Conditions: Small Cell Lung Cancer
Keywords: Small Cell Lung Cancer CDK 4/6 Inhibitor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 122
Healthy volunteers: no

Brief summary:
This is a study to investigate the potential clinical benefit of trilaciclib (G1T28) in preserving the bone marrow and the immune system, and enhancing chemotherapy antitumor efficacy when administered prior to carboplatin and etoposide in first line treatment for patients with newly diagnosed extensive-stage SCLC.

The study consists of 2 parts: a limited open-label, dose-finding portion (Part 1), and a randomized double-blind portion (Part 2). Both parts include 3 study phases: Screening Phase, Treatment Phase, and Survival Follow-up Phase. The Treatment Phase begins on the day of first dose with study treatment and completes at the Post-Treatment Visit. Approximately, 90 patients will be enrolled in the study; 20 patients in the Part 1 and 70 patients in the Part 2 portion.

Detailed description:

Arms:
arm 1: All patients in part 1 will receive trilaciclib (G1T28) prior to standard chemotherapy- carboplatin and etoposide. Patients will have PK assessments completed on days 1 and 3 in cycle 1 only. All patents will be monitored for safety and tumor response based on RECIST version 1.1. Safety surveillance reporting of AEs and concomitant medications commences at the time that informed consent is obtained and continues through the Post Treatment Visit. arm 2: All patients enrolled in part 2 will be randomized to receive either trilaciclib (G1T28) or placebo administered prior to standard chemotherapy- carboplatin and etoposide. All patents will be monitored for safety and tumor response based on RECIST version 1.1. Safety surveillance reporting of AEs and concomitant medications commences at the time that informed consent is obtained and continues through the Post Treatment Visit.

Interventions: intervention 1: Carboplatin intervention 2: Placebo intervention 3: Trilaciclib intervention 4: Etoposide
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_000.pdf: 
G1 Therapeutics CONFIDENTIAL 
 
 
 
 
 
Phase 1b/2a Safety and Pharmacokinetic Study of G1T28 in Patients with 
Extensive-Stage Small Cell Lung Cancer (SCLC) Receiving Etoposide and Carboplatin 
Chemotherapy 
 
Clinical Study Protocol G1T28-02  
EudraCT # 2016-001583-11 
 
 
Original Protocol Issue Date: 27 April 2015 
Amendment 7 Issue Date: 15 September 2016 
Version: 8.0 
 
Investigational Phase: 1b/2a 
 
Sponsored by: 
G1 Therapeutics 
79 T.W. Alexander Drive 
4501 Research Commons, Suite 100 
Research Triangle Park, NC 27709 
919-213-9835 
 
 
 
 
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. 


G 1 Therapeutics, Inc. 
Clinical Study Protocol G 1 T28-02 
GlT28 
SPONSOR SIGNATURE PAGE 
SPONSOR:GlTHERAPEUTICS 
I have read and understand the contents of this clinical protocol for Study G 1 T28-02 dated 15 
September 2016 and I agree to meet all obligations of the sponsor as detailed in all applicable 
regulations and guidelines. In addition, I will inform the principal investigator and all other 
investigators of all relevant information that becomes available during the conduct of this 
study. 
Approved by: 
Rajesh~ 
f~~2o(C 
Date 
Chief Medical Officer, G 1 Therapeutics 
Version: 8.0, dated 15 September 2016 
Page 2 of 105 
G 1 Therapeutics CONFIDENTIAL 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-02 
G1T28 
 
Version: 8.0, dated 15 September 2016 
 
Page 3 of 105  
G1 Therapeutics CONFIDENTIAL 
PROTOCOL SIGNATURE PAGE 
Clinical Study Protocol G1T28-02: Phase 1b/2a Safety and Pharmacokinetic Study of 
G1T28 in Patients with Extensive-Stage Small Cell Lung Cancer (SCLC) Receiving 
Etoposide and Carboplatin Chemotherapy 
Original Protocol Issue Date: 27 April 2015 
Version: 8.0, dated 15 September 2016 
By signing below, the investigator agrees to adhere to the protocol as outlined. 
Principal Investigator: 
 
 
Principal Investigator Signature 
Date 
Principal Investigator Name 
Institution 
 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-02 
G1T28 
 
Version: 8.0, dated 15 September 2016 
 
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1. 
TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ........................................................................................................................... 2 
PROTOCOL SIGNATURE PAGE ........................................................................................................................ 3 
1. 
TABLE OF CONTENTS ............................................................................................................................... 4 
1.1. 
List of In-Text Tables ....................................................................................................................... 8 
1.2. 
List of In-Text Figures ...................................................................................................................... 8 
2. 
LIST OF ABBREVIATIONS ........................................................................................................................ 9 
3. 
SYNOPSIS .................................................................................................................................................. 13 
4. 
INTRODUCTION ....................................................................................................................................... 25 
4.1. 
Background ..................................................................................................................................... 25 
4.2. 
Summary of Clinical Data ............................................................................................................... 26 
4.3. 
Summary of Nonclinical Data ......................................................................................................... 27 
4.3.1. 
Pharmacology Studies ................................................................................................... 27 
4.3.2. 
Pharmacokinetic Studies ............................................................................................... 28 
4.3.3. 
Toxicity and Safety Studies........................................................................................... 29 
4.3.4. 
Potential Risks ............................................................................................................... 29 
4.4. 
Study and Dose Rationale ............................................................................................................... 30 
4.5. 
Risk/Benefit Assessment ................................................................................................................. 31 
5. 
STUDY OBJECTIVES ................................................................................................................................ 32 
6. 
INVESTIGATIONAL PLAN ...................................................................................................................... 33 
6.1. 
Overall Study Design and Plan ....................................................................................................... 33 
6.1.1. 
Part 1 ............................................................................................................................. 33 
6.1.1.1. 
Definition of Dose-Limiting Toxicities (Applicable to 
Cycle 1 of the Phase 1b Dose-Finding Portion of Part 1) ........................ 34 
6.1.1.2. 
Criteria for Adjusting G1T28 Dose Based on 
Pharmacokinetic Parameters .................................................................... 35 
6.1.1.3. 
G1T28 Dose Evaluation ........................................................................... 35 
6.1.1.4. 
Safety Monitoring Committee ................................................................. 37 
6.1.2. 
Part 2 ............................................................................................................................. 37 
6.1.3. 
Criteria for Subsequent Cycles and Study Duration ...................................................... 38 
6.1.4. 
Safety Assessments ....................................................................................................... 39 
6.1.5. 
Tumor Assessment ........................................................................................................ 39 
7. 
STUDY POPULATION .............................................................................................................................. 41 
7.1. 
Selection of Patients ........................................................................................................................ 41 
7.1.1. 
Inclusion Criteria ........................................................................................................... 41 
7.1.2. 
Exclusion Criteria.......................................................................................................... 42 
8. 
TREATMENTS ........................................................................................................................................... 44 
8.1. 
Treatments Administered ................................................................................................................ 44 
8.2. 
Investigational Products .................................................................................................................. 45 
8.2.1. 
Identity .......................................................................................................................... 45 
8.2.1.1. 
G1T28 ...................................................................................................... 45 
8.2.1.2. 
Placebo ..................................................................................................... 45 
8.2.1.3. 
Etoposide and Carboplatin ....................................................................... 45 
8.2.2. 
Packaging and Labeling ................................................................................................ 45 
8.2.2.1. 
G1T28 ...................................................................................................... 45 
8.2.2.2. 
Placebo ..................................................................................................... 45 


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8.2.2.3. 
Etoposide and Carboplatin ....................................................................... 45 
8.2.3. 
Storage .......................................................................................................................... 46 
8.2.3.1. 
G1T28 ...................................................................................................... 46 
8.2.3.2. 
Placebo ..................................................................................................... 46 
8.2.3.3. 
Etoposide and Carboplatin ....................................................................... 46 
8.2.4. 
Procedure for Dispensing .............................................................................................. 46 
8.2.5. 
Investigational Product Accountability ......................................................................... 46 
8.3. 
Method of Assigning Patients to Treatment Groups ....................................................................... 47 
8.4. 
Dose, Dosing Regimen, and Route ................................................................................................. 47 
8.4.1. 
G1T28 ........................................................................................................................... 47 
8.4.2. 
Placebo .......................................................................................................................... 48 
8.4.3. 
Etoposide and Carboplatin ............................................................................................ 48 
8.4.3.1. 
Carboplatin............................................................................................... 48 
8.4.3.2. 
Etoposide ................................................................................................. 49 
8.4.4. 
Dose Modifications ....................................................................................................... 49 
8.4.4.1. 
G1T28 ...................................................................................................... 49 
8.4.4.2. 
Modification of Etoposide and Carboplatin Dosing .................................. 49 
8.5. 
Randomization and Blinding........................................................................................................... 55 
8.6. 
Prior and Concomitant Medications and Procedures ...................................................................... 55 
8.7. 
Transfusions .................................................................................................................................... 57 
8.8. 
Prophylactic Cranial Irradiation ...................................................................................................... 57 
8.9. 
Treatment Compliance .................................................................................................................... 57 
9. 
STUDY FLOWCHART .............................................................................................................................. 58 
10. SCHEDULE OF STUDY PROCEDURES ................................................................................................. 62 
10.1. 
Screening......................................................................................................................................... 62 
10.2. 
Enrollment....................................................................................................................................... 62 
10.3. 
Cycle 1 ............................................................................................................................................ 63 
10.4. 
Cycle 2 ............................................................................................................................................ 64 
10.5. 
Cycles 3, 4, and Subsequent Cycles ................................................................................................ 65 
10.6. 
Post-Treatment Visit ....................................................................................................................... 66 
10.7. 
Survival Follow-up Phase ............................................................................................................... 66 
10.8. 
Study Drug Discontinuation ............................................................................................................ 67 
10.9. 
Unscheduled Visits ......................................................................................................................... 67 
11. STUDY ASSESSMENTS ........................................................................................................................... 68 
11.1. 
Efficacy Assessments ...................................................................................................................... 68 
11.2. 
Pharmacokinetic Assessments ........................................................................................................ 68 
11.3. 
Safety Assessments ......................................................................................................................... 71 
11.3.1. 
Adverse Events and Serious Adverse Events ................................................................ 72 
11.3.1.1. 
Definition of Adverse Event .................................................................... 72 
11.3.1.2. 
Definition of Serious Adverse Event ....................................................... 73 
11.3.1.3. 
Assessment of the Severity of Adverse Events ........................................ 74 
11.3.1.4. 
Assessment of the Relationship of Adverse Events to 
Study Drug ............................................................................................... 74 
11.3.1.5. 
Assessment of the Outcome of Adverse Events....................................... 74 
11.3.1.6. 
Method, Frequency, and Time Period for Detecting 
Adverse Events and Serious Adverse Events ........................................... 75 
11.3.1.7. 
Documentation of Adverse Events and Serious Adverse 
Events ...................................................................................................... 75 
11.3.1.8. 
Adverse Event Coding ............................................................................. 76 
11.3.1.9. 
Reporting of Serious Adverse Events ...................................................... 76 
11.3.1.10. 
Follow-up of Adverse Events .................................................................. 76 
11.3.1.11. 
Regulatory Aspects of Adverse Event Reporting .................................... 77 
11.3.1.12. 
Handling of Overdoses and Toxicity ....................................................... 78 


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11.3.1.13. 
Reporting of Pregnancies ......................................................................... 78 
11.3.2. 
Clinical Laboratory Assessments .................................................................................. 78 
11.3.3. 
Demographics and Vital Signs ...................................................................................... 79 
11.3.4. 
Physical Examination .................................................................................................... 79 
11.3.5. 
Electrocardiogram Assessments .................................................................................... 79 
11.3.6. 
Concomitant Medications ............................................................................................. 79 
11.4. 
Central Pathology Review to Confirm Diagnosis of SCLC ............................................................ 80 
11.5. 
Tumor Response ............................................................................................................................. 80 
11.5.1. 
Tumor Assessments ...................................................................................................... 80 
11.5.2. 
Tumor Lesions: Identification and Follow-up ............................................................... 80 
11.5.2.1. 
Measurable Lesions ................................................................................. 80 
11.5.2.2. 
Nonmeasurable Lesions ........................................................................... 81 
11.5.2.3. 
New Lesions ............................................................................................ 81 
11.5.3. 
Definitions of Tumor Response and Disease Progression ............................................. 82 
11.5.3.1. 
Evaluation of Target Lesion Response .................................................... 82 
11.5.3.2. 
Evaluation of Nontarget Lesions .............................................................. 82 
11.5.3.3. 
Evaluation of Overall Response ............................................................... 82 
11.6. 
Patient Reported Outcomes ............................................................................................................. 83 
11.7. 
Immunologic Markers ..................................................................................................................... 83 
11.8. 
Appropriateness of Measurements .................................................................................................. 84 
12. STUDY TERMINATION OR STUDY DRUG DISCONTINUATION ..................................................... 85 
12.1. 
Study Termination........................................................................................................................... 85 
12.2. 
Site Termination .............................................................................................................................. 85 
12.3. 
Discontinuation of Study Drug ....................................................................................................... 85 
12.4. 
Withdrawal of Patients from the Study ........................................................................................... 86 
13. STATISTICS ............................................................................................................................................... 87 
13.1. 
Sample Size and Power ................................................................................................................... 87 
13.2. 
General Considerations ................................................................................................................... 87 
13.2.1. 
Analysis Populations/Sets ............................................................................................. 87 
13.2.2. 
Timing of Analyses ....................................................................................................... 87 
13.2.2.1. 
Interim Safety Reviews ............................................................................ 87 
13.2.2.2. 
Final Analysis .......................................................................................... 88 
13.2.2.3. 
End of Study Analysis ............................................................................. 88 
13.2.3. 
General Considerations for Data Analysis .................................................................... 88 
13.3. 
Baseline and Demographic Characteristics ..................................................................................... 89 
13.4. 
Efficacy Analysis ............................................................................................................................ 89 
13.4.1. 
Efficacy Endpoints ........................................................................................................ 89 
13.4.2. 
Methods of Analysis for Efficacy Endpoints ................................................................ 90 
13.4.2.1. 
Analysis of Hematologic Parameter Kinetic Endpoints ........................... 90 
13.4.2.2. 
Analysis of Hematologic Toxicity Endpoints .......................................... 92 
13.4.2.3. 
Analysis of Chemotherapy Exposure and Compliance ............................ 92 
13.4.2.4. 
Other Efficacy Endpoints ......................................................................... 93 
13.4.2.5. 
Analysis of Exploratory Efficacy Endpoints ............................................ 93 
13.5. 
Safety Analysis ............................................................................................................................... 93 
13.5.1. 
Safety Endpoints ........................................................................................................... 93 
13.5.2. 
Methods of Analysis for Safety Endpoints .................................................................... 94 
13.6. 
Exploratory Analyses ...................................................................................................................... 95 
13.7. 
Pharmacokinetic Analysis ............................................................................................................... 95 
13.8. 
Immunologic Markers ..................................................................................................................... 95 
14. QUALITY CONTROL AND QUALITY ASSURANCE ........................................................................... 96 
15. ETHICS AND PROTECTION OF HUMAN PATIENTS .......................................................................... 97 
15.1. 
Ethical Conduct Statement .............................................................................................................. 97 


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15.2. 
Institutional Review Board/Independent Ethics Committee ........................................................... 97 
15.3. 
Informed Consent ............................................................................................................................ 97 
15.4. 
Patient Confidentiality .................................................................................................................... 97 
15.5. 
Adherence to the Protocol ............................................................................................................... 98 
15.6. 
Protocol Amendments ..................................................................................................................... 98 
15.7. 
Patient Compliance ......................................................................................................................... 98 
15.8. 
Study Discontinuation ..................................................................................................................... 98 
16. DATA HANDLING AND RECORD KEEPING ........................................................................................ 99 
16.1. 
Data Collection and Retrieval ......................................................................................................... 99 
16.2. 
Data Monitoring Committee ........................................................................................................... 99 
16.3. 
Investigator Reporting Requirements.............................................................................................. 99 
16.4. 
Records Retention ........................................................................................................................... 99 
16.5. 
Study Monitoring .......................................................................................................................... 100 
16.6. 
Audits and Inspections .................................................................................................................. 100 
17. PUBLICATION POLICY ......................................................................................................................... 101 
18. REFERENCES .......................................................................................................................................... 102 
19. APPENDICES ........................................................................................................................................... 105 
 
 


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1.1. 
List of In-Text Tables 
Table 5-1 
G1T28-02: Study Objectives ......................................................................................... 32 
Table 8-1 
Etoposide and Carboplatin Dose Reductions ................................................................ 50 
Table 8-2 
Etoposide and Carboplatin Dose Adjustments Based on Lack of 
Recovery of Absolute Neutrophil or Platelet Counts on the First 
Day of Cycle 2 and Each Successive Cycle .................................................................. 51 
Table 8-3 
Etoposide and Carboplatin Dose Adjustments Based on Absolute 
Neutrophil Count Nadir With or Without Fever ........................................................... 52 
Table 8-4 
Etoposide and Carboplatin Dose Adjustment Based on Platelet 
Nadir ............................................................................................................................. 53 
Table 8-5 
Etoposide and Carboplatin Reduction for Hepatic Toxicity.......................................... 54 
Table 9-1 
Schedule of Assessments .............................................................................................. 59 
Table 11-1 
Day 1 of Cycle 1 Blood Sampling Scheme Based on Predicted 
Administration Times of G1T28, Carboplatin, and Etoposide ...................................... 69 
Table 11-2 
Day 3 of Cycle 1 Blood Sampling Scheme Based on Predicted 
Administration Times of G1T28 and Etoposide ........................................................... 70 
Table 11-3 
Pharmacokinetic Parameters ......................................................................................... 71 
Table 11-4 
Evaluation of Overall Response at Each Time Point .................................................... 83 
 
 
1.2. 
List of In-Text Figures 
Figure 6-1 
Study Schema: Phase 1b Dose-Finding Portion of Part 1 ............................................. 34 
Figure 6-2 
G1T28 Dose Evaluation in the Phase 1b Dose-Finding Portion of 
Part 1 ............................................................................................................................. 36 
Figure 6-3 
Study Schema: Part 2 .................................................................................................... 38 
 


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2. 
LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
ADR 
adverse drug reaction 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUCEDC 
area under the concentration-time curve from predose to end of cycle 
AUCNadir 
area under the concentration-time curve from predose to nadir  
AUCNEDC 
area under the concentration-time curve from nadir to end of cycle 
BCRP 
breast cancer resistance protein  
BED 
biologically effective dose 
β-hCG 
beta human chorionic gonadotropin  
bpm 
beats per minute 
BSA 
body surface area 
BSEP 
bile salt export pump   
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CDK2/4/6 
cyclin-dependent kinase 2/4/6 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum concentration 
CR 
complete response 
CT 
computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
D5W 
dextrose 5% in water 
DDI 
drug-drug interaction 
DLT 
dose-limiting toxicity 


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Abbreviation 
Definition 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic case report form 
EEG 
electroencephalogram 
EOI 
end of infusion 
E/P 
etoposide and carboplatin 
E/P therapy 
etoposide and carboplatin on Day 1 and etoposide on Days 2 and 3 of 21-day cycles 
ESA 
erythropoietin stimulating agent 
FACT 
Functional Assessment of Cancer Therapy quality of life instrument 
FACT-An 
Functional Assessment of Cancer Therapy –Anemia quality of life instrument 
FACT-L 
Functional Assessment of Cancer Therapy –Lung quality of life instrument 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FDG-PET 
positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose 
G1 
gap 1 phase of the cell cycle 
G2 
gap 2 phase of the cell cycle 
G1T28 
formerly G1T28-1 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GFR 
glomerular filtration rate 
GLP 
Good Laboratory Practice 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
γH2AX 
phosphorylated histone H2AX  
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HSPC 
hematopoietic stem and progenitor cell 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICH 
International Conference on Harmonization 
IRB 
institutional review board 
IV 
intravenous 
IWRS 
interactive web-response system 
LD 
longest diameter 


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Abbreviation 
Definition 
LDH 
lactate dehydrogenase 
LS 
least square 
M 
mitosis phase of cell cycle 
MATE1 or 2-K 
multidrug and toxin extrusion 1 or 2-K  
MDR1 
p-glycoprotein  
MedDRA 
MHRA 
Medical Dictionary for Regulatory Activities 
Medicines and Healthcare Products Regulatory Agency 
MRI 
magnetic resonance imaging 
MRP1 or 2 
multidrug resistance protein 1 or 2 
NCI 
National Cancer Institute 
NCI-H69 
human small cell lung cancer cell line 
NE 
not evaluable 
NYHA 
New York Heart Association 
OAT1 or 3 
organic anion transporter 1 or 3  
OATP1B1 or 1B3 
organic anion transporting polypeptide 1B1 or 1B3   
OCT1 or 2  
organic cation transporter 1 or 2 
PCI 
prophylactic cranial irradiation 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PK/PD 
pharmacokinetic/pharmacodynamic 
PP 
per protocol 
PR 
partial response 
PRO 
patient-reported outcome 
QOL 
quality of life 
Rb 
retinoblastoma protein 
RB-1 
retinoblastoma gene 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors  
RH 
relative humidity 
RNA 
ribonucleic acid 
RNASeq 
RNA sequencing  
S 
synthesis phase of cell cycle in which DNA is replicated 
SAE 
serious adverse event 
SAP 
statistical analysis plan 


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Abbreviation 
Definition 
SCLC 
small cell lung cancer 
SD 
stable disease 
SMC 
safety monitoring committee 
SOP 
standard operating procedure 
t1/2 
terminal half-life 
Tmax 
time to reach Cmax 
TP53 
tumor protein 53 
UGT1A1 
uridine disphosphate glucuronosyltransferase 1 family, polypeptide A1 
ULN 
upper limit of normal 
Vz 
volume of distribution in the terminal elimination phase 
WBC 
white blood cell 
WHO 
World Health Organization 
 


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3. 
SYNOPSIS 
Title 
Phase 1b/2a Safety and Pharmacokinetic Study of G1T28 in Patients 
with Extensive-Stage Small Cell Lung Cancer (SCLC) Receiving 
Etoposide and Carboplatin Chemotherapy 
Study Rationale 
Chemotherapy-induced myelosuppression is a significant issue in 
cancer treatment, including treatment of SCLC. G1T28 (formerly 
G1T28-1) is a highly potent and selective cyclin-dependent kinase 4/6 
(CDK4/6) inhibitor that causes a transient and reversible gap 1 phase 
(G1) cell cycle arrest of hematopoietic stem and progenitor cells 
(HSPCs) within the bone marrow, thus protecting their 
deoxyribonucleic acid (DNA) from damage by coadministered 
chemotherapy and preserving long-term function. In animal studies, 
administration of G1T28 just prior to dose(s) of 5-fluorouracil (5-FU) 
resulted in a more rapid recovery of all hematopoietic lineages. This 
effect persisted following administration of multiple cycles of 
chemotherapy. Bone marrow obtained from mice that received 
4 cycles of G1T28 administered prior to every dose of 5-FU was 
more robust at hematopoietic reconstitution of lethally irradiated mice 
following bone marrow transplantation compared with bone marrow 
obtained from mice that received 4 cycles of 5-FU alone, suggesting 
that G1T28 administered with chemotherapy can preserve stem cell 
function.  
The Phase 1a, first-in-human Study G1T28-1-01 demonstrated that 
G1T28 was well tolerated following administration of a single 
intravenous (IV) dose. The pharmacokinetics (PK) of G1T28 suggests 
that drug accumulation following repeated administration is unlikely 
to occur. Based on PK and pharmacodynamic parameters from the 
Phase 1a study and a preclinical PK/pharmacodynamic (PK/PD) 
model, a biologically effective dose (BED) of 192 mg/m2 of G1T28 
was identified. Twenty-four hours following administration of the 
BED, a significant decrease was noted in the number of bone marrow 
HSPCs in the synthesis (S)/gap 2 (G2)/mitosis (M) phases of the cell 
cycle (ie, an increase in the proportion of cells in G1 arrest), which 
persisted at 32 hours. Thus, dosing of G1T28 200 mg/m2 (rounded up 
from the BED of 192 mg/m2) prior to the administration of etoposide 
and carboplatin on Day 1 and administration of etoposide on Days 2 
and 3 of 21-day cycles (hereafter referred to as E/P therapy) should 
maintain the bone marrow HSPCs in G1 arrest during and for several 
half-lives after chemotherapy administration, thus protecting their 
DNA from cytotoxic damage. The goals of this study are to assess the 
safety and tolerability of combining G1T28 with E/P therapy and to 
evaluate the effect of G1T28 on chemotherapy-induced 
myelosuppression. 
Clinical Phase 
1b/2a 
Indication 
Reduction of chemotherapy-induced myelosuppression 


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Objectives 
 
Phase 1b 
Dose-
Finding 
Portion of 
Part 1 
Phase 2a 
Expansion 
Portion of 
Part 1 
Phase 2a 
Part 2 
Primary Objectives 
Assess the DLTs and define the 
Phase 2 dose of G1T28 
administered with E/P therapy 
X 
 
 
Assess the safety and 
tolerability of G1T28 
administered with E/P therapy 
X  
X 
X 
Secondary Objectives 
Assess the PK profile of G1T28 
X 
 
 
Assess the PK profile of 
etoposide and carboplatin when 
administered with G1T28 
X 
 
 
Assess the hematologic profile 
(kinetics and 
incidence/duration/frequency of 
toxicities) of G1T28 
administered with E/P therapy 
X  
 
X 
X 
Assess the incidence of febrile 
neutropenia 
X 
X 
X 
Assess the incidence of 
infections 
X 
X 
X 
Assess the utilization of RBC 
and platelet transfusions 
X 
X 
X 
Assess the utilization of 
hematopoietic growth factors  
X 
X 
X 
Assess the utilization of 
systemic antibiotics 
X 
X 
X 
Assess the incidence of 
chemotherapy dose reductions 
and dose interruptions overall 
X 
X 
X 
Assess the incidence of Grade 2 
or greater nephrotoxicity  
X 
X 
X 
Assess tumor response based on 
RECIST, Version 1.1 
X 
X 
X 
Assess PFS and overall survival 
X 
X 
X 
Exploratory Objectives 
Assess the incidence of 
mucositis 
X 
X 
X 


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Phase 1b 
Dose-
Finding 
Portion of 
Part 1 
Phase 2a 
Expansion 
Portion of 
Part 1 
Phase 2a 
Part 2 
Assess the incidence of 
alopecia 
X 
X 
X 
Assess the incidence of fatigue 
X 
X 
X 
Assess patient-reported QOL 
X 
X 
X 
Assess immunologic markers 
 
 
X 
DLT = dose-limiting toxicity; E/P therapy = etoposide + carboplatin on Day 1 and 
etoposide on Days 2 and 3 of 21-day cycles; PFS = progression-free survival; 
PK = pharmacokinetic; QOL = quality of life; RBC = red blood cell; 
RECIST = Response Evaluation Criteria in Solid Tumors 
Study Design 
This is a randomized, double-blind, placebo-controlled, multicenter 
Phase 1b/2a study of the safety and PK of G1T28 in combination with 
E/P therapy for patients with newly diagnosed extensive-stage SCLC. 
The study consists of 2 parts: Part 1 will be a limited Phase 1b, 
open-label, dose-finding portion followed by a Phase 2a, open-label, 
expansion portion in up to 18 patients at the selected dose to be used 
in Part 2. Prior to initiating Part 2, up to a total of 24 patients will be 
enrolled at the chosen Part 2 dose (6 patients in the Phase 1b 
dose-finding portion of Part 1 and up to 18 patients in the Phase 2a 
expansion portion of Part 1). Part 2 will consist of a randomized, 
double-blind cohort (70 patients will be randomly assigned to G1T28 
administered IV with E/P therapy or placebo administered IV with 
E/P therapy). All 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 first dose with study treatment 
and completes at the Post-Treatment Visit.  
Part 1 
The goal of the Phase 1b dose-finding portion of Part 1 is to assess 
the safety, including dose-limiting toxicities (DLTs), and PK of 
G1T28 administered at a starting dose of 200 mg/m2 (derived from 
Study G1T28-1-01, a Phase 1a, safety, PK, and pharmacodynamic 
study of G1T28 in healthy male and female patients) on Days 1 to 3 
of E/P therapy.  
The goal of the Phase 2a expansion cohort of Part 1 is to obtain 
additional safety and efficacy data for G1T28 in combination with 
E/P to inform further development in newly diagnosed 
extensive-stage SCLC. 
Six patients will initially be enrolled in the Phase 1b dose-finding 
portion of Part 1. Depending on the evaluation of DLTs and PK 
parameters from these initial patients in Cycle 1, additional cohorts of 
6 patients may be enrolled at higher or lower doses. The PK profile of 
G1T28 is well established in healthy subjects, with good estimates of 
key parameters such as maximum concentration (Cmax), area under the 
concentration-time curve (AUC), and Clearance (CL). In addition, the 


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intersubject variability in these PK parameters is low (see 
Section 4.2). Therefore, for the initial cohort of 6 patients treated with 
200 mg/m2, the target AUC0-24.5h is 3100 h•ng/mL. If the mean 
AUC0-24.5h is not within 20% of this target (AUC 2480 to 
3720 h•ng/mL), the dose of G1T28 will be adjusted in the next cohort 
of 6 patients to achieve a mean AUC0-24.5h of 3100 h•ng/mL. Any 
available PK data from additional cohort(s) of the Phase 1b dose 
finding portion of Part 1 may be utilized for modifying the G1T28 
dose (if required). If the G1T28 dose level for a subsequent cohort 
requires escalation, the increase will not exceed 30% from the 
previous dose level.  The magnitude of the dose modification is based 
upon the fact that G1T28 displays linear PK over the dose range 
studied to date. The adjusted dose, if necessary, will be tested in 
6 additional patients enrolled in the Phase 1b dose-finding portion of 
Part 1, and up to 18 patients will be enrolled at the chosen Part 2 dose 
in the Phase 2a expansion portion of Part 1, prior to initiating the 
randomized part (Part 2) of the study.    
All dose escalation/de-escalation decisions will be based on Cycle 1 
safety data from all patients enrolled into the cohort and available PK 
data, which will be reviewed by a safety monitoring committee 
(SMC) comprised of the sponsor, medical monitor, and the principal 
investigator(s) to determine the next dose level. If the G1T28 dose 
level for a subsequent cohort is adjusted by the SMC, the SMC may 
also recommend that all patients currently receiving G1T28 in 
combination with E/P therapy should have their G1T28 dose adjusted 
accordingly, starting with their next scheduled cycle. Additional 
cohorts for the Phase 1b dose-finding portion of Part 1 will be 
considered based on the review of safety and available PK data by the 
SMC. The dose for Part 2 will be obtained by utilizing all available 
safety and available PK data from patients enrolled in the Phase 1b 
dose-finding portion of Part 1. Once the dose for Part 2 has been 
established, additional patients will be enrolled at the selected Part 2 
dose in a Phase 2a expansion cohort in Part 1 until up to 24 patients in 
total have been enrolled at that dose. The Phase 2a expansion cohort 
in Part 1 will complete enrollment before enrollment to Part 2 of the 
study commences.  
Each patient will be evaluated for toxicity during each cycle. The 
toxicity of G1T28 administered IV with E/P therapy will be assessed 
by the investigators using National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.03. 
If there is ≤ 1 dose-limiting toxicity (as defined below) in any of the 
first cohort of patients (6 patients) during Cycle 1 of the Phase 1b 
dose-finding portion of Part 1, and the target PK parameters are 
achieved, then the dose-finding portion of Part 1will end and 
subsequent patients will be enrolled into the Phase 2a expansion 
cohort, utilizing a dose of G1T28 200 mg/m2 in combination with 
E/P therapy. If an additional cohort(s) of 6 patients is enrolled in the 
Phase 1b dose-finding portion of Part 1, then the dose for Part 2 will 
be defined following evaluation of safety and available PK data from 
the additional cohort(s) of patients and enrollment into the Phase 2a 


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expansion cohort will commence at that dose.  
Dose-limiting toxicities (applicable to Cycle 1 of the Phase 1b 
dose-finding portion of Part 1) are drug-related toxicities defined as 
follows: 
• 
Absolute neutrophil count (ANC) < 0.5 × 109/L lasting for 
≥ 7 days 
• 
≥ Grade 3 neutropenic infection/febrile neutropenia 
• 
Grade 4 thrombocytopenia or ≥ Grade 3 thrombocytopenia 
with bleeding 
• 
Unable to start next cycle of chemotherapy due to lack of 
recovery to an ANC ≥ 1.5 × 109/L and platelet count 
≥ 100 × 109/L 
• 
≥ Grade 3 nonhematologic toxicity (nausea, vomiting, and 
diarrhea failing maximal medical management; fatigue 
lasting for > 72 hours) 
Toxicities not clearly related to etoposide/carboplatin (E/P) therapy 
will also be considered for the purposes of determining DLTs. 
Part 2 
In Part 2, eligible patients will be randomized (1:1 fashion) to G1T28 
or placebo administered IV once daily on Days 1 to 3 of E/P therapy. 
Randomization will be stratified by Eastern Cooperative Oncology 
Group (ECOG) performance status (0 to 1 versus 2). There will be no 
intrapatient dose modifications of G1T28 in Part 2 of the study. 
Criteria for Subsequent Cycles and Study Duration 
In both parts of the study, study drug administration will continue 
until disease progression per Response Evaluation Criteria in Solid 
Tumors (RECIST), Version 1.1, unacceptable toxicity, withdrawal of 
consent, or discontinuation by investigator (eg, after completing 
6 cycles), whichever occurs first. Treatment cycles will occur 
consecutively without interruption, except when necessary to manage 
toxicities or for administrative reasons as described below. 
In order to start Cycle 2 and subsequent cycles as scheduled, patients 
must have an ANC ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and 
nonhematologic drug-related toxicities (except alopecia) must be 
≤ Grade 1 or have returned to baseline. A delay of up to 2 weeks is 
permitted to allow recovery from any toxicity in order to meet the 
continuation criteria for organ function. If patients meet the criteria 
for starting the subsequent cycle as stated in Section 6.1.3, a delay of 
up to 1 week is permitted for administrative reasons (eg, holiday, 
vacation, etc.). If the subsequent cycle is delayed, the patient should 
still complete the clinical laboratory assessments and the FACT-L and 
FACT-An questionnaires on the scheduled Day 1, as well as on the 
actual first dosing day of the next cycle. A patient will be 
discontinued from the study if recovery from any toxicity, in order to 
meet the continuation criteria for organ function, and any delay for 


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administrative reasons requires a total delay of > 2 weeks. 
After discontinuation of study drug, patients should be strongly 
encouraged to complete all scheduled assessments through the end of 
their current 21-day treatment cycle, including the patient-reported 
outcome (PRO) scales; CBC assessment on Day 22; the 
Post-Treatment Visit; and the Survival Follow-up Phase of the study, 
which is to continue until at least 50% of the patients randomized to 
Part 2 of the study have died. The G1T28-02 study will be completed 
when the Survival Follow-up Phase has been completed, or upon 
sponsor termination of the study. 
Safety Assessments 
Safety assessments will include monitoring of adverse events (AEs), 
vital signs measurements, physical examinations, electrocardiograms 
(ECGs), clinical laboratory studies, infusion-related reactions, tumor 
response based on RECIST, Version 1.1, progression-free survival 
(PFS), and overall survival. Safety surveillance reporting of AEs and 
concomitant medications commences at the time that informed 
consent is obtained and continues through the Post-Treatment Visit. 
An independent data monitoring committee (DMC) will monitor 
accumulating safety and disposition data approximately every 
4 months during the Treatment Phase of Part 2 of the study, 
depending upon the enrollment rate. Details of the DMC, including 
objectives, composition, scope, and frequency, will be described in a 
DMC charter. 
Tumor Assessment 
For tumor assessment, all sites of disease should be assessed 
radiologically by computed tomography (CT) or magnetic resonance 
imaging (MRI) at screening and after every even cycle, until the 
occurrence of disease progression. CT or MRI scans obtained as 
standard of care prior to informed consent will not need to be 
repeated if performed within 14 days prior to dosing. Assessments 
should be performed within 7 days of starting the subsequent cycle.  
Additional scans may be obtained at the discretion of the investigator, 
if clinically indicated. If a patient shows a radiological response 
(complete response [CR] or partial response [PR]), a confirmatory 
radiological assessment will be performed at least 4 weeks after the 
response was first noted. For patients who have a confirmed CR, it is 
strongly recommended that they receive prophylactic cranial 
irradiation (PCI) after completion of chemotherapy. Patients with a 
confirmed PR should also consider PCI after completion of 
chemotherapy based on the investigator’s judgment. For those 
patients who have not progressed at the time of study drug 
discontinuation, tumor assessments, including all sites of disease, will 
be assessed radiologically by CT or MRI, as performed at screening, 
every 2 months (approximately 60 ± 7 days) until the occurrence of 
progressive disease or study completion. The same method of 
assessment (CT or MRI) should be used to characterize tumors at 
screening and at all follow-up assessments. If positron emission 
tomography (PET) is used, it should also be accompanied by spiral 


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CT or MRI.    
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 (eg, after 
completing 6 cycles), whichever occurs first. 
Study Duration 
The total study duration is at least 29 months.  
Part 1 is expected to be approximately 18 months, assuming 
12 months of accrual, 2 weeks for screening, 4.5 months of treatment 
(assuming 6 cycles), and 1 month of safety follow-up. 
Part 2 will begin after the Part 2 dose is identified from the Phase 1b 
dose-finding portion of Part 1 and the Phase 2a expansion of Part 1 
has completed enrollment, which is expected to occur approximately 
12 months after Part 1 begins. Part 2 is expected to be approximately 
17 months, assuming 11 months of accrual, 2 weeks of screening, 
4.5 months of treatment (assuming 6 cycles), and 1 month of safety 
follow-up. 
The Survival Follow-up Phase will continue until at least 50% of the 
randomized patients in Part 2 have died. 
Approximate Number of 
Patients 
Overall, up to 110 patients will be enrolled in the study. In Part 1, 
approximately 40 patients will be enrolled, assuming up to 3 cohorts.  
Cohorts will consist of 6 patients each in the Phase 1b dose-finding 
portion of Part 1 and up to 18 patients in the Phase 2a expansion 
portion of Part 1 at the selected dose to be used in Part 2. Additional 
patients may be enrolled in the Phase 1b dose-finding portion of 
Part 1 if more than 1 cohort is enrolled. In Part 2, 70 patients will be 
randomly assigned to 1 of 2 groups as follows: G1T28 administered 
IV with E/P therapy (Group 1) or placebo administered IV with 
E/P therapy (Group 2). 
Number of Study Centers 
Up to 80 centers in North America and Europe 
Diagnosis and Main Criteria 
for Inclusion 
For a patient to be eligible for participation in this study, all of the 
following criteria must apply. 
1. 
Age ≥ 18 years  
2. 
Unequivocally confirmed diagnosis of SCLC by histology or 
cytology, preferably including the presence of 
neuroendocrine features by immunohistochemistry 
3. 
Extensive-stage disease 
4. 
At least 1 target lesion that is unirradiated and measurable by 
RECIST, Version 1.1 (Eisenhauer 2009) 
5. 
Hemoglobin ≥ 9.0 g/dL 
6. 
Absolute neutrophil count ≥ 1.5 × 109/L 
7. 
Platelet count ≥ 100 × 109/L 
8. 
Creatinine ≤ 1.5 mg/dL OR glomerular filtration rate (GFR) 
of ≥ 60 mL/minute (by Cockcroft-Gault formula [Cockcroft 


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and Gault 1976]); creatinine clearance calculated from an 
isotopic method or 24-hour urine collection may be used 
instead of an estimated GFR by the Cockcroft-Gault formula  
9. 
Total bilirubin ≤ 1.5 × upper limit of normal (ULN) 
10. Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 2.5 × ULN; ≤ 5 × ULN in the 
presence of liver metastases  
11. Serum albumin ≥ 3 g/dL 
12. Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 to 2 
13. Predicted life expectancy of ≥ 3 months 
14. Contraception: 
a. For females: All females of childbearing potential must 
have a negative serum beta human chorionic 
gonadotropin (β-hCG) test result at screening and at 
baseline. Females must be either postmenopausal, 
surgically sterile, or using an acceptable method of 
contraception. Acceptable surgical sterilization 
techniques are hysterectomy, bilateral tubal ligation with 
surgery at least 6 months prior to dosing, and bilateral 
oophorectomy, with surgery at least 2 months prior to 
dosing. Acceptable methods of contraception are an 
intrauterine device, contraceptive implant, oral 
contraceptive (stable dose of the same hormonal 
contraceptive product for at least 3 months prior to 
dosing), a vasectomized partner, and a barrier method 
(condom or diaphragm) during the study and for 3 months 
after discontinuation of treatment 
b. For males: Patients with female partner of childbearing 
potential must agree to use a highly effective form of 
birth control, which entails the use of oral, injected, or 
implanted hormonal methods of contraception or an 
intrauterine device/system by the female partner, in 
combination with a barrier method (eg, condom, 
diaphragm, cervical cap) during the study and for 
3 months after discontinuation of treatment, and will also 
refrain from sperm donation for 3 months following 
completion of the study 
15. Able to understand and sign an informed consent 
Criteria for Exclusion 
A patient will not be eligible for participation in this study if any of 
the following criteria apply. 
1. 
Prior chemotherapy for limited or extensive-stage SCLC 
2. 
Presence of symptomatic brain metastases requiring 


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immediate treatment with radiation therapy or steroids 
3. 
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 
4. 
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) 
5. 
Known history of stroke or cerebrovascular accident within 
6 months prior to enrollment 
6. 
Serious active infection 
7. 
Psychiatric illness/social situations that would limit study 
compliance 
8. 
Other uncontrolled serious chronic disease or conditions that 
in the investigator’s opinion could affect compliance or 
follow-up in the protocol 
9. 
Known human immunodeficiency virus (HIV), known 
hepatitis B virus (HBV), or known hepatitis C virus (HCV) 
positive that is symptomatic or requiring active therapy 
10. Concurrent radiotherapy to any site or radiotherapy within 
2 weeks prior to enrollment or previous radiotherapy to the 
target lesion sites (the sites that are to be followed for 
determination of a response) 
11. Receipt of any investigational medication within 4 weeks 
prior to enrollment 
12. Hypersensitivity to any of the components of the formulation 
of etoposide or etoposide phosphate 
13. Hypersensitivity to cisplatin or other platinum-containing 
compounds, or mannitol  
14. Legal incapacity or limited legal capacity  
15. Pregnant or lactating women 
Chemotherapy Treatment 
Carboplatin dose calculated using the Calvert formula with a target 
AUC = 5 (maximum dose of 750 mg) administered IV over 
30 minutes on Day 1 and 100 mg/m2 etoposide administered IV over 
60 minutes daily on Days 1, 2, and 3 of each 21-day cycle 
Test Articles Dosage and 
Administration 
A starting dose of G1T28 200 mg/m2 in 250 mL of dextrose 5% in 
water (D5W) or in sodium chloride solution 0.9% administered as an 
IV infusion over 30 minutes once daily on Days 1 to 3 of each 21-day 
cycle prior to the dose(s) of chemotherapy 


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Comparator Dosage and 
Administration 
Placebo formulation of 250 mL of D5W or sodium chloride solution 
0.9% administered as an IV infusion over 30 minutes once daily on 
Days 1 to 3 of each 21-day cycle prior to the dose(s) of chemotherapy  
Efficacy Evaluation 
Efficacy evaluation will be based on the following: kinetics of 
changes in complete blood counts (CBCs); hematologic toxicities, 
including febrile neutropenia and infections; red blood cell (RBC) and 
platelet transfusions; hematopoietic growth factor utilization; 
systemic antibiotic use; chemotherapy dose reductions and dose 
interruptions; alopecia; mucositis; nephrotoxicity; fatigue; and PROs 
using the Functional Assessment of Cancer Therapy (FACT) quality 
of life (QOL) instruments for lung cancer (FACT-L) and anemia 
(FACT-An). 
Safety Evaluation 
Safety will be assessed by evaluation of AEs, physical examinations, 
vital sign measurements, clinical laboratory data, infusion-related 
reactions, ECGs, tumor response based on RECIST, Version 1.1, 
PFS, and overall survival.  
Pharmacokinetics Evaluation 
In the Phase 1b dose-finding portion of Part 1 of the study, blood 
samples will be collected for the measurement of G1T28, etoposide, 
and carboplatin concentrations in plasma as described below.  
Phase 1b dose-finding portion of Part 1: Cycle 1 Day 1 
Blood samples will be collected at the following time points relative 
to the start of G1T28 infusion on Cycle 1 Day 1 for all Cohort 1 
patients enrolled in the Phase 1b dose-finding portion of Part 1 of the 
study: predose (0 hour; prior to dosing of G1T28) and at 0.5 (end of 
infusion [EOI] of G1T28), 1 (EOI of carboplatin), 1.5, 2 (EOI of 
etoposide), 2.5, 3, 4.5, 6.5, 8.5 (this time point  may be optional if 
approved by sponsor in advance), and 24.5 (prior to G1T28 dose on 
Day 2) hours. The EOI sample for G1T28 should be drawn 2 to 
5 minutes prior to the EOI. Collection of PK blood samples from 
patients enrolled in additional cohorts of the Phase 1b dose-finding 
portion of Part 1 is optional. 
Phase 1b dose-finding portion of Part 1: Cycle 1 Day 3 
Blood samples will be collected at the following time points relative 
to the start of G1T28 infusion on Cycle 1 Day 3 for all Cohort 1 
patients enrolled in the Phase 1b dose-finding portion of Part 1 of the 
study: predose (0 hour; prior to dosing of G1T28) and at 0.5 (EOI of 
G1T28), 1, 1.5 (EOI of etoposide), 2, 2.5, 3.5, 4.5, 6.5, 8.5 (this time 
point may be optional if approved by sponsor in advance), and 24.5 
hours. The EOI sample for G1T28 should be drawn 2 to 5 minutes 
prior to the EOI. Collection of PK blood samples from patients 
enrolled in additional cohorts of the Phase 1b dose-finding portion of 
Part 1 is optional. 
Pharmacokinetic parameters (eg, Cmax, time to reach Cmax [Tmax], 
AUC0-t, AUC0-∞, terminal half-life [t1/2], volume of distribution in the 
terminal elimination phase [Vz], and CL) will be derived from 
G1T28, etoposide, and carboplatin plasma concentration-time data. 


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Pharmacokinetic samples may also be obtained from additional 
patients in the Phase 2a expansion cohort of Part 1 and Part 2 
depending on the outcome of initial Phase 1b PK analysis. 
Patient-Reported Outcomes 
Functional Assessment of Cancer Therapy QOL instruments for lung 
cancer (FACT-L) and anemia (FACT-An) 
Immunologic Marker 
Assessment 
In Part 2 of the study, peripheral blood samples will be collected at 
predose on Day 1 of Cycles 1, 3, and 5; at the Post-Treatment Visit; 
and at 60 days after the Post-Treatment Visit. 
Statistical Analysis 
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 G1T28 + 
E/P therapy minus Placebo + E/P therapy. Select 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 means, medians, standard deviations, and 
minimum and maximum values. The descriptive summaries of time to 
event data will include median, twenty-fifth and seventy-fifth 
percentiles, and standard error. All data will be listed for all patients. 
This study is descriptive in nature, and no formal hypothesis testing 
will be performed across treatment groups. All confidence intervals 
(CIs) will be 95%, unless stated otherwise. 
A DMC will review accumulating safety and disposition data during 
the Treatment Phase for patients randomized in Part 2. The final 
analysis will be performed after all patients have completed the 
Post-Treatment Visit. A supplemental analysis including the 
cumulative data collected during the Survival Follow-up Phase will 
be completed at the end of study. 
The full analysis set (FAS) includes all patients who received at least 
1 dose of study drug and will be the primary population for efficacy 
and exploratory endpoints. Full analysis set analyses will be 
conducted on the basis of the assigned treatment. The safety 
population includes all patients who received at least 1 dose of study 
drug and will be the population used for the analysis of safety 
endpoints. The safety population will be conducted on the basis of the 
actual treatment received. A per-protocol (PP) subset may also be 
used to analyze select endpoints and will be based on study drug 
exposure (compliance and/or time on study drug) and major protocol 
deviations. The PK analysis set will include all dosed patients in the 
Phase 1b dose-finding portion of Part 1 with evaluable PK data. 
Summaries of efficacy will be performed using the FAS on 
hematologic kinetics, hematologic toxicity, infections, growth factor 
and antibiotic use, transfusions, chemotherapy exposure, and 
patient-reported QOL scores. Select summaries will also be repeated 
in the PP analysis set. Unless noted otherwise, hematologic endpoints 
will be summarized separately by each parameter type (ie, ANC, 


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lymphocytes, etc.). Analyses comparing treatment groups for Part 2 
will adjust for baseline ECOG and other relevant parameters. Event 
rates will be calculated based on cumulative E/P exposure to account 
for potential differences in E/P exposure across treatment arms. 
Summaries of safety data will be performed using the safety 
population. Adverse event data will be coded to system organ class 
and preferred term using the Medical Dictionary for Regulatory 
Activities (MedDRA; Version 17.1 or later). The number and 
percentage of patients experiencing any treatment-emergent AE, 
overall, and by system organ class and preferred term will be 
tabulated. The incidence rates adjusted by cumulative exposure will 
also be presented overall and by cycle. Absolute values and changes 
from baseline in vital signs, ECG readings, and hematology and 
clinical chemistry parameters will be tabulated at each visit during the 
Treatment Phase. Toxicities for clinical labs will be characterized 
according to the CTCAE, Version 4.03. Shifts in toxicity grades from 
baseline to each visit will be summarized. Overall disease responses 
as determined by RECIST, Version 1.1 will be summarized by 
response level at each visit and best overall response. 
Progression-free survival and overall survival will be summarized 
using Kaplan-Meier methods. 
Blood samples will be collected in the Phase 1b dose-finding portion 
of Part 1 of the study for the determination of G1T28, etoposide, and 
carboplatin plasma concentrations. Plasma PK parameters will be 
calculated for each analyte, when possible, including Cmax, Tmax, 
AUC0-t, AUC0-∞, t1/2, Vz, and CL. Pharmacokinetic results will be 
analyzed and reported for the PK analysis set, separately for each 
analyte. Plasma concentration-time data will be tabulated 
descriptively and graphed for each blood sampling day. 
Pharmacokinetic parameters will be calculated using 
noncompartmental methods based on the plasma concentration-time 
data. Pharmacokinetic parameters will be summarized descriptively 
by visit and analyte. If applicable, G1T28 PK data will also be 
summarized by dose level. 
Rationale for Number of 
Patients 
The sample size for this study is determined by clinical rather than 
statistical considerations. Up to 40 patients (open-label, dose-finding 
cohort[s] and an open-label, expansion cohort) will be enrolled in 
Part 1 of the study and 70 patients will be enrolled in Part 2 of the 
study (randomized). 


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4. 
INTRODUCTION 
4.1. 
Background 
Chemotherapy-induced myelosuppression continues to represent the major dose-limiting 
toxicity (DLT) of cytotoxic chemotherapy, including the etoposide and platinum (cisplatin or 
carboplatin) combination used to treat extensive-stage small cell lung cancer (SCLC) 
(Schmittel 2006; Socinski 2009). Whether using cisplatin or carboplatin, the combination of 
a platinum agent with etoposide results in significant myelosuppression (neutropenia 47% to 
92%, leukopenia 8% to 66%, thrombocytopenia 10% to 46%, and anemia 7% to 34%) 
(Eckardt 2006; Noda 2002; Hanna 2006; Socinski 2009; Hermes 2008; Schmittel 2011). 
Myelosuppression is the source of many of the important side effects of cancer treatment, 
such as infection, sepsis, bleeding, and fatigue, leading to the need for hospitalizations, 
hematopoietic growth factor support, and transfusions (red blood cells [RBCs] and/or 
platelets). Moreover, clinical concerns raised by myelosuppression commonly lead to 
chemotherapy dose reductions and limit therapeutic dose intensity. 
G1T28 (formerly G1T28-1) is a highly potent and selective, reversible, cyclin-dependent 
kinase 4/6 (CDK4/6) inhibitor that transiently induces gap 1 (G1) phase (resting phase in the 
cell cycle in which cells exist in a quiescent state) cell cycle arrest of hematopoietic stem and 
progenitor cells (HSPCs) in the bone marrow. These cells are dependent upon CDK4/6 for 
proliferation and enter the G1 phase of the cell cycle upon exposure to G1T28. When the 
HSPCs are transiently arrested in the G1 phase of the cell cycle, they are more resistant to the 
deoxyribonucleic acid (DNA) damaging effects of chemotherapy, thus potentially reducing 
subsequent myelosuppression. The initial indication for intravenous (IV) G1T28 is the 
reduction of chemotherapy-induced myelosuppression. 
The principal component of this therapeutic approach is to transiently arrest HSPCs in the 
G1 phase of the cell cycle while chemotherapy is administered. It is imperative that this 
therapeutic approach provides selective bone marrow protection without antagonizing the 
tumor efficacy of chemotherapy. To ensure this second feature, patients are required to have 
CDK4/6-indpendent tumors. The downstream target of CDK4/6 is the retinoblastoma (Rb) 
protein, which is phosphorylated upon CDK4/6 activation, allowing the cell to enter into the 
S phase of the cell cycle (synthesis phase of cell cycle in which DNA is replicated). In order 
to promote G1 cell cycle arrest by utilizing a CDK4/6 inhibitor, a functional Rb protein is 
required. For SCLC, historical reports have consistently shown the most prevalent 
inactivated tumor suppressor genes are tumor protein 53 (TP53) and retinoblastoma 1 (RB-1) 
(D’Amico 1992; Heighway 2004; Yuan 1999; Cagle 1997; Gouyer 1994), and it has been 
accepted that almost all cases of SCLC are functionally Rb null. In addition, 2 recent reports 
provided a detailed characterization of the genomic landscape of SCLC using next generation 
sequencing approaches, including full exome sequencing, transcriptome profiling by RNA 
sequencing (RNASeq), copy number analyses, and limited whole genome sequencing to 
identify translocations (Peifer 2012; Rudin 2012). These reports confirmed what had been 
previously proposed in studies that examined a smaller number of tumors, namely that 
concomitant inactivation of TP53 and RB-1 are driver mutations and occur nearly universally 
in SCLC. Consistent with these data, preclinical in vitro and in vivo studies have 
demonstrated that G1T28 exposure prior to chemotherapy does not diminish the effect of 


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chemotherapy in tumors that are RB-1 inactive, including SCLC. Therefore, as a result of 
near universal RB-1 inactivation, SCLC is inherently CDK4/6-independent, which should 
allow selective protection of the HSPCs but not the tumor from the effects of chemotherapy.  
4.2. 
Summary of Clinical Data 
A brief summary of the clinical data is provided in the following sections. Detailed 
information is presented in the G1T28 Investigator’s Brochure (IB). 
Study G1T28-1-01 was a Phase 1a, safety, PK, and pharmacodynamic study of G1T28.  
Forty-five healthy male and female subjects were enrolled into 7 dose cohorts where G1T28 
was administered IV as a 30-minute infusion (randomized, double-blind, placebo-controlled 
ascending doses of 6, 12, 24, 48, 96, or 192 mg/m2, and an open-label expanded 
pharmacodynamic cohort at 192 mg/m2). 
The most frequently (> 10% of subjects) reported adverse events (AEs) were the following: 
headache (17 subjects, 38%), nausea (10 subjects, 22%), pain in extremity (8 subjects, 18%), 
and procedural pain (7 subjects, 16%). The treatment-emergent AEs of headache and nausea 
occurred more frequently in the combined 192 mg/m2 dose group (14 events of headache 
reported by 13 subjects [72%] and 10 events of nausea reported by 9 subjects [50%]) than in 
the lower dose groups. Most treatment-emergent AEs were mild in intensity; 13 subjects 
experienced a total of 19 treatment-emergent AEs of moderate intensity. Four AEs of 
moderate intensity occurred in the 96 mg/m2 dose group (2 events of headache [possibly 
related], 1 event of back pain [unlikely related], and 1 event of nausea [possibly related]). 
Fifteen AEs of moderate intensity occurred in the combined 192 mg/m2 dose group (7 events 
of headache [all possibly related], 6 events of nausea [all possibly related], 1 event of 
procedural anxiety [not related], and 1 event of loss of appetite [possibly related]). No severe 
or life-threatening events were reported. There were no deaths, other serious adverse events 
(SAEs), or treatment-emergent AEs resulting in withdrawal from the study. All 
treatment-emergent AEs were transient and recovered/resolved by the end of the study. No 
significant changes were noted in 12-lead electrocardiograms (ECGs), vital signs, or 
laboratory values (including complete blood counts [CBCs]). 
Following a single 30-minute IV infusion of G1T28, the median time to reach the maximum 
concentration (Tmax) ranged between 0.25 and 0.47 hour after the start of infusion. The 
maximum concentration (Cmax) increased in a dose-proportional manner following a single 
30-minute IV infusion of G1T28 over the dose range of 6 to 192 mg/m2. Total systemic (area 
under the concentration-time curve [AUC]) exposure increased more than dose 
proportionally over the dose range of 6 to 192 mg/m2 of G1T28. The elimination kinetics of 
G1T28 appeared to follow a 3-compartment model. The geometric mean half-life (t1/2) was 
12.9 to 14.7 hours for the 48 to 192 mg/m2 dose levels. The interpatient variability (%CV) of 
the PK parameters at the 192 mg/m2 dose level was low (<15%). The PK of G1T28 suggests 
that drug accumulation following repeated administration is unlikely to occur. Urinary 
excretion appears to be a minor route of elimination for unchanged G1T28. 
G1T28 showed positive pharmacodynamic effects in 2 assays. Dose-dependent inhibition of 
ex vivo whole blood stimulation occurred following a single IV infusion of G1T28 at 96 and 
192 mg/m2 (maximum mean inhibition of 37.2% and 60%, respectively, occurred 4 hours 


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after the end of infusion). Lymphocyte proliferation started to recover 8 hours after the end of 
infusion, but inhibition of proliferation persisted until the last sampling time point of 
24 hours. Assessment of bone marrow 24 hours after administration of G1T28 at the 
biologically effective dose (BED) of 192 mg/m2 revealed a significant decrease in the 
number of HSPCs in the synthesis (S)/gap 2 (G2)/mitosis (M) phases of the cell cycle (ie, an 
increase in the proportion of cells in G1 arrest). This G1 arrest persisted in the different 
progenitor lineages 32 hours after dosing. However, no changes were noted in the peripheral 
blood counts, indicating that the bone marrow arrest is transient and reversible and is 
consistent with the effects seen in animals.  
4.3. 
Summary of Nonclinical Data 
A brief summary of the nonclinical data is provided in the following sections. Detailed 
information is presented in the G1T28 IB. 
4.3.1. 
Pharmacology Studies 
Through a structure-based design approach to optimize potency, selectivity, and drug 
metabolism and PK properties, G1 Therapeutics, Inc. identified G1T28 as a highly potent 
inhibitor of CDK4 and CDK6 (half maximal inhibitory concentration [IC50] values of 0.8 and 
6 nM, respectively) that is highly selective for CDK4 versus cyclin-dependent kinase 
2 (CDK2) (> 2000-fold selectivity). 
The G1T28-induced G1 arrest of HSPCs has been shown to be transient and readily 
reversible in both in vitro and in vivo models. In vivo analysis has demonstrated that 
coadministration of G1T28 with myelosuppressive chemotherapy leads to improved CBC 
recovery of all blood lineages and increased survival. In addition, administration of G1T28 
with every cycle of the highly myelosuppressive chemotherapy 5-fluorouracil (5-FU) for a 
total of 4 cycles demonstrated that the reduction in chemotherapy-induced myelosuppression 
persisted following Cycle 4. While the extent and duration of nadir in CBCs worsened after 
each cycle of 5-FU administered alone, coadministration of G1T28 with 5-FU ameliorated 
this worsening effect and the animals that received G1T28 + 5-FU demonstrated a faster rate 
of recovery of CBCs compared with the 5-FU alone group following Cycle 4. In accordance 
with the single-dose study, G1T28 administration with all cycles of 5-FU maintained the 
protective effect against 5-FU-induced DNA damage in HSPCs over multiple cycles, leading 
to an effect that persisted and was greater following multiple cycles of G1T28 + 5-FU 
compared with 5-FU alone. In addition, bone marrow obtained from mice that received 
4 cycles of G1T28 administered prior to every dose of 5-FU was more robust at 
hematopoietic reconstitution of lethally irradiated mice following bone marrow 
transplantation compared with bone marrow obtained from mice that received 4 cycles of 
5-FU alone, suggesting that G1T28 administered with chemotherapy can preserve stem cell 
function. 
Retinoblastoma is the direct downstream target of CDK4/6 and its expression is required for 
CDK4/6-dependent cells. Importantly, cancers that delete Rb do not require CDK4/6 activity 
for cell cycle progression (Fry 2004); therefore, loss of Rb is a hallmark identifier of 
CDK4/6 independence. Since inactivation of RB-1 is an obligate event in SCLC 
development (D’Amico 1992; Heighway 2004; Yuan 1999; Cagle 1997; Gouyer 1994, 


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Peifer 2012; Rudin 2012), this tumor type is highly resistant to CDK4/6 inhibitors and 
coadministration of CDK4/6 inhibitors with DNA damaging chemotherapeutic agents such as 
those used in SCLC are not expected to antagonize the efficacy of such agents. In vitro 
analysis has shown that RB-1 inactive cells are resistant to CDK4/6 inhibition and therefore 
are not protected from chemotherapy when cotreated with G1T28. To expand these findings 
in vivo, G1T28 was tested alone and in combination with topotecan or an etoposide and 
carboplatin (E/P) combination regimen in a cell-based xenograft SCLC model (H69) in 
immune-deficient mice. G1T28 administered alone or 30 minutes before E/P or topotecan 
was well tolerated, with no additive weight loss or toxicity. Single agent G1T28 was inactive 
towards NCI-H69 SCLC tumors and combination with an E/P regimen did not result in 
additive efficacy, nor did it antagonize the intended effects of E/P. Combination of G1T28 
and topotecan was superior to topotecan alone during dosing and the addition of G1T28 
extended the statistically significant (p < 0.05) antitumor effect of topotecan after dosing. 
Thus, G1T28 was well tolerated and did not antagonize the effects of chemotherapy in a 
CDK4/6-independent (RB-1 inactive) SCLC tumor model. 
4.3.2. 
Pharmacokinetic Studies 
Pharmacokinetic studies in rats and dogs showed that the relationship between dose level and 
plasma exposure to G1T28 was generally similar between males and females and did not 
change with repeated daily dosing. Exposure to G1T28 increased with dose level, but not 
always proportionally. Plasma half-life values for G1T28 after IV administration were 
approximately 4 hours in rats and dogs. 
In vitro analyses of direct and time-dependent inhibition suggest that drug interactions based 
on inhibition of cytochrome P40 (CYP)1A2-, 2B6-, 2C8-, 2C9-, 2C19-, and 2D6-mediated 
metabolic pathways are unlikely at concentrations of G1T28 below 100 µM (44,600 ng/ml). 
Drug interactions based on G1T28 mechanism-based inhibition of CYP3A4-mediated 
metabolic pathways are possible. Additionally, in vitro induction studies of the 3 major 
inducible CYP enzymes (CYP1A2, CYP3A4, and CYP2B6) in human hepatocytes suggest 
that G1T28-mediated induction is unlikely.   
While etoposide is a CYP3A4 substrate, there are no specific label warnings regarding 
coadministration with CYP3A4 inhibitors. This may in part be due to the relatively equal 
contributions of renal and hepatic clearance to the total clearance of etoposide. In addition, 
administration of oral ketoconazole, a potent CYP3A4 and uridine disphosphate 
glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) inhibitor, with oral etoposide 
for 3 of every 5-week cycles resulted in an increase of the median AUC of oral etoposide of 
only 20% and did not alter its toxicity profile (Yong 2007). In the present Study G1T28-02, 
IV G1T28 will be administered prior to IV etoposide on Days 1 to 3 of 21-day cycles in 
patients with adequate renal function. In the Phase 1b dose-finding portion of Part 1 of the 
study, PK of etoposide, carboplatin, and G1T28 will be assessed on Days 1 and 3 of the first 
cycle. In addition, frequent CBCs will be assessed. Since myelotoxicity is the major toxicity 
of etoposide, this will be monitored closely in this study.  
In vitro inhibition studies with membrane transporter model systems also suggest G1T28 is 
unlikely to cause a drug-drug interaction (DDI) based on inhibition of breast cancer 
resistance protein (BCRP)-, bile salt export pump (BSEP)-, organic anion transporter 


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1 (OAT1)-, organic anion transporter 3 (OAT3)-, organic anion transporting polypeptide 1B1 
(OATP1B1)-, p-glycoprotein (MDR1)-, multidrug resistance protein 1 (MRP1)-, multidrug 
resistance protein 2 (MRP2)-, organic cation transporter 1 (OCT1)-, or organic anion 
transporting polypeptide 1B3 (OATP1B3)-mediated transport. G1T28 is a potent inhibitor of 
multidrug and toxin extrusion 1 (MATE1), multidrug and toxin extrusion 2-K (MATE2-K), 
and organic cation transporter 2 (OCT2) (IC50 values were 0.175, 0.071, and 0.152 µM, 
respectively), and therefore, may be a cause of a DDI if coadministered with substrates of 
these transporters.      
Carboplatin has been reported (Yonezawa 2006) to not be a substrate for OCT2, MATE1, or 
MATE2. Etoposide has not been reported to be a substrate for any of these 3 transporters, 
and by structure is not expected to be a substrate. Based upon these data, a clinically 
significant alteration of carboplatin or etoposide PK due to G1T28 inhibition of OCT2, 
MATE1, or MATE2-K is not expected. 
4.3.3. 
Toxicity and Safety Studies 
The toxicity of IV and oral G1T28 was evaluated in single- and repeat-dose studies of up to 
14 days duration in rats and dogs and in a battery of in vitro genotoxicity studies. In addition, 
the compatibility of G1T28 clinical drug product with human blood was evaluated in vitro. 
For further information, please refer to the G1T28 IB. 
4.3.4. 
Potential Risks 
When administered IV daily for 7 days, G1T28 was tolerated in rats at up to 50 mg/kg 
(approximately 300 mg/m2) and in dogs at up to 15 mg/kg (approximately 300 mg/m2), with 
toxicity characterized chiefly by reduced hematopoiesis that involved all cell lineages and 
was a reflection of the drug’s intended pharmacodynamic activity. The magnitude and/or 
duration of effect differed among cell lineages, but were dose related in all lineages. Effects 
on hematopoiesis were readily monitored by peripheral blood cell counts and were reversible 
when dosing stopped. Clinically significant leukopenia occurred in rats and dogs given IV 
G1T28 for 7 days at ≥ 150 and 300 mg/m2, respectively, and it led to morbidity and mortality 
in dogs given daily doses for 6 days at 900 mg/m2. 
In addition to the intended effects on hematopoiesis, animal studies with G1T28 suggest that 
potential side effects in human patients might include the following: 
• Pulmonary macrophage accumulation: In rats, daily oral doses of G1T28 for 14 days at 
≥ 5 mg/kg (≥ 30 mg/m2) resulted in minimal to mild accumulation of foamy macrophages 
in alveoli. The magnitude of this finding increased with dose level, but it was not 
associated with any discernable change in the rate or character of respiration. 
Macrophage accumulation showed evidence of resolving within 3 weeks after dosing 
stopped. Pulmonary macrophage accumulation was also seen in dogs given daily IV 
doses of G1T28 by 30-minute infusion at 45 mg/kg (900 mg/m2) for 5 days, at which 
point dosing was stopped due to toxicity. The DLT in these dogs was considered to be 
severe immunocompromise secondary to inhibition of myelopoiesis and lymphopoiesis; 
ie, an extension of the primary pharmacodynamic activity of G1T28. 


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• Increased heart rate: In dogs, single IV doses of G1T28 at ≥ 15 mg/kg (≥ 300 mg/m2) 
produced increases in heart rate that were relatively mild (30 to 60 beats per minute 
[bpm]) and resolved within a few hours. 
• Effects on liver: Daily IV doses of G1T28 in rats at ≥ 10 mg/kg/day (≥ 60 mg/m2/day) 
and in dogs at ≥ 15 mg/kg/day (approximately 300 mg/m2/day) resulted in slightly 
increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
levels. Liver-related effects in both species were reversible within 2 weeks after the last 
dose. There were no effects on liver in rats given daily oral doses for 14 days at up to 
30 mg/kg (180 mg/m2). 
• Local irritation at the infusion site: Dogs given daily doses of G1T28 for 7 days had 
occasional episodes of swelling/edema at the infusion site. This was considered likely to 
be due to leakage or accidental injection of dosing solution into the perivenous tissue. 
Although G1T28 induced micronucleus formation in human lymphocytes exposed in vitro, 
G1T28 is not considered to pose a hazard to human patients, as G1T28 was negative for 
mutagenic potential in a Good Laboratory Practice (GLP) (and non-GLP) Ames assay, and 
did not induce phosphorylated histone H2AX (γH2AX) formation in primary human 
fibroblasts. In the present study, G1T28 will be administered in conjunction with 
etoposide/carboplatin, which presents a genotoxic hazard to human subjects. In this context, 
any slight additional genotoxic hazard posed by G1T28 is negligible. 
In female rats, daily administration of G1T28 for 7 days resulted in lower ovary and uterus 
weights and more rats in metestrus/diestrus, and these effects were reversible within 2 weeks 
after the last dose. These findings in rats raise the possibility that G1T28 may affect 
menstrual cycling in women; however, no studies have been done specifically to evaluate the 
effects of G1T28 on fertility in animals of either sex. For men, studies in rats and dogs do not 
suggest any potential for impairment of fertility; specifically, there were no pathologic 
findings in reproductive organs of male rats or dogs given daily doses of G1T28 for 7 days. 
Nevertheless, patients who are pregnant or lactating should not receive G1T28. Heterosexual 
couples in which the female is of childbearing potential must use appropriate birth control 
methods. 
The nonclinical package as a whole indicates that rats and dogs were appropriate species for 
evaluating the toxicity of G1T28. In both species, the toxicity profile was similar. 
4.4. 
Study and Dose Rationale 
Chemotherapy-induced myelosuppression is a significant issue in cancer treatment, including 
treatment of SCLC. G1T28 is a highly potent and selective CDK4/6 inhibitor that induces a 
transient and reversible G1 cell cycle arrest of HSPCs within the bone marrow, thus 
protecting their DNA from damage by coadministered chemotherapy and preserving 
long-term function. In animal studies, administration of G1T28 just prior to dose(s) of 5-FU 
resulted in a more rapid recovery of all hematopoietic lineages. This effect persisted 
following administration of multiple cycles of chemotherapy. Bone marrow obtained from 
mice that received 4 cycles of G1T28 administered prior to every dose of 5-FU was more 
robust at hematopoietic reconstitution of lethally irradiated mice following bone marrow 
transplantation compared with bone marrow obtained from mice that received 4 cycles of 


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5-FU alone, suggesting that G1T28 administered with chemotherapy can preserve stem cell 
function. 
Since inactivation of RB-1 is an obligate event in SCLC development (D’Amico 1992; 
Heighway 2004; Yuan 1999; Cagle 1997; Gouyer 1994, Peifer 2012; Rudin 2012), this tumor 
type is highly resistant to CDK4/6 inhibitors and coadministration of CDK4/6 inhibitors with 
DNA damaging chemotherapeutic agents, such as those used in SCLC, are not expected to 
antagonize the efficacy of such agents. In vitro analysis has shown that Rb-null cells are 
resistant to CDK4/6 inhibition. In vivo, G1T28 administered alone or 30 minutes before E/P 
or topotecan was well tolerated and did not antagonize the effects of chemotherapy in a 
cell-based xenograft model (H69) representing SCLC in immune-deficient mice (see details 
in Section 4.3.1).  
Study G1T28-1-01 was a Phase 1a, safety, PK, and pharmacodynamic study of G1T28.  
Forty-five healthy male and female subjects were enrolled into 7 dose cohorts where G1T28 
was administered IV as a 30-minute infusion (randomized, double-blind, placebo-controlled 
ascending doses of 6, 12, 24, 48, 96, or 192 mg/m2, and an open-label expanded 
pharmacodynamic cohort at 192 mg/m2). G1T28 was well tolerated, with no DLTs or SAEs 
reported. Additionally, over the dose range of 6 to 192 mg/m2, Cmax increased in a 
dose-proportional manner, total systemic (AUC) exposure increased more than dose 
proportionally, and clearance (CL) was relatively constant. The PK of G1T28 suggests that 
drug accumulation following repeated administration is unlikely to occur. Based on PK/PD 
parameters from the Phase 1a study and a preclinical PK/PD model, a BED of 192 mg/m2 of 
G1T28 was identified. Twenty-four hours following administration of the BED, a significant 
decrease was noted in the number of bone marrow HSPCs in the S/G2/M phases of the cell 
cycle (ie, an increase in the proportion of cells in G1 arrest), which persisted to 32 hours. 
Thus, dosing of G1T28 200 mg/m2 (rounded up from the BED of 192 mg/m2) prior to the 
administration of etoposide and carboplatin on Day 1 and administration of etoposide on 
Days 2 and 3 of 21-day cycles (hereafter referred to as E/P therapy) should maintain the bone 
marrow HSPCs in G1 arrest during and for several half-lives after chemotherapy 
administration, thus protecting their DNA from cytotoxic damage. The goals of this study are 
to assess the safety and tolerability of combining G1T28 with E/P therapy and to evaluate the 
effect of G1T28 on chemotherapy-induced myelosuppression. 
4.5. 
Risk/Benefit Assessment 
G1T28 is being developed to reduce chemotherapy-induced myelosuppression, which is a 
significant issue. Bone marrow HSPCs require CDK4/6 for proliferation. SCLC tumors are 
almost universally CDK4/6 independent by virtue of various genetic mutations in the RB-1 
gene that result in the loss of the Rb protein, which is the downstream target of CDK4/6. 
Therefore, the risk of producing a G1 cell cycle arrest of the tumor cells, and thereby 
protecting the tumor from chemotherapy, is small. As stated in Section 4.4, the BED of IV 
G1T28 is 192 mg/m2 and a dose of 200 mg/m2 will be used as the starting dose for 
administration on Days 1 to 3 of every 21-day cycle of E/P therapy in the present study. In 
conclusion, the potential benefits of combining G1T28 at a dose of 200 mg/m2 with 
E/P therapy to protect the bone marrow HSPCs outweigh the potential risks. 


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5. 
STUDY OBJECTIVES  
The primary, secondary, and exploratory objectives of this study are presented in Table 5-1. 
Table 5-1 
G1T28-02: Study Objectives 
 
Phase 1b 
Dose-Finding 
Portion of 
Part 1 
Phase 2a 
Expansion 
Portion of 
Part 1 
Phase 2a 
Part 2 
Primary Objectives 
Assess the DLTs and define the Phase 2 dose of G1T28 
administered with E/P therapy 
X 
 
 
Assess the safety and tolerability of G1T28 administered 
with E/P therapy 
X  
X 
X 
Secondary Objectives 
Assess the PK profile of G1T28 
X 
 
 
Assess the PK profile of etoposide and carboplatin when 
administered with G1T28 
X 
 
 
Assess the hematologic profile (kinetics and 
incidence/duration/frequency of toxicities) of G1T28 
administered with E/P therapy 
X  
 
X 
X 
Assess the incidence of febrile neutropenia 
X 
X 
X 
Assess the incidence of infections 
X 
X 
X 
Assess the utilization of RBC and platelet transfusions 
X 
X 
X 
Assess the utilization of hematopoietic growth factors  
X 
X 
X 
Assess the utilization of systemic antibiotics 
X 
X 
X 
Assess the incidence of chemotherapy dose reductions and 
dose interruptions overall 
X 
X 
X 
Assess the incidence of Grade 2 or greater nephrotoxicity  
X 
X 
X 
Assess tumor response based on RECIST, Version 1.1 
X 
X 
X 
Assess PFS and overall survival 
X 
X 
X 
Exploratory Objectives 
Assess the incidence of mucositis 
X 
X 
X 
Assess the incidence of alopecia 
X 
X 
X 
Assess the incidence of fatigue 
X 
X 
X 
Assess patient-reported QOL 
X 
X 
X 
Assess immunologic markers 
 
 
X 
DLT = dose-limiting toxicity; E/P therapy = etoposide + carboplatin on Day 1 and etoposide on Days 2 and 3 of 21-day 
cycles; PFS = progression-free survival; PK = pharmacokinetic; QOL = quality of life; RBC = red blood cell; 
RECIST = Response Evaluation Criteria in Solid Tumors  


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design and Plan 
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 1b/2a study of the 
safety and PK of G1T28 in combination with E/P therapy for patients with newly diagnosed 
extensive-stage SCLC. The study consists of 2 parts: Part 1 will be a limited Phase 1b, 
open-label, dose-finding portion followed by a Phase 2a, open-label, expansion portion in up 
to 18 patients at the selected dose to be used in Part 2. Prior to initiating Part 2, up to a total 
of 24 patients will be enrolled at the chosen Part 2 dose (6 patients in the dose-finding 
portion of Part 1 and up to 18 patients in the Phase 2a, open-label, expansion portion of Part 
1). Part 2 will consist of a randomized, double-blind cohort (70 patients will be randomly 
assigned to G1T28 administered IV with E/P therapy or placebo administered IV with 
E/P therapy). All 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 
first dose with study treatment and completes at the Post-Treatment Visit. 
The initial diagnosis of SCLC should be made based on standard pathological examination, 
preferably including immunohistochemical staining for neuroendocrine features. Archived 
tumor samples should be available for sending to a central pathology laboratory to confirm 
the diagnosis of SCLC. If central pathology review does not confirm SCLC diagnosis, the 
patient may be withdrawn from the study after consultation between the principal 
investigator, medical monitor, and sponsor. Available tissue after confirming the diagnosis of 
SCLC will be banked for assessment of relevant DNA, ribonucleic acid (RNA), and protein 
markers, such as those involved in the CDK4/6 pathway. 
6.1.1. 
Part 1 
The goal of the Phase 1b dose-finding portion of Part 1 is to assess the safety, including 
DLTs (see Section 6.1.1.1), and PK (see Section 6.1.1.2) of G1T28 administered at a starting 
dose of 200 mg/m2 (derived from Study G1T28-1-01, a Phase 1a, safety, PK, and 
pharmacodynamic study of G1T28 in healthy male and female patients) once daily on Days 1 
to 3 of E/P therapy (Figure 6-1).  


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Figure 6-1 
Study Schema: Phase 1b Dose-Finding Portion of Part 1 
 
E/P = etoposide + carboplatin  
a  
Safety and available PK data from Cycle 1 will be considered in making dose escalation/de-escalation decisions (if 
required) and enrolling additional cohorts 
b  
G1T28 + E/P will continue until disease progression, unacceptable toxicity, or discontinuation by the patient or 
investigator (eg, after completing 6 cycles). The tumor should be assessed after every even cycle using Response 
Evaluation Criteria in Solid Tumors (RECIST), Version 1.1. Assessments should be performed within 7 days of 
starting the subsequent cycle. 
c  
G1T28 will be administered prior to the administration of etoposide and carboplatin on Day 1 and administration of 
etoposide on Days 2 and 3 of 21-day cycles 
d 
Patients will return to the study center for a Post-Treatment Visit at 30 + 3 days after the last dose of study drug. 
e 
The Survival Follow-up Phase will continue until at least 50% of the patients randomized to Part 2 of the study have 
died. 
 
6.1.1.1. 
Definition of Dose-Limiting Toxicities (Applicable to Cycle 1 of the Phase 1b 
Dose-Finding Portion of Part 1) 
Dose-limiting toxicities are drug-related toxicities defined as follows: 
• Absolute neutrophil count (ANC) < 0.5 × 109/L lasting for ≥ 7 days 
• ≥ Grade 3 neutropenic infection/febrile neutropenia 
• Grade 4 thrombocytopenia or ≥ Grade 3 thrombocytopenia with bleeding 
• Unable to start next cycle of chemotherapy due to lack of recovery to an 
ANC ≥ 1.5 × 109/L and platelet count ≥ 100 × 109/L 
• ≥ Grade 3 nonhematologic toxicity (nausea, vomiting, and diarrhea failing maximal 
medical management; fatigue lasting for > 72 hours) 
 
Toxicities not clearly related to etoposide/carboplatin (E/P) therapy will also be considered 
for the purposes of determining DLTs. 
 


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6.1.1.2. 
Criteria for Adjusting G1T28 Dose Based on Pharmacokinetic Parameters 
The PK profile of G1T28 is well established in healthy subjects, with good estimates of key 
parameters such as Cmax, AUC, and CL. In addition, the intersubject variability in these PK 
parameters is low (see Section 4.2). However, patients with SCLC enrolled in this study will 
likely be older and have more comorbidities compared with subjects enrolled in the Phase 1a 
G1T28-1-01 study, and therefore, could demonstrate differences in PK.  
Based on the observed PK profile of G1T28 in Study G1T28-1-01, the extrapolated 
AUC0-24.5h for a 200 mg/m2 dose is 3100 h•ng/mL. If the mean AUC0-24.5h in the initial cohort 
of patients (6 patients) in the Phase 1b, dose-finding portion of Part 1 is not within 20% of 
the target (eg, 2480 to 3720 h•ng/mL), then the dose of G1T28 will be adjusted in the next 
cohort of 6 patients to achieve a mean AUC0-24.5h of 3100 h•ng/mL. The magnitude of the 
dose modification is based upon the fact that G1T28 displays linear PK over the dose range 
studied to date.  Any available PK data from additional cohort(s) of the Phase 1b 
dose-finding portion of Part 1 may be utilized for modifying the G1T28 dose (if required). If 
the G1T28 dose level for a subsequent cohort requires escalation, the increase will not 
exceed 30% from the previous dose level.  A G1 cell cycle arrest of a minimum of 24 hours 
after G1T28 administration is desired to ensure that the bone marrow arrest is maintained 
long enough to avoid releasing HSPCs into the S (DNA synthesis) phase of the cell cycle in 
the presence of high concentrations of chemotherapy and thereby potentially exacerbating 
myelosuppression.  
If the dose is adjusted due to DLTs and the PK was within the expected target range, then a 
new target AUC0-24.5h will be calculated for the modified dose as follows:  
Y = 2.11 + 1.1*X, where Y is the ln(AUC0-24.5) h*ng/mL and X is the ln(dose) mg/m2 
6.1.1.3. 
G1T28 Dose Evaluation 
Six patients will initially be enrolled into the Phase 1b, dose-finding portion of Part 1 and 
will receive G1T28 200 mg/m2 in combination with standard E/P therapy (see Section 8.1). 
Safety and available PK parameters from this initial cohort of 6 patients during Cycle 1 will 
be considered in making dose escalation/de-escalation decisions (if required). If a patient is 
withdrawn prior to completing all assessments in Cycle 1 for reasons other than toxicity in 
any cohort in the Phase 1b, dose-finding portion of Part 1, the patient will be replaced. 
G1T28 dose evaluation criteria are listed below and are presented as a decision tree in 
Figure 6-2. While the dose evaluation criteria below will be used to guide all dose decisions, 
the SMC will be responsible for all dose and cohort recommendations.  
• If there is ≤ 1 DLT in the first cohort of 6 patients during Cycle 1 of the Phase 1b, 
dose-finding portion of Part 1 and the available G1T28 PK parameters are as predicted 
(Section 6.1.1.2), the dose-finding portion of Part 1 will end and subsequent patients will 
be enrolled into the Phase 2a expansion cohort of Part 1, utilizing a dose of G1T28 of 
200 mg/m2 in combination with E/P therapy. 
• If there is ≤ 1 DLT in the first cohort of 6 patients during Cycle 1 of the Phase 1b 
dose-finding portion of Part 1, and the available G1T28 PK parameters suggest that the 
G1T28 dose needs to be escalated or de-escalated (see Section 6.1.1.2), a second cohort 


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of 6 patients will be enrolled at the higher or lower predicted G1T28 dose in combination 
with E/P therapy. For assessment of data from the second cohort enrolled in the Phase 1b 
dose-finding portion of Part 1, please see the decision tree in Figure 6-2. 
• If there is > 1 DLT in the first cohort of 6 patients during Cycle 1 of the Phase 1b 
dose-finding portion of Part 1 and the available G1T28 PK parameters suggest that the 
G1T28 dose needs to be escalated or de-escalated (ie, in order to increase or decrease the 
magnitude and duration of G1 cell cycle arrest of HSPCs predicted by the PK/PD model 
and data from the Phase 1a Study G1T28-1-01; see Section 6.1.1.2), a second cohort of 6 
patients will be enrolled at the modified G1T28 dose in combination with E/P therapy. 
For assessment of data from the second cohort enrolled in the Phase 1b dose-finding 
portion of Part 1, please see the decision tree in Figure 6-2. 
• If there is > 1 DLT in the first cohort of 6 patients enrolled in the Phase 1b dose-finding 
portion of Part 1 and the available G1T28 PK parameters from these 6 patients are as 
predicted (Section 6.1.1.2), the dose of G1T28 should be decreased to 160 mg/m2 and an 
additional 6 patients should be enrolled at the modified G1T28 dose in combination with 
E/P therapy. For assessment of data from the second cohort enrolled in the Phase 1b 
dose-finding portion of Part 1, please see the decision tree in Figure 6-2.  
• If there is > 1 DLT following a G1T28 dose of 160 mg/m2 in combination with 
E/P therapy in the second cohort of patients and if available, PK parameters are as 
predicted (Section 6.1.1.2), an additional cohort of 6 patients will be enrolled at a further 
decreased G1T28 dose of 130 mg/m2 in combination with E/P therapy. For assessment of 
data from the third cohort enrolled in the Phase 1b dose-finding portion of Part 1, please 
see the decision tree in Figure 6-2.  
• If there is > 1 DLT following the second dose reduction of G1T28 and if available, PK 
parameters from the third cohort are as predicted (Section 6.1.1.2), no further dose 
modifications will be made and the study will be terminated. 
• At any time, if ≥ 2 DLTs are observed in any given cohort, further enrollment into that 
cohort will be stopped until the SMC can review the available data and make dose and 
cohort recommendations. 
Figure 6-2 
G1T28 Dose Evaluation in the Phase 1b Dose-Finding Portion of Part 1 
 
a      Assess the adjusted G1T28 dose in the next cohort of 6 patients based on DLTs and PK (if available) per the decision     
        tree 
b 
Maximum of 2 G1T28 dose reductions are allowed 
 


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All dose-escalation/de-escalation decisions will be based on Cycle 1 safety data from all 
patients enrolled into the cohort and available PK data and will be reviewed by a safety 
monitoring committee (SMC) comprised of the sponsor, medical monitor, and the principal 
investigator(s) to determine the next dose level. If the G1T28 dose level for a subsequent 
cohort is adjusted by the SMC, the SMC may also recommend that all patients currently 
receiving G1T28 in combination with E/P therapy should have their G1T28 dose adjusted 
accordingly, starting with their next scheduled cycle. Additional cohorts for the Phase 1b 
dose-finding portion of Part 1 will be considered based on review of the safety data from all 
patients enrolled into the cohort and available PK data by the SMC. The dose for Part 2 will 
be obtained by utilizing all available safety and available PK data from patients enrolled in 
Part 1. Once the dose for Part 2 has been established, additional patients will be enrolled at 
the selected Part 2 dose in a Phase 2a expansion cohort in Part 1 until up to a total of 
24 patients (6 from the Phase 1b dose-finding portion of Part 1 and up to 18 from the 
Phase 2a expansion cohort) have been enrolled at that dose. The Phase 2a expansion cohort 
in Part 1 will complete enrollment before enrollment into Part 2 commences.    
There will be no intrapatient dose modifications of G1T28 in the Phase 2a expansion cohort 
of Part 1 and Part 2 of the study. 
Each patient will be evaluated for toxicity during each cycle. The toxicity of IV G1T28 
administered with E/P therapy will be assessed by the investigators using National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. 
6.1.1.4. 
Safety Monitoring Committee 
The SMC will be set up to review safety of G1T28 for all patients enrolled in the Phase 1b 
dose-finding portion of Part 1 of the study. The SMC will consist of the clinical 
investigator(s), the medical monitor, and G1 Therapeutics representatives and/or 
designees. During the Phase 1b dose-finding portion of Part 1, the SMC will review any 
DLTs, SAEs, PK, and all other available data. The committee will make recommendations 
for dose escalation/de-escalation based on the criteria listed in Sections 6.1.1.1 to 6.1.1.3. 
While the dose evaluation criteria will be used to guide all dose decisions, the SMC will be 
responsible for all dose and cohort recommendations, including any adjustments to the PK 
collection schedule. If the G1T28 dose level for a subsequent cohort is adjusted by the SMC, 
the SMC may also recommend that all patients currently receiving G1T28 in combination 
with E/P therapy should have their G1T28 dose adjusted accordingly, starting with their next 
scheduled cycle.  
In the Phase 2a expansion cohort of Part 1, the SMC will review any SAEs, efficacy, and all 
other available data. The SMC may make recommendations for continuing with the Phase 2a 
expansion cohort in Part 1 with enrollment of up to 18 patients, or moving to Part 2 based on 
safety and efficacy. 
6.1.2. 
Part 2 
In Part 2, eligible patients will be randomized (1:1 fashion) to G1T28 or placebo 
administered IV once daily on Days 1 to 3 of E/P therapy (Figure 6-3). Randomization will 


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be stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 to 1 
versus 2). There will be no intrapatient dose modifications of G1T28 in Part 2 of the study. 
Figure 6-3 
Study Schema: Part 2 
 
E/P = etoposide + carboplatin 
a  
G1T28 + E/P will continue until disease progression, unacceptable toxicity, or discontinuation by the patient or 
investigator (eg, after completing 6 cycles). The tumor should be assessed after every even cycle using Response 
Evaluation Criteria in Solid Tumors (RECIST), Version 1.1. Assessments should be performed within 7 days of 
starting the subsequent cycle. 
b 
G1T28 will be administered prior to the administration of etoposide and carboplatin on Day 1 and administration of 
etoposide on Days 2 and 3 of 21-day cycles 
c 
Patients will return to the study center for a Post-Treatment Visit at 30 + 3 days after the last dose of study drug. 
d 
The Survival Follow-up Phase will continue until at least 50% of the patients randomized to Part 2 of the study have 
died. 
 
An independent data monitoring committee (DMC) will monitor accumulating safety and 
disposition data approximately every 4 months during the Treatment Phase of Part 2 of the 
study, depending upon the enrollment rate. Details of the DMC, including objectives, 
composition, scope, and frequency, will be described in a DMC charter. 
6.1.3. 
Criteria for Subsequent Cycles and Study Duration 
In all parts of the study, study drug administration will continue until disease progression per 
Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, unacceptable toxicity, 
withdrawal of consent, or discontinuation by investigator (eg, after completing 6 cycles), 
whichever occurs first. Treatment cycles will occur consecutively without interruption, 
except when necessary to manage toxicities or for administrative reasons as described below.   
In order to start Cycle 2 and subsequent cycles as scheduled, patients should meet all of the 
following criteria: 
• ANC ≥ 1.5 × 109/L  
• Platelet count ≥ 100 × 109/L 


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• Nonhematologic drug-related toxicities (except alopecia) must be ≤ Grade 1 or have 
returned to baseline 
A delay of up to 2 weeks is permitted to allow recovery from any toxicity in order to meet 
the continuation criteria for organ function. If patients meet the criteria for starting the 
subsequent cycle as described above, a delay of up to 1 week is permitted for administrative 
reasons (eg, holiday, vacation, etc.). If the subsequent cycle is delayed, the patient should still 
complete the clinical laboratory assessments and the FACT-L and FACT-An questionnaires 
on the scheduled Day 1, as well as on the actual first dosing day of the next cycle. A patient 
will be discontinued from the study if recovery from any toxicity, in order to meet the 
continuation criteria for organ function, and any delay for administrative reasons requires a 
total delay of > 2 weeks (see Section 8.4.4.2.1 and Table 8-2).  
After discontinuation of study drug, patients should be strongly encouraged to complete all 
scheduled assessments through the end of their current 21-day treatment cycle, including the 
patient-reported outcome (PRO) scales; CBC assessment on Day 22; the Post-Treatment 
Visit; and the Survival Follow-up Phase of the study.  
The G1T28-02 study will be completed when the Survival Follow-up Phase has been 
completed, or upon sponsor termination of the study. 
The total study duration is at least 29 months.  
Part 1 is expected to be approximately 18 months, assuming 12 months of accrual, 2 weeks 
for screening, 4.5 months of treatment (assuming 6 cycles), and 1 month of safety follow-up. 
Part 2 will begin after the Part 2 dose is identified from the Phase 1b dose-finding portion of 
Part 1 and the Phase 2a expansion portion of Part 1 has completed enrollment, which is 
expected to occur approximately 12 months after Part 1 begins. Part 2 is expected to be 
approximately 17 months, assuming 11 months of accrual, 2 weeks of screening, 4.5 months 
of treatment (assuming 6 cycles), and 1 month of safety follow-up. 
The Survival Follow-up Phase of the study will continue until at least 50% of the randomized 
patients in Part 2 have died. 
6.1.4. 
Safety Assessments 
Safety assessments will include monitoring of AEs, vital signs measurements, physical 
examinations, ECGs, and clinical laboratory studies as described in Section 11.3. Safety 
surveillance reporting of AEs commences at the time that informed consent is obtained and 
continues through the Post-Treatment Visit.  
6.1.5. 
Tumor Assessment 
For tumor assessment, all sites of disease should be assessed radiologically according to 
RECIST, Version 1.1 using computed tomography (CT) or magnetic resonance imaging 
(MRI) at screening; after every even cycle, until the occurrence of disease progression. CT or 
MRI scans obtained as standard of care prior to informed consent will not need to be repeated 
if performed within 14 days prior to dosing. Assessments should be performed within 7 days 


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of starting the subsequent cycle. Additional scans may be obtained at the discretion of the 
investigator, if clinically indicated. If a patient shows a radiological response (complete 
response [CR] or partial response [PR]), a confirmatory radiological assessment will be 
performed at least 4 weeks after the response was first noted. For patients who have a 
confirmed CR, it is strongly recommended that they receive prophylactic cranial irradiation 
(PCI) after completion of chemotherapy. Patients with a confirmed PR should also consider 
PCI after completion of chemotherapy based on the investigator’s judgment (see 
Section 8.8). For those patients who have not progressed at the time of study drug 
discontinuation, tumor assessments, including all sites of disease, will be assessed 
radiologically by CT or MRI, as performed at screening, every 2 months (approximately 
60 ± 7 days) until the occurrence of progressive disease or study completion. The same 
method of assessment (CT or MRI) should be used to characterize tumors at screening and at 
all follow-up assessments. If positron emission tomography (PET) is used, it should also be 
accompanied by spiral CT or MRI. Tumor assessment is further described in Section 11.5. 


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7. 
STUDY POPULATION  
7.1. 
Selection of Patients 
Overall, up to 110 patients will be enrolled in the study.  
In Part 1, approximately 40 patients will be enrolled, assuming up to 3 cohorts. Cohorts will 
consist of 6 patients each in the Phase 1b dose-finding portion of Part 1 and up to 18 patients 
in the Phase 2a expansion portion of Part 1 at the selected dose to be used in Part 2. 
Additional patients may be enrolled in the Phase 1b dose-finding portion of Part 1 if more 
than 1 cohort is enrolled.   
In Part 2, 70 patients will be randomly assigned (1:1 ratio) to 1 of 2 groups: G1T28 
administered IV with E/P therapy (Group 1) or placebo administered IV with E/P therapy 
(Group 2). 
The study will be conducted at up to 80 centers in North America and Europe. 
7.1.1. 
Inclusion Criteria 
For a patient to be eligible for participation in this study, all of the following criteria must 
apply. 
1. Age ≥ 18 years  
2. Unequivocally confirmed diagnosis of SCLC by histology or cytology, preferably 
including the presence of neuroendocrine features by immunohistochemistry 
3. Extensive-stage disease 
4. At least 1 target lesion that is unirradiated and measurable by RECIST, Version 1.1 
(Eisenhauer 2009) 
5. Hemoglobin ≥ 9.0 g/dL 
6. Absolute neutrophil count ≥ 1.5 × 109/L 
7. Platelet count ≥ 100 × 109/L 
8. Creatinine ≤ 1.5 mg/dL OR glomerular filtration rate (GFR) of ≥ 60 mL/min (by 
Cockcroft-Gault formula [Cockcroft and Gault 1976]); creatinine clearance calculated 
from an isotopic method or a 24-hour urine collection may be used instead of an 
estimated GFR by the Cockcroft-Gault formula 
9. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) 
10. AST and ALT ≤ 2.5 × ULN; ≤ 5 × ULN in the presence of liver metastases  
11. Serum albumin ≥ 3 g/dL 


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12. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 
13. Predicted life expectancy of ≥ 3 months 
14. Contraception: 
a. For females: All females of childbearing potential must have a negative serum beta 
human chorionic gonadotropin (β-hCG) test result at screening and at baseline. 
Females must be either postmenopausal, surgically sterile, or using an acceptable 
method of contraception. Acceptable surgical sterilization techniques 
are hysterectomy, bilateral tubal ligation with surgery at least 6 months prior to 
dosing, and bilateral oophorectomy, with surgery at least 2 months prior to dosing. 
Acceptable methods of contraception are an intrauterine device, contraceptive 
implant, oral contraceptive (stable dose of the same hormonal contraceptive product 
for at least 3 months prior to dosing), a vasectomized partner, and a barrier method 
(condom or diaphragm) during the study and for 3 months after discontinuation of 
treatment 
b. For males: Patients with female partner of childbearing potential must agree to use a 
highly effective form of birth control, which entails the use of oral, injected, or 
implanted hormonal methods of contraception or an intrauterine device/system by the 
female partner, in combination with a barrier method (eg, condom, diaphragm, 
cervical cap) during the study and for 3 months after discontinuation of treatment, and 
will also refrain from sperm donation for 3 months following completion of the study 
 
15. Able to understand and sign an informed consent 
 
7.1.2. 
Exclusion Criteria 
A patient will not be eligible for participation in this study if any of the following criteria 
apply. 
1. Prior chemotherapy for limited or extensive-stage SCLC 
2. Presence of symptomatic brain metastases requiring immediate treatment with radiation 
therapy or steroids 
3. 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 
4. 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) 
5. Known history of stroke or cerebrovascular accident within 6 months prior to enrollment 
6. Serious active infection 


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7. Psychiatric illness/social situations that would limit study compliance 
8. Other uncontrolled serious chronic disease or conditions that in the investigator’s opinion 
could affect compliance or follow-up in the protocol 
9. Known human immunodeficiency virus (HIV), known hepatitis B virus (HBV), or known 
hepatitis C virus (HCV) positive that is symptomatic or requiring active therapy 
10. Concurrent radiotherapy to any site or radiotherapy within 2 weeks prior to enrollment or 
previous radiotherapy to the target lesion sites (the sites that are to be followed for 
determination of a response) 
11. Receipt of any investigational medication within 4 weeks prior to enrollment 
12. Hypersensitivity to any of the components of the formulation of etoposide or etoposide 
phosphate 
13. Hypersensitivity to cisplatin or other platinum-containing compounds, or mannitol  
14. Legal incapacity or limited legal capacity  
15. Pregnant or lactating women 
Patients may withdraw from study drug or from the study at their own discretion (or at the 
discretion of the investigator) for any reason at any time (see Section 12.3 and 12.4).  


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8. 
TREATMENTS 
8.1. 
Treatments Administered 
The initial group of patients in Part 1 of the study will receive G1T28 200 mg/m2 
administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. All dose 
escalation/de-escalation decisions and additional cohorts of patients to be enrolled in the 
Phase 1b dose-finding portion of Part 1, if any, will be based on Cycle 1 safety and available 
PK data (see Section 6.1.1). If the G1T28 dose level for a subsequent cohort is adjusted by 
the SMC, the SMC may also recommend that all patients currently receiving G1T28 in 
combination with E/P therapy should have their G1T28 dose adjusted accordingly, starting 
with their next scheduled cycle. 
Patients enrolled to the Phase 2a expansion portion of Part 1 and Part 2 will receive the dose 
of G1T28 derived from the Phase 1b dose-finding portion of Part 1 or placebo administered 
IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. There will be no 
intrapatient dose modifications of G1T28 in the Phase 2a expansion portion of Part 1 and 
Part 2 of the study. 
Patients will receive standard E/P chemotherapy in 21-day cycles. The carboplatin dose will 
be calculated using the Calvert formula with a target AUC = 5 (maximum 750 mg) IV on 
Day 1, and 100 mg/m2 etoposide will be administered IV daily on Days 1, 2, and 3 of each 
21-day cycle.  
The interval between doses of G1T28 or placebo on successive days should not be 
greater than 28 hours. The interval between the dose of G1T28 or placebo and the first 
dose of chemotherapy on a given day (etoposide or carboplatin) should not be greater 
than 4 hours.  
G1T28 or placebo will only be administered with E/P therapy. If administration of 
E/P therapy is discontinued, G1T28 or placebo will also be discontinued.  
Chemotherapy cannot be administered until after completion of the G1T28 or placebo 
infusion. If the second or third dose of G1T28 or placebo in any given cycle is not 
administered for any reason, do not administer the dose of etoposide chemotherapy on 
that day, since this could potentially exacerbate myelosuppression (see Section 8.4.4.1). 
Study drug administration will continue until disease progression, unacceptable toxicity, 
withdrawal of consent, or discontinuation by investigator (eg, after completing 6 cycles), 
whichever occurs first. Treatment cycles will occur consecutively without interruption, 
except when necessary to manage toxicities or for up to a 1 week delay for administrative 
reasons, for a maximum total delay of up to 2 weeks. If the subsequent cycle is delayed, the 
patient should still complete the clinical laboratory assessments and the FACT-L and 
FACT-An questionnaires on the scheduled Day 1, as well as on the actual first dosing day of 
the next cycle.  
Patients should meet the laboratory parameter requirements outlined in Section 10.4 before 
initiation of Cycle 2 and each subsequent cycle of E/P therapy. All nonhematologic 


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drug-related toxicities (except alopecia) should have resolved to Grade 1 or baseline before 
initiation of the next cycle of E/P therapy.  
8.2. 
Investigational Products 
8.2.1. 
Identity 
8.2.1.1. 
G1T28 
G1T28 is supplied as a single-use, sterile powder with 40 or 100 mg G1T28 in each 10-mL 
flint glass vial. D-mannitol, USP is added as a cake forming agent and citrate buffer is added 
to maintain the reconstituted pH at 4.0 to 5.0. The process for reconstitution of study drug is 
detailed in the Pharmacy Manual. 
8.2.1.2. 
Placebo 
The placebo formulation of 250 mL of dextrose 5% in water (D5W) or sodium chloride 
solution 0.9% will be prepared by the pharmacist/designee on site.  
8.2.1.3. 
Etoposide and Carboplatin 
Descriptions of the formulations of commercially-available etoposide and carboplatin can be 
found in the respective current prescribing information (see Appendix 2).  
8.2.2. 
Packaging and Labeling 
8.2.2.1. 
G1T28 
G1T28 sterile powder is manufactured and packaged by University of Iowa Pharmaceuticals, 
Iowa City, Iowa, United States of America. 
Individual vials of G1T28 will be labeled and supplied to the unblinded pharmacist/designee 
who will inventory the contents and document them according to the drug accountability 
requirements (Section 8.2.5). 
8.2.2.2. 
Placebo 
The placebo formulation of 250 mL of D5W or sodium chloride solution 0.9% will be 
prepared by the pharmacist/designee on site, and labeled with the randomization number. 
8.2.2.3. 
Etoposide and Carboplatin 
Descriptions of the packaging and labeling of commercially-available carboplatin and 
etoposide can be found in the respective current prescribing information (see Appendix 2).  


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8.2.3. 
Storage 
8.2.3.1. 
G1T28 
The G1T28 sterile powder 40-mg/10 mL or 100-mg/10 mL vial should be stored refrigerated 
at 2°C to 8°C. 
Stability data for the current formulation of G1T28 sterile powder 40-mg/10 mL vial 
demonstrates satisfactory stability for up to 6 months at 5°C and 25°C/60% relative humidity 
(RH). Based on these data, stability is expected to exceed 18 months at refrigerated storage 
conditions.  
Stability data for the current formulation of G1T28 sterile powder 100-mg/10 mL vial 
demonstrates satisfactory stability for up to 1 month at 40°C/75% RH. Based on these data, 
stability is expected to exceed 12 months at refrigerated storage conditions. 
Study drugs will be stored in a locked refrigerator under applicable storage conditions at the 
site and only the pharmacist/designee and designated personnel will have access to the study 
drugs. 
8.2.3.2. 
Placebo 
The placebo formulation of 250 mL of D5W or sodium chloride solution 0.9% will be stored 
identically to G1T28 to protect the integrity of the blind. 
8.2.3.3. 
Etoposide and Carboplatin 
Information regarding the storage of commercially-available carboplatin and etoposide can 
be found in the respective current prescribing information (see Appendix 2). 
8.2.4. 
Procedure for Dispensing  
Dispensing instructions, including instructions for masking the G1T28 or placebo infusion 
bags, will be provided in the Pharmacy Manual and will be maintained in the pharmacy 
records.  
8.2.5. 
Investigational Product Accountability 
The pharmacist/designee will verify the integrity of the clinical trial supplies (storage 
conditions, correct amount received, condition of shipment, kit numbers, etc.) according to 
the investigative site’s standard operating procedures (SOPs). 
At a minimum, the following data will be tracked on the drug accountability log at the site 
pharmacy: 
• Date received 
• Lot number 
• Vial number 
• Date dispensed 


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• Patient number 
• Identification of the person dispensing the drug 
Records of study medication (used, lost, destroyed, and returned containers, individual vials) 
should be made at each visit in the drug accountability and dispensing forms. Drug 
accountability and reconciliation will be checked and verified by the pharmacy team during 
the study and by the site monitor during and at the completion of the study. 
Once the site monitor has verified drug accountability at the site, any used drug remaining at 
the completion of the study will be destroyed. Unused and unopened study medication will 
be returned by the site monitor to the sponsor or may be destroyed on site according to the 
investigative site’s SOPs. 
8.3. 
Method of Assigning Patients to Treatment Groups 
A unique patient identification number (screen number) will be assigned to each patient who 
signs an informed consent form. Once a patient is determined eligible, ie, meets all 
inclusion/exclusion criteria, an enrollment number will be assigned by an interactive 
web-response system (IWRS).  
Part 1 of the study (dose-finding and expansion cohorts) is open-label and there will be no 
randomization. 
Part 2 is randomized and blinded. Patients meeting all inclusion and exclusion criteria in 
Part 2 will be randomized 1:1 to receive G1T28 or placebo as described in Section 8.5. Each 
patient will be assigned a unique randomization number, which will not be reused.   
8.4. 
Dose, Dosing Regimen, and Route 
8.4.1. 
G1T28  
The starting dose level for the Phase 1b dose-finding portion of Part 1 will be 200 mg/m2, 
which is derived from the G1T28-1-01 study, a Phase 1a safety, PK, and pharmacodynamic 
study of G1T28 in healthy male and female subjects. See Section 6.1 for possible dose 
escalation/de-escalation decisions based on safety and available PK data.   
G1T28 diluted in 250 mL of D5W or sodium chloride solution 0.9% is to be administered by 
IV infusion over 30 minutes. If there is any study drug remaining in the infusion bag at the 
end of the 30 minutes, the infusion should be continued at the same rate until the entire 
contents of the bag have been administered to ensure patients receive the full dose. Details 
regarding the reconstitution and dilution of G1T28 vials are detailed in the Pharmacy 
Manual. 
The interval between doses of G1T28 on successive days should not be greater than 
28 hours. G1T28 will only be administered with E/P therapy. If administration of 
E/P therapy is discontinued, G1T28 will also be discontinued. 


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8.4.2. 
Placebo 
The placebo formulation of 250 mL of D5W or sodium chloride solution 0.9% will be 
administered over 30 minutes. If there is any volume remaining in the infusion bag at the end 
of the 30 minutes, the infusion should be continued at the same rate until the entire contents 
of the bag have been administered to ensure patients receive the full dose. 
The interval between doses of placebo on successive days should not be greater than 
28 hours. Placebo will only be administered with E/P therapy. If administration of 
E/P therapy is discontinued, placebo will also be discontinued. 
8.4.3. 
Etoposide and Carboplatin 
Etoposide and carboplatin will be administered IV in accordance with the prescribing 
information (see Appendix 2) and according to the study site’s standard practice.  
Needles or IV administration sets containing aluminum parts that may come in contact with 
carboplatin should not be used for the preparation or administration of the drug. Aluminum 
can react with carboplatin causing precipitate formation and loss of potency. 
The interval between the dose of G1T28 or placebo and the first dose of chemotherapy 
on a given day (etoposide or carboplatin) should not be greater than 4 hours. 
Chemotherapy cannot be administered until after completion of the G1T28 or placebo 
infusion. If the second or third dose of G1T28 in any given cycle is not administered for 
any reason, do not administer the dose of etoposide chemotherapy on that day, since 
this could potentially exacerbate myelosuppression (see Section 8.4.4.1).    
8.4.3.1. 
Carboplatin 
The carboplatin dose will be calculated using the Calvert formula with a target AUC = 5 on 
Day 1 of each 21-day cycle and administered as an IV infusion over 30 minutes. The Calvert 
formula is as follows: 
Total carboplatin dose (mg) = (target AUC) × (GFR + 25)  
Because each patient’s estimated GFR will be based on serum creatinine measurements 
obtained using standardized isotope dilution mass spectrometry, the dose of carboplatin 
should be capped at 750 mg to avoid potential toxicity due to overdosing. The cap dose of 
750 mg for carboplatin is based on a GFR estimate that is capped at 150 mL/min for patients 
with normal renal function (ie, maximum carboplatin dose = target AUC of 
5 mg•min/mL × 150 mL/min = 750 mg). 
Refer to the carboplatin prescribing information (see Appendix 2) for details regarding 
preparation, administration, instructions and precautions. Premedications may be provided 
per local standard of care. 


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8.4.3.2. 
Etoposide 
Etoposide 100 mg/m2 will be administered as an IV infusion over 60 minutes on Days 1, 2, 
and 3 of each 21-day cycle. 
Refer to the etoposide prescribing information (see Appendix 2) for details regarding 
preparation, administration, instructions, and precautions. 
8.4.4. 
Dose Modifications 
8.4.4.1. 
G1T28 
To ensure the greatest level of safety when G1T28 is coadministered with chemotherapeutic 
agents, the magnitude and duration of G1T28-induced HSPC arrest was simulated using a 
PK/PD model and verified by performing bone marrow cell cycle analysis before or after 
administration of G1T28 IV at 192 mg/m2 to different groups of human subjects in the 
Phase 1a Study G1T28-1-01. G1T28 at a dose of 192 mg/m2 (rounded to 200 mg/m2 for this 
study) demonstrated robust bone marrow HSPC arrest for > 24 hours and was determined to 
be the BED (Section 4.2). It is unknown if lower doses will produce the same magnitude and 
duration of HSPC cell cycle arrest. Insufficient HSPC arrest (ie, for too short a duration) 
could result in the release of HSPCs into the S (DNA synthesis) phase of the cell cycle while 
chemotherapy is present, thereby potentially exacerbating myelosuppression. To minimize 
this risk, the dose of G1T28 will not be modified and will remain at 200 mg/m2 (or the 
adjusted dose from the Phase 1b dose-finding portion of Part 1 as described in 
Section 6.1.1) throughout the study. 
8.4.4.2. 
Modification of Etoposide and Carboplatin Dosing 
Patients should meet the laboratory parameter requirements outlined in Section 10.4 before 
initiation of Cycle 2 and each subsequent cycle of E/P therapy. All nonhematologic 
drug-related toxicities (except alopecia) should have resolved to Grade 1 or baseline before 
initiation of the next cycle of E/P therapy. 
Dose adjustments 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. Initiation 
of the next cycle of E/P therapy may be delayed by no more than 2 weeks to allow recovery 
from toxicity due to the chemotherapy agents. A treatment delay of > 2 weeks due to toxicity 
will lead to discontinuation of E/P therapy. 
No more than 2 dose reductions in total are allowed for any patient. Simultaneous reduction 
in the doses of etoposide and carboplatin will count as 1 dose reduction. Toxicity that 
requires dose reduction more than twice will lead to discontinuation of E/P therapy. Under 
this circumstance, administration of G1T28 should also be discontinued. All dose reductions 
are permanent and no dose increases are allowed. 
Since fatigue can be a symptom of cancer progression, dose reduction will only be performed 
if it is deemed to be drug-related in the opinion of the investigator. 


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The dose reductions in Table 8-1 will be utilized for the purpose of dose modifications for 
toxicity. 
Table 8-1 
Etoposide and Carboplatin Dose Reductions 
Dose level 
Etoposide (mg/m2) 
Carboplatin (AUC) 
Dose level -1 (first dose reduction) 
Reduce to 75 mg/m2 
Reduce to AUC = 4 
Dose level -2 (second dose reduction) 
Reduce to 50 mg/m2 
Reduce to AUC = 3 
AUC = area under the concentration-time curve 
 
Dose Modifications for Hematologic Toxicity 
First Day of Cycle 2 and Beyond 
In order to start Cycle 2 and subsequent cycles as scheduled, on Day 1 of the cycle, patients 
must have an ANC ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and nonhematologic 
drug-related toxicities (except alopecia) must be ≤ Grade 1 or have returned to baseline. The 
dose adjustments in Table 8-2 are based on the ANC and platelet counts on the first day of 
treatment for Cycle 2 and each subsequent cycle. 


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Table 8-2 
Etoposide and Carboplatin Dose Adjustments Based on Lack of Recovery 
of Absolute Neutrophil or Platelet Counts on the First Day of Cycle 2 and 
Each Successive Cycle 
Absolute Neutrophil 
Count < 1.5 × 109/L 
 
Etoposide 
 
Carboplatin 
First episode 
No change. Use G-CSF with subsequent 
cycles. Refer to the American Society of 
Clinical Oncology (ASCO) guidelines 
(Smith 2006). 
No change. Use G-CSF with 
subsequent cycles. Refer to ASCO 
guidelines (Smith 2006). 
 
Second episode 
 
First dose reduction 
 
First dose reduction 
 
Third episode 
 
Second dose reduction 
 
Second dose reduction 
 
Fourth episode 
 
Discontinue drug 
 
Discontinue drug 
Platelet Count < 100 x 109/L 
 
Etoposide 
 
Carboplatin 
First episode 
First dose reduction 
 
First dose reduction 
 
Second episode 
 
Second dose reduction 
 
Second dose reduction 
 
Third episode 
 
Discontinue drug 
 
Discontinue drug 
G-CSF = granulocyte colony-stimulating factor 
 
Neutrophils 
The dose adjustments in Table 8-3 are based on the ANC nadir with or without fever during 
the preceding treatment cycle. 


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Table 8-3 
Etoposide and Carboplatin Dose Adjustments Based on Absolute 
Neutrophil Count Nadir With or Without Fever 
Absolute Neutrophil 
Count Nadir 
 
Etoposide 
 
Carboplatin 
Grade 3 (without fever) 
No Change 
No change 
Grade 4 for ≥ 7 days  
(without fever) 
 
 
 
 
 
 
First episode 
No change. Use G-CSF with subsequent 
cycles. Refer to the ASCO guidelines 
(Smith 2006). 
No change. Use G-CSF with 
subsequent cycles.  Refer to ASCO 
guidelines (Smith 2006). 
 
Second episode 
 
First dose reduction 
 
First dose reduction 
 
Third episode 
 
Second dose reduction 
 
Second dose reduction 
 
Fourth episode 
 
Discontinue drug 
 
Discontinue drug 
Grade 3/4 with fever 
 
 
First episode 
No change. Use G-CSF with subsequent 
cycles. Refer to the ASCO guidelines 
(Smith 2006). 
No change. Use G-CSF with 
subsequent cycles. Refer to ASCO 
guidelines (Smith 2006). 
Second episode 
First dose reduction 
First dose reduction 
 
Third episode 
 
Second dose reduction 
 
Second dose reduction 
Fourth episode 
Discontinue drug 
Discontinue drug 
G-CSF = granulocyte colony-stimulating factor 
 
Platelets 
The dose adjustments in Table 8-4 are based on the platelet nadir during the preceding 
treatment cycle. 


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Table 8-4 
Etoposide and Carboplatin Dose Adjustment Based on Platelet Nadir 
Platelet Count Nadir 
Etoposide 
Carboplatin 
Grade 4 or ≥ Grade 3 with bleeding 
First episode 
First dose reduction 
First dose reduction 
 
Second episode 
 
Second dose reduction 
 
Second dose reduction 
 
Third episode 
 
Discontinue drug 
 
Discontinue drug 
 
Colony Stimulating Factors 
Patients will not receive colony stimulating factors (eg, granulocyte colony-stimulating 
factor [G-CSF]; granulocyte-macrophage colony-stimulating factor [GM-CSF]) or 
erythropoiesis stimulating agents (ESAs) during Cycle 1 (ie, prior to the actual Cycle 2 
Day 1 dosing visit). Subsequent use will be based on toxicities as outlined above. Please also 
refer to the ASCO guidelines (Smith 2006) for neutropenia. For a hemoglobin level 
< 9.0 g/dL or symptomatic anemia, ESAs may be used per the current prescribing 
information.  
When indicated, as outlined above in Table 8-2 and Table 8-3, either filgrastim or 
pegfilgrastim may be used per the prescribing information detailed in the package inserts (see 
Appendix 3). In the event a patient has a neutropenic event requiring G-CSF in the 
subsequent cycle, then filgrastim or pegfilgrastim should not be initiated until at least 
24 hours after dosing of the next subsequent cycle is complete (ie, no earlier than Day 4 of 
the next subsequent cycle). Filgrastim or pegfilgrastim should not be used to increase low 
neutrophil counts mid-cycle or prior to the start of the subsequent cycle.   
When indicated, epoetin alfa or darbepoetin alfa may be used to treat patients with anemia 
per the prescribing information detailed in the package inserts (see Appendix 4).     
8.4.4.2.1. 
Dose Modifications for Nonhematologic Toxicity 
Hepatic Toxicity 
The following dose adjustments for E/P are based on serum AST/ALT and bilirubin levels 
(Table 8-5) during the preceding treatment cycle. 


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Table 8-5 
Etoposide and Carboplatin Reduction for Hepatic Toxicity 
AST/ALT 
 
Bilirubin 
Etoposide 
Carboplatin 
 Grade 1 
> Grade 2a 
 
First episode 
 
Second episode 
 
Third episode 
and/ or 
and/or 
< Grade 2 
>Grade 3 
 
First episode 
 
Second episode 
 
Third episode 
No change 
 
 
First dose reduction 
 
Second dose reduction 
 
Discontinue drug 
No change 
 
 
First dose reduction 
 
Second dose reduction 
 
Discontinue drug 
a  
If baseline is Grade 2 in the presence of liver metastases, an increase of 1 Grade will result in the first dose level 
reduction 
 
Gastrointestinal toxicity 
Nausea and vomiting should be managed with the use of adequate antiemetic therapy. 
Prophylactic anti-emetic therapy can be used at the discretion of the treating physician. 
Patients are encouraged to take plenty of oral fluids. 
Diarrhea should be managed with appropriate antidiarrheal therapy. Patients should be 
encouraged to take plenty of oral fluids. 
Hypersensitivity Reactions 
For patients who had a mild to moderate hypersensitivity reaction and have been successfully 
re-challenged, careful attention to prophylaxis and bedside monitoring of vital signs is 
recommended for all subsequent doses. 
Mild symptoms (eg, mild flushing, rash, pruritus): complete infusion. Supervise at bedside. 
No treatment required. 
Moderate symptoms (eg, moderate rash, flushing, mild dyspnea, chest discomfort): stop 
infusion. Give IV diphenhydramine 25 mg and IV dexamethasone 10 mg. Resume infusion 
after recovery of symptoms at a low rate, 20 mg/hour. If no further symptoms occur after 
15 minutes, the rate may be increased to the full rate until the infusion is complete. If 
symptoms recur, the infusion must be stopped. The patient should receive no additional 
etoposide or carboplatin for that cycle, but may receive additional doses at the discretion of 
the investigator. 
Severe life-threatening symptoms (eg, hypotension requiring vasopressor therapy, 
angioedema, respiratory distress requiring bronchodilation therapy, generalized urticarial): 
stop infusion immediately. Give IV diphenhydramine and dexamethasone as above. Add 
epinephrine or bronchodilators if indicated. If wheezing is present, that is not responsive to 
bronchodilators, epinephrine is recommended. Patient should not receive any further doses of 
etoposide or carboplatin. Report this occurrence as an AE. 


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Other Toxicities 
For the first occurrence of any nonhematologic Grade 2 chemotherapy-related toxicity 
(except alopecia), all study treatments should be withheld until the toxicity recovers to Grade 
1 or baseline. Treatment may then be resumed at the same dose level. For the second 
occurrence of any nonhematologic Grade 2 chemotherapy-related toxicity (except alopecia), 
following recovery of the toxicity to Grade 1 or baseline, treatment should be resumed at 
dose level -1; for the third occurrence, the dose should be reduced to dose level -2. A fourth 
occurrence will result in discontinuation of E/P therapy. No dose reduction should be made 
for Grade 1 toxicities. 
For any Grade 3 or 4 chemotherapy-related toxicities not mentioned above, all study 
treatments should be withheld until the toxicity recovers to Grade 1 or baseline. Treatment 
should then be resumed at dose level -1 for the first occurrence and dose level -2 for the 
second occurrence. A third occurrence will result in discontinuation of E/P therapy. 
8.5. 
Randomization and Blinding 
Part 1 is open-label and no randomization or blinding will be required. 
Part 2 is randomized and blinded. Patients meeting all inclusion and exclusion criteria in 
Part 2 will be randomized 1:1 to receive G1T28 or placebo by an IWRS according to a 
randomization schedule generated by an unblinded statistician. Randomization of patients 
will be performed centrally and will be stratified by ECOG performance status (0 to 1 versus 
2). Each patient will be assigned a unique randomization number, which will not be reused.  
Each site will have an unblinded pharmacist/designee, who will have access to the treatment 
assignment to label and distribute the blinded study drug. The patients, investigators, other 
site staff involved in the clinical care of the patients, and the sponsor or designees involved in 
the conduct of the study will not be aware of the treatment group to which a particular patient 
has been randomized. If an investigator determines that a patient’s assignment should be 
unblinded for reasons of safety, this should be discussed with the medical monitor prior to 
unblinding, unless an urgent and immediate intervention is required that precludes this 
discussion. If unblinding of the treatment assignment is necessary, the investigator will 
obtain the treatment assignment details from the IWRS. Any unplanned unblinding must be 
communicated to the project manager and study statistician for documentation in the study 
files and the clinical study report.   
8.6. 
Prior and Concomitant Medications and Procedures 
All concomitant medications including prescription medications, over-the-counter 
preparations, growth factors, blood products, and parenteral nutrition taken during the 
14 days before the date of enrollment, during the study treatment, and through 30 days after 
the last dose of study drug will be documented. Documentation will include information 
regarding start and stop dates, dose(s), and reasons for the medication use.   
Administration of other concomitant nonprotocol anticancer therapies prior to progression is 
not permitted while on this study. 


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Administration of other concomitant investigational agents for any indication is not permitted 
while on this study. 
Concomitant radiation therapy treatment for SCLC will be regarded as disease progression, 
and is not permitted while on this study.  
Caution should be exercised when administering etoposide phosphate with drugs that are 
known to inhibit phosphatase activities (eg, levamisole hydrochloride). Although carboplatin 
has limited nephrotoxic potential, caution should be exercised when administering 
carboplatin with aminoglycosides, which has resulted in increased renal and/or audiologic 
toxicity. Any medication that is contraindicated when using etoposide or carboplatin is not 
permitted, and special warnings and precautions for use of carboplatin and etoposide should 
be observed.  
Necessary supportive care such as antiemetics, antidiarrheals, etc., per the standard of care at 
the study center will be permitted. Administration of hematopoietic growth factors in 
Cycle 1 will not be permitted (ie, no growth factors should be used prior to the actual 
Cycle 2 Day 1 dosing visit). However, hematopoietic growth factors may be utilized in 
subsequent cycles at the investigator’s discretion as stated in Section 8.4.4.2. To reduce 
potential immune system interactions, the use of dexamethasone as an antiemetic should be 
minimized where possible.  
G1T28 is a time-dependent inhibitor of CYP3A4 and is a substrate for CYP3A4. G1T28 
exposure may be altered by concomitant use of drugs that are strong CYP3A inhibitors or 
inducers. The exposure of drugs that are CYP3A substrates may be altered by concomitant 
use of G1T28 (Section 4.3.2).  
• Caution should be exercised with concomitant use of drugs that are strong CYP3A 
inhibitors (eg, aprepitant, clarithromycin, itraconazole, ketoconazole, nefazodone, 
posaconazole, telithromycin, verapamil, and voriconazole).  
• Caution should be exercised with concomitant use of drugs that are strong or 
moderate CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St John’s Wort, 
bosentan, modafinil, and nafcillin).   
• Caution should be exercised with concomitant use of drugs that are extensively 
metabolized by CYP3A. 
 
G1T28 is a potent inhibitor of MATE1, MATE2-K, OCT2 membrane transporters and 
therefore caution should be exercised with concomitant use of drugs that are substrates for 
these transporters (Section 4.3.2). 
Any diagnostic, therapeutic, or surgical procedures performed during the study period will be 
documented. Documentation will include information regarding the date(s), indication(s), 
description of the procedure(s), and any clinical or pathological findings.  
Medications will be coded using the most recent World Health Organization (WHO) Drug 
Dictionary version. 


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8.7. 
Transfusions 
Platelets should be transfused at a threshold of ≤ 10,000/µL. Platelets should also be 
transfused in any patient who is bleeding with a platelet count < 50,000/µL (100,000/µL for 
central nervous system or ocular bleeding). Please also refer to the American Society of 
Clinical Oncology (ASCO) guidelines (Smith 2006). 
Patients with hemoglobin < 8.0 g/dL or with symptomatic anemia can be treated with RBC 
transfusions at the investigators discretion.  
8.8. 
Prophylactic Cranial Irradiation  
Prophylactic cranial irradiation for patients without detectable brain metastases has been 
shown to decrease the frequency of subsequent intracranial relapse and improve survival for 
patients with SCLC (Aupérin A 1999; Slotman 2007). Therefore, patients with a confirmed 
CR are strongly encouraged to receive PCI after completion of chemotherapy. Patients with a 
confirmed PR should also consider PCI after completion of chemotherapy based on the 
investigator’s judgment. 
8.9. 
Treatment Compliance 
The investigator or designee will dispense the study medication, via an unblinded 
pharmacist/designee, 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. The investigator or other study staff will supervise each dose of the study drug 
administered in the clinic. The clinical study site will maintain records of study drug receipt, 
preparation, and dispensing, including the applicable lot numbers; patient’s height, body 
weight, and BSA; date and time of the start and end of each G1T28 or placebo, etoposide, 
and carboplatin infusion; and total drug administered in milligrams. Any discrepancy 
between the calculated dose and dose administered and the reason for the discrepancy will be 
recorded on the electronic case report form (eCRF) and in the source documents. 
 


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9. 
STUDY FLOWCHART 
The procedures and assessments to be performed during the study are outlined in Table 9-1.


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Table 9-1 
Schedule of Assessments 
  
Screen-
ing  
Enroll 
Cycle 1 and Every Odd Cyclea 
(21 days) 
Cycle 2 and Every Even Cyclea 
(21 days) 
Last Cycle 
Post-
Treatment 
Visitb 
Survival 
Follow-upc 
Cycle Day  
-14  
-3 to 1 
1 
2 
3 
8 
10 
15 
1 
2 
3 
8 
10 
15 
22 
 
 
Informed Consentd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Eval. 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance Status 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Physical Exam 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Height, Weight & 
Vital Signsf 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Clinical Chemistry 
X 
 
Xg 
 
 
X 
 
X 
Xg 
 
 
X 
 
X 
 
X 
 
Hematology 
X 
 
Xh 
 
X 
X 
X 
X 
Xh 
 
X 
X 
X 
X 
X 
X 
Xi 
Urinalysis 
X 
 
Xg 
 
 
 
 
 
Xg 
 
 
 
 
 
 
X 
 
ECG 
X 
 
Xj 
 
Xj 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy testk 
X 
  
X  
  
  
 
 
 
X  
  
  
 
 
 
 
  
 
Randomizationl 
X 
  
  
  
 
 
 
  
  
  
 
 
 
 
  
 
Tumor 
Assessmentm 
Xm2 
 
 
 
 
 
 
 
 
X 
 
Xm1,m2 
Xm1 
Tumor Testingn 
 X 
  
  
  
 
 
 
  
  
  
 
 
 
 
  
 
PKo 
  
X 
  
X 
 
 
 
  
  
  
 
 
 
 
  
 
G1T28 or Placebop 
  
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
 
  
 
Carboplatin 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Etoposide 
  
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
 
 
FACT-L and 
FACT-Anq 
  
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
Immunologic 
Markerr 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
AEss 
X 
X 
 
Con. Medications 
X 
X 
 
Survival 
Follow-upc 
 
 
X 
AE = adverse event; ECG = electrocardiogram; FACT-AN = Functional Assessment of Cancer Therapy – Anemia quality of life instrument; FACT-L = Functional Assessment of Cancer Therapy –
Lung quality of life instrument; PRO = patient reported outcome; Eval. = evaluation; PK = pharmacokinetics 


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a 
G1T28 or placebo + E/P therapy will continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator (eg, after completing 6 cycles). The tumor should 
be assessed after every even cycle. Assessments should be performed within 7 days of starting the subsequent cycle.  
b 
Patients will return to the study center for a Post-Treatment Visit at 30 days (+ 3 days) after the last dose of study drug.  
c 
Monthly phone calls will be made to each patient that is in the long-term Survival Follow-up Phase. Patients will be followed for survival until at least 50% of the patients in Part 2 have died. 
Any anticancer therapies used will be collected. In addition, blood samples for hematology and immunologic marker assessment will be collected at 60 ± 7 days after the Post-Treatment Visit for 
patients in Part 2 only.    
d 
Informed consent may be obtained up to 28 days prior to the first study treatment administration. 
e 
Including medical, surgical, radiation history, smoking history, family history, documentation of tumor diagnosis, baseline signs and symptoms within 4 weeks prior to randomization, weight 
loss in the 6 months prior to randomization (≤ 5% or > 5%), and medications taken within 14 days of enrollment. 
f 
Height will only be measured at the screening visit. Body surface area calculation (based on actual body weight) will be completed on Day 1 of each cycle and vital signs obtained immediately 
before and after G1T28 or placebo and E/P infusions. Vitals only need to be taken once between infusions.   
g 
Clinical chemistry will be obtained (albumin, alkaline phosphatase, total bilirubin, calcium, chloride, creatinine, glucose, inorganic phosphorus, potassium, total protein, ALT, AST, lactate 
dehydrogenase [LDH], sodium, and blood urea nitrogen [BUN]); see Section 11.3.2. Clinical chemistry and urine analysis may be obtained up to 72 hours prior to the first dose of each cycle of 
G1T28 or placebo + E/P therapy.  
h 
Hematology will be obtained (hemoglobin, hematocrit, WBCs with differential, and platelet counts); see Section 11.3.2. Hematology may be obtained up to 24 hours prior to first dose of each 
cycle of G1T28/placebo + EP therapy. 
i 
In Part 2 only, hematology will be collected at 60 days after the Post-Treatment Visit. 
j 
Patients participating in the Phase 1b dose-finding portion of Part 1 of the study, who have PK samples obtained, will have ECGs completed at the following time points on Days 1 and 3 of 
Cycle 1: predose, end of infusion (EOI) of G1T28, 2 hours (± 10 minutes) after the start of G1T28, and 6.5 hours (± 15 minutes) after the start of G1T28. The 2-hour ECG will be completed once 
the etoposide infusion is complete. 
k 
For female patients of childbearing potential, serum ß-hCG at screening; serum or urine ß-hCG  obtained up to 72 hours prior to Day 1 dose of G1T28 or placebo + E/P chemotherapy in each 
cycle.   
l 
For patients enrolled in Part 2, randomization is to be done within 3 days prior to first dose of G1T28 or placebo + E/P chemotherapy, following confirmation that the patient is eligible for the 
study. 
m 
For tumor assessment, all sites of disease should be assessed radiologically by CT or MRI at screening and after every even cycle, until the occurrence of disease progression. Additional scans 
may be obtained at the discretion of the investigator, if clinically indicated. If a patient shows a radiological response (CR or PR), a confirmatory radiological assessment will be performed at 
least 4 weeks after the response was first noted. Assessments should be performed within 7 days of starting the subsequent cycle. The same method of assessment (CT or MRI) should be used to 
characterize tumors at screening and at all follow-up assessments. If positron emission tomography is used, it should also be accompanied by spiral CT or MRI.  
 
m1: At the Post-Treatment Visit, obtain tumor assessment for patients who have not progressed at the time of study drug discontinuation (may be performed within 4 weeks). For those patients in 
the survival follow-up who have not progressed at the time of study drug discontinuation, tumor assessments, including all sites of disease, will be assessed radiologically by CT or MRI, as 
performed at screening, every 2 months (approximately 60 ± 7 days) until the occurrence of progressive disease or study completion. 
 
m2: Brain scans with contrast (by CT or MRI) to be obtained with tumor assessment at screening (within 28 days of dosing) and at the Post-Treatment Visit 
n 
Send archived tumor samples to a central pathology laboratory to confirm the diagnosis of SCLC. Available tissue after confirming the diagnosis of SCLC will be banked for assessment of 
relevant DNA, RNA, and protein markers, such as those involved in the CDK4/6 pathway. If central pathology review does not confirm SCLC diagnosis, the patient may be withdrawn from the 
study after consultation between the principal investigator, medical monitor, and sponsor. This should be done as soon as possible after a patient has enrolled in the study. 
o 
Patients enrolled in Cohort 1 of the Phase 1b dose-finding portion of Part 1 will have G1T28, etoposide, and carboplatin PK samples collected on Days 1 and 3 (as applicable) of Cycle 1 at the 
time points specified in Section 11.2. Collection of PK blood samples from patients enrolled in additional cohorts of the Phase 1b dose-finding portion of Part 1 is optional.  


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p 
G1T28 or placebo will be administered as an IV infusion in 250 mL of D5W or sodium chloride solution 0.9% over 30 minutes prior to E/P chemotherapy on Days 1 to 3 of every cycle (see 
Section 8.1). If there is any volume remaining in the G1T28 or placebo infusion bag at the end of the 30 minutes, the infusion should be continued at the same rate until the entire contents of the 
bag have been administered to ensure patients receive the full dose.  The interval between doses of G1T28 or placebo on successive days should not be greater than 28 hours. The interval 
between the dose of G1T28 or placebo and the first dose of chemotherapy on a given day (etoposide or carboplatin) should not be greater than 4 hours. G1T28 or placebo will only be 
administered with E/P therapy. If administration of E/P therapy is discontinued, G1T28 or placebo should also be discontinued. Chemotherapy cannot be administered until after completion of 
the G1T28 or placebo infusion. If the second or third dose of G1T28 in any given cycle is not administered for any reason, do not administer the dose of etoposide or carboplatin chemotherapy 
on that day (see Section 8.1). After discontinuation of study drug, patients should be strongly encouraged to complete all scheduled assessments through the end of their current 21-day treatment 
cycle, including the patient-reported outcome (PRO) scales; CBC assessment on Day 22; the Post-Treatment Visit; and the Survival Follow-up Phase of the study. 
q 
Patient-reported outcomes should be completed at Days 1 and 10 of each cycle and at the Post-Treatment Visit. If a cycle is delayed, the patient should still complete the PRO on the scheduled 
Day 1 of the next cycle, as well as the actual first dosing day of the next cycle of G1T28 or placebo + E/P therapy. Patient-reported outcomes may be obtained up to 24 hours prior to the first 
dose of each cycle of G1T28 or placebo + E/P therapy.  
r 
In Part 2 only, peripheral blood samples for immunologic marker assessment will be collected at predose on Day 1 of Cycles 1, 3, and 5; at the Post-Treatment Visit, and at 60 days after the 
Post-Treatment Visit. 
s 
Adverse events will be recorded from the time of informed consent. 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. 
SCHEDULE OF STUDY PROCEDURES 
Study procedures are summarized across all study visits within the schedule of assessments 
(Table 9-1). Both Parts 1 and 2 of the study will follow the same study schedule, except 
where noted below. 
10.1. 
Screening 
Patients should be screened no more than 14 days before the first dose of study treatment is 
administered. Written informed consent must be obtained from each patient before the 
initiation of any screening procedures. Informed consent and brain scans may be obtained up 
to 28 days prior to the first study treatment administration. After a patient has given informed 
consent, eligibility will be determined by a review of the inclusion/exclusion criteria and 
completion of all screening procedures outlined in Table 9-1 and listed below.  
• Collection of demographics 
• Collection of medical history 
• ECOG performance status evaluation 
• Physical examination 
• Height, weight, and vital signs measurements 
• Clinical chemistry, hematology, and urinalysis tests  
• Electrocardiogram  
• Pregnancy test 
• Tumor assessment (by CT scan or MRI; see details in Section 11.5.1); CT or MRI scans 
obtained prior to informed consent will not need to be repeated if performed within 
14 days prior to dosing.  
• Brain scan with contrast (by MRI or CT); brain MRI or CT scans obtained prior to 
informed consent will not need to be repeated if performed within 28 days prior to 
dosing.  
Adverse events and concomitant medications will be monitored continuously from the time 
of informed consent through the Post-Treatment Visit.  
10.2. 
Enrollment  
Eligibility will be determined prior to enrollment, randomization (Part 2), and the start of 
study treatment. Eligible patients will be instructed on all protocol requirements, including 
any restrictions on concomitant medication usage. 
For Part 2 of the study, randomization will be performed within 3 days of the first dose of 
G1T28 or placebo + E/P chemotherapy, following confirmation that the patient is eligible for 
the study. 
Archived tumor samples must be sent to a central pathology laboratory to confirm the 
diagnosis of SCLC. Available tissue after confirming the diagnosis of SCLC will be banked 
for assessment of relevant DNA, RNA, and protein markers, such as those involved in the 
CDK4/6 pathway (see Section 11.4). This should be done as soon as possible after a patient 


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has enrolled in the study. If central pathology review does not confirm SCLC diagnosis, the 
patient may be withdrawn from the study after consultation between the principal 
investigator, medical monitor, and sponsor. For additional guidance regarding the shipment 
of samples to the central pathology laboratory, please refer to the Laboratory Manual. 
10.3. 
Cycle 1 
Adverse events and concomitant medications will be monitored throughout the study. Safety 
surveillance reporting of AEs commences at the time informed consent and continues 
through the Post-Treatment Visit.  
Cycle 1 Day 1 
Enrolled patients will return to the study center on study Day 1. The following procedures 
will be performed and results reviewed before study drug administration: 
• ECOG performance status evaluation 
• Physical examination 
• Weight and vital signs measurements 
• Clinical chemistry, hematology, and urinalysis tests (note: clinical chemistry and 
urinalysis tests may be obtained up to 72 hours prior to the first dose of each cycle of 
study treatments, and hematology tests may be obtained up to 24 hours prior to the first 
dose of each cycle of study treatments). For the Phase 1b dose-finding portion of 
Part 1, Cycle 1 only, the clinical chemistry and hematology results may be reviewed 
prior to or after dosing, depending on the availability of the lab report. For Day 1 of all 
subsequent cycles, the clinical chemistry and hematology results should be reviewed 
before dosing. 
• Electrocardiogram (as applicable and optional after Cohort 1, predose, Cycle 1 in the 
Phase 1b dose-finding portion of Part 1 only) 
• Plasma PK sample (as applicable and optional after Cohort 1, predose, Cycle 1 in the 
Phase 1b dose-finding portion of Part 1 only) 
• Pregnancy test (note: may be obtained up to 72 hours prior to the first dose of each cycle) 
• Functional Assessment of Cancer Therapy – Lung quality of life (QOL) instrument 
(FACT-L) and Functional Assessment of Cancer Therapy –Anemia QOL instrument 
(FACT-An) Questionnaires 
• Immunologic marker blood sample collection (predose, Part 2 only) 
The timing for critical assessments/procedures is outlined in Table 9-1.  
Patients that still meet all of the eligibility criteria will begin treatment Cycle 1. The first 
dose of study treatments (G1T28 or placebo + E/P chemotherapy) will be administered (as 
described in Section 8.1) and all Day 1 postdose procedures outlined in Table 9-1 will be 
completed. Postdose assessments on Day 1 are as follows: 
• Vital signs (obtained immediately before and after G1T28 or placebo infusion, and 
etoposide and carboplatin infusions; only needed once between infusions) 
• Electrocardiogram (as applicable, end of infusion [EOI] of G1T28, 2 hours 
(± 10 minutes) after the start of G1T28, and 6.5 hours (± 15 minutes) after the start of 


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G1T28, Cycle 1 in the Phase 1b dose-finding portion of Part 1 only). The 2-hour ECG 
will be completed once the etoposide infusion is complete. 
• Plasma PK samples (as applicable and optional after Cohort 1, postdose samples as 
described in Section 11.2, Cycle 1 in the Phase 1b dose-finding portion of Part 1 only) 
 
Cycle 1 Days 2, 3, 8, 10, and 15 
All procedures and assessments to be conducted during Cycle 1 Days 2, 3, 8, 10, and 15 are 
outlined in Table 9-1. The DMC may recommend decreasing the frequency of hematological 
evaluations based on accumulating data. The investigators and institutional review boards 
(IRBs) will be notified if the frequency is reduced. 
At Day 2 and Day 3, study treatments (G1T28 or placebo + etoposide) will be administered 
(as described in Section 8.1). 
At Day 3 in Cycle 1 of the Phase 1b dose-finding portion of Part 1 only, the following 
additional assessments will be performed: 
• Electrocardiogram (as applicable, predose, EOI, and 2 hours (± 10 minutes) and 6.5 hours 
(± 15 minutes) after the start of G1T28) 
• Plasma PK sample (as applicable and optional after Cohort 1, predose and postdose 
samples as described in Section 11.2) 
10.4. 
Cycle 2 
Adverse events and concomitant medications will be monitored throughout the study. Safety 
surveillance reporting of AEs commences at the time of informed consent and continues 
through the Post-Treatment Visit. 
Cycle 2 Day 1 
Patients will return to the study center on Cycle 2 Day 1. The following procedures will be 
performed and results reviewed before study drug administration: 
• ECOG performance status evaluation 
• Physical examination 
• Weight and vital signs measurements (calculate BSA)  
• Clinical chemistry, hematology, and urinalysis tests (note: clinical chemistry and 
urinalysis tests may be obtained up to 72 hours prior to the first dose of each cycle of 
study treatments, and hematology tests may be obtained up to 24 hours prior to the first 
dose of each cycle of study treatments) 
• Pregnancy test (note: may be obtained up to 72 hours prior to the first dose of each cycle) 
• FACT-L and FACT-An Questionnaires 
Vital signs should be obtained immediately before and after G1T28 or placebo, etoposide, 
and carboplatin infusions; only once between infusions. 


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In order to start Cycle 2 and subsequent cycles as scheduled, on Day 1 of the cycle, patients 
must have an ANC ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and nonhematologic 
drug-related toxicities (except alopecia) must be ≤ Grade 1 or have returned to baseline. Dose 
modifications based on lack of recovery to these absolute neutrophil and platelet counts on 
the first day of treatment for Cycle 2 are outlined in Table 8-2. A delay of up to 2 weeks is 
permitted to allow recovery from any toxicity in order to meet the continuation criteria for 
organ function. If the patient meets the criteria for starting the subsequent cycle as stated in 
protocol Section 6.1.3, a delay of up to 1 week is permitted for administrative reasons (eg, 
holiday, vacation, etc.). If a cycle is delayed, the patient should still complete the clinical 
laboratory assessments and the FACT-L and FACT-An questionnaires on the scheduled Day 
1 of the next cycle, as well as the actual first dosing day of the next cycle of G1T28 or 
placebo + E/P therapy. 
A patient will be discontinued from the study if recovery from any toxicity, in order to meet 
the continuation criteria for organ function, and any delay for administrative reasons requires 
a total delay of > 2 weeks.   
Study treatments (G1T28 or placebo + E/P chemotherapy) will be administered as described 
in Section 8.1.  
Cycle 2 Days 2, 3, 8, 10, and 15 
All procedures and assessments to be conducted during Cycle 2 Days 2, 3, 8, 10, and 15 are 
outlined in Table 9-1. The DMC may recommend decreasing the frequency of hematological 
evaluations based on accumulating data. The investigators and IRBs will be notified if the 
frequency is reduced. 
For Cycle 2 Day 2 and Day 3, study treatments (G1T28 or placebo + etoposide) will be 
administered as described in Section 8.1. 
For tumor assessment, all sites of disease should be assessed radiologically by CT or MRI at 
screening and after every even cycle, until the occurrence of disease progression. CT or MRI 
scans obtained as standard of care prior to informed consent will not need to be repeated if 
performed within 14 days prior to dosing. Additional scans may be obtained at the discretion 
of the investigator, if clinically indicated. If a patient shows a radiological response (CR or 
PR), a confirmatory radiological assessment will be performed at least 4 weeks after the 
response was first noted. The same method of assessment (CT or MRI) should be used to 
characterize tumors at screening and at all follow-up assessments. 
10.5. 
Cycles 3, 4, and Subsequent Cycles 
Procedures and assessments to be performed during Cycle 3 and all subsequent odd 
numbered cycles are similar to Cycle 1 (see Section 10.3 and Table 9-1).  
Procedures and assessments to be performed during Cycle 4 and all subsequent even 
numbered cycles are similar to Cycle 2 (see Section 10.4 and Table 9-1).  
In order to start each subsequent cycle as scheduled on the first day of the cycle, patients 
must have an ANC ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and nonhematologic 


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drug-related toxicities (except alopecia) must be ≤ Grade 1 or have returned to baseline. Dose 
modifications based on lack of recovery to these absolute neutrophil and platelet counts on 
the first day of treatment for each subsequent cycle are outlined in Table 8-2. A delay of up to 
2 weeks is permitted to allow recovery from any toxicity in order to meet the continuation 
criteria for organ function. If the patient meets the criteria for starting the subsequent cycle as 
stated in protocol Section 6.1.3, a delay of up to 1 week is permitted for administrative 
reasons (eg, holiday, vacation, etc.). A patient will be discontinued from the study if recovery 
from any toxicity, in order to meet the continuation criteria for organ function, and any delay 
for administrative reasons requires a total delay of > 2 weeks. 
After discontinuation of study drug, patients should be strongly encouraged to complete all 
scheduled assessments through the end of their current 21-day treatment cycle, including the 
patient-reported outcome (PRO) scales; CBC assessment on Day 22; the Post-Treatment 
Visit; and the Survival Follow-up Phase of the study, which is to continue until at least 50% 
of randomized patients in Part 2 have died. 
10.6. 
Post-Treatment Visit 
Patients will return to the study center for a Post-Treatment Visit within 30 days from the last 
dose (+ 3 days). The following procedures will be performed at this visit: 
• ECOG performance status evaluation 
• Physical examination 
• Weight and vital signs measurements 
• Clinical chemistry, hematology, and urinalysis tests  
• Electrocardiogram 
• Tumor assessment (obtain tumor assessment by CT scan or MRI for patients who have 
not progressed at the time of study drug discontinuation [may be performed within 
4 weeks]); see details in Section 11.5.1) 
• Brain scan with contrast (obtain brain scans by MRI or CT for patients who have not 
progressed at the time of study drug discontinuation [may be performed within 4 weeks]) 
• FACT-L and FACT-An Questionnaires 
• Immunologic markers blood sample collection (Part 2 only) 
 
For patients who have a confirmed CR, it is strongly recommended that they receive PCI 
after completion of chemotherapy. Patients with a confirmed partial response should also 
consider PCI after completion of chemotherapy based on the investigator’s judgment. 
After completing the Post-Treatment Visit, patients will enter the long-term Survival 
Follow-up Phase. 
10.7. 
Survival Follow-up Phase 
Monthly phone calls will be made to each patient that is in the long-term Survival Follow-up 
Phase. Patients will be followed for survival at a minimum until 50% of the patients 
randomized to Part 2 of the study have died. In addition, for patients who have not had 
disease progression at the time of study drug discontinuation, tumor assessments, including 
all sites of disease, will be assessed radiologically by CT or MRI, as performed at screening, 


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every 2 months (approximately 60 ± 7 days) until the occurrence of progressive disease or 
study completion.   
The following information will be collected monthly for all patients: 
• Survival status 
• Details of any anticancer treatment  
The following additional information will be collected at 60 ± 7 days after the 
Post-Treatment Visit (Part 2 only):  
• Immunologic markers blood sample collection  
• Hematology sample collection  
10.8. 
Study Drug Discontinuation 
After discontinuation of study drug, patients should be strongly encouraged to complete all 
scheduled assessments through the end of their current 21-day treatment cycle, including the 
patient-reported outcome (PRO) scales; CBC assessment on Day 22; the Post-Treatment 
Visit; and the Survival Follow-up Phase of the study, which is to continue until at least 50% 
of randomized patients in Part 2 have died. Any abnormal results that are believed to be 
related to the study drug treatment should be repeated as often as deemed appropriate by the 
investigator until the abnormality resolves, returns to predose levels, or is otherwise 
explained. 
10.9. 
Unscheduled Visits 
Additional visits can be performed as appropriate and at the discretion of the investigator. 


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11. 
STUDY ASSESSMENTS  
11.1. 
Efficacy Assessments 
Efficacy evaluation will be based on the following: kinetics of changes in CBCs; 
hematologic toxicities, including febrile neutropenia and infections; RBC and platelet 
transfusions; hematopoietic growth factor utilization; systemic antibiotic use; chemotherapy 
dose reductions and dose interruptions; alopecia; mucositis; nephrotoxicity; fatigue; and 
FACT-L and FACT-An. All of these variables, except for the PROs, will be assessed as 
described in the safety assessments (monitoring of AEs, clinical laboratory assessments, 
study treatment exposure, and concomitant medications) (see Section 11.3 and Table 9-1). 
PROs are described in Section 11.6. 
The toxicity of G1T28 administered IV with E/P therapy will be assessed using the NCI 
CTCAE, Version 4.03. 
11.2. 
Pharmacokinetic Assessments  
In the Phase 1b dose-finding portion of Part 1 of the study, serial blood samples (5-mL 
samples) will be collected for measurement of G1T28, etoposide, and carboplatin 
concentrations in plasma at the time points outlined below and in Table 9-1. Comprehensive 
information on blood sample acquisition, the specific type of collection tube with 
anticoagulant, and handling and storage are to be found in the Laboratory Manual. The 
analytical laboratory will measure plasma concentrations of G1T28, etoposide, and 
carboplatin using a validated method. Any remaining sample may be stored long term for the 
future analysis of G1T28 drug metabolites. 


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Phase 1b Dose-Finding Portion of Part 1: Cycle 1 Day 1 
Blood samples will be collected at the following time points on Cycle 1 Day 1 for all patients 
enrolled in Cohort 1 of the Phase 1b dose-finding portion of Part 1 of the study: predose 
(0 hour; prior to dosing of G1T28) and at 0.5 (end of infusion [EOI] of G1T28), 1 (EOI of 
carboplatin), 1.5, 2 (EOI of etoposide), 2.5, 3, 4.5, 6.5, 8.5 (optional time point, if approved 
by the sponsor in advance), and 24.5 hours postdose (relative to the start of G1T28 infusion).  
Collection of PK blood samples in additional cohorts of the Phase 1b dose-finding portion of 
Part 1 is optional. The EOI sample for G1T28 should be drawn 2 to 5 minutes prior to the 
EOI. The EOI samples for G1T28, carboplatin, and etoposide must be drawn after 
completing infusion of the drugs and the actual times at which the samples were drawn 
should be documented. A ± 5-minute time window will be allowed for samples collected 
between the following time points: predose to 2.5 hours after the end of G1T28 infusion. 
A ± 10-minute time window will be allowed for samples collected between the following 
time points: 3 to 8.5 hours after the end of G1T28 infusion. A ± 1-hour time window will be 
allowed for the 24.5 hours after the end of G1T28 infusion time point. The actual time of 
blood sample collection should be documented in the eCRF. The Cycle 1 Day 1 sampling 
scheme is summarized in Table 11-1.   
Table 11-1 
Day 1 of Cycle 1 Blood Sampling Scheme Based on Predicted 
Administration Times of G1T28, Carboplatin, and Etoposide 
Sample 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Sample  
Time (h) 
0 
(Predosea) 
0.5b 
(G1T28 
EOI) 
1 
(Carbo 
EOI) 
1.5 
2 
(Etop 
EOI) 
2.5 
3 
4.5 
6.5 
8.5 
(optionalc) 
24.5 
Carbo = carboplatin; EOI = end of infusion; Etop = etoposide; h = hour 
Times are approximate. For simplicity, assumptions were based on 0.5 hour increments. Actual times will be recorded and 
may vary from those listed here. 
a 
Predose is defined as prior to dosing of G1T28. 
b 
The EOI sample for G1T28 should be drawn 2 to 5 minutes prior to the EOI. 
c 
8.5 hour sample (optional time point, if approved by the sponsor in advance) 
 


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Phase 1b Dose-Finding Portion of Part 1: Cycle 1 Day 3 
Blood samples will be collected at the following time points on Cycle 1 Day 3 for all 
Cohort 1 patients enrolled in the Phase 1b dose-finding portion of Part 1 of the study: predose 
(0 hour; prior to dosing of G1T28) and at 0.5 (EOI of G1T28), 1, 1.5 (EOI of etoposide), 2, 
2.5, 3.5, 4.5, 6.5, 8.5 (optional time point, if approved by the sponsor in advance), and 
24.5 hours postdose (relative to the start of G1T28 infusion). Collection of PK blood samples 
in additional cohorts of the Phase 1b dose-finding portion of Part 1 is optional. The EOI 
sample for G1T28 should be drawn 2 to 5 minutes prior to the EOI. The EOI samples for 
G1T28 and etoposide must be drawn after completing infusion of the drugs and the actual 
times at which the samples were drawn should be documented. Time window parameters 
noted above for Cycle 1 Day 1 also apply to Cycle 1 Day 3. The Cycle 1 Day 3 sampling 
scheme is summarized in Table 11-2. 
Table 11-2 
Day 3 of Cycle 1 Blood Sampling Scheme Based on Predicted 
Administration Times of G1T28 and Etoposide 
Sample 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Sample  
Time (h) 
0 
(Predosea) 
0.5b 
(G1T28 
EOI) 
1 
1.5 
(Etop 
EOI) 
2 
2.5 
3.5 
4.5 
6.5 
8.5 
(optionalc) 
24.5 
EOI = end of infusion; Etop = etoposide; h = hour 
Times are approximate. For simplicity, assumptions were based on 0.5 hour increments. Actual times will be recorded and 
may vary from those listed here. 
a 
Predose is defined as prior to dosing of G1T28. 
b 
The EOI sample for G1T28 should be drawn 2 to 5 minutes prior to the EOI. 
c 
8.5 hour sample (optional time point, if approved by the sponsor in advance) 
 
Pharmacokinetic Parameters 
Pharmacokinetic parameters to be derived from G1T28, etoposide, and carboplatin plasma 
concentration-time data are presented in Table 11-3. 


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Table 11-3 
Pharmacokinetic Parameters 
Cmax 
The observed peak plasma concentration determined from the plasma concentration vs. time data 
Tmax 
The time to reach the observed peak plasma concentration from the plasma concentration vs. time 
data 
AUC0-t 
Area under the plasma concentration-time curve from 0 to t hours after dosing, calculated by 
linear/log trapezoidal method 
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. The correlation coefficient (r2) for the 
goodness of the fit of the regression line through the data points has to be 0.80 or higher, for the 
value to be considered reliable.   
t1/2 
Terminal half-life, defined as 0.693 divided by λz 
AUC0-∞ 
Area under the concentration-time curve from time-zero extrapolated to infinity, calculated as: 
z
Clast
AUClast
AUC
l
+
=
inf
 
where Clast is the last quantifiable concentration in the terminal elimination phase. 
CL 
Clearance after intravenous administration, calculated as: 
inf
AUC
Dose
CL =
 
Vz 
Volume of distribution in the terminal elimination phase, calculated as: 
z
λ
CL
Vz =
 
 
Pharmacokinetic samples may also be obtained from additional patients depending on the 
outcome of initial PK analysis. 
11.3. 
Safety Assessments 
Safety evaluations will be conducted at baseline and throughout the study. Safety evaluations 
will include monitoring of AEs, vital signs measurements, physical examinations, ECGs, 
clinical laboratory studies, infusion-related reactions, tumor response based on RECIST, 
Version 1.1 (see Section 11.5), PFS, and overall survival. 
The toxicity of G1T28 administered IV with chemotherapy will be assessed by the 
investigators using the NCI CTCAE, Version 4.03. 


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11.3.1. 
Adverse Events and Serious Adverse Events 
11.3.1.1. 
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. 
An abnormal laboratory value is not an AE unless it is considered to be clinically significant. 
Adverse events include the following: 
• All suspected adverse drug reactions (ADRs) 
• 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 will 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 
• Disease progression 
An unexpected AE is any AE that is not identified in nature, severity, or frequency in the 
current Investigator Brochure or product information. 
• 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 


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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 International Conference on Harmonisation (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 remain alert to 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. 
In the event of an AE, the primary concern is the safety of the patient. If necessary, 
appropriate medical intervention should be provided, and the investigational drug 
discontinued. 
11.3.1.2. 
Definition of Serious Adverse Event 
The 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 11.3.1.9) 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. 


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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 
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. 
11.3.1.3. 
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). 
11.3.1.4. 
Assessment of the Relationship of Adverse Events to Study Drug 
The investigator will determine the assessment of the causal relationship of the AE to the 
study drug. 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. 
• Unlikely Related: There is a temporal relationship to study drug administration, but there 
is not a reasonable causal relationship between the study drug and the AE (ie, the AE is 
doubtfully related to study drug). 
• Possibly Related: There is a reasonable causal relationship between the study drug and 
the AE. Information related to withdrawal of study drug is lacking or unclear. 
• Probably Related: There is a reasonable causal relationship between the study drug and 
the AE. The event responds to withdrawal of study drug. Re-challenge is not required. 
• Definitely 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. 
11.3.1.5. 
Assessment of the Outcome of Adverse Events 
The action taken for study drugs (eg, dose increased, dose not changed, dose reduced, dose 
interrupted, drug withdrawn, not applicable, unknown) will be recorded on the eCRF.  
Other actions (eg, none, concomitant medication given, new or prolonged hospitalization, 
procedural surgery) will also be recorded on the eCRF. 


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The outcome will be assessed according to the following: 
• Fatal 
• Not recovered/not resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Recovered/resolved 
• Unknown 
11.3.1.6. 
Method, Frequency, and Time Period for Detecting Adverse Events and 
Serious Adverse Events 
Safety surveillance reporting of AEs commences at the time of informed consent and 
continues through 30 days after last dose of study drug (eg, the Post-Treatment Visit). 
11.3.1.7. 
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 11.3.1.2) will be additionally documented on the SAE report 
form. For AEs occurring while the patient is in the clinic setting, ie, before, during, or after 
study drug administration, the start time and stop time of the AE should be recorded in the 
source document. 
The following will be recorded for each AE in the eCRF: 
• A description of the AE in medical terms, not as reported by the patient. Whenever 
possible, a diagnosis should be given when signs and symptoms are due to common 
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be 
reported as “upper respiratory infection”). 
• Date of onset (start date) 
• Date of recovery (stop date) 
• Grade as assessed by the investigator according to the definitions in the AE Grading 
Scale. If the AE is not specifically listed in Appendix 1, use the following grades: 
Grade 1 
mild 
Grade 2  
moderate 
Grade 3 
severe 
Grade 4 
life-threatening or disabling 
Grade 5 
death 


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11.3.1.8. 
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 Medical Dictionary for Regulatory Activities 
(MedDRA) as specified in the statistical analysis plan (SAP). 
11.3.1.9. 
Reporting of Serious Adverse Events 
The reporting period for SAEs begins from the time of informed consent through and 
including 30 calendar days after the last administration of G1T28 or placebo + E/P therapy. 
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. 
All SAEs must be entered into the eCRF and the initial SAE form should be completed and 
sent to the safety team within 24 hours of first knowledge of the event by the study 
personnel. The contact information for the safety team will be provided in the Site Reference 
Manual. 
In addition, any known untoward event that occurs subsequent to the AE-reporting period 
that the investigator assesses as related to the investigational medication should also be 
reported as an AE. 
11.3.1.10. 
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 death or AE occurring at any time after a patient has discontinued or 
terminated study participation that may reasonably be related to the study drug.  


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After study conclusion, the investigator should notify G1 Therapeutics of any death or AE 
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. G1 Therapeutics 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. 
11.3.1.11. 
Regulatory Aspects of Adverse Event Reporting 
Unexpected serious adverse reactions are subject to expedited reporting to the Food and Drug 
Administration (FDA), the Medicines and Healthcare Products Regulatory Agency (MHRA), 
and European National Competent Authorities in other Member States, if applicable, in an 
expedited time frame in compliance with current legislation. All SAEs must be entered into 
the eCRF and the initial SAE form should be completed and sent to the medical monitor 
/drug safety team within 24 hours of first knowledge of the event by the study personnel. 
The investigator is encouraged to discuss with the medical monitor any adverse experiences 
for which the issue of reportability is unclear or questioned. 
It is important that the investigator provide his/her assessment of relationship to study drug at 
the time of the initial report. The following information must be reported on the eCRF SAE 
report form: 
• Protocol number 
• Site and/or investigator number 
• Patient number 
• Demographic data 
• Brief description of the event 
• Onset date and time 
• Resolution date and time, if the event has resolved 
• Current status, if event has not yet resolved 
• Any concomitant treatment and medication 
• Investigator’s assessment of whether the SAE was related to investigative product or not 
• Outcome of the event if available 
 
The medical monitor or member of the safety team will contact the site for clarification of 
data entered in the eCRF, or to obtain missing information. In the event of questions 
regarding SAE reporting, the site may contact the medical monitor or a member of the safety 
team. The contact information for the medical monitor and safety team will be provided in 
the Site Reference Manual. 
G1 Therapeutics, or their designee, is responsible for submitting reports of AEs associated 
with the use of the drug that are both serious and unexpected to FDA, MHRA, and European 
National Competent Authorities in other Member States, if applicable, in an expedited time 
frame in compliance with current legislation. Unexpected serious adverse that are already 
reported to the European Medicines Agency Eudravigilance database do not have to be 
reported again to the relevant authorities.  All investigators participating in ongoing clinical 


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studies with the study medication will receive copies of these reports for prompt submission 
to their IRB or independent ethics committee. 
11.3.1.12. 
Handling of Overdoses and Toxicity 
No information on treatment of overdose of G1T28 is currently available. General supportive 
measures should be used as appropriate. 
11.3.1.13. 
Reporting of Pregnancies  
Pregnancy per se 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. Hospitalization for normal delivery of a healthy newborn should not be 
considered a SAE. 
Each pregnancy in a study patient or partner of a study patient must be reported to the 
sponsor within 24 hours of learning of its occurrence. If a patient becomes pregnant, study 
drug administration must be discontinued immediately. The pregnancy should be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. Follow-up and documentation must occur even if the patient 
withdraws from the study or the study is completed. 
The avoidance of pregnancy or fathering a child (including sperm donation) is suggested for 
3 months following the discontinuation of study drug. No information is currently available 
regarding the effects of G1T28 on fertility, gestation, or subsequent child development. 
11.3.2. 
Clinical Laboratory Assessments 
Blood samples will be collected for clinical laboratory assessments as outlined in Table 9-1. 
The following clinical laboratory tests will be performed: 
• Hematology (hemoglobin, hematocrit, white blood cells [WBCs] with differential and 
platelet counts) 
• Chemistry (albumin, alkaline phosphatase [ALP], total bilirubin, calcium, chloride, 
creatinine, glucose, inorganic phosphorus, potassium, total protein, ALT, AST, LDH, 
sodium, and BUN) 
• Urinalysis (semiquantitative dipstick: specific gravity, pH, evaluation of glucose, protein, 
bilirubin, ketones, leukocytes, and hemoglobin; and a microscopic examination, 
including RBC, WBC, and casts will be performed, if necessary) 
If the subsequent cycle is delayed, the patient should still complete the clinical laboratory 
assessments on the scheduled Day 1, as well as on the actual first dosing day of the next 
cycle.  
Laboratory parameters will be analyzed by a local certified laboratory and a report of the 
laboratory values will be sent to the study center. The investigator will review the laboratory 
report within 24 hours (except during clinic holidays, when review will be performed within 
72 hours) after receipt of the results and indicate the clinical significance of all abnormal 


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values, and subsequently sign and file the laboratory report with the patient’s source 
records/charts. Laboratory parameters for which clinically significant values are noted will be 
re-measured on the appropriate clinical follow-up arranged by the investigator. Values will 
be documented on the laboratory report until stabilized, or the laboratory value returns to a 
clinically acceptable range (regardless of relationship to study medication). Any laboratory 
value that remains abnormal at the end of the study and that is considered clinically 
significant will 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 will be assessed using the NCI CTCAE, Version 4.03 (see Appendix 1). 
The DMC may recommend decreasing the frequency of hematological evaluations based on 
accumulating data. The investigators and IRBs will be notified if the frequency is reduced. 
11.3.3. 
Demographics and Vital Signs 
The following will be collected: 
• Height in centimeters (cm) 
• Body weight in kilogram (kg) 
• Body temperature (Celsius) 
• Systolic and diastolic blood pressure, pulse rate, and respiration rate will be measured 
with the patient. Blood pressure should be assessed after 5 minutes of rest. 
11.3.4. 
Physical Examination 
Full physical examination evaluations at screening should include general appearance, skin, 
neck, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and 
neurological examinations. Subsequent physical exams should include body systems as 
appropriate. 
Information about the physical examination must be present in the source documentation at 
the study site. The result of the physical examination prior to the start of study drug must be 
included in the relevant eCRF. Clinically relevant findings made after the start of study drug, 
which meet the definition of an AE, must be recorded on the AE eCRF. 
11.3.5. 
Electrocardiogram Assessments 
Standard 12-lead ECGs will be performed as outlined in Table 9-1. Obtain ECGs in the 
Phase 1b dose-finding portion of Part 1 only if PK samples are also obtained. Patients should 
rest for 5 minutes prior to each ECG assessment.  
The investigator or designee should review the ECGs for any abnormalities as compared with 
predose ECGs.  
11.3.6. 
Concomitant Medications 
Review of concomitant medications will occur at the times outlined in Table 9-1. See 
Section 8.6 for more information on concomitant medications. 


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11.4. 
Central Pathology Review to Confirm Diagnosis of SCLC  
Archived tumor samples should be sent to the central pathology laboratory as soon as 
possible after enrollment to confirm the diagnosis of SCLC. Available tissue after confirming 
the diagnosis of SCLC will be banked for assessment of relevant DNA, RNA, and protein 
markers, such as those involved in the CDK4/6 pathway (as described in the Laboratory 
Manual). If central pathology review does not confirm SCLC diagnosis, the patient may be 
withdrawn from the study after consultation between the principal investigator, medical 
monitor, and sponsor. Archived tumor samples may also be used for future genomic testing 
related to the mechanism of drug action. 
11.5. 
Tumor Response 
11.5.1. 
Tumor Assessments 
For tumor assessment, all sites of disease should be assessed radiologically by CT or MRI at 
screening and after every even cycle, until the occurrence of disease progression (see 
Table 9-1). CT or MRI scans obtained prior to informed consent will not need to be repeated 
if performed within 14 days prior to dosing. Assessments should be performed within 7 days 
of starting the subsequent cycle. Additional scans may be obtained at the discretion of the 
investigator, if clinically indicated. If a patient shows a radiological response (CR or PR), a 
confirmatory radiological assessment will be performed at least 4 weeks after the response 
was first noted. For patients who have a confirmed CR, it is strongly recommended that they 
receive PCI after completion of chemotherapy. Patients with a confirmed partial response 
should also consider PCI after completion of chemotherapy based on the investigator’s 
judgment (see Section 8.8). For those patients who have not progressed at the time of study 
drug discontinuation, tumor assessments, including all sites of disease, will be assessed 
radiologically by CT or MRI, as performed at screening, every 2 months (approximately 
60 ± 7 days) until the occurrence of progressive disease or study completion. 
The same method of assessment (CT or MRI) should be used to characterize tumors at 
screening and at all follow-up assessments. If PET is used, it should also be accompanied by 
spiral CT or MRI. 
Investigators should follow the RECIST, Version 1.1 guidelines (Eisenhauer 2009) for tumor 
assessments.  
11.5.2. 
Tumor Lesions: Identification and Follow-up 
11.5.2.1. 
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 
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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. 
11.5.2.2. 
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 nontarget lesions and recorded in the eCRF. Measurements of these lesions are 
not required, but the presence, absence, or unequivocal progression of each nontarget lesion 
should be recorded in the eCRF at each follow-up time point. Multiple nontarget lesions in 
the same organ may be noted as a single item on the eCRF.  
11.5.2.3. 
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 


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• 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 exiting bone lesions, necrosis of a liver lesion) should not be considered new 
lesions. 
11.5.3. 
Definitions of Tumor Response and Disease Progression 
The determination of SCLC 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: 
11.5.3.1. 
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.  
• 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. 
11.5.3.2. 
 Evaluation of Nontarget Lesions 
• Complete response (CR): Disappearance of all nontarget lesions and normalization of 
tumor marker level. All lymph nodes must be < 10 mm short axis. 
• Non-CR/Non-PD: Persistence of 1 or more nontarget lesions and/or maintenance of 
tumor marker level above the normal limits. 
• Progressive Disease (PD): Unequivocal progression of existing nontarget lesions or the 
appearance of at least 1 new lesion.  
11.5.3.3. 
Evaluation of Overall Response 
Patients who have at least 1 postdose tumor assessment (CT scan or MRI) will be considered 
evaluable for tumor response.  
Table 11-4 describes the evaluation of overall response at each time point based on target and 
nontarget lesion responses at each time point, as well as the appearance of new lesions. The 


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best overall response is the best response recorded from the start of the treatment until 
disease progression. Confirmation of CR and PR is required as described in Sections 11.5.3.1 
and 11.5.3.2.  
Table 11-4 
Evaluation of Overall Response at Each Time Point 
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) 
11.6. 
Patient Reported Outcomes 
The FACT-L and FACT-An instruments will be administered to the patients by a designated 
trained study site staff member. The instruments will be administered in the clinic for the 
baseline assessment (on or within 1 day prior to initiation of study treatment), at Day 1 of 
each cycle, Day 10 of each cycle (may be administered by phone if the patient is unable to 
return to clinic), and at the Post-Treatment visit. If the subsequent cycle is delayed, the 
patient should still complete the PRO on the scheduled Day 1, as well as on the actual first 
dosing day of the next cycle. Where possible, the same staff member will administer the 
instrument at each site. 
Both the FACT-L and FACT-An contain a core general questionnaire that measures physical, 
social/family, emotional, and functional well-being. The FACT-L has an additional lung 
cancer subscale (FACT-L) (Cella 1995). The FACT-An has an additional subscale that 
measures the impact of fatigue and other anemia-related symptoms on patients with cancer 
(FACT-An) (Yellen 1997). The core general questionnaire is the same for both instruments; 
as such, at each assessment, the core questionnaire will be administered once along with the 
lung and anemia subscales.   
11.7. 
Immunologic Markers 
The addition of G1T28 to standard chemotherapy could provide clinical benefit to patients 
with CDK4/6-independent cancers through the reduction of myelosuppression-related side 
effects and improved chemotherapy activity. There are at least 2 potential mechanisms by 
which G1T28 may improve chemotherapy activity: maintaining dose intensity and 
maintaining immune system function through repeated cycles of chemotherapy. In addition 
to the common side effects that result from myelosuppression, chemotherapy-induced 
immunosuppression may limit response rates and survival due to an inability of the damaged 
host immune system to effectively mount a response against the cancer. The impact of 
chemotherapy on the host immune system has been shown to be a double-edged sword, 
where the specific chemotherapeutic agent and dosing regimen (low dose versus standard 


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dosing) dictate the impact on the immune system. Chemotherapeutic agents may elicit part of 
their antitumor efficacy by modulating the immune system to enhance antigen presentation, 
uptake, and processing; prime the immune response through immunodepletion; inhibit 
regulatory cells; and stimulate immune effector cells (Zitvogel 2008; McDonnell 2011; 
Bracci 2014). Conversely, immunosuppression from direct cytotoxicity to the bone marrow 
and immune system over repeated cycles of chemotherapy may counterbalance the positive 
immunostimulatory effects of chemotherapy. Preclinical mouse models have shown that 
chemotherapeutic response is more robust in tumors transplanted into immunocompetent 
mice compared to immunodeficient mice, suggesting that the loss of immune system function 
is detrimental to the overall efficacy of the chemotherapy (Apetoh 2007; Casares 2005). In 
support of these data, severe lymphopenia (< 1000 cells/µL) in patients with breast cancer, 
advanced soft tissue sarcoma, and non-Hodgkin lymphoma has been shown to negatively 
affect progression-free and overall survival (Ray-Coquard 2009). Since immune 
reprogramming is now believed to be an important mechanism of chemotherapy response, 
therapeutic approaches to maintain bone marrow health and immune system function should 
enhance this activity. Therefore, to evaluate the impact of G1T28 administration on 
chemotherapy-induced changes of the immune system, peripheral blood immune subsets will 
be characterized in patients enrolled into Part 2 of the study. Immunophenotypic changes will 
be compared between patients receiving E/P therapy plus placebo or G1T28. To assess these 
changes, peripheral blood will be collected at predose on Day 1 of Cycles 1, 3, and 5; at the 
Post-Treatment Visit, and at 60 days after the Post-Treatment Visit. 
 
Immunophenotyping 
Whole blood samples (15 mL) for immunophenotyping will be obtained from patients 
enrolled in Part 2. Comprehensive information on the blood sample acquisition, the specific 
type of collection tubes with anticoagulant, and handling and storage are to be found in the 
laboratory manual.   
11.8. 
Appropriateness of Measurements 
The measures of efficacy, PK, and safety evaluated in this study are based on the mechanism 
and activity of G1T28, standard types of assessments typically performed in patients with 
SCLC, and prior clinical observations derived from patients receiving E/P therapy for SCLC. 
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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12. 
STUDY TERMINATION OR STUDY DRUG 
DISCONTINUATION 
12.1. 
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  
 
12.2. 
Site Termination 
A study site will 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. 
12.3. 
Discontinuation of Study Drug 
Study drug will 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 
• 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 radiologically documented disease progression 
In the event of study drug discontinuation, patients should be strongly encouraged to 
complete all scheduled assessments through the end of their current 21-day treatment cycle, 
including the PRO scales; CBC assessment on Day 22; the Post-Treatment Visit; and the 
Survival Follow-up Phase of the study. A patient who discontinues study treatment for 
reasons other than PD will have a CT or MRI scan at the Post-Treatment Visit, if they have 
not had a scan within the prior 4 weeks.  
The investigator will document the reason for study drug discontinuation on the applicable 
eCRF page.   
When discontinuation is due to a SAE or a Grade 3 or 4 toxicity considered to be related to 
study medication, the investigator should follow the event until resolution, return to baseline, 


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or it is deemed that further recovery is unlikely. Data on these events should be collected on 
the AE CRF. 
In the event a patient discontinues due to an AE or pregnancy, the investigator should notify 
the medical monitor by telephone within 48 hours of study drug discontinuation. 
12.4. 
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. The following list of reasons for withdrawing 
patients from the study may include but are not limited to: 
• Withdrawal of informed consent 
• Lost to follow-up (must have at least 2 documented attempts to contact the patient; 
1 attempt must be written to the patient and sent via certified letter) 
• If central pathology review does not confirm SCLC diagnosis, the patient may be 
withdrawn from the study after consultation between the principal investigator, medical 
monitor, and sponsor 
All data collected prior to the date of withdrawal of consent will remain in the clinical 
database.  
 


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13. 
STATISTICS 
Full details on the statistical analyses to be performed will be provided in a separate 
statistical analysis plan (SAP). 
13.1. 
Sample Size and Power 
The sample size for this study is determined by clinical rather than statistical considerations. 
Up to 40 patients (open-label, dose-finding cohort[s] and an open-label, expansion cohort) 
will be enrolled in Part 1 of the study and 70 patients will be enrolled in Part 2 of the study 
(randomized). With 35 patients, the precision for point estimates in each arm is as follows: 
the 95% confidence interval (CI) width for binary endpoints based on Wilson score intervals 
are at most the observed proportion ± 0.157. The 95% CI width for continuous endpoints 
using the t-distribution are the observed mean ± 0.344*standard deviation of the endpoint. 
13.2. 
General Considerations 
13.2.1. 
Analysis Populations/Sets 
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 population for analysis. 
The safety population includes all enrolled patients who received at least 1 dose of study 
drug. The safety population will be conducted on the basis of the actual treatment received. 
All safety analyses will be assessed using the safety population. 
A per-protocol (PP) subset may also be used to analyze select endpoints and will be based on 
study drug exposure (compliance and/or time on study drug) and major protocol deviations. 
The criteria for inclusion in the PP subset will be finalized and documented prior to 
unblinding patients in Part 2 of the study. 
The PK set will include all dosed patients in Part 1 with evaluable PK data. 
13.2.2. 
Timing of Analyses 
13.2.2.1. 
Interim Safety Reviews 
A DMC will monitor accumulating safety data according to a charter that defines its roles 
and responsibilities. The DMC will perform reviews approximately every 4 months during 
the Treatment Phase of Part 2, depending upon the enrollment rate. Additional reviews may 
occur based on DMC requests. The committee will consist of individuals with extensive 
multicenter clinical study experience drawn from the fields of clinical oncology (specifically, 
SCLC) 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 
and strategy for maintaining study blind, are described in the DMC charter. 


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No interim analyses of efficacy are planned. 
13.2.2.2. 
Final Analysis 
The final analysis will occur when the last patient completes the Post-Treatment Visit. All 
study data collected up through the time of the final analysis data cut, including Follow-Up 
Survival Phase results, will be included in the final analysis. Unblinding will occur at the 
time of the final analysis. 
13.2.2.3. 
End of Study Analysis 
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. 
13.2.3. 
General Considerations for Data Analysis 
All statistical analyses will be performed using SAS® version 9 or higher.  
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 G1T28 + E/P therapy minus placebo + E/P 
therapy. Select safety summaries will include combined data from both Part 1 and Part 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 means, 
medians, standard deviations, and minimum and maximum values. The descriptive 
summaries of time to event data will include median, twenty-fifth and seventy-fifth 
percentiles and standard error. All data will be listed for all patients. Unless specified 
otherwise, safety summaries will include all collected data, and summaries of efficacy will 
include data collected through the Treatment Phase. 
This study is descriptive in nature, and no formal hypothesis testing will be performed across 
treatment groups. All CIs will be 95%, unless stated otherwise. 
The effects of covariates and withdrawal from study treatment due to reasons other than 
death, disease progression, and toxicity will be assessed to determine the impact on the 
general applicability of results from this study. Further details of the analysis, including the 
handling of missing data, impact of variable chemotherapy dose exposure including dose 
reductions, transformations and other data handling procedures will be provided in a separate 
SAP. Exploratory analyses of the data will be conducted as deemed appropriate.  
Summaries that are based on within-cycle, including changes, events, or findings, will 
require a clear definition of “end of cycle” that accounts for variable durations in the cycle 
due to within-cycle dosing delays, delays in subsequent cycle initiation, and incomplete 
cycles. This will be discussed in the SAP for each applicable endpoint. 
Protocol violations will be fully defined and documented before unblinding. 


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13.3. 
Baseline and Demographic Characteristics 
Demographics and baseline characteristics will be summarized descriptively.  
13.4. 
Efficacy Analysis 
13.4.1. 
Efficacy Endpoints 
Unless otherwise stated, the terminology ‘hematologic parameters’ refers to ANC, 
lymphocyte, hemoglobin, and platelet counts; the terminology ‘hematologic toxicities’ refers 
to neutropenia, lymphopenia, anemia, and thrombocytopenia. Each parameter and toxicity 
will be evaluated individually, but are described as such to avoid repetition. Hematologic 
toxicities are assigned based on CTCAE, Version 4.03.  
• Hematologic kinetic endpoints: 
• Change and percent change in hematologic parameter values from baseline to the 
Post-Treatment Visit 
• Change and percent change in hematologic parameter values from predose for a 
particular cycle to the end of that cycle 
• Change and percent change in hematologic parameter values from predose for a 
particular cycle to nadir for that cycle 
• Rate of change in hematologic parameter values from predose for a particular cycle to 
nadir for that cycle 
• Change and percent change in hematologic parameter values from nadir for a 
particular cycle to the end of that cycle 
• Rate of change in hematologic parameter values from nadir for a particular cycle to 
the end of that cycle 
• Area under the curve in hematologic parameter values from predose for a particular 
cycle to the end of that cycle 
• Area under the curve in hematologic parameters from predose for a particular cycle to 
nadir for that cycle 
• Area under the curve in hematologic parameter values from nadir for a particular 
cycle to the end of that cycle 
• By cycle and overall study hematologic parameter nadir values 
• Time to hematologic parameter value nadir by cycle 
• Time to return to predose hematologic parameter values by cycle 
• Proportion of patients with a return to predose hematologic parameter values by cycle 
 
• Hematologic toxicity endpoints: 
• Incidence of Grade 3 and 4 hematologic toxicities 
• Total number of Grade 3 and 4 hematologic toxicities 
• Proportion of patients with a hematologic toxicity recovery by cycle 
• Time to hematologic toxicity recovery by cycle 
 


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• Chemotherapy exposure and compliance endpoints: 
• Duration on treatment 
• Number of cycles received 
• Dose intensity and cumulative dose 
• Incidence of dose interruptions, delays, and reductions  
• Incidence of dose delays due to hematologic toxicity 
• Incidence of study treatment termination due to hematologic toxicity 
 
• Other efficacy endpoints: 
• Incidence of infections overall and by severity 
• Incidence of RBC and platelet transfusions  
• Incidence of hematopoietic growth factors use 
• Incidence and duration of systemic antibiotic use 
 
• Exploratory efficacy endpoints: 
• Incidence of Grade 2 or greater nephrotoxicity 
• Incidence of alopecia and mucositis 
• Functional Assessment of Cancer Therapy QOL instrument (FACT) total scale score 
(general) 
• FACT domain scores (physical, social/family, emotional, and functional well-being) 
• FACT-L total scale score 
• FACT-L lung cancer subscale score 
• FACT-L trial outcome index score 
• FACT-An total scale score 
• FACT-An anemia subscale score 
• FACT-An trial outcome index score 
• Composite hematologic score (this will be specified a priori in a SAP) 
• Composite efficacy score (this will be specified a priori in a SAP) 
 
13.4.2. 
Methods of Analysis for Efficacy Endpoints 
Summaries of efficacy will be performed using the FAS. Select summaries will also be 
repeated in the PP analysis set. Unless noted otherwise, hematologic endpoints will be 
summarized separately by each parameter type (ie, ANC, lymphocytes, etc.). The SAP will 
describe in detail the minimum sampling and dosing requirements for inclusion in the 
analysis of each endpoint for a given cycle or overall, particularly for those that involve 
AUC, nadir, and end of cycle results. Sensitivity analyses may be performed to assess the 
impact of incomplete dosing within a cycle or missing sampling times.  
13.4.2.1. 
Analysis of Hematologic Parameter Kinetic Endpoints 
Hematologic parameter values will be tabulated with descriptive statistics using absolute 
counts, change, and percent change values. By-visit tabulations will include values at study 


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baseline (ie, prior to first dose of study treatment) and each postbaseline visit through all 
cycles and the Post-Treatment Visit. Changes and percent changes will be calculated at each 
postbaseline value. Additional tabulations for each cycle of treatment will include predose, 
nadir, maximum postnadir, and end of cycle values. The change and percent changes from 
predose to nadir, predose to end of cycle, nadir to maximum postnadir, and nadir to end of 
cycle values will also be tabulated for each cycle of treatment. Analysis of covariance 
(ANCOVA) models will be performed for summaries on Part 2, separately at each visit and 
for each of the following parameters as dependent variables: change from baseline and 
percent change from baseline. Analysis of covariance models will be performed separately at 
each cycle and for each of the following parameters as dependent variables: predose (for 
cycles 2 and onward), nadir, the Post-Treatment Visit counts, change from predose to nadir, 
predose to end of cycle, nadir to maximum postnadir, and nadir to end of cycle; and percent 
change from predose to nadir, predose to end of cycle, nadir to maximum postnadir, and 
nadir to end of cycle. The models will include terms for treatment, ECOG at entry (0 and 1 or 
2), and baseline hematologic parameter value. The least square (LS) mean for each treatment 
group and LS mean difference between treatment groups will be reported. The treatment by 
ECOG interaction and treatment by baseline hematologic value will be tested. If a significant 
treatment by ECOG interaction exists, the LS means and LS mean differences will be 
reported at each level of ECOG at entry. If a treatment by baseline hematologic parameter 
interaction exists, the LS means and LS mean differences will also be reported at various 
levels of the covariate (10%, 25%, 50%, 75%, 90%). Two-sided 95% CIs will be constructed 
around the LS mean differences in treatment groups. 
The most extreme Treatment Phase nadir value and the cycle at which the most extreme 
nadir occurred will be summarized descriptively. Time to nadir will be summarized 
descriptively for each cycle and is calculated for each cycle and defined as date of nadir 
minus predose date + 1. 
The AUC in hematologic parameters will be tabulated for each cycle, separately for the 
following windows within a cycle: predose to end of cycle (AUCEOC), predose to nadir 
(AUCNadir), and nadir to end of cycle (AUCNEOC). Analysis of covariance models similar to 
those described above will be performed separately at each cycle using each of the AUC 
parameters as dependent variables. Additionally, a repeated-measures model of AUC 
parameters over all cycles will be performed for each AUC measure separately, with fixed 
effects for treatment, treatment cycle, treatment by cycle interaction, baseline hematologic 
value, and ECOG at entry. The unstructured covariance model will be used to tabulate the LS 
means for each treatment group and the LS mean difference between treatment groups at 
each cycle. Two-sided 95% CIs will be constructed around the LS mean differences in AUC 
between treatment groups. An analysis accounting for cumulative dose exposure at each 
cycle will be performed to support the evaluation of AUC over cycles. 
The proportion of subjects that return to predose values will be summarized by cycle for each 
hematologic parameter. Percentages for by-cycle summaries will be based on the number of 
patients treated in the cycle. For tabulations performed based on data collected in Part 2, the 
difference in rates between treatment groups will be calculated. Two-sided 95% CIs will be 
constructed around the difference in treatment groups. If there are substantial dose 
reductions, an incidence rate, adjusting for cumulative exposure, may be reported to account 
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Time to return to predose levels will be estimated for each cycle using the Kaplan-Meier 
method. Time to return to predose levels is defined for all patients as the number of days 
from nadir to the first postnadir date of levels greater or equal to predose levels prior to end 
of cycle. A clinically meaningful +/- predose level window will be defined for each 
hematologic parameter and specified in the SAP. Time to return to postnadir predose levels is 
also calculated from the start of the cycle (first dose in the cycle). Patients who do not return 
to predose levels within the window will be censored at the last date with nonmissing results. 
The same analysis will be repeated on the subset of patients that had a Grade 3 or higher 
toxicity.  
13.4.2.2. 
Analysis of Hematologic Toxicity Endpoints 
The number and percentage of patients with Grade 3 and 4 hematologic toxicities at each 
cycle and overall during the Treatment Phase will be tabulated for each type of hematologic 
toxicity and across all type of hematologic toxicities. Percentages for by-cycle summaries 
will be based on the number of patients treated in the cycle. For tabulations performed based 
on data collected in Part 2, the difference in rates between treatment groups will be 
calculated. Two-sided 95% CIs will be constructed around the difference in treatment groups. 
If there are substantial dose reductions, an incidence rate, adjusting for cumulative exposure, 
may be reported to account for differing amount of exposure by cycle. 
The total number of Grade 3 and 4 hematologic toxicities will be summed over the entire 
Treatment Phase per patient, separately for each type of hematologic toxicity and across all 
types of hematologic toxicities. To account for differing amount of exposure, a toxicity rate 
will be calculated for each patient, and defined relative to cumulative exposure (total number 
of toxicities divided by cumulative exposure). A recurrent events model may be performed to 
estimate the incidence of Grade 3 or higher hematologic toxicities and test for the difference 
between treatment groups.  
For each hematologic parameter and cycle, the following shift summaries will be performed: 
from predose toxicity to maximum ontreatment toxicity; from predose toxicity to end of 
cycle toxicity; from maximum postdose toxicity to end of cycle toxicity.  
Hematologic recovery will be defined in the SAP. The number and percentage of patients 
with hematologic recovery will be calculated at each cycle. Time to postdose recovery within 
a cycle will be estimated using the Kaplan-Meier method. A Cox proportional hazard model 
adjusted for baseline hematologic toxicity and ECOG will also be performed. 
13.4.2.3. 
Analysis of Chemotherapy Exposure and Compliance 
The following parameters will be summarized by treatment group and overall: total duration 
of treatment, total number of cycles received, cumulative dose of E/P therapy received, and 
number and percentage of patients experiencing one or more dose delay, interruption, and 
reduction. The following parameters will be summarized for each cycle by treatment group 
and overall: number and percentage of patients receiving dose at the cycle, experiencing one 
or more dose delay, interruption, and reduction, and cumulative dose of E/P therapy received. 
The number and percentage of patients experiencing a treatment cycle delay due to a 
hematologic toxicity will be summarized by cycle and overall. The number and percentage of 


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patients discontinuing study treatment due to a hematologic toxicity and cycle of 
discontinuation will also be summarized. 
13.4.2.4. 
Other Efficacy Endpoints 
Infections, RBC and platelet transfusions, systemic antibiotic use, and hematopoietic growth 
factor use will be summarized with the number and percentage of patients experiencing the 
event any time during the Treatment Phase of the study. For tabulations performed based on 
data collected in Part 2, the difference between treatment groups will be calculated and 
reported as described for the incidence of hematologic endpoints. 
The number and percent of infections will also be summarized by maximum severity. The 
infection rate will be calculated as the number of infections occurring during the Treatment 
Phase divided by cumulative exposure.  
13.4.2.5. 
Analysis of Exploratory Efficacy Endpoints 
Grade 2 or higher nephrotoxicity, alopecia, and mucositis will be summarized with the 
number and percentage of patients experiencing the event any time during the Treatment 
Phase. For tabulations performed based on data collected in Part 2, the difference between 
treatment groups will be calculated and reported as described for the incidence of 
hematologic toxicity. 
The FACT scores will be calculated per the FACIT version 4 scoring instructions and 
summarized by visit. The change from baseline in each score will be calculated and 
presented at each postbaseline visit. Additionally the change from predose to Day 10 and 
change from predose to end of cycle values will be calculated and presented at each cycle. 
Analysis of covariance models may be performed for summaries on Part 2, similarly to those 
described in Section 13.4.2.1. The extreme (best and worst) onstudy values and minimum 
and maximum change will also be analyzed. The number and percent of patients that have 
clinically relevant improvements or deteriorations will be summarized. 
A single composite endpoint taking into account multiple types of hematologic parameters 
and other clinically relevant measures is of interest to capture the efficacy of G1T28 + E/P 
therapy. A composite endpoint will be defined a priori in a SAP. Factors such as infection 
rate, toxicity rates, chemotherapy dose reductions and/or interruptions, incidence of 
transfusions, incidence of growth factor use, AUC, etc. may be included. The association 
between composite endpoints and best overall response, overall survival, and PFS may be 
explored.  
Similarly, identifying a composite hematologic score that represents ANC, lymphocytes, 
platelets, and hemoglobin in a meaningful way will be defined a priori in the SAP. 
13.5. 
Safety Analysis 
13.5.1. 
Safety Endpoints 
• Incidence of treatment-emergent AEs, SAEs, related AEs, related SAEs, and AEs leading 
to study drug discontinuation 


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• Infusion-related reactions 
• Vital signs 
• Physical examination 
• ECG readings 
• Clinical hematology, chemistry, and urinalysis results 
• Concomitant medications 
• Tumor response and best overall response based on RECIST, Version 1.1 
• Progression-free survival 
• Overall survival 
13.5.2. 
Methods of Analysis for Safety Endpoints 
The safety analysis will be performed in all patients who have received at least 1 dose of 
study drug. Adverse event data will be coded to system organ class and preferred term using 
MedDRA (Version 17.1, or later). Treatment emergence is defined as any AE occurring on 
or after the day of first dose through the Post-Treatment Visit. The number and percentage of 
patients experiencing any treatment-emergent AE overall and by system organ class and 
preferred term will be tabulated. The incidence rates by cycle and adjusted by exposure time 
will also be presented. Each AE will be counted only once for a given patient at each level of 
summarization. In analyses of grade and causality, if the same AE occurs on multiple 
occasions, the highest grade and strongest relationship to study drug will be assumed. 
Infusion-related reactions will be tabulated separately from the AEs. 
Absolute values and changes from baseline in vital signs, ECG readings, and hematology and 
clinical chemistry parameters will be tabulated at each visit during the Treatment Phase. 
Toxicities for clinical labs will be characterized according to the CTCAE, Version 4.03. 
Shifts in toxicity grades from baseline to each visit will be summarized.  
Overall disease responses as determined by RECIST, Version 1.1 will be summarized by 
response level at each visit and best overall response. The number of patients with a 
confirmed objective disease response, defined as patients with a best overall response of 
confirmed CR or PR obtained during the Treatment Phase, will be summarized.  
Progression-free survival is measured from date of first dose date until date of documented 
disease progression or death and will be estimated using the Kaplan-Meier method. Patients 
who have not died or had documented disease progression at the time of analysis will be 
censored on the last onstudy date with nonmissing tumor response data.  
Overall survival is measured from date of enrollment until death and will be estimated using 
the Kaplan-Meier method. Patients alive at the time of analysis will be censored on the last 
date the patient was known to be alive.  
Censoring techniques that account for missing tumor assessments and potential differences in 
the duration of time patient has onstudy tumor assessments may be applied for PFS data. The 
methods will be described in the SAP. 


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13.6. 
Exploratory Analyses 
Exploratory analyses examining the relationship between hematologic toxicity rates and 
hematologic changes with study drug exposure will be performed based on rate of 
chemotherapy interruptions and rate of chemotherapy reductions.  
Exploratory analyses will be performed to assess the impact of hematologic kinetics on 
overall survival, PFS, and best overall response rate. Similarly, exploratory analyses will be 
performed to assess the impact of cumulative chemotherapy exposure on overall survival, 
PFS, and best overall response rate. Exploratory analyses will be described in the SAP. 
The relationship between G1T28 plasma concentration and hematologic parameter values 
will be assessed with the Pearson product-moment correlation statistics.  
13.7. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be based on the PK set, and all analysis and reporting of 
plasma concentration and PK parameter data will be performed separately for each analyte.  
During Part 1 of the study, serial blood samples will be collected on Days 1 and 3 of Cycle 1 
to determine G1T28, etoposide, and carboplatin plasma concentrations. Plasma concentration 
data will be tabulated descriptively and graphed at each visit and time point. Pharmacokinetic 
parameters will be calculated with noncompartmental methods (WinNonlin Version 6.3 or 
higher) based on the plasma concentration-time data. The following PK parameters will be 
calculated (when data permit their calculation): Cmax, Tmax, AUC0-t, AUC0-∞, t1/2, CL, and Vz. 
Pharmacokinetic parameters will be summarized descriptively by visit and analyte. If 
applicable, G1T28 plasma concentration and PK parameters will also be summarized by dose 
level.  
Exploratory PK modeling and simulations may also be performed. 
13.8. 
Immunologic Markers 
To evaluate the impact of G1T28 administration on chemotherapy-induced changes of the 
immune system, peripheral blood immune subsets will be characterized in patients enrolled 
into Part 2 of the study. The immunophenotypic change from baseline will be listed and 
summarized by treatment arm, if data warrant. 
  
Additional exploratory analyses on the relationship between the immunophenotypic changes 
and safety and efficacy findings may be performed.  
 


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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
An eCRF must be completed for each patient enrolled. Each completed eCRF, as well as 
records for those patients who discontinue the study, will require a signature by the principal 
investigator at the study site. If a patient withdraws from the study, the reason must be noted 
on the eCRF, and if a patient is withdrawn from the study because of a treatment-limiting 
AE, thorough efforts should be made to clearly document the outcome. The investigator 
should 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 by the investigator.  
A comprehensive validation check program will verify the data and discrepancy reports will 
be generated accordingly for resolution by the investigator. As patients complete the study 
(or withdraw) and their signed eCRFs become available for review, a comparison check will 
be run to identify and resolve any discrepancies in the data base.  


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15. 
ETHICS AND PROTECTION OF HUMAN PATIENTS 
15.1. 
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 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. 
15.2. 
Institutional Review Board/Independent Ethics Committee 
The protocol and all associated amendments and consent/assent materials will be reviewed 
and approved by the investigative site’s local IRB or a central 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 IRB prior to 
initiating the study. Approval must be obtained in writing via a letter identifying the protocol, 
the date of the IRB meeting, and the date of approval. Any modifications made to the 
protocol after receipt of the IRB approval must also be submitted by the investigator to the 
IRB in accordance with local procedures and regulatory requirements. Any updates to the 
protocol should receive IRB approval or favorable opinion, which should be documented in a 
letter to the investigator, prior to implementation. 
15.3. 
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. 
15.4. 
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, 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. 


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15.5. 
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 sponsor 
will provide this protocol to the IRB and appropriate local regulatory authorities for approval. 
Any protocol amendments will be done in accordance with the provisions agreed upon in 
Section 15.6. 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. 
15.6. 
Protocol Amendments 
Protocol modifications must be prepared by a representative of the sponsor and initially 
reviewed and approved by the sponsor. 
All protocol modifications must be submitted to the appropriate IRB or independent ethics 
committee for information in accordance with local requirements. Approval must be awaited 
before changes can be implemented (ie, if the risk benefit ratio is affected and/or the 
modification represents a change in basic trial definitions such as objectives, design, sample 
size, and outcome measures), except for those changes which would decrease risk to the 
patient or administrative changes.  All substantial protocol amendments must have approval 
from the relevant competent regulatory authority before changes can be implemented.   
15.7. 
Patient Compliance 
Patients must be available for all scheduled study visits. Any reason for patient 
noncompliance will be documented. 
15.8. 
Study Discontinuation 
Both the sponsor and the investigator reserve the right to terminate the study at any time, 
according to the terms specified in the study contract. The investigator should notify the IRB 
in writing of the study’s completion or early termination. In terminating the study, the 
sponsor and the investigator will assure that adequate consideration is given to the protection 
of the patient’s interests. 


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Clinical Study Protocol G1T28-02 
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Version: 8.0, dated 15 September 2016 
 
Page 99 of 105  
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16. 
DATA HANDLING AND RECORD KEEPING 
16.1. 
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 
medication 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. 
Additional checks of the consistency of the source data with the eCRFs are to be performed 
according to the study-specific monitoring plan. 
16.2. 
Data Monitoring Committee 
An external DMC will be used to evaluate safety of Part 2 of the study in an ongoing manner 
(see Section 13.2.2 for further details). 
16.3. 
Investigator Reporting Requirements 
Local regulations may require the investigator to provide periodic safety updates on the 
conduct of the study and to notify the IRB of study closure. Such updates and notifications 
are the responsibility of the investigator. 
16.4. 
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, IRB and governmental 
approval with correspondence, informed consent, drug records, staff curriculum vitae and 
authorization forms, and other appropriate documents and correspondence.  


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Version: 8.0, dated 15 September 2016 
 
Page 100 of 105  
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Patient clinical source documents may include (but not limited to) patient hospital records, 
physician's and nurse's notes, original laboratory reports, ECG, electroencephalogram (EEG), 
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 
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. After that period of time, the documents may be destroyed, subject to local 
regulations. 
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.  
16.5. 
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.  
16.6. 
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. 


G1 Therapeutics 
Clinical Study Protocol G1T28-02 
G1T28 
 
Version: 8.0, dated 15 September 2016 
 
Page 101 of 105  
G1 Therapeutics CONFIDENTIAL 
17. 
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 trial. 


G1 Therapeutics 
Clinical Study Protocol G1T28-02 
G1T28 
 
Version: 8.0, dated 15 September 2016 
 
Page 102 of 105  
G1 Therapeutics CONFIDENTIAL 
18. 
REFERENCES 
Apetoh L, Ghiringhelli F, Tesniere A, et al. The interaction between HMGB1 and TLR4 
dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev. 
2007 Dec;220:47-59. 
Aupérin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with 
small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview 
Collaborative Group. N Engl J Med. 1999 Aug 12;341(7):476-484. 
Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic 
chemotherapy: implications for the design of novel and rationale-based combined treatments 
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Cagle PT, el-Naggar AK, Xu HJ, Hu SX, Benedict WF. Differential retinoblastoma protein 
expression in neuroendocrine tumors of the lung. Potential diagnostic implications. Am J 
Pathol. 1997;150:393-400. 
Casares N, Pequignot MO, Tesniere A, et al. Caspase-dependent immunogenicity of 
doxorubicin-induced tumor cell death. J Exp Med. 2005 Dec 19;202(12):1691-1701. 
Cella DF, Bonomi AE, Lloyd SR, Tulsky DS, Kaplan E, Bonomi P. Reliability and validity 
of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. 
Lung Cancer. 1995 Jun;12(3):199-220. 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16:31-41. 
D'Amico D, Carbone D, Mitsudomi T, et al. High frequency of somatically acquired p53 
mutations in small-cell lung cancer cell lines and tumors. Oncogene. 1992;7:339-346. 
Eckardt JR, von Pawel J, Papai Z, et al. Open-label, multicenter, randomized, phase III study 
comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy 
naive patients with extensive-disease small-cell lung cancer. J Clin Oncol. 
2006;24:2044-2051. 
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. 
Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by 
PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 
2004 Nov;3(11):1427-1438. 
Gouyer V, Gazzeri S, Brambilla E, et al. Loss of heterozygosity at the RB locus correlates 
with loss of RB protein in primary malignant neuro-endocrine lung carcinomas. Int J Cancer. 
1994;58:818-824. 


G1 Therapeutics 
Clinical Study Protocol G1T28-02 
G1T28 
 
Version: 8.0, dated 15 September 2016 
 
Page 103 of 105  
G1 Therapeutics CONFIDENTIAL 
Hanna N, Bunn PA, Jr., Langer C, et al. Randomized phase III trial comparing 
irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive 
stage disease small-cell lung cancer. J Clin Oncol. 2006;24:2038-2043. 
Heighway J, Betticher DC. Lung: small cell cancer. Atlas of Genetics and Cytogenetics in 
Oncology and Haematology. June 2004 URL : 
http://atlasgeneticsoncology.org/Tumors/LungSmallCellID5142.html. 
Hermes A, Bergman B, Bremnes R, et al. Irinotecan plus carboplatin versus oral etoposide 
plus carboplatin in extensive small-cell lung cancer: a randomized phase III trial. J Clin 
Oncol. 2008;26:4261-4267. 
McDonnell AM, Nowak AK, Lake RA. Contribution of the immune system to the 
chemotherapeutic response. Semin Immunopathol. 2011 Jul;33(4):353-367. 
Noda K, NishiwakiY, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide 
plus cisplatin for extensive small cell-lung cancer. N Engl J Med. 2002;346:85-91. 
Peifer M, Fernandez-Cuesta L, Sos ML, et al. Integrative genome analyses identify key 
somatic driver mutations of small-cell lung cancer. Nat Genet. 2012;44:1104-1110. 
Ray-Coquard I, Cropet C, Van Glabbeke M, et al. Lymphopenia as a prognostic factor for 
overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res. 
2009 Jul 1;69(13):5383-5391. 
Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 
as a frequently amplified gene in small-cell lung cancer. Nat Genet.2012;44:1111-1116. 
Schmittel A, Fischer von Weikersthal L, Sebastian M, et al. A randomized phase II trial of 
irinotecan plus carboplatin versus etoposide plus carboplatin treatment in patients with 
extended disease small-cell lung cancer. Ann Oncol. 2006;17:663-667. 
Schmittel A, Sebastian M, Fischer von Weikersthal L, et al. A German multicenter, 
randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as 
first-line therapy for extensive-disease small-cell lung cancer. Ann Oncol. 
2011;22:1798-1804. 
Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive 
small-cell lung cancer. N Engl J Med. 2007 Aug 16;357(7):664-672. 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 Update of recommendations for the use 
of white blood cell growth factors: an evidence based clinical practice guideline. J Clin 
Oncol. 2006 Jul 1;24(19):3187-3205. 
Socinski M, Smit E, Lorigan P, et al. Phase III study of pemetrexed plus carboplatin 
compared with etoposide plus carboplatin in chemotherapy-naive patients with 
extensive-stage small-cell lung cancer. J Clin Oncol. 2009;27(28):4787-4792. 


G1 Therapeutics 
Clinical Study Protocol G1T28-02 
G1T28 
 
Version: 8.0, dated 15 September 2016 
 
Page 104 of 105  
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Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other 
anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) 
measurement system. J Pain Symptom Manage. 1997 Feb;13(2):63-74. 
Yonezawa A, Masuda S, Yokoo S, Katsura T, Inui K. Cisplatin and oxaliplatin, but not 
carboplatin and nedaplatin, are substrates for human organic cation transporters (SLC22A1-3 
and multidrug and toxin extrusion family). J Pharmacol Exp Ther. 2006 
Nov;319(2):879-886. 
Yong WP, Desai AA, Innocenti F, et al. Pharmacokinetic modulation of oral etoposide by 
ketoconazole in patients with advanced cancer. Cancer Chemother Pharmacol. 2007 
Nov;60(6):811-819.  
Yuan J, Knorr J, Altmannsberger M, et al. Expression of p16 and lack of pRB in primary 
small cell lung cancer. J Pathol. 1999;189:358-362. 
Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer 
chemotherapy. Nat Rev Immunol. 2008 Jan;8(1):59-73. 


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Clinical Study Protocol G1T28-02 
G1T28 
 
Version: 8.0, dated 15 September 2016 
 
Page 105 of 105  
G1 Therapeutics CONFIDENTIAL 
19. 
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: Package Inserts for Chemotherapy Agents 
Etopophos® (etoposide phosphate) package insert link: 
http://packageinserts.bms.com/pi/pi_etopophos.pdf   
Paraplatin® (carboplatin) package insert link: 
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-
4180b_03_05_Carboplatin%20label%201-9-04%20FDA.pdf 
APPENDIX 3: Package Inserts for Colony Stimulating Factors 
Neupogen® (filgrastim) package insert link: 
http://pi.amgen.com/united_states/neupogen/neupogen_pi_hcp_english.pdf 
Neulasta® (pegfilgrastim) package insert link: 
http://pi.amgen.com/united_states/neulasta/neulasta_pi_hcp_english.pdf 
APPENDIX 4: Package Inserts for Erythropoiesis Stimulating Agents  
Aranesp® (darbepoetin alfa) package insert link: 
http://pi.amgen.com/united_states/aranesp/ckd/aranesp_pi_hcp_english.pdf 
Epogen® (epoetin alfa) package insert link: 
http://pi.amgen.com/united_states/epogen/epogen_pi_hcp_english.pdf 
 

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G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-02                                       
Statistical Analysis Plan  
Version date: 14Feb2018 
 
CONFIDENTIAL 
      Page 3 of 60 
 
                                                 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................9 
2. 
STUDY DETAILS .....................................................................................................10 
2.1. 
Study Objectives .........................................................................................................10 
2.2. 
Study Design ...............................................................................................................10 
2.3. 
Number of Patients .....................................................................................................18 
3. 
ANALYSIS SETS ......................................................................................................19 
3.1. 
Definition of Analysis Sets .........................................................................................19 
3.1.1. 
Full Analysis Set .........................................................................................................19 
3.1.2. 
Safety Analysis Set .....................................................................................................19 
3.1.3. 
Per Protocol (PP) Analysis Set ...................................................................................19 
3.1.4. 
Response Evaluable Analysis Set ...............................................................................19 
3.2. 
Protocol Deviations ....................................................................................................19 
4. 
PROSPECTIVELY DEFINED ANALYSES.............................................................21 
5. 
PRIMARY AND SECONDARY ENDPOINTS ........................................................23 
5.1. 
Efficacy endpoints ......................................................................................................23 
5.1.1. 
Primary Prospectively-Defined Clinical Endpoints for Efficacy ...............................23 
5.1.1.1. 
Febrile Neutropenia AEs ............................................................................................23 
5.1.1.2. 
RBC Transfusions .......................................................................................................24 
5.1.1.3. 
Platelet Transfusions ...................................................................................................24 
5.1.1.4. 
GCSF Administrations................................................................................................24 
5.1.1.5. 
ESA Administrations ..................................................................................................25 
5.1.1.6. 
IV Antibiotic Uses ......................................................................................................25 
5.1.1.7. 
Infection SAEs and Pulmonary Infection SAEs .........................................................26 
5.1.1.8. 
Duration of Grade 4 Neutropenia ...............................................................................27 
5.1.1.9. 
Duration of Grade 3/4 Neutropenia ............................................................................28 
5.1.1.10. 
ANC, Platelet Count, and  Hemoglobin Change over Time .......................................29 
5.1.1.11. 
Time to First Major Adverse Hematologic Event (MAHE) .......................................29 
5.1.2. 
Exploratory Efficacy Endpoints .................................................................................30 
5.1.2.1 
Grade 2 or Greater Nephrotoxicity .............................................................................30 
5.1.2.2 
Occurrence of Alopecia and Mucositis .......................................................................30 
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G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-02                                       
Statistical Analysis Plan  
Version date: 14Feb2018 
 
CONFIDENTIAL 
      Page 4 of 60 
 
                                                 
 
5.1.2.3 
FACT-L and FACT-An ..............................................................................................31 
5.1.2.4 
Neutrophil-lymphocyte Ratio (NLR) and Platelet-lymphocyte Ratio (PLR) .............34 
5.1.3. 
Chemotherapy Exposure And Compliance Endpoints ...............................................34 
5.1.3.1 
Duration of Exposure ..................................................................................................34 
5.1.3.2 
Number of Cycles Received .......................................................................................34 
5.1.3.3 
Dose Intensity and Cumulative Dose .........................................................................34 
5.1.3.4 
Modifications of Study Therapy, Including Cycle (Dose) Delay, Missed 
Doses, Dose Interruptions, and Dose Reductions .......................................................35 
5.2. 
Safety Endpoints .........................................................................................................35 
5.2.1. 
Adverse Events (AEs) .................................................................................................35 
5.2.2. 
Vital Signs ..................................................................................................................37 
5.2.3. 
Laboratory ...................................................................................................................37 
5.2.4. 
Electrocardiograms .....................................................................................................38 
5.2.5. 
Physical Examination .................................................................................................39 
5.2.6. 
Tumor Responses and Clinical Benefit ......................................................................39 
5.2.6.1. 
Target Lesions (TLs) ..................................................................................................39 
5.2.6.2. 
Non-Target Lesions (NTLs) and New Lesions ..........................................................40 
5.2.6.3. 
Time Point Response (TPR) .......................................................................................41 
5.2.6.4. 
Best Overall Response (BOR) ....................................................................................41 
5.2.7. 
Progression-free Survival ...........................................................................................43 
5.2.8. 
Overall Survival ..........................................................................................................44 
6. 
ANALYSIS METHODS ............................................................................................45 
6.1. 
General Principles of Analysis ...................................................................................45 
6.1.1. 
General Methodology .................................................................................................45 
6.1.2. 
Handling of Missing Data ...........................................................................................46 
6.1.3. 
Visit Windowing .........................................................................................................46 
6.1.4. 
Adjustment for Covariates ..........................................................................................48 
6.2. 
Analysis Methods .......................................................................................................48 
6.2.1. 
Patient Disposition ......................................................................................................48 
6.2.2. 
Demographic and Other Baseline Characteristics ......................................................48 
6.2.3. 
Disease Characteristics and Prior Therapies ...............................................................48 
6.2.4. 
Medical History ..........................................................................................................49 
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G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-02                                       
Statistical Analysis Plan  
Version date: 14Feb2018 
 
CONFIDENTIAL 
      Page 5 of 60 
 
                                                 
 
6.2.5. 
Concomitant Medications ...........................................................................................49 
6.2.6. 
Prior and Subsequent Anti-cancer Therapy ................................................................50 
6.2.7. 
Efficacy Analyses .......................................................................................................50 
6.2.7.1. 
Prospectively-Defined Efficacy Analyses ..................................................................50 
6.2.7.2. 
Exploratory Efficacy Analyses ...................................................................................51 
6.2.7.3. 
Exposure Endpoints ....................................................................................................51 
6.2.8. 
Safety Analyses ..........................................................................................................52 
6.2.8.1. 
Adverse Events ...........................................................................................................52 
6.2.8.2. 
Laboratory Evaluations ...............................................................................................52 
6.2.8.3. 
Vital Signs ..................................................................................................................53 
6.2.8.4. 
Performance Status .....................................................................................................53 
6.2.8.5. 
Physical Examination .................................................................................................53 
6.2.8.6. 
ECG ............................................................................................................................53 
6.2.8.7. 
Analyses of Objective Response ................................................................................53 
6.2.8.8. 
Analyses of PFS and OS .............................................................................................54 
6.2.9. 
Subgroup Analyses .....................................................................................................54 
6.2.10. 
Assess Genetic and/or Expression (RNA/Protein) Biomarkers in Tumors and 
Blood...........................................................................................................................54 
6.2.11. 
Planned Analysis ........................................................................................................55 
7. 
CHANGE FROM THE PROTOCOL ........................................................................56 
8. 
REFERENCES ...........................................................................................................58 
 
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Clinical Study Protocol G1T28-02                                       
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event 
ALC 
Absolute Lymphocyte Count 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under Curve 
Β-HCG 
Beta Human Chorionic Gonadotropin  
BICR 
Blinded Independent Central Review 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BPM 
Beats Per Minute 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CBR 
Clinical Benefit Rate 
CDK 
Cyclin Dependent Kinase 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CSR  
Clinical Study Report 
CT 
Computed Tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
DLT 
Dose-Limiting Toxicity 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
ECRF 
Electronic Case Report Form 
EOI 
End of Infusion 
E/P 
Etoposide and Carboplatin 
E/P THERAPY 
Etoposide and Carboplatin on Day 1 and Etoposide on Days 2 and 3 of 21-Day Cycles 
ESA 
Erythropoietin Stimulating Agent 
EWB 
Emotional Well-Being 
FACT 
Functional Assessment of Cancer Therapy 
FACT-G 
Functional Assessment of Cancer Therapy-General   
FACT-AN 
Functional Assessment of Cancer Therapy –Anemia  
FACT-L 
Functional Assessment of Cancer Therapy –Lung  
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Abbreviation 
Term 
FAS 
Full Analysis Set 
FWB 
Functional Well-Being 
G-CSF/GCSF 
Granulocyte Colony-Stimulating Factor 
HR 
Hazard Ratio 
ICH 
International Conference on Harmonization 
IV 
Intravenous 
LCS 
Lung Cancer Subscale 
LD 
Longest Diameter 
LDH 
Lactate Dehydrogenase 
MAHE 
Major Adverse Hematologic Event 
MEDDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NADIR 
The Lowest Point 
NE 
Not Evaluable 
NLR 
Neutrophil-Lymphocyte Ratio 
NTL 
Non-Target Lesion 
OC 
Observed Case 
ORR 
Objective Response Rate 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic  
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PLR 
Platelet-Lymphocyte Ratio 
PP 
Per Protocol 
PR 
Partial Response 
PRO 
Patient-Reported Outcome 
PT 
Preferred Term 
PWB 
Physical Well-Being 
QOL 
Quality Of Life 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumors  
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SCLC 
Small Cell Lung Cancer 
SD 
Stable Disease 
SD 
Standard Deviation 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
SWB 
Social/Family Well-Being 
TEAE 
Treatment-Emergent AE 
TL 
Target Lesion 
TLFs 
Tables, Listings, and Figures 
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Abbreviation 
Term 
TOI 
Trial Outcome Index 
TPR 
Time Point Response 
ULN 
Upper Limit of Normal Range 
WBC 
White Blood Cell 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
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Clinical Study Protocol G1T28-02                                       
Statistical Analysis Plan  
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CONFIDENTIAL 
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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the analyses to be performed 
following the completion of Study G1T28-02, Phase 1b/2a Safety and Pharmacokinetic Study of 
G1T28 in Patients with Extensive-Stage SCLC Receiving Etoposide and Carboplatin 
Chemotherapy.  The SAP is based on the G1T28-02 Protocol Version 8, dated 15 September 
2016.   
Study measurements and assessments, planned statistical methods, and derived variables are 
summarized in this plan.  Planned tables, figures, and listings are specified.  All decisions 
regarding final analyses, as defined in this SAP document, have been made prior to locking the 
database. Any deviations from these guidelines will be documented in the clinical study report 
(CSR).  
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2. 
STUDY DETAILS 
2.1. 
Study Objectives 
The primary, secondary, and exploratory objectives of this study are presented in Table 1. 
Table 1 
G1T28-02: Study Objectives 
 
Phase 1b 
Dose-Finding 
Portion of 
Part 1 
Phase 2a 
Expansion 
Portion of 
Part 1 
Phase 2a 
Part 2 
Primary Objectives 
Assess the DLTs and define the Phase 2 dose of G1T28 
administered with E/P therapy 
X 
 
 
Assess the safety and tolerability of G1T28 administered 
with E/P therapy 
X  
X 
X 
Secondary Objectives 
Assess the PK profile of G1T28 
X 
 
 
Assess the PK profile of etoposide and carboplatin when 
administered with G1T28 
X 
 
 
Assess the hematologic profile (kinetics and 
incidence/duration/frequency of toxicities) of G1T28 
administered with E/P therapy 
X  
 
X 
X 
Assess the incidence of febrile neutropenia 
X 
X 
X 
Assess the incidence of infections 
X 
X 
X 
Assess the utilization of RBC and platelet transfusions 
X 
X 
X 
Assess the utilization of hematopoietic growth factors  
X 
X 
X 
Assess the utilization of systemic antibiotics 
X 
X 
X 
Assess the incidence of chemotherapy dose reductions 
and dose interruptions overall 
X 
X 
X 
Assess the incidence of Grade 2 or greater nephrotoxicity  
X 
X 
X 
Assess tumor response based on RECIST, Version 1.1 
X 
X 
X 
Assess PFS and overall survival 
X 
X 
X 
Exploratory Objectives 
Assess the incidence of mucositis 
X 
X 
X 
Assess the incidence of alopecia 
X 
X 
X 
Assess the incidence of fatigue 
X 
X 
X 
Assess patient-reported QOL 
X 
X 
X 
Assess immunologic markers 
 
 
X 
DLT = dose-limiting toxicity; E/P therapy = etoposide + carboplatin on Day 1 and etoposide on Days 2 and 3 of 21-day cycles; 
PFS = progression-free survival; PK = pharmacokinetic; QOL = quality of life; RBC = red blood cell; RECIST = Response 
Evaluation Criteria in Solid Tumors  
2.2. 
Study Design 
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 1b/2a study of the 
safety and PK of G1T28 in combination with E/P therapy for patients with newly diagnosed 
extensive-stage SCLC. The study consists of 2 parts: Part 1 will be a limited Phase 1b, 
open-label, dose-finding portion followed by a Phase 2a, open-label, expansion portion in up to 
18 patients at the selected dose to be used in Part 2. Prior to initiating Part 2, up to a total of 24 
patients will be enrolled at the chosen Part 2 dose (6 patients in the dose-finding portion of Part 1 
and up to 18 patients in the Phase 2a, open-label, expansion portion of Part 1). Part 2 will consist 
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of a randomized, double-blind cohort (70 patients will be randomly assigned to G1T28 
administered IV with E/P therapy or placebo administered IV with E/P therapy). All 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 first dose with study treatment and completes at the 
Post-Treatment Visit. 
Part 1 
Part 1 starts with a dose finding portion which will be followed by an expansion portion. The 
goal of the Phase 1b dose-finding portion of Part 1 is to assess the safety, including dose-limiting 
toxicities (DLTs) and PK of G1T28 administered at a starting dose of 200 mg/m2 once daily on 
Days 1 to 3 of E/P therapy. DLTs are defined in Protocol section 6.1.1.1. The schema of Part 1 is 
shown in Figure 1. 
Figure 1 
Study Schema: Part 1 
 
E/P = etoposide + carboplatin 
a  
Safety and PK data from Cycle 1 will be considered in making dose escalation/de-escalation decisions (if required) and 
enrolling  additional cohorts 
b  
G1T28 + E/P will continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator 
(eg, after completing 6 cycles). The tumor should be assessed after every even cycle using Response Evaluation Criteria in 
Solid Tumors (RECIST), Version 1.1. Assessments should be performed within 7 days of starting the subsequent cycle. 
c  
G1T28 will be administered prior to the administration of etoposide and carboplatin on Day 1 and administration of 
etoposide on Days 2 and 3 of 21-day cycles 
d 
Patients will return to the study center for a Post-Treatment Visit at 30 ± 3 days after the last dose of study drug. 
e      The Survival Follow-up Phase will continue until at least 50% of the patients randomized to Part 2 of the study have died. 
Part 1b Dose Finding  
For the dose finding portion, it is an open-label, ascending dose trial of G1T28 administered at a 
dose of 200 mg/m2 intravenous (IV) once daily on Days 1 to 3 of E/P therapy to patients with 
unequivocally confirmed newly diagnosed extensive-stage SCLC. Enrollment in the dose finding 
portion is planned to include up to 22 male and female patients (depending on the number of 
dose escalation cohorts required, assuming up to 3 cohorts) at least 18 years old to evaluate 
safety, including DLTs and PK.  
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Six patients will initially be enrolled into the Phase 1b, dose-finding portion of Part 1 and will 
receive G1T28 200 mg/m2 in combination with standard E/P therapy. Safety and available PK 
parameters from this initial cohort of 6 patients during Cycle 1 will be considered in making dose 
escalation/de-escalation decisions (if required).   
 
a      Assess the adjusted G1T28 dose in the next cohort of 6 patients based on DLTs and PK (if available) per the decision     
        tree 
b 
Maximum of 2 G1T28 dose reductions are allowed 
 If there is ≤ 1 DLT in the first cohort of 6 patients during Cycle 1 of the Phase 1b, 
dose-finding portion of Part 1 and the available G1T28 PK parameters are as predicted, 
the dose-finding portion of Part 1 will end and subsequent patients will be enrolled into 
the Phase 2a expansion cohort of Part 1, utilizing a dose of G1T28 of 200 mg/m2 in 
combination with E/P therapy. 
 
 If there is ≤ 1 DLT in the first cohort of 6 patients during Cycle 1 of the Phase 1b 
dose-finding portion of Part 1, and the available G1T28 PK parameters suggest that the 
G1T28 dose needs to be escalated or de-escalated, a second cohort of 6 patients will be 
enrolled at the higher or lower predicted G1T28 dose in combination with E/P therapy.   
 
 If there is > 1 DLT in the first cohort of 6 patients during Cycle 1 of the Phase 1b 
dose-finding portion of Part 1 and the available G1T28 PK parameters suggest that the 
G1T28 dose needs to be escalated or de-escalated (ie, in order to increase or decrease the 
magnitude and duration of G1 cell cycle arrest of HSPCs predicted by the PK/PD model 
and data from the Phase 1a Study G1T28-1-01; a second cohort of 6 patients will be 
enrolled at the modified G1T28 dose in combination with E/P therapy.  
 
 If there is > 1 DLT in the first cohort of 6 patients enrolled in the Phase 1b dose-finding 
portion of Part 1 and the available G1T28 PK parameters from these 6 patients are as 
predicted, the dose of G1T28 should be decreased to 160 mg/m2 and an additional 6 
patients should be enrolled at the modified G1T28 dose in combination with E/P therapy.  
   
 If there is > 1 DLT following a G1T28 dose of 160 mg/m2 in combination with 
E/P therapy in the second cohort of patients and if available, PK parameters are as 
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predicted, an additional cohort of 6 patients will be enrolled at a further decreased G1T28 
dose of 130 mg/m2 in combination with E/P therapy.  
 
 If there is > 1 DLT following the second dose reduction of G1T28 and if available, PK 
parameters from the third cohort are as predicted, no further dose modifications will be 
made and the study will be terminated. 
 
 At any time, if ≥ 2 DLTs are observed in any given cohort, further enrollment into that 
cohort will be stopped until the SMC can review the available data and make dose and 
cohort recommendations. 
All dose-escalation/de-escalation decisions will be based on Cycle 1 safety data from all patients 
enrolled into the cohort and available PK data and will be reviewed by a safety monitoring 
committee (SMC) comprised of the sponsor, medical monitor, and the principal investigator(s) to 
determine the next dose level. If the G1T28 dose level for a subsequent cohort is adjusted by the 
SMC, the SMC may also recommend that all patients currently receiving G1T28 in combination 
with E/P therapy should have their G1T28 dose adjusted accordingly, starting with their next 
scheduled cycle. Additional cohorts for the Phase 1b dose-finding portion of Part 1 will be 
considered based on review of the safety data from all patients enrolled into the cohort and 
available PK data by the SMC. The dose for Part 2 will be obtained by utilizing all available 
safety and available PK data from patients enrolled in Part 1.  
Part 1 Phase2a Expansion  
Once the dose for Part 2 has been established, additional patients will be enrolled at the selected 
Part 2 dose in a Phase 2a expansion cohort in Part 1 until up to a total of 24 patients (6 from the 
Phase 1b dose-finding portion of Part 1 and up to 18 from the Phase 2a expansion cohort) have 
been enrolled at that dose. The Phase 2a expansion cohort in Part 1 will complete enrollment 
before enrollment into Part 2 commences. 
Part 2 
In Part 2, eligible patients will be randomized (1:1 fashion) to G1T28 or placebo administered IV 
once daily on Days 1 to 3 of E/P therapy (Figure 2). Randomization will be stratified by Eastern 
Cooperative Oncology Group (ECOG) performance status (0 to 1 versus 2). There will be no 
intrapatient dose modifications of G1T28 in Part 2 of the study. 
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Figure 2 
Study Schema: Part 2 
 
E/P = etoposide + carboplatin 
a  
G1T28 + E/P will continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator 
(eg, after completing 6 cycles). The tumor should be assessed after every even cycle using Response Evaluation Criteria in 
Solid Tumors (RECIST), Version 1.1. Assessments should be performed within 7 days of starting the subsequent cycle. 
b 
G1T28 will be administered prior to the administration of etoposide and carboplatin on Day 1 and administration of 
etoposide on Days 2 and 3 of 21-day cycles 
c 
Patients will return to the study center for a Post-Treatment Visit at 30 + 3 days after the last dose of study drug. 
d 
The Survival Follow-up Phase will continue until at least 50% of the patients randomized to Part 2 of the study have died. 
An independent data monitoring committee (DMC) will monitor accumulating safety and 
disposition data approximately every 4 months during the Treatment Phase of Part 2 of the study, 
depending upon the enrollment rate. Details of the DMC, including objectives, composition, 
scope, and frequency, will be described in a DMC charter. 
Criteria for Subsequent Cycles and Study Duration 
In all parts of the study, study drug administration will continue until disease progression per 
Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, unacceptable toxicity, 
withdrawal of consent, or discontinuation by investigator (eg, after completing 6 cycles), 
whichever occurs first. Treatment cycles will occur consecutively without interruption, except 
when necessary to manage toxicities or for administrative reasons as described below.   
In order to start Cycle 2 and subsequent cycles as scheduled, patients should meet all of the 
following criteria: 
 Absolute neutrophil count (ANC) ≥ 1.5 × 109/L  
 Platelet count ≥ 100 × 109/L 
 Nonhematologic drug-related toxicities (except alopecia) must be ≤ Grade 1 or have 
returned to baseline 
A delay of up to 2 weeks is permitted to allow recovery from any toxicity in order to meet the 
continuation criteria for organ function. If patients meet the criteria for starting the subsequent 
cycle as described above, a delay of up to 1 week is permitted for administrative reasons (eg, 
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holiday, vacation, etc.). If the subsequent cycle is delayed, the patient should still complete the 
clinical laboratory assessments and the Functional Assessment of Cancer Therapy –Lung 
(FACT-L) and Functional Assessment of Cancer Therapy – Anemia (FACT-An) questionnaires 
on the scheduled Day 1, as well as on the actual first dosing day of the next cycle. A patient will 
be discontinued from the study if recovery from any toxicity, in order to meet the continuation 
criteria for organ function, and any delay for administrative reasons requires a total delay of 
> 2 weeks. 
After discontinuation of study drug, patients should be strongly encouraged to complete all 
scheduled assessments through the end of their current 21-day treatment cycle, including the 
patient-reported outcome (PRO) scales; complete blood count (CBC) assessment on Day 22; the 
Post-Treatment Visit; and the Survival Follow-up Phase of the study.  
The G1T28-02 study will be completed when the Survival Follow-up Phase has been completed, 
or upon sponsor termination of the study. The total study duration is at least 29 months.  
Part 1 is expected to be approximately 18 months, assuming 12 months of accrual, 2 weeks for 
screening, 4.5 months of treatment (assuming 6 cycles), and 1 month of safety follow-up. 
Part 2 will begin after the Part 2 dose is identified from the Phase 1b dose-finding portion of Part 
1 and the Phase 2a expansion portion of Part 1 has completed enrollment, which is expected to 
occur approximately 12 months after Part 1 begins. Part 2 is expected to be approximately 17 
months, assuming 11 months of accrual, 2 weeks of screening, 4.5 months of treatment 
(assuming 6 cycles), and 1 month of safety follow-up. 
The Survival Follow-up Phase of the study will continue until at least 50% of the randomized 
patients in Part 2 have died. The study scheduled assessments are presented in Table 2 below: 
 
 
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Table 2 
Schedule of Assessments 
  
Scree
ning  
Enr
oll 
Cycle 1 and Every Odd 
Cyclea 
(21 days) 
Cycle 2 and Every Even 
Cyclea 
(21 days) 
Last 
Cycle 
Post-
Treatme
nt Visitb 
Survival 
Follow-up 
Callsc 
Cycle Day  
-14  
-3 to 
1 
1 
2 
3 
8 
10 
15 
1 
2 
3 
8 
10 
15 
22 
 
 
Informed Consentd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Eval. 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance Status 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Physical Exam 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Height, Weight & 
Vital Signsf 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Clinical Chemistry 
X 
 
X
g 
 
 
X 
 
X 
X
g 
 
 
X 
 
X 
 
X 
 
Hematology 
X 
 
X
h 
 
X 
X 
X 
X 
X
h 
 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
X
g 
 
 
 
 
 
X
g 
 
 
 
 
 
 
X 
 
ECG 
X 
 
Xi 
 
Xi 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy testj 
X 
  
X  
  
  
 
 
 
X  
  
  
 
 
 
 
  
 
Randomizationk 
 
X 
  
  
  
 
 
 
  
  
  
 
 
 
 
  
 
Tumor Assessmentl 
X 
  
  
  
  
 
 
 
  
  
  
 
 
X 
 
Xl1 
 
Tumor Testingm 
 
 X 
  
  
  
 
 
 
  
  
  
 
 
 
 
  
 
PKn 
 
  
X 
  
X 
 
 
 
  
  
  
 
 
 
 
  
 
G1T28 or Placeboo 
 
  
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
 
  
 
Carboplatin 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Etoposide 
 
  
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
 
 
 
FACT-L and 
FACT-Anp 
 
  
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
Immunologic 
Marker 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
AEsq 
X 
 
X 
 
Con. Medications 
X 
 
X 
 
Survival Follow-upc 
 
 
 
X 
AE = adverse event; ECG = electrocardiogram; FACT-AN = Functional Assessment of Cancer Therapy – Anemia quality of life 
instrument; FACT-L = Functional Assessment of Cancer Therapy –Lung quality of life instrument; PRO = patient reported 
outcome; Eval. = evaluation; PK = pharmacokinetics 
a 
G1T28 or placebo + E/P therapy will continue until disease progression, unacceptable toxicity, or discontinuation by the 
patient or investigator (eg, after completing 6 cycles). The tumor should be assessed after every even cycle. Assessments 
should be performed within 7 days of starting the subsequent cycle.  
b 
Patients will return to the study center for a Post-Treatment Visit at 30 days (+ 3 days) after the last dose of study drug.  
c 
Monthly phone calls will be made to each patient that is in the long-term Survival Follow-up Phase. Patients will be 
followed for survival until at least 50% of the patients in Part 2 have died. Any anticancer therapies used will be collected. 
In addition, blood samples for hematology and immunologic marker assessment will be collected at 60 ± 7 days after the 
Post-Treatment Visit for patients in Part 2 only.    
d 
Informed consent may be obtained up to 28 days prior to the first study treatment administration. 
e 
Including medical, surgical, radiation history, smoking history, family history, documentation of tumor diagnosis, baseline 
signs and symptoms within 4 weeks prior to randomization, weight loss in the 6 months prior to randomization (≤ 5% or > 
5%), and medications taken within 14 days of enrollment. 
f 
Height will only be measured at the screening visit. Body surface area calculation (based on actual body weight) will be 
completed on Day 1 of each cycle and vital signs obtained immediately before and after G1T28 or placebo and E/P 
infusions. Vitals only need to be taken once between infusions.   
g 
Clinical chemistry will be obtained (albumin, alkaline phosphatase, total bilirubin, calcium, chloride, creatinine, glucose, 
inorganic phosphorus, potassium, total protein, ALT, AST, lactate dehydrogenase [LDH], sodium, and blood urea nitrogen 
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[BUN]). Clinical chemistry and urine analysis may be obtained up to 72 hours prior to the first dose of each cycle of G1T28 
or placebo + E/P therapy.  
h 
Hematology will be obtained (hemoglobin, hematocrit, WBCs with differential, and platelet counts); Hematology may be 
obtained up to 24 hours prior to first dose of each cycle of G1T28/placebo + EP therapy. 
i 
In Part 2 only, hematology will be collected at 60 days after the Post-Treatment Visit. 
j 
Patients participating in the Phase 1b dose-finding portion of Part 1 of the study, who have PK samples obtained, will have 
ECGs completed at the following time points on Days 1 and 3 of Cycle 1: predose, end of infusion (EOI) of G1T28, 2 hours 
(± 10 minutes) after the start of G1T28, and 6.5 hours (± 15 minutes) after the start of G1T28. The 2-hour ECG will be 
completed once the etoposide infusion is complete. 
k 
For female patients of childbearing potential, serum beta human chorionic gonadotropin (ß-hCG) at screening; serum or 
urine ß-hCG  obtained up to 72 hours prior to Day 1 dose of G1T28 or placebo + E/P chemotherapy in each cycle.   
l 
For patients enrolled in Part 2, randomization is to be done within 3 days prior to first dose of G1T28 or placebo + E/P 
chemotherapy, following confirmation that the patient is eligible for the study. 
m 
For tumor assessment, all sites of disease should be assessed radiologically by computed tomography (CT) or magnetic 
resonance imaging (MRI) at screening and after every even cycle, until the occurrence of disease progression. Additional 
scans may be obtained at the discretion of the investigator, if clinically indicated. If a patient shows a radiological response 
(CR or PR), a confirmatory radiological assessment will be performed at least 4 weeks after the response was first noted. 
Assessments should be performed within 7 days of starting the subsequent cycle. The same method of assessment (CT or 
MRI) should be used to characterize tumors at screening and at all follow-up assessments. If positron emission tomography 
is used, it should also be accompanied by spiral CT or MRI.  
 
m1: At the Post-Treatment Visit, obtain tumor assessment for patients who have not progressed at the time of study drug 
discontinuation (may be performed within 4 weeks). For those patients in the survival follow-up who have not progressed at 
the time of study drug discontinuation, tumor assessments, including all sites of disease, will be assessed radiologically by 
CT or MRI, as performed at screening, every 2 months (approximately 60 ± 7 days) until the occurrence of progressive 
disease or study completion. 
 
m2: Brain scans with contrast (by CT or MRI) to be obtained with tumor assessment at screening (within 28 days of dosing) 
and at the Post-Treatment Visit 
n 
Send archived tumor samples to a central pathology laboratory to confirm the diagnosis of SCLC. Available tissue after 
confirming the diagnosis of SCLC will be banked for assessment of relevant deoxyribonucleic acid (DNA), ribonucleic acid 
(RNA), and protein markers, such as those involved in the CDK4/6 pathway. If central pathology review does not confirm 
SCLC diagnosis, the patient may be withdrawn from the study after consultation between the principal investigator, medical 
monitor, and sponsor. This should be done as soon as possible after a patient has enrolled in the study. 
o 
Patients enrolled in Cohort 1 of the Phase 1b dose-finding portion of Part 1 will have G1T28, etoposide, and carboplatin PK 
samples collected on Days 1 and 3 (as applicable) of Cycle 1 at the time points specified in the protocol. Collection of PK 
blood samples from patients enrolled in additional cohorts of the Phase 1b dose-finding portion of Part 1 is optional.  
p 
G1T28 or placebo will be administered as an IV infusion in 250 mL of D5W or sodium chloride solution 0.9% over 30 
minutes prior to E/P chemotherapy on Days 1 to 3 of every cycle. If there is any volume remaining in the G1T28 or placebo 
infusion bag at the end of the 30 minutes, the infusion should be continued at the same rate until the entire contents of the 
bag have been administered to ensure patients receive the full dose.  The interval between doses of G1T28 or placebo on 
successive days should not be greater than 28 hours. The interval between the dose of G1T28 or placebo and the first dose of 
chemotherapy on a given day (etoposide or carboplatin) should not be greater than 4 hours. G1T28 or placebo will only be 
administered with E/P therapy. If administration of E/P therapy is discontinued, G1T28 or placebo should also be 
discontinued. Chemotherapy cannot be administered until after completion of the G1T28 or placebo infusion. If the second 
or third dose of G1T28 in any given cycle is not administered for any reason, do not administer the dose of etoposide or 
carboplatin chemotherapy on that day. After discontinuation of study drug, patients should be strongly encouraged to 
complete all scheduled assessments through the end of their current 21-day treatment cycle, including the patient-reported 
outcome (PRO) scales; CBC assessment on Day 22; the Post-Treatment Visit; and the Survival Follow-up Phase of the 
study. 
q 
Patient-reported outcomes should be completed at Days 1 and 10 of each cycle and at the Post-Treatment Visit. If a cycle is 
delayed, the patient should still complete the PRO on the scheduled Day 1 of the next cycle, as well as the actual first dosing 
day of the next cycle of G1T28 or placebo + E/P therapy. Patient-reported outcomes may be obtained up to 24 hours prior to 
the first dose of each cycle of G1T28 or placebo + E/P therapy.  
r 
In Part 2 only, peripheral blood samples for immunologic marker assessment will be collected at predose on Day 1 of Cycles 
1, 3, and 5; at the Post-Treatment Visit, and at 60 days after the Post-Treatment Visit. 
s 
Adverse events will be recorded from the time of informed consent. 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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2.3. 
Number of Patients 
Overall, up to 110 patients will be enrolled in the study.  The sample size for this study is 
determined by clinical rather than statistical considerations. 
In Part 1, approximately 40 patients will be enrolled, assuming up to 3 cohorts. Cohorts will 
consist of 6 patients each in the Phase 1b dose-finding portion of Part 1 and up to 18 patients in 
the Phase 2a expansion portion of Part 1 at the selected dose to be used in Part 2. Additional 
patients may be enrolled in the Phase 1b dose-finding portion of Part 1 if more than 1 cohort is 
enrolled.  In Part 2, 70 patients will be randomly assigned (1:1 ratio) to 1 of 2 groups: G1T28 
administered IV with E/P therapy (Group 1) or placebo administered IV with E/P therapy (Group 
2). With 35 patients, the precision for point estimates in each arm is as follows: the 95% 
confidence interval (CI) width for binary endpoints based on Wilson score intervals are at most 
the observed proportion ± 0.157. The 95% CI width for continuous endpoints using the t-
distribution are the observed mean ± 0.344*standard deviation of the endpoint. 
The study will be conducted at up to 80 centers in North America and Europe. 
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3. 
ANALYSIS SETS 
3.1. 
Definition of Analysis Sets  
Data analyses will be based on the four analysis sets defined below. Analysis sets, including 
exclusions based on major deviations, will be reviewed and approved by G1 Therapeutics prior 
to the study unblinding.  
3.1.1. 
Full Analysis Set 
The full analysis set (FAS) includes all randomized patients who received at least 1 dose of study 
drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS will be conducted on the 
basis of the assigned treatment. All efficacy analyses will be assessed using the FAS. The FAS 
will be used for analyses of tumor response, progression-free survival (PFS) and overall survival 
(OS). 
3.1.2. 
Safety Analysis Set 
The safety analysis set includes all enrolled patients who received at least 1 dose of study drug 
(etoposide, carboplatin, or trilaciclib). Analyses using the safety analysis set will be conducted 
on the basis of the actual treatment. All safety analyses will be assessed using the safety 
population.  
3.1.3. 
Per Protocol (PP) Analysis Set 
The per-protocol (PP) analysis set will include only those patients in FAS who have no major 
protocol deviations (as described in Section 3.2) and who received the treatment to which they 
were randomized or assigned. For patients who took the wrong treatment for part of the study, 
their data will be excluded from the PP analysis set. PP analysis set may be used to analyze 
selected endpoints to test the robustness of results. The criteria for inclusion in the PP subset will 
be finalized and documented prior to unblinding patients in Part 2 of the study. 
3.1.4. 
Response Evaluable Analysis Set 
The Response Evaluable Analysis Set will include all patients who are in the Safety Analysis Set 
and have at least 1 post-baseline tumor assessment, or have clinical progression as noted by the 
investigator before their first post-baseline tumor scan, or have died due to disease progression 
before their first post-baseline tumor scan.  The response evaluable analysis set will be used for 
analyses of tumor response.   
3.2. 
Protocol Deviations  
Certain protocol deviations are major in that they may affect the ability to assess the safety and 
efficacy of study drug. Patients with important deviations will be excluded from the PP analysis 
set. All patients who meet the definition of the FAS analysis set will be included in the FAS 
analysis set regardless of these deviations. 
The criteria for inclusion in the PP set will be finalized and documented prior to unblinding 
patients in Part 2 of the study. 
If a patient is randomized or assigned to a treatment group, but fails to receive treatment, the 
reason for not receiving treatment will be noted in the CSR. Any such patients who are not 
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treated will be excluded from the FAS, safety, and PP analysis sets but will be included in 
patients listings for the CSR.   
If the wrong treatment is administered to a patient, and the reason for the incorrect treatment is 
documented, this will be noted in the CSR and the patient’s data included in the Safety Analysis 
Set based on the actual treatment received.  A listing of patients whose blind was broken during 
the study (Part 2) will also be provided in the CSR, if appropriate; data from un-blinded patients 
will be included in the FAS and excluded from the PP population. Additional protocol deviations 
will be reviewed in a data review meeting to classify protocol deviations as minor or major, and 
to discuss the potential impact on statistical analysis.  
    
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4. 
PROSPECTIVELY DEFINED ANALYSES  
As outlined in the protocol, trilaciclib is an IV cyclin dependent kinase (CDK) 4/6 inhibitor 
being evaluated for its ability to decrease chemotherapy-induced myelosuppression when 
administered in combination with cytotoxic chemotherapy.  Unlike granulocyte-colony 
stimulating factor (GCSF), which stimulates production of neutrophils, and transfusions, which 
only replace red blood cell (RBC) or platelets, trilaciclib is hypothesized to facilitate 
myelopreservation of all hematopoietic lineages including neutrophils, RBC, platelets, 
lymphocytes, etc.  
Based on the mechanism of action, it is also hypothesized that the effects of trilaciclib-induced 
myelopreservation may be more obvious after patients receive repeated rounds of chemotherapy.  
For example, SCLC patients treated with carboplatin and etoposide often have more dosing 
delays and hematologic-related adverse events (AEs) after multiple cycles due to repeated 
damage to the bone marrow.  In contrast, addition of trilaciclib to carboplatin and etoposide is 
theorized to counteract the chemotherapy-induced damage and allow patients to receive multiple 
cycles of therapy with less dose delays and fewer hematologic-related AEs.   
To capture these two aspects of trilaciclib benefit, the following analyses are prospectively 
proposed in Table 3 and their associated endpoint derivation and analysis methods will be 
detailed in Sections 5.1.1 and 6.2.7.1.  
Table 3 
Prospectively Defined Analyses 
Proportion of patients with febrile neutropenia during the treatment period 
Duration of Grade 4 neutropenia   
Duration of Grade 3/4 neutropenia   
Average ANC over time (for all cycles; with and without GCSF subset analysis) 
Average ANC NADIR over time (for all cycles; with and without GCSF subset analysis) 
Average ANC at each scheduled Day 1 of a cycle (for all cycles; with and without GCSF subset 
analysis) 
Average hemoglobin over time (for all cycles)  
Average platelet count over time (for all cycles) 
Average lymphocyte count over time (for all cycles) 
Proportion of patients with RBC transfusions (includes actual or eligible) during the treatment period 
Proportion of patients with platelet transfusions (includes actual or eligible) during the treatment period 
Proportion of patients with GCSF use during the treatment period 
Proportion of patients with ESA use during the treatment period 
Proportion of patients with IV antibiotic use during the treatment period 
Proportion of patients with infectious SAEs during the treatment period 
Proportion of patients with pulmonary infectious SAEs during the treatment period 
Time to first major adverse hematologic event (MAHE) which is defined to include components as the 
following: 
 
hospitalization for a hematologic event (e.g. febrile neutropenia, thrombocytopenia, hemoptysis, 
etc.) 
 
febrile neutropenia 
 
death related to treatment (including backbone chemotherapy and trilaciclib) 
 
dose delay/reduction due to ANC or platelet counts 
 
duration of Grade 4 ANC > 5 days 
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 
RBC transfusion (actual or eligible) 
 
platelet transfusion (actual or eligible) 
ANC = absolute neutrophil count; ESA = erythropoiesis stimulating agent; GCSF = granulocyte-colony stimulating factor; IV 
= intravenous; NADIR = the lowest point; SAEs = serious AEs. 
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5. 
PRIMARY AND SECONDARY ENDPOINTS  
The following general definitions will be applied to all endpoints derivation unless otherwise 
specified. 
Term 
Definition 
Grade 4 neutropenia 
ANC lab value that meets the common terminology criteria for adverse 
events (CTCAE) criteria for ≥ Grade 4 toxicity 
Grade 3/4 neutropenia 
ANC lab value that meets the CTCAE criteria for ≥ Grade 3 toxicity 
Cycle baseline 
The last non-missing value within the window starting from 3 days prior to 
the date/time of study drug administration on Day 1 of Cycle 1 and 1 day 
prior to Day 1 of each subsequent cycle (i.e. Cycle 2, Cycle 3, etc); must be 
prior to the time of study drug administration 
Cycle NADIR 
The lowest value for a given hematologic parameter that occurs between 
start of cycle and end of cycle and is less than the cycle baseline. 
Duration of cycle 
Total number of days from start of cycle to end of cycle, that is, date of end 
of a cycle - date of start of cycle + 1. 
End of cycle* 
Day 1 of the subsequent cycle.  For example, the end of cycle for Cycle 1 is 
Day 1 of Cycle 2. For the last cycle (where no subsequent cycle is given), 
the end of cycle will be defined as Day 36.  
Start of cycle 
Day 1 of each cycle starts with the administration of study drug(s) 
(etoposide, carboplatin or trilaciclib) 
Start of study 
Day 1 of Cycle 1 
Study baseline 
The last non-missing value prior to, or on the date of administration of 
study drug(s) (etoposide, carboplatin or trilaciclib); must be prior to the 
time of study drug administration 
Change from baseline 
Calculated as the post-baseline value minus the baseline value. If the 
baseline value is missing for a particular endpoint, change from baseline 
will be missing. 
Treatment period 
Total number of days from start of cycle for Cycle 1 and end of cycle for 
the last cycle 
* For various hematologic parameter analyses, the last assessment prior to end of cycle will be utilized in the analyses. 
Situations where this applies will be indicated as such. 
5.1. 
Efficacy endpoints 
5.1.1. 
Primary Prospectively-Defined Clinical Endpoints for Efficacy   
5.1.1.1. 
Febrile Neutropenia AEs 
A cycle is considered to have a febrile neutropenia AE if any date between the start and stop date 
of the AE overlaps with any date between the start of cycle and end of cycle. If an event ends on 
the cycle start day, it will not be counted as an event in that cycle unless the event also started on 
that day. For the treatment period, the total number of febrile neutropenia AE events is the 
number of cycles where at least one febrile neutropenia AE is observed. If a patient did not have 
any febrile neutropenia AE events, the value of 0 will be assigned to that patient.  AEs during the 
study is captured in the electronic database. The event terms are coded using the Medical 
Dictionary for Regulatory Affairs (MedDRA Version 20.1) and “FEBRILE NEUTROPENIA” is 
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a preferred term which can be used to identify the proper AE records. Data handling conventions 
for missing start and stop dates for AEs are described in Section 5.2.1.  
Any occurrence of a febrile neutropenia AE during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of febrile neutropenia AE events ≥ 1 is observed, No 
for other scenarios.  
5.1.1.2. 
RBC Transfusions 
Within a cycle, a RBC transfusion event is defined as either (1) an actual RBC transfusion, OR 
(2) eligible for RBC transfusion = hemoglobin < 8.0 g/dL. Therefore, for the treatment period, a 
total number of RBC transfusions (i.e. a RBC transfusion event = Yes) is obtained as the number 
of cycles in which there is at least one RBC transfusion event. If a patient did not have any RBC 
transfusion events, the value of 0 will be assigned to that patient. Hence, the total number of 
cycles without RBC transfusion is calculated as the total number of treatment cycles received – 
total number of cycles with RBC transfusion.  
To define those cycles where a patient was eligible for a RBC transfusion, the lab value of 
hemoglobin (< 8.0 g/dL) must fall between start of cycle and end of cycle for that cycle. Any 
unscheduled data and the actual assessment date (rather than visit date) will be included in the 
derivation. 
Hence, any occurrence of a RBC transfusion during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of cycles with RBC transfusion ≥ 1 is observed, No for 
other scenarios.   
5.1.1.3. 
Platelet Transfusions 
Similarly, within a cycle, a platelet transfusion event is defined as either (1) an actual platelet 
transfusion, OR (2) eligible for platelet transfusion = platelet count ≤ 10 × 109/L. Therefore, for 
the treatment period, a total number of platelet transfusions (i.e. a platelet transfusion event = 
Yes) is the number of cycles in which there is at least one platelet transfusion event. If a patient 
did not have any platelet transfusion events, the value of 0 will be assigned to that patient. 
Therefore, the total number of cycles without a platelet transfusion is calculated as the total 
number of treatment cycles received – total number of cycles with platelet transfusion.   
To define those cycles where a patient was eligible for a platelet transfusion, the lab value of 
platelet count (≤ 10 × 109/L) must fall between start of cycle and end of cycle for that cycle. Any 
unscheduled data and the actual assessment date (rather than visit date) will be included in the 
derivation.  
Hence, any occurrence of a platelet transfusion during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of cycles with platelet transfusion ≥ 1 is observed, No 
for other scenarios.   
5.1.1.4. 
GCSF Administrations 
Administration of GCSF is collected with the concomitant medications which are coded using 
World Health Organization Drug Dictionary (WHO-DD Version Sep2017).  The criterion to 
select proper records is as follows: If the chemical subgroup from WHO-DD Version Sep2017 
(i.e. TEXT4 for CODE4) takes value “COLONY STIMULATING FACTOR”, the medication is 
classified as GCSF. 
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A cycle where GCSF is administered concurrently will be identified by comparing the start and 
stop dates of each administration of GCSF to the start of cycle and end of cycle.  If any of the 
dates of administration of GCSF overlap with any dates between the start of cycle and end of 
cycle, that cycle will be considered as having GCSF administered. Data handling conventions for 
missing start and stop dates are described in Section 6.2.5. 
For the treatment period, the total number GCSF administration is the number of cycles in which 
there is at least one GCSF dose administered. If a patient did not have any GCSF use, the value 
of 0 will be assigned to that patient. The number of cycles where GCSF was NOT given is 
calculated as total number of treatment cycles received – total number of cycles where GCSF 
was administered. 
Therefore, any occurrence of a GCSF administration during the treatment period is defined as a 
binary variable (Yes or No); Yes if total number of cycles with GCSF administration ≥ 1 is 
observed, No for other scenarios.    
5.1.1.5. 
ESA Administrations 
Administration of erythropoiesis stimulating agents (ESAs) is collected with the concomitant 
medications which are coded using WHO-DD Version Sep2017.  The criterion to select proper 
records is as follows: If the chemical subgroup from WHO-DD Version Sep2017 (i.e. TEXT4 for 
CODE4) takes value “OTHER ANTIANEMIC PREPARATIONS”, the medication is classified 
as ESAs.  If a patient did not receive an ESA, then the patient will be set to 0.  
Those cycles where ESAs are administered concurrently will be identified by comparing the start 
and stop dates of each ESA to the start of cycle and end of cycle.  If any of the dates of 
administration of an ESA overlap with any dates between the start of cycle and end of cycle, that 
cycle will be considered as having an ESA administered. Data handling conventions for missing 
start and stop dates are described in Section 6.2.5.   
For the treatment period, the total number GCSF administration is the total number of cycles in 
which there is at least one ESAs dose administered;. If a patient did not have any ESA use, the 
value of 0 will be assigned to that patient. The number of cycles where ESAs were NOT given is 
calculated as total number of treatment cycles received – total number of cycles where ESAs 
were administered. 
Therefore, any occurrence of an ESAs administration during the treatment period is defined as a 
binary variable (Yes or No); Yes if total number of cycles with ESAs administration ≥ 1 is 
observed, No for other scenarios.   
5.1.1.6. 
IV Antibiotic Uses 
IV antibiotic administration is collected with concomitant medications which are coded using 
WHO-DD Version Sep2017.  The criteria for identifying an IV antibiotic administration event is 
 If the Therapeutic subgroup from WHO-DD Version Sep2017 (i.e. TEXT2 for CODE2) 
takes value “ANTIBACTERIALS FOR SYSTEMIC USE”, and  
 The route of medication is “intravenous” or the route is “other” with the detailed 
specification as “IVPB”.  
Those cycles where IV antibiotics are administered concurrently will be identified by comparing 
the start and stop dates of each antibiotic to the start of cycle and end of cycle.  If any of the 
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dates of administration of any IV antibiotic overlap with any dates between the start of cycle and 
end of cycle, that cycle will be considered as having an IV antibiotic administered. Data handling 
conventions for missing start and stop dates are described in Section 6.2.5. 
For the treatment period, the total number IV antibiotics administration is the total number of 
cycles where IV antibiotics were administered. If a patient did not have any IV antibiotic use, the 
value of 0 will be assigned to that patient. The number of cycles where IV antibiotics were NOT 
given is calculated as total number of treatment cycles received – total number of cycles where 
IV antibiotics were administered. 
Therefore, any occurrence of an IV antibiotics administration during the treatment period is 
defined as a binary variable (Yes or No); Yes if total number of cycles with IV antibiotics 
administration ≥ 1 is observed, No for other scenarios.     
5.1.1.7. 
Infection SAEs and Pulmonary Infection SAEs 
Each infection SAE and pulmonary infection SAE is captured in the electronic database. The 
event terms are coded using the MedDRA Version 20.1. The criterion for identifying the proper 
infection SAE and pulmonary infection SAEs records is as follows: if the system organ class 
(SOC) from MedDRA takes value “INFECTIONS AND INFESTATIONS”, the preferred term 
(PT) takes values from Table 4, and the AE is a serious event.    
Table 4 
PT List for Grouping Infection AEs and Pulmonary Infection AEs 
Category 
Preferred terms 
Pulmonary Infection AEs 
Bronchitis 
 
Influenza 
 
Pneumonia 
 
Pneumonia bacterial 
 
Respiratory tract infection 
 
Upper respiratory tract infection 
 
Viral upper respiratory tract infection 
 
 
 
Infection AEs 
Anal abscess 
Oral herpes 
 
Bacteraemia 
Pharyngitis streptococcal 
 
Bronchitis 
Pneumonia 
 
Candida infection 
Pneumonia bacterial 
 
Chronic sinusitis 
Respiratory tract infection 
 
Conjunctivitis 
Sepsis 
 
Infection 
Skin infection 
 
Influenza 
Upper respiratory tract infection 
 
Nasopharyngitis 
Urinary tract infection 
 
Oral candidiasis 
Urosepsis 
 
 
Viral upper respiratory tract infection 
A cycle is considered to have an infection SAE if any date between the start and stop date of the 
AE overlaps with any date between the start of cycle and end of cycle. If an event ends on the 
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cycle start day, it will not be counted as an event in that cycle unless the event also started on 
that day. For the treatment period, the total number of infection SAE events is the number of 
cycles where at least one infection SAE is observed. If a patient did not have any infection SAE 
events, the value of 0 will be assigned to that patient. Data handling conventions for missing start 
and stop dates for AEs are described in Section 5.2.1.    
Any occurrence of an infection SAE during the treatment period is defined as a binary variable 
(Yes or No); Yes if total number of infection SAE events ≥ 1 is observed, No for other scenarios.  
Similarly, a cycle is considered to have a pulmonary infection SAE if any date between the start 
and stop date of the AE overlaps with any date between the start of cycle and end of cycle. If an 
event ends on the cycle start day, it will not be counted as an event in that cycle unless the event 
also started on that day. For the treatment period, the total number of pulmonary infection SAE 
events is the number of cycles where at least one pulmonary infection SAE is observed. If a 
patient did not have any pulmonary infection SAE events, the value of 0 will be assigned to that 
patient. Data handling conventions for missing start and stop dates for AEs are described in 
Section 5.2.1.     
Any occurrence of a pulmonary infection SAE during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of pulmonary infection SAE events ≥ 1 is observed, No 
for other scenarios.  
5.1.1.8. 
Duration of Grade 4 Neutropenia 
Grade 4 neutropenia is defined as the lab value of ANC ≥ Grade 4 event CTCAE toxicity grade 
criteria (i.e. ANC value is < 0.5 x 109/L). For the treatment period, the total number of Grade 4 
neutropenia events is the number of cycles where at least one ANC value is < 0.5 x 109/L.  For 
example, if Cycle 2 has two ANC values that are both < 0.5 x 109/L, this only counts as one 
event. If a patient did not have any ANC ≥ Grade 4 events, the value of 0 will be assigned to that 
patient.  Unscheduled data and the actual assessment date (rather than visit date) will be included 
in the derivation.   
Within each cycle, the duration (days) of each reported Grade 4 neutropenia event is defined as 
the number of days from the date of first ANC value of <0.5 x 109/L observed between start of 
cycle and end of cycle, to the date of first ANC value ≥ 0.5 x 109/L that meets the following 
criteria: (1) occurs after the ANC value of <0.5 x 109/L and (2) no other ANC values <0.5 x 
109/L occur between this day and end of cycle. The following censoring rules will be applied in 
the calculation:   
(i) For a cycle where the Grade 4 neutropenia event does not resolve by end of the cycle, the 
duration will be assigned as above except the end date will be the end of cycle.   
(ii) For a cycle where the patient dies, withdraws consent, or is lost to follow-up during the 
Grade 4 neutropenia event, the duration will be assigned as above except the end date will 
be the date of the last ANC assessment prior to the end of cycle.    
For the treatment period, the overall duration (days) of Grade 4 neutropenia events is the median 
value among the duration (days) of Grade 4 neutropenia events from all cycles. The following 
data handling conventions will apply: 
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 
For those patients where all event duration values are derived from cycles with censored 
data, the median value for that patient will be the median censored value. It will be a 
considered a censored value; 
 
For those patients where a subset of event duration values are derived from cycles with 
censored data, the median value for that patient will be estimated using the KM method. It 
will be considered as an observed value (i.e. no censored value); 
 
For those patients where the median event duration cannot be derived (e.g. ≤ 2 values), the 
longest event duration amongst all the cycles will be used regardless of censoring, but the 
corresponding censoring flag will be carried over for analysis.  
5.1.1.9. 
Duration of Grade 3/4 Neutropenia  
Grade 3/4 neutropenia is defined as the lab value of ANC ≥ Grade 3/4 event per CTCAE toxicity 
grade criteria (i.e. ANC value is < 1.0 x 109/L). For the treatment period, the total number of 
Grade 3/4 neutropenia events is the number of cycles where at least one ANC value is < 1.0 x 
109/L.  For example, if Cycle 2 has two ANC values that are both < 1.0 x 109/L, this only counts 
as one event. If a patient did not have any ANC ≥ Grade 3/4 events, the value of 0 will be 
assigned to that patient.  Unscheduled data and the actual assessment date (rather than visit date) 
will be included in the derivation.    
Within each cycle, the duration (days) of each reported Grade 3/4 neutropenia event is defined as 
the number of days from the date of first ANC value of <1.0 x 109/L observed between start of 
cycle and end of cycle, to the date of first ANC value ≥ 1.0 x 109/L that meets the following 
criteria: (1) occurs after the ANC value of <1.0 x 109/L and (2) no other ANC values <1.0 x 
109/L occur between this day and end of cycle. The following censoring rules will be applied in 
the calculation:   
(i) For a cycle where the Grade 3/4 neutropenia event does not resolve by end of the cycle, the 
duration will be assigned as above except the end date will be the end of cycle.    
(ii) For a cycle where the patient dies, withdraws consent, or is lost to follow-up during the 
Grade 3/4 neutropenia event, the duration will be assigned as above except the end date will 
be the date of the last ANC assessment prior to the end of cycle.    
For the treatment period, the overall duration (days) of Grade 3/4 neutropenia events is the 
median value among the duration (days) of Grade 3/4 neutropenia events from all cycles. The 
following data handling conventions will apply: 
 
For those patients where all event duration values are derived from cycles with censored 
data, the median value for that patient will be the median censored value. It will be a 
considered a censored value; 
 
For those patients where a subset of event duration values are derived from cycles with 
censored data, the median value for that patient will be estimated using the KM method. It 
will be considered as an observed value (i.e. no censored value); 
 
For those patients where the median event duration cannot be derived (e.g. ≤ 2 values), the 
longest event duration amongst all the cycles will be used regardless of censoring, but the 
corresponding censoring flag will be carried over for analysis.  
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5.1.1.10. ANC, Platelet Count, Absolute Lymphocytes, and Hemoglobin Change over 
Time  
For the hematologic parameters consisting of ANC, hemoglobin, platelet count, and absolute 
lymphocytes, the observed lab values in each windowed visit as detailed in Section 6.1.3 will be 
appropriately identified for further analysis. For the ANC, the cycle NADIR will also be 
obtained.  
Also, for the ANC, the observed lab value at each scheduled Day 1 of a cycle will be properly 
flagged for further analysis. The scheduled Day 1 of cycle will follow the scheme defined in the 
protocol regardless of the potential cycle delay, for example, if Cycle 2 is delayed 7 days from 
Cycle 1 due to ANC recovery, Day 22 from the first dose date of study drug in Cycle 1 will the 
scheduled Day 1 of Cycle 2.  
5.1.1.11. Time to First Major Adverse Hematologic Event (MAHE) 
As a composite measure of trilaciclib effect, MAHE is based on a combination of individual 
components specified in Table 5, which also include details about the derivation or data source 
for each component. Time to first occurrence of a MAHE event is defined as the first time to 
observe an interested event among all the component, starting from the first dose date of study 
drug administration.  
Therefore, for a patient with presence of MAHE events, time (months) to first occurrence of a 
MAHE event will be the minimum among the 7 potentially derived duration (i.e. calculated as 
(date of first occurrence of a MAHE component event – first dose date of study drug 
administration + 1)/30).   
Table 5 
Component of MAHE and the Suggested Data Source/Derivation Algorithm 
Seq # 
Component of MAHE 
Criteria to identify the date of first occurrence of event 
1 
Hospitalization for a 
hematologic event (e.g. 
febrile neutropenia, 
thrombocytopenia, 
hemoptysis, etc) 
Each hospitalization for a hematologic event (e.g. febrile 
neutropenia, thrombocytopenia, hemoptysis, etc.) is 
captured in AE data of electronic database. The event terms 
are coded using the MedDRA Version 20.1. Some 
suggested PTs are listed in Table 6. These PTs will be 
broken into those that are always counted if they result in 
hospitalization, and those that will be subject to a case by 
case medical review to determine if the hospitalization is a 
hematologic event. All review will be finalized prior to 
study unblinding.  
2 
Febrile neutropenia 
Detailed in Section 5.1.1.1 
3 
Death related to 
treatment (including 
backbone chemotherapy 
and trilaciclib) 
An AE with its outcome being death, if its relationship to 
any of the study drugs (etoposide, carboplatin, or 
trilaciclib) is “Possibly Related”, “Probably Related”, or 
“Definitely Related”. 
4 
Dose delay/reduction due 
to ANC or platelet counts Detailed in Section 5.1.3.4 
5 
Duration of Grade 4 
neutropenia > 5 days 
Detailed in Section 5.1.1.8. If the duration (days) within a 
cycle is censored, even the duration of Grade 4 neutropenia 
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Seq # 
Component of MAHE 
Criteria to identify the date of first occurrence of event 
is ≤ 5 days, the event will still be considered to meet the 
criteria. 5.1.1.2 
6 
RBC transfusion (actual 
or eligible) 
Detailed in Section 5.1.1.2 
7 
Platelet transfusion 
(actual or eligible) 
Detailed in Section 5.1.1.3 
A patient with absence of any MAHE events will be censored at the date of the last 
assessment/contact date prior to or on the day of study completion/discontinuation, or lost to 
follow-up, whichever is earlier.  
Table 6 
PT list for Meeting the Criteria of Hospitalization for a Hematologic Event 
PTs always included 
PTs to be reviewed for possible inclusion 
FEBRILE NEUTROPENIA 
RESPIRATORY FAILURE 
NEUTROPENIA 
PNEUMONIA 
ANAEMIA 
HAEMOPTYSIS 
THROMBOCYTOPENIA 
 
NEUTROPHIL COUNT DECREASED 
 
HEMOGLOBIN DECREASED 
 
ANAEMIA MACROCYTIC 
 
RED BLOOD CELL COUNT DECREASED 
 
PLATELET COUNT DECREASED 
 
5.1.2. 
Exploratory Efficacy Endpoints  
5.1.2.1 Grade 2 or Greater Nephrotoxicity 
For any post-baseline creatinine assessment, an event of grade ≥ 2 nephrotoxicity is defined as 
the observed value >1.5 × baseline value, or > 1.5 × Upper Limit of Normal Range (ULN). 
Within a cycle, for each nephrotoxicity event, the occurrence of a creatinine value meeting the 
criteria outlined above is described using a binary variable (Yes or No); Yes, if the designated 
event is observed, No for other scenarios. For the treatment period, the total number of 
nephrotoxicity events where the creatinine value meets the criteria is the number of cycles where 
at least one lab value meets the criteria.  For example, if Cycle 2 has two values that both meet 
criteria, this only counts as one event. If a patient does not have any lab values meeting the 
criteria, the value of 0 will be assigned to that patient.  Unscheduled data and the actual 
assessment date (rather than visit date) will be used for these analyses. 
Any occurrence of a Grade ≥ 2 nephrotoxicity during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of Grade ≥ 2 nephrotoxicity events ≥ 1 is observed, No 
for other scenarios.  
5.1.2.2 Occurrence of Alopecia and Mucositis 
Alopecia will be identified by the preferred term of “alopecia”, and mucositis will be identified 
by the high level term ‘stomatitis and ulceration’, or the preferred terms ‘mucosal inflammation’, 
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‘mucosal ulceration’, or ‘oesophagitis’  used in MedDRA Version 20.1 coding for AE data, and 
these terms will be used to identify the occurrence of events during the treatment period.  
Separate analyses will be done for each term.  
Any occurrence of an alopecia (or mucositis) event during the treatment period is defined as a 
binary variable (Yes or No); Yes if total number of alopecia (or mucositis) events ≥ 1 is 
observed, No for other scenarios. Total number of events per subject will also be summarized. 
Data handling conventions for missing start/stop dates of AEs are in Section 5.2.1. 
5.1.2.3 FACT-L and FACT-An 
The FACT-L is a 36-item self-report instrument that measures multidimensional quality of life 
(QoL) by asking patients to rate a series of statements. FACT-L consists of the 27-item FACT—
general (FACT-G) combined with the 9-item lung cancer-specific subscale (2 of the 9 items are 
not scored, that is, B5 = “I am bothered by hair loss” and L5 = “I regret my smoking”).  
The FACT-G contains four generic cancer-specific subscales including the 7-item physical well-
being (PWB), 7-item social/family well-being (SWB), 6-item emotional well-being (EWB), and 
7-item functional well-being (FWB) subscales. The 7-item Lung Cancer Subscale (LCS) assesses 
the impact of symptoms commonly reported by lung cancer patients, including shortness of 
breath, loss of weight, and chest tightness. The 20-item anemia subscale consists of the 13-item 
fatigue component and 7 items for non-fatigue; hence, fatigue and other symptoms of anemia 
(e.g., dizziness, joint aches, etc) are measured using an anemia-specific symptom scale that 
assesses self-report of the cognitive, physical, and emotional manifestations of anemia. All the 
questions are rated on a five-point Likert-type scale ranging from 0 (not at all) to 4 (very much). 
Table 7 
List of Items Which Need Subtraction before Subscale or Total Score Calculation 
Subscale Item ID 
Items description 
Value to be used for score 
calculation  
PWB 
All 7 items 
 
4 - observed value 
EWB 
GE1 
I feel sad 
4 - observed value 
 
GE3 
I am losing hope in the fight against my 
illness 
4 - observed value 
 
GE4 
I feel nervous 
4 - observed value 
 
GE5 
I worry about dying 
4 - observed value 
 
GE6 
I worry that my condition will get 
worse 
4 - observed value 
LCS 
B1 
I have been short of breath 
4 - observed value 
 
C2 
I am losing weight 
4 - observed value 
 
L2 
I have been coughing 
4 - observed value 
 
L3 
I feel tightness in my chest 
4 - observed value 
Anemia 
HI7 
I feel fatigued 
4 - observed value 
 
HI12 
I feel weak all over 
4 - observed value 
 
An1 
I feel listless (“washed out”) 
4 - observed value 
 
An2 
I feel tired 
4 - observed value 
 
An3 
I have trouble starting things because I 
am tired 
 
4 - observed value 
 
An4 
I have trouble finishing things because I 
am tired 
4 - observed value 
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Subscale Item ID 
Items description 
Value to be used for score 
calculation  
 
An6 
I have trouble walking 
4 - observed value 
 
An8 
I need to sleep during the day 
 
4 - observed value 
 
An9 
I feel lightheaded (dizzy) 
4 - observed value 
 
An10 
I get headaches 
4 - observed value 
 
B1 
I have been short of breath 
4 - observed value 
 
An11 
I have pain in my chest 
4 - observed value 
 
An12 
I am too tired to eat 
4 - observed value 
 
An14 
I need help doing my usual activities 
4 - observed value 
 
An15 
I am frustrated by being too tired to do 
the things I want to do 
4 - observed value 
 
An16 
I have to limit my social activity 
because I am tired 
4 - observed value 
Calculation of the FACT scores and methods to deal with missing data will be handled according 
to the standard scoring guidelines. Based on the FACT scoring guide, Table 7 identifies those 
items that must be subtracting the response from “4”.  After the subtraction in proper items, the 
subscale score or relevant total score can be calculated. When there are missing data, a subscale 
with at least 50% answered items enables valid subscale score calculation (e.g., a minimum of 4 
answered items from 7 items, 4 answered items of 6 items).   
The total score is then calculated as the sum of the un-weighted subscale scores. However, two 
rules are defined as follows for a valid total score when there are missing data 
 ALL of the component subscales have valid scores; 
 at least 80% answered items in overall (e.g. e.g., at least 22 of 27 FACT-G items completed); 
The detailed algorithms to calculate the subscale or relevant total score are defined in Table 8. 
For both subscale and total score, higher scores represent better functioning and better QoL. 
Table 8 
Algorithm for Subscale Score and Total Score 
Scale (no. of items) Algorithm of score calculation 
FACT-G (27)  
 
PWB subscale (7) 
It is calculated as 7 × [Sum of item scores] ÷ [N of items answered]. If there 
are ≥ 4 missing items scores, the subscale score is set to missing. The subscale 
score ranges from 0 to 28.  
SWB subscale (7) 
It is calculated as 7 × [Sum of item scores] ÷ [N of items answered]. If there 
are ≥ 4 missing items scores, the subscale score is set to missing. The subscale 
score ranges from 0 to 28. 
EWB subscale (6) 
It is calculated as 6 × [Sum of item scores] ÷ [N of items answered]. If there 
are ≥ 4 missing items scores, the subscale score is set to missing. The subscale 
score ranges from 0 to 24. 
FWB subscale (7) 
It is calculated as 7 × [Sum of item scores] ÷ [N of items answered]. If there 
are ≥ 4 missing items scores, the subscale score is set to missing. The subscale 
score ranges from 0 to 28. 
Total FACT-G 
score (27) 
Sum of subscale scores from PWB, SWB, EWB, and FWB, then it is 
calculated as 27 × [Sum of subscale scores] ÷ [N of items answered], however,  
 if any of the subscale score is missing, the total score is set to missing; or  
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Scale (no. of items) Algorithm of score calculation 
 if there are ≥ 6 missing items scores, the total score is set to missing; 
total FACT-G score ranges from 0 to 108.  
LCS subscale (7) 
  
Total LCS 
subscale (7) 
It is calculated as 7 × [Sum of item scores] ÷ [N of items answered]. If there 
are ≥ 4 missing items scores, the subscale score is set to missing. The subscale 
score ranges from 0 to 28. 
Total FACT-L 
(FACT-G + LCS 
subscale; 34) 
Sum of subscale scores from PWB, FWB, EWB, FWB, and LCS, then it is 
calculated as 34 × [Sum of subscale scores] ÷ [N of items answered], however,  
 if any of the subscale score is missing, the total score is set to missing; or  
 if there are ≥ 7 missing items scores, the total score is set to missing; 
total FACT-L score ranges from 0 to 136.  
Trial Outcome 
Index (TOI) (21) 
Sum of subscale scores from PWB, SWB, and LCS, then it is calculated as 21 
× [Sum of subscale scores] ÷ [N of items answered], however,  
 if any of the subscale score is missing, the total score is set to missing; or  
 if there are ≥ 5 missing items scores, the total score is set to missing; 
TOI ranges from 0 to 84.  
Anemia subscale (20) 
 
Fatigue subscale 
(13) 
It is calculated as 13 × [Sum of item scores] ÷ [N of items answered]. If there 
are ≥ 6 missing items scores, the subscale score is set to missing. The subscale 
score ranges from 0 to 52. 
Non-fatigue 
subscale (7) 
It is calculated as 7 × [Sum of item scores] ÷ [N of items answered]. If there 
are ≥ 4 missing items scores, the subscale score is set to missing. The subscale 
score ranges from 0 to 28. 
Total anemia 
subscale (20) 
It is calculated as 20 × [Sum of item scores] ÷ [N of items answered]. If there 
are ≥ 11 missing items scores, the subscale score is set to missing. The 
subscale score ranges from 0 to 80. 
Total FACT-An 
(FACT-G + 
anemia subscale; 
47) 
Sum of subscale scores from PWB, FWB, EWB, FWB, and anemia, then it is 
calculated as 47 × [Sum of subscale scores] ÷ [N of items answered], however,  
 if any of the subscale score is missing, the total score is set to missing; or  
 if there are ≥ 10 missing items scores, the total score is set to missing; 
total FACT-L score ranges from 0 to 188.  
Anemia TOI (34) 
Sum of subscale scores from PWB, SWB, and anemia, then it is calculated as 
34 × [Sum of subscale scores] ÷ [N of items answered], however,  
 if any of the subscale score is missing, the total score is set to missing; or  
 if there are ≥ 7 missing items scores, the total score is set to missing; 
anemia TOI ranges from 0 to 136.   
The extreme (best and worst) on study values and minimum and maximum change for each 
FACT subscale and total score will be derived. 
Clinically meaningful improvement in LCS is a binary variable (Yes or No) — Yes if the LCS 
subscale score is ≥7% increase from baseline, or ≥ 2 change from baseline, No for other non-
missing scenarios. Similarly, clinically meaningful deterioration is a binary variable (Yes or No) 
— Yes if the LCS subscale score is ≥7% reduction from baseline, or ≤ -2 change from baseline, 
No for other non-missing scenarios.   
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5.1.2.4 Neutrophil-lymphocyte Ratio (NLR) and Platelet-lymphocyte Ratio (PLR)  
NLR will be derived using the ANC and absolute lymphocyte count (ALC), and PLR will be 
calculated using platelet count and ALC.  Both NLR and PLR may have prognostic value in 
patients with various solid tumors. That is, the lower the value, the better the clinical prognosis. 
If data permit, NLR and PLR will be correlated with various anti-tumor efficacy analyses [e.g. 
objective response rate (ORR), PFS, and etc.]. 
5.1.3. 
Chemotherapy Exposure And Compliance Endpoints 
5.1.3.1 Duration of Exposure 
Duration of exposure (days) = First dose date of study drug from the last cycle – first dose date 
of study drug + 21.  
5.1.3.2 Number of Cycles Received 
Patients are considered to have started a cycle if they have received at least one dose of any study 
drug (etoposide, carboplatin, and trilaciclib).  In addition to the numeric summary for the number 
of cycles, the number of cycles will be categorized as 1, 2, 3, 4, 5, and ≥ 6.  
5.1.3.3 Dose Intensity and Cumulative Dose 
Algorithms for calculating parameters relevant to the dose exposure and intensity are included in 
Table 9.   
Table 9  
Algorithms for Calculating Parameters Relevant to the Dose Exposure and 
Intensity 
Parameter 
Trilaciclib § 
Etoposide 
Carboplatin 
Dosing schedule 
per protocol 
200 mg/m2 IV on 
Days 1 to 3 of a 3-
week cycle 
100 mg/m2 IV on 
Days 1 to 3 of a 3-
week cycle  
5 AUC on Day 1 of a 3-
week cycle 
Dose by cycle  
Total dose 
administered (mg) 
/most recent BSA (m2) 
[(mg/m2)].  
Total dose 
administered 
(mg)/most recent BSA 
(m2) [(mg/m2)].  
Total dose administered 
(Prescribed AUC and 
actual dose in mg) 
Cumulative dose  
Sum of the doses 
administered to a 
patient in the duration 
of exposure [(mg/m2)] 
Sum of the doses 
administered to a 
patient in the duration 
of exposure [(mg/m2)]  
Sum of the doses 
administered to a 
patient in the duration 
of exposure (in total 
prescribed AUC and 
total dose in mg) 
Dose intensity  
Cumulative dose 
(mg/m2) / (duration of 
exposure / 7) 
[(mg/m2/week)] 
Cumulative Dose 
(mg/m2) / (duration of 
exposure / 7) 
[(mg/m2/week)] 
Cumulative Dose (total 
prescribed AUC) / 
(duration of exposure / 
7) [AUC/ week] 
Relative dose 
intensity (%) 
 
 
100 * [Dose intensity 
(mg/m2/week) / (600 
/3 (mg/m2/week)]  
100 * [Dose intensity 
(mg/m2/week) / (300 
/3 (mg/m2/week)]  
100 * [Dose intensity 
(AUC/week) / (5/3) 
(AUC/week)]   
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Parameter 
Trilaciclib § 
Etoposide 
Carboplatin 
Relative Dose (%) 
100 * [Cumulative 
dose (mg/m2) / (600 × 
number of cycles 
(mg/m2)]  
100 * [Cumulative 
dose (mg/m2) / (300 × 
number of cycles 
(mg/m2)]  
100 * [Cumulative dose 
(AUC) / (5 × number of 
cycles (AUC)]  
§ Two different doses (200mg/m2 and 240mg/m2) of trilaciclib were evaluated in Part 1.  
240mg/m2 trilaciclib was the planned dose for all patients in Part 2.  The calculation of relevant 
parameters will be adjusted accordingly based on the example presented in this table.  
AUC = area under curve; BSA = body surface area; IV = intravenous.  
5.1.3.4 Modifications of Study Therapy, Including Cycle (Dose) Delay, Missed Doses, Dose 
Interruptions, and Dose Reductions 
 After Cycle 1, patients need to meet pre-specified laboratory parameter criteria before 
initiating Cycle 2 and each subsequent cycle of chemotherapy. Cycle (dose) delay and its 
associated reasons are collected at the beginning of each cycle in an electronic case report 
form (eCRF) page titled “Beginning Cycle Assessment”.  The reasons for delay will be 
summarized in the following categories: (1) Adverse event, (2) Logistical/Administrative 
Issues, (3) Hematologic Toxicity (which is a sum of those patients who fall into either 
category 3a or 3b), (3a) ANC < 1.5 x 109/L, (3b) Platelet Count < 100 x 109/L, (5) 
Nonhematologic Toxicity and (6) Other. Note that categories 3a and 3b are sub-bullets of 
category (3).  
 
Missed doses are identified on the dosing page.  The reasons for missed doses will be 
summarized in the following categories: (1) Adverse Event, (2) Logistical/Administrative 
Issues, and (3) Other. 
 Dose (mg/m2) reductions are not permitted for trilaciclib. Dose reductions for carboplatin and 
etoposide are collected on the dosing page; the reasons for reduction will be summarized in 
the following categories: (1) Adverse Event, (2) Change recommendation by SMC, and (3) 
Other.  
 Dose interruptions for all drugs are also captured on the dosing page and will be summarized 
for each study drug. 
5.2. 
Safety Endpoints  
5.2.1. 
Adverse Events (AEs) 
All AEs will be coded from verbatim text to PTs and grouped by SOC using the MedDRA 
Version 20.1. AEs will be collected from the time of signature of informed consent throughout 
the treatment period and including the post-treatment visit. AEs are graded by investigator 
according to CTCAE, Version 4.03.  
Any AE that started on or after the first dose of study drugs and up to the last dose +30 days will 
be included as a treatment-emergent AE (TEAE). AEs with an unknown/not reported onset date 
will also be included.  
Other AE variables include drug-related AEs, AEs leading to study drug discontinuation or study 
withdrawal, AEs leading to death, SAEs.  
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AEs with onset/end dates that are partially/completely missing will be imputed as follows: 
(i) For onset date: 
 If only the day part of the AE onset date is missing and occurs in the same month and year as 
the first dose date of study drug, the date of first dose of study drug will be used as the onset 
date of the AE. Otherwise, the first day of the month will be used to complete the onset date 
of the AE; 
 If the day and month parts of the AE onset date are missing and occur in the same year as the 
first dose of study drug, the date of the first dose of study drug will be used as the onset date 
of the AE. Otherwise, January 1st will be used to complete the onset date of the AE; 
 If the AE onset date is completely missing, the date of the first dose of study drug will be 
used as the onset date of the AE. 
(ii) For end date: 
 If only the day part of the AE end date is missing, the last day of the month will be used to 
complete the end date of the AE;  
 If the day and month parts of the AE end date are missing, December 31st will be used to 
complete the end date of the AE; 
 If the AE end date is completely missing and the onset date of the AE occurs after the date of 
the first dose of study drug, the last date during the treatment period +30 days will be used as 
the AE end date. If the AE end date is completely missing and the onset date of the AE 
occurs prior to the date of the first dose of study drug the date of the first dose of study drug 
will be used as the AE end date. 
AEs related to hematologic toxicity will be pooled based on the preferred MedDRA Version 
20.1. Table 10 outlines those terms that will be consolidated.  
Table 10 
Preferred Terms to Be Consolidated 
Presented term in the table  Preferred Term 
Neutropenia 
Neutropenia 
 
Febrile neutropenia 
 
Neutrophil count decreased 
Anaemia 
Anaemia 
 
Anaemia macrocytic 
 
Red blood cell count decreased 
 
Hemoglobin decreased 
Thrombocytopenia 
Thrombocytopenia 
 
Platelet count decreased 
Lymphopenia 
Lymphopenia 
 
Lymphocyte count decreased 
Leukopenia 
Leukopenia 
 
White blood cell count decreased 
AEs potentially related to infusion reactions will be pooled based on the PTs of MedDRA 
Version 20.1.  The events described by the PTs listed below that have a start date on the same 
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date study drug is administered will be summarized and presented in order of decreasing 
frequency: angioedema, back pain, bronchospasm, wheezing, chest pain, non-cardiac chest pain, 
hyperhidrosis, malignant dysphagia, dysphagia, oedema, swelling face, flushing, dysphonia, 
hypotension, hypoxia, paraesthesia oral, pain, phlebitis, pruritic, pyrexia, rash, dermatitis 
allergic, drug eruption, infusion site rash, injection site rash, rash pruritic, erythema, infusion site 
erythema, injection site erythema, chills, dyspnoea, syncope, tachycardia, throat tightness, 
injection site ulcer and mucocutaneous ulceration.   
5.2.2. 
Vital Signs 
Vital signs include pulse rate, respiratory rate, systolic blood pressure (SBP), diastolic blood 
pressure (DBP), weight, height (only measured at screening), and body temperature. Body Mass 
Index (BMI) will be computed as weight (kg)/[height (m)]2, BSA will be computed using 
DuBois-DuBois formula as 0.20247 × [height (m)]0.725 × [weight (kg)]0.425.  
For vital signs, change from baseline to each post-baseline visit and timepoint will be calculated. 
Vitals will be summarized by visit as collected and not windowed. 
The potentially clinically significant findings of vital signs will also be defined based on criteria 
defined in Table 11: 
Table 11 
Potentially Clinically Significant Criteria for Vital Signs 
 Vital Sign Parameter   
 Criterion value   
 Change from baseline  
 SBP   
 ≥180 mmHg   
 Increase ≥40 mmHg   
    
 ≤ 90 mmHg   
 Decrease ≥40 mmHg   
    
    
    
 DBP   
 ≥105 mmHg   
 Increase ≥20 mmHg   
    
 ≤ 50 mmHg   
 Decrease ≥20 mmHg   
 Pulse   
 ≥ 120 bpm   
 Increase ≥40 bpm   
    
  ≤ 50 bpm   
 Decrease ≥40 bpm  
    
    
    
 Weight   
 n/a   
 Change ≥10%   
bpm  = beats per minute 
5.2.3. 
Laboratory 
Blood and urine samples for the determination of clinical chemistry, hematology, and urinalysis 
laboratory variables described in Table 12 will be measured.  
Table 12 
Laboratory Assessment 
Lab Category 
Lab tests 
Hematology  
hemoglobin, hematocrit, white blood cell (WBC) with differential, platelet counts, 
ANC, ALC, Monocyte Absolute, Basophil Absolute, Eosinophil Absolute, and 
other non-protocol specified tests 
Chemistry  
albumin, Alkaline Phosphatase (ALP), total bilirubin, calcium, chloride, creatinine, 
glucose, inorganic phosphorus, potassium, total protein, Alanine Aminotransferase 
(ALT), Aspartate Aminotransferase (AST), Lactate Dehydrogenase (LDH), 
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Lab Category 
Lab tests 
sodium, and Blood Urea Nitrogen (BUN), and other non-protocol specified tests 
Urinalysis  
semiquantitative dipstick: specific gravity, pH, evaluation of glucose, protein, 
bilirubin, ketones, leukocytes, and hemoglobin microscopic examination, including 
RBC, WBC, and casts will be performed, if necessary 
Change from baseline in laboratory test results to each assessment will be calculated; for 
hematology parameters, the change from cycle baseline will also be obtained. The non-protocol 
specified tests and urinalysis results will not be summarized; they will only be included in 
listings. 
Clinical laboratory results will be graded according to CTCAE criteria, Version 4.03 which can 
be found in Table A-1 of Appendix.  Any graded abnormality that occurs following the initiation 
of study drug and represents at least a 1-grade increase from the baseline assessment is defined 
as treatment emergent. Any assessment for which CTCAE toxicity grades are not available, will 
not be included in any analyses for which toxicity grades are required. 
Analysis of Abnormal Hepatic Laboratory Values 
The following categories of abnormal hepatic laboratory values will be evaluated for any 
occurrence among all post baseline assessments.  
 ALT and/or AST >3x ULN, ALP < 2xULN, and Total Bilirubin> 2x ULN 
 AST > 3,5,8,10, and 20x ULN, AST>5x ULN for more than 5 weeks 
 ALT > 3,5,8,10, and 20x ULN, ALT > 5x ULN for more than 5 weeks 
 Total Bilirubin >1.5 or >2x ULN  
5.2.4. 
Electrocardiograms 
Electrocardiogram (ECG) parameters include heart rate, PR interval, and QT, QTcB, QTcF and 
QRS intervals. Change from baseline to each post-baseline visit will be calculated and 
summarized by visit as collected and not windowed. Visits and timepoints only collected for PK 
subjects in Part 1 will be listed but not summarized. 
Potentially clinically significant ECG findings will be identified using the criteria which are 
included in Table 13. ECG results are interpreted as normal, abnormal but not clinically 
significant, or abnormal and clinically significant.  
Table 13 
Potentially Clinically Significant Criteria for ECG 
 ECG Parameter   
 Criterion value   
 Heart Rate   
 >120 bpm   
    
  <50 bpm   
 PR Interval   
 ≥ 210ms   
 QRS Interval   
 ≥ 120ms   
    
  ≤ 50ms   
 QT Interval   
 ≥ 500ms   
    
 ≤ 300ms   
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 ECG Parameter   
 Criterion value   
 QTcB, QTcF Intervals   
 ≥ 500ms   
    
 ≥ 480ms   
    
 ≥ 450ms   
    
 ≤ 300ms   
    
 Change from baseline ≥ 30 ms  
    
 Change from baseline ≥ 60 ms  
5.2.5. 
Physical Examination 
Physical examination is conducted during screening, on Day 1 of each cycle, and at the post-
treatment visit. Abnormal findings in PE were to be reported as AEs.  These data will not be 
summarized, i.e. they will only be available in listings.  
5.2.6. 
Tumor Responses and Clinical Benefit 
For tumor assessment, all sites of disease will be assessed radiologically by CT or MRI at 
screening, every other cycle while on treatment and every 2 months in survival followup, until 
the date of (i) disease progression as defined by RECIST 1.1 (Eisenhauer et al, 2009) or by 
clinical criteria; or (ii) withdrawal of consent; or (iii) receiving subsequent anti-cancer therapy, 
whichever is earlier. At each tumor assessment visit, the overall visit response by RECIST will 
determined three ways: (1) derived programmatically using the information from target lesions 
(TL), non-target lesions (NTLs) and new lesions as entered into the eCRF, (2) by the investigator 
and collected in the eCRF and (3) by Blinded Independent Central Review (BICR) which is 
described in the Independent Review Charter.  
For all patients, the RECIST tumor response data will be used to determine each patient’s visit 
response according to RECIST version 1.1 and the best overall response (BOR).  
5.2.6.1. 
Target Lesions (TLs) 
Measurable disease 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 computed tomography (CT) or magnetic resonance imaging (MRI); or  
 ≥10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable); or 
 ≥ 20 mm by chest X-ray. 
Previously irradiated lesions (or lesions treated with loco-regional therapies) 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 is recorded 
then measurements from the one that is closest to start of treatment will be used to define the 
baseline sum of TLs. Table 14 gives definition of TL visit responses. 
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Table 14 
Definition of TL Visit Responses 
Visit Reponses 
Description 
Complete Response 
(CR) 
Disappearance of all target lesions. Any pathological lymph nodes selected as 
target lesions must have a reduction in short axis to <10mm. 
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 of diameters (i.e. nadir) 
since treatment started including the baseline sum of diameters. 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD.  
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). 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.  
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 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 0 cm. 
Change in method of assessment of target lesions 
CT, MRI and clinical examination are the only methods of assessment that can be used within a 
trial, with CT and MRI being the preferred methods and clinical examination only used in special 
cases. If a change in method of assessment occurs between CT and MRI this will be considered 
acceptable and no adjustment within the programming is needed.  
5.2.6.2. 
Non-Target Lesions (NTLs) and New Lesions 
The non-target lesion response will be based on the Investigator’s overall assessment of NTLs as 
Table 15: 
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Table 15 
Definition of NTLs Visit Responses 
Visit Reponses 
Description 
CR 
Disappearance of all NTLs present at baseline with all lymph nodes non-
pathological in size (<10mm short axis). 
PD 
Unequivocal progression of existing NTLs, which may be due to an important 
progression in one lesion only or in several lesions 
Non-CR/Non-PD 
Persistence of one or more NTLs with no evidence of progression 
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 responses. 
5.2.6.3. 
Time Point Response (TPR) 
Table 16 defines how the previously defined TL and NTL visit responses will be combined with 
new lesion information to give a TPR. The possible TPRs at a visit are CR, PR, SD, PD, and NE.  
Table 16  
Evaluation of Time Point Response 
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 
Not all evaluated 
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 
At each visit, patients will be programmatically assigned a RECIST TPR of CR, PR, SD, PD or 
NE depending on the status of their disease compared to baseline and previous assessments as 
discussed in the Sections 5.2.6.1 and 5.2.6.2.  
For a scheduled tumor scan assessment, it is expected that there will be a variation for the actual 
timing of scans among target, non-target, and new lesions. In assigning a date for the derived 
overall assessment at a visit, the earliest date collected at that visit will be used 
5.2.6.4. 
Best Overall Response (BOR) 
BOR will be determined using TPRs up until the last evaluable TPR prior to or on the date of (i) 
disease progression as defined by RECIST 1.1 (Eisenhauer et al, 2009) or by clinical criteria 
(this will not apply to the BICR analysis); or (ii) withdrawal of consent; or (iii) receiving 
subsequent anti-cancer therapy, whichever is earlier.   
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A patient’s BOR will be determined based on Table 17.  For data-driven scenarios which may 
not be covered by Table 17, the BOR will be reviewed and determined by the medical advisors 
and statisticians prior to unblinding the study.    
For patients who progress and subsequently have a response, the best overall 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). 
There are two ways of assigning BOR for a patient when the minimum interval for confirmation 
of CR and PR is not satisfied or if there are no confirmatory scans for CR and PR: 
 Adding two more response categories as: unconfirmed CR, unconfirmed PR; 
 Assigning BOR as SD, that is, both the unconfirmed CR and unconfirmed PR will be SD. 
Both ways of assigning BOR will be implemented.  
The number and percentage of patients in each category of derived BOR (Confirmed CR, 
Confirmed PR, SD, PD, or NE) will be summarized.  
 
Table 17  
Best Overall Response When Confirmation of CR and PR are Required [a] 
First TPR Second TPR 
Best overall response*^ for 
ORR 
Best Overall Response for 
ORRUNCONFIRMED 
CR 
CR 
CR 
CR 
CR 
PR 
SD [b] or PD 
Unconfirmed CR 
CR 
SD 
SD [b] or PD  
Unconfirmed CR 
CR 
PD 
SD [b] or PD  
Unconfirmed CR 
CR 
NE or NA 
SD [c] or NE or NA 
Unconfirmed CR 
PR 
CR 
PR 
Unconfirmed CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD [d] 
Unconfirmed PR 
PR 
PD 
SD [b] or PD 
Unconfirmed PR 
PR 
NE or NA 
SD [c] or NE or NA 
Unconfirmed PR 
NE 
NE 
NE 
NE 
NE 
CR 
SD 
Unconfirmed CR 
NE 
PR 
SD 
Unconfirmed PR 
NE 
SD 
SD 
SD 
NE or NA 
PD 
PD 
PD 
SD 
PD 
SD [b] or PD 
SD [b] or PD 
SD 
CR 
SD 
SD 
SD 
PR 
SD 
SD 
SD 
SD 
SD 
SD 
SD 
NE or NA 
SD [c] or NE or NA 
SD [c] or NE 
PD 
No further 
evaluation 
PD 
PD 
CR = complete response, PR= partial response, SD = stable disease, PD = progressive disease, NE = not evaluable, NA = not 
available. 
a. The minimum interval for confirmation of CR and PR is 4 weeks.  
b.  Best response will be SD if the first time point overall response is after 35 days on study.  Otherwise, the best response will be 
PD. 
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c. Best response will be SD if the first time point overall response if after 35 days on study.  Otherwise, the best response will be 
NE. 
d. Best response will be SD provided the criteria for PD have not been met from the first to second assessment. 
* A best overall response of SD can only be made after the subject is on study for a minimum of 35 days (counted from Cycle 1 
Day 1).  If the subject is on study for less than 35 days, any tumor assessment indicating stable disease before this time period 
will have a best response of NE unless PD is identified.  
^Subsequent documentation of a CR may provide confirmation of a previously identified CR even with an intervening 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 confirmation of the first PR. 
 
Objective response rate (ORR) will be calculated using two methods: 
Method #1: ORR will be calculated using a strict interpretation of RECIST v1.1. 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, ORR is defined as the proportion of patients with objective response being “Yes”.  
Method #2: ORRUNCONFIRMED will be calculated using all responses regardless of confirmation.  
Objective response 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 objective response being “Yes”.  
Duration of Response (DOR) is the time between first response by RECIST of CR or PR and the 
first date that progressive disease is documented by RECIST (or clinical progression for 
investigator or derived analyses, whichever comes first) or death. Patients who do not experience 
PD or death will be censored at the last tumor assessment date.  Only those patients with 
confirmed responses will be included in this analysis. Censoring will follow the rules outlined 
below for PFS in Section 5.2.7.  
Clinical benefit rate (CBR) is defined as the proportion of patients with a BOR of confirmed CR, 
confirmed PR, or SD.  
ORR, ORRUNCONFIRMED, DOR and CBR will be calculated using the derived responses, BICR 
responses, and investigator responses. 
ORR, ORRUNCONFIRMED, DOR and CBR will be summarized for Part 1, Part 2, and Part 1 + Part 
2 patients treated with 240mg/m2. 
5.2.7. 
Progression-free Survival  
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. 
Hence, progression-free survival (PFS) is defined as the time (months) from date of first dose 
date of study drug for patients in Part 1 or date of randomization for patients in Part 2 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) disease progression as defined by RECIST 1.1 (Eisenhauer et al, 
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2009) or by clinical criteria (this will not apply to the BICR analysis); or (ii) withdrawal of 
consent; or (iii) receiving subsequent anti-cancer therapy, whichever is earlier. 
PFS will be calculated using two response data sets: derived and BICR.  For PFS determined by 
BICR, only progression per RECIST will be considered.  For PFS as determined by derived, 
either clinical progression or progression by RECIST (whichever comes first) will be considered. 
Death, regardless of cause, is always considered as a PD event. The detailed censoring rules for 
the analysis are summarized in Table 18. 
Table 18  
Assignment of Progression or Censoring Based on Radiological Assessment 
Situation 
Date of Progression or Censoring 
Outcome 
No Baseline assessment  
  
Date of first dose of study drug for 
patients in Part 1 or date of 
randomization for patients in Part 2 
Censored 
No progression  
Date of last adequate radiological 
disease assessment  
Censored 
Treatment discontinuation 
for reasons other than 
disease progression 
Date of last progression assessment 
with no documented progression 
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  
Date of the first reported progression  
Progressed 
Death without a PD  
Date of death 
Progressed 
Investigator claim of 
clinical progression  
Date of the investigator assigned PD   Progressed 
Note: An adequate radiologic assessment is defined as an assessment where the Investigator 
determined radiological response is CR, PR, SD, or PD.  If PD and new anti-cancer therapy 
occur on the same day, will assume that the progression was documented first, e.g. outcome is 
progression and the date is the date of the assessment of progression. 
5.2.8. 
Overall Survival  
Overall survival is calculated as the time (months) from date of first dose of study drug for 
patients in Part 1 or date of randomization for patients in Part 2 to the date of death due to any 
cause. Patients who do not die during the study will be censored at the date last known to be 
alive. Patients lacking data beyond the day of first dose of study drug for patients in Part 1 or 
date of randomization for patients in Part 2 will have their survival time censored at day of first 
dose of study drug for patients in Part 1 or date of randomization for patients in Part 2. OS will 
not be censored if a patient receives other anti-tumor treatments after the study drugs.    
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6. 
ANALYSIS METHODS 
6.1. 
General Principles of Analysis 
6.1.1. 
General Methodology 
In general, all efficacy, safety and PK variables will be summarised using descriptive statistics 
and graphs as appropriate. Continuous variables will be summarised by descriptive statistics 
(sample size (n), mean, standard deviation (SD), minimum, median, and maximum). Categorical 
variables will be summarised in frequency tables (frequencies and percentages). For PK 
variables, the geometric mean and coefficient of variation (CV) will be used instead of the 
arithmetic mean and SD, if appropriate. Time to event variables will be analysed with Kaplan-
Meier method and summarized with median, twenty-fifth and seventy-fifth percentiles, and 95% 
confidence intervals (CI), if applicable. Individual data will be presented in patient listings.  
Analyses will be implemented using SAS® 9.1 or higher (SAS Institute, Cary, North Carolina, 
USA). The International Conference on Harmonisation (ICH) numbering convention, i.e. ICH-
E3, will be used for all tables and listings. Upon completion, all SAS programs will be 
validated by an independent programmer within the staff of the third-party vendor doing the 
primary analysis.  In addition, the programming needed to generate a subset of outputs will be 
validated by an independent validation vendor.  The validation process will be used to confirm 
that statistically valid methods have been implemented and that all data manipulations and 
calculations are accurate.  Checks will be made to ensure accuracy, consistency with this plan, 
consistency within tables, and consistency between tables and corresponding data listings. 
All summary tables, listings, and figures (TLFs) will be presented by treatment groups as defined 
in Table 19. 
Table 19  
Treatment Display in TLFs 
Study Part  
G1T28 Dose 
Treatment Description in Data Display 
Part 1  
200 mg/m2 
G1T28 200 mg/m2 
Part 1  
240 mg/m2 
G1T28 240 mg/m2 
Part 1 
 
G1T28 Total [a]   
Part 2 
240 mg/m2 
G1T28 240 mg/m2 
Part 2 
Placebo 
Placebo   
Parts 1 and 2 
240 mg/m2 
G1T28 240 mg/m2 [b]   
[a] Summarize all G1T28 dose groups in Part 1. 
[b] Summarize all G1T28 dose group 240 mg/m2 in Part 1 and Part 2, it will be included in the summary for safety data.   
All statistical tests will be conducted at a two-sided significance level of 20% unless otherwise 
specified. For Part 2 data, the G1T28 + E/P therapy will be compared to the placebo + E/P 
therapy group. Where appropriate, model-based point estimates, together with their 80% CIs will 
be presented along with the two-sided p-values for the tests. P-value will be presented to 4 
decimal places, if the p-value <0.0001, the value will be presented as “<0.0001”. 
For continuous data, the same number of decimal places as in the raw data will be presented 
when reporting mean, median, minimum and maximum; one more decimal place than in the raw 
data will be presented when reporting SD and standard error (SE).  The derived variables will be 
presented with 1 decimal place. Percentages will be reported with 1 decimal point; if the count is 
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0, no percentage will be presented. Value of percentage less than 1% will be presented as “<1%.” 
Value of percentage less than 100% but ≥ 99.5% will be presented as “>99%.” 
6.1.2. 
Handling of Missing Data 
In general, the observed case (OC) data for a visit will consist of the actual observations recorded 
for the visit. If missing, the OC data will remain missing — no missing imputation will be 
performed. Safety analyses will be conducted on the OC data only. However, imputation of 
missing AE and concomitant medication onset and stop dates will be used to determine the status 
of each AE and the prior/concomitant status of each medication. Please refer to Section 5.2.1 for 
the method of imputation of missing AE onset and stop date and Section 6.2.5 for the method of 
imputation of missing concomitant onset and stop dates.  
For demographic and baseline characteristics, each variable will be analyzed and/or summarized 
using the available data. Patients with missing data will be excluded only from analyses for 
which data are not available. 
6.1.3. 
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 within each cycle  defined as Day 1  to the dates 
that the scheduled visits 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 (relative to the 
Day 1 of each cycle). The visit-window mapping is described in Table 20. Visit-based 
summaries will be based on the windowed visits. All data, whether or not within the visit 
windows, will be presented in patients listings.  
For windowed visits during the treatment cycles, if more than 1 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. If there are multiple assessments on the same day, the worst case will be used.  For the 
assigned follow-up visit, the last assessment in the window will be included in the summary. 
For a patient who prematurely discontinues the study, the visit will be slotted accordingly. The 
window for post-treatment visit will be "the first dose date of the last cycle + 36 to last 
assessment date prior to the start of survival follow-up". For the survival follow-up visit, it will 
only be applicable for the hematologic parameters.  
 
 
 
 
 
 
 
 
 
 
 
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Table 20  
Visit Windowing  
 
 
Cycle 1/ Odd cycle (2X-1) 
Cycle 2/ Even cycle (2X) 
Post-
treatment  
Survival 
follow-up [e]  
Visit 
C1D1 
C1D3 
C1D8 
C1D10 
C1D15 
EOC1 
C2D1 
C2D3 
C2D8 
C2D10 
C2D15 
EOC2 
 
 
Scheduled 
Day [a] 
1 
3[f] 
8[f] 
10[f] 
15 
22 
1 
3[f] 
8[f] 
10[f] 
15 
22 
 
 
ECOG 
Day 1 
 
 
 
 
 
Day 1 
 
 
 
 
 
First dose 
date of last 
cycle + 36 
to last 
assessmen
t date prior 
to the start 
of survival 
follow-up 
Relative to the 
date of post-
treatment, the 
last 
assessment 
falling in the 
window 
between 1 and 
67.  
Clinical 
Chemistry 
[b] 
Day -3 
- 1 
 
1-11 
 
12-
EOC 
 
Day -3 
- 1 
 
1-11 
 
12-
EOC 
 
Hematology 
[c] 
Day -3 
- 1 
1 to 5 
6 to 9 
10 to 
12 
13 to 
18 
19 to 
EOC 
Day -1 
- 1 
1 to 5 
6 to 9 
10 to 12 
13 to 18 
19 to 
EOC 
Urinalysis 
[b] 
Day -3 
- 1 
 
 
 
 
 
Day -3 
- 1 
 
 
 
 
 
FACT-L and 
FACT-An 
[d] 
Day -1 
- 1 
 
 
1 to 
EOC 
 
 
Day -1 
- 1 
 
 
1 to 
EOC 
 
 
[a] The scheduled day is relative to the Day 1 of each cycle. 
[b] Hematology, clinical chemistry and urine analysis may be obtained up to 72 hours prior to the first dose of each cycle of G1T28 or placebo + E/P therapy. 
[c] Hematology may be obtained up to 3 days prior to first dose of G1T28/placebo + EP therapy in Cycle 1, and 1 day prior to first dose for subsequent cycles. 
[d] Patient-reported outcomes should be completed at Days 1 and 10 of each cycle and at the Post-Treatment Visit. If a cycle is delayed, the patient should still complete the PRO on the 
scheduled Day 1 of the next cycle, as well as the actual first dosing day of the next cycle of G1T28 or placebo + E/P therapy. Patient-reported outcomes may be obtained up to 24 
hours prior to the first dose of each cycle of G1T28 or placebo + E/P therapy.  
[e] 60 ± 7 days after the post-treatment visit only for hematologic parameters and immunologic biomarker. The data is collected only for patients in Part 2.  
[f] If Day 1 is included in the windowing, the associated assessment must be post G1T28 infusion. 
Note: The end date of a cycle (EOC) is defined as the date of Day 1 study drug administration of its next cycle. For the last cycle (where no subsequent cycle is given), the end of cycle 
will be defined as Day 36 relative to the first dose of the cycle. Hence, for the last cycle, the window for EOC is 19-36. 
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6.1.4. 
Adjustment for Covariates 
The baseline ECOG status (0, 1, and 2) which was used as the stratification factor will be 
included as a covariate in relevant statistical modeling for data from Part 2. 
6.2. 
Analysis Methods  
6.2.1. 
Patient Disposition 
A summary table will be generated to provide the following by study part, as appropriate: 
 
Number of patients screened 
 
Number and percentage of screening failures 
 
Reason for screening failure 
 
Number of patients dosed (Part 1 only) 
 
Number of patients randomized (Part 2 only) 
 
Number of patients randomized and not dosed (Part 2 only) 
 
Number of patients dosed and not randomized (Part 2 only) 
A separate table will be presented to show the patients included in each analysis set and reason 
for exclusion from an analysis set. 
Patient status at treatment and study completion will be listed and summarized.  The listing will 
include whether patients discontinued from the treatment and the reasons for the discontinuation, 
along with the date of first and last dose and the date of completion or discontinuation from the 
treatment.  The same information will be provided for patients who discontinued from the study.  
The following summaries will be added to the disposition table: 
 
End of treatment status (discontinued study drug or continue on study drug)   
 
Number and percentage of patients in the FAS who discontinued study drug 
 
Number and percentage of patients in the FAS who discontinued study drug before 6 cycles 
 
Number and percentage of patients in the FAS who discontinued study drug after 6 cycles 
 
Reason for study drug discontinuation  
 
End of study status (discontinued study or continue in the survival follow-up)  
 
Number and percentage of patients in the FAS who discontinued the study 
 
Reason for study discontinuation 
 
Death and reason for death 
6.2.2. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics, such as age at informed consent date, age groups 
(18-65, >65-75, >75), race, ethnicity, gender, height, body weight, ECOG status (0, 1, and 2), 
smoking history (never smoker, former smoker and current smoker, smokeless tobacco, etc), and 
BMI will be summarized and listed.   
6.2.3. 
Disease Characteristics and Prior Therapies 
Disease characteristics including confirmation of diagnosis using neuroendocrine markers (Yes 
or No) and weight loss in the 6 months prior to randomization (Yes or No, if Yes, ≤5% or >5%), 
will be summarized and listed. Family history of cancer and age at initial diagnosis of lung 
cancer will be listed only. 
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The prior anti-cancer therapies, such as prior systemic anti-cancer therapy (Yes or No), prior 
anti-cancer surgery (Yes or No, and if Yes, related to lung cancer), and prior radiotherapy (Yes 
or No), will be summarized and listed. 
6.2.4. 
Medical History  
Medical history will be coded to SOC and PT using MedDRA Version 20.1. 
The number and percentage of randomized patients with any past medical history within each 
SOC and PT will be provided. A patient will only be counted once within a particular SOC (PT) 
even if he/she has multiple conditions/diseases in the same SOC (PT). The conditions/diseases 
from medical history are those conditions/diseases that stopped prior to the study entry. 
6.2.5. 
Concomitant Medications 
All medication verbatim terms collected will be coded to Anatomical Therapeutic Classification 
(ATC) and PT using the WHO-DD Version Sep2017.  
Prior medications are defined as those taken by the patient prior to the administration of study 
drug. Concomitant medications are defined as those taken by the patient at any time between the 
date of study drug administration and study completion/discontinuation. Medication with start 
date/time being partially or completely missing will be assumed to be concomitant if it cannot be 
definitely shown that the medication did not occur during the treatment period.   
Medications with onset/end dates that are partially/completely missing will be imputed as 
follows: 
(i) For onset date: 
 If only the day part of the medication onset date is missing and occurs in the same month and 
year as the first dose date of study drug, the date of first dose of study drug will be used as 
the onset date of the medication. Otherwise, the first day of the month will be used to 
complete the onset date of the medication;  
 If the day and month parts of medication onset date are missing and occur in the same year as 
the first dose of study drug, the date of the first dose of study drug will be used as the onset 
date of the medication. Otherwise, January 1st will be used to complete the onset date of the 
medication; 
 If the medication onset date is completely missing, the date of the first dose of study drug 
will be used as the onset date of the medication. 
(ii) For end date: 
 If only the day part of the medication end date is missing, the last day of month will be used 
to complete the end date of the medication;  
 If the day and month parts of medication end date are missing, December 31st will be used to 
complete the onset date of the medication; 
 If the medication end date is completely missing and the onset date of the medication occurs 
after the date of the first dose of study drug, the last date during the treatment period will be 
used as the medication end date. Otherwise, the date of the first dose of study drug will be 
used as the medication end date.    
Concomitant medications will be summarized by presenting the number and percentage of 
patients by PT and ATC. Patients taking the same medication multiple times will only be 
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counted once for that PT or ATC. Each summary will be ordered by descending order of 
incidence of ATC class and PT within each ATC class.  
All prior and concomitant medications will be presented in a patient listing. 
6.2.6. 
Prior and Subsequent Anti-cancer Therapy 
All verbatim terms collected of prior and subsequent anti-cancer therapy will be coded to 
Anatomical Therapeutic Classification (ATC) and PT using the WHO-DD Version Sep2017.  
The prior and subsequent anti-cancer therapy will be summarized separately by presenting the 
number and percentage of patients by PT and ATC. Patients taking the same medication multiple 
times will only be counted once for that PT or ATC. Each summary will be ordered by 
descending order of incidence of ATC class and PT within each ATC class.  The data will be 
presented in a patient listing. 
For subsequent anti-cancer therapy, if the term contains the word “RADIATION”, the therapy 
will be classified to radiotherapy; it is classified as systemic anti-cancer therapy unless the 
therapy can be grouped to surgery.   The number and percentage of randomized patients 
receiving subsequent anti-cancer therapy will be provided by systemic anti-cancer therapy (by 
drug name and by line), radiotherapy, and surgery. All subsequent anti-cancer therapies will be 
presented in a patient listing. 
6.2.7. 
Efficacy Analyses 
All the efficacy variables will be summarized using descriptive statistics by cycle or visit, with 
the supportive data provided in patient listings.  Part 1 will be summarized using only descriptive 
statistics. For Part 2, in addition to the descriptive summary, the between treatment comparison 
(trilaciclib vs placebo), if applicable, will be performed only for those prospectively-defined 
endpoints outlined in Section 5.1.1. For these comparisons, all statistical tests will be conducted 
at a two-sided significance level of 20% unless otherwise specified. Where appropriate, model-
based point estimates, together with their two-sided 80% CIs will be presented along with the 
two-sided p-value for the test.  Graphical presentation of efficacy results will be appropriately 
performed as needed. 
6.2.7.1. 
Prospectively-Defined Efficacy Analyses 
Detailed information for the prospectively-defined efficacy endpoints can be found in Section 
5.1.1. A binary response variable (Yes, No) will be analyzed to compare G1T28 and placebo 
using stratum-adjusted method to account for the ECOG status (0-1 vs 2) as the stratification 
factor. The adjusted proportion difference (trilaciclib vs placebo) and its 80% CIs will be 
calculated using CMH weight outlined in Kim et al. 2013. The two-sided p-value will be 
calculated using stratified exact Cochran-Mantel-Haenszel (CMH) method. The following binary 
response variables will be analyzed: 
 Occurrence of a febrile neutropenia AE during the treatment period (refer to Section 5.1.1.1); 
 Occurrence of a RBC transfusion (actual and eligible) during the treatment period (refer to 
Section 5.1.1.2); 
 Occurrence of a platelet transfusion (actual and eligible) during the treatment period (refer to 
Section 5.1.1.3); 
 Occurrence of a GCSF administration during the treatment period (refer to Section 5.1.1.4); 
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 Occurrence of an ESA administration during the treatment period (refer to Section 5.1.1.5); 
 Occurrence of an IV antibiotic administration during the treatment period (refer to Section 
5.1.1.6); 
 Occurrence of an infection SAE during the treatment period (refer to Section 5.1.1.7); 
 Occurrence of a pulmonary infection SAE during the treatment period (refer to Section 
5.1.1.7). 
Time (days) to event endpoints will be summarized using Kaplan-Meier method, and the 
descriptive statistics of median, 25% and 75% percentiles along with their 95% CIs will be 
calculated for endpoints described in Sections 5.1.1.8, 5.1.1.9, and 5.1.1.11.  
In addition to the summary from Kaplan-Meier method, for the endpoints of 
 Overall duration (days) of Grade 4 neutropenia; 
 Overall duration (days) of Grade 3/4 neutropenia; 
 Time (days) to first occurrence of a MAHE event,   
the two-sided p-value will be obtained from the stratified Kaplan-Meier method to account for 
the ECOG status (0-1 vs 2) as the stratification factor. The hazard ratio (HR) between the two 
treatments (trilaciclib vs placebo), together with its 80% CIs will be calculated from a Cox 
proportional hazard model in which treatment and baseline ECOG status (0-1 vs 2) will be 
included as fixed effects. For the time (days) to first occurrence of a MAHE event, a graphical 
display of cumulative incidence will be presented. 
For the endpoints specified in Section 5.1.1.10, in addition to descriptive statistics summary, 
appropriate graphical display will be provided to help viewing the trend of change over time. 
Moreover, each of the ANC change over time (i.e. observed value at windowed visit, cycle 
NADIR, and ANC at each scheduled Day 1 of a cycle) specified above will be done using three 
distinct data sets to evaluate the confounding effect of GCSF administration: all patients or 
cycles regardless of GCSF administration; inclusion of only those patients or cycles who had 
concurrent GCSF administration; and inclusion of only those patients or cycles who did NOT 
have concurrent GCSF administration.  The “with” and “without” GCSF analyses are subsets of 
the total patient or cycles.  
6.2.7.2. 
Exploratory Efficacy Analyses 
For all these exploratory endpoints listed in Sections 5.1.2.1, 5.1.2.2, 5.1.2.3, and 5.1.2.4, the 
data will only be summarized using descriptive statistics, hence, the general rules outlined in 
Section 6.1.1 will be followed. Moreover, the supportive data listings will be provided.  
6.2.7.3. 
Exposure Endpoints 
The extent of drug exposure and dose modifications is considered as important efficacy 
endpoints for trilaciclib. The study dosing records and the derived dosing endpoints will be 
listed. 
Duration on treatment and number of cycles will be summarized by treatment. For each study 
drug, the dosing endpoints described in Section 5.1.3 will be summarized by treatment.   
Dose modification will be summarized for each study drug (trilaciclib, etoposide and 
carboplatin) including the following: 
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 Number of cycles received; 
 Number of missed doses; 
 Number of dose reductions; 
 Number of dose interruptions;  
 Number of patients with missed dose and its reason;  
 Number of patients with dose reductions and its reason; 
 Number of patients with dose interruption and its reason. 
The number of cycles delayed, the number and percentage of patients experiencing a treatment 
cycle delay and reason for cycle delay will be summarized by treatment. The number of patients 
discontinuing study drug will also be summarized along with the reason for discontinuation. 
6.2.8. 
Safety Analyses 
All safety analyses will be based on the safety analysis set, as defined in Section 3.1.2.  
Descriptive statistics will be used to summarize the safety outcomes. The continuous safety 
variables will be summarized at each visit including end of each cycle (the last non-missing 
assessment during the cycle), end of treatment (the last non-missing assessment during the 
treatment period), and end of study (the last non-missing assessment during the whole study), if 
applicable. No inferential analyses of safety data are planned unless otherwise specified. 
6.2.8.1. 
Adverse Events 
Number and incidences rates of AEs will be summarized by SOC and/or PT for the following 
categories of TEAEs: all AEs, SAEs, AEs leading to death, and AEs leading to study drug 
discontinuation or study withdrawal. Patients with more than one occurrence of the same SOC 
(PT) will be counted only once within the SOC (PT) categorization.   
AEs will also be summarized similarly by CTCAE grade and relationship to study drug 
(trilaciclib, carboplatin, and etoposide), and the drug related AE summary will be appropriately 
evaluated by each drug. Should a patient experience more than one occurrence of the same SOC 
(PT), the patient’s worst occurrence (worst grade/most related causality) will be retained in the 
tabulation.    
All AEs, including AEs that started prior to the study medication, will be presented in patient 
listings. In addition, separate listings of all SAEs, AEs leading to death, drug-related AEs, and 
AEs leading to study drug discontinuation or study withdrawal will be provided. 
For the AEs related to infusion and related to hematologic toxicity, the criteria for identifying 
them are described in Section 5.2.1. A summary table showing incidence of AEs related to 
infusion and related to hematologic toxicity will be presented along with its supportive data 
listing.     
6.2.8.2. 
Laboratory Evaluations 
For hematology and clinical chemistry labs the observed values and change from baseline will be 
summarized for each visit during the treatment period using descriptive statistics.   
Toxicities for clinical labs will be characterized according to CTCAE, Version 4.03 (Table A-1 
of Appendix when possible), and the frequency and percentage of patients with each CTCAE 
grade for each visit during the treatment period will be described. Moreover, any occurrence of 
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grade 3 or grade 4 during the treatment period will be summarized, and shift in grade from 
baseline to the worst post-baseline value will be summarized. Both the scheduled and 
unscheduled assessments will be used to identify the worst post-baseline values. 
Listings of all laboratory data, its normal reference ranges, and its CTCAE grade (when possible) 
will be provided.    
6.2.8.3. 
Vital Signs 
For vital sign parameters Systolic Blood Pressure, Diastolic Blood Pressure, Pulse Rate, 
Temperature, Weight, the observed values and change from baseline will be summarized using 
descriptive statistics at each visit during the treatment period.  
Additionally, the frequency and percentage of patients with any potentially clinically significant 
findings (defined in Table 11) during the treatment period will be presented. A listing of all vital 
sign data will be provided.  
6.2.8.4. 
Performance Status  
Descriptive statistics will be presented for ECOG score for the observed values and change from 
baseline. A listing of ECOG score for all patients will be provided.   
6.2.8.5. 
Physical Examination 
A listing of physical examination findings for all patients will be provided. 
6.2.8.6. 
ECG 
Descriptive statistics will be presented for each ECG parameter for the observed values and 
change from baseline to post baseline. A listing of all ECG data will be provided.  
The criteria of potentially clinically significant findings are defined in Table 13. The frequency 
and percentage of patients with any potentially clinically significant findings during the 
treatment period will be presented. The supportive data will be provided in patient data listings.  
6.2.8.7. 
Analyses of Objective Response 
The number and percentage of patients in each category of TPR according to the investigator 
tumor assessment (CR, PR, SD, PD, or NE) will be presented. Also, the number and percentage 
of patients in each category of derived BOR (Confirmed CR, Confirmed PR, SD, PD, or NE), 
ORR, ORRUNCONFIRMED and CBR according to the investigator tumor assessment (Confirmed 
CR, Confirmed PR, SD, PD, or NE) will be summarized. Detailed information of deriving tumor 
relevant responses is provided in Section 5.2.6.    
Similar analyses will be repeated based on the derived responses according to the RECIST 1.1, 
and based on the data from BICR. A cross tabulation of BICR BOR versus the derived BOR will 
be presented, by treatment group.  
Estimates of response rate, along with its associated exact 95% two-sided CIs using Clopper-
Pearson method will be computed for ORR and CBR within each treatment group.  
DOR (investigator, derived, and BICR) will be summarized using the Kaplan-Meier method, 
displayed graphically when appropriate, and summarized with median, 25% and 75% 
percentiles, and their 95% CIs.   
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The binary endpoint (Yes, No) of ORR for the two treatments (trilaciclib and placebo) in Part 2 
will be analyzed to compare trilaciclib and placebo using stratum-adjusted method to account for 
the ECOG status (0-1 vs 2) as the stratification factor. The adjusted proportion difference 
(trilaciclib vs placebo) and its 80% CIs will be calculated using CMH weight outlined in Kim et 
al. 2013. The two-sided p-value will be calculated using stratified exact CMH method.   
The analyses are based on the response evaluable population and FAS population. The 
supportive data listings will also be provided.  
6.2.8.8. 
Analyses of PFS and OS 
The analysis method as described in Section 6.2.7.1 for time to event data will be applied to the 
following variables 
 PFS (BICR and derived) 
 OS 
The analyses are based on the FAS. The supportive data listings will also be provided.   
For the PFS from both BICR and derived responses and OS, a comparison will be conducted 
between G1T28 and placebo in Part 2. The two-sided p-value from a Cox proportional hazard 
model will be presented, the model includes treatment and baseline ECOG status (0-1 vs 2) as 
fixed effects. The hazard ratio (HR) between the two treatment groups, together with its 95% CIs 
will be presented. 
6.2.9. 
Subgroup Analyses 
The PFS, OS, ORR may be examined in the following subgroups: 
 Age group (ages 18 to 65; 65-75; >75). 
 Gender (Male; Female). 
 ECOG performance status (0-1; 2). 
 Race (Caucasian; non-Caucasian). 
 Baseline LDH (≤ ULN; > ULN). 
Descriptive statistics by treatment group will be presented for each subgroup of patients.  
Additional subgroups or endpoints may be identified and explored.  
6.2.10. 
Pharmacokinetic Analysis 
The PK analysis for a subset of patients will be documented separately, and is not covered in this SAP. 
6.2.11. 
Assess Genetic and/or Expression (RNA/Protein) Biomarkers in Tumors and 
Blood 
A detailed description of the biomarker analysis plan will be documented separately.  In general, as data 
permits, the analyses may include, but not be limited to: 
1. SCLC tumor samples may be assessed for markers of CDK 4/6 dependence and independence 
including Ki68, RB, and CCND1.   
2. SCLC tumor samples may be assessed for markers to predict sensitivity to trilaciclib treatment. 
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3. Peripheral blood samples may be assessed for biomarkers examining the role of trilaciclib in the 
preservation of hematopoietic and immune populations during chemotherapy treatment 
4. Peripheral blood samples may be assessed for biomarkers examining the role of trilaciclib in anti-
tumor immunity 
6.2.12. 
Planned Analysis  
The final analysis will occur after the last patient has completed the Post-Treatment Visit. All 
study data collected up through the time of the final analysis data cut-off, including Follow-Up 
Survival Phase results, will be summarized in the final analysis. Unblinding will occur at the 
time of the final analysis.  
The end of study analysis for the CSR will be conducted when the OS data of Part 2 are 
approximately 70% mature (approximately 55 death events). Reported results will include the 
subset of data not previously reported during the final analysis.  
 
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7. 
CHANGE FROM THE PROTOCOL 
The endpoints and analyses listed below are based on the Statistics Section in the Protocol 
Amendment 7, dated 11 May 2016. The list displays the endpoints and analyses which are 
removed from the initial analysis and are therefore not described in the SAP..    
Protocol Section 13.3.1 (Efficacy Endpoints): 
 Hematologic kinetic endpoints: 
o Change and percent change in hematologic parameter values from predose for a 
particular cycle to the end of that cycle 
o Change and percent change in hematologic parameter values from predose for a 
particular cycle to nadir for that cycle 
o Rate of change in hematologic parameter values from predose for a particular cycle to 
nadir for that cycle 
o Change and percent change in hematologic parameter values from nadir for a 
particular cycle to the end of that cycle 
o Rate of change in hematologic parameter values from nadir for a particular cycle to 
o the end of that cycle 
o Area under the curve in hematologic parameter values from predose for a particular 
cycle to the end of that cycle 
o Area under the curve in hematologic parameters from predose for a particular cycle to 
nadir for that cycle 
o Area under the curve in hematologic parameter values from nadir for a particular 
cycle to the end of that cycle 
o Time to hematologic parameter value nadir by cycle 
o Time to return to predose hematologic parameter values by cycle 
o Proportion of patients with a return to predose hematologic parameter values by cycle 
 Exploratory efficacy endpoints: 
o Composite hematologic score 
Protocol Section 13.3.2.1 (Analysis of Hematologic Parameter Kinetic Endpoints) 
 Additional tabulations for each cycle of treatment in maximum postnadir values. 
 The tabulation of the changes and percent changes from predose to nadir, predose to end of 
cycle, nadir to maximum postnadir, and nadir to end of cycle values for each cycle of 
treatment. 
 Analysis of covariance (ANOVA) models on hematologic parameter kinetic endpoints 
 Summarization of time to nadir. 
 Descriptive statistics and ANOVA of AUC in hematologic parameters 
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 Repeated-measures model of AUC 
 Summary of proportion of patients return to predose value for each cycle. calculation on 
incidence rate, adjusting for cumulative exposure 
 Analysis of time to return to predose level for each cycle using Kaplan-Meier method. 
 Analysis of Time to return to postnadir predose levels 
Protocol Section 13.3.2.2 (Analysis of Hematologic Toxicity Endpoints)  
 Calculation and analysis of incidence rate of hematologic toxicity, adjusting for cumulative 
exposure 
 Calculation and analysis of toxicity rate relative to cumulative exposure (total number of 
toxicities divided by cumulative exposure).  
 Recurrent events model estimating the incidence of Grade 3 or higher hematologic toxicities 
and testing for the difference between treatment groups. 
 For each hematologic parameter and cycle, the shift summaries of the following: 
o From predose toxicity to maximum on treatment toxicity;  
o from predose toxicity to end of cycle toxicity; 
o from maximum postdose toxicity to end of cycle toxicity. 
Protocol Section 13.3.2.4 (Other Efficacy Endpoints) 
 The number and percent of infections summarized by maximum severity 
 The infection rate: The number of infections occurring during the Treatment divided by 
cumulative exposure. 
 ANOVA on FACT scores 
 The association between composite endpoints and BOR, OS, and PFS 
Protocol Section 13.5 (Exploratory Analyses) 
The analysis in the section is not covered in the SAP 
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8. 
REFERENCES 
Eisenhauer, E., Therasse, P., Bogaerts, J., Schwartz, L.H., Sargent, D., Ford, R., Dancey, J., 
Arbuck, S., Gwyther, S., Mooney, M. and Rubinstein, L., 2009. New response evaluation criteria 
in solid tumours: revised RECIST guideline (version 1.1). European journal of cancer, 45(2), 
228-247.  
Kim Y, Won S. (2013) Adjusted proportion difference and confidence interval in stratified 
randomized trials. PharmaSUG; Paper SP-04  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table A-1 Clinical Laboratory Parameters CTCAE Criteria 
Parameter 
Grade 
1 
2 
3 
4 
5 
Albumin 
<LLN – 3 g/dL; <LLN – 30 g/L 
<3 – 2 g/dL; <30 – 20 g/L 
<2 g/dL; <20 g/L 
- 
- 
ALP 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
- 
ALT 
>ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
- 
AST 
>ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
- 
Bilirubin 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
- 
Calcium (Hypercalcemia) 
Corrected serum calcium of 
>ULN – 11.5 mg/dL; >ULN – 
2.9 mmol/L 
Corrected serum calcium of 
>11.5 – 12.5 mg/dL;  >2.9 
– 3.1 mmol/L 
Corrected serum calcium of 
>12.5 – 13.5 mg/dL; >3.1 – 
3.4 mmol/L 
Corrected serum calcium of 
>13.5 mg/dL; >3.4 mmol/L 
- 
Calcium (Hypocalcemia) 
Corrected serum calcium of 
<LLN – 8.0 mg/dL; <LLN – 
2.0 mmol/L 
Corrected serum calcium of 
<8.0 – 7.0 mg/dL;  <2.0 – 
1.75 mmol/L 
Corrected serum calcium of 
<7.0 – 6.0 mg/dL; <1.75 – 
1.5 mmol/L 
Corrected serum calcium of 
<6.0 mg/dL; <1.5 mmol/L 
- 
CK 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5 x ULN 
>5 x ULN – 10 x ULN 
>10 x ULN 
- 
Creatinine 
>1 – 1.5 x baseline;  >ULN – 
1.5 x ULN 
>1.5 – 3.0 x baseline; >1.5 
– 3.0 x ULN 
>3.0 x baseline; >3.0 – 6.0 
x ULN 
>6.0 x ULN 
- 
GGT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
- 
Glucose (Hyperglycemia) 
Fasting glucose value >ULN – 
160 mg/dL; Fasting glucose 
value >ULN – 8.9 mmol/L 
Fasting glucose value >160 
– 250 mg/dL; Fasting 
glucose value >8.9 – 13.9 
mmol/L 
Fasting glucose value >250 
– 500 mg/dL; Fasting 
glucose value >13.9 – 27.8 
mmol/L 
Fasting glucose value >500 
mg/dL; Fasting glucose value 
>27.8 mmol/L 
- 
Glucose (Hypoglycemia) 
<LLN – 55 mg/dL;  <LLN – 
3.0 mmol/L 
<55 – 40 mg/dL;  <3.0 – 
2.2 mmol/L 
<40 – 30 mg/dL;  <2.2 – 
1.7 mmol/L mmol/L 
<30 mg/dL;  <1.7 mmol/L  
- 
Hemoglobin 
<LLN – 10.0 g/dL; <LLN – 6.2 
mmol/L; <LLN – 100 g/L 
<10.0 – 8.0 g/dL; <6.2 – 
4.9 mmol/L; <100 – 80 g/L 
<8.0 g/dL; <4.9 mmol/L; 
<80 g/L 
- 
- 
Potassium 
(Hyperkalemia) 
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
>7.0 mmol/L 
- 
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G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-02                                       
Statistical Analysis Plan  
Version date: 14Feb2018 
 
CONFIDENTIAL 
      Page 60 of 60 
 
Table A-1 Clinical Laboratory Parameters CTCAE Criteria 
Parameter 
Grade 
1 
2 
3 
4 
5 
Potassium (Hypokalemia) <LLN – 3.0 mmol/L 
- 
<3.0 – 2.5 mmol/L 
<2.5 mmol/L 
- 
Lymphocyte 
<LLN – 800/mm3; <LLN – 0.8 
x 10e9 /L 
<800 – 500/mm3; <0.8 – 
0.5 x 10e9 /L 
<500 – 200/mm3; <0.5 – 
0.2 x 10e9 /L 
<200/mm3; <0.2 x 10e9 /L 
- 
ANC 
<LLN – 1500/mm3; <LLN – 
1.5 x 10e9 /L 
<1500 – 1000/mm3; <1.5 – 
1.0 x 10e9 /L 
<1000 – 500/mm3; <1.0 – 
0.5 x 10e9 /L 
<500/mm3; <0.5 x 10e9 /L 
- 
Phosphates 
<LLN – 2.5 mg/dL; <LLN – 
0.8 mmol/L 
<2.5 – 2.0 mg/dL; <0.8 – 
0.6 mmol/L 
<2.0 – 1.0 mg/dL; 0.6 – 0.3 
mmol/L 
<1.0 mg/dL; <0.3 mmol/L 
- 
Platelet Count 
<LLN – 75,000/mm3; <LLN – 
75.0 x 10e9 /L 
<75,000 – 50,000/mm3; 
<75.0 – 50.0 x 10e9 /L 
<50,000 – 25,000/mm3; 
<50.0 – 25.0 x 10e9 /L 
<25,000/mm3; <25.0 x 10e9 
/L 
- 
Sodium (Hypernatremia) 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
>160 mmol/L 
- 
Sodium (Hyponatremia) 
<LLN – 130 mmol/L 
- 
<130 – 120 mmol/L 
<120 mmol/L 
- 
Urate 
>ULN – 10 mg/dL (0.59 
mmol/L) without physiologic 
consequences 
- 
>ULN – 10 mg/dL (0.59 
mmol/L) with physiologic 
consequences 
>10 mg/dL; >0.59 mmol/L 
- 
White blood cell 
<LLN – 3000/mm3; <LLN – 
3.0 x 10e9 /L 
<3000 – 2000/mm3; <3.0 – 
2.0 x 10e9 /L 
<2000 – 1000/mm3; <2.0 – 
1.0 x 10e9 /L 
<1000/mm3; <1.0 x 10e9 /L 
- 
LLN=lower limit of normal range; ULN=upper limit of normal range. 
 
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