in 
Table 10-2. G1T38 must be administered by clinic staff on Cycle 1 Day -16 and 
Cycle 1 Day -2.  
Pharmacokinetic blood samples for the measurement of osimertinib trough concentration and 
the G1T38 pre-dose concentration in plasma will be collected from all patients in Part 1 on 
Cycle 1 Day -2. These samples should be taken prior to (within 60 minutes) the morning 
dose of osimertinib and G1T38.  The doses of G1T38 and osimertinib should be taken 
together, but G1T38 may be given up to 60 minutes after the osimertinib dose. 
The actual times of blood sample collections should be documented in the eCRF.  
Table 10-2 
Part 1: Cycle 1 Day -16 and Cycle 1 Day -2 Blood Sampling Scheme  
 
Time Point (h) Relative to G1T38 dose on Cycle 1 Day -16 and on Cycle 1 Day -2 
Sample  
 
0 
(Pre-
dose) 
1 
 
2 
 
3 
 
4 
 
6 
 
8 
 
24 
 
 
32 
48  
 
Window 
-60 
minutes 
(± 10 minutes) 
(± 20 minutes) 
(± 3 hoursa) 
h = hour 
Actual times will be recorded in the eCRF. 
a 
Samples must be a minimum of 5 hours apart. 
 
Part 2 
Patients Randomized to G1T38 + Osimertinib 
Sparse blood sampling for population PK analysis of G1T38 will be collected during Part 2 
for patients randomized to G1T38 + osimertinib. The goal of this sparse sampling is to obtain 
G1T38 steady-state blood samples from participating patients at the following time 
points/intervals relative to G1T38 dosing: predose and at 1 to 3, 3 to 6, and 6 to 8 hours 
postdose. Each participating patient should have a total of 4 blood samples taken, 1 during 
each time point/interval (see Table 10-2). 
On Cycle 1 Day 15, patients shall be instructed to not take their G1T38 dose at home as the 
dose will be administered in the clinic following collection of the predose blood sample. In 
addition, on Cycle 1 Day 15, a blood sample shall be obtained at 1 to 3 hours postdose. It is 
strongly encouraged that the site contact the patient via telephone prior to the Cycle 1 Day 15 
visit to remind the patient not to take the morning dose of G1T38.   


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On Cycle 1 Day 22, a blood sample shall be obtained 3 to 6 hours postdose. On Cycle 2 
Day 1, a blood sample shall be obtained 6 to 8 hours postdose. It is anticipated that patients 
will self-administer G1T38 at a range of times during the day and that clinic visits may occur 
at any time throughout the day during normal business hours. The investigator is encouraged 
to work with the patient to schedule visits at an appropriate time of day in order to obtain the 
blood samples during the specified time intervals. 
Table 10-3 
Part 2 Blood Sampling Scheme for G1T38 Population PK Analysis 
Sample 
1 
2 
3 
4 
Cycle/Day 
Cycle 1 Day 15 
Cycle 1 Day 22 
Cycle 2 Day 1 
Time point 
Predose 
1-3 hours postdose 
3-6 hours postdose 
6-8 hours postdose 
Notes 
G1T38 administered in clinic 
 
 
 
 
10.5.2. 
Pharmacokinetic Parameters 
Pharmacokinetic parameters to be derived for G1T38 
 are listed in 
Table 10-4. Pharmacokinetic parameters will not be estimated for osimertinib.  
Additionally, for Part 2, a population PK model will be developed to estimate the PK 
parameters of G1T38 
 


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Table 10-4 
Pharmacokinetic Parameters for G1T38
  
Cmax 
The observed peak plasma concentration determined from the plasma concentration versus time 
data  
Tmax 
The time to reach the observed peak plasma concentration from the plasma concentration versus 
time data  
λz 
Terminal phase rate constant, determined by linear regression of at least 3 points on the terminal 
phase of the log-linear plasma concentration-time curve.  
t1/2 
Terminal half-life, defined as 0.693 divided by λz 
AUClast 
Area under the concentration-time curve from time zero to the last quantifiable concentration 
using the linear-up log-down trapezoidal rule. 
AUCinf 
Area under the concentration-time curve from time zero extrapolated to infinity using the linear-
up log-down trapezoidal rule. 
CL/F 
Clearance after oral administration, calculated as: 
CL/F = Dose/AUC0-∞ (G1T38 only) 
Vz/F 
Volume of distribution in the terminal elimination phase, calculated as: 
Vz/F = (CL/F)/λz (G1T38 only) 
 
M/P Ratio 
Metabolite to parent ratio calculated as G1T30AUCinf/G1T38AUCinf 
 
10.6. 
Safety Assessments 
Safety evaluations will begin after the first dose of any study drug and continue throughout 
the study. Safety evaluations will include monitoring of AEs, vital signs measurements, 
physical examinations, ECGs, echocardiograms/ multigated acquisition (MUGA) scans, 
ophthalmic exams, and clinical laboratory assessments. 
Toxicity will be graded by the investigators using the NCI CTCAE, Version 4.03. 
10.6.1. 
Adverse Events and Serious Adverse Events 
Adverse events are captured following the first dose of study drug. All AEs should be 
reported within 30 days of the last dose of study drug, and followed until they are resolved, 
have returned to baseline, or it is deemed that further recovery is unlikely. 


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10.6.1.1. 
Definition of Adverse Event 
An AE is defined as any untoward medical occurrence in a patient administered a medicinal 
product that does not necessarily have a causal relationship with this treatment. An AE can, 
therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the study (investigational) product. 
Adverse events include the following: 
• All suspected study drug-related adverse events 
• All reactions from medication overdose, abuse, withdrawal, sensitivity, or toxicity 
• Apparently unrelated illnesses, including the worsening of a pre-existing illness (see 
pre-existing conditions below) 
• Injury or accidents (Note that if a medical condition is known to have caused the 
injury or accident [eg, a fall secondary to dizziness], the medical condition [dizziness] 
and the accident [fall] should be reported as 2 separate AEs). The outcome of the 
accident (eg, hip fracture secondary to the fall) should be recorded under comments. 
• Abnormalities in physiological testing or physical examination (findings that require 
clinical intervention or further investigation beyond ordering a repeat [confirmatory] 
test) 
• Laboratory abnormalities that are clinically significant and require clinical 
intervention or further investigation (beyond ordering a repeat [confirmatory] test) 
unless they are associated with an already reported clinical event. Laboratory 
abnormalities associated with a clinical event (eg, elevated liver enzymes in a patient 
with jaundice) should be described under comments on the report of the clinical event 
rather than listed as a separate AE. 
An AE does not include: 
• Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, 
transfusion); the condition that leads to the procedure may be an AE 
• Pre-existing diseases or conditions present or detected at the start of the study that do 
not worsen 
• Situations where an untoward medical occurrence has not occurred (eg, 
hospitalization for elective surgery, social, and/or convenience admissions) 
• Overdose of either study drug or concomitant medication without any signs or 
symptoms 
• Progression of the malignancy under study, including signs and symptoms 
progression  
• Disease progression can be considered as a worsening of a patient’s condition 
attributable to the disease for which the investigational product is being studied. It 
may be an increase in the severity of the disease under study and/or increases in 
the symptoms of the disease. The development of new, or progression of existing 
metastasis to the primary cancer under study should be considered as disease 
progression and not an AE 
• Hospitalization due to signs and symptoms of disease progression 


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An unexpected AE is any AE that is not identified in nature, severity, or frequency in the 
current IB or product information. The sponsor or designee shall be responsible for 
determining expectedness; this is not the responsibility of the investigator. 
• An Adverse Drug Reaction (ADR) is defined as an AE that is caused by a drug (aka 
drug-related AE). An unexpected ADR is an adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (eg, IB for an 
unapproved investigational medicinal product). All noxious and unintended responses 
to a medicinal product related to any dose should be considered ADRs. The phrase 
“responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility, ie, the relationship 
cannot be ruled out. All serious and unexpected ADRs will have expedited reporting 
to the regulatory agencies following the ICH requirements 
It is the responsibility of the investigator to document all AEs that occur during the study and 
every effort should be made to adequately capture all possible AEs. Patients should be 
encouraged to report AEs spontaneously or in response to general, nondirected questioning. 
Adverse events should be reported on the appropriate page of the eCRF. 
10.6.1.2. 
Definition of Serious Adverse Event 
The International Council for Harmonisation (ICH) topic E2A on Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting defines an SAE as any 
untoward medical occurrence that at any dose:  
• Results in death 
• Is life threatening 
NOTE: The term "life threatening" in the definition of "serious" refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe.  
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
(see Section 10.6.1.9) is appropriate in other situations, such as important medical events that 
may not be immediately life threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes listed 
in the definition above. These should also usually be considered serious. Examples of such 
events are intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
To ensure there is no confusion or misunderstanding of the difference between the terms 
“serious” and “severe”, the following note of clarification is provided: 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 


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relatively minor medical significance (such as severe headache). This is not the same as 
“serious,” which is based on patient/event outcome or action criteria usually associated with 
events that pose a threat to a patient’s life or functioning. Seriousness (not severity) serves as 
a guide for defining regulatory reporting obligations. 
Hy’s Law  
Prompt reporting (via the SAE expedited reporting system) of cases meeting Hy’s law 
criteria (AST or ALT ≥ 3 × ULN and total bilirubin ≥ 2 × ULN) is required for compliance 
with regulatory guidelines. The investigator is responsible for, without delay, determining 
whether a patient meets potential Hy’s law criteria. Any patient with liver function test 
abnormalities meeting Hy’s Law criteria must have all study drugs permanently 
discontinued. 
Additional Reporting Requirements for Osimertinib 
The following will also be reported to pharmacovigilance: any osimertinib overdose; if a 
patient taking osimertinib begins lactating; or if a male patient taking osimertinib fathers a 
child during the treatment period, including the Post-Treatment Follow-up visit.  If these 
events also meet the criteria to be considered an SAE, they shall be reported as such. 
Handling of Deaths 
 
All deaths that occur during the study, or within the follow-up period after the administration 
of the last dose of investigational product, should be reported as described below. 
Death, which is unequivocally due to disease progression, should be communicated to the 
study monitor at the next monitoring visit and should be documented in the eCRF module, 
but should not be reported as a SAE during the study 
Where death is not clearly due to disease progression, the AE causing the death should be 
reported to the study monitor as an SAE within 24 hours. The report should contain a 
comment regarding the co-involvement of progression of disease, if appropriate, and should 
assign a single primary cause of death together with any contributory causes. 
Deaths with an unknown cause should always be reported as a SAE but every effort should 
be made to establish a cause of death. A postmortem may be helpful in the assessment of the 
cause of death, and if performed, a copy of the post-mortem results (with translation of 
important parts into English) shall be reported, if possible, to the sponsor. 


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10.6.1.3. 
Assessment of the Severity of Adverse Events 
The severity (toxicity grade) of AEs will be graded according to the NCI CTCAE, 
Version 4.03 (see Appendix 1). 
10.6.1.4. 
Assessment of the Causal Relationship of Adverse Events to Study Drug 
The investigator will assess causal relationship between study drug and each Adverse Event 
and classify each AE as either related or unrelated. In determining if an AE is study drug 
related, the Investigator shall take into account the following question: “Is there a reasonable 
possibility that the event may have been caused by the study drug?” Investigators shall use 
their knowledge of the patient, the circumstances surrounding the event, and an evaluation of 
any potential alternative causes to determine whether or not an adverse event is considered to 
be related or unrelated to study drug. The following guidance shall be taken into 
consideration when determining causality: 
• Temporal relationship of event onset to the initiation of study drug 
• Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• Known association of the event with the study drug or with similar treatments 
• Known association of the event with the disease under study 
• Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
The following terms for assessment of the causality to study drug or study procedures are to 
be used: 
• Unrelated: There is not a temporal relationship to study drug administration (eg, too 
early, too late, or study drug not taken), or there is a reasonable causal relationship 
between another drug, concurrent disease, or circumstance and the AE. 
• Related: There is a reasonable causal relationship between the study drug and the 
AE. The event responds to withdrawal of study drug, and recurs with re-challenge, 
when clinically feasible. 
 
For patients receiving combination therapy, causality will be assessed individually for each 
study drug. 
10.6.1.5. 
Assessment of the Outcome of Adverse Events 
The outcome will be assessed according to the following: 
• Fatal 
• Not recovered/not resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Recovered/resolved 


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• Unknown 
10.6.1.6. 
Method, Frequency, and Time Period for Detecting Adverse Events and 
Serious Adverse Events 
Adverse events and SAEs are reported following the first dose of study drug through 30 days 
after last dose of study drug (ie, the Post-Treatment Visit). 
10.6.1.7. 
Documentation of Adverse Events and Serious Adverse Events 
All AEs will be documented in the appropriate section of the eCRF. The CTCAE, 
Version 4.03 grading scale referenced in Appendix 1 is provided to assist in categorizing and 
grading AEs. All SAEs (see Section 10.6.1.2) will be additionally documented on the SAE 
report form.  
10.6.1.8. 
Adverse Event Coding 
Adverse event verbatim terms provided by the investigator will be coded by G1 Therapeutics 
or its designee using the latest version of the MedDRA as specified in the statistical analysis 
plan (SAP). 
10.6.1.9. 
Reporting of Serious Adverse Events 
The reporting period for SAEs begins from the time of first dose of study drug through and 
including 30 calendar days after the last administration of G1T38. Any SAE that is thought to 
be related to the study drug and that occurs after the reporting period must be reported within 
24 hours of discovery of the SAE PPD Pharmacovigilance.  SAEs that occur prior to the first 
dose of study drug that are a direct result of a study-related procedure shall additionally be 
reported as an SAE to PPD Pharmacovigilance. 
SAE information will be collected on the eCRFs, therefore it is imperative that any SAE be 
entered onto the electronic SAE Form within 24 hours of learning of the event. If the EDC 
system is not operational, the paper SAE Form must be completed within 24 hours and faxed 
to the number below. 
PPD Pharmacovigilance: 
 
North America 
 
24 hour Safety Phone: 1-888-483-7729 
24 hour Safety Fax: 1-888-529-3580 
 
EMEA/APAC   
 
24 hour Safety Phone:   +44 1223 374 240 
24 hour Safety  Fax:  +44 1223 374 102       
 


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10.6.1.10. 
Follow-up of Adverse Events 
All AEs (both serious and nonserious) will be followed up in accordance with good medical 
practice until resolution, return to baseline, or it is deemed that further recovery is unlikely. 
All measures required for AE management and the ultimate outcome of the AE will be 
recorded in the source document and reported to the sponsor. 
All unresolved AEs should be followed by the investigator until the events are resolved, the 
patient is lost to follow-up, or the AE is otherwise explained, or further recovery is not 
deemed to be feasible. At the last scheduled visit, the investigator should instruct each patient 
to report any subsequent event(s) that the patient, or the patient’s personal physician, believes 
might reasonably be related to participation in this study.  
Prior to the conclusion of the study at the site, the investigator should notify the medical 
monitor of any SAE occurring at any time after a patient has discontinued or terminated 
study participation that may reasonably be related to the study drug. While the study is 
ongoing, all deaths should be reported via the electronic data capture system regardless of 
relationship to study drug, even if the patient has discontinued participation in the study. 
After study conclusion, the investigator should notify the sponsor of any death or SAE they 
are aware of occurring at any time after a patient has discontinued or terminated study 
participation that may reasonably be related to the study drug. The sponsor should also be 
notified if the investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a patient that has participated in 
this study. 
10.6.1.11. 
Regulatory Aspects of Adverse Event Reporting 
The sponsor or its representative will report the following suspected unexpected serious 
adverse reactions (SUSARs) to the independent ethics committee (IEC)/institutional review 
board (IRB) in an expedited time frame: 
 
• SUSARs that have arisen in the current clinical study that was assessed by the 
IEC/IRB 
 
The sponsor or its representative will report all SUSARs to the Competent Authority, the 
Medicine Evaluation Board, and the Competent Authorities in other Member States, if 
applicable in an expedited time frame. 
 
SUSARs that are already reported to the European Medicines Agency Eudravigilance 
database do not have to be reported again to the Competent Authority and the Medicine 
Evaluation Board because they have direct access to the Eudravigilance database. 
 
The expedited reporting will occur no later than 15 calendar days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life-threatening cases the term will be a 
maximum of 7 calendar days for a preliminary report with another 8 days for completion of 
the final report. The investigator is encouraged to discuss with the medical monitor any 
adverse experiences for which the issue of reportability is unclear or questioned.   


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It is important that the investigator provide his/her assessment of relationship to study drug at 
the time of the initial report. 
10.6.1.12. 
Handling of Overdose 
In the context of a clinical study, an overdose is any dose which exceeds the daily dose that is 
defined in the clinical study protocol.  
If an overdose on a study drug occurs in the course of the study, then the investigator or other 
site personnel shall inform the appropriate sponsor representatives immediately, or no later 
than 24 hours of when he or she becomes aware of it. The designated sponsor representative 
shall work with the investigator to ensure that all relevant information is provided to the 
sponsor or designee. 
For overdoses associated with a SAE, the standard reporting timelines apply, see 
Section 10.6.1.9. 
G1T38 
A maximum tolerated dose of G1T38 has not been established. 
There is no specific treatment in the event of G1T38 overdose, and symptoms of overdose 
are not established. In the event of an overdose, physicians should follow general supportive 
measures and should treat symptomatically. 
Osimertinib 
A maximum tolerated dose has not been established for osimertinib.  
Such overdoses should be recorded as follows:  
• An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module 
• An overdose without associated symptoms is only reported on the Overdose eCRF 
module  
There is no specific treatment in the event of osimertinib overdose, and symptoms of 
overdose are not established. In the event of an overdose, physicians should follow general 
supportive measures and should treat symptomatically. 
10.6.1.13. 
Reporting of Pregnancies  
Pregnancy is not considered an AE unless there is cause to believe that the investigational 
drug may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs.  
Hospitalization for normal delivery of a healthy newborn should not be considered a SAE. 
Each pregnancy, including ectopic pregnancy, which occurs during the course of the study 
and within 6 weeks of the last dose of study drug, in a study patient or partner of a study 
patient must be reported to the safety team within 24 hours of learning of its occurrence. If a 
patient becomes pregnant, all study drug administration must be discontinued immediately. 
The pregnancy should be followed up to determine outcome, including spontaneous or 


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voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications and documented, even if 
the subject was discontinued from the study. 
The avoidance of pregnancy or fathering a child (including sperm donation) is recommended 
for 4 months following the discontinuation of study drug. Pregnancy of the subject’s partner 
is not considered to be an AE. No information is currently available regarding the effects of 
G1T38 on fertility, gestation, or subsequent child development. 
To capture information about a pregnancy from the partner of a male subject, the male 
subject’s partner consent must be obtained to collect information related to the pregnancy 
and outcome; the male subject should not be asked to provide this information. A consent 
form specific to this situation must be used. The outcome of any conception occurring from 
the date of the first dose until 4 months after dosing ends should be followed up and 
documented.  
10.6.2. 
Clinical Laboratory Assessments 
Blood samples will be collected for clinical laboratory assessments as outlined in Table 9-1 
(Part 1) and Table 9-2 (Part 2). Hematology, clinical chemistry, and urinalysis samples may 
be obtained up to 48 hours prior to the scheduled visit. If screening hematology, clinical 
chemistry, and urinalysis assessments have been performed within 7 days of Cycle 1 Day -16 
for Part 1 or within 7 days of Cycle 1 Day 1 for Part 2, then these tests do not have to be 
repeated prior to commencing first treatment with study drug as long as the patient's clinical 
condition has not changed. After baseline assessment (Day -16 in Part 1, Cycle 1 Day 1 in 
Part 2), Cystatin C shall be evaluated only in the event that the serum creatinine is elevated. 
The measurement of Cystatin C to estimate glomerular filtration rate is included in this study 
because G1T38 may inhibit MATE transporters in the renal tubule and induce a 
nonpathologic increase in serum creatinine. The clearance of Cystatin C is not dependent 
upon the MATE transporters and thus can help differentiate the effect of G1T38 on the 
MATE transporter from a true decline in renal function. 
Absolute neutrophil counts will be monitored weekly for the first 8 weeks (2 cycles), then 
every 2 weeks for the next 2 cycles. Beginning with Cycle 5 Day 1, patients with stable 
≤ Grade 2 hematologic parameters may have hematology monitored monthly on Day 1 of 
each cycle; patients that do not meet this criteria will continue to have every other week 
assessment of hematologic parameters. 
Clinical chemistry will be monitored every 2 weeks for the first 4 cycles. Beginning with 
Cycle 5 Day 1, clinical chemistry will be monitored monthly on Day 1 of each cycle.   
Clinical laboratory tests to be performed are presented in Table 10-5.  


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Table 10-5 
Clinical Laboratory Tests 
Hematology  
Hemoglobin 
Hematocrit 
WBCs with differential  
Platelets 
Chemistry  
Albumin 
Alkaline phosphatase 
Total bilirubin 
Calcium 
Chloride 
Creatinine 
Glucose 
Inorganic phosphorus 
 
Potassium 
Total protein 
ALT 
AST 
Lactate dehydrogenase 
Sodium 
Blood urea nitrogen/urea 
Cystatin Ca 
Urinalysis  
Specific gravity 
pH 
Glucose 
Protein 
Bilirubin 
Ketones 
Leukocytes 
Hemoglobin 
Microscopic examination (including RBC, WBC, 
and casts will be performed, if necessary) 
Pregnancy test 
Blood or urine tests are 
acceptable based on the site’s 
standard clinical practice; 
applicable to women of 
childbearing potential only. 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; RBC = red blood cell; WBC = white blood cell 
a 
Postbaseline Cystatin C to be evaluated in the event that serum creatinine is elevated 
 
If treatment is interrupted, the patient should still complete all clinical laboratory assessments 
as scheduled, as well as on the actual dosing day when treatment is reinitiated.  
Laboratory parameters shall be analyzed by a local certified laboratory and a report of the 
laboratory values shall be sent to the study center. The investigator shall review the 
laboratory report promptly after receipt of the results and indicate the clinical significance of 
all abnormal values, and subsequently sign and maintain the laboratory report with the 
patient’s source records/charts. Laboratory parameters for which clinically significant values 
are noted shall be re-measured on the appropriate clinical follow-up arranged by the 
investigator. Any laboratory value that remains abnormal at the end of the study and that is 
considered clinically significant shall be followed according to accepted medical standards 
for up to 30 days or until resolution of the abnormality, or it is deemed that recovery is not 
feasible. 
Laboratory toxicities shall be assessed using the NCI CTCAE, Version 4.03 (see 
Appendix 1). 
Laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Section 10.6.1.  
The SMC/IDMC may modify the frequency of laboratory monitoring based on cumulative 
safety data.  


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10.6.3. 
Demographics and Vital Signs 
The following will be collected at the time points outlined in Table 9-1 (Part 1) and Table 9-2 
(Part 2): 
1. 
Height in centimeters (cm) 
2. 
Body weight in kilogram (kg) 
3. 
Body temperature (Celsius) 
4. 
Systolic and diastolic blood pressure, pulse rate, and respiration rate; blood pressure 
should be assessed after 5 minutes of rest and should be assessed predose 
10.6.4. 
Physical Examination 
Physical examinations will be performed at the time points outlined in Table 9-1 (Part 1) and 
Table 9-2 (Part 2). 
Full physical examination evaluations at screening and the Post-Treatment visit shall include 
general appearance, skin, neck, eyes, ears, nose, throat, lungs/respiratory, 
heart/cardiovascular, abdomen, back, lymph nodes, thyroid, musculoskeletal (including spine 
and extremities), and neurological examinations. Subsequent physical exams shall be 
symptom directed and include body systems as appropriate.  
Clinically significant findings on physical examination prior to administration of the first 
dose of study drug must be recorded as medical history in the eCRF. Clinically significant 
findings on physical examination made after the first dose of study drug, which meet the 
definition of an AE, must be recorded as an AE in the eCRF. 
10.6.5. 
Electrocardiogram Assessments 
All patients will have three 12-lead ECGs performed at the visits indicated in Table 9-1 
(Part 1) and Table 9-2 (Part 2).   
Part 1 ECG requirements are as follows: 
Cycle and Day 
 
Time Points 
Screening 
Anytime during visit (one set of 3 ECGs) 
Cycle 1 Day -16 
Predose and at 2 and 6 hours (± 15 minutes) after 
the G1T38 dose 
Cycle 1 Day -2 
Predose and at 2 and 6 hours (± 15 minutes) after 
the G1T38 dose 
Cycle 2 Day 1 and Day 1 of each cycle thereafter 
Anytime during visit (one set of 3 ECGs) 
 
Patients enrolled in Part 2 of the study will have three 12-lead ECGs performed at screening 
and Day 1 of each cycle.   
A 12-lead ECG will be obtained after the patient has been resting semi-supine for at least 
10 minutes prior to times indicated and should be recorded at 25 mm/sec. All ECGs shall be 
recorded with the patient in the same physical position. The three ECG recordings shall be 
taken within an approximate 5 minute period. A standardized ECG machine shall be used 


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and the patient shall be examined using the same ECG machine throughout the study if 
possible.   
After paper 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 paper 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 must be reported as a concurrent 
condition. For all ECGs, details of rhythm, ECG intervals, and an overall evaluation will be 
recorded.  
ECG data shall be collected digitally and shall be transferred electronically for central 
analysis. The investigator may choose to perform a nondigital ECG at the time of the 
screening visit in order to identify patients eligible for study entry. If a nondigital ECG is 
performed at the screening visit it cannot subsequently be used as a baseline recording, in this 
situation an ECG will need to be collected on the baseline visit in digital form.  
Heart rate, PR, R-R, QRS, and QT intervals will be determined and reviewed during central 
analysis by an external cardiologist.  
If there is a clinically significant abnormal ECG finding during the Treatment Phase, this 
should be recorded on the AE eCRF, according to standard AEs collection and reporting 
processes. A 30-day follow-up assessment will be required if an on treatment assessment was 
abnormal at the time of discontinuation of study therapy, to confirm reversibility of the 
abnormality.  
The investigator or designee shall review the ECGs for any abnormalities as compared with 
the baseline ECGs.  
10.6.6. 
Ophthalmic Examination 
Full ophthalmic assessment, including slit-lamp examination, shall be performed at screening 
and if a patient experiences any visual symptoms (including blurring of vision), with 
additional tests if clinically indicated (Table 9-1 [Part 1] and Table 9-2 [Part 2]). 
Ophthalmology examination results shall be recorded in the eCRF.  
Any clinically significant findings, including those confirmed by the ophthalmologist must 
be reported as an AE. Photographs should be performed to record any clinically significant 
findings. These photographs should be available for central review by the sponsor and 
sponsor representatives if necessary.  
Patients experiencing corneal ulceration will not be permitted to restart study treatment.  
10.6.7. 
Echocardiogram/MUGA 
An echocardiogram/MUGA scan to assess LVEF shall be performed at the time points 
outlined in Table 9-1 (Part 1) and Table 9-2 (Part 2). The modality of the cardiac function 
assessments must be consistent throughout the study for an individual patient (ie, if 
echocardiogram is used for the screening assessment then echocardiogram shall also be used 
for subsequent scans). The patients shall also be examined using the same machine and 
operator whenever possible. A 30-day (+10 days) follow-up assessment will be required if an 
on treatment assessment was abnormal and clinically significant at the time of 
discontinuation of study therapy, to confirm reversibility of the abnormality. 


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10.7. 
Biomarker Analysis 
The subject’s consent to the use of donated biological samples is mandatory. 
10.8. 
Appropriateness of Measurements 
The measures of efficacy, PK, and safety evaluated in this study are based on the mechanism 
and activity of G1T38 and standard types of assessments typically performed in patients with 
NSCLC. The measurement of tumor response based on the RECIST, Version 1.1 
(Eisenhauer 2009) is standard. The PK and safety measures included in this study are also 
standard.  


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11. 
STUDY TERMINATION OR STUDY DRUG 
DISCONTINUATION 
11.1. 
Study Termination 
The entire study may be terminated in the event of any of the following: 
• Occurrence of AEs unknown to date with respect of their nature, severity, and duration, 
or the unexpected incidence of known AEs 
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of patients 
• Cancellation of the drug development program 
• Sponsor decision for other reasons  
 
11.2. 
Site Termination 
A study site may be closed if there is evidence of fraud, other unethical conduct, or 
significant regulatory noncompliance to the protocol or to Good Clinical Practice (GCP), or 
if insufficient patients have been enrolled to meet the site objectives. 
11.3. 
Discontinuation of Study Drug 
Study drug(s) shall be discontinued if any of the following events occur during the study: 
• A patient suffers an AE that, in the judgment of the investigator, sponsor, or medical 
monitor, presents an unacceptable risk to the patient (see Section 8.3.3.2 for 
additional details). 
• General or specific changes in the patient’s condition (eg, a significant intercurrent 
illness or complication) that, in the judgment of the investigator, are unacceptable for 
further administration of study drug 
• Occurrence of pregnancy 
• Significant noncompliance with protocol requirements 
• The sponsor or legal representative of the sponsor requests the patient to withdraw 
• Patient has radiographically documented or clinically determined disease progression, 
with the exception of patients in Part 2 that crossover from osimertinib alone to 
G1T38 + osimertinib at the time of disease progression. 
In the event of study drug discontinuation, patients shall be strongly encouraged to complete 
all scheduled assessments; the Post-Treatment Visit; and the Survival Follow-up Phase of the 
study. A patient who discontinues study drug for reasons other than PD shall have a CT or 
MRI scan at the Post-Treatment Visit, if they have not had a scan within the prior 4 weeks 
and the patient does not plan to return for subsequent post-treatment scans.  
When discontinuation is due to a SAE or a Grade 3 or 4 toxicity considered to be related to 
study drug, the investigator shall follow the event until resolution, return to baseline, or it is 
deemed that further recovery is unlikely. 


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In the event a patient discontinues due to an AE or pregnancy, the investigator shall notify 
the medical monitor or PPD Safety Services by telephone within 24 hours of study drug 
discontinuation. 
11.4. 
Withdrawal of Patients from the Study 
Patients may withdraw from the study at their own discretion (or at the discretion of the 
investigator) for any reason at any time.  
All data and lab samples collected prior to the date of withdrawal of consent will remain in 
the clinical database and at laboratory vendor.  
 


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12. 
STATISTICS 
Full details on the statistical analyses to be performed will be provided in a separate 
Statistical Analysis Plan (SAP). 
12.1. 
Sample Size and Power 
It is estimated that up to 36 patients will be enrolled in the dose-escalation part of the study 
(Part 1). The actual number of patients will depend on the number of dose levels/cohorts that 
are tested.   
For the randomized part of the study (Part 2), it is assumed that the overall 1-sided type I 
error rate is 0.1 and the type II error rate used to compute sample size is 0.20 (corresponding 
to 80% power). Patients will be randomized using a 1:1 treatment allocation ratio between 
the 2 treatment groups (osimertinib versus G1T38 + osimertinib).  
Assuming a 10.1 month median PFS for the osimertinib group from historical data 
(Mok et al, 2017) and a hazard ratio (HR) of 0.6 (corresponding to a median PFS of 
16.8 months for the G1T38 + osimertinib group), the required number of PFS events is 70. 
Assuming an accrual period of 12 months and an additional follow-up period of 18 months 
after the last patient is enrolled, the calculated total sample size for Part 2 is 98 patients. 
Allowing for a dropout/ lost-to-follow-up rate of approximately 10% gives an adjusted total 
sample size of 108. 
These calculations were carried out using the POWER procedure in SAS® Version 9.4. 
12.2. 
General Considerations 
12.2.1. 
Analysis Populations 
The safety analysis set will include all enrolled patients who were administered at least 
1 dose of study drug. All safety analyses will be assessed using the safety analysis set. 
Analyses using the safety analysis set will be conducted on the basis of the actual treatment 
received. 
The full analysis set (FAS) includes all patients who received at least 1 dose of study drug. 
Analyses using the FAS will be conducted on the basis of the assigned treatment. All efficacy 
analyses will be assessed using the FAS and the FAS is the primary analysis set for efficacy 
analysis. The FAS will only be applicable for the Part 2 of the study.  
The response evaluable analysis set will include all patients who are in the safety analysis set 
and who have measurable tumor lesions at baseline and at least 1 postbaseline tumor 
assessment, have clinical progression as noted by the investigator before their first postdose 
tumor scan, or die due to disease progression before their first postdose tumor scan. The 
response evaluable analysis set will be used for analyses of tumor response and PFS.  
The per-protocol (PP) analysis set will include all patients in the safety analysis set who have 
no major protocol deviations and who received the treatment to which they were randomized. 
For patients who took the wrong treatment for Part 2 of the study, their data will be excluded 
from the PP analysis set. The PP analysis set may be used to analyze selected endpoints to 


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test the robustness of results. The criteria for inclusion in the PP analysis set will be finalized 
and documented prior to database lock. 
The PK analysis set will include all dosed patients with evaluable PK data; it will be the basis 
of PK-related summaries.  
12.2.2. 
Timing of Analyses 
12.2.2.1. 
Interim Safety Reviews 
Following completion of data collection for each dose cohort of Part 1, the SMC will review 
all safety and available PK data in order to determine the subsequent dose level. At the end of 
Part 1 of the study, the SMC will review all cumulative safety and PK data in order to 
determine the RP2D.  
12.2.2.2. 
Independent Data Monitoring Committee 
During Part 2, an IDMC will evaluate accumulating safety data according to a charter that 
defines its roles and responsibilities. The IDMC will perform interim reviews approximately 
every 4 months during the Part 2 of the study, depending upon the enrollment rate. 
Additional reviews may occur based on IDMC requests. The IDMC shall make 
recommendations regarding continuation of the study, suggested modification of the study, 
or cessation of the study based on cumulative safety and efficacy data, including cessation 
for futility. The committee will consist of individuals with extensive multicenter clinical 
study experience drawn from the fields of clinical oncology (specifically, NSCLC), clinical 
pharmacology, and biostatistics. These individuals will be entirely independent of the 
conduct of the study. 
Additional details regarding the committee procedures and policies, including table displays, 
will be described in the IDMC charter.  
12.2.2.3. 
Final Analysis 
The final analysis will utilize data obtained by BICR and will be conducted after at least 
70 PFS events (65%) have occurred or 18 months after the end of accrual for Part 2 of the 
study, whichever occurs first.  
 
12.2.2.4. 
End of Study Analysis 
The Survival Follow-up Phase will continue until at least 50% of the patients in Part 2 have 
died. If the Follow-up Survival Phase of the study continues after the final analysis, a 
supplementary analysis will be done at the time of study completion. Reported results will be 
cumulative in nature, including all data collected during the entire study. 
12.2.3. 
General Considerations for Data Analysis 
Detailed methods of statistical analyses will be presented in the SAP. All statistical analyses 
will be performed using SAS® Version 9 or higher.  


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In general, data will be summarized separately by study part (Part 1 and Part 2). Data from 
Part 1 will be summarized descriptively by dose level, if applicable, and overall. Data from 
Part 2 will be summarized descriptively by treatment group and overall. Treatment 
differences between treatment groups for Part 2 will be calculated as G1T38 + osimertinib 
minus osimertinib alone. Selected safety summaries will include combined data from both 
Parts 1 and 2 of the study.  
The descriptive summary for the categorical variables will include counts and percentages. 
The descriptive summary for the continuous variables will include mean, median, standard 
deviation (StD), and minimum and maximum values. The descriptive summaries of 
time-to-event data will include median, 25% and 75% percentiles, and standard error. The 
Kaplan-Meier method will also be used to summarize the time-to-event data. All data will be 
listed for all patients. All confidence intervals (CIs) for treatment differences between 
treatment groups for Part 2 will be 2-sided 80%, and other CIs will be 2-sided 95%, unless 
stated otherwise.  
Part 1 of the study is descriptive in nature. For the Part 2 of the study, all statistical tests will 
be conducted at a 1-sided significance level of 10% unless otherwise specified 
(G1T38 + osimertinib versus osimertinib alone). Where appropriate, model based point 
estimates, together with their 80% CIs will be presented along with the 1-sided p-value for 
the test. 
12.3. 
Part 1 (Phase 1b) Statistical Analyses  
The primary analysis is based on the assessment of safety and tolerability endpoints for 
Part 1 of the study. The data will be analyzed by descriptive statistics. All CIs of data 
summary will be 2-sided 95%, unless stated otherwise.  
Adverse event data will be coded to system organ class and preferred term using MedDRA 
(Version 17.1 or later). The number and percentage of patients experiencing any TEAE, 
overall, and by system organ class and preferred term will be tabulated. Adverse events 
related to treatment will be further summarized by the treatment to which it is attributed (eg, 
G1T38 or osimertinib). DLTs and withdrawals due to AEs will be summarized or listed; 
further details with respect to these events can be found in Section 6.1.1.2 and 11.3. Severity 
will be tabulated based on greatest severity observed for each patient. If a patient experiences 
an AE more than once during the study, the greatest severity will be tabulated.  
 
Any AE occurring within the defined 30 day follow-up period after the last dose of study 
drug will be included in the AE summaries. Any adverse events in this period that occur after 
a patient has received further therapy for cancer (following discontinuation of study drug) 
will be flagged in the data listings. AEs occurring after the 30 day follow-up period after last 
dose of study drug will be listed separately, but not included in the summaries. 
12.3.1. 
Other Safety Endpoints 
Observed values and changes from baseline in vital signs, ECG readings, 
echocardiogram/MUGA scan results, and hematology, clinical chemistry, and liver function 
parameters will be tabulated at each visit. Toxicities for clinical labs will be characterized 
according to CTCAE, Version 4.03. Shifts in toxicity grades from baseline to each visit, and 


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from baseline to the worst grade during the study will be summarized. Summaries examining 
maximum and minimum post-baseline changes will consider both scheduled and 
unscheduled data.  
Graphical presentations of safety data will be presented as is deemed appropriate. This may 
include, but is not restricted to, presentation of parameters against time, concentration or shift 
plots. For example, graphical presentations of average changes over time will provide 
additional focus to be placed on neutrophils and platelet data. 
Dose reductions/modifications, interruptions, compliance, and patient exposure will be 
summarized for each study therapy component, where appropriate. 
12.3.2. 
Efficacy Endpoints 
Antitumor efficacy endpoints include the following: 
• 
Best overall response (BOR) according to RECIST v1.1  
• 
Objective response (OR) (CR or PR) according to RECIST v1.1 
• 
Duration of OR, and time to first objective response according to RECIST v1.1 
• 
Clinical benefit rate (CBR) according to RECIST v1.1 
• 
Progression-free survival (PFS) according to RECIST v1.1 
• 
Overall survival (OS) 
BOR will be determined using visit responses up until the last evaluable overall visit 
response prior to or on the date of (i) radiographic or clinical disease progression; (ii) 
withdrawal of consent to obtain scans; or (iii) receiving subsequent anticancer therapy, 
whichever is earlier. At each tumor assessment visit, an overall time point response by 
RECIST 1.1 will be determined programmatically - using the information from target lesions, 
NTLs, and new lesions.   
For patients who progress and subsequently have a response, then the best objective response 
is only derived from assessments up to and including the time of the progression (ie, it will 
not include the response after the patient has progressed). 
When the minimum interval for confirmation of CR and PR is not satisfied or if there are no 
confirmatory scans for CR and PR for a patient, then 2 ways of assigning BOR will be 
implemented in the analysis. In the primary analysis, BOR will be assigned as SD according 
to RECIST 1.1, which requires confirmation of CR and PR; in the other method, 2 or more 
response categories will be added as unconfirmed CR and unconfirmed PR. Both ways of 
assigning BOR will be implemented in the analysis.  
Objective response will be derived as No/Yes (0/1) variable. Patients with a BOR of 
confirmed CR or PR will be assigned “Yes”. Patients not having a BOR of confirmed CR or 
PR will be assigned “No.” Hence, objective response rate (ORR) is defined as the proportion 
of patients with objective response being “Yes.”  
Clinical benefit rate (CBR) is defined as the proportion of patients with a BOR of confirmed 
CR or confirmed PR or SD at the 8 week (end of Cycle 2) or later assessment. A patient will 


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be considered to have a SD for 8 weeks or longer if a SD response is recorded at 8 weeks or 
later from first date of study drug administration.   
Duration of Objective Response (DOR) is the time between first objective response of CR or 
PR and the first date that progressive disease is objectively documented or death. Patients 
who do not experience objective PD or death will not be included in the analysis.  
Time to first objective response is the time from first dose of study drug to first objective 
response of CR or PR. Patients who do not experience objective response of CR or PR will 
be censored at the last adequate assessment date.  
PFS is defined as the time (number of months) from date of first dose of study drug until date 
of documented disease progression or death due to any cause, whichever comes first. More 
specifically, PFS will be determined using all the assessment data up until the last evaluable 
visit prior to or on the date of (i) radiographic or clinical disease progression; (ii) withdrawal 
of consent to obtain scans; or (iii) receiving subsequent anticancer therapy, whichever is 
earlier. Death is always categorized as a confirmed PD event. Censoring methods for patients 
who do not experience PD or death will be described in the study SAP. 
OS is calculated as the time (number of months) from date of first dose of study drug to the 
date of death due to any cause. Patients who do not experience fatalities during the course of 
the study will be censored at the date last known to be alive. Patients lacking data beyond the 
day of first dose of G1T38 will have their survival time censored at day of first dose. OS will 
not be censored if a subject receives other antitumor treatments after the study drugs.   
The BOR, ORRs, and CBR and their corresponding 95% exact CIs will be calculated by 
Clopper-Pearson method. DOR, time to first objective response, PFS, and OS will be 
analyzed based on time-to-event summary method. For PFS and OS, Kaplan-Meier estimates 
will be plotted and tabulated at selected landmark time points (ie, 6 months, 1 year, 1.5 years, 
and 2 years).   
12.4. 
Part 2 Statistical Analyses 
For Part 2 of the study, the primary efficacy endpoint is PFS assessed by BICR according to 
RECIST 1.1. Other antitumor efficacy endpoints include the following: 
• 
BOR according to RECIST 1.1  
• 
OR (CR or PR) according to RECIST 1.1 
• 
Duration of OR, and time to first objective response according to RECIST 1.1 
• 
CBR according to RECIST v1.1 
 
The derivation of these endpoints follows the similar practice as described in Section 12.3.2, 
except for the following: 
• 
For the CBR, a patient will be considered to have SD if an SD response is recorded at 
the 8 week (end of Cycle 2) or later assessment from the date of randomization 
• 
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• 
For those patients who have crossed over from osimertinib to G1T38 + osimertinib in 
Part 2, the date of first dose of G1T38 administered during the crossover period will be 
utilized as a reference data for endpoint derivations  
 
Because patients who progressed on osimertinib alone are allowed to crossover to G1T38 + 
osimertinib, there will be 4 types of summaries for PFS and other antitumor efficacy 
endpoints (with the first one being the primary source) as follows: 
1. Summaries and listings based on assessments collected in the randomized portion of the 
study (ie, A versus B + D in Figure 12-1).   
2. Summaries and listings based on assessments collected in the randomized portion of the 
study (ie, A versus D in Figure 12-1).  
3. Summaries and listings based on assessments collected in the randomized portion of the 
study for the G1T38 + osimertinib group and crossover portion for the osimertinib alone 
group (ie, A versus C in Figure 12-1). 
4. Summaries and listings based on assessments collected in the crossover portion (ie, 
C alone in Figure 12-1). 
Figure 12-1 
Categories of Source Data for Patients 
 
 
For time-to-event data such as PFS and OS, the 1-sided stratified log-rank test, stratified by 
presence of CNS metastases (yes versus no) and ethnicity (Asian versus non-Asian), will be 
used to test the null hypothesis that the distributions in the 2 treatment groups are equal. A 
Cox regression analysis with a fixed effect for treatment arm and stratification factors will be 
used to estimate the HR and its 80% CI. Kaplan-Meier estimates will be plotted and tabulated 
at selected landmark time points (ie, 6 months, 1 year, 1.5 years, and 2 years). The median 
value and a 95% CI will also be provided (assuming the median can be estimated).  
For the overall tumor response data such as ORR and CBR, the 1-sided stratified CMH test 
will be used to compare the 2 treatment groups. The odds ratio and its associated 80% CI will 
be presented. 
Patients who progressed on osimertinib alone are allowed to crossover to G1T38 + 
osimertinib. Despite the crossover design, the primary analysis of OS (ie, A versus D + (B + 
C) in Figure 12-1) will use the strict intention-to-treat (ITT) approach based on FAS, ie, 
“analyze as randomized” and ignore the treatment switch following progression (and ignore 
additional anticancer therapies administered after study drug discontinuation). This approach 


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represents a gold standard. However, osimertinib patients who switch to G1T38 + 
osimertinib after disease progression may benefit from the delayed administration of G1T38; 
therefore, the survival treatment estimate becomes confounded. Under such circumstances, 
the statistical test of the treatment effect is known to be biased towards the null hypothesis of 
no difference (Robins and Tsiatis 1991; Korhonen et al 1999; Greenland et al 2008). 
Therefore, 2 additional supportive analyses will be performed to obtain an estimate of 
survival treatment effect corrected for treatment crossover: rank-preserving structural failure 
time (RPSFT) method and Cox model with inverse probability of censoring weighting 
(IPCW). More detailed information will be provided in SAP.  
In terms of OS, there will be 3 additional types of summaries as follows:  
1. Summaries and listings based on assessments collected in the randomized portion of the 
study (ie, A versus D in Figure 12-1) 
2. Summaries and listings based on assessments collected in the randomized portion of the 
study for group of G1T38 + osimertinib and crossover portion for group of osimertinib 
alone (ie, A versus C in Figure 12-1) 
3. Summaries and listings based on assessments collected in the crossover portion (ie, 
C alone in Figure 12-1).  
Moreover, post progression survival will be evaluated for A versus D and C versus D in 
Figure 12-1, and it is calculated as the time (number of months) from the date of first 
documented progression to the date of death due to any cause, or to the date of last contact 
(censored observation). For patients who progress on osimertinib alone and crossover to 
G1T38 + osimertinib, the date of first documented progression on osimertinib alone will be 
used for the analysis. Patients without documented progression will be excluded from the 
post progression survival analysis.    
In addition, potential influences of baseline patient characteristics such as age, ECOG 
performance status, and selected biomarkers on the endpoints may be evaluated to compare 
the treatment groups.   
12.4.1. 
Safety evaluation  
The assessment of safety will be based mainly on the frequency of TEAEs and on the number 
of laboratory values that fall outside of predetermined ranges according to CTCAE, 
Version 4.03. Other safety data (eg, ECG, vital signs, and echocardiogram/MUGA scan 
results) will be considered as appropriate.   
 
Dose reductions/modifications, interruptions, compliance, and patient exposure will be 
summarized for each study therapy component, where appropriate. 
Since patients who progressed on osimertinib alone are allowed to crossover to G1T38 + 
osimertinib, there will be 3 types of safety summaries (with the first one being the primary 
source of safety assessment) as follows: 
 




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13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
An eCRF must be completed for each patient enrolled. Once a patient is no longer on the 
study and the eCRF is completed, the principal investigator will be required to review and 
sign the eCRF for that patient. The investigator shall ensure the accuracy, completeness, 
legibility, and timeliness of the data reported to the sponsor in the eCRFs and in all required 
reports. 
Accurate and reliable data collection will be assured by verification and cross-check of the 
eCRFs against the investigator’s records by the study monitor (source document 
verification), and the maintenance of a drug-dispensing log. 


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14. 
ETHICS AND PROTECTION OF HUMAN PATIENTS 
14.1. 
Ethical Conduct Statement 
The investigator will ensure that this study is conducted in full conformance with the 
principles of the Declaration of Helsinki (as amended in Tokyo, Venice, Hong Kong, and 
South Africa) or with the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the individual. The investigator will 
ensure adherence to the basic principles of GCP as outlined in the current version of 21 Code 
of Federal Regulations (CFR), subchapter D, part 312, Responsibilities of Sponsors and 
Investigators, part 50, Protection of Human Subjects, and part 56, Institutional Review 
Boards, and ICH E6 GCP. The investigator will follow all national, state, and local laws of 
the pertinent regulatory authorities. 
14.2. 
Independent Ethics Committee/Institutional Review Board 
The protocol and all associated amendments and consent/assent materials will be reviewed 
and approved by the investigative site’s local IEC/IRB or a central IEC/IRB. It is the 
investigator’s responsibility to obtain approval of the study protocol and informed consent, 
and any other study related materials such as advertising or information leaflets, from their 
IEC/IRB prior to initiating the study. Approval must be obtained in writing via a letter 
identifying the protocol, the date of the IEC/IRB meeting, and the date of approval. 
14.3. 
Informed Consent 
It is the responsibility of the investigator to obtain written informed consent from each 
patient participating in this study, after adequate explanation of the goals, methods, potential 
benefits, and hazards of the study. The investigator or designee must also explain that the 
patients are allowed to withdraw from the study at any time and for any reason. All patients 
should be given a copy of the informed consent and any updates. Original signed consent 
forms will be maintained at the site and be made available for inspection, as appropriate. 
14.4. 
Patient Confidentiality 
The investigator must assure that patients’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. Patient names will not be supplied to the 
sponsor and only the patient number will be recorded in the eCRF and study findings stored 
on a computer will be stored in accordance with local data protection laws. The patients will 
be informed that representatives of the sponsor, IEC/IRB, or regulatory authorities may 
inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
14.5. 
Adherence to the Protocol 
The study shall be conducted as described in this protocol, except for an emergency situation 
in which proper care of the patient requires immediate alternative intervention. The protocol 
will be provided to the IEC/IRB and appropriate local regulatory authorities for approval. 


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Any protocol amendments will be done in accordance with the provisions agreed upon in 
Section 14.6. Any deviation from the design of the study as set forth in this document will be 
recorded as a protocol deviation and will be explained in detail as it occurs and/or is detected. 
14.6. 
Protocol Amendments 
All protocol amendments (both nonsubstantial and substantial amendments) must be 
submitted to the appropriate IEC/IRB and competent authorities (as required) in accordance 
with local requirements. Approval for substantial amendments must be received in writing 
before changes can be implemented (ie, if the risk benefit ratio is affected and/or the 
modification represents a change in basic study definitions such as objectives, design, sample 
size, and outcome measures, etc.), except for those changes which would decrease risk to the 
patient. 
14.7. 
Patient Compliance 
Patients must be available for all scheduled study visits. Any reason for patient 
noncompliance will be documented. 


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15. 
DATA HANDLING AND RECORD KEEPING 
15.1. 
Data Collection and Retrieval 
This study will use a 21 CFR Part 11 compliant electronic data capture system. An eCRF will 
be used for data recording. All data requested on the eCRF must be entered and all missing 
data must be accounted for. 
Accurate and reliable data collection will be assured by verification and cross-check of the 
eCRF against the investigator’s records by the study monitor (source document verification), 
and the maintenance of a study drug-dispensing log by the investigator. 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a sponsor 
representative will review the protocol and eCRFs with the investigators and their staff. 
During the study, a monitor will visit the site regularly to check the completeness of patient 
records, the accuracy of entries on the eCRFs, the adherence to the protocol and to GCP, and 
the progress of enrollment. The monitor will ensure during on-site visits that study drug is 
being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the monitors during these visits. 
The investigator must give the monitor access to relevant hospital or clinical records to 
confirm their consistency with the eCRF entries. No information in these records about the 
identity of the patients will leave the study center. Monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion 
criteria, documentation of SAEs, and the recording of primary efficacy and safety variables.  
15.2. 
Investigator Reporting Requirements 
Local regulations may require the investigator to provide periodic safety updates on the 
conduct of the study and to notify the IEC/IRB of study closure. Such updates and 
notifications are the responsibility of the investigator. 
15.3. 
Records Retention 
After closure of the study, the investigator will maintain copies of all study records (ie, 
investigator files and patient files) in a secure location. The investigator’s study file will 
contain the protocol, protocol amendments, eCRF and query forms, IEC/IRB and 
governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and 
correspondence.  
Patient clinical source documents may include (but not limited to) patient hospital records, 
physician's and nurse's notes, original laboratory reports, ECG, electroencephalogram, X-ray, 
signed informed consent forms, consultant letters, and patient screening and enrollment logs.  
These documents must be kept on file by the investigator for a period of 2 years following 
the date the marketing application is approved for the drug indication for which it is being 
investigated. If no application is to be filed or if the application is not approved for such 


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indication, all records pertaining to the conduct of the clinical study must be adequately 
maintained until 2 years after the investigation is discontinued and the regulatory authorities 
are notified or longer as required by applicable regulatory authorities.  
The investigator must not destroy any records associated with the study without receiving 
approval from the sponsor. The investigator must notify the sponsor in the event of 
accidental loss or destruction of any study records and should notify the sponsor of any 
reassignment of study records to another party or move to another location.  
15.4. 
Study Monitoring 
Qualified representatives of the sponsor or sponsor designees (study monitors) will monitor 
the study according to a predetermined monitoring plan. The investigator must permit the 
study monitors to periodically review all eCRFs and source documents supporting the 
participation of each patient in the study. The eCRFs and other documentation supporting the 
study must be kept up to date by the investigator and the staff at the study site. These study 
materials must be available for review by the study monitor, and/or other qualified 
representatives of the sponsor, at each monitoring visit and must be provided in a way such 
that the patient’s confidentiality is maintained in accordance with local institution, state, 
country, and federal requirements.  
15.5. 
Audits and Inspections 
At some point during the study or after the study, appropriately qualified personnel from the 
sponsor’s Quality Assurance group, or their authorized representative, or a representative 
from a regulatory authority may visit the investigator to conduct an inspection of the study 
and the site. During this audit, the investigator agrees to give the auditor direct access to all 
relevant documents supporting the eCRFs and other study-related documents and to discuss 
any findings with the auditor. In the event of an inspection by a regulatory agency, the 
investigator agrees to give the inspector direct access to all relevant documents and to discuss 
any findings with the inspector. 


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16. 
PUBLICATION POLICY 
By signing the study protocol, the investigator and his or her institution agree that the results 
of the study may be used by G1 Therapeutics for the purposes of national and international 
registration, publication, and information for medical and pharmaceutical professionals. If 
necessary, the authorities will be notified of the investigator’s name, address, qualifications, 
and extent of involvement. 
Initial publication of the results of this study will be of a cooperative nature that may include 
authors representing the sponsor, investigator(s), and collaborating scientists. Independent 
publications by involved individuals may follow. Investigators and their institutions agree not 
to publish or publicly present any interim results of studies without the prior written consent 
of G1 Therapeutics. 
At least 60 days prior to expected submission to the intended publisher or meeting 
committee, the investigator will submit a copy of the desired presentation (oral or written) or 
publication manuscript to the sponsor. This review period may be shortened upon mutual 
consent where circumstances require expeditious review. The sponsor reserves the right to 
request modification of any publication, presentation or use by the investigator if such 
activity may jeopardize a patent application, an existing patent, or other proprietary rights. 
The sponsor shall determine order of authorship of any publication combining all clinical 
results of this study. 


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17. 
REFERENCES 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16:31-41. 
Cristofanilli M, Turner N, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant 
plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast 
cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the 
multicentre, double-blind, phase 3 randomised controlled trial. The Lancet Oncology. 2016; 
17(4):425-439. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247. 
Greenland S, Lanes S, Jara M. Estimating effects from randomized trials with 
discontinuations: the need for intent-to-treat design and G-estimation. Clinical Trials. 
2008;5: 5-13. 
Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for 
HR-positive, advanced breast cancer. N Engl J Med. 2016;375: 1738-1748. 
Ko B, He T, Gadgeel S, Halmos B. MET/HGF pathway activation as a paradigm of 
resistance to targeted therapies. Ann Transl Med. 2017;5(1):4. 
Korhonen P, Laird NM, Palmgren J. Correcting for non-compliance in randomized trials: an 
application to the ATBC study. Statistics in Medicine. 1999;18: 2879-2897. 
Minari R, Bordi P, Tiseo M. Third-generation epidermal growth factor receptor-tyrosine 
kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged 
mechanism of resistance. Transl Lung Cancer Res. 2016; 5(6):695-708. 
Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR 
T790M-positive lung cancer. N Engl J Med. 2017;376: 629-640. 
Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and 
cancer. Biochimica et Biophysica Acta-Reviews on Cancer. 2002; 1602(1):73-87. 
Prescribing information: Abemaciclib (Verzenio®) 
http://uspl.lilly.com/verzenio/verzenio.html#pi 
 
Prescribing information: Osimertinib (Tagrisso®) 
https://www.azpicentral.com/tagrisso/tagrisso.pdf#page=1 
Prescribing information: Palbociclib (IBRANCE®) 
http://labeling.pfizer.com/ShowLabeling.aspx?id=2191 


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Prescribing information: Ribociclib (KISQALI®) 
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kisqali.pdf 
Ramalingam SS, Yang JCH, Lee CK, et al. Osimertinib as first-line treatment of EGFR 
mutation-positive advanced non-small-cell lung cancer. J Clin Oncol. 2017;35. 
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models (RPSFTM). Commun. Statist.-Theory Meth. 
1991;20(8): 2609-2631. 
Sequist LV, Neal JW. Personalized, genotype-directed therapy for advanced non-small cell 
lung cancer. In: Lilenbaum, ed. UpToDate. Waltham, Mass.: UpToDate; 2017. 
www.uptodate.com. Accessed August 1, 2017. 
Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. Journal of 
Clinical Oncology. 2006; 24 (11):1770-1783. 
 
 


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18. 
APPENDICES 
APPENDIX 1: 
Common Terminology Criteria for Adverse Events 
(CTCAE) –Version 4.03 
The NCI CTCAE Version 4.03 (CTCAE 4.03 14 June 2010) can be accessed from the 
following National Cancer Institute (NCI) website: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
APPENDIX 2: Prescribing Information for Osimertinib 
Tagrisso® (osimertinib) PI, March 2017 link:  
https://www.azpicentral.com/tagrisso/tagrisso.pdf#page=1 
APPENDIX 3: Drugs that May Prolong the QT Interval 
The drugs listed in this section are taken from information provided by The Arizona Center 
for Education and Research on Therapeutics and The Critical Path Institute, Tucson, Arizona 
and Rockville, Maryland. Ref: http://www.arizonacert.org/medical-pros/drug-lists/drug­ 
lists.htm. 
Drugs Known to Prolong the QT Interval 
The following drugs are known to prolong QT interval or induce Torsades de Pointes and 
should not be combined with osimertinib. Recommended withdrawal periods following 
cessation of treatment with these agents are provided in Table 18-1. 
Table 18-1 
Drugs Known to Prolong the QT Interval 
Contraindicated Drug 
Withdrawal Period Prior to Initiating 
Osimertinib  
Clarithromycin, droperidol, erythromycin, procainamide 
2 days 
Cisapride, disopyramide, dofetilide, domperidone, ibutilide, 
quinidine, sotalol, sparfloxacin, thioridazine 
7 days 
Bepridil, chlorpromazine, halofantrine, haloperidol, mesoridazine 
14 days 
Levomethadyl, methadone, pimozide 
4 weeks 
Arsenic trioxide 
6 weeksa 
Pentamidine 
8 weeks 
Amiodarone, chloroquine 
1 year 
a 
Estimated value as pharmacokinetics of arsenic trioxide has not been studied. 
Drugs that May Possible Prolong the QT Interval 
Use of the drugs in Table 18-2 is permitted (notwithstanding other exclusions and 
restrictions) provided the patient has been stable on therapy for the periods indicated. 


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Table 18-2 
Drugs that May Prolong QT Interval 
Drug 
Minimum Treatment Period on Drug 
Prior to Initiating Osimertinib  
Alfuzosin, chloral hydrate, ciprofloxacin, dolasetron, foscarnet, 
galantamine, gemifloxacin, isridipine, ketoconazole, levofloxacin, 
mexiletine, nicardipine, octreotide, ofloxacin, ondansetron, 
quetiapine, ranolazine, telithromycin, tizanidine, vardenafil, 
venlafaxine, ziprasidone 
2 days 
Amantadine, amitriptyline, amoxapine, clozapine, doxepin, 
felbamate, flecainide, ibutilide, quinidine, sotalol, sparfloxacin, 
thioridazine, fluconazole, fosphenytoin, gatifloxacin, 
granisetron, imipramine, indapamide, lithium, 
moexipril/HCTZ, moxifloxacin, risperidone, roxithromycin, 
sertraline, trimethoprin-sulfa, trimipramine, voriconazole 
7 days 
Azithromycin, citalopram, clomipramine, itraconazole, nortriptyline, 
paroxetine, solifenacin, tacrolimus 
14 days 
Fluoxetine 
5 weeks 
Protriptyline 
6 weeks 
Tamoxifen 
8 weeks 
 
APPENDIX 4: 
Drugs Known to Interact with the P-glycoprotein, 
BCRP, MATE1, MATE2-K, and OCT1 and 2 
Membrane Transporters  
The following lists of drugs known to interact with membrane transporters is a representative 
sample of potentially G1T38-interacting drugs. Caution should be exercised if any of these 
drugs are concurrently used with G1T38. Use of strong inhibitors of BCRP is prohibited. 
Strong Inhibitors of P-gp (use with caution): 
• Cyclosporine 
• Elacridar 
• Ketoconazole 
• Reserpine 
• Ritonavir 
• Tacrolimus 
• Valspodar 
• Verapamil 
• Zouquidar 
• Amiodarone 
• Carvedilol 
• Clarithromycin 
• Dronedarone 
• Itraconazole 
• Lapatinib 
• Propafenone 


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• Quinidine 
• Ranolazine 
• Telaprevir 
Strong Inhibitors of BCRP (use prohibited): 
• Elacridar 
• Fumitremorgin C 
• Ko134 
• Ko143 
• Novobiocin 
• Sulfasalazine 
• Curcumin 
• Cyclosporine A 
• Eltrombopag 
Strong Inducers of P-gp (use with caution): 
• Carbamazepine 
• Phenytoin 
• Rifampin 
• St. John’s Wort 
• Tipranavir 
MATE1 and MATE2-K Substrates (use with caution): 
• Metformin 
• MPP+ 
• Tetraethylammonium (TEA) 
• Dofetilide 
OCT1 and OCT2 Substrates (use with caution): 
• OCT1: metformin, oxaliplatin, aciclovir, ganciclovir 
• OCT2: metformin, pindolol, procainamide, ranitidine, amantadine, amiloride, oxaliplatin, 
varenicline, cisplastin, debrisoquine, proplanolol, guanidine, D-tubocurarine, 
pancuronium 
P-gp Substrates (use with caution): 
• Digoxin 
• Fexofenadine 
• Loperamide 
• Quinidine 
• Talinolol 
• Vinblastine 
• Dabigatran 


G1 Therapeutics 
Clinical Study Protocol G1T38-03 
G1T38 
 
Version: 4.0, dated 02 September 2019  
Page 103 of 103  
G1 Therapeutics CONFIDENTIAL 
BCRP Substrates (use with caution): 
• 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) 
• Coumestrol 
• Daidzein 
• Dantrolene 
• Estrone-3-sulfate 
• Genistein 
• Prazosin 
• Sulfasalazine 
• Rosuvastatin 
APPENDIX 5: 
RECIST Version 1.1 Time Point Response Evaluation 
Guidelines for Patients with Nontarget Disease Only 
 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease 
a 
Non-CR/non-PD is preferred over stable disease for nontarget disease since stable disease is increasingly used as 
endpoint for assessment of efficacy in some studies, so to assign this category when no lesions can be measured is not 
advised. 
Source: Table modified from Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247. 
 
 
APPENDIX 6: Radiotherapy Guidance for Symptomatic Lesions 
 
• Palliative radiotherapy to control symptoms (including gamma knife technique), eg to 
control brain disease, is permitted.  
• For brain and thoracic radiotherapy (only to control symptoms), a 7- to 10-day study drug 
washout period before the procedure and 1 week period after the procedure before 
restarting study drug(s) is advised. 
• All radiotherapy related toxicities should be managed and ideally resolved before 
restarting study drug(s). 
• Investigators should consider the radiotherapy when assessing causality if there are any 
localized AEs following the procedure. 
• If any lesions (including brain or thoracic disease) are asymptomatic, then radiation 
would not be permitted. 
 

SAP_001.pdf: 
 
 
  
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Study Title: 
Phase 1b/2 Safety, Pharmacokinetic, and Efficacy Study of 
G1T38 in Combination with Osimertinib in Patients with 
EGFR Mutation-Positive Metastatic Non-Small Cell Lung 
Cancer (NSCLC) 
 
 
 
Sponsor 
G1 Therapeutics 
 
700 Park Offices Drive, Suite 200 
 
P.O. Box 110341 
 
Research Triangle Park, North Carolina 27709, USA 
 
 
 
Name of Test Drug: 
G1T38 (Lerociclib) 
 
 
Protocol Number: 
G1T38-03 
 
 
Phase: 
Phase 1b/2   
 
Analysis Plan Version 
Version 1.0 
 
 
Analysis Plan Date 
10FEB2021 


 
 
 
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Statistical Analysis Plan 
 
 
CONFIDENTIAL                                         Page 2 of 38                                 Date: 10FEB2021 
 
 
 
 
 
APPROVAL SIGNATURES 
 
 
 
AUTHOR: 
  
 
 
 
 
 
__________________________________________________________ 
 
                                                               Date         
 
                                                                             
 
 
 
 
 
 
__________________________________________________________ 
 
                                                                      Date        
 
                                                                             
 
 
 
 
APPROVED BY: 
 
 
__________________________________________________________
                                                                    Date 
 
 
 
 
 
 
 
__________________________________________________________ 
 
                                                      Date 
 
 
 
 
 
 
 
__________________________________________________________ 
 
                                            Date 
                                                               
  


 
 
 
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Statistical Analysis Plan 
 
 
CONFIDENTIAL                                         Page 3 of 38                                 Date: 10FEB2021 
 
 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................7 
2. 
STUDY DESIGN OVERVIEW (PART 1) ..................................................................7 
2.1. 
Study Objectives ...........................................................................................................7 
2.2. 
Study Design .................................................................................................................8 
2.3. 
Number of Patients .......................................................................................................8 
3. 
ANALYSIS POPULATIONS (PART 1) .....................................................................9 
3.1  
Definition of Analysis Populations ...............................................................................9 
3.1.1. 
All Screened Patients ....................................................................................................9 
3.1.2. 
All Enrolled Patients .....................................................................................................9 
3.1.3. 
Safety Population ..........................................................................................................9 
3.1.4. 
Response Evaluable Analysis Set (RES) ......................................................................9 
3.1.5. 
Full Analysis Set (FAS) ................................................................................................9 
4.  
PRIMARY AND SECONDARY ENDPOINTS ..........................................................9 
4.1 
Efficacy Endpoints ......................................................................................................10 
4.1.1 
General Consideration for Tumor Response Assessment ..........................................10 
4.1.2 
Definitions of Efficacy Endpoints ..............................................................................10 
4.2. 
Safety Endpoints .........................................................................................................18 
4.2.1. 
Adverse Events (AEs) .................................................................................................18 
4.2.2. 
Dose-Limiting Toxicities (DLTs) ...............................................................................21 
4.2.3. 
Vital Signs ..................................................................................................................21 
4.2.4. 
Laboratory ...................................................................................................................21 
4.2.5. 
Electrocardiograms (ECGs) ........................................................................................22 
4.2.6. 
Echocardiogram/MUGA .............................................................................................24 
4.2.7. 
Treatment Exposure and Compliance .........................................................................24 
5. 
ANALYSIS METHODS (PART 1) ...........................................................................24 
5.1  
General Principles .......................................................................................................24 


 
 
 
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5.1.1. 
General Statistical Considerations ..............................................................................24 
5.1.2. 
Handling of Missing Data ...........................................................................................25 
5.1.3. 
Study Days and Visit Windowing ..............................................................................26 
5.2  
Analysis Methods (Part 1) ..........................................................................................27 
5.2.1. 
Patient Disposition ......................................................................................................27 
5.2.2. 
Protocol Deviations ....................................................................................................28 
5.2.3. 
Demographic and Other Baseline Characteristics ......................................................28 
5.2.4. 
Prior Cancer Therapy ..................................................................................................29 
5.2.5. 
Medical History ..........................................................................................................29 
5.2.6. 
Prior and Concomitant Medications ...........................................................................29 
5.2.7. 
Treatment Duration .....................................................................................................30 
5.2.8 
Treatment Compliance ................................................................................................31 
5.2.9. 
Efficacy Analyses .......................................................................................................31 
5.2.10. 
Safety Analyses (Part 1) .............................................................................................32 
6. 
PLANNED ANALYSIS (PART 1) ............................................................................36 
7. 
CHANGE FROM THE PROTOCOL (PART 1)........................................................36 
8. 
REFERENCES ...........................................................................................................38 
 
 
 
 


 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
BICR 
blinded independent central review 
BOR 
best overall response 
CBR 
clinical benefit rate 
cfDNA 
cell-free DNA 
CI 
confidence interval 
CR  
complete response 
CSR 
clinical study report 
CT 
computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
FAS 
full analysis set 
HR 
hazard ratio 
IDMC 
independent data monitoring committee 
IMP 
investigational medicinal product 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MUGA 
multigated acquisition 
NCI 
National Cancer Institute 
NE 
not evaluable 
NSCLC 
non-small cell lung cancer 
NTL 
nontarget lesion 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease  
PFS 
progression-free survival 


 
 
 
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Abbreviation 
Term 
PK  
pharmacokinetic(s) or PK analysis set, per context 
PP 
per protocol 
PR 
partial response 
PT 
preferred term 
QTcF 
QT interval corrected by Fridericia's formula 
RECIST 
Response Evaluation Criteria in Solid Tumors  
RES 
response evaluable analysis set 
RP2D 
recommended Phase 2 dose 
SAE  
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SMC 
safety monitoring committee 
SOC 
system organ class 
StD 
standard deviation 
TEAE 
treatment-emergent adverse event 
TL 
target lesion 
WHO 
World Health Organization 
WHODrug 
World Health Organization Drug Dictionary 


 
 
 
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1. INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the detailed analysis and 
reporting, including tables, listings, and figures, for G1T38-03 (“38-03”), the study of G1T38 in 
combination with Osimertinib in patients with EGFR mutation-positive metastatic non-small cell 
lung cancer (NSCLC). The analyses specified in this SAP will be used to support the clinical 
study report (CSR).  
Study measurements and assessments, planned statistical methods, and derived variables are 
summarized in this plan.  Planned tables, figures, and listings to accompany this SAP are 
specified in a Tables, Figures, and Listings (TLF) shells.  All decisions regarding final analyses, 
as defined in this SAP document, have been made prior to locking the database. Any significant 
change from the planned analysis in this SAP to provide results for inclusion in the CSR, will be 
clearly documented in the CSR. 
This version of the SAP is based on the protocol version 4.0 dated 02 September 2019. Although 
the protocol includes study Part 1 and Part 2, Part 2 will not be conducted due to a corporate 
strategy shift. This SAP describes the analyses of the data collected from Part 1 only.   
2. STUDY DESIGN OVERVIEW (PART 1) 
This section provides high level information of the study design.  Unless as documented in 
Section 7 (Change From the Protocol), any discrepancies between the protocol language and the 
text in this section are inadvertent and should not be interpreted as a change to the protocol 
design. 
2.1. Study Objectives 
Primary Objective  
The primary objectives of Part 1 (Phase 1b) of the study are to: 
• Evaluate dose-limiting toxicities (DLTs) associated with G1T38 administered with 
osimertinib 
• Determine the recommended Phase 2 dose (RP2D) of G1T38 administered with 
osimertinib 
• Evaluate the safety and tolerability of G1T38 administered with osimertinib 
Secondary Objectives  
The secondary objectives of the study are to: 
• Assess PFS using investigator assessments (RECIST v1.1) 
• Assess response rate and disease control rate (DCR) based on RECIST v1.1 (investigator 
assessed) 
• Assess overall survival (OS) 


 
 
 
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• Assess 1-year PFS (investigator assessed) 
• Assess the effect of osimertinib on pharmacokinetic (PK) parameters of G1T38 
Refer to protocol Section 5 for other study objectives and endpoints. 
2.2. Study Design 
Study 38-03 is an open-label study evaluating the effect of osimertinib on the PK parameters of 
G1T38 and the safety and tolerability of escalating doses of G1T38 in combination with 
osimertinib to determine the RP2D. The study includes 3 phases: Screening Phase, Treatment 
Phase, and Survival Follow-up Phase. The Treatment Phase begins on the day of the first dose of 
study drug and completes at the Post-Treatment Visit. 
Six patients will be enrolled in the first cohort to assess the potential effect of osimertinib on the 
PK parameters of G1T38. Projected dose levels are presented in Table 6-1 of the Protocol. 
Patients will receive a single oral dose of G1T38 200 mg on Cycle 1 Day -16 and blood samples 
for G1T38 PK evaluation will be collected over the subsequent 48-hour period. Patients will then 
receive oral osimertinib 80 mg once daily without G1T38 on Cycle 1 Days -14 to -3, and then 
both G1T38 and osimertinib on Cycle 1 Day -2, after which blood samples for G1T38 PK 
evaluation will be collected over the subsequent 48-hour period. Osimertinib once-daily dosing 
will continue on Cycle 1 Day -1 and through the end of the Treatment Phase. On Cycle 1 Day 1, 
patients will begin G1T38 once-daily dosing, which will continue through the end of the 
Treatment Phase (note: there is no Day 0 in the study). DLTs will be evaluated from Cycle 1 Day 
-16 through Cycle 1 Day 28 (the DLT period). A safety monitoring committee (SMC) will 
evaluate all safety and available PK data through the DLT period for Cohort 1 prior to the 
enrollment of additional cohorts.     
Thereafter, additional sequential dose-escalation cohorts may be enrolled using a standard 3 + 3 
design and will follow the same schedule as described for the first cohort. 
All dose escalation/de-escalation recommendations made by the SMC will be based on review of 
safety and available PK from the DLT period of the current cohort, as well as the cumulative 
safety data from all patients enrolled. Further details with respect to decision making will be 
described in the SMC Charter. 
Patients will be observed for a DLT during the first cycle of treatment (Cycle 1 Day -16 through 
Cycle 1 Day 28).  Please refer to protocol sections 6.1.1.1. for more information regarding the 
dose escalation plan as it relates to DLT findings.   
2.3. Number of Patients 
For Part 1, six patients will be enrolled in the first cohort and additional cohorts may be enrolled 
using a standard 3 + 3 design with a maximum of 36 patients. The actual number of patients will 
depend on the number of dose levels/cohorts that are tested. 


 
 
 
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3. ANALYSIS POPULATIONS (PART 1) 
3.1  Definition of Analysis Populations 
3.1.1. All Screened Patients 
The all screened patients set includes all subjects who consented to participate in the study and 
completed any screening assessments. 
3.1.2. All Enrolled Patients 
Enrolled patients are those who consented to participate in the study and have met entry criteria. 
3.1.3. Safety Population 
The safety population will include all enrolled patients who were administered at least 1 dose of 
study drug (G1T38 or osimertinib). All safety analyses will be assessed using the safety 
population. Analyses using the safety population will be conducted on the basis of the actual 
treatment received. 
3.1.4. Response Evaluable Analysis Set (RES)   
The response evaluable analysis set (RES) will include all patients who are in the safety population 
and who have at least one measurable tumor lesion (target lesion(s)) at the baseline tumor 
assessment, and either (i) have at least one post-baseline tumor assessment, or (ii) do not have 
post-baseline tumor assessment but have clinical progression as noted by the investigator, or (iii) 
have died due to disease progression before their first post-baseline tumor scan. The RES will be 
used for analyses of tumor response. 
3.1.5. Full Analysis Set (FAS)   
The Full Analysis Set (FAS) will include all enrolled patients who were administered at least one 
dose of continuous daily of G1T38 (i.e., Cycle 1 Day 1). All analyses using FAS will be 
conducted by the dose level cohort that was assigned at enrollment. The FAS is the primary 
analysis set for efficacy analyses, unless otherwise specified. 
4.  PRIMARY AND SECONDARY ENDPOINTS 
For safety endpoints, baseline is defined as the last non-missing value prior to or on the date/time 
of first administration of investigational medicinal product (IMP) (G1T38 or osimertinib) during 
the PK period (i.e., Cycle 1 Day -16 for G1T38, or Cycle 1 Day -14 for osimertinib). If the latest 
pre-dose value is collected on the day of treatment, the time of treatment if available will be used 
to identify the baseline value.  Change from baseline to post-baseline will be calculated as post-
baseline value minus the baseline value. Change from baseline is calculated only when both post 
baseline value and baseline value are non-missing.  For efficacy endpoints, the last non-missing 
value prior to or on the date/time of first administration of daily (i.e., continuous) dosing of the 
IMP (i.e., Cycle 1 Day 1) will be used as baseline.  


 
 
 
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4.1  
Efficacy Endpoints 
4.1.1 General Consideration for Tumor Response Assessment 
Progressive disease (PD) and tumor response status will be derived per RECIST v1.1 based on 
tumor assessment data entered into the EDC by investigators. 
The methods used at baseline (i.e., the screening visit) for assessment of tumor burden 
(computed tomography [CT] or magnetic resonance imaging [MRI] scans of chest and abdomen 
[including liver and adrenal glands]) must be used at each subsequent follow-up assessment. The 
baseline assessment shall be performed within 21 days of treatment start. CT or MRI scans 
obtained prior to informed consent will not need to be repeated if performed within 21 days prior 
to the first dose of study drug. Subsequent assessments are to be performed every 8 weeks 
relative to Cycle 1 Day 1 until the date of (i) radiographic disease progression as defined by 
RECIST 1.1 (Eisenhauer et al, 2009); or (ii) withdrawal of consent to obtain scans; or (iii) 
receiving subsequent anti-cancer therapy, whichever is earlier. After 18 months of treatment, 
subsequent tumor assessments shall be performed every 12 weeks (± 1 week).  
At each tumor assessment visit, an overall visit response by RECIST will be determined 
programmatically - using the information from investigator’s measurement of target lesions 
(TL), non-target lesions (NTLs) and new lesions collected on electronic case report form 
(eCRF). The overall response at each time point is also assessed by the investigators and is 
collected on eCRF. 
Antitumor efficacy endpoints include the following based on RECIST v1.1 
• Best Overall Response (BOR)  
• Objective response rate (ORR) (complete response [CR] or partial response [PR])  
• Duration of objective response (DOR), and time to first objective response  
• DCR at week 8 (complete response [CR] or partial response [PR] or stable disease [SD])  
• PFS 
 
4.1.2 Definitions of Efficacy Endpoints 
4.1.2.1 Tumor Responses  
Target lesions (TLs) 
Measurable disease at baseline is defined as having at least one measurable lesion which is  
• ≥10 mm in the longest diameter (LD) (except lymph nodes which must have short axis 
≥15 mm) with CT or MRI; or  
• ≥10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable); or for lymph nodes which 
must have short axis ≥15 mm by clinical exam; or 
• ≥ 20 mm by chest X-ray. 


 
 
 
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In rare cases, lesions measured by methods other than CR, MRI, caliper, or X-ray should be 
discussed with G1 medical team to determine if the lesions should be counted as measurable 
disease.  
A tumor lesion that has been previously irradiated may be considered measurable if unequivocal 
growth of the lesion has been demonstrated. A patient can have a maximum of 5 measurable 
lesions representative of all involved organs (maximum of 2 lesions per organ, both the lymph 
node and skin will be considered as a single organ) recorded at baseline and these are referred to 
as target lesions. If more than one baseline scan (prior to or on Cycle 1 Day 1) is recorded, then 
measurements from the scan that is closest to Cycle 1 Day 1 will be used to define the baseline 
sum of TLs. 
Table 1 gives definition of TL visit responses. 
Table 1  Definition of TL visit responses 
Visit Responses 
Description 
Complete 
Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes 
selected as target lesions 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 of diameters as long as criteria for PD are 
not met. 
Progressive 
disease (PD) 
A ≥ 20% increase in the sum of diameters of target lesions and an 
absolute increase of ≥ 5mm, taking as reference the smallest sum on 
study (i.e. nadir) since treatment started including the baseline sum if that 
is the smallest on study.   
Stable disease 
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while 
on study.  
Not Evaluable 
(NE) 
Any target lesion measurements are missing and PD status could not be 
determined based on lesions with non-missing measurements. 
 
Rounding of TL data 
For calculation of PD and PR for TLs percentage changes from baseline and previous minimum 
should be rounded to 1 decimal place before assigning a target lesion response. For example, 
19.95% should be rounded to 20.0% but 19.94% should be rounded to 19.9%.  
Missing TL data 
If any target lesion measurements are missing, then the target lesion visit response is Not 
Evaluable (NE), unless a convincing argument can be made that the contribution of the 
individual missing lesions(s) would not change the assigned time point response. The overall 
visit response will also be NE, unless there is a progression of non-target lesions or new lesions, 
in which case the response will be PD.  


 
 
 
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TL too small to measure 
If a target lesion becomes too small to measure a value of 5mm will be entered into the database 
and used in TL calculations, unless the radiologist has indicated and entered a smaller value that 
can be reliably measured.  
Lesions that split 
If a TL splits, then the LDs of the split lesions should be summed up and reported as the LD for 
the lesion that split. 
Lesions that merge 
If target lesions merge, then the LD of the merged lesion should be recorded for one of the TL 
sizes and the other TL size should be recorded as 0mm. 
Modality change 
The same method of assessment (CT or MRI) should be used to characterize tumors at screening 
and at all follow-up assessments. In case of modality changes, for programmatically derived 
response, each case should be discussed with medical team to determine if data from substituted 
approaches should be used, if not, the patient should be considered not evaluable from that point 
forward. However, a response from the investigator that differs from the programmatically 
derived response is acceptable if a definitive response assessment can be justified based on the 
available information.  
Non-Target Lesions (NTLs)  
All other lesions, including measurable lesions that are not selected as target lesions and all small 
lesions that do not meet the measurable disease criteria.   
The non-target lesion response will be based on the derived timepoint response assessment(s) of 
NTLs as defined in Table 2: 
Table 2  Definition of NTLs visit responses 
Visit Responses 
Description 
CR 
Disappearance of all NTLs.  All lymph nodes must be < 10 mm short 
axis. 
Non-CR/Non-PD 
Persistence of one or more NTLs with no evidence of progression. 
PD 
Unequivocal progression of existing NTLs.  Unequivocal progression is 
defined as, “an overall substantial worsening in nontarget disease, such 
that, even in the presence of SD or PR in target lesions, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A 
modest “increase” in size of one or more nontarget lesions is usually not 
sufficient to qualify for unequivocal progression status 


 
 
 
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NE 
Only relevant when one or some of the NTLs have not been assessed and 
in the Investigator’s opinion they are not able to provide an evaluable 
overall NTL assessment. 
 
New lesions 
New lesions will be identified via a Yes/No tick box. The absence and presence of new lesions at 
each visit should be listed alongside the TL and NTL visit responses. 
A new lesion indicates progression so the overall visit response will be PD irrespective of the TL 
and NTL response. 
 
Time Point Response (TPR) 
Table 3-1 defines how the previously defined TL and NTL responses will be combined with new 
lesion information to give an overall response at each time point. The possible overall responses 
at a visit are CR, PR, SD, PD, and NE. 
Table 3-1  Evaluation of Overall Response at Each Time Point – patients with target 
lesion(s) 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/not all evaluated 
No 
PR 
SD 
Non-PD/not all evaluated 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR= partial response, SD = stable disease, PD = progressive disease, 
NE = not evaluable 
Source: (Eisenhauer et al, 2009) 
For patients without any target lesion, Table 3-2 defines how the previously defined NTL 
responses will be combined with new lesion information to give an overall response at each time 
point. The possible overall responses at a visit are CR, Non-CR/Non-PD, PD, and NE. 
 


 
 
 
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Table 3-2 
 Evaluation of Overall Response at Each Time Point – patients without 
target lesion(s) 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD  
NE 
No 
NE 
PD 
Yes or No  
PD 
Any 
Yes 
PD 
CR = complete response, PD = progressive disease, NE = not evaluable 
Source: (Eisenhauer et al, 2009) 
At each tumor assessment visit, an overall time point response of CR, PR, SD, Non-CR/Non-PD, 
PD or NE by RECIST Version 1.1 will be determined programmatically, using the information 
from TL, NTLs, and new lesions.   
Best Overall Response 
Best overall response is defined as the best overall response across all time points. BOR will be 
determined using overall time point responses up until the last evaluable time point response 
prior to or on the date of (i) radiographic disease progression as defined by RECIST 1.1 
(Eisenhauer et al, 2009); or (ii) withdrawal of consent; or (iii) receiving subsequent anti-cancer 
therapy, whichever is earlier.  
A patient’s BOR will be determined based on Table 4. For data-driven scenarios which may not 
be covered by Table 4, the BOR will be reviewed and determined by the medical advisors and 
statisticians prior to database lock.  
For patients who progress and subsequently have a response, then the best objective response is 
only derived from assessments up to and including the time of the progression (i.e., it will not 
include the response after the patient has progressed). 
According to tumor assessment schedule (Table 9-1 in protocol), the first post-baseline disease 
assessment will be obtained at the end of Cycle 2 (study day 56) with a window ±7 days (study 
day 49 through day 63). Therefore, a patient will be considered to have BOR of SD or Non-
CR/Non-PD if a SD or Non-CR/Non-PD time point response is recorded no earlier than Day 49 
since first G1T38 daily continuous dosing (Cycle 1 Day 1).  
When the minimum interval (i.e., 4 weeks) for confirmation of CR and PR is not satisfied or if 
there are no confirmatory scans for CR and PR for a patient, then two ways of assigning BOR 
will be implemented in the analysis (Table 4). In the primary analysis, BOR will be assigned as 
stable disease (SD) according to RECIST 1.1, provided minimum 49 days SD duration criteria 
met, otherwise BOR will be assigned as PD or NE depends on the response of the confirmation 
assessment.in the other method, two more response categories will be added as unconfirmed CR 
and unconfirmed PR.  


 
 
 
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Clinical Study Protocol G1T38-03 
Statistical Analysis Plan 
 
 
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Table 4  Best Overall Response When Confirmation of CR and PR are Required [a] 
First TPR[b] Subsequent TPR 
Best overall response ( 
confirmed CR and PR) 
Best Overall 
Response*(Confirmed 
and unconfirmed CR and 
PR) 
CR 
CR 
CR 
CR 
CR 
PR 
SD [c] or PD 
Unconfirmed CR 
CR 
SD or Non-
CR/Non-PD 
SD or Non-CR/Non-PD [c] or 
PD 
Unconfirmed CR 
CR 
PD 
SD or Non-CR/Non-PD [c] or 
PD 
Unconfirmed CR 
CR 
NE or NA 
SD or Non-CR/Non-PD[d] or 
NE  
Unconfirmed CR 
PR 
CR 
PR 
Unconfirmed CR 
PR 
PR 
PR 
PR 
PR 
SD  
SD  
Unconfirmed PR 
PR 
PD 
SD [c]or PD 
Unconfirmed PR 
PR 
NE or NA 
SD [d] or NE  
Unconfirmed PR 
NE  
NE 
NE 
NE 
CR = complete response, PR= partial response, SD = stable disease, PD = progressive disease, NE = not 
evaluable, NA = not available; ORR = Objective Response Rate, TPR = time point response. 
a. The minimum interval for confirmation of CR and PR is 4 weeks (28 days). 
b. First appearance of CR or PR per RECIST 1.1. 
c. Best response will be SD or Non-CR/Non-PD if the first time point overall response is on or after 
49 days on study. Otherwise, the best response will be PD. 
d. Best response will be SD or Non-CR/Non-PD if the first time point overall response is on or after 49 
days on study. Otherwise, the best response will be NE. 
. 
A best overall response of SD or Non-CR/Non-PD can only be made after the patient has tumor 
assessment on day 49 (counted from first once-daily dosing date, Cycle 1 Day 1) or later. 
Otherwise, any tumor assessment indicated stable disease before this time period will have a best 
response of NE unless PD is identified.  If a PD is indicated for the first TPR, then the BOR will 
be PD regardless of subsequent TPRs. 
Subsequent documentation of a CR may provide confirmation of a previously identified CR even 
with an intervening not evaluable (NE) (e.g., CR NE CR). Subsequent documentation of a PR 
may provide confirmation of a previously identified PR even with an intervening NE or SD (e.g., 
PR NE PR or PR SD PR). However, only one (1) intervening NE or SD will be allowed between 
PRs for confirmation. Note: in the following scenario, PR SD NE PR, the second PR is not a 
confirmed PR. 
 


 
 
 
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Clinical Study Protocol G1T38-03 
Statistical Analysis Plan 
 
 
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Objective Response Rate 
Objective response rate will be calculated based on either (1) confirmed tumor responses or (2) 
confirmed and unconfirmed tumor responses 
Objective response will be derived as No/Yes (0/1) variable. For confirmed objective response 
(ORCONFIRMED), patients with a BOR of confirmed CR or PR will be assigned “Yes”. Patients not 
having a BOR of confirmed CR or PR will be assigned “No.” Hence, ORR is defined as the 
proportion of patients with confirmed objective response being “Yes”among the analysis set.  
Unconfirmed objective response (ORUNCONFIRMED) will be derived as No/Yes (0/1) variable. 
Patients with a BOR of confirmed CR, confirmed PR, unconfirmed CR or unconfirmed PR will 
be assigned “Yes”. All patients with other BOR values will be assigned “No”. Hence, 
ORRUNCONFIRMED is defined as the proportion of patients with ORUNCONFIRMED being “Yes”. 
Disease Control Rate at Week 8 
Disease control rate (DCR) at Week 8 is defined as the proportion of patients with a BOR of 
confirmed CR or confirmed PR or SD or Non-CR/Non-PD at 8 weeks. For patients without 
measurable lesions at baseline, a BOR of Non-CR/Non-PD will be considered achieving disease 
control. 
Duration of Objective Response 
Duration of objective response (DOR) is the time between first objective response of CR or PR 
and the first date that progressive disease (PD) is objectively documented or death. Patients who 
experienced an objective response but who do not experience objective PD or death at the time 
of analysis will be censored at the last adequate assessment date. Adequate assessment is defined 
as there is sufficient data to evaluate a patient’s disease status.  DOR will be calculated only for 
patients who experience a confirmed objective response. 
Time to First Objective Response 
Time to first objective response is the time from first dose of once-daily dosing of G1T38 (Cycle 
1 Day 1) to first objective response of CR or PR. This variable will be calculated only for 
patients who experience a confirmed objective response. 
Progression-free Survival  
Progressive disease (PD) is defined as radiographical determined disease progression based on the 
criteria by RECIST Version 1.1, which is also referred to as “documented disease progression” in 
the SAP. PD status is derived from the radiographical assessments by investigators that have been 
entered to the EDC. A PFS event is defined as a PD event or a death due to any cause. 
PFS is defined as the time (months) from start date of continuous daily of G1T38 (i.e. Cycle 1 Day 
1) to the date of the first documented PFS event, and the time from start date of continuous daily 
of G1T38 to the censoring date for those patients that did not experience a PFS event. That is, PFS 
is calculated as (date of PFS event or censoring – start date of continuous daily of G1T38 + 1)/ 




 
 
 
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Statistical Analysis Plan 
 
 
CONFIDENTIAL                                         Page 18 of 38                                 Date: 10FEB2021 
 
 
 
Treatment discontinuation 
for reasons other than 
disease progression, and 
disease progression 
documented post last dose 
of study drug 
Date of the last adequate 
radiological disease assessment  
PFS event 
Treatment discontinuation 
for reasons other than 
disease progression, and 
no disease progression 
documented post last dose 
of study drug 
Date of the last adequate 
radiological disease assessment  
Censored 
New anticancer treatment 
started prior to documented 
disease progression 
Date of last adequate radiologic 
assessment no later than the 
initiation of new anticancer 
treatment 
Censored 
Disease progression per 
RECIST Version 1.1 
Date of the first documented 
progression 
PFS event 
Death without a PD 
Date of death 
PFS event 
 
4.2. Safety Endpoints 
The safety variables include: 
4.2.1. Adverse Events (AEs) 
The severity (toxicity grade) of AEs will be graded according to the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. 
All AEs will be classified by System Organ Class (SOC) and Preferred Term (PT) according to 
the Medical Dictionary for Regulatory Activities (MedDRA) version 23.0. 
Treatment-emergent AEs (TEAEs) are defined as any AE occurring on or after the first dose of 
study drug (i.e., C1D-16) until 30 days after the last dose of study drug (G1T38 or Osimertinib, 
which is later) but prior to the start of survival follow-up. For AEs with an incomplete or 
unknown/not reported onset date, the imputed onset date will be used to determine if the AE is 
treatment-emergent. 
AEs with onset dates that are partially/completely missing will be imputed as follows: 
If the start date has month and year but day is missing, 
• If the month and year is the same as the first dose date, then the first dose date will be 
used, otherwise, the first day of the month will be used 


 
 
 
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Statistical Analysis Plan 
 
 
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If the start date has year, but day and month are missing, 
• If the year is the same as the first dose date, then the first dose date will be used, 
otherwise 1st Jan will be used 
If the start date of an event is completely missing, then AE start date is imputed with the first 
dose date. 
After imputation, the imputed start date will be compared with the complete or imputed (if 
missing or partial) AE stop date. If the imputed start date is later than the stop date, the stop date 
will be used as imputed start date instead. 
Imputation rules for missing or partial AE stop date are defined below: 
• If the stop date has month and year but day is missing, the last day of the month will be 
imputed 
• If the stop date has year, but day and month are missing, the 31st of December will be 
imputed 
• If the AE end date is completely missing, the last dose date +30 days will be used as the 
AE end date. 
After the imputation, the imputed AE stop dates will be compared against the date of 
death, if available. If the date is later than the date of death, the date of death will be used 
as the imputed date instead. 
The following durations will be derived for an AE, AE leading to death, AE leading to 
discontinuation of any study drug as appropriate and will be displayed in the corresponding AE 
listings. Cycle 1 Day -16 is used for date of first dose. 
• Relative study day for the onset of AE:  (AE onset date – date of first dose + 1) if AE 
onset date is on or after the date of first dose; otherwise (AE onset date – date of first 
dose) 
• Relative study day for the end of AE:  (AE stop date – date of first dose + 1) if AE stop 
date is on or after the date of first dose; otherwise (AE stop date – date of first dose) 
• The duration of AE:  AE stop date – AE onset date + 1 
Drug related AEs are defined as related if causality is related.  
Every attempt will be made to obtain complete information for AEs regarding severity (i.e., 
CTCAE Grade) and relationship to drug; however, in the rare case of missing data, the following 
conservative approach will be taken for summary purpose. The non-imputed raw data will be 
presented in AE listings,  
• Missing AE grade will be classified as ‘Grade 3’  
• Missing AE relationship will be classified as “Related”  
 




 
 
 
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Statistical Analysis Plan 
 
 
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4.2.2. Dose-Limiting Toxicities (DLTs) 
DLTs will be evaluated from Cycle 1 Day -16 through Cycle 1 Day 28 (the DLT period). DLTs are 
drug-related AEs defined as follows: 
• Grade 4 neutropenia 
• ≥ Grade 3 neutropenic infection/febrile neutropenia 
• Grade 4 thrombocytopenia 
• ≥ Grade 3 thrombocytopenia with bleeding 
• ≥ Grade 3 nonhematologic toxicity (additional criteria for nausea, vomiting, diarrhea, or 
fatigue: lasting > 5 days with maximal medical management) 
• Liver function test abnormalities meeting Hy’s Law criteria (aspartate aminotransferase 
[AST] or alanine aminotransferase [ALT] >= 3 × upper limit of normal [ULN] and total 
bilirubin >= 2 × ULN). 
4.2.3. Vital Signs 
Vital signs include weight, temperature, systolic blood pressure (SBP) and diastolic blood 
pressure (DBP), pulse rate, and respiration rate. 
Vital sign potentially clinically significant criteria are defined in the Table 7 below: 
Table 7 Vital Sign Potentially Clinically Significant Criteria 
Vital Sign Parameter 
Criterion value 
Change from 
baseline 
SBP 
≥180 mmHg 
Increase ≥30 mmHg 
≤ 90 mmHg 
Decrease ≥20 mmHg 
DBP 
≥105 mmHg 
Increase ≥20 mmHg 
≤ 50 mmHg 
Decrease ≥10 mmHg 
Pulse 
≥ 120 bpm 
Increase ≥20 bpm 
≤ 50 bpm 
Decrease ≥20 bpm 
Weight 
n/a 
Change ≥15% 
bpm = beats per minute 
4.2.4. Laboratory 
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis will 
be collected. The laboratory variables in Table 8 will be measured. 


 
 
 
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Statistical Analysis Plan 
 
 
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Laboratory toxicities will be assessed using the NCI CTCAE, Version 4.03. Details on CTCAE 
grading criteria are presented in the Appendix Table A1. Change from baseline and percent 
change from baseline in laboratory test results to each assessment will also be derived. 
Table 8 Clinical Laboratory Tests 
Hematology 
Hemoglobin 
Hematocrit 
WBCs with differential 
Platelets 
Chemistry 
Albumin 
Alkaline phosphatase 
Total bilirubin 
Calcium 
Chloride 
Creatinine 
Glucose 
Phosphorus 
Potassium 
Total protein 
ALT 
AST 
Lactate dehydrogenase 
Sodium 
Blood urea nitrogen/urea 
Cystatin Ca 
Urinalysis 
Pregnancy test 
Specific gravity 
Blood or urine tests are 
pH 
acceptable based on the site’s 
Glucose 
standard clinical practice; 
Protein 
applicable to women of 
Bilirubin 
childbearing potential only. 
Ketones 
Leukocytes 
Hemoglobin 
Microscopic examination (including RBC, WBC, 
and casts will be performed, if necessary) 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; RBC = red blood cell; WBC = white blood cell 
a Postbaseline Cystatin C to be evaluated in the event that serum creatinine is elevated, if it is available as a local test 
 
Collected serum calcium will not be summarized in tables, instead, corrected serum calcium will 
be derived from calcium and albumin results based on the following formula: 
 
Corrected Calcium = Calcium (mmol/L) + 0.02 (40 - [Albumin] (g/L) 
 
Laboratory Values with < or > Inequality Symbols 
Some continuous laboratory data include “<” or “>” symbols. Data will be presented in listings 
with their inequality symbol; however, for tabulation of summary statistics of safety laboratory 
results, the given numeric value will be used in the summary statistics, ignoring the nonnumeric 
qualifier. 
  
4.2.5. Electrocardiograms (ECGs) 
All patients will have three 12-lead electrocardiograms (ECGs) performed at the visits indicated 
in Table 9-1 of the protocol. 




 
 
 
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Statistical Analysis Plan 
 
 
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4.2.6. Echocardiogram/MUGA 
An echocardiogram/ multigated acquisition (MUGA) scan to assess LVEF (left ventricular 
ejection fraction) shall be performed at the time points outlined in Table 9-1 of the protocol. 
4.2.7. Treatment Exposure and Compliance 
Prescribed duration of treatment (days) is defined as the total number of days that the patient will 
have been prescribed study medication, that is, including days on treatment before Cycle 1 Day 1 
and days on treatment from Cycle 1 Day 1 to treatment end day. Prescribed duration of G1T38 
(months) is calculated as (last dose date on the dosing log – first date of continuous daily dosing 
(C1D1) + x + 1)/30.4375, where x is the number of days patient received G1T38 before C1D1. 
For example, for a patient who took one dose of G1T38 each on C1D-16 and C1D-2 respectively 
and took last dose on or after the first date of continuous, daily dosing of G1T38 (C1D1), Days 
on Treatment = Date of last dose – C1D1 date + 3; for patients who did not start continuous daily 
dosing, total number of days on dosing of G1T38 before C1D1 will be used as prescribed 
duration. Prescribed duration of Osimertinib (months) is calculated as (last dose date on the 
dosing log - the first date of daily osimertinib (only) dosing (i.e., C1D-14) + 1)/30.4375.  
The exposure to G1T38 (months) is calculated by (prescribed G1T38 duration - days of 
interruption as captured in dosing log)/30.4375. Days of interruption is defined as (start date of 
next record – end date of current record – 1).  
For subjects with last dose date is missing from dosing log, if end of treatment date is not 
missing, date of end of treatment will be used as last dose date. Otherwise, the later date between 
the last visit date during the treatment phase and last contact date will be used, but the date must 
be prior to the start of survival follow-up. 
Compliance of G1T38 is expressed as a percentage of days G1T38 was actually taken during the 
treatment phase and will be calculated as exposure to G1T38 divided by prescribed G1T38 
duration multiplied by 100. 
Dose reduction will be flagged when a total daily dose recorded in G1T38 dosing log is less than 
the previous entry. Patient with dose interval change but total daily dose unchanged (e.g. 300 mg 
QD vs 150 mg BID) will not be considered as dose reduction. 
5. ANALYSIS METHODS (PART 1) 
5.1  General Principles  
5.1.1. General Statistical Considerations 
All statistical analyses will be performed using SAS® Version 9 or higher. 
Data will be summarized descriptively by dose level and overall.  


 
 
 
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Statistical Analysis Plan 
 
 
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The descriptive summary for the categorical variables will include counts and percentages. The 
descriptive summary for the continuous variables will include mean, median, standard deviation 
(SD), and minimum and maximum values. The descriptive summary statistics of time to first 
objective response will include median, 25% and 75% percentiles, and minimum and maximum 
values. The Kaplan-Meier method will be used to estimate the probability of survival (PFS and 
DOR) and the respective the time-to-event percentiles.  
In general, the precision of descriptive statistics for continues variables min and max will always 
be consistent with the precision of the variable of summarization. Additional rounding rules are 
listed as follows: 
• If the original value has <= 1 decimal places, mean and median will have one more 
decimal as the original value. Measures of variability (e.g, SD will be rounded two more 
decimal places than the precision of the original measure.  
• If the original value has two decimal places, mean and median will have the same 
decimal places as the original value. Measures of variability will be rounded one more 
decimal place than the precision of the original measure. 
• If the original value has >2 decimal places, all the descriptive statistics will have the same 
decimal places as the original value. 
For categorical variables, non-zero percentages will be displayed with 1 decimal place, zero-
percentages will not be displayed. A percentage value less than 0.1% will be displayed as 
“<0.1%.” A percentage value less than 100% but greater than 99% will be displayed as “>99%.”  
Part 1 of the study is descriptive in nature. No formal statistical test will be conducted. Two-
sided 95% exact CI will be provided for tumor response rate by using Clopper-Pearson method. 
95% CI will be provided for PFS percentiles by using log-log transformation approach. 
Any rounding will be done after all calculations are made. 
Safety assessments (other than AEs) during treatment period is defined as assessment that is 
evaluated between the date of first dose of study drug and the date of last dose of study drug + 29 
days. Assessments occur on or after last dose of study drug + 30 days will be counted as 
assessments during post-treatment period. If start date of survival follow up is available, 
assessments during post-treatment period should occur prior to the start of survival. If the last 
dose date of study drug is missing, any assessment/event occurring after the start of study drug 
will be considered as during treatment period.  
All data will be listed for all enrolled patients. 
5.1.2. Handling of Missing Data 
All data will be analyzed as they were collected in the database.  In general, missing data, unless 
noted otherwise, will not be imputed.  However, imputation of missing AE (Section 4.2.1) and 
concomitant medication (Section 5.2.6) onset and stop dates will be used to determine the status 
of each AE and the prior/concomitant status of each medication. 


 
 
 
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Statistical Analysis Plan 
 
 
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For demographic and baseline characteristics, each variable will be analyzed and/or summarized 
using available data. For continuous variables, subjects with missing data will be excluded from 
analyses for which data are not available. For categorical variables, a “Missing” category will be 
added for subjects with missing data.  
5.1.3. Study Days and Visit Windowing 
Study Days Relative to First Administration of Study Medication on Cycle 1 Day 1 
Study Day 1 is the day continuous daily doses of G1T38 and osimertinib commences.   
Negative Study Days occur prior to first administration of study medication on C1D1; and 
positive Study Days are those after the first administration of study medication on C1D1– e.g., 
Study Day -1 is the day immediately preceding the first administration of study medication on 
C1D1, Study Day 2 is the day immediately following the first administration of study medication 
on C1D1. 
Visit Windowing 
It is expected that there will be a variation between patients in the actual number of study days 
from the start of administration of study drug on C1D1 – defined as Day 1 – to the dates that the 
scheduled visit occurs. To handle this, for tables and figures where data are grouped by visit, 
assessments will be categorized using visit windows based on study days. The visit-window 
mapping is described in Table 10 for Part 1 for safety assessments. Visit-based summaries will 
be based on the windowed visits. All data, whether or not within the visit windows, will be 
presented in by patient listings. 
For windowed visit between the treatment start date (i.e., Cycle 1 Day -16) through post-
treatment visit, if more than one visit occurs during a visit window, the visit closest to the 
scheduled day will be assigned to the windowed visit. If two visits are equidistant from the 
scheduled day, the later visit will be assigned to the windowed visit.  
For a patient who prematurely discontinues treatment, the visit will be slotted accordingly. The 
window for post-treatment visit will be from the "last dose date + 30 to date of last assessment 
prior to the start of survival follow-up". 
 
Table 10 Windowing Algorithm for Part 1 
Visit 
Scheduled 
Day 
Vital Signs 
Clinical 
Chemistry 
Hematology 
Urinalysis 
and ECOG 
ECG 
Screening 
NA 
-37 to -17 
-37 to -17 
-37 to -17 
-37 to -17 
-37 to -17 
C1D-16 
-16 
-16 
-16 
-16 
-16 
-16 
C1D-2 
-2 
-15 to -1 
 
 
 
-15 to -1 
C1D1 
1 
1 to 3  
-15 to 3 
-15 to 3 
-15 to 3 
 
C1D8 
8 
 
 
4 to 11 
 
 
C1D15 
15 
4 to 21 
4 to 21 
12 to 18 
 
 
C1D22 
22 
 
 
19 to 25 
 
 
C2D1 
29 
22 to 35 
22 to 35 
26 to 32 
4 to 42 
1 to 42 


 
 
 
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C2D8 
36 
 
 
33 to 39 
 
 
C2D15 
43 
36 to 49 
36 to 49 
40 to 46 
 
 
C2D22 
50 
 
 
47 to 53 
 
 
C3D1 
57 
50 to 70 
50 to 63 
54 to 63 
43 to 70 
43 to 70 
C3D15 
71 
 
64 to 77 
64 to 77 
 
 
C4D1 
85 
71 to 98 
78 to 91 
78 to 91 
71 to 98 
 
C4D15 
99 
 
92 to 105 
92 to 105 
 
 
C5D1 
113 
99 to 126 
106 to 126 
106 to 126 
99 to 126 
 
CYD1a 
28(Y-1)+1 
28(Y-1)-13 to 
28(Y-1)+14 
28(Y-1)-13 to 
28(Y-1)+14 
28(Y-1)-6 to  
28(Y-1)+7 
28(Y-1)-13 to 
28(Y-1)+14 
28(Y-1)-13 to 
28(Y-1)+14 
CYD15a 
28(Y-1)+15 
 
 
28(Y-1)+8 to  
28(Y-1)+21 
 
 
Post-
treatment 
visit 
Last dose 
date + 30 
days 
 
 
 
 
 
 
Absolute neutrophil counts will be monitored weekly for the first 8 weeks (2 cycles), then every 2 
weeks for the next 2 cycles. Beginning with Cycle 5 Day 1, patients with stable ≤ Grade 2 
hematologic parameters may have hematology monitored monthly on Day 1 of each cycle; patients 
that do not meet this criteria will continue to have every other week assessment of hematologic 
parameters. 
Clinical chemistry will be monitored every 2 weeks for the first 4 cycles. Beginning with Cycle 5 
Day 1, clinical chemistry will be monitored monthly on Day 1 of each cycle. 
 
5.2  Analysis Methods (Part 1) 
5.2.1. Patient Disposition 
o The number of patients in following categories will be summarized for all screened 
patients without percentages, only for the overall treatment: 
• Screened patients  
• Screen failures and reasons for screen failure 
o The number of patients and percentages will be summarized for all screened patients by 
treatment for: 
• Enrolled patients 
o The number of patients and percentages in the following categories will be summarized 
based on the safety population by treatment group and overall, unless otherwise 
specified:  
• Patients treated (safety population) 
• Patients not treated 


 
 
 
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• Full analysis Set  
• Response evaluable analysis set 
• Treatment disposition along with reason for discontinuation 
• Continued with study survival follow-up at end of treatment 
• Study disposition along with the reasons for discontinuation  
• Death summary (death and reasons) 
Listings will be provided for enrollment information (country, date of protocol version, date of 
informed consent, and date of first dose), end of treatment disposition, end of study disposition 
and death. 
5.2.2. Protocol Deviations 
Protocol deviations will be classified as major or minor for severity based on if they may affect 
the ability to assess the safety and efficacy of study drug. The classification of protocol 
deviations will be finalized at the Classification Meeting prior to database lock.  
The number and percentage of patients by dose level and overall and deviation type will be 
presented for all major protocol deviations for safety population. All protocol deviations will be 
listed including detailed description, deviation type and subtype and classification for major or 
minor based on data recorded on Protocol Deviation Logs, including unavoidable protocol 
deviations due to COVID-19 illness and/or COVID-19 control measures, provided by 
PAREXEL Medical.  
5.2.3. Demographic and Other Baseline Characteristics 
Demographics – age (at informed consent), sex, child-bearing potential (female patients only), 
race, ethnicity – and baseline patient characteristics including height (cm), weight (kg), BMI 
(kg/m2), and smoking history (history of smoking – Y/N, average packs per day, and years 
smoking) will be tabulated by dose level and overall, using all patients in the safety population to 
descriptively assess the comparability of the groups. Body mass index (BMI) (kg/m2) is 
calculated by weight (kg)/[height (m)]2. 
The following baseline lung cancer characteristics will be summarized as continuous or 
categorical variables, where appropriate: 
• Tumor type at initial diagnosis 
• Stage of disease at initial diagnosis 
• Time from initial diagnosis to first dose day (in months) 
• Current status of brain metastases 
• EGFR mutation status and the identified mutations 


 
 
 
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• Eastern Cooperative Oncology Group (ECOG) performance status 
All data will be listed for all enrolled patients. 
5.2.4. Prior Cancer Therapy 
Patient prior cancer therapy will be tabulated by dose level and overall using all patients in the 
safety population. This table will include the total number of prior treatments in the 
advanced/metastatic setting per patient (summarized as both continuous variable and categorical 
variable (0, 1, 2, 3, and >=4)); the treatment type of prior treatment by treatment setting; time 
since the last prior systemic anti-cancer therapy; the reason for discontinuation of the last prior 
systemic anti-cancer therapy; any prior cancer surgery (lung) (yes/no); any radiation treatment 
(yes/no); the number of patients with prior EGFR TKI treatment (i.e., Osimertinib or Other) and 
any discontinuation of EGFR TKI treatment due to disease progression.  Prior cancer treatments 
will be listed and are coded according to the World Health Organization (WHO) Drug Dictionary 
(WHODrug) March 2020 DDE B3. 
Time since the Last Prior Systemic Anti-Cancer Therapy (Months) is calculated as (first dosing 
date for pharmacokinetics assessments (i.e. C1D-16) – date of last prior systemic anti-cancer 
therapy + 1)/30.4375. If the month and year of the therapy are provided but the day is missing, 
the missing day is imputed as 15. If only the year is provided, then the missing month and day 
are imputed as July 1 for the calculation. If the year is missing, the patient will be excluded from 
the analysis. 
5.2.5. Medical History  
Medical history will be coded using MedDRA Version 23.0.  Medical history will be listed for 
all enrolled patients (SOC, PT, and verbatim term) by dose level and overall. 
5.2.6. Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the WHODrug version dated March 2020 
DDE B3. Prior medications include medications that were taken prior to the first dose of any 
study treatment. Concomitant medications during the treatment period include medications that 
started at any time and were taken at any time after the start of study treatment until 29 days after 
the end of study treatment. Post-treatment medications are those medications were started on or 
after the last dose of study drug (G1T38 or osimertinib, which is later) + 30 days.  
Medications with incomplete start and/or end dates will be imputed for the purpose of 
classification of prior and concomitant according to the specifications described below.  
Medications with incomplete start and/or end dates will be assumed to be concomitant if it cannot 
be shown that the medication was not taken during the treatment period.   
Imputation rules for missing or partially missing medication start/stop dates are defined below: 
Missing or partially missing medication start date: 
If the start date has month and year but day is missing, 


 
 
 
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o If the month and year is the same as the first dose date, then the first dose date will be 
used, otherwise, the first day of the month will be used 
If the start date has year, but day and month are missing, 
o If the year is the same as the first dose date, then the first dose date will be used, 
otherwise 1st Jan will be used 
If the start date of an event is completely missing, then the start date will be imputed as the 
earlier date between 
o 
the first dose date of study drug 
o 
the end date of the medication (if complete date) 
Any above imputed started date should be no later than the end date, if available. In case the 
imputed started date is later than the end date, the start date will be imputed as the end date of the 
medication. 
Missing or partial medication stop date: 
o If the stop date has month and year but day is missing, the last day of the month will be 
imputed 
o If the stop date has year, but day and month are missing, the 31st of December will be 
imputed 
o If the medication is not ongoing, the end date is completely missing, the end date will be 
imputed as the later date between: 
o the date of last study visit 
o the start date of the medication (if complete date) 
After the imputation, the imputed dates will be compared against the date of death, if available. 
If the date is later than the date of death, the date of death will be used as the imputed date 
instead. 
The number and percentage of patients taking concomitant medications during the treatment 
period will be summarized by anatomical therapeutic chemical (ATC) class level 4 (chemical 
subgroup) and PT for the safety population. Although a patient may have taken the same 
medication multiple times, the patient is counted only once within an ATC classification. The 
same patient may contribute to two or more PTs in the same classification. 
All medications will be listed for enrolled patients with a flag for prior and/or concomitant, or 
post-treatment. 
5.2.7. Treatment Duration 
Study drug exposures will be summarized for the safety population using descriptive statistics.   


 
 
 
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Exposure to G1T38 and Osimertinib will be categorized in intervals (<3 Months, 3 - <6 Months, 
6 - <9 Months, 9 - <12 Months, 12 - <15 Months, 15 - <18 Months, 18 - <21 Months, 21 - <24 
Months, >=24 Months) and summarized by dose level and overall. Interval in Months is 
calculated by duration in days/30.4375. 
5.2.8 Treatment Compliance 
G1T38 drug compliance will be summarized using descriptive statistics. The compliance 
summaries will include the prescribed G1T38 duration (in months), the exposure to G1T38 (in 
months), and the proportion (%) of days G1T38 is taken.  The proportion (%) of days G1T38 is 
taken will also be summarized in categories “<70%”, “≥70% - <80%”, “≥80% - <90%”, “≥90% - 
<100%”, and “=100%.”  The number and percentage of patients with any G1T38 dose reductions 
will also be summarized. 
Study drug compliance summaries will be based on the safety population. 
A listing of exposure and compliance data containing the information described in the sections 
above will be provided. 
5.2.9. Efficacy Analyses 
5.2.9.1 Analysis of Tumor Response 
The number and percentage of subjects in each category of BOR according to programmatically-
derived tumor response (CR, PR, SD, PD, or NE) based on investigator’s measurements will be 
presented by dose level and overall. Also, the number and percentage of subjects in each 
category of BOR (Confirmed CR, Confirmed PR, SD, PD, or NE) based on CRF collected 
timepoint response (confirmed) will be summarized by dose level and overall. Similar analyses 
will be repeated for ORR and DCR. 
Estimates of response rate, along with its associated exact 95% two-sided CIs using Clopper- 
Pearson method will be computed for ORR, BOR, and DCR within each treatment group. 
The above analyses will be based on the RES. Analysis will be repeated for FAS based on 
programmatically derived BOR (confirmed) and DCR with additional category of Non-CR/Non-
PR.  
In addition to confirmed response (CRconfirmed, PR confirmed and ORRconfirmed) in BOR summary, 
both confirmed response and unconfirmed response (CRunconfirmed, PR unconfirmed, and 
ORRunconfirmed) will be presented in a separated BOR summary based on programmatically 
derived response for response evaluable population.  
Detailed tumor assessment data from CRF will be listed together with derived response for target 
lesion(s) and derived time point response for all enrolled patients.  
5.2.9.2 Analysis of DOR and time to first objective response 
Summary of DOR and time to first objective response will be presented for patients with 
objective response in RES. DOR will be analyzed using Kaplan-Meier analyses. The following 


 
 
 
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summaries will be presented: a summary of the number of censored and event observation; 
estimated statistics, including median, 25% and 75% percentiles and associated 95% confidence 
interval (CI).  
Descriptive statistics of median and range will be produced for time to first response based on 
patients with an objective response in the RES. 
5.2.9.3 Analysis of PFS 
PFS will be analyzed using Kaplan-Meier analyses based on FAS. The following summaries will 
be presented: a summary of the number of event and censored observation, along with the 
censoring reasons; estimated statistics, including median, 25% and 75% percentiles and 
associated 95% confidence interval (CI). In addition, estimated the probability of survival at pre-
specified landmarks (every 6 months from month 6 through month 24) and the 95% confidence 
interval (CI) will be presented in PFS tables. The estimated probability of PFS over time will be 
displayed graphically, when appropriate. 
All efficacy data will also be listed by patient. 
5.2.10. Safety Analyses (Part 1) 
Adverse Events  
Details for imputing missing or partial start dates of AEs are described in Section 4.2.1.  
AE overall summary tables will be presented for TEAEs only and will include the following: 
• Number of TEAEs (all events are counted) 
And, patients with any, 
• TEAEs 
• Grade 3 or higher TEAEs 
• TEAEs related to either G1T38 or Osimertinib  
• G1T38-related TEAEs 
• Osimertinib-related TEAEs 
• G1T38 and Osimertinib-related TEAEs 
• Grade 3 or higher TEAEs related to either G1T38 or Osimertinib 
• Grade 3 or higher G1T38-related TEAEs 
• Grade 3 or higher Osimertinib-related TEAEs 
• Grade 3 or higher G1T38 and Osimertinib-related TEAEs 
• Serious TEAEs 


 
 
 
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• Grade 5 TEAEs or TEAEs with fatal outcome (death) 
• Serious TEAEs related to either G1T38 or Osimertinib 
• G1T38-related serious TEAEs 
• Osimertinib-related serious TEAEs 
• G1T38 and Osimertinib-related serious TEAEs 
• TEAE leading to G1T38 dose reduction 
• TEAEs leading to discontinuation of either G1T38 or osimertinib 
• TEAEs leading to discontinuation of G1T38  
• TEAEs leading to discontinuation of Osimertinib 
• TEAEs leading to discontinuation of G1T38 and Osimertinib 
TEAEs will be summarized in descending frequency of all dose levels combined as follows: 
• TEAEs by SOC and PT (without collapsed terms);  
• Serious TEAEs by SOC and PT; 
• TEAEs by PT and by CTCAE grade; 
• G1T38-related TEAEs by PT and by CTCAE grade; 
• Osimertinib-related TEAEs by PT and by CTCAE grade; 
• G1T38-related and Osimertinib-related TEAEs by PT and by CTCAE grade; 
• G1T38-related or Osimertinib-related TEAEs by PT and by CTCAE grade; 
• G1T38-related TEAEs by SOC and PT; 
• Osimertinib-related TEAEs by SOC and PT; 
• G1T38-related and Osimertinib-related TEAEs by SOC and PT; 
• G1T38-related or Osimertinib-related TEAEs by SOC and PT; 
• G1T38-related serious TEAEs by SOC and PT ; 
• Osimertinib-related serious TEAEs by SOC and PT; 
• G1T38-related and Osimertinib-related serious TEAEs by SOC and PT; 
• G1T38-related or Osimertinib-related serious TEAEs by SOC and PT; 
• Grade 3 or higher TEAEs by PT; 
• Grade 3 or higher G1T38-related TEAEs by PT; 


 
 
 
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• Grade 3 or higher Osimertinib-related TEAEs by PT; 
• G1T38 or Osimertinib-related, Grade 3 or higher TEAEs by PT; 
• G1T38 and Osimertinib-related, Grade 3 or higher TEAEs by PT; 
• TEAEs leading to G1T38 reduction by SOC and PT 
• TEAEs leading to G1T38 discontinuation by SOC and PT; 
• TEAEs leading to Osimertinib discontinuation by SOC and PT; 
• TEAEs leading to G1T38 and Osimertinib discontinuation by SOC and PT; 
• TEAEs leading to death by SOC and PT 
Where a patient has the same adverse event, based on preferred terminology, reported multiple 
times, the patient will only be counted once at the preferred terminology level in adverse event 
frequency tables. Where a patient has multiple adverse events within the same system organ 
class, the subject will only be counted once at the system organ class level in adverse event 
frequency tables.  When reporting adverse events by CTCAE grade, summary table will also be 
provided based on the most severe grade.  
The collapsed preferred terms as mentioned in Table 6-1 and Table 6-2 will be presented unless 
otherwise specified. In summaries by SOC and PT, AEs will be sorted by decreasing frequency 
within each SOC and PT according to the overall group. In summaries by PT, AEs will be sorted 
by decreasing frequency according to the overall group. Summaries will be provided by dose 
level for the safety population. 
Listings will be presented for all AEs with details including dictionary SOC/PT (non-collapsed), 
verbatim term, start/stop dates (non-imputed) and duration, severity grade, drug-relationship, 
action taken, and outcome.  Listings will be flagged with during treatment period, prior-treatment 
or post-treatment period.  
Listings will be repeated for all serious adverse events (SAEs), AEs leading to discontinuation of 
any study drug, and AEs with a fatal outcome. 
Vital Signs 
For vital sign parameters, the observed values and changes from Baseline will be summarized 
using descriptive statistics for each scheduled visit, last assessment during treatment period, and 
maximum and minimum post-baseline values during treatment period. 
Additionally, the proportions of subjects who meet the potentially clinically significant criteria, 
defined in Table 7, will be tabulated as at any time during the treatment period. 
A listing of observed vital signs values and change from baseline with the abnormality flag by 
subject will be produced. 
 


 
 
 
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ECOG Performance Status 
ECOG performance status will be summarized using descriptive statistics at each scheduled visit 
during the treatment period. Number and percentage of patients will be summarized for each 
status. In addition, the maximum post-baseline performance status during treatment period will 
be presented, including assessment at unscheduled visits. 
ECOG performance status (0, 1, 2, 3, 4, and 5) will be listed.  
Electrocardiograms 
ECG parameter (e.g., QT interval corrected by Fridericia's formula [QTcF]) observed values and 
changes from Baseline will be summarized using descriptive statistics for each scheduled visit, 
last assessment during treatment period and maximum and minimum post-baseline during 
treatment period. Both scheduled and unscheduled assessments will be used to identify last and 
worst post-baseline values during treatment period. For the triple assessments as a specific time 
point, the average will be summarized for that time point. 
Incidence of ECG meeting potentially clinically significant criteria (Table 9) will be summarized 
with frequencies and percentages. 
An accompanying listing of subjects will be produced and it will display all ECG measurements 
collected on CRF together with derived values (RR, QTcB and QTcF) and findings during the 
study in subjects with abnormal ECGs, as determined by the investigator. 
Laboratory Results 
For the purposes of summarization in both the tables and listings, all laboratory values will be 
converted and presented in SI units. 
Clinical laboratory parameters observed values, changes from Baseline, and percent changes 
from Baseline will be summarized using descriptive statistics for each scheduled visit, last value 
during treatment period, maximum and minimum post-baseline value during treatment period. 
Last value during treatment period, maximum and minimum values will be based on both 
scheduled and unscheduled visits. Graphical presentations of median and change from baseline 
over time will provide additional focus to be placed on absolute neutrophil count. 
Toxicities for clinical labs will be characterized according to CTCAE, Version 4.03. Shifts in 
toxicity grades from baseline to the worst post-baseline value will be summarized. The worst post-
baseline values will consider both scheduled and unscheduled data. Any graded abnormality that 
occurs following the initiation of study drug and represents at least 1- grade increase from the 
baseline assessment is defined as treatment emergent. Summary of treatment-emergent worst 
clinical laboratory abnormalities based on CTCAE Grade will be presented. Worst is referring to 
the worst scenario during the post-baseline period. Hepatic abnormalities will be summarized 
using frequency tabulation.  


 
 
 
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Observed values of clinical labs (hematology, chemistry, and urinalysis) and CTCAE grades will 
included and values outside the normal range will be flagged in the listings of individual subject 
data. In addition, a separate listing will be prepared for patients who met Hy’s law. 
Echocardiogram/MUGA  
For quantitative echocardiogram/MUGA results, descriptive statistics will be used to summarize 
parameters based on the observed value and the change from baseline value at each visit. 
Echocardiogram/MUGA results will be listed. 
Pregnancy Test  
The pregnancy test data will be presented in listings. 
6. PLANNED ANALYSIS (PART 1) 
No formal interim analysis is planned. 
The final analysis will be conducted after all Part 1 patients discontinued treatment and database 
is locked 
7. CHANGE FROM THE PROTOCOL (PART 1) 
Following changes specified in the protocol are noted: 
• Due to an internal G1 corporate strategy shift, the sponsor decided not to open Part 2 of 
the study. Both original study design and original planned analysis for Part 2 will not be 
included in this SAP  
• The Protocol includes “Final analysis” and “End of study analysis”.  The SAP includes 
final analysis for Part 1due to the strategy shift mentioned above . 
• In order to reduce any harm or burden to the patients, data of 
 
, data of overall survival and data of subsequent anti-cancer 
treatment are no longer required (since 29 January 2020).  No cfDNA related analysis or 
the overall survival analysis detailed in the protocol will be conducted for Part 1 due to 
limited data in Part 1.   
• All tumor assessments are conducted by the investigators or site radiologist. No Blinded 
Independent Central Review (BICR) assessment will be implemented for PFS as opposed 
to both BICR and investigator assessment mentioned in protocol. 
• In the protocol, Hy’s law criteria is described as, “AST or ALT ≥ 3 × upper limit of 
normal [ULN] and total bilirubin ≥ 2 × ULN.”   Hy’s law criteria is defined in the SAP 


 
 
 
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as,  “ALT and/or AST > 3 × ULN x 3 and total bilirubin ≥ 2 × ULN and ALP < 2 × 
ULN.”  
• The protocol refers to Clinical benefit rate (CBR), which is defined as the proportion of 
patients with a BOR of confirmed CR or confirmed PR or SD at the 8 week (end of Cycle 2) 
or later assessment.  The SAP replaces the term CBR with Disease Control Rate (DCR) with 
the same definition. 
• The protocol defines time to first objective response as the time from first dose of study drug 
to first objective response of CR or PR and states, “patients who do not experience objective 
response of CR or PR will be censored at the last adequate assessment date.”  The SAP 
removes the KM analysis for the time to first objective response and calculates time to first 
objection response for patients who experience objective response only.  
• The protocol defines DOR as the time between first objective response of CR or PR and the 
first date that progressive disease is objectively documented or death and states, “patients 
who do not experience objective PD or death will not be included in the analysis.”  The SAP 
SAP clarifies that the DOR analysis is based on patients who achieve objective response. 
In addition, the SAP states, “patients who achieve objective response but do not 
experience objective PD or death will be censored at the last adequate assessment date.”  
 
 


 
 
 
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8. REFERENCES 
Eisenhauer EA et al, New response evaluation criteria in solid tumors: Revised RECIST guidelines 
(version 1.1).