Phase 1b/2a Safety and Pharmacokinetic Study of G1T28 in Patients With Previously Treated Extensive Stage Small Cell Lung Cancer (SCLC) Receiving Topotecan Chemotherapy
Phase: PHASE1
Conditions: Small Cell Lung Cancer
Sponsor: G1 Therapeutics, Inc.

G1 Therapeutics CONFIDENTIAL 
 
 
 
 
 
Phase 1b/2a Safety and Pharmacokinetic Study of G1T28 in Patients with Previously 
Treated Extensive-Stage Small Cell Lung Cancer (SCLC) Receiving Topotecan 
Chemotherapy 
 
Clinical Study Protocol G1T28-03 
EudraCT # 2016-004611-13 
 
 
Original Protocol Issue Date: 11 June 2015 
Amendment 5 Issue Date: 27 June 2018 
Version: 6.0 
Investigational Phase: 1b/2a 
 
Sponsored by:  
G1 Therapeutics 
79 T.W. Alexander Drive 
4501 Research Commons, Suite 100 
Research Triangle Park, NC 27709 
 
 
 
 
 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND/OR TRADE SECRET 
INFORMATION THAT IS DISCLOSED ONLY IN CONNECTION WITH THE 
LICENSING AND/OR REGISTRATION OF PRODUCTS FOR G1 THERAPEUTICS.  
THIS DOCUMENT SHOULD NOT BE DISCLOSED OR USED, IN WHOLE OR IN 
PART, FOR ANY OTHER PURPOSE WITHOUT THE PRIOR WRITTEN CONSENT OF 
G1 THERAPEUTICS. 

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Clinical Study Protocol G1T28-03 
G1T28 
 
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G1 Therapeutics CONFIDENTIAL 
PROTOCOL SIGNATURE PAGE 
Clinical Study Protocol G1T28-03: Phase 1b/2a Safety and Pharmacokinetic Study of 
G1T28 in Patients with Previously Treated Extensive-Stage Small Cell Lung Cancer (SCLC) 
Receiving Topotecan Chemotherapy 
Original Protocol Issue Date: 11 June 2015 
Version:  6.0 (Amendment 5), dated 27 June 2018 
 
By signing below, the investigator agrees to adhere to the protocol as outlined. 
Principal Investigator: 
 
 
Principal Investigator Signature 
Date 
Principal Investigator Name 
Institution 
 

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Clinical Study Protocol G1T28-03 
G1T28 
 
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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 ....................................................................................................................................... 26 
4.1. 
Background ..................................................................................................................................... 26 
4.2. 
Summary of Clinical Data ............................................................................................................... 27 
4.2.1. 
Study G1T28-1-01 ........................................................................................................ 27 
4.2.2. 
Study G1T28-02 ............................................................................................................ 28 
4.2.3. 
Study G1T28-03 (Current Study) .................................................................................. 29 
4.3. 
 31 
4.3.1. 
Pharmacology Studies ................................................................................................... 31 
4.3.2. 
Pharmacokinetic Studies ............................................................................................... 32 
4.3.3. 
Toxicity and Safety Studies ........................................................................................... 33 
4.3.4. 
Potential Risks ............................................................................................................... 33 
4.4. 
Study and Dose Rationale ............................................................................................................... 34 
4.4.1. 
Selection of G1T28 and Topotecan Doses for Part 2A ................................................. 35 
4.4.2. 
Selection of G1T28 and Topotecan Dose for Part 2B ................................................... 36 
4.5. 
Risk/Benefit Assessment ................................................................................................................. 37 
5. 
STUDY OBJECTIVES ................................................................................................................................ 39 
6. 
INVESTIGATIONAL PLAN ...................................................................................................................... 40 
6.1. 
Overall Study Design and Plan ....................................................................................................... 40 
6.1.1. 
Part 1 ............................................................................................................................. 40 
6.1.1.1. 
Definition of Dose-Limiting Toxicities (Applicable to 
Cycle 1 of Part 1) ..................................................................................... 41 
6.1.1.2. 
Criteria for Adjusting G1T28 Dose Based on 
Pharmacokinetic Parameters .................................................................... 41 
6.1.1.3. 
G1T28 Dose Evaluation ........................................................................... 42 
6.1.1.4. 
Topotecan Dose Evaluation ..................................................................... 44 
6.1.1.5. 
Safety Monitoring Committee ................................................................. 44 
6.1.2. 
Part 2A .......................................................................................................................... 45 
6.1.3. 
Part 2B .......................................................................................................................... 46 
6.1.4. 
Criteria for Subsequent Cycles and Study Duration ...................................................... 47 
6.1.5. 
Safety Assessments ....................................................................................................... 48 
6.1.6. 
Tumor Assessment ........................................................................................................ 48 
7. 
STUDY POPULATION .............................................................................................................................. 49 
7.1. 
Selection of Patients ........................................................................................................................ 49 
7.1.1. 
Inclusion Criteria ........................................................................................................... 49 
7.1.2. 
Exclusion Criteria .......................................................................................................... 50 
8. 
TREATMENTS ........................................................................................................................................... 52 
8.1. 
Treatments Administered ................................................................................................................ 52 
8.2. 
Investigational Products .................................................................................................................. 53 

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8.2.1. 
Identity .......................................................................................................................... 53 
8.2.1.1. 
G1T28 ...................................................................................................... 53 
8.2.1.2. 
Placebo ..................................................................................................... 53 
8.2.1.3. 
Topotecan ................................................................................................ 53 
8.2.2. 
Packaging and Labeling ................................................................................................ 53 
8.2.2.1. 
G1T28 ...................................................................................................... 53 
8.2.2.2. 
Placebo ..................................................................................................... 53 
8.2.2.3. 
Topotecan ................................................................................................ 53 
8.2.3. 
Storage .......................................................................................................................... 53 
8.2.3.1. 
G1T28 ...................................................................................................... 53 
8.2.3.2. 
Placebo ..................................................................................................... 54 
8.2.3.3. 
Topotecan ................................................................................................ 54 
8.2.4. 
Procedure for Dispensing .............................................................................................. 54 
8.2.5. 
Investigational Product Accountability ......................................................................... 54 
8.3. 
Method of Assigning Patients to Treatment Groups ....................................................................... 55 
8.4. 
Dose, Dosing Regimen, and Route ................................................................................................. 55 
8.4.1. 
G1T28 ........................................................................................................................... 55 
8.4.2. 
Placebo .......................................................................................................................... 55 
8.4.3. 
Topotecan ...................................................................................................................... 56 
8.4.4. 
Dose Modifications ....................................................................................................... 56 
8.4.4.1. 
G1T28 ...................................................................................................... 56 
8.4.4.2. 
Modification of Topotecan Dosing ........................................................... 56 
8.5. 
Randomization and Blinding ........................................................................................................... 62 
8.6. 
Prior and Concomitant Medications and Procedures ...................................................................... 62 
8.7. 
Transfusions .................................................................................................................................... 64 
8.8. 
Treatment Compliance .................................................................................................................... 64 
9. 
STUDY FLOWCHART .............................................................................................................................. 65 
10. SCHEDULE OF STUDY PROCEDURES ................................................................................................. 69 
10.1. 
Screening......................................................................................................................................... 69 
10.2. 
Enrollment....................................................................................................................................... 69 
10.3. 
Cycle 1 ............................................................................................................................................ 70 
10.4. 
Cycle 2 ............................................................................................................................................ 71 
10.5. 
Cycles 3, 4, and Subsequent Cycles ................................................................................................ 72 
10.6. 
Post-Treatment Visit ....................................................................................................................... 73 
10.7. 
Survival Follow-up Phase ............................................................................................................... 73 
10.8. 
Details of any anticancer treatment Study Drug Discontinuation ................................................... 74 
10.9. 
Unscheduled Visits ......................................................................................................................... 74 
11. STUDY ASSESSMENTS ........................................................................................................................... 75 
11.1. 
Efficacy Assessments ...................................................................................................................... 75 
11.2. 
Pharmacokinetic Assessments ........................................................................................................ 75 
11.3. 
Safety Assessments ......................................................................................................................... 78 
11.3.1. 
Adverse Events and Serious Adverse Events ................................................................ 79 
11.3.1.1. 
Definition of Adverse Event .................................................................... 79 
11.3.1.2. 
Definition of Serious Adverse Event ....................................................... 80 
11.3.1.3. 
Assessment of the Severity of Adverse Events ........................................ 81 
11.3.1.4. 
Assessment of the Relationship of Adverse Events to 
Study Drug ............................................................................................... 81 
11.3.1.5. 
Assessment of the Outcome of Adverse Events ....................................... 82 
11.3.1.6. 
Method, Frequency, and Time Period for Detecting 
Adverse Events and Serious Adverse Events ........................................... 82 
11.3.1.7. 
Documentation of Adverse Events and Serious Adverse 
Events ...................................................................................................... 82 
11.3.1.8. 
Adverse Event Coding ............................................................................. 83 

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11.3.1.9. 
Reporting of Serious Adverse Events ...................................................... 83 
11.3.1.10. 
Follow-up of Adverse Events .................................................................. 83 
11.3.1.11. 
Regulatory Aspects of Adverse Event Reporting .................................... 84 
11.3.1.12. 
Infusion-Related Reactions ...................................................................... 85 
11.3.1.13. 
Handling of Overdoses and Toxicity ....................................................... 85 
11.3.1.14. 
Reporting of Pregnancies ......................................................................... 85 
11.3.2. 
Clinical Laboratory Assessments .................................................................................. 86 
11.3.3. 
Demographics and Vital Signs ...................................................................................... 86 
11.3.4. 
Physical Examination .................................................................................................... 87 
11.3.5. 
Electrocardiogram Assessments .................................................................................... 87 
11.3.6. 
Concomitant Medications ............................................................................................. 87 
11.4. 
Central Pathology Review to Confirm Diagnosis of SCLC ............................................................ 87 
11.5. 
Tumor Response ............................................................................................................................. 87 
11.5.1. 
Tumor Assessments ...................................................................................................... 87 
11.5.2. 
Tumor Lesions: Identification and Follow-up ............................................................... 88 
11.5.2.1. 
Measurable Lesions ................................................................................. 88 
11.5.2.2. 
Nonmeasurable Lesions ........................................................................... 89 
11.5.2.3. 
New Lesions ............................................................................................ 89 
11.5.3. 
Definitions of Tumor Response and Disease Progression ............................................. 90 
11.5.3.1. 
Evaluation of Target Lesion Response .................................................... 90 
11.5.3.2. 
Evaluation of Nontarget Lesions .............................................................. 90 
11.5.3.3. 
Evaluation of Overall Response ............................................................... 90 
11.6. 
Patient Reported Outcomes ............................................................................................................. 91 
11.7. 
Immunologic Markers (Optional) ................................................................................................... 91 
11.8. 
Appropriateness of Measurements .................................................................................................. 92 
12. STUDY TERMINATION OR STUDY DRUG DISCONTINUATION ..................................................... 93 
12.1. 
Study Termination........................................................................................................................... 93 
12.2. 
Site Termination .............................................................................................................................. 93 
12.3. 
Discontinuation of Study Drug ....................................................................................................... 93 
12.4. 
Withdrawal of Patients from the Study ........................................................................................... 94 
13. STATISTICS ............................................................................................................................................... 95 
13.1. 
Sample Size and Power ................................................................................................................... 95 
13.2. 
General Considerations ................................................................................................................... 95 
13.2.1. 
Analysis Populations/Sets ............................................................................................. 95 
13.2.2. 
Timing of Analyses ....................................................................................................... 95 
13.2.2.1. 
Interim Safety Reviews ............................................................................ 96 
13.2.2.2. 
Final Myelopreservation Analysis and Interim Anti-
Tumor Efficacy Analysis ......................................................................... 96 
13.2.2.3. 
Final analysis and End of Study Analysis ................................................ 96 
13.2.3. 
General Considerations for Data Analysis .................................................................... 97 
13.3. 
Baseline and Demographic Characteristics ..................................................................................... 97 
13.4. 
Efficacy Analysis ............................................................................................................................ 97 
13.4.1. 
Efficacy Endpoints ........................................................................................................ 97 
13.4.2. 
Methods of Analysis for Efficacy Endpoints ................................................................ 99 
13.4.2.1. 
Analysis of Hematologic Parameter Kinetic Endpoints ........................... 99 
13.4.2.2. 
Analysis of Hematologic Toxicity Endpoints ........................................ 101 
13.4.2.3. 
Analysis of Chemotherapy Exposure and Compliance .......................... 101 
13.4.2.4. 
Other Efficacy Endpoints ....................................................................... 101 
13.4.2.5. 
 102 
13.5. 
Safety Analysis ............................................................................................................................. 102 
13.5.1. 
Safety Endpoints ......................................................................................................... 102 
13.5.2. 
Methods of Analysis for Safety Endpoints .................................................................. 103 
13.6. 
 103 
13.7. 
Pharmacokinetic Analysis ............................................................................................................. 104 

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13.8. 
Immunologic Markers ................................................................................................................... 104 
14. QUALITY CONTROL AND QUALITY ASSURANCE ......................................................................... 105 
15. ETHICS AND PROTECTION OF HUMAN PATIENTS ........................................................................ 106 
15.1. 
Ethical Conduct Statement ............................................................................................................ 106 
15.2. 
Institutional Review Board/Independent Ethics Committee ......................................................... 106 
15.3. 
Informed Consent .......................................................................................................................... 106 
15.4. 
Patient Confidentiality .................................................................................................................. 106 
15.5. 
Adherence to the Protocol ............................................................................................................. 107 
15.6. 
Protocol Amendments ................................................................................................................... 107 
15.7. 
Patient Compliance ....................................................................................................................... 107 
15.8. 
Study Discontinuation ................................................................................................................... 107 
16. DATA HANDLING AND RECORD KEEPING ...................................................................................... 108 
16.1. 
Data Collection and Retrieval ....................................................................................................... 108 
16.2. 
Data Monitoring Committee ......................................................................................................... 108 
16.3. 
Investigator Reporting Requirements............................................................................................ 108 
16.4. 
Records Retention ......................................................................................................................... 108 
16.5. 
Study Monitoring .......................................................................................................................... 109 
16.6. 
Audits and Inspections .................................................................................................................. 109 
17. PUBLICATION POLICY ......................................................................................................................... 110 
18. REFERENCES .......................................................................................................................................... 111 
19. APPENDICES ........................................................................................................................................... 114 
 
 

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1.1. 
List of In-Text Tables 
Table 4-1 
G1T28-03: Summary of Dose-Limiting Toxicities in Part 1 of 
the Study ....................................................................................................................... 30 
Table 4-2 
 G1T28-03: Comparison of Topotecan Pharmacokinetic 
Parameters ..................................................................................................................... 37 
Table 5-1 
G1T28-03: Study Objectives ......................................................................................... 39 
Table 8-1 
Topotecan Dose Reductions .......................................................................................... 57 
Table 8-2 
Topotecan Dose Adjustments Based on Lack of Recovery of 
Absolute Neutrophil or Platelet Counts on the First Day of Cycle 
2 and Each Successive Cycle ........................................................................................ 58 
Table 8-3 
Topotecan Dose Adjustments Based on Absolute Neutrophil 
Count Nadir With or Without Fever .............................................................................. 58 
Table 8-4 
Topotecan Dose Adjustment Based on Platelet Nadir................................................... 59 
Table 8-5 
Patient Risk Factors for Poor Clinical Outcomes Resulting from 
Febrile Neutropenia or Infection ................................................................................... 60 
Table 8-6 
Topotecan Reduction for Hepatic Toxicity ................................................................... 61 
Table 9-1 
Schedule of Assessments .............................................................................................. 66 
Table 11-1 
Day 1 of Cycle 1 Blood Sampling Scheme Based on Predicted 
Administration Times of G1T28 and Topotecan ........................................................... 76 
Table 11-2 
Part 1: Day 4 of Cycle 1 Blood Sampling Scheme Based on 
Predicted Administration Times of G1T28 and Topotecan ........................................... 77 
Table 11-3 
Pharmacokinetic Parameters ......................................................................................... 78 
Table 11-4 
G1T28-03: Infusion-Related Reaction Symptoms ........................................................ 85 
Table 11-5 
Evaluation of Overall Response at Each Time Point .................................................... 91 
 
 
1.2. 
List of In-Text Figures 
Figure 6-1 
Study Schema: Part 1 .................................................................................................... 41 
Figure 6-2 
G1T28 Dose Evaluation ................................................................................................ 43 
Figure 6-3 
Study Schema: Part 2A ................................................................................................. 45 
Figure 6-4 
Study Schema: Part 2B .................................................................................................. 46 
 

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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 
CrCl 
creatinine clearance 
CT 
computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
D5W 
dextrose 5% in water 
DDI 
drug-drug interaction 

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Abbreviation 
Definition 
DLT 
DMC 
dose-limiting toxicity 
data monitoring committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic case report form 
EEG 
electroencephalogram 
EOI 
end of infusion 
ESA 
erythropoietin stimulating agent 
 
 
 
 
 
 
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 
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 
IEC 
independent ethics committees 
IRB 
institutional review board 
IV 
intravenous 
IWRS 
interactive web-response system 
LD 
longest diameter 
LDH 
lactate dehydrogenase 

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Abbreviation 
Definition 
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 
Medical Dictionary for Regulatory Activities 
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 
PD 
PET 
progressive disease 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PK 
pharmacokinetic 
PP 
per protocol 
PR 
partial response 
 
 
 
 
Rb 
retinoblastoma protein 
RB-1 
retinoblastoma gene 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors  
RH 
relative humidity 
 
 
RNASeq 
RNA sequencing  
S 
synthesis phase of cell cycle in which DNA is replicated 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCLC 
small cell lung cancer 
SD 
stable disease 
SMC 
safety monitoring committee 

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Abbreviation 
Definition 
SOP 
standard operating procedure 
t1/2 
terminal half-life 
Tmax 
time to reach Cmax 
TP53 
tumor protein 53 
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 Previously Treated Extensive-Stage Small Cell Lung Cancer 
(SCLC) Receiving Topotecan Chemotherapy 
Study Rationale 
Chemotherapy-induced myelosuppression is a significant issue in 
cancer treatment, including treatment of SCLC. G1T28 (trilaciclib; 
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/pharmacodynamics 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 topotecan 
on Days 1 to 5 of 21-day cycles 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 topotecan 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 
 
Part 1 
(Phase 
1b) 
Parts 2A 
and 2B 
(Phase 
2a) 
Primary Objectives 
Assess the DLTs and define the Phase 2 dose of 
G1T28 administered with topotecan 
X 
 
Assess the safety and tolerability of G1T28 
administered with topotecan 
X  
X 
Secondary Objectives 
Assess the PK profile of G1T28 
X 
Xa 
Assess the PK profile of topotecan when 
administered with G1T28 
X 
Xa 
Assess the hematologic profile (kinetics and 
incidence/duration/frequency of toxicities) of 
G1T28 administered with topotecan 
X  
 
X 
Assess the incidence of febrile neutropenia 
X 
X 
Assess the incidence of infections 
X 
X 
Assess the utilization of RBC and platelet 
transfusions 
X 
X 
Assess the utilization of hematopoietic growth 
factors  
X 
X 
Assess the utilization of systemic antibiotics 
X 
X 
Assess the incidence of chemotherapy dose 
reductions and dose interruptions overall 
X 
X 
Assess the incidence of Grade 2 or greater 
nephrotoxicity  
X 
X 
Assess tumor response based on RECIST, 
Version 1.1 
X 
X 
Assess PFS and overall survival 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLT = dose-limiting toxicity; PFS = progression-free survival; 
PK = pharmacokinetic; QOL = quality of life; RBC = red blood cell; 
RECIST = Response Evaluation Criteria in Solid Tumors;  
a 
Limited population PK sampling in Parts 2A and 2B 

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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 
topotecan for patients with previously treated extensive-stage SCLC. 
The study consists of 2 parts: a limited open-label, dose-finding 
portion (Part 1), and a randomized, double-blind, portion (Parts 2A 
and 2B). All 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.  
Part 1 
The goal of Part 1 is to assess the safety, including dose-limiting 
toxicities (DLTs), and PK of G1T28 administered at an initial 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) in combination with topotecan on Days 1 to 5 of each 
21-day chemotherapy cycle.  
Six patients will initially be enrolled in Part 1. Depending on the 
evaluation of DLTs and PK parameters of G1T28 and topotecan 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 intersubject 
variability in these PK parameters is low (see Section 4.2). Therefore, 
for the initial cohort of 6 subjects treated with 200 mg/m2, the target 
AUC0-24 5h is 3100 h•ng/mL. If the mean AUC0-24 5h of the cohort 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. 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 Part 1 prior to 
initiating Parts 2A and 2B of the study. If the G1T28 dose level for a 
subsequent cohort requires escalation, the increase will not exceed 
30% from a previous dose level.  
Since G1T28 has been shown to inhibit renal transporters for which 
topotecan is a substrate, there is a potential for increasing topotecan 
exposure when administered after G1T28. If topotecan exposure is 
significantly altered resulting in potential safety concerns, the safety 
monitoring committee (SMC) will evaluate the data and modify the 
dose of topotecan as appropriate. In particular, the SMC will closely 
evaluate the safety data if the mean topotecan CL in the first 
6 patients is ≤ 0.14 L/min/m2.   
All dose escalation/de-escalation decisions will be based on Cycle 1 
safety and PK data, which will be reviewed by a SMC composed of 
the sponsor, medical monitor, and the principal investigator(s) to 
determine the next dose level. If the G1T28 and/or topotecan dose 
level for a subsequent cohort is adjusted by the SMC, the SMC may 
also recommend that all patients currently receiving G1T28 in 

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combination with topotecan should have their G1T28 and/or 
topotecan dose adjusted accordingly, starting with their next 
scheduled cycle. Additional cohorts for Part 1 will be considered 
based on the review of safety and PK data by the SMC. The G1T28 
and topotecan doses for Arm 1 of Parts 2A and 2B will be obtained 
by utilizing all available safety and PK data from patients enrolled in 
Part 1.  
Each patient will be evaluated for toxicity during each cycle. The 
toxicity of G1T28 administered IV with topotecan 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 6 patients during Cycle 1 of Part 1, and the target PK parameters 
are achieved, then Part 1 will end and all subsequent patients will be 
enrolled into Parts 2A and 2B, utilizing a dose of G1T28 200 mg/m2 
in combination with topotecan. If an additional cohort(s) of 6 patients 
is enrolled in Part 1, then the dose for Parts 2A and 2B will be defined 
following evaluation of safety and PK data from the additional 
cohort(s) of patients.  
Dose-limiting toxicities (applicable to Cycle 1 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; a delay of up to 1 week from the scheduled 
start of Cycle 2 is allowed for recovery of ANC and platelet 
count, and is not considered a DLT 
• 
≥ Grade 3 nonhematologic drug-related toxicity (nausea, 
vomiting, and diarrhea failing maximal medical management; 
fatigue lasting for > 72 hours) 
Toxicities not clearly related to topotecan will also be considered for 
the purposes of determining DLTs. 
Part 2A 
In Part 2A, eligible patients will be randomized (2:1) to receive 
G1T28 or placebo administered IV once daily with topotecan on 
Days 1 to 5 of each 21-day chemotherapy cycle. In Arm 1, patients 
will receive the G1T28 (240 mg/m2) + topotecan (0.75 mg/m2) doses 
determined in Part 1 of the study, and in Arm 2, patients will receive 
placebo + topotecan 1.5 mg/m2. There will be no intrapatient dose 
modifications of G1T28 in Part 2 of the study. 
 

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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 
commences at the time that informed consent is obtained and 
continues through the Post-Treatment Visit. 
A SMC will review safety and PK of G1T28 and topotecan for all 
patients enrolled in Part 1 of the study. The committee will make 
recommendations for dose escalation/de-escalation based on the 
criteria listed in Sections 6.1.1.1 to 6.1.1.4. 
An independent data monitoring committee (DMC) will monitor 
accumulating safety and patient disposition data approximately every 
4 months during the Treatment Phase of Part 2A of the study, 
depending upon the enrollment rate. The independent DMC will also 
monitor accumulating safety and disposition data in Part 2B, with the 
first meeting occurring after approximately 10 patients have been 
enrolled, and then approximately every 4 months during the 
Treatment Phase, 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 (including brain metastases, 
if present at screening) 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. Brain scans with contrast (by CT or MRI) should be 
obtained with tumor assessment at screening. For those without brain 
metastases at screening, an additional scan should be performed at the 
Post-Treatment Visit for patients who have not progressed at the time 
of study drug discontinuation. For those with brain metastases, brain 
scans should be done with each tumor assessment. 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 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, within 4 weeks of study drug 
discontinuation and then 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 

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accompanied by spiral 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, whichever 
occurs first. 
Study Duration 
The total study duration is at least 33 months.  
Part 1 is expected to be approximately 17 months, assuming 
12 months of accrual, 2 weeks for screening, 3 months of treatment 
(assuming 4 cycles), and 1 month of safety follow-up. 
Part 2A will begin after the Phase 2 doses of G1T28 and topotecan 
(for Arm 1 of Part 2A) are identified from Part 1, which is expected to 
occur approximately 17 months after Part 1 begins (based on 12 
months of accrual, 2 weeks of screening, 3 months of treatment, and 
time for the analysis of safety and PK data to identify the Phase 2 
dose). Part 2A is expected to be approximately 16 months, assuming 
11 months of accrual, 2 weeks of screening, 3 months of treatment 
(assuming 4 cycles), and 1 month of safety follow-up. 
Part 2B will begin after enrollment in Part 2A is complete (ie, when 
approximately 45 patients are enrolled) and is expected to be 
approximately 14 months, assuming 9 months of accrual, 2 weeks of 
screening, 3 months of treatment (assuming 4 cycles), and 1 month of 
safety follow-up. 
The Survival Follow-up Phase will continue until at least 50% of the 
patients in Parts 2A and 2B have died. 
Approximate Number of 
Patients 
Up to 130 patients will be enrolled in the study. In Part 1, 
approximately 40 patients will be enrolled assuming 9 to 10 cohorts. 
In Part 2A, approximately 45 patients will be enrolled. In Part 2B, 
approximately 45 patients will be enrolled. 
Number of Study Centers 
Up to 60 centers in the 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. 
Progression during or after prior first- or second-line 
chemotherapy and eligible to receive topotecan therapy 
(immunotherapy treatment alone, ie, not administered with 
chemotherapy, should not be counted as a line of 
chemotherapy) 
4. 
At least 1 target lesion that is measurable by RECIST, 
Version 1.1  
5. 
Absolute neutrophil count ≥ 1.5 × 109/L 
6. 
Platelet count ≥ 100 × 109/L 

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7. 
Creatinine ≤ 1.5 mg/dL and creatinine clearance (CrCl) of 
≥ 60 mL/minute)  
8. 
Total bilirubin ≤ 1.5 × upper limit of normal (ULN) 
9. 
Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 2.5 × ULN; ≤ 5 × ULN in the 
presence of liver metastases  
10. Serum albumin ≥ 3 g/dL 
11. Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 to 2 
12. All clinically significant toxicities from previous anticancer 
therapy must have resolved to ≤ Grade 1 (except for 
hemoglobin) 
13. 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 
negative serum or urine β-hCG test result at baseline. 
Females must be either postmenopausal, surgically 
sterile, or using an acceptable method of contraception in 
combination with a barrier method. 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 to be used in combination with a barrier 
method are an intrauterine device, contraceptive implant, 
oral contraceptive (stable dose of the same hormonal 
contraceptive product for at least 3 months prior to 
dosing), or a vasectomized partner. These methods are to 
be utilized 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 
14. 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. 

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1. 
History of topotecan treatment for SCLC 
2. 
Presence of 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 
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. 
History of upper gastrointestinal bleeding, ulceration, 
perforation, or significant gastrointestinal disease within 
12 months prior to study enrollment 
10. Known human immunodeficiency virus (HIV) positive;  
known hepatitis B virus (HBV) positive; or known  hepatitis 
C virus (HCV) positive that is symptomatic or requiring 
active therapy 
11. 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) 
12. Receipt of any systemic chemotherapy regimen within 4 
weeks prior to enrollment or a noncytotoxic investigational 
medication within 2 weeks prior to enrollment 
13. Receipt of any low-dose systemic chemotherapeutic agent 
given for a nononcologic purpose within 4 weeks prior to 
enrollment (eg, low-dose methotrexate for rheumatoid 
arthritis) 
14. Hypersensitivity to any of the components of the formulation 
of topotecan 
15. Legal incapacity or limited legal capacity 
16. Pregnant or lactating women 

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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. All confidence intervals (CIs) will be 95%, unless 
stated otherwise. 
A SMC will review safety and PK of G1T28 and topotecan for all 
patients enrolled in Part 1 of the study. The committee will make 
recommendations for dose escalation/de-escalation based on the 
criteria listed in Sections 6.1.1.1 to 6.1.1.4. A DMC will review 
accumulating safety and disposition data during the Treatment Phase 
for patients randomized in Parts 2A and 2B. 
 
A final analysis for myelopreservation endpoints, and the first interim 
analysis for anti-tumor efficacy endpoints (including response rate, 
PFS and OS), will be performed after all patients have had the 
opportunity to receive at least 12 weeks (4 cycles) of treatment.  The 
final anti-tumor analysis will coincide with the end of study analysis 
which will occur after at least 50% of patients have died.  Additional 
anti-tumor analysis may be done with the timing to occur between the 
first interim anti-tumor analysis and the final anti-tumor analysis. 
 
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 
 endpoints. 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. 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 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, 
lymphocytes, etc.). 
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. Treatment-emergent AEs will also be presented 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 

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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 the Kaplan-Meier method. 
Blood samples will be collected in Part 1 of the study for the 
determination of G1T28 and topotecan plasma concentrations. 
Limited blood samples will also be collected in Parts 2A and 2B of 
the study for the determination of G1T28 plasma concentrations and 
population PK analysis. Plasma PK parameters will be calculated for 
each analyte, when possible, including Cmax, Tmax, AUC0-t, AUC0-∞, 
t1/2, Vz, and CL. PK 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. PK parameters will be calculated using 
noncompartmental methods based on the plasma concentration-time 
data. PK 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 
Approximately 40 patients will be enrolled in Part 1 of the study 
(dose ranging), approximately 45 patients will be enrolled in Part 2A, 
and approximately 45 patients will be enrolled in Part 2B of the study. 
The Part 1 sample size is based on standard sample size for dose 
escalation to determine a tolerable G1T28 dose administered prior to 
topotecan on Days 1 to 5 of 21-day cycles. In Part 2 of the study, 
approximately 90 patients will be enrolled into 3 groups 
(G1T28 + topotecan 0.75 mg/m2, G1T28 + topotecan 1.5 mg/m2, and 
placebo + topotecan 1.5 mg/m2). With 30 patients per group, the 
precision for point estimates in each group is as follows: the 95% 
confidence interval (CI) width for binary endpoints based on Wilson 
score intervals are at most the observed proportion ± 0.167; and the 
95% CI width for continuous endpoints using the t-distribution are the 
observed mean ± 0.373*standard deviation of the endpoint. 
Moreover, as there are approximately 130 patients for all data from 
Part 1, Part 2A, and Part 2B; the precision for point estimates is as 
follows: the 95% CI width for binary endpoints based on Wilson 
score intervals are at most the observed proportion ± 0.081; and the 
95% CI width for continuous endpoints using the t-distribution are the 
observed mean ± 0.174*standard deviation of the endpoint. 

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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 topotecan used to treat extensive-stage 
small cell lung cancer (SCLC) after failure of first line (von Pawel 2014; Eckardt 2007). In 
Phase 3 clinical trials, topotecan 1.5 mg/m2 resulted in significant myelosuppression 
(neutropenia 54% to 86%, leukopenia 75%, thrombocytopenia 43% to 54%, and anemia 30% 
to 31%), requiring frequent transfusions (50% to 53%) and growth factor use 
(von Pawel 2014; Eckardt 2007). 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 (trilaciclib; 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-independent 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 and Betticher 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 chemotherapy in tumors that are RB-1 inactive, including SCLC. Therefore, as a 

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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 
G1T28 has been evaluated in 1 completed Phase 1 study in healthy male and female 
volunteers (Study G1T28-1-01). Two Phase 1b/2a studies are currently ongoing in patients 
with SCLC: Study G1T28-02 and Study G1T28-03 (current study). A brief summary of the 
clinical data for all 3 studies is provided below and detailed information is presented in the 
G1T28 Investigator’s Brochure (IB).  
Please note that all data (except for Study G1T28-1-01) are from an open and active database 
and are subject to change.  
4.2.1. 
Study G1T28-1-01 
Study G1T28-1-01 was a Phase 1a, first-in-human, 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 

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12.9 to 14.7 hours for the 48 to 192 mg/m2 dose levels. The intersubject 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 
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 and PK/pharmacodynamic model simulations. 
4.2.2. 
Study G1T28-02 
This is an ongoing randomized, double-blind, placebo-controlled, multicenter, Phase 1b/2a 
study of the safety and PK of G1T28 in combination with etoposide/carboplatin therapy for 
patients with newly diagnosed extensive-stage SCLC. The study consists of 2 parts: Part 1 is 
a limited open-label, dose-finding portion followed by an open-label, expansion portion at 
the selected dose to be used in Part 2. Part 2 is a randomized, double-blind, Phase 2a portion 
with 2 arms: etoposide (100 mg/m2) on Days 1, 2, and 3 and carboplatin (AUC5) on Day 1 
(EP) administered with G1T28 IV (240 mg/m2) or placebo once daily on Days 1 to 3 of each 
21-day cycle of E/P chemotherapy. 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. 
 
As of 03 May 2017, Part 1 had completed enrollment, with 19 patients enrolled in Part 1: 
10 in Cohort 1 (EP + G1T28 200 mg/m2) and 9 in Cohort 2 (EP + G1T28 240 mg/m2). All 
patients had discontinued study medication as follows: 13 due to treatment completion, 3 due 
to disease progression, 2 due to AEs considered unrelated to G1T28 (Grade 1 neutropenia 
unrelated to G1T28 and Grade 5 hypoxia unrelated to G1T28), and 1 decided to enter 
hospice. Nine patients had died, all due to their underlying SCLC. Three patients experienced 
DLTs that were used in combination with additional supporting data to select 240mg/m2 
G1T28 as the recommended Phase 2 dose to evaluate in Part 2. In Cohort 1, the DLTs were 
an asymptomatic Grade 2 neutropenia event leading to a delay in starting Cycle 2 and an 
asymptomatic Grade 4 thrombocytopenia event. In Cohort 2, the DLT was also an 
asymptomatic Grade 2 neutropenia event leading to a delay in starting Cycle 2. The most 
common (≥ 30%) treatment-emergent AEs (TEAEs) were neutropenia (63.2%), fatigue 
(57.9%), nausea (52.6%), constipation (47.4%), alopecia (42.1%), vomiting (42.1%), anemia 
(36.8%), and arthralgia (31.6%). The most common (≥ 15%) G1T28-related TEAEs were 
nausea (21.1%), vomiting (21.1%), fatigue (21.1%), and diarrhea (15.8%). There was 
1 G1T28-related ≥ Grade 3AE (creatinine increased) and no G1T28-related SAEs. 

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As of 15 June 2017, Part 2 had completed enrollment, with a total of 77 patients but the data 
remains blinded. Of the 77 patients who were evaluable for safety as of the data cutoff date, 
23 had discontinued study medication as follows: 9 due to treatment completion, 7 due to 
disease progression, 3 due to AEs (Grade 2 infusion reaction unlikely related to G1T28, 
Grade 2 platelet count decreased unlikely related to G1T28, and Grade 5 respiratory failure 
unrelated to G1T28), 2 due to other (Grade 5 respiratory failure unlikely related to G1T28 
and therapy withheld for > 2 weeks), 1 due to withdrawal of consent, and 1 withdrawal by 
the investigator. Four of the 77 patients have died; 3 due to their underlying SCLC and 1 due 
to Grade 5 respiratory failure considered unrelated to any study medications. The most 
common (≥ 20%) TEAEs were neutropenia (41.1%), fatigue (26.0%), anemia (24.7%), 
nausea (24.7%), and thrombocytopenia (23.3%). Please note that these data are confounded 
by the fact that unblinding has not occurred and that approximately 50% of these patients did 
not receive G1T28. 
 
4.2.3. 
Study G1T28-03 (Current Study)  
In the current study (G1T28-03), as of 15 June 2017, Part 1 has completed enrollment, with 
32 patients enrolled in 7 cohorts (Table 4-1); while Part 2 is ongoing and remains blinded, 
with 17 patients in total enrolled. In the previous protocol Version 4 (Amendment 3), Part 2 
(designated Part 2A in the present protocol Version 5 [Amendment 4]) had 2 arms: topotecan 
(0.75 mg/m2) IV once daily administered with G1T28 (240 mg/m2) IV once daily on Days 1 
to 5 versus topotecan (1.5 mg/m2) IV once daily administered with placebo once daily on 
Days 1 to 5.   

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Table 4-1 
G1T28-03: Summary of Dose-Limiting Toxicities in Part 1 of the Study 
 
Cohort 
1 
2 
3 
4 
5 
6 
7 
Topotecan Dose (mg/m2) 
1.5 
 1.25 
0.75 
0.75  
0.75  
0.75  
1.0  
G1T28 Dose (mg/m2) 
200  
200  
200  
240  
280  
240  
240  
Subjects Enrolled (N) 
2 
3 
4 
5 
7 
3 
8a 
DLTs (n) 
2 (100%) 
2 (67%) 
2 (50%) 
0 
3 (43%) 
0 
2 (33%) 
ANC < 0.5 × 109/L lasting for 
> 7 days  
2 (100%) 
2 (67%) 
2 (50%) 
0 
0 
0 
1 (14%) 
Grade 4 thrombocytopenia or 
> Grade 3 thrombocytopenia 
with bleeding 
1 (50%) 
1 (33%) 
0 
0 
2 (29%) 
0 
1 (14%) 
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 
within 1 week of the planned 
start date (ie, > 1 week delay) 
0 
0 
0 
0 
1 (14%) 
0 
0 
a 
Eight patients were enrolled, but only 6 were evaluable for DLTs. One patient discontinued study drug after Day 1 due 
to a peripheral IV site reaction (subject withdrew to receive topotecan off study) and did not complete the 
chemotherapy cycle and 1 patient was incorrectly dosed with  200 mg/m2 G1T28.  
 
Of the 32 patients enrolled in Part 1, 30 have discontinued study medication as follows: 
25 due to disease progression, 3 due to withdrawal of consent, and 2 due to AEs (Grade 2 
myocardial infarction unlikely related to G1T28 and Grade 2 fatigue unrelated to G1T28). 
Twenty of the 32 patients have died, with 18 deaths due to the underlying SCLC, 1 death due 
to respiratory failure and encephalopathy, and 1 death for which the cause of death was 
unknown. Of the 32 patients enrolled in Part 1, 30 were evaluable for DLTs and 11 (37%) 
experienced a DLT as described above in Table 4-1; no DLTs were observed in Cohort 6, in 
which patients received the dose determined to be taken forward in Part 2. The most common 
(≥ 30%) TEAEs were neutropenia (71.9%), anemia (68.8%), thrombocytopenia (68.8%), 
fatigue (53.1%), nausea (40.6%), constipation (34.4%), dyspnea (34.4%), and white blood 
cell decreased (31.1%). The only G1T28-related TEAE that occurred with a frequency 
≥ 10% was headache. There were no G1T28-related SAEs and 3 patients with G1T28-related 
≥ Grade 3/4 AEs (anemia, thrombocytopenia, and neutropenia).  
Of the 17 patients enrolled in Part 2 (designated Part 2A in the current protocol 
Amendment 4), 6 have discontinued study medication as follows: 3 due to disease 
progression, 2 due to withdrawal of consent, and 1 due to an AE (Grade 4 pancytopenia 
considered unrelated to G1T28). Two patients have died, both due to their underlying SCLC. 
The most common (≥ 15%) TEAEs were thrombocytopenia (41.2%), neutropenia (35.3%), 
anemia (29.4%), fatigue (29.4%), nausea (29.4%), diarrhea (23.5%), vomiting (23.5%), 
dehydration (23.5%), hyponatremia (17.6%), and febrile neutropenia (17.6%). Please note 
that these data are confounded by the fact that unblinding has not occurred and that 
approximately 33% of these patients did not receive G1T28. 

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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/pharmacodynamic parameters from the Phase 1a study and a preclinical 
PK/pharmacodynamic 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 topotecan on Days 1 
to 5 of 21-day cycles 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 topotecan and to evaluate the effect of G1T28 on 
chemotherapy-induced myelosuppression. 
4.4.1. 
Selection of G1T28 and Topotecan Doses for Part 2A 
Pharmacokinetic assessments across Study G1T28-02 and G1T28-03 revealed that the PK 
parameters for G1T28 at 200 mg/m2 were similar in each study. Additionally, it was 
observed that the exposure (AUC) of 200 mg/m2 G1T28 was slightly lower than expected in 
patients based on the extrapolated AUC (3100 h*ng/mL) seen in the previous healthy 
volunteer study at 192 mg/m2 (Study G1T28-1-01). Based on these observations and relevant 
safety data, the SMC (Section 6.1.1.5) from both studies independently decided to increase 
the dose of G1T28 to 240 mg/m2, and the G1T28-03 SMC subsequently recommended 
testing 280 mg/m2. In Study G1T28-03, the 240 mg/m2 dose achieved the target AUC of 
3100 h*ng/mL (3180 and 3120 h*ng/mL, on Days 1 and 4, respectively). However, 
exposures following administration of 280 mg/m2 were significantly higher and resulted in 
accumulation (3570 and 4750 h*ng/mL on Days 1 and Day 4, respectively), which had not 
been observed at lower dose levels. Due to the level of accumulation and accompanying 
safety data, the 280 mg/m2 dose was not recommended by the G1T28-03 SMC as the 
Phase 2a dose. 
Evaluation of DLTs in both studies (Section 4.2.2 and 4.2.3) supported the selection of 
G1T28 240 mg/m2 as the Phase 2a dose. In Study G1T28-02, two DLTs were observed with 
G1T28 200 mg/m2, whereas only 1 DLT was observed with G1T28 240 mg/m2. Review of 
hematology data presented by cohort and by G1T28 dose level also supported the selection of 
240 mg/m2 as the recommended Phase 2a dose.  
Determination of the recommended Phase 2a dose for G1T28 administered prior to topotecan 
(Arm 1 of Part 2A in the current protocol Amendment 4) was complicated by a presumed 
DDI, which resulted in an apparent reduced topotecan CL and increased topotecan exposure 
(as discussed in Section 4.4.2) compared to historical controls (Saltz 1993; Van Warmerdam 
1995; O'Reilly 1996; Gallo 2000; Montazeri 2002; Mould 2002). Based on available safety, 
PK, and preliminary response data, the SMC considered 2 potential dose regimens for the 
Phase 2a portion (designated Arm 1 of Part 2A in current protocol Amendment 4) of the 

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present Study G1T28-03 (G1T28 240 mg/m2 + topotecan 0.75 mg/m2, Cohorts 4/6, or G1T28 
240 mg/m2 + topotecan 1.0 mg/m2, Cohort 7). Pharmacokinetic data demonstrated that the 
mean 5-day AUC of topotecan 0.75 mg/m2 dosed with G1T28 240 mg/m2 (Cohorts 4 and 6) 
was within the expected range of the 5-day AUC of topotecan 1.5 mg/m2 monotherapy 
compared to historical controls, whereas the mean 5-day AUC of topotecan 1 mg/m2 dosed 
with G1T28 240 mg/m2 (Cohort 7) was at the upper end of the historical range and for a few 
patients was higher than the upper end of the historical control range. In addition, as outlined 
above in Section 4.2.3, 2 of 6 evaluable patients (33%) in Cohort 7 experienced DLTs, 
whereas no patients in Cohorts 4 and 6 (of 8 evaluable patients) experienced a DLT. 
4.4.2. 
Selection of G1T28 and Topotecan Dose for Part 2B 
At the first G1T28-03 DMC meeting for Part 2 (held in June 2017; Section 6.1.2), available 
topotecan PK data collected from patients enrolled thus far in Arms 1 and 2 of Part 2A (per 
the current protocol Amendment 4) were reviewed by the unblinded clinical 
pharmacokineticist. It was noted that the topotecan PK parameters observed for the 
12 patients enrolled in Arm 1 (G1T28 240 mg/m2 + topotecan 0.75 mg/m2) were similar to 
the data obtained in Part 1 of the study for patients receiving the same doses of G1T28 and 
topotecan (Table 4-2). However, the topotecan PK parameters for the 6 patients enrolled in 
Arm 2 (placebo + topotecan 1.5 mg/m2) were inconsistent with the historical controls from 
published literature. Two more contemporary topotecan PK studies, that were not included in 
the original historical controls from published literature, reported similar topotecan CL 
values to those of patients in Arm 2 of Part 2A, with mean CL values of 0.157 and 
0.121 L/min/m2 (Stewart 2014; Molina 2008).   
In order to accurately assess the impact of G1T28 on the safety and efficacy of topotecan, it 
is critical that topotecan exposures are similar in the topotecan + G1T28 and topotecan + 
placebo arms. Therefore, an additional arm of G1T28 240 mg/m2 + topotecan 1.5 mg/m2 will 
be investigated as Arm 1 in Part 2B of this study. As described in the rationale presented in 
Section 4.4.1, the dose of G1T28 will remain at 240 mg/m2 for Arm 1 of Part 2B.    

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Table 4-2 
 G1T28-03: Comparison of Topotecan Pharmacokinetic Parameters 
 
N 
CL 
(L/min/m 2) 
5-Day AUC 
(min*nM) 
Historical literature 1993-2002a 
 
0.34 
(0.19 to 0.57) 
48,127 
(28,735 to 84,866) 
Historical literature 2008-2014 
 
0.14b,c 
(0.11 to 0.17) 
60,144b 
(22,996 to 93,033) 
Topotecan 0.75 mg/m2 
(with G1T28; G1T28-03 Part 1) 
19 
0.17 
(0.080 to 0.41) 
54,900 
(20,000 to 102,000) 
Topotecan 0.75 mg/m2 
(Arm 1 with G1T28; Study G1T28-03 Part 2A) 
12 
0.17 
(0.12-0.33) 
50,800 
(24,600 to 70,500) 
Topotecan 1.5 mg/m2 
(Arm 2 with placebo; Study G1T28-03 Part 2A) 
6 
0.13 
(0.09 to 0.18) 
133,000 
(91,100 to 180,000) 
a 
Historical mean clearance values from 6 published reports were used to generate a range of AUC × 5 values 
(Saltz 1993; Van Warmerdam 1995; O'Reilly 1996; Gallo 2000; Montazeri 2002; Mould 2002). 
b 
Stewart 2014 
c 
Molina 2008 
 
Available safety data from Arms 1 and 2 of Part 2A (current protocol Amendment 4) were 
also reviewed at the G1T28-03 DMC meeting. The DMC did not note any safety concerns in 
either arm and recommended to continue the study without modification. Topotecan is highly 
myelosuppressive, and preliminary data suggests that G1T28 does not appear to add to the 
myelotoxicity of topotecan, consistent with the underlying hypothesis that transient CDK4/6 
inhibition in combination with cytotoxic chemotherapy can provide myeloprotection. Data 
observed in Study G1T28-02 (G1T28 in combination with EP [first-line therapy for SCLC]) 
also support this hypothesis.   
Therefore, it is reasonable to test an additional arm of G1T28 240 mg/m2 + topotecan 
1.5 mg/m2 in Part 2B of this study. However, since there are currently no available data for 
this combination, the DMC will review safety data after approximately 10 patients have been 
enrolled in Part 2B. The frequency of additional meetings will be determined following 
review of the safety findings from the first meeting, and on the anticipated enrollment rate; at 
a minimum, the DMC will meet approximately every 4 months. 
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 5 of every 21-day cycle of topotecan therapy in the present 

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study. In conclusion, the potential benefits of combining G1T28 at a dose of 200 mg/m2 with 
topotecan to protect the bone marrow HSPCs outweigh the potential risks. 

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5. 
STUDY OBJECTIVES  
The primary, secondary, 
 objectives of this study are presented in Table 5-1. 
Table 5-1 
G1T28-03: Study Objectives 
 
Part 1  
(Phase 1b) 
Parts 2A 
and 2B  
(Phase 2a) 
Primary Objectives 
Assess the DLTs and define the Phase 2 dose of G1T28 
administered with topotecan 
X 
 
Assess the safety and tolerability of G1T28 administered with 
topotecan 
X  
X 
Secondary Objectives 
Assess the PK profile of G1T28 
X 
Xa 
Assess the PK profile of topotecan when administered with G1T28 
X 
Xa 
Assess the hematologic profile (kinetics and 
incidence/duration/frequency of toxicities) of G1T28 administered 
with topotecan 
X  
 
X 
Assess the incidence of febrile neutropenia 
X 
X 
Assess the incidence of infections 
X 
X 
Assess the utilization of RBC and platelet transfusions 
X 
X 
Assess the utilization of hematopoietic growth factors  
X 
X 
Assess the utilization of systemic antibiotics 
X 
X 
Assess the incidence of chemotherapy dose reductions and dose 
interruptions overall 
X 
X 
Assess the incidence of Grade 2 or greater nephrotoxicity  
X 
X 
Assess tumor response based on RECIST, Version 1.1 
X 
X 
Assess PFS and overall survival 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLT = dose-limiting toxicity; PFS = progression-free survival; PK = pharmacokinetic; 
 RBC = red 
blood cell; RECIST = Response Evaluation Criteria in Solid Tumors 
a 
Limited population PK sampling in Parts 2A and 2B 

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Figure 6-1 
Study Schema: Part 1 
 
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 + topotecan will continue until disease progression, unacceptable toxicity, or discontinuation by the patient or 
investigator. 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 topotecan on Days 1 to 5 of 21-day cycles 
d 
Patients will return to the study center for a Post-Treatment Visit at 30 days +3 days after the last dose of study drug. 
e 
The Survival Follow-up Phase will continue until at least 50% of the patients in Parts 2A and 2B of the study have 
died. 
 
6.1.1.1. 
Definition of Dose-Limiting Toxicities (Applicable to Cycle 1 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; a delay of up to 1 week from the 
scheduled start of Cycle 2 is allowed for recovery of ANC and platelet count, and is not 
considered a DLT 
• ≥ Grade 3 nonhematologic toxicity (nausea, vomiting, and diarrhea failing maximal 
medical management; fatigue lasting for > 72 hours) 
Toxicities not clearly related to topotecan will also be considered for the purposes of 
determining DLTs. 
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 

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likely be older and have more comorbidities compared with subjects enrolled in the Phase 1a 
G1T28-1-01 study, and therefore, the present study 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 
6 patients in 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. The adjusted dose, if necessary, will 
be tested in 6 additional patients enrolled in Part 1 prior to initiating Parts 2A and 2B of the 
study. 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. The same criteria for the mean PK parameters (AUC0-24.5h) 
should be used for modifying the G1T28 dose (if required) for patients enrolled in additional 
cohort(s) in Part 1. 
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 in Part 1 and will receive an initial dose of G1T28 
200 mg/m2 in combination with standard topotecan therapy (see Section 8.1). Safety and 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 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.  
• If there is ≤ 1 DLT in the first cohort of 6 patients during Cycle 1 of Part 1 and the 
G1T28 PK parameters are as predicted (Section 6.1.1.2), Part 1 will end and all 
subsequent patients will be enrolled into Parts 2A and 2B, utilizing a dose of G1T28 of 
200 mg/m2 in combination with topotecan. 
• If there is ≤ 1 DLT in the first cohort of 6 patients during Cycle 1 of Part 1, and the 
G1T28 PK parameters suggest that the G1T28 dose needs to be escalated or de-escalated 
(see Section 6.1.1.2), a second cohort of 6 patients will be enrolled at the higher or lower 
predicted G1T28 dose in combination with topotecan. For assessment of data from the 
second cohort enrolled in 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 Part 1 and the 
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/pharmacodynamic 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 

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modified G1T28 dose in combination with topotecan. For assessment of data from the 
second cohort enrolled in 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 Part 1 and the 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 topotecan. For assessment of data from the 
second cohort enrolled in 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 topotecan 
and the PK parameters from these 6 patients 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 topotecan. For assessment of data from the third cohort 
enrolled in Part 1, please see the decision tree in Figure 6-2. 
• If there is > 1 DLT following the second dose reduction of G1T28 and the PK parameters 
from these 6 patients 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 pending SMC review and recommendations for either continued 
enrollment or permanent closure of the cohort 
Figure 6-2 
G1T28 Dose Evaluation 
 
 
a      Assess the adjusted G1T28 dose in the next cohort of 6 patients based on DLTs and PK per the decision tree 
b 
Maximum of 2 G1T28 dose reductions are allowed (first dose reduction to 160 mg/m2 and second dose reduction to 
130 mg/m2) 
 
All dose-escalation/de-escalation decisions will be based on Cycle 1 safety and available PK 
data and will be reviewed by a safety monitoring committee (SMC) composed of the 
sponsor, medical monitor, and the principal investigator(s) to determine the next dose level. 
If the G1T28 and/or topotecan 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 
topotecan should have their G1T28 and/or topotecan dose adjusted accordingly, starting with 
their next scheduled cycle. Additional cohorts for Part 1 will be considered based on review 
of the safety and PK data by the safety monitoring committee. The doses of G1T28 and 
topotecan for Arm 1 of Parts 2A and 2B will be obtained by utilizing all available safety and 

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PK data from patients enrolled in Part 1. There will be no intrapatient dose modifications of 
G1T28 in Parts 2A and 2B of the study. 
Each patient will be evaluated for toxicity during each cycle. The toxicity of IV G1T28 
administered with topotecan 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. 
Topotecan Dose Evaluation 
Since G1T28 has been shown to inhibit renal transporters for which topotecan is a substrate, 
there is a potential for increasing topotecan exposure when administered after G1T28 (see 
Section 4.3.2). However, the relative contribution of these transporters in topotecan clearance 
has not been established. Therefore, in Part 1 of the present Study G1T28-03, PK of G1T28 
and topotecan will be assessed on Days 1 and 4 of the first cycle.  
Previous studies of the most frequently used topotecan schedule (ie, 30-minute IV infusion 
on Days 1 to 5 every 21 days) have shown that total topotecan AUC (ie, from Day 1 to 
Day 5) of higher than 75,000 nM·min was associated with a high probability of major 
toxicity (myelosuppression), whereas patients with a total AUC of lower than 
37,500 nM·min had a limited decrease in neutrophil count (Grochow 1992; O’Reilly 1996a; 
O’Reilly 1996b; Gerrits 1998; Montazeri 2002). In the guidelines provided by the 
manufacturer, dose adjustments for renal clearance are suggested for moderate renal 
impairment (creatinine clearance [CrCl] 20 to 39 mL/min). Patients with moderate renal 
impairment have been shown to have a topotecan clearance of 0.14 L/min/m2 compared to 
0.4 L/min/m2 in patients with normal renal function (CrCl ≥ 60 mL/min, which is required 
for inclusion in the study; Section 7.1.1).   
Since myelosuppression is the major toxicity of topotecan and G1T28 is being developed to 
reduce myelosuppression following cytotoxic chemotherapy, CBC monitoring will be 
followed closely in this study. If topotecan exposure is significantly altered resulting in 
potential safety concerns, the SMC will evaluate the data and modify the dose of topotecan as 
appropriate. In particular, the SMC will closely evaluate the safety data if the mean topotecan 
CL in the first 6 patients is ≤ 0.14 L/min/m2.   
6.1.1.5. 
Safety Monitoring Committee 
The SMC will be set up to review safety of G1T28 for all patients enrolled in Part 1 of the 
study. The SMC will consist of the principal investigator(s), the medical monitor, and 
G1 Therapeutics representatives and/or designees. The SMC will review any DLTs, SAEs, 
PK, and all other available data. The committee will make recommendations for dose 
escalation/de-escalation of G1T28 and/or topotecan based on the criteria listed in 
Sections 6.1.1.1 to 6.1.1.4. While the dose evaluation criteria will be used to guide all dose 
decisions, the SMC will be responsible for all G1T28 and/or topotecan dose and cohort 
recommendations, including any adjustments to the PK collection schedule. If the G1T28 
and/or topotecan 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 topotecan 
should have their G1T28 and/or topotecan dose adjusted accordingly, starting with their next 
scheduled cycle. 

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6.1.2. 
Part 2A 
In Part 2A, eligible patients will be randomized (2:1) to receive G1T28 or placebo 
administered IV once daily with topotecan on Days 1 to 5 of each 21-day chemotherapy 
cycle (Figure 6-3). In Arm 1, patients will receive the G1T28 (240 mg/m2) + topotecan 
(0.75 mg/m2) doses originally determined in Part 1 of the study, and in Arm 2, patients will 
receive placebo + topotecan 1.5 mg/m2.  
Randomization will be stratified on the basis of Eastern Cooperative Oncology group 
(ECOG) performance status (0 to 1 versus 2) and sensitivity to first-line treatment (sensitive: 
complete response [CR], partial response [PR], or stable disease [SD] after first-line therapy 
and recurrence- or progression-free interval ≥ 90 days after completion of first-line therapy 
versus resistant to first line treatment: progressive disease [PD] as best response to first-line 
therapy or progression-free interval < 90 days after completion of first line therapy). There 
will be no intrapatient dose modifications of G1T28 in Parts 2A of the study. 
Figure 6-3 
Study Schema: Part 2A 
 
a  
G1T28 or placebo + topotecan will continue until disease progression, unacceptable toxicity, or discontinuation by the 
patient or investigator. 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 or placebo will be administered prior to the administration of topotecan on Days 1 to 5 of 21-day cycles 
c 
Patients will return to the study center for a Post-Treatment Visit at 30 days +3 days after the last dose of study drug. 
d 
The Survival Follow-up Phase will continue until at least 50% of the patients in Parts 2A and 2B 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 2A 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. 

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6.1.3. 
Part 2B 
In Part 2B, eligible patients will be randomized (2:1) to receive G1T28 or placebo 
administered IV once daily with topotecan on Days 1 to 5 of each 21-day chemotherapy 
cycle (Figure 6-4). In Arm 1, patients will receive G1T28 (240 mg/mg2) + topotecan 
(1.5 mg/m2) and in Arm 2, patients will receive placebo + topotecan (1.5 mg/m2).  
As described above in Section 6.1.2 for Part 2A, randomization for Part 2B will also be 
stratified on the basis of ECOG performance status (0 to 1 versus 2) and sensitivity to 
first-line treatment (sensitive: CR, PR, or SD after first-line therapy and recurrence- or 
progression-free interval ≥ 90 days after completion of first-line therapy versus resistant to 
first line treatment: PD as best response to first-line therapy or progression-free interval 
< 90 days after completion of first-line therapy). There will be no intrapatient dose 
modifications of G1T28 in Part 2B of the study. 
Figure 6-4 
Study Schema: Part 2B 
 
a  
G1T28 or placebo + topotecan will continue until disease progression, unacceptable toxicity, or discontinuation by the 
patient or investigator. 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 or placebo will be administered prior to the administration of topotecan on Days 1 to 5 of 21-day cycles 
c 
Patients will return to the study center for a Post-Treatment Visit at 30 days +3 days after the last dose of study drug. 
d 
The Survival Follow-up Phase will continue until at least 50% of the patients in Parts 2A and 2B of the study have 
died. 
An independent DMC will monitor accumulating safety and patient disposition data in 
Part 2B, with the first meeting occurring after approximately 10 patients have been enrolled, 
and then approximately every 4 months during the Treatment Phase, depending upon the 
enrollment rate. Details of the DMC, including objectives, composition, scope, and 
frequency, will be described in a DMC charter. 

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of accrual, 2 weeks of screening, 3 months of treatment (assuming 4 cycles), and 1 month of 
safety follow-up. 
The Survival Follow-up Phase of the study will continue until at least 50% of the patients in 
Parts 2A and 2B have died. 
6.1.5. 
Safety Assessments 
Safety assessments 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 6.1.6), progression-free survival (PFS), and 
overall survival 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.  
6.1.6. 
Tumor Assessment 
For tumor assessment, all sites of disease (including brain metastases, if present at screening) 
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. Brain scans with contrast (by CT or MRI) should 
be obtained with tumor assessment at screening. For those without brain metastases at 
screening, an additional scan should be performed at the Post-Treatment Visit for patients 
who have not progressed at the time of study drug discontinuation. For those with brain 
metastases, brain scans should be done with each tumor assessment. 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 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, within 
4 weeks of study drug discontinuation and then 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 130 patients will be enrolled in the study.  
In Part 1, approximately 40 patients will be enrolled assuming 9-10 cohorts. 
In Part 2A, approximately 45 patients will be enrolled. 
In Part 2B, approximately 45 patients will be enrolled. 
The study will be conducted at up to 60 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. Progression during or after prior first- or second-line chemotherapy and eligible to 
receive topotecan therapy (immunotherapy treatment alone, ie, not administered with 
chemotherapy, should not be counted as a line of chemotherapy) 
4. At least 1 target lesion that is measurable by RECIST, Version 1.1 (Eisenhauer 2009) 
5. Absolute neutrophil count ≥ 1.5 × 109/L 
6. Platelet count ≥ 100 × 109/L 
7. Creatinine ≤ 1.5 mg/dL and CrCl of ≥ 60 mL/min  
8. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) 
9. AST and ALT ≤ 2.5 × ULN; ≤ 5 × ULN in the presence of liver metastases  
10. Serum albumin ≥ 3 g/dL 
11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 
12. All clinically significant toxicities from previous anticancer therapy must have resolved 
to ≤ Grade 1 (except for hemoglobin) 

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13. 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 negative serum or 
urine β-hCG test result at baseline. Females must be either postmenopausal, 
surgically sterile, or using an acceptable method of contraception in combination with 
a barrier method. 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 to be used in combination with a barrier method are an intrauterine 
device, contraceptive implant, oral contraceptive (stable dose of the same hormonal 
contraceptive product for at least 3 months prior to dosing), or a vasectomized 
partner. These methods are to be utilized 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. 
 
14. 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. History of topotecan treatment for SCLC 
2. Presence of 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 
7. Psychiatric illness/social situations that would limit study compliance 

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8. Other uncontrolled serious chronic disease or conditions that in the investigator’s opinion 
could affect compliance or follow-up in the protocol 
9. History of upper gastrointestinal bleeding, ulceration, perforation, or significant 
gastrointestinal disease within 12 months prior to study enrollment 
10. Known human immunodeficiency virus (HIV) positive; known hepatitis B virus (HBV) 
positive; or known hepatitis C virus (HCV) positive that is symptomatic or requiring 
active therapy 
11. 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) 
12. Receipt of any systemic chemotherapy regimen within 4 weeks prior to enrollment or a 
noncytotoxic investigational medication within 2 weeks prior to enrollment 
13. Receipt of any low-dose systemic chemotherapeutic agent given for a nononcologic 
purpose within 4 weeks prior to enrollment (eg, low-dose methotrexate for rheumatoid 
arthritis) 
14. Hypersensitivity to any of the components of the formulation of topotecan 
15. Legal incapacity or limited legal capacity 
16. 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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8.2. 
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. 
Topotecan 
Descriptions of the formulation of commercially-available topotecan 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 
 
 
Individual vials of G1T28 will be labeled and supplied to the 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. 
 
8.2.2.3. 
Topotecan 
A description of the packaging and labeling of commercially-available topotecan can be 
found in the respective current prescribing information (see Appendix 2).  
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. 

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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 
Commercially-available D5W or sodium chloride solution 0.9% will be stored per the 
manufacturer’s specifications. 
8.2.3.3. 
Topotecan 
Information regarding the storage of commercially-available topotecan can be found in the 
respective current prescribing information (see Appendix 2). 
8.2.4. 
Procedure for Dispensing  
Dispensing instructions 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)/or working practice guidance 
document. 
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 
• 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. 

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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) is open-label and there will be no randomization. Parts 2A 
and 2B are randomized and blinded. Patients meeting all inclusion and exclusion criteria in 
Parts 2A and 2B will be randomized 2:1 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 
For G1T28, placebo, and topotecan dosing, the body surface area (BSA) calculation should 
use the actual body weight, not the ideal body weight. If a patient’s weight fluctuates from 
visit to visit, the doses of G1T28 or placebo and topotecan can be adjusted at each visit, OR 
the dose need not be adjusted unless the change in actual body weight is ≥ 10%. 
  
8.4.1. 
G1T28  
The starting dose level for Part 1 will be 200 mg/m2. See Section 6.1 for possible dose 
escalation/de-escalation decisions based on safety and PK data.   
G1T28 diluted in 250 mL of D5W or sodium chloride solution 0.9% is to be administered by 
IV infusion over 30 (±5) minutes. If there is any study drug remaining in the G1T28 infusion 
bag at the end of the 30 (±5) 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 infusion rate may be decreased to manage an infusion-related AE; for example, if a 
patient experiences a burning sensation during infusion, the infusion time may be increased 
to 45 minutes (or longer if clinically indicated) to alleviate the symptoms. 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 topotecan. If administration of 
topotecan is discontinued, G1T28 will also be discontinued. 
8.4.2. 
Placebo 
The placebo formulation of 250 mL of D5W or sodium chloride solution 0.9% will be 
administered over 30 (±5) minutes. If there is any volume remaining in the infusion bag at 
the end of the 30 (±5) minutes, the infusion should be continued at the same rate until the 
entire contents of the bag have been administered to protect the integrity of the blind. The 

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infusion rate may be decreased to manage an infusion-related AE; for example, if a patient 
experiences a burning sensation during infusion, the infusion time may be increased to 
45 minutes (or longer if needed) to alleviate the symptoms. 
The interval between doses of placebo on successive days should not be greater than 
28 hours. Placebo will only be administered with topotecan. If administration of 
topotecan is discontinued, placebo will also be discontinued. 
 
8.4.3. 
Topotecan 
The starting dose level of topotecan will be 1.5 mg/m2 administered as an IV infusion over 
30 (±5) minutes daily on Days 1 to 5 of each 21-day cycle. See Section 6.1 for possible dose 
adjustments based on safety and PK data. 
Refer to the topotecan prescribing information (see Appendix 2) for details regarding 
preparation, administration, instructions, and precautions. 
The interval between the dose of G1T28 or placebo and topotecan on a given day should 
not be greater than 4 hours. 
Chemotherapy cannot be administered until after completion of the G1T28 or placebo 
infusion. If the second, third, fourth, or fifth dose of G1T28 or placebo in any given 
cycle is not administered for any reason, do not administer the dose of topotecan 
chemotherapy on that day, since this could potentially exacerbate myelosuppression 
(see Section 8.4.4.1).    
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/pharmacodynamic 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 Part 1 as described in Section 6.1.1) throughout 
the study. 
8.4.4.2. 
Modification of Topotecan Dosing 
Patients should meet the laboratory parameter requirements outlined in Section 10.4 before 
initiation of Cycle 2 and each subsequent cycle of topotecan. 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 topotecan. 
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 topotecan 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 
and/or administrative reasons will lead to discontinuation of topotecan. 
No more than 2 dose reductions in total are allowed for any patient. Toxicity that requires 
dose reduction more than twice will lead to discontinuation of topotecan. 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. 
The dose reductions in Table 8-1 will be utilized for the purpose of dose modifications for 
toxicity. 
Table 8-1 
Topotecan Dose Reductions 
Dose Level 
Topotecana 
Starting 
Dose level 
1.5 mg/m2 
1.25 mg/m2 
1.0 mg/m2 
0.75 mg/m2 
Dose level -1  
(first dose reduction) 
1.25 mg/m2  
1.00 mg/m2 
0.8 mg/m2 
0.6 mg/m2 
Dose level -2  
(second dose reduction) 
1.00 mg/m2 
0.8 mg/m2 
0.65 mg/m2 
0.5 mg/m2 
a 
If the topotecan dose was adjusted in Part 1 (Section 6.1.1.4), Dose level -1 will consist of a 20% dose reduction from 
the adjusted Part 1 dose and Dose level -2 will consist of a 20% dose reduction from Dose level -1. Example dose 
reductions are shown for specified starting dose levels.   
 
8.4.4.2.1. 
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 meet the following criteria: 
• 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 
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 
Topotecan 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 
Topotecan 
First episode 
No change. Use G-CSF with subsequent cycles. Refer to the 
American Society of Clinical Oncology (ASCO) guidelines 
(Smith 2015). 
 
Second episode 
 
First dose reduction 
 
Third episode 
 
Second dose reduction 
 
Fourth episode 
 
Discontinue drug 
Platelet Count < 100 x 109/L 
 
Topotecan 
First episode 
First dose reduction 
 
Second episode 
 
Second dose reduction 
 
Third episode 
 
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. 
Table 8-3 
Topotecan Dose Adjustments Based on Absolute Neutrophil Count Nadir 
With or Without Fever 
Absolute Neutrophil Count Nadir 
Topotecan 
Grade 3 (without fever) 
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 2015). 
 
Second episode 
 
First dose reduction 
 
Third episode 
 
Second dose reduction 
 
Fourth episode 
 
Discontinue drug 

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Grade 3/4 with fever 
 
First episode 
No change. Use G-CSF with subsequent cycles. Refer to the 
ASCO guidelines (Smith 2015). 
Second episode 
First dose reduction 
Third episode 
Second dose reduction 
Fourth episode 
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. 
Table 8-4 
Topotecan Dose Adjustment Based on Platelet Nadir 
Platelet Count Nadir 
Topotecan 
Grade 4 or ≥ Grade 3 with bleeding 
First episode 
First dose reduction 
 
Second episode 
 
Second dose reduction 
 
Third episode 
 
Discontinue drug 
 

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Colony Stimulating Factors:  
Use of prophylactic colony stimulating factors (eg, granulocyte colony-stimulating factor 
[G-CSF]; granulocyte-macrophage colony-stimulating factor [GM-CSF]) during Cycle 1 (ie, 
prior to the actual Cycle 2 Day 1 dosing visit) is not allowed. In subsequent cycles (Cycle 2 
and beyond), prophylactic colony stimulating factors are allowed as outlined above in 
Table 8-2 and Table 8-3, which are based on the ASCO guidelines (Smith 2015) and package 
inserts (see Appendix 3). Note that colony stimulating factors should not be administered 
until at least 24 hours after the last dose of chemotherapy is administered in a given cycle.  
For example, if a patient has a neutropenic event in Cycle 1 that requires initiation of 
prophylactic G-CSF in Cycle 2, the G-CSF should not be started until 24 hours after the last 
dose of topotecan in Cycle 2. 
If in any cycle (including Cycle 1), a patient experiences febrile neutropenia and is at high 
risk for infection-associated complications OR has prognostic factors that are predictive of 
poor clinical outcomes (Table 8-5), colony stimulating factors may be used to treat the febrile 
neutropenia event per the ASCO guidelines and package insert.   
Table 8-5 
Patient Risk Factors for Poor Clinical Outcomes Resulting from Febrile 
Neutropenia or Infection 
Risk Factor 
Sepsis syndrome 
Age > 65 years 
Profound neutropenia (absolute neutrophil count < 0.1 × 109/L) 
Neutropenia expected to last > 10 days 
Pneumonia 
Invasive fungal infection 
Other clinically documented infections 
Hospitalization at time of fever 
Prior episode of febrile neutropenia 
Source: Table recreated from Table 2 of the ASCO guidelines (Smith 2015; Smith 2006) 
 
 
Erythropoietin stimulating agents (ESAs):  
ESAs may not be used in Cycle 1. If a patient experiences a hemoglobin level < 9.0 g/dL or 
symptomatic anemia in subsequent cycles, ESAs may be used per the current prescribing 
information (see Appendix 4). 
8.4.4.2.2. 
Dose Modifications for Nonhematologic Drug-Related Toxicity 
Hepatic Toxicity 
The following dose adjustments for topotecan are based on serum AST/ALT and bilirubin 
levels (Table 8-6) during the preceding treatment cycle. 

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Table 8-6 
Topotecan Reduction for Hepatic Toxicity 
AST/ALT 
 
Bilirubin 
Topotecan 
 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 
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 anti-emetic 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 
rechallenged, 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 at 
a low rate (20 mg/hour) after recovery of symptoms. 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 
topotecan 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, then epinephrine is recommended. Patient should not receive any further 
doses of topotecan. 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 topotecan. 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 topotecan. 
8.5. 
Randomization and Blinding 
Part 1 is open-label and no randomization or blinding will be required. 
Parts 2A and 2B are randomized and blinded. Patients meeting all inclusion and exclusion 
criteria in Parts 2A and 2B will be randomized 2:1 to receive G1T28 or placebo by an 
interactive web response system (IWRS) according to a randomization schedule generated by 
an unblinded statistician. Randomization will be stratified on the basis of ECOG performance 
status (0 to 1 versus 2) and sensitivity to first-line treatment (sensitive: CR, PR, or SD after 
first-line therapy and recurrence- or progression-free interval ≥ 90 days after completion of 
first-line therapy versus resistant to first line treatment: PD as best response to first-line 
therapy or progression-free interval < 90 days after completion of first line therapy). 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 first dose of study drug, 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.   

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Administration of other concomitant nonprotocol anticancer therapies prior to progression is 
not permitted while on this study. This includes any low-dose systemic chemotherapeutic 
agent given for a nononcologic purpose (eg, low-dose methotrexate for rheumatoid arthritis). 
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.  
Any medication that is contraindicated when using topotecan is not permitted, and special 
warnings and precautions for use of topotecan should be observed.  
Necessary supportive care such as antiemetics, antidiarrheals, etc., per the standard of care at 
the study center will be permitted. See Section 8.4.4.2.1 for guidance on the use of growth 
factors (colony stimulating factors and ESAs) during the study. 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). Since G1T28 has been shown to inhibit renal transporters 
for which topotecan is a substrate, there is a potential for increasing topotecan exposure when 
administered after G1T28 (see Section 4.3.2). However, the relative contribution of these 
transporters in topotecan clearance has not been established. Therefore, in Part 1 of the study, 
PK of G1T28 and topotecan will be assessed on Days 1 and 4 of the first cycle and any 
recommendations for dose modifications will be made by the SMC based on safety and PK 
data (Section 6.1.1.4).  
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.  

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Medications will be coded using the most recent World Health Organization (WHO) Drug 
Dictionary version. 
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).  
Patients with hemoglobin < 8.0 g/dL or with symptomatic anemia can be treated with RBC 
transfusions at the investigators discretion.  
8.8. 
Treatment Compliance 
The investigator or designee will dispense the study medication, via a 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, placebo, or topotecan 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 
  
Screening  
Enroll 
 
 
Cycle 1 and Odd Cyclesa 
(21 days) 
 
Cycle 2 and Even Cyclesa 
(21 days) 
Last 
Cycle 
Post-
Treatment 
Visitb 
Survival 
Follow-
upc 
Cycle Day  
-14  
-3 
to 
1 
1 
2 
3 
4  
5  
10 
12 
15 
1 
2 
3 
4 
5 
10 
12 
15 
22 
30 +3  
 
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 
Xg 
 
 
 
 
 
 
X 
 
X 
 
Hematology 
X 
 
Xh 
 
 
 
X 
X 
X 
Xs 
Xh 
 
 
 
X 
X 
X 
Xs 
X 
X 
 
Urinalysis 
X 
 
Xg 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
X 
 
Immunologic 
markersi 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
ECGj 
X 
 
Xj 
 
 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy testk 
X 
  
X  
  
  
 
  
 
 
 
X 
  
  
 
  
 
 
 
  
 
Randomizationr 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor 
Assessmentl 
Xl2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Xl1, l2 
X l1 
Tumor 
Testingm 
 X 
  
  
  
 
  
 
 
 
  
  
  
 
  
  
 
 
 
  
 
PKn 
  
X 
  
X 
  
 
 
 
  
  
  
 
  
  
 
  
 
  
 
G1T28 or 
placeboo 
 
  
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Topotecan 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 

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Screening  
Enroll 
 
 
Cycle 1 and Odd Cyclesa 
(21 days) 
 
Cycle 2 and Even Cyclesa 
(21 days) 
Last 
Cycle 
Post-
Treatment 
Visitb 
Survival 
Follow-
upc 
Cycle Day  
-14  
-3 
to 
1 
1 
2 
3 
4  
5  
10 
12 
15 
1 
2 
3 
4 
5 
10 
12 
15 
22 
30 +3  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEsq 
X 
X 
 
Prior and Con. 
Medications 
X 
X 
 
Survival 
Follow-upc 
 
 
X 
AE = adverse event; ECG = electrocardiogram; 
val. = evaluation; PK = pharmacokinetic 
a 
G1T28 + topotecan will continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator. 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. Any anticancer therapies used will be collected. Patients will be followed for survival until at 
least 50% of the patients in Parts 2A and 2B 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, every 2 months (approximately 60 ± 7 days) until the occurrence of progressive disease or study 
completion. 
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, documentation of tumor diagnosis, baseline signs and symptoms within 4 weeks prior to the first dose of study drug, weight loss in 
the 6 months prior to the first dose of study drug (≤ 5% or > 5%), and medications taken within 14 days prior to the first dose of study drug 
f 
Height will only be measured at the screening visit. Body surface area calculation (based on actual body weight taken prior to study drug administration) will be completed on Day 1 of each 
cycle and vital signs obtained immediately before and after G1T28 and topotecan infusions on Day 1.  Vitals only need to be taken once between the infusions.   
g 
Clinical chemistry will be obtained (albumin, alkaline phosphatase [ALP], 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 + topotecan. 
h 
Hematology will be obtained (hemoglobin, hematocrit, white blood cells (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 + topotecan.  
i 
 
j 
 Patients participating in Part 1 of the study will have ECGs completed at the following time points on Days 1 and 4 of Cycle 1: predose, 0.5 hour (end of infusion [EOI] of G1T28), 1 hour 
(± 10 minutes), and 6.5 hours (± 15 minutes) after start of G1T28 infusion. Patients participating in Parts 2A and 2B of the study will have ECGs completed at the following time points on Day 4 
of Cycle 1: predose, 0.5 hour (EOI of G1T28), 1 hour (± 10 minutes), and between 3.5 to 6.5 hours (± 15 minutes) after start of G1T28 infusion. 

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hematological evaluations based on accumulating data. The investigators and institutional 
review boards (IRBs) or independent ethics committees (IECs) will be notified if the 
frequency is reduced. 
At Days 2, 3, 4, and 5, study treatments (G1T28 or placebo + topotecan) will be administered 
(as described in Section 8.1). 
At Day 4 in Cycle 1 of Parts 1, 2A, and 2B, the following additional assessments will be 
performed: 
• Electrocardiogram (predose, 0.5 hour [EOI of G1T28 or placebo], 1 hour [± 10 minutes], 
and 6.5 hours [± 15 minutes] after start of G1T28 or placebo infusion in Part 1 of the 
study; and predose, 0.5 hour [EOI of G1T28 or placebo], 1 hour [± 10 minutes], and 
between 3.5 to 6.5 hours [± 15 minutes] after start of G1T28 or placebo infusion in 
Parts 2A and 2B of the study) 
• Plasma PK sample (predose and postdose samples as described for Parts 1, 2A, and 2B of 
the study 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 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) 
• CD4/CD8 immunologic markers (as applicable) 
• Pregnancy test (note: may be obtained up to 72 hours prior to the first dose of each cycle) 
• 
 
Vital signs should be obtained immediately before and after G1T28 or placebo and topotecan 
infusions; only needed once between infusions. 
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 

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criteria for organ function. If the patient meets the criteria for starting the subsequent cycle as 
stated in Section 6.1.4, 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 
PRO scales, CBC and CD4/CD8 immunologic marker (as applicable) assessments on 
Day 22, return for the Post-Treatment Visit, and the Survival Follow-up Phase of the study, 
which is to continue until at least 50% of the patients in Parts 2A and 2B have died. 
10.6. 
Post-Treatment Visit 
Patients will return to the study center for a Post-Treatment Visit at 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  
• CD4/CD8 immunologic markers (as applicable) 
• 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]) 
• 
 
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 in 
Parts 2A and 2B 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, every 
2 months (approximately 60 ± 7 days) until the occurrence of progressive disease or study 
completion.   

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The following information will be collected monthly for all patients: 
• Survival status 
10.8. 
Details of any anticancer treatment 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 
completion of the 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 patients in 
Parts 2A and 2B 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; 
 
. 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 topotecan will be assessed using the NCI 
CTCAE, Version 4.03. 
11.2. 
Pharmacokinetic Assessments  
In Parts 1, 2A, and 2B of the study, serial blood samples (5-mL samples) will be collected for 
measurement of G1T28 and topotecan 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 and topotecan using a validated method. Any remaining sample may be stored long 
term for the future analysis of G1T28 drug metabolites. 

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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 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 topotecan), 1.5, 2, 2.5, 3, 4.5, 6.5, 8.5 (optional time 
point, if approved by the sponsor in advance), and 24.5 hours postdose (prior to G1T28 dose 
on Day 2). Blood samples collected at the following time points are relative to the start of 
G1T28: 1.5 to 24.5 hours.  The EOI sample for G1T28 should be drawn 2 to 5 minutes prior 
to the EOI.  The EOI sample for topotecan 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 start 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 start of G1T28 infusion. A ± 1-hour time window will be allowed for the 24.5 hours after 
the start 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 and Topotecan 
Sample 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Sample  
Time (h) 
0 
(Predosea) 
0.5 
(G1T28 
EOI) 
1 
(Topo 
EOI) 
1.5 
2 
2.5 
3 
4.5 
6.5 
8.5 
(optionalb) 
24.5 
EOI = end of infusion; h = hour; Topo = topotecan 
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 
8.5 hour sample (optional time point, if approved by the sponsor in advance)   
 
 

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Part 1: Cycle 1 Day 4 
Blood samples will be collected at the following time points on Cycle 1 Day 4 for all patients 
enrolled in Part 1 of the study: predose (0 hour; prior to dosing of G1T28) and at 0.5 (EOI of 
G1T28), 1 (EOI of topotecan), 1.5, 2, 2.5, 3, 4.5, 6.5, 8.5 (optional time point, if approved by 
the sponsor in advance), and 24.5 hours postdose (prior to G1T28 dose on Day 5). Blood 
samples collected at the following time points are relative to the start of G1T28: 1.5 to 
24.5 hours. The EOI sample for G1T28 should be drawn 2 to 5 minutes prior to the EOI.  The 
EOI sample for topotecan 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 1also apply to Cycle 1 Day 4. The Cycle 1 Day 4 
sampling scheme is summarized in Table 11-2. 
Table 11-2 
Part 1: Day 4 of Cycle 1 Blood Sampling Scheme Based on Predicted 
Administration Times of G1T28 and Topotecan 
Sample 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Sample  
Time (h) 
0 
(Predosea) 
0.5 
(G1T28 
EOI) 
1 
(Topo 
EOI) 
1.5 
2 
2.5 
3 
4.5 
6.5 
8.5 
(optionalb) 
24.5 
EOI = end of infusion; h = hour; Topo = topotecan 
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 
8.5 hour sample (optional time point, if approved by the sponsor in advance) 
 
 
Parts 2A and 2B: Cycle 1 Day 4 
Limited PK samples will be collected on Cycle 1 Day 4 in Parts 2A and 2B of the study for 
population PK analysis. Blood samples will be collected at the following time points relative 
to the start of G1T28 infusion on Cycle 1 Day 4 for all patients enrolled in Parts 2A and 2B 
of the study: predose (0 hour; prior to dosing of G1T28) and at 0.5 (EOI of G1T28), 1 (EOI 
of topotecan), between 3 to 4 hours and between 5.5 to 6.5 hours. The EOI sample for G1T28 
should be drawn 2 to 5 minutes prior to the EOI. A ± 5-minute time window will be allowed 
for samples collected predose and 1 hour after the end of G1T28 infusion. A ± 10-minute 
time window will be allowed for samples collected between 3 to 6.5 hours from the start of 
G1T28 infusion. 

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Pharmacokinetic Parameters 
Pharmacokinetic parameters to be derived from G1T28 and topotecan plasma 
concentration-time data are presented in Table 11-3. 
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 =
 
 
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. 
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 IB 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 
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 

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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 

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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. 
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. 

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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. 
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 + topotecan. 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. If the EDC system is not operational, the paper SAE Form must be completed 
within 24 hours and faxed to the number below. 
 
PPD Pharmacovigilance: 
EMEA/APAC 24 Hour Safety Hotline: +44 1223 374 240 
24 Hour Safety Hotline Fax: +44 1223 374 102 
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.  
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 

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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) and European National Competent Authorities, the Medicine 
Evaluation Board, and the 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 the FDA and European 
National Competent Authorities, the Medicine Evaluation Board, and the Competent 
Authorities in other Member States, if applicable, in an expedited time frame in compliance 
with current legislation.  Unexpected serious adverse events 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 studies with the study 
medication will receive copies of these reports for prompt submission to their IRB or IEC. 

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The expedited reporting will occur no later than 15 calendar days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life-threatening cases the term will be a 
maximum of 7 calendar days for a preliminary report with another 8 days for completion of 
the final report. The investigator is encouraged to discuss with the medical monitor any 
adverse experiences for which the issue of reportability is unclear or questioned.   
11.3.1.12. 
Infusion-Related Reactions  
An infusion-related reaction is defined as “an adverse reaction to the infusion of 
pharmacological or biological substances” and can be divided into 2 categories: local effects 
and systemic effects (CTCAE, Version 4.03). Those AEs that are infusion-related should be 
recorded in the eCRF as “infusion-related reactions.” Any associated symptoms as outlined 
in Table 11-4 below should also be recorded as AEs. The associated symptoms and details 
(ie, local versus systemic) will also be captured on the infusion/dosing page in the EDC 
system. 
Table 11-4 
G1T28-03: Infusion-Related Reaction Symptoms 
Redness 
Pyrexia 
Hoarseness 
Edema 
Angioedema 
Hypoxia 
Ulceration 
Flushing 
Mouth tingling 
Pain 
Rigors/chills 
Diaphoresis 
Phlebitis 
Bronchospasm/wheezing 
Rash (nonspecific) 
Warmth 
Chest pain 
Syncope 
Pruritis 
Back pain 
Tachycardia 
Hypotension 
Difficulty swallowing 
Throat tightness 
Shortness of breath/dyspnea 
Facial swelling 
 
 
 
11.3.1.13. 
Handling of Overdoses and Toxicity 
No information on treatment of overdose of G1T28 is currently available. General supportive 
measures should be used as appropriate. 
11.3.1.14. 
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.  

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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, WBCs with differential and platelet counts) 
• Chemistry (albumin, 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) 
Patients with an ANC < 0.5 × 109/L on Day 15 shall be followed (eg, every 24 to72 hours) 
until ANC is at least > 0.5 x 109/L (to ensure the duration of ANC < 0.5 × 109/L does not 
exceed 7 days). 
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 
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 
remeasured 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 or IECs 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) 

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metastases at screening, an additional scan should be performed at the Post-Treatment Visit 
for patients who have not progressed at the time of study drug discontinuation (may be 
performed within 4 weeks of treatment discontinuation). For those with brain metastases at 
baseline, brain scans should be done with each tumor assessment.  
CT or MRI scans obtained prior to informed consent will not need to be repeated if 
performed within 14 days prior to dosing. Brain MRI or CT scans obtained prior to informed 
consent will not need to be repeated if performed within 28 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. Assessments may be performed 
within 7 days of starting the subsequent cycle. 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, within 4 weeks of study 
drug discontinuation and then 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 
follow-up. 
Lytic bone lesions or mixed lytic-blastic lesions with a soft tissue component meeting the 
definition of measurability above can be considered measurable lesions. Cystic lesions 
representing cystic metastases that meet the definition of measurability described above can 
be considered measurable lesions. If present, noncystic lesions should be selected as target 
lesions for this study. 
A tumor lesion that has been previously irradiated may be considered measurable if 
unequivocal growth of the lesion has been demonstrated.  
Target lesions: At baseline, up to 5 measurable tumor lesions/lymph nodes (with a 
maximum of 2 lesions per organ) should be identified as target lesions that will be followed 
to quantitate the status of disease during the study. Lesions with the longest diameter, that are 

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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 
• 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. 

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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 11-5 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 
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.  

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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 
• Treatment delay greater than 2 weeks 
• 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 progressive disease 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.   

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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, 
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). For any differences in analyses between the protocol and 
SAP, the plan as outlined in the SAP will supersede the protocol. 
13.1. 
Sample Size and Power 
Approximately 40 patients will be enrolled in Part 1 of the study (dose ranging), 
approximately 45 patients will be enrolled in Part 2A of the study, and approximately 
45 patients will be enrolled in Part 2B of the study. The Part 1 sample size is based on 
standard sample size for dose escalation to determine a tolerable G1T28 dose administered 
prior to topotecan on Days 1 to 5 of 21-day cycles. In Part 2 of the study, approximately 
90 patients will be enrolled into 3 groups (G1T28 + topotecan 0.75 mg/m2, G1T28 + 
topotecan 1.5 mg/m2, and placebo + topotecan 1.5 mg/m2). With 30 patients per group, the 
precision for point estimates in each group is as follows: the 95% confidence interval (CI) 
width for binary endpoints based on Wilson score intervals are at most the observed 
proportion ± 0.167; and the 95% CI width for continuous endpoints using the t-distribution 
are the observed mean ± 0.373*standard deviation of the endpoint. Moreover, as there are 
approximately 130 patients for all data from Part 1, Part 2A, and Part 2B; the precision for 
point estimates is as follows: the 95% CI width for binary endpoints based on Wilson score 
intervals are at most the observed proportion ± 0.081; and the 95% CI width for continuous 
endpoints using the t-distribution are the observed mean ± 0.174*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. 
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. 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 Parts 2A and 2B of the study. 
The PK set will include all dosed patients in Part 1 with evaluable PK data. 
13.2.2. 
Timing of Analyses 
Recent clinical results from Study G1T28-02 in patients with treatment-naïve extensive-stage 
SCLC comparing trilaciclib plus etoposide/carboplatin to placebo + etoposide/carboplatin, 
provided compelling evidence that trilaciclib decreased myelosuppression across three 

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lineages: neutrophils, red blood cells and lymphocytes and achieved a meaningful level of 
myelopreservation. While this trial was specifically designed to evaluate myelosuppression 
endpoints in SCLC patients receiving topotecan, the current design requires all patients to 
complete treatment prior to unblinding and analysis.  Since patients in this trial may be 
treated indefinitely, i.e. until progression of disease, unacceptable toxicity etc, it is not 
possible to definitively predict when unblinding and analysis may occur.  Therefore, an 
additional analysis (as described below) is to be added in this protocol amendment, which 
will enable evaluation of myelosuppression endpoints prior to all patients discontinuing 
treatment.  The timing of the analysis has been chosen to (1) ensure that all patients will have 
had the opportunity to receive at least 12 weeks (4 cycles) of topotecan with the majority 
having completed therapy, and (2) that the myelopreservation results will be sufficiently 
mature such that the data generated by any patients still on trial will not alter the overall 
myelopreservation conclusions in a clinically meaningful way. 
 
13.2.2.1. 
Interim Safety Reviews 
A SMC will review safety and PK of G1T28 and topotecan for all patients enrolled in Part 1 
of the study. The SMC will consist of the clinical investigator(s), the medical monitor, and 
G1 Therapeutics representatives and/or designees. The committee will make 
recommendations for dose escalation/de-escalation based on the criteria listed in 
Sections 6.1.1.1 to 6.1.1.4.  
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 Parts 2A and 2B, 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. 
13.2.2.2. 
Final Myelopreservation Analysis and Interim Anti-Tumor Efficacy Analysis 
A final analysis for myelopreservation endpoints, and the first interim analysis for anti-tumor 
efficacy endpoints (including response rate, PFS and OS), will be performed after all patients 
have had the opportunity to receive at least 12 weeks (4 cycles) of treatment.  At the time of 
this final analysis, the Sponsor will be unblinded, however investigators and patients will 
remain blinded. 
13.2.2.3. 
Final analysis and End of Study Analysis 
The final anti-tumor efficacy analysis will coincide with the end of study analysis which will 
occur after at least 50% of patients have died.  Additional anti-tumor efficacy analyses may 
be done with the timing to occur between the first interim anti-tumor efficacy analysis and 
the final anti-tumor efficacy analysis. 

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13.2.3. 
General Considerations for Data Analysis 
All statistical analyses will be performed using SAS® version 9 or higher.  
Data will be summarized descriptively by dose level, if applicable, and overall. Patients with 
the same dose level (Phase 2 dose level) in Parts 1, 2A, and 2B will be summarized together, 
unless described otherwise. In that case, patients with the same dose level will be 
summarized at the Phase 2 dose level together and separately by study part (Parts 1, 2A, and 
2B). 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. 
95% confidence intervals will be presented for efficacy 
 endpoints. 
The effects of covariates (eg, ECOG, extent of prior chemotherapy, prior response to 
chemotherapy) 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. 
  
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. 
13.3. 
Baseline and Demographic Characteristics 
Disposition, demographics, and baseline characteristics will be summarized descriptively.  
Summaries will be done overall, by dose level, and separately by study part (Parts 1, 2A, and 
2B) for summaries at the Phase 2 dose level.  
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.  

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• 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 
 
• 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 dose reductions 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  

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postnadir, and nadir to end of cycle. The models will include terms for treatment, ECOG at 
entry (0 and 1 or 2), sensitivity to first-line treatment (sensitive: CR, PR, or SD after first-line 
therapy and recurrence- or progression-free interval ≥ 90 days after completion of first-line 
therapy versus resistant to first line treatment: PD as best response to first-line therapy or 
progression-free interval < 90 days after completion of first line therapy), 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, ECOG at entry, and sensitivity to first-line treatment (sensitive: CR, PR, or SD after 
first-line therapy and recurrence- or progression-free interval ≥ 90 days after completion of 
first-line therapy versus resistant to first line treatment: PD as best response to first-line 
therapy or progression-free interval < 90 days after completion of first line therapy). 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 patients whose blood counts 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 Parts 2A and 2B, 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. 
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 

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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 Parts 2A and 2B, 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.  
For each hematologic parameter and cycle, the following shift summaries will be performed: 
from predose toxicity to maximum on-treatment 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.  
13.4.2.3. 
Analysis of Chemotherapy Exposure and Compliance 
The following parameters will be summarized: total duration of treatment, total number of 
cycles received, cumulative dose of topotecan received, and number and percentage of 
patients experiencing one or more dose delay, interruption, and reduction. Summaries of 
exposure will be done overall, by dose level, and separately by study part (Parts 1, 2A, and 
2B) for summaries at the Phase 2 dose level.  
The following parameters will be summarized for each cycle and overall: number and 
percentage of patients receiving any dose of chemotherapy, experiencing one or more dose 
delay, interruption, and reduction, and cumulative dose of topotecan received. The number 
and percentage of patients experiencing a dose reduction or treatment cycle delay due to a 
hematologic toxicity will also be summarized by cycle and overall. The number and 
percentage of 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 

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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 or designee (subinvestigator) 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 IEC 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 or IEC prior to initiating the study. Approval must be obtained in writing via a letter 
identifying the protocol, the date of the IRB or IEC meeting, and the date of approval. Any 
modifications made to the protocol after receipt of the IRB or IEC approval must also be 
submitted by the investigator to the IRB or IEC in accordance with local procedures and 
regulatory requirements. Any updates to the protocol should receive IRB or IEC 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 IEC, 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 or IEC 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 IEC 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 
or IEC 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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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 Parts 2A and 2B 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 or IEC 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 or IEC, 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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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. 

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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. 

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18. 
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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 Insert for Chemotherapy Agent   
Hycamtin® (topotecan hydrochloride) package insert link: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020671s020lbl.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