Clinical trial NCT02514447
Conditions: Small Cell Lung Cancer
Keywords: SCLC CDK4/6 Inhibitor
Sponsor: G1 Therapeutics, Inc.
Start date: 2015-10-05; Completion date: 2021-10-04
Enrollment: 123 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a study to investigate the potential clinical benefit of trilaciclib (G1T28), a Cyclin Dependent Kinase (CDK) 4/6 inhibitor, in preserving the bone marrow and the immune system, in order to decrease chemotherapy-induced myelosuppression and improve anti-tumor efficacy when administered prior to topotecan in patients previously treated for extensive-stage SCLC.

The study consisted of 2 parts: a limited open-label, dose-finding portion (Part 1), and a randomized double-blind portion (Part 2). Both parts included 3 study phases: Screening Phase, Treatment Phase, and Survival Follow-up Phase. The Treatment Phase began on the day of first dose with study treatment and completes at the Post-Treatment Visit.

Detailed description:
Overall, up to 130 patients were planned to be enrolled in the study. In Part 1, approximately 40 patients were planned to be enrolled, assuming 9 to 10 cohorts. Part 1 was open-label, and no randomization or blinding was required. In Part 2A, approximately 45 patients were to be enrolled and randomly assigned (2:1) to trilaciclib (240 mg/m2) and topotecan (0.75 mg/m2) or placebo and topotecan (1.5 mg/m2). In Part 2B, approximately 45 patients were to be enrolled and randomly assigned (2:1) to trilaciclib (240 mg/mg2) and topotecan (1.5 mg/m2) or placebo and topotecan (1.5 mg/m2).

Patients who received placebo in Part 2A and Part 2B were to be combined into a single placebo group for the analysis to compare with trilaciclib+topotecan 1.5 mg/m2 with placebo + topotecan 1.5 mg/m2 (proximately 30 per treatment group).

The sample size calculation was to demonstrate the superiority of trilaciclib + topotecan 1.5 mg/m2 over placebo + topotecan 1.5 mg/m2 with respect to at least 1 of the primary endpoints. The overall type I error rate was 1-sided 0.10. Using the most conservative Bonferroni procedure for the 2 primary endpoints, a 1-sided individual type I error rate 0.10/2=0.05 was assigned to each outcome variable (DSN in Cycle 1 and occurrence of SN) in the sample size calculation. Assuming a common standard deviation of 2.5, a difference in the duration of SN in Cycle 1 of at least 2 days between the treatment groups, a sample size of 28 per arm was required to have 90% power to detect the assumed treatment effect. For occurrence of SN, assuming the event rate was 45% for placebo group, to detect an absolute reduction of 37% by trilaciclib group with 90% power would require a sample size of at least 29 per arm. Thus, 30 per arm was needed to ensure 90% power to detect assumed treatment effect for DSN in Cycle 1 and occurrence of SN. All calculations were carried out using the POWER procedure in SAS®, Version 9.4 procedure in SAS®, Version 9.4 or higher.

The results from endpoints that were commonly collected at Part 1 and part 2 are presented together in this report.

The posted results represent the final results of Study G1T28-03, a Phase 1b/2a safety and pharmacokinetic (PK) study of trilaciclib (G1T28) in patients with previously treated extensive-stage small cell lung cancer (SCLC) receiving topotecan chemotherapy in the second/third-line (2/3L) setting. The final myelopreservation efficacy results for both parts and exposure for Part 1 are from database lock 1 (data cut-off \[DCO\] for Primary Completion Date \[PCD\] 28 September 2018). The final anti-tumor efficacy (BOR, DOR, PFS) for both parts, final overall survival for Part 1 and exposure data from Part 2 are from a second database lock 2 (DCO 31 May 2019) and the final overall survival for Part 2 and safety (adverse events) are through the end of the study on October 4, 2021 which resulted in the final database lock (DCO 01 Nov 2021).

The maximum time frames provided reflect the time from when the first patient could be evaluated for an endpoint (ie. date of first dose of first patient) to the time when the data from both parts presented for that endpoint was considered final.

Arms: arm 1: Patients in Parts 2a and 2b were randomized 1:2 to placebo. Patients received placebo administered IV once daily on Days 1 to 5 of each 21-day topotecan chemotherapy cycle.

Following administration of placebo on Days 1 to 5, patients received IV topotecan (1.5 mg/m²). arm 2: Patients in Part 2a were randomized 2:1 to trilaciclib. Patients received trilaciclib (240 mg/m²) administered IV once daily on Days 1 to 5 of each 21-day topotecan chemotherapy cycle.

Following administration of trilaciclib on Days 1 to 5, patients received IV topotecan (0.75 mg/m²). arm 3: Patients in Part 2b were randomized 2:1 to trilaciclib. Patients received trilaciclib (240 mg/m²) administered IV once daily on Days 1 to 5 of each 21-day topotecan chemotherapy cycle.

Following administration of trilaciclib on Days 1 to 5, patients received IV topotecan (1.5 mg/m²). arm 4: Patients received trilaciclib (200 mg/m²) administered intravenously (IV) once daily on Days 1 to 5 of each 21-day topotecan chemotherapy cycle.

Following administration of trilaciclib on Days 1 to 5, patients received IV topotecan (1.50 mg/m²). arm 5: Patients received trilaciclib (200 mg/m²) administered intravenously (IV) once daily on Days 1 to 5 of each 21-day topotecan chemotherapy cycle.

Following administration of trilaciclib on Days 1 to 5, patients received IV topotecan (1.25 mg/m²). arm 6: Patients received trilaciclib (200 mg/m²) administered intravenously (IV) once daily on Days 1 to 5 of each 21-day topotecan chemotherapy cycle.

Following administration of trilaciclib on Days 1 to 5, patients received IV topotecan (0.75 mg/m²). arm 7: Patients received trilaciclib (240 mg/m²) administered intravenously (IV) once daily on Days 1 to 5 of each 21-day topotecan chemotherapy cycle.

Following administration of trilaciclib on Days 1 to 5, patients received IV topotecan (0.75 mg/m²). arm 8: Patients received trilaciclib (280 mg/m²) administered intravenously (IV) once daily on Days 1 to 5 of each 21-day topotecan chemotherapy cycle.

Following administration of trilaciclib on Days 1 to 5, patients received IV topotecan (0.75 mg/m²). arm 9: Patients received trilaciclib (240 mg/m²) administered intravenously (IV) once daily on Days 1 to 5 of each 21-day topotecan chemotherapy cycle.

Following administration of trilaciclib on Days 1 to 5, patients received IV topotecan (1.0 mg/m²).
Interventions: intervention 1: Trilaciclib intervention 2: Placebo intervention 3: Topotecan
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
SAP_002.pdf: 
  
 
 
 
 
STATISTICAL ANALYSIS PLAN 
- Region 2 - 
 
Study 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   
 
 
 
Sponsor 
G1 Therapeutics 
 
79 T.W. Alexander Drive 
 
4501 Research Commons, Suite 100 
 
Research Triangle Park, NC 27709 
 
 
Name of Test Drug: 
G1T28 
 
 
Protocol Number: 
G1T28-03 
 
 
Phase: 
Phase 1b/2a   
 
 
Analysis Plan Version 
Version 1.0 
 
 
Version Date 
05 December 2018 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03              
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
 
CONFIDENTIAL 
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APPROVAL SIGNATURES 
 
 
 
AUTHOR: 
  
 
 
 
 
 
 
 
____________________________________________________ 
 
Signature                                                                           Date 
 
Zack Scott, MS 
Manager, Biostatistics 
Pharpoint Research 
 
 
APPROVED BY: 
 
 
 
 
 
 
 
 
 
 
 
 
Signature                                                                           Date 
 
Zhao (Tony) Yang, PhD 
Associate Director of Biostatistics  
G1 Therapeutics Inc 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________ 
 
Signature                                                                           Date 
 
Shannon Morris, M.D. PhD 
VP, Clinical Development 
G1 Therapeutics Inc 
05-Dec-2018 | 09:42 AM E
05-Dec-2018 | 09:45 AM
05-Dec-2018 | 10:11 AM ES


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Clinical Study Protocol G1T28-03              
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................9 
2. 
STUDY DETAILS .....................................................................................................10 
2.1. 
Study Objectives .........................................................................................................10 
2.2. 
Study Design ...............................................................................................................11 
2.3. 
Number of Patients .....................................................................................................21 
3. 
ANALYSIS SETS ......................................................................................................22 
3.1. 
Definition of Analysis Sets .........................................................................................22 
3.1.1. 
Intent-to-Treat Analysis Set ........................................................................................22 
3.1.2. 
Modified ITT Analysis Set .........................................................................................22 
3.1.3. 
Safety Analysis Set .....................................................................................................22 
3.1.4. 
Per Protocol (PP) Analysis Set ...................................................................................22 
3.1.5. 
Response Evaluable Analysis Set ...............................................................................22 
3.2. 
Protocol Deviations ....................................................................................................23 
4. 
PROSPECTIVELY DEFINED ANALYSES .............................................................24 
5. 
PRIMARY AND SECONDARY ENDPOINTS ........................................................25 
5.1. 
Efficacy endpoints ......................................................................................................25 
5.1.1. 
Primary Endpoints ......................................................................................................25 
5.1.1.1. 
Occurrence of Severe (Grade 4) Neutropenia ............................................................25 
5.1.1.2. 
Duration of Severe (Grade 4) Neutropenia (DSN) .....................................................26 
5.1.2. 
Key Secondary Endpoints ...........................................................................................28 
5.1.2.1. 
Occurrence of RBC Transfusions ...............................................................................28 
5.1.2.2. 
Occurrence of GCSF Administrations ........................................................................29 
5.1.2.3. 
Occurrence of Platelet Transfusions ...........................................................................29 
5.1.2.4. 
Occurrence of All-Cause Dose Reductions ................................................................29 
5.1.2.5. 
Overall Survival ..........................................................................................................29 
5.1.3. 
Supportive Secondary Efficacy Endpoints .................................................................30 
5.1.3.1. 
Total Number of Major Adverse Hematologic Event (MAHE) .................................30 
5.1.3.2. 
Best Overall Response, Duration of Response, and Progression-Free 
Survival .......................................................................................................................31 
5.1.3.3. 
Occurrence of Grade 3 and 4 Hematologic toxicities .................................................37 


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5.1.3.4. 
ANC Nadir by Cycle ..................................................................................................37 
5.1.3.5. 
ANC, Platelet Count, Absolute Lymphocyte Counts (ALC), and 
Hemoglobin Change over Time ..................................................................................38 
5.1.3.6. 
Occurrence of Erythropoietin Stimulating Agent (ESA) Administrations .................38 
5.1.3.7. 
Occurrence of IV Antibiotic Uses ..............................................................................38 
5.1.3.8. 
Occurrence of Infection Serious Adverse Events (SAEs) ..........................................38 
5.1.3.9. 
Occurrence of Pulmonary Infection SAEs .................................................................39 
5.1.3.10. 
Occurrence of Febrile Neutropenia ............................................................................39 
5.1.3.11. 
Occurrence of Grade 4 and Grade 3/4 Thrombocytopenia .........................................40 
5.1.3.12. 
Myelosuppression Endpoints with All data up to End of Cycle 4 ..............................40 
5.1.4. 
Exploratory Efficacy Endpoints .................................................................................41 
5.1.4.1. 
FACT-L and FACT-An ..............................................................................................41 
5.1.4.2. 
Grade 2 or Greater Nephrotoxicity .............................................................................41 
5.1.4.3. 
Occurrence of Alopecia and Mucositis .......................................................................41 
5.1.4.4. 
Neutrophil-lymphocyte Ratio (NLR) and Platelet-lymphocyte Ratio (PLR) .............41 
5.2. 
Safety Endpoints .........................................................................................................41 
5.2.1. 
Chemotherapy Exposure Endpoints ...........................................................................41 
5.2.1.1. 
Duration of Exposure ..................................................................................................41 
5.2.1.2. 
Number of Cycles Received .......................................................................................42 
5.2.1.3. 
Dose Intensity and Cumulative Dose .........................................................................42 
5.2.1.4. 
Modifications of Study Therapy, Including Cycle (Dose) Delay, Missed 
Doses, Dose Interruptions, and Dose Reductions .......................................................43 
5.2.2. 
Adverse Events ...........................................................................................................43 
5.2.3. 
Vital Signs ..................................................................................................................45 
5.2.4. 
Laboratory ...................................................................................................................45 
5.2.5. 
Electrocardiograms .....................................................................................................46 
5.2.6. 
Physical Examination .................................................................................................47 
6. 
ANALYSIS METHODS ............................................................................................48 
6.1. 
General Principles of Analysis ...................................................................................48 
6.1.1. 
General Methodology .................................................................................................48 
6.1.2. 
Handling of Missing Data ...........................................................................................49 
6.1.3. 
Visit Windowing .........................................................................................................49 


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6.1.4. 
Adjustment for Covariates ..........................................................................................51 
6.2. 
Analysis Methods .......................................................................................................51 
6.2.1. 
Patient Disposition ......................................................................................................51 
6.2.2. 
Demographic and Other Baseline Characteristics ......................................................51 
6.2.3. 
Disease Characteristics ...............................................................................................51 
6.2.4. 
Medical History ..........................................................................................................52 
6.2.5. 
Concomitant Medications ...........................................................................................52 
6.2.6. 
Prior and Subsequent Anti-cancer Therapy ................................................................53 
6.2.7. 
Efficacy Analyses .......................................................................................................53 
6.2.7.1. 
Primary and Key Secondary Efficacy Analyses .........................................................54 
6.2.7.2. 
Supportive Efficacy Analyses .....................................................................................61 
6.2.7.3. 
Exploratory Efficacy Analyses ...................................................................................64 
6.2.8. 
Safety Analyses ..........................................................................................................64 
6.2.8.1. 
Chemotherapy Exposure and Compliance Analyses ..................................................64 
6.2.8.2. 
Adverse Events ...........................................................................................................65 
6.2.8.3. 
Laboratory Evaluations ...............................................................................................65 
6.2.8.4. 
Vital Signs ..................................................................................................................65 
6.2.8.5. 
Performance Status .....................................................................................................66 
6.2.8.6. 
Physical Examination .................................................................................................66 
6.2.8.7. 
ECG ............................................................................................................................66 
6.2.9. 
Subgroup Analyses .....................................................................................................66 
6.2.10. 
Pharmacokinetic Analysis ..........................................................................................66 
6.2.11. 
Assess Genetic and/or Expression (RNA/Protein) Biomarkers in Tumors and 
Blood ...........................................................................................................................66 
6.2.12. 
Planned Analysis ........................................................................................................67 
7. 
CHANGE FROM THE PROTOCOL ........................................................................68 
8. 
REFERENCES ...........................................................................................................70 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event 
ALC 
Absolute Lymphocyte Count 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ANCOVA 
Analysis of Covariance 
aRR 
Adjusted Rate Ratio 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under Curve 
β-HCG 
Beta Human Chorionic Gonadotropin  
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BPM 
Beats Per Minute 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CBR 
Clinical Benefit Rate 
CDK 
Cyclin Dependent Kinase 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CSR  
Clinical Study Report 
CT 
Computed Tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
DLT 
Dose-Limiting Toxicity 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
DOR 
Duration of Response 
DSN 
Duration of Severe Neutropenia 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic Case Report Form 
EOI 
End of Infusion 
ESA 
Erythropoietin Stimulating Agent 
FACT 
Functional Assessment of Cancer Therapy 
FACT-AN 
Functional Assessment of Cancer Therapy –Anemia  
FACT-L 
Functional Assessment of Cancer Therapy –Lung  
G1T28 
Trilaciclib 
GCSF 
Granulocyte Colony-Stimulating Factor 


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Abbreviation 
Term 
HGB 
Hemoglobin 
HR 
Hazard Ratio 
ICH 
International Conference on Harmonization 
ITT 
Intent-to-Treat 
IV 
Intravenous 
LD 
Longest Diameter 
LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal Range 
MAHE 
Major Adverse Hematologic Event 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MRI 
Magnetic Resonance Imaging 
Nadir 
The Lowest Point 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NLR 
Neutrophil-Lymphocyte Ratio 
NTL 
Non-Target Lesion 
OC 
Observed Case 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic  
PLR 
Platelet-Lymphocyte Ratio 
PP 
Per Protocol 
PR 
Partial Response 
PRO 
Patient-Reported Outcome 
PT 
Preferred Term 
QOL 
Quality of Life 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumors  
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SCLC 
Small Cell Lung Cancer 
SD 
Stable Disease 
SMC 
Safety Monitoring Committee 
SVN 
Severe Neutropenia 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent AE 
TL 
Target Lesion 
TLFs 
Tables, Listings, and Figures 


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Abbreviation 
Term 
TPR 
Time Point Response 
ULN 
Upper Limit of Normal Range 
WBC 
White Blood Cell 
WHO-DD 
World Health Organization Drug Dictionary 
 


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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the analyses to be performed for 
Study G1T28-03, Phase 1b/2a Study of the Safety, Efficacy, and Pharmacokinetics of trilaciclib 
in Patients with Previously Treated Extensive-Stage Small Cell Lung Cancer (SCLC) Receiving 
Topotecan Chemotherapy.  The SAP is based on the G1T28-03 Protocol Version 6, dated 27 
June 2018.   
Study measurements and assessments, planned statistical methods, and derived variables are 
summarized in this plan.  Planned tables, figures, and listings are specified.  All decisions 
regarding final analyses, as defined in this SAP document, have been made prior to locking the 
database. Any deviations from these guidelines will be documented in the clinical study report 
(CSR).  
The myelosuppression efficacy endpoints and statistical analysis methods described in this SAP 
are reflective of scientific advice obtained in both the US and EU for evaluation of trilaciclib for 
the reduction of chemotherapy-induced myelosuppression.  
Although G1T28-03 does not explicitly state that the trial has been designed to evaluate the 
effects of trilaciclib on chemotherapy-induced myelosuppression, the endpoints of AEs and 
laboratory values used to evaluate safety and tolerability are the same endpoints used to evaluate 
effects on chemotherapy-induced myelosuppression. The data collected for this trial was 
appropriate for the analysis of these myelosuppression endpoints, and the defined endpoints in 
this SAP are consistent with the overall strategy/rationale for Study G1T28-03. 


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2. 
STUDY DETAILS 
2.1. 
Study Objectives 
The primary, secondary, and exploratory objectives of this study are presented in Table 1. 
Table 1 
G1T28-03: Study Objectives 
 
Part 1  
(Phase 1b) 
Parts 2A 
and 2B  
(Phase 2a) 
Primary Objectives 
Assess the DLTs and define the Phase 2 dose of trilaciclib 
administered with topotecan 
X 
 
Assess the safety and tolerability of trilaciclib administered with 
topotecan 
X  
X 
Secondary Objectives 
Assess the PK profile of trilaciclib 
X 
Xa 
Assess the PK profile of topotecan when administered with 
trilaciclib 
X 
Xa 
Assess the hematologic profile (kinetics and 
incidence/duration/frequency of toxicities) of trilaciclib 
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 
Exploratory Objectives 
Assess the incidence of mucositis 
X 
X 
Assess the incidence of alopecia 
X 
X 
Assess the incidence of fatigue 
X 
X 
Assess patient-reported QOL 
X 
X 


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Assess immunologic markers 
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 
  
2.2. 
Study Design 
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 1b/2a study of the 
safety, efficacy, and PK of trilaciclib 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, placebo-controlled 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 
pharmacokinetics (PK) of trilaciclib administered at an initial dose of 200 mg/m2 once daily in 
combination with topotecan on Days 1 to 5 of each 21-day chemotherapy cycle (Figure 1). DLTs 
are defined in Protocol section 6.1.1.1. 
Figure 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  
trilaciclib + 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  
trilaciclib 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 
(topotecan or trilaciclib/placebo). 
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. 


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Trilaciclib Dose Evaluation  
Six patients will initially be enrolled in Part 1 and will receive an initial dose of trilaciclib 
200 mg/m2 in combination with standard topotecan therapy. 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. Trilaciclib dose evaluation criteria are listed below and are presented as a decision tree 
in Figure 2.  
• If there is ≤ 1 DLT in the first cohort of 6 patients during Cycle 1 of Part 1 and the 
trilaciclib PK parameters are as predicted (Protocol 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 trilaciclib 
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 
trilaciclib PK parameters suggest that the trilaciclib dose needs to be escalated or 
de-escalated (see Protocol Section 6.1.1.2), a second cohort of 6 patients will be enrolled 
at the higher or lower predicted trilaciclib dose in combination with topotecan. For 
assessment of data from the second cohort enrolled in Part 1, please see the decision tree 
in Figure 2. 
• If there is > 1 DLT in the first cohort of 6 patients during Cycle 1 of Part 1 and the 
trilaciclib PK parameters suggest that the trilaciclib dose needs to be escalated or 
de-escalated (see Protocol Section 6.1.1.2), a second cohort of 6 patients will be enrolled 
at the modified trilaciclib dose in combination with topotecan. For assessment of data 
from the second cohort enrolled in Part 1, please see the decision tree in Figure 2. 
• If there is > 1 DLT in the first cohort of 6 patients enrolled in Part 1 and the trilaciclib PK 
parameters from these 6 patients are as predicted (Protocol Section 6.1.1.2), the dose of 
trilaciclib should be decreased to 160 mg/m2 and an additional 6 patients should be 
enrolled at the modified trilaciclib dose in combination with topotecan. For assessment of 
data from the second cohort enrolled in Part 1, please see the decision tree in Figure 2.  
• If there is > 1 DLT following a trilaciclib dose of 160 mg/m2 in combination with 
topotecan and the PK parameters from these 6 patients are as predicted (Protocol Section 
6.1.1.2), an additional cohort of 6 patients will be enrolled at a further decreased 
trilaciclib 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 2. 
• If there is > 1 DLT following the second dose reduction of trilaciclib and the PK 
parameters from these 6 patients are as predicted (Protocol 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 safety monitoring committee (SMC) review and 
recommendations for either continued enrollment or permanent closure of the cohort 


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Figure 2 
Trilaciclib Dose Evaluation 
 
 
a      Assess the adjusted trilaciclib dose in the next cohort of 6 patients based on DLTs and PK per the decision tree 
b 
Maximum of 2 trilaciclib 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 SMC composed of the sponsor, medical monitor, and the principal 
investigator(s) to determine the next dose level. If the trilaciclib and/or topotecan dose level for a 
subsequent cohort is adjusted by the SMC, the SMC may also recommend that all patients 
currently receiving trilaciclib in combination with topotecan should have their trilaciclib 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 trilaciclib and topotecan 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. There will be no 
intrapatient dose modifications of trilaciclib in Parts 2A and 2B of the study. 
Each patient will be evaluated for toxicity during each cycle. The toxicity of IV trilaciclib 
administered with topotecan will be assessed by the investigators using National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. 
Topotecan Dose Evaluation 
Since trilaciclib has been shown to inhibit renal transporters for which topotecan is a substrate, 
there is a potential for increasing topotecan exposure when administered after trilaciclib. 
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 trilaciclib and topotecan 
will be assessed on Days 1 and 4 of the first cycle.    
Since myelosuppression is the major toxicity of topotecan and trilaciclib is being developed to 
reduce myelosuppression following cytotoxic chemotherapy, complete blood count (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.   


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Clinical Study Protocol G1T28-03              
Statistical Analysis Plan for Region 2  
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Part 2A 
In Part 2A, eligible patients will be randomized (2:1) to receive trilaciclib or placebo 
administered IV once daily with topotecan on Days 1 to 5 of each 21-day chemotherapy cycle 
(Figure 3). In Arm 1, patients will receive the trilaciclib (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 or 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 trilaciclib in Parts 2A of the study. 
Figure 3 
Study Schema: Part 2A 
 
a  
Trilaciclib 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 
Trilaciclib 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 
(topotecan or trilaciclib/placebo). 
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. 
 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03              
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
 
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Part 2B 
Unblinded topotecan PK data in Part 2A suggested differences in the topotecan exposures in 
Arm 1 compared to Arm 2, with the differences being attributed to use of less accurate historical 
controls for topotecan.  In order to accurately assess the impact of trilaciclib on the safety and 
efficacy of topotecan, it is critical that topotecan exposures are similar in the trilaciclib and 
placebo arms.  Therefore, an additional arm of trilaciclib 240 mg/m2 + topotecan 1.5 mg/m2 will 
be investigated in Arm 1 of Part 2B in this study.  In Part 2B, eligible patients will be 
randomized (2:1) to receive trilaciclib or placebo administered IV once daily with topotecan on 
Days 1 to 5 of each 21-day chemotherapy cycle (Figure 4). In Arm 1, patients will receive 
trilaciclib (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 Part 2A, randomization for Part 2B will also be stratified on the basis of 
ECOG performance status (0 or 1 versus 2) and sensitivity to first-line treatment (sensitive: 
CR/PR/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 trilaciclib in Part 2B of the study. 
Figure 4 
Study Schema: Part 2B 
 
a  
Trilaciclib 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 
Trilaciclib 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 
(topotecan or trilaciclib/placebo). 
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 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03              
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
 
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      Page 16 of 73 
 
                                                 
 
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. 
Criteria for Subsequent Cycles and Study Duration 
In both parts of the study, study drug (topotecan or trilaciclib/placebo) 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, 
whichever occurs first. Treatment cycles will occur consecutively without interruption, except 
when necessary to manage toxicities or for administrative reasons as described below.   
In order to start Cycle 2 and subsequent cycles as scheduled, patients should meet all of the 
following criteria: 
• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L  
• Platelet count ≥ 100 × 109/L 
• Nonhematologic drug-related toxicities (except alopecia) must be ≤ Grade 1 or have 
returned to baseline 
A delay of up to 2 weeks is permitted to allow recovery from any toxicity in order to meet the 
continuation criteria for organ function. If patients meet the criteria for starting the subsequent 
cycle as described above, a delay of up to 1 week is permitted for administrative reasons (eg, 
holiday, vacation, etc.). If the subsequent cycle is delayed, the patient should still complete the 
clinical laboratory assessments and the FACT-L and FACT-An questionnaires on the scheduled 
Day 1, as well as on the actual first dosing day of the next cycle. A patient will be discontinued 
from the study if recovery from any toxicity, in order to meet the continuation criteria for organ 
function, and any delay for administrative reasons requires a total delay of > 2 weeks.  
After discontinuation of study drug (topotecan or trilaciclib/placebo), 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 patient-reported outcome (PRO) scales, CBC 
assessment on Day 22, the Post-Treatment Visit, and the Survival Follow-up Phase of the study.  
The G1T28-03 study will be completed when the Survival Follow-up Phase has been completed, 
or upon sponsor termination of the study. The total study duration is at least 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 trilaciclib 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. 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03              
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
 
CONFIDENTIAL 
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The Survival Follow-up Phase of the study will continue until at least 50% of the patients in 
Parts 2A and 2B have died. The study scheduled assessments are presented below: 
 
 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
 
CONFIDENTIAL 
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Table 2 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trilaciclib or 
placeboo 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
 
CONFIDENTIAL 
      Page 19 of 73 
 
                                                 
 
  
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  
 
Topotecan 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
FACT-L 
and 
FACT-Anp 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
AEsq 
X 
X 
 
Prior and Con. 
Medications 
X 
X 
 
Survival 
Follow-upc 
 
 
X 
AE = adverse event; ECG = electrocardiogram; FACT-AN = Functional Assessment of Cancer Therapy – Anemia quality of life instrument; FACT-L = Functional Assessment of Cancer Therapy –
Lung quality of life instrument; PRO = patient reported outcome; Eval. = evaluation; PK = pharmacokinetic 
a 
Trilaciclib + 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 (topotecan or trilaciclib/placebo).  
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 (topotecan or trilaciclib/placebo) 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 (topotecan or 
trilaciclib/placebo), weight loss in the 6 months prior to the first dose of study drug (topotecan or trilaciclib/placebo) (≤ 5% or > 5%), and medications taken within 14 days prior to the first dose 
of study drug (topotecan or trilaciclib/placebo). 
f 
Height will only be measured at the screening visit. Body surface area calculation (based on actual body weight taken prior to study drug (topotecan or trilaciclib/placebo) administration) will be 
completed on Day 1 of each cycle and vital signs obtained immediately before and after trilaciclib 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 Protocol 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 trilaciclib + topotecan. 
h 
Hematology will be obtained (hemoglobin, hematocrit, white blood cells (WBCs) with differential, and platelet counts); see Protocol Section 11.3.2.  Hematology may be obtained up to 24 hours 
prior to first dose of each cycle of trilaciclib + topotecan.  


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
 
CONFIDENTIAL 
      Page 20 of 73 
 
                                                 
 
i 
For patients who choose to participate in the optional immunophenotyping portion of the study, peripheral blood will be collected at predose on Day 1 and Day 15 of each cycle; Day 22 of the 
last cycle; and at the Post-Treatment Visit. Immunophenotyping samples may be obtained up to 24 hours prior to first dose of each cycle of trilaciclib + topotecan. 
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 trilaciclib), 1 hour 
(± 10 minutes), and 6.5 hours (± 15 minutes) after start of trilaciclib 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 trilaciclib), 1 hour (± 10 minutes), and between 3.5 to 6.5 hours (± 15 minutes) after start of trilaciclib infusion. 
k 
For female patients of childbearing potential, serum ß-hCG at screening; serum or urine ß-hCG, obtained up to 72 hours prior to each dose of trilaciclib + topotecan chemotherapy in each cycle 
l 
For tumor assessment, all sites of disease (including brain metastases, if present at screening) should be assessed radiologically by CT or MRI at screening and after every even cycle, until the 
occurrence of disease progression. Additional scans may be obtained at the discretion of the investigator, if clinically indicated. If a patient shows a radiological response (CR or PR), a 
confirmatory radiological assessment will be performed at least 4 weeks after the response was first noted. Assessments may be performed within 7 days of starting the subsequent cycle. The 
same method of assessment (CT or MRI) should be used to characterize tumors at screening and at all follow-up assessments. If PET is used, it should also be accompanied by spiral CT or MRI.  
 
l1: At the Post-Treatment Visit, obtain tumor assessment for patients who have not progressed at the time of study drug (topotecan or trilaciclib/placebo) discontinuation (may be performed 
within 4 weeks of treatment discontinuation). For those patients in the survival follow-up who have not progressed at the time of study drug (topotecan or trilaciclib/placebo) 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. 
 
l2: Brain scans with contrast (by CT or MRI) to be obtained with tumor assessment at screening (within 28 days of dosing). 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 (topotecan or trilaciclib/placebo) discontinuation (may be performed within 4 
weeks of treatment discontinuation). For those with brain metastases, brain scans should be done with each tumor assessment.  
m 
Send archived tumor samples to a central pathology laboratory to confirm the diagnosis of SCLC. Available tissue after confirming the diagnosis of SCLC will be banked for assessment of 
relevant DNA, RNA, and protein markers, such as those involved in the CDK4/6 pathway. If central pathology review does not confirm SCLC diagnosis, the patient may be withdrawn from the 
study after consultation between the principal investigator, medical monitor, and sponsor. This should be done as soon as possible after a patient has enrolled in the study. 
n 
Patients enrolled in Part 1 will have trilaciclib and topotecan PK samples collected on Days 1 and 4 (as applicable) of Cycle 1 at the time points specified in Protocol Section 11.3.2. In addition, 
limited PK samples will be collected on Cycle 1 Day 4 in Parts 2A and 2B of the study for trilaciclib population PK analysis. Blood samples will be collected in Parts 2A and 2B of the study at 
the time points specified in Protocol Section 11.3.2. 
o 
Trilaciclib or placebo will be administered as an IV infusion in 250 mL of D5W or sodium chloride solution 0.9% over 30 (± 5) minutes prior to topotecan chemotherapy on Days 1 to 5 of every 
cycle (see Protocol Section 11.3.2). If there is any study drug (topotecan or trilaciclib/placebo) remaining in the trilaciclib 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 interval between doses of trilaciclib on successive days should 
not be greater than 28 hours. The interval between the dose of trilaciclib and the dose of topotecan on a given day should not be greater than 4 hours. Trilaciclib will only be administered with 
topotecan. If administration of topotecan is discontinued, trilaciclib should also be discontinued. Chemotherapy cannot be administered until after completion of the trilaciclib infusion. If the 
second, third, fourth, or fifth dose of trilaciclib in any given cycle is not administered for any reason, do not administer the dose of topotecan on that day (see Protocol Section 11.3.2). After 
discontinuation of study drug (topotecan or trilaciclib/placebo), patients should be strongly encouraged to complete all scheduled assessments through the end of their current 21-day treatment 
cycle, including the patient-reported PRO (scales), CBC assessment on Day 22, the Post-Treatment Visit, and the Survival Follow-up Phase of the study. 
p 
Patient-reported outcomes should be completed at Days 1 and 10 of each cycle and at the Post-Treatment Visit. If a cycle is delayed, the patient should still complete the PRO on the scheduled 
Day 1 of the next cycle, as well as the actual first dosing day of the next cycle of trilaciclib + topotecan. Patient-reported outcomes may be obtained up to 24 hours prior to the first dose of each 
cycle of trilaciclib + topotecan.  
q 
Adverse events will be recorded from the time of informed consent. All AEs should be reported within 30 days of the last dose of study drug (topotecan or trilaciclib/placebo), and followed until 
they are resolved, have returned to baseline, or it is deemed that further recovery is unlikely. 
r 
For patients enrolled in Parts 2A and 2B, randomization is to be done within 3 days prior to the first dose of trilaciclib or placebo + topotecan, following confirmation that the patient is eligible 
for the study. 
s 
Patients with an ANC < 0.5 × 109/L on Day 15 shall be followed (eg, every 24 to72 hours) for recovery (to ensure that duration of ANC < 0.5 × 109/L does not exceed 7 days).


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
CONFIDENTIAL 
      Page 21 of 73 
 
                                                 
 
2.3. 
Number of Patients 
Overall, approximately 130 patients will be enrolled in the study. In Part 1, approximately 40 
patients will be enrolled, assuming 9-10 cohorts. Part 1 is open label and no randomization or 
blinding will be required. In Part 2A, approximately 45 patients will be enrolled and randomly 
assigned (2:1) to Arm 1 (trilaciclib (240 mg/m2) + topotecan (0.75 mg/m2)) or Arm 2 (placebo+ 
topotecan (1.5 mg/m2)). In Part 2B, approximately 45 patients will be enrolled and randomly 
assigned (2:1) to Arm 1 (trilaciclib (240 mg/mg2) + topotecan (1.5 mg/m2)) or Arm 2 (placebo + 
topotecan (1.5 mg/m2)).   
The sample size is not determined from a statistical perspective, but rather is based on clinical 
feasibility. Subjects who receive placebo in Part 2A and Part 2B will be combined into a single 
placebo group for the analysis. Thus, approximately 90 patients will be enrolled into Part 2 of the 
study (30 per treatment group). 
With the changes to the protocol detailed in this SAP, the sample size calculation is now based 
on demonstrating the superiority of trilaciclib (240 mg/m2) + topotecan (1.5 mg/m2) vs. placebo+ 
topotecan with respect to at least one of the primary endpoints. 
With the changes, the overall type I error rate is now 0.10 (1-sided) and the type II error rate 
used to compute sample size is 0.10 (corresponding to 90% power).  
To maintain the overall type I error rate, by using the most conservative Bonferroni procedure 
for the 2 primary endpoints, a 1-sided individualized type I error rate 0.10/2=.05 is assigned to 
each outcome variable in the sample size calculation. Assuming a common standard deviation of 
2.5, a true difference in the duration of severe (Grade 4) neutropenia in Cycle 1 of at least 2 days 
between the trilaciclib (240 mg/m2) + topotecan (1.5 mg/m2) group and the placebo+ topotecan 
group requires, 56 evaluable patients (28 per treatment arm in the trilaciclib (240 mg/m2) + 
topotecan (1.5 mg/m2) group and the placebo + topotecan group). This implies that 90 patients 
need to be randomized for all 3 groups assuming a 95% evaluability rate. For occurrence 
endpoints (occurrence of severe (Grade 4) neutropenia, assuming its proportion of 45% for 
placebo + topotecan group, testing for an absolute reduction of 37% to 8% with the trilaciclib 
(240 mg/m2) + topotecan (1.5 mg/m2) group would require a sample size of at least 56 patients 
(29 per treatment arm in the trilaciclib (240 mg/m2) + topotecan (1.5 mg/m2) group and the 
placebo + topotecan group). Assuming a 95% evaluability rate, at least 90 patients for Part 2 of 
the study need to be randomized for all 3 groups to complete the study. Therefore, the final 
adjusted sample size is 90 for Part 2 of the study to account for the evaluation of 2 primary 
endpoints. All calculations were carried out using the POWER procedure in SAS® version 9.4. 
The study will be conducted at up to 60 centers in North America and Europe. 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
CONFIDENTIAL 
      Page 22 of 73 
 
                                                 
 
3. 
ANALYSIS SETS 
3.1. 
Definition of Analysis Sets  
Data analyses will be based on the four analysis sets defined below. Analysis sets, including 
exclusions based on key deviations, will be reviewed and approved by G1 Therapeutics prior to 
study unblinding.  
3.1.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat analysis set (ITT) includes all randomized patients in Part 2 and all enrolled 
patients who received at least one dose of study drugs in Part 1. Analyses using the ITT will be 
conducted on the basis of the assigned treatment. The ITT is the primary analysis set for all 
efficacy analysis. 
3.1.2. 
Modified ITT Analysis Set 
The modified ITT (mITT) analysis set is a subset of the ITT analysis set and will only include 
the ITT patients who received at least 1 dose of study drug (topotecan or trilaciclib/placebo). 
Supportive sensitivity analyses will be conducted on the mITT analysis set for primary and key 
secondary efficacy endpoints to evaluate the robustness of the results. Analyses using the mITT 
will be conducted on the basis of the assigned treatment. 
3.1.3. 
Safety Analysis Set 
The safety analysis set includes all enrolled patients who received at least 1 dose of study drug 
(topotecan or trilaciclib/placebo). Analyses using the safety analysis set will be conducted on the 
basis of the actual treatment received. All safety analyses will be assessed using the safety 
population.  
3.1.4. 
Per Protocol (PP) Analysis Set 
The per-protocol (PP) analysis set is a subset of the mITT analysis set. The criteria for inclusion 
in the PP analysis set will be based on study drug (topotecan or trilaciclib/placebo) 
administration and key protocol deviations; the list of patients to be included in this analysis set 
will be finalized and documented prior to unblinding patients in Parts 2 of the study. 
It will include only those patients who have no exclusionary protocol deviations (as described in 
Section 3.2) and who received the treatment to which they were randomized or assigned. For any 
patients who received the wrong treatment during any part of the study, their data will be 
excluded from the PP analysis set. The PP analysis set may be used to analyze selected endpoints 
to test the robustness of results.  
3.1.5. 
Response Evaluable Analysis Set 
The Response Evaluable Analysis Set will include all patients who are in the mITT, have 
measurable disease (target lesions) at the baseline tumor assessment, and either (i) have at least 1 
post-baseline tumor assessment, (ii) have clinical progression as noted by the investigator before 
their first post-baseline tumor scan, or (iii) have died due to disease progression before their first 
post-baseline tumor scan. The response evaluable analysis set will be used for sensitivity 
analyses of tumor response.   


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
CONFIDENTIAL 
      Page 23 of 73 
 
                                                 
 
3.2. 
Protocol Deviations  
Certain protocol deviations are designated as key in that they may affect the ability to assess the 
safety and efficacy of study drug (topotecan or trilaciclib/placebo). All key protocol deviations 
will be reviewed in a data review meeting to discuss the potential impact on the statistical 
analysis and classify each key deviation as exclusionary or non-exclusionary. This will be 
documented in a note to file prior to database lock and Part 2 unblinding. 
Patients with key deviations determined to impact the analysis will be excluded from the PP 
analysis set. All patients who meet the definition of the ITT/mITT analysis sets will be included 
in the ITT/mITT analysis sets regardless of these deviations. 
If a patient is randomized or assigned to a treatment group, but fails to receive treatment, the 
reason for not receiving treatment will be noted in the CSR. Any such patients who are not 
treated will be excluded from the mITT, safety, response evaluable, and PP analysis sets but will 
be included in the ITT (for Part 2) and in the patient listings for the CSR.   
If the wrong treatment is administered to a patient, and the reason for the incorrect treatment is 
documented, this will be noted in the CSR and the patient’s data included in the Safety Analysis 
Set based on the actual treatment received. 


 
 
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Clinical Study Protocol G1T28-03                                       
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4. 
PROSPECTIVELY DEFINED ANALYSES  
As outlined in the protocol, trilaciclib is an IV Cyclin Dependent Kinase (CDK) 4/6 inhibitor 
being evaluated for its ability to decrease chemotherapy-induced myelosuppression when 
administered in combination with cytotoxic chemotherapy.  Unlike granulocyte-colony 
stimulating factor (GCSF), which stimulates production of neutrophils, and transfusions, which 
only replace red blood cell (RBC) or platelets, trilaciclib is hypothesized to facilitate 
myelopreservation of all hematopoietic lineages including neutrophils, RBC, platelets, 
lymphocytes, etc.  
To capture these two aspects of trilaciclib benefit, the following analyses are prospectively 
proposed in Table 3 and their associated endpoint derivation and analysis methods will be 
detailed in Sections 5.1.1 and 6.2.7.1 with the multiplicity adjustments described in Section 
5.1.1.  
Table 3 
Prospectively Defined Analyses 
Occurrence (proportion of patients) of severe (Grade 4) neutropenia 
Duration of severe (Grade 4) neutropenia in Cycle 1 
Occurrence (proportion of patients) of RBC transfusions on/after 5 weeks 
Occurrence (proportion of patients) of GCSF administration 
Occurrence (proportion of patients) of Platelet transfusion 
Cumulative incidence of major adverse hematologic events (MAHE) which is defined to 
include components as the following: 
• All-cause hospitalizations 
• All-cause dose reductions 
• Febrile neutropenia 
• RBC transfusion on/after 5 weeks 
• Prolonged severe (Grade 4) neutropenia (duration > 5 days) 
• Platelet transfusion 
All-cause hospitalizations in the MAHE composite 
All-cause dose reductions in the MAHE composite 
Febrile neutropenia in the MAHE composite 
RBC transfusions on/after 5 weeks in the MAHE composite 
Prolonged severe (Grade 4) neutropenia in the MAHE composite 
Platelet transfusions in the MAHE composite 
RBC = Red Blood Cell; GCSF = granulocyte-colony stimulating factor; 
 


 
 
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5. 
PRIMARY AND SECONDARY ENDPOINTS  
The following general definitions will be applied to all endpoint derivations unless otherwise 
specified. 
Term 
Definition 
Severe Neutropenia 
(SVN) 
ANC lab value that meets the common terminology criteria for 
adverse events (CTCAE) criteria for ≥ Grade 4 toxicity 
Cycle baseline 
The last non-missing value within the window starting from 3 days 
prior to the date/time of study drug (topotecan or trilaciclib/placebo) 
administration on Day 1 of Cycle 1 and 1 day prior to Day 1 of each 
subsequent cycle (i.e. Cycle 2, Cycle 3, etc.); must be prior to the 
time of study drug (topotecan or trilaciclib/placebo) administration 
Cycle nadir 
The lowest value for a given hematologic parameter that occurs 
between start of cycle and end of cycle and is less than the cycle 
baseline. 
Duration of cycle 
Total number of days from start of cycle to end of cycle, that is, date 
of end of a cycle - date of start of cycle + 1. 
End of cycle* 
Day 1 of the subsequent cycle.  For example, the end of cycle for 
Cycle 1 is Day 1 of Cycle 2. For the last cycle (where no subsequent 
cycle is given), the end of cycle will be defined as Day 38 after the 
first dose of the cycle.  
Start of cycle 
Day 1 of each cycle starts with the administration of study drug(s) 
(topotecan or trilaciclib/placebo) 
Start of study 
Date of enrollment in Part 1 or Date of randomization in Part 2 
Study baseline 
The last non-missing value prior to, or on the date of administration 
of study drug(s) (topotecan or trilaciclib/placebo); must be prior to 
the time of study drug administration 
Change from baseline 
Calculated as the post-baseline value minus the baseline value. If the 
baseline value is missing for a particular endpoint, change from 
baseline will be missing. 
Treatment period 
Total number of days from start of cycle for Cycle 1 and end of 
cycle for the last cycle 
* For various hematologic parameter analyses, the last assessment prior to end of cycle will 
be utilized in the analyses. Situations where this applies will be indicated as such. 
5.1. 
Efficacy endpoints 
5.1.1. 
Primary Endpoints  
5.1.1.1. 
Occurrence of Severe (Grade 4) Neutropenia 
For the treatment period, the total number of SVN events is the number of cycles where at least 
one ANC value is < 0.5 x 109/L.  For example, if Cycle 2 has two ANC values that are both < 0.5 
x 109/L, this only counts as one event. If a patient did not have any SVN events, the value of 0 
will be assigned to that patient. The number of cycles without SVN is calculated as the total 


 
 
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number of cycles received – total number of cycles with SVN. Unscheduled data and the actual 
assessment date (rather than visit date) will be included in the derivation.  
Therefore, any occurrence of an SVN during a cycle or the treatment period is defined as a 
binary variable (Yes or No); Yes, if total number of cycles with SVN ≥ 1 is observed, No for 
other scenarios.    
5.1.1.2. 
Duration of Severe (Grade 4) Neutropenia (DSN)  
There will be three different strategies for assessing DSN in each cycle. All strategies will be 
applied to derive the DSN, with strategy 1 considered as the primary, and strategy 2 and strategy 
3 being supportive sensitivity analyses. The DSN in Cycle 1 is considered the primary endpoint. 
Any unscheduled data and the actual assessment date (rather than visit date) will be included in 
the derivation of each strategy.  
5.1.1.2.1. 
Strategy 1: Without Imputation of Missing ANC Values 
Within each cycle, the DSN (days) is defined as the number of days from the date of first ANC 
value of <0.5×109/L observed between start of cycle and end of cycle, to the date of first ANC 
value ≥ 0.5×109/L that meets the following criteria: (1) occurs after the ANC value of 
<0.5×109/L and (2) no other ANC values <0.5×109/L occur between this day and end of cycle. 
DSN is set to 0 in patients who did not experience SVN in a cycle. Any unscheduled data and the 
actual assessment date (rather than visit date) will be included in the derivation. The following 
rules will be applied in the calculation:    
• For a cycle where the SVN event does not resolve by end of the cycle, DSN will be 
assigned as above except the end date will be the end of cycle.   
• For a cycle where the patient dies, during the SVN event, DSN will be assigned as above 
except the end date will be the date of death. 
• For a cycle where the patient withdraws consent or is lost to follow-up during the SVN 
event, DSN will be assigned as above except the end date will be the date of the last ANC 
assessment prior to the end of study. 
5.1.1.2.2. 
Strategy 2: Without Imputation, Censoring Unresolved SVN 
Within each cycle, DSN (days) is defined as the number of days from the date of first ANC value 
of <0.5 x 109/L observed between start of cycle and end of cycle, to the date of first ANC value ≥ 
0.5 x 109/L that meets the following criteria: (1) occurs after the ANC value of <0.5 x 109/L and 
(2) no other ANC values <0.5 x 109/L occur between this day and end of cycle. The following 
censoring rules will be applied in the calculation:   
• For a cycle where the SVN event does not resolve by end of the cycle, DSN will be 
assigned as above except the end date will be the earlier of end of cycle or date of last 
contact.   
• For a cycle where the patient dies, withdraws consent, or is lost to follow-up during the 
SVN event, DSN will be assigned as above except the end date will be the date of the last 
ANC assessment prior to the end of study.    


 
 
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For the treatment period, the overall DSN (days) is the median value among the DSN (days) 
from all cycles. The following data handling conventions will apply: 
• For those patients where all event duration values are derived from cycles with censored 
data, the median value for that patient will be the median censored value. It will be a 
considered a censored value; 
• For those patients where a subset of event duration values are derived from cycles with 
censored data, the median value for that patient will be estimated using the Kaplan-Meier 
method. It will be considered as an observed value (i.e. no censored value); 
• 
For those patients where the median event duration cannot be derived (e.g. ≤ 2 values), 
the longest event duration amongst all the cycles will be used regardless of censoring, but 
the corresponding censoring flag will be carried over for analysis. 
5.1.1.2.3. 
Strategy 3: With Imputation of Missing ANC Values 
DSN (days) in a cycle is defined as the number of consecutive days with SVN, for patients who 
experienced several episodes of SVN, the number of days for each episode will be summed up. 
DSN is set to 0 in patients who did not experience SVN in a cycle.  
To impute the missing daily ANC value, the following algorithms will be applied in the 
calculation, 
(1) Missing ANC values for Days 1-5 in each cycle will be imputed using linear interpolation, 
any recorded measurement will not be replaced. The missing values for Day 1 and Day 5 
may be potentially imputed with this algorithm. 
Figure 5 
Graphical Demonstration of Linear Interpolation  
Note: The slopes are calculated for each treatment group, where 𝑌𝑌ത1 and 𝑌𝑌ത2 are the 
mean of ANC values at relevant timepoint. For a time interval, e.g. interval of Day 
1 and Day 5 (inclusive), 𝑌𝑌ത1 is the average of the earliest point in the interval and 𝑡𝑡1 
is the average of the earliest day in the interval. Similarly, 𝑌𝑌ത2 is the average of the 
latest point in the interval and 𝑡𝑡2 is the average of the latest day in the interval.  
• If there are at least two assessments within the interval of Day 1 and Day 5 (inclusive), 
calculate the slope between the first available ANC value and last available ANC value: 


 
 
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− If the sign of slope agrees with the sign of slopes calculated from its treatment group, 
the interpolation will be conducted to appropriate schemes as demonstrated in Fig.1 (a) 
and Fig. 1(b); 
− If the sign of slope does not agree with the sign of slopes calculated from its treatment 
group, the interpolation will be done within the patient by using the calculated slope 
from the observed values. 
• If there is only one assessment within the interval of Day 1 and Day 5 (inclusive),  
− If the ANC value is < 0.5×109/L, then the subsequent missing days will be set to this 
value; 
− If ANC value is ≥ 0.5×109/L, SVN cannot be determined, and the data remains missing. 
• If there is no assessment within the interval of Day 1 and Day 5 (inclusive), SVN cannot 
be determined, and the data remains missing.  
(2) A similar algorithm as in (1) will be performed to impute missing ANC values for Days 6-10 
in each cycle using linear interpolation. Day 5 will be used as the earliest date in the 
calculations only if it is recorded; it will be interpolated in this interval. Any other recorded 
measurements will not be replaced.  
(3) Rules of imputation of missing values at Day 11 of a cycle: 
• The ANC before and after the missing day was ≥ 0.5×109/L: the day is ignored as a 
potential day of severe neutropenia. 
• If at either neighboring days the ANCs were < 0.5×109/L, and both are non-missing, then 
the missing day is set to severe neutropenia. 
• If any of the neighboring days were also missing, severe neutropenia cannot be 
determined, and the data remains missing. 
(4) A similar algorithm as in (1) will be performed to impute missing ANC values for Days 12-
15 in each cycle using linear interpolation. Any recorded measurements will not be replaced.  
(5) A similar algorithm as in (1) will be performed to impute missing ANC values between Days 
16 and end of cycle in each cycle using linear interpolation. Day 15 will be used as the 
earliest date in the calculations only if it is recorded; it will be interpolated in this interval. 
Any other recorded measurements will not be replaced.   
(6) For a cycle where the SVN event does not resolve by end of the cycle, the all values between 
the last assessment and the end of cycle are set to SVN.  
(7) For a cycle where the patient dies, during the SVN event, the end date of the SVN is the date 
of death. 
5.1.2. 
Key Secondary Endpoints 
5.1.2.1. 
Occurrence of RBC Transfusions 
Each RBC transfusion with a unique start date on/after 5 weeks on study during the treatment 
period will be defined as a separate event and included in the efficacy analyses. A sensitivity 
analysis including all events occurring during the treatment period will also be performed.  


 
 
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Clinical Study Protocol G1T28-03                                       
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Occurrence of an RBC transfusion during the treatment period is defined as a binary variable 
(Yes or No); Yes if total number of RBC transfusions ≥ 1 is observed, No for other scenarios. 
5.1.2.2. 
Occurrence of GCSF Administrations 
Administration of GCSF is collected with the concomitant medications which are coded using 
World Health Organization Drug Dictionary (WHO-DD Version Sep2017).  The criterion to 
select proper records is as follows: If the chemical subgroup from WHO-DD Version Sep2017 
(i.e. TEXT4 for CODE4) takes value “COLONY STIMULATING FACTOR”, the medication is 
classified as GCSF. 
A cycle where GCSF is administered concurrently will be identified by comparing the start and 
stop dates of each administration of GCSF to the start of cycle and end of cycle.  If any of the 
dates of administration of GCSF overlap with any dates between the start of cycle and end of 
cycle, that cycle will be considered as having GCSF administered. Data handling conventions for 
missing start and stop dates are described in Section 6.2.5. 
For the treatment period, the total number GCSF administrations is the number of cycles in 
which there is at least one GCSF dose administered. If a patient did not have any GCSF use, the 
value of 0 will be assigned to that patient. The number of cycles where GCSF was NOT given is 
calculated as total number of treatment cycles received – total number of cycles where GCSF 
was administered. 
Therefore, any occurrence of a GCSF administration during a cycle or the treatment period is 
defined as a binary variable (Yes or No); Yes if total number of cycles with GCSF administration 
≥ 1 is observed, No for other scenarios.  
5.1.2.3. 
Occurrence of Platelet Transfusions 
Each platelet transfusion with a unique start date during the treatment period will be defined as 
separate event.   
Occurrence of a platelet transfusion during the treatment period is defined as a binary variable 
(Yes or No); Yes if total number of platelet transfusions ≥ 1 is observed, No for other scenarios.   
5.1.2.4. 
Occurrence of All-Cause Dose Reductions  
Dose (mg/m2) reductions are not permitted for trilaciclib. Dose reductions for topotecan are 
collected on the dosing page.  
No more than 2 dose reductions for toxicity in total are allowed for any patient. All dose 
reductions will be counted as a separate event. For more details see Section 5.2.1.4. 
5.1.2.5. 
Overall Survival  
Although OS is a key secondary endpoint, OS will be analyzed with a descriptive intention and 
will not be factored into multiplicity adjustment as described in Section 6.2.7.1.4. That is, no 
formal statistical testing will be planned. The analysis of OS will be primarily aimed at showing 
lack of harm from trilaciclib. 
Overall survival is calculated as the time (months) from date of first dose of study drug 
(topotecan or trilaciclib/placebo) for patients in Part 1 or date of randomization for patients in 
Part 2 to the date of death due to any cause. Patients who do not die during the study will be 


 
 
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Clinical Study Protocol G1T28-03                                       
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censored at the date last known to be alive. Patients lacking data beyond the day of first dose of 
study drug (topotecan or trilaciclib/placebo) for patients in Part 1 or date of randomization for 
patients in Part 2 will have their survival time censored at day of first dose of study drug 
(topotecan or trilaciclib/placebo) for patients in Part 1 or date of randomization for patients in 
Part 2. OS will not be censored if a patient receives other anti-tumor treatments after the study 
drugs (topotecan or trilaciclib/placebo). 
5.1.3. 
Supportive Secondary Efficacy Endpoints  
5.1.3.1. 
Total Number of Major Adverse Hematologic Event (MAHE) 
As a composite measure of trilaciclib effect, MAHE is based on a combination of individual 
components specified in Table 4, which also include details about the derivation or data source 
for each component. For each component of composite MAHE, the number of events is derived 
as the number of episodes with a unique start date during the treatment period between the date 
of the start of Cycle 1 and the end of the last cycle (i.e. last cycle of placebo or trilaciclib plus 
topotecan). A patient without an episode will be assigned a value of 0 for the number of events 
for this component. Then, the total number of MAHE during the treatment period is obtained as 
the summation over all components of composite MAHE during the treatment period.   
Table 4 
Component of MAHE and the Suggested Data Source/Derivation Algorithm 
Seq # 
Component of MAHE Details 
1 
All-cause 
hospitalizations 
Each hospitalization is captured in the AE data of the 
electronic database. Each recorded Preferred Term (PT) 
with a unique start date will be counted as an event, e.g. if 
a patient is hospitalized and several preferred terms are 
attributed to that hospitalization with the same start date, 
then the event is only counted once. The event terms are 
coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 20.1.  
2 
All-cause dose 
reductions 
Detailed in Section 5.1.2.4 
3 
Febrile neutropenia 
Detailed in Section 5.1.3.9 
4 
Prolonged severe 
(Grade 4) neutropenia 
(duration > 5 days) 
Detailed in Section 5.1.1.2.1. Each cycle with a duration 
greater than 5 days will be counted as an event with the 
date of the first grade 4 lab value defined as the start date 
for the time-to-first event analysis. 
5 
RBC transfusion 
on/after 5 weeks 
Detailed in Section 5.1.2.1 
6 
Platelet transfusion 
Detailed in Section 5.1.2.3 
A patient without an episode of MAHE will be assigned a value of 0 for the overall total number 
of MAHE. Additionally, a sensitivity analysis will be done for dose reductions and RBC 
transfusions on/after 5 weeks, that excludes patients who do not start a second cycle of treatment. 


 
 
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Time to first occurrence of a MAHE will be used as a sensitivity analysis in support of the total 
number of MAHE. It is defined as the first time to observe an event among all the components, 
starting from the date of the start of Cycle 1. Therefore, for a patient with a MAHE, time 
(months) to first occurrence of a MAHE will be the minimum among the 6 potentially derived 
durations (i.e. calculated as (date of first occurrence of a MAHE component event – date of Start 
of Cycle 1 + 1)/30). A patient without any MAHE will be censored at the end of the last cycle 
(i.e. last cycle of placebo or trilaciclib), death, end of study, or date of last contact, whichever is 
earlier.  
5.1.3.1.1. 
All-Cause Hospitalizations 
See Section 5.1.3.1 
5.1.3.1.2. 
Prolonged severe (Grade 4) neutropenia (duration > 5 days) 
See Section 5.1.3.1. 
5.1.3.2. 
Best Overall Response, Duration of Response, and Progression-Free Survival 
For tumor assessment, all sites of disease will be assessed radiologically by computed 
tomography (CT) or magnetic resonance imaging (MRI) at screening and every 2 months 
thereafter, until the date of (i) disease progression as defined by RECIST Version 1.1 
(Eisenhauer et al, 2009) or by clinical criteria; or (ii) withdrawal of consent; or (iii) receiving 
subsequent anti-cancer therapy, whichever is earlier. At each tumor assessment visit, the overall 
visit response by RECIST will determined two ways: (1) derived programmatically using the 
information from target lesions (TL), non-target lesions (NTLs) and new lesions as entered into 
the eCRF, and (2) by the investigator and collected in the eCRF.  
For all patients, the RECIST tumor response data will be used to determine each patient’s visit 
response according to RECIST version 1.1 and the best overall response (BOR). 
5.1.3.2.1. 
Target Lesions (TLs) 
Measurable disease is defined as having at least one measurable lesion which is  
• ≥10 mm in the longest diameter (LD) (except lymph nodes which must have short axis ≥15 
mm) with CT or MRI; or  
• ≥10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable); or 
• ≥ 20 mm by chest X-ray. 
Previously irradiated lesions (or lesions treated with loco-regional therapies) may be considered 
measurable if unequivocal growth of the lesion has been demonstrated. A patient can have a 
maximum of 5 measurable lesions representative of all involved organs (maximum of 2 lesions 
per organ, both the lymph node and skin will be considered as a single organ) recorded at 
baseline and these are referred to as target lesions. If more than one baseline scan is recorded, 
then measurements from the one that is closest to start of treatment will be used to define the 
baseline sum of TLs. Table 5 gives definition of TL visit responses. 


 
 
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Table 5 
Definition of TL Visit Responses 
Visit Reponses 
Description 
Complete 
Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes selected as 
target lesions must have a reduction in short axis to <10mm. 
Partial response 
(PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum of diameters as long as criteria for PD are not met. 
Progressive disease 
(PD) 
A ≥ 20% increase in the sum of diameters of target lesions and an absolute 
increase of ≥ 5mm, taking as reference the smallest sum of diameters (i.e. 
nadir) since treatment started including the baseline sum of diameters. 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD.  
 
 
Rounding of TL data 
For calculation of PD and PR for TLs, percentage changes from baseline and previous minimum 
should be rounded to 1 decimal place before assigning a target lesion response. For example 
19.95% should be rounded to 20.0% but 19.94% should be rounded to 19.9%.  
Missing TL data 
If any target lesion measurements are missing, then the target lesion visit response is Not 
Evaluable (NE). The overall visit response will also be NE, unless there is a progression of non-
target lesions or new lesions, in which case the response will be PD.  
TL too small to measure 
If a target lesion becomes too small to measure a value of 5mm will be entered into the database 
and used in TL calculations, unless the radiologist has indicated and entered a smaller value that 
can be reliably measured.  
Lesions that split 
If a TL splits, then the LDs of the split lesions should be summed and reported as the LD for the 
lesion that split. 
Lesions that merge 
If target lesions merge, then the LD of the merged lesion should be recorded for one of the TL 
sizes and the other TL size should be recorded as 0 cm. 
Change in method of assessment of target lesions 
CT, MRI, chest x-ray and clinical examination are the only methods of assessment that can be 
used within a trial, with CT and MRI being the preferred methods and clinical examination and 
chest x-ray only used in special cases. If a change in method of assessment occurs between CT 
and MRI this will be considered acceptable and no adjustment within the programming is 
needed.  


 
 
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5.1.3.2.2. 
Non-Target Lesions (NTLs) and New Lesions 
The non-target lesion response will be based on the Investigator’s overall assessment of NTLs as 
Table 6: 
Table 6 
Definition of NTLs Visit Responses 
Visit Reponses 
Description 
CR 
Disappearance of all NTLs present at baseline with all lymph nodes non-
pathological in size (<10mm short axis). 
PD 
Unequivocal progression of existing NTLs, which may be due to an important 
progression in one lesion only or in several lesions 
Non-CR/Non-PD 
Persistence of one or more NTLs with no evidence of progression 
NE 
Only relevant when one or some of the NTLs have not been assessed and in the 
Investigator’s opinion, they are not able to provide an evaluable overall NTL 
assessment. 
 
New lesions 
New lesions will be identified via a Yes/No tick box. The absence and presence of new lesions at 
each visit should be listed alongside the TL and NTL visit responses. A new lesion indicates 
progression, so the overall visit response will be PD irrespective of the TL and NTL responses. 
5.1.3.2.3. 
Time Point Response (TPR) 
Table 7 defines how the previously defined TL and NTL visit responses will be combined with 
new lesion information to give a TPR. The possible TPRs at a visit are CR, PR, SD, PD, and NE.  
Table 7  
Evaluation of Time Point Response 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/not all evaluated 
No 
PR 
SD 
Non-PD/not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR= partial response, SD = stable disease, PD = progressive disease, NE = not evaluable 
At each visit, patients will be programmatically assigned a RECIST Version 1.1 TPR of CR, PR, 
SD, PD or NE depending on the status of their disease compared to baseline and previous 
assessments as discussed in the Sections 5.1.3.1.1 and 5.1.3.1.2.  
For a scheduled tumor assessment, it is expected that there will be a variation for the actual 
timing of scans among target, non-target, and new lesions. In assigning a date for the derived 
overall assessment at a visit, the earliest date collected at that visit will be used. Within a 
grouped timepoint, if there are multiple assessments on different dates for the same target 
lesions, the last assessment will be used. 


 
 
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5.1.3.2.4. 
Best Overall Response (BOR) and Duration of Response (DOR) 
BOR will be determined using TPRs up until the last evaluable TPR prior to or on the date of (i) 
disease progression as defined by RECIST Version 1.1 (Eisenhauer et al, 2009) or by clinical 
criteria; or (ii) withdrawal of consent; or (iii) receiving subsequent anti-cancer therapy, 
whichever is earlier. BOR will not be derived for those patients who do not have measurable 
target lesions.   
A patient’s BOR will be determined based on Table 8.  For data-driven scenarios which may not 
be covered by Table 8, the BOR will be reviewed and determined by the medical advisors and 
statisticians prior to unblinding the study.    
For patients who progress and subsequently have a response, the best overall response is only 
derived from assessments up to and including the time of the progression (i.e., it will not include 
the response after the patient has progressed). 
There are two ways of assigning BOR for a patient when the minimum interval for confirmation 
of CR and PR is not satisfied or if there are no confirmatory scans for CR and PR: 
• Adding two more response categories as: unconfirmed CR, unconfirmed PR; 
• Assigning BOR as SD, that is, both the unconfirmed CR and unconfirmed PR will be SD. 
Both ways of assigning BOR will be implemented.  
The number and percentage of patients in each category of derived BOR (Confirmed CR, 
Confirmed PR, SD, PD, or NE) will be summarized.  
 
 


 
 
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Table 8  
Best Overall Response When Confirmation of CR and PR are Required [a] 
First 
TPR 
Second TPR 
Best overall response*^ for 
ORR 
Best Overall Response for 
ORRUNCONFIRMED 
CR 
CR 
CR 
CR 
CR 
PR 
SD [b] or PD 
Unconfirmed CR 
CR 
SD 
SD [b] or PD  
Unconfirmed CR 
CR 
PD 
SD [b] or PD  
Unconfirmed CR 
CR 
NE or NA 
SD [c] or NE or NA 
Unconfirmed CR 
PR 
CR 
PR 
Unconfirmed CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD [d] 
Unconfirmed PR 
PR 
PD 
SD [b] or PD 
Unconfirmed PR 
PR 
NE or NA 
SD [c] or NE or NA 
Unconfirmed PR 
NE 
NE 
NE 
NE 
NE 
CR 
SD 
Unconfirmed CR 
NE 
PR 
SD 
Unconfirmed PR 
NE 
SD 
SD 
SD 
NE or NA 
PD 
PD 
PD 
SD 
PD 
SD [b] or PD 
SD [b] or PD 
SD 
CR 
SD 
SD 
SD 
PR 
SD 
SD 
SD 
SD 
SD 
SD 
SD 
NE or NA 
SD [c] or NE or NA 
SD [c] or NE 
PD 
No further 
evaluation 
PD 
PD 
CR = complete response, PR= partial response, SD = stable disease, PD = progressive disease, NE = not evaluable, NA = not 
available. 
a. The minimum interval for confirmation of CR and PR is 4 weeks.  
b.  Best response will be SD if the first time point overall response is after 35 days on study.  Otherwise, the best response will be 
PD. 
c. Best response will be SD if the first time point overall response if after 35 days on study.  Otherwise, the best response will be 
NE. 
d. Best response will be SD provided the criteria for PD have not been met from the first to second assessment. 
* A best overall response of SD can only be made after the subject is on study for a minimum of 35 days (counted from Cycle 1 
Day 1).  If the subject is on study for less than 35 days, any tumor assessment indicating stable disease before this time period 
will have a best response of NE unless PD is identified.  
^Subsequent documentation of a CR may provide confirmation of a previously identified CR even with an intervening NE (e.g., 
CR NE CR). Subsequent documentation of a PR may provide confirmation of a previously identified PR even with an 
intervening NE or SD (e.g., PR NE PR or PR SD PR). However, only one (1) intervening NE or SD will be allowed between PRs 
for confirmation. Note: in the following scenario, PR SD NE PR, the second PR is not a confirmation of the first PR. 
Objective response rate (ORR) will be calculated using two methods: 
Method #1: ORR will be calculated using a strict interpretation of RECIST Version 1.1. 
Objective response will be derived as no/yes (0/1) variable. Patients with a BOR of confirmed 
CR or PR will be assigned ‘Yes’. Patients not having a BOR of confirmed CR or PR will be 
assigned ‘No’. Hence, ORR is defined as the proportion of patients with objective response being 
“Yes”.  


 
 
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Method #2: ORRUNCONFIRMED will be calculated using all responses regardless of confirmation.  
Objective response will be derived as no/yes (0/1) variable.  Patients with a BOR of confirmed 
CR, confirmed PR, unconfirmed CR or unconfirmed PR will be assigned “Yes”.  All patients 
with other BOR values will be assigned “No”.  Hence, ORRUNCONFIRMED is defined as the 
proportion of patients with objective response being “Yes”.  
Duration of Response (DOR) is the time between first response by RECIST Version 1.1 of CR or 
PR and the first date that progressive disease is documented by RECIST Version 1.1 or death. 
Patients who do not experience PD or death will be censored at the last tumor assessment date.  
Only those patients with confirmed responses will be included in this analysis. Censoring will 
follow the rules outlined below for progression-free survival (PFS) in Section 5.1.3.1.5.  
Clinical benefit rate (CBR) is defined as the proportion of patients with a BOR of confirmed CR, 
confirmed PR, or SD.  
ORR, ORRUNCONFIRMED, DOR and CBR will be calculated using the derived responses and 
investigator responses. 
5.1.3.2.5. 
Progression-free Survival  
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. 
Hence, PFS is defined as the time (months) from date of first dose date of study drug (topotecan 
or trilaciclib/placebo) for patients in Part 1 or date of randomization for patients in Part 2 until 
date of documented disease progression or death due to any cause, whichever comes first. More 
specifically, PFS will be determined using all the assessment data up until the last evaluable visit 
prior to or on the date of (i) disease progression as defined by RECIST Version 1.1 (Eisenhauer 
et al, 2009); or (ii) withdrawal of consent; or (iii) receiving subsequent anti-cancer therapy, 
whichever is earlier. 
PFS will be calculated using derived responses and progression by RECIST Version 1.1 will be 
considered. 
Death, regardless of cause, is always considered as a PD event. The detailed censoring rules for 
the analysis are summarized in Table 9. 
Table 9  
Assignment of Progression or Censoring Based on Radiological Assessment 
Situation 
Date of Progression or Censoring 
Outcome 
No Baseline assessment  
  
Date of first dose of study drug 
(topotecan or trilaciclib/placebo) for 
patients in Part 1 or date of 
randomization for patients in Part 2 
Censored 
No progression - treatment 
not started 
Date of first dose of study drug 
(topotecan or trilaciclib/placebo) for 
patients in Part 1 or date of 
randomization for patients in Part 2 
Censored 


 
 
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Clinical Study Protocol G1T28-03                                       
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Situation 
Date of Progression or Censoring 
Outcome 
No progression  
Date of last adequate radiological 
disease assessment  
Censored 
Treatment discontinuation 
for reasons other than 
disease progression 
Date of last progression assessment 
with no documented progression 
Censored 
New anticancer treatment 
started prior to documented 
disease progression   
Date of last adequate radiologic 
assessment no later than the 
initiation of new anticancer treatment  
Censored 
Disease progression per 
RECIST Version 1.1  
Date of the first reported progression  Progressed 
Death without a PD  
Date of death 
Progressed 
Determination of clinical 
progression per the 
investigator 
Date of the investigator assigned PD   Progressed [a] 
[a] For the primary derivation of PFS, the clinical progression will not be included (i.e. it will 
only be based on radiologic progression), but it will be incorporated as a separate derivation 
of PFS, and its analysis will be considered to be supportive. 
Note: An adequate radiologic assessment is defined as an assessment where the Investigator 
determined radiological response is CR, PR, SD, or PD.  If PD and new anti-cancer therapy 
occur on the same day, will assume that the progression was documented first, e.g. outcome 
is progression and the date is the date of the assessment of progression. 
5.1.3.3. 
Occurrence of Grade 3 and 4 Hematologic toxicities  
Hematologic toxicity events are defined as any cycle where any hematologic lab value occurs 
that meets the CTCAE toxicity grade criteria for ≥ Grade 3 and the value is treatment emergent. 
For details on which parameters are included and the definition of treatment emergent see 
Section 5.2.4. 
For the treatment period, the total number of hematologic toxicity events is the number of cycles 
in which there is at least one hematologic toxicity event. If a patient did not have any 
hematologic toxicity events, the value of 0 will be assigned to that patient. The number of cycles 
without hematologic toxicity events is calculated as total number of treatment cycles received – 
total number of cycles with a hematologic toxicity event. 
Therefore, any occurrence of a hematologic toxicity event during a cycle or the treatment period 
is defined as a binary variable (Yes or No); Yes if total number of cycles with a hematologic 
toxicity event ≥ 1 is observed, No for other scenarios. 
5.1.3.4. 
ANC Nadir by Cycle 
See table in Section 5 for the definition of cycle nadir. 


 
 
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5.1.3.5. 
ANC, Platelet Count, Absolute Lymphocyte Counts (ALC), and Hemoglobin 
Change over Time 
For the hematologic parameters consisting of ANC, hemoglobin, platelet count, and ALC, the 
observed lab values in each windowed visit as detailed in Section 6.1.3 will be appropriately 
identified for further analysis.  
5.1.3.6. 
Occurrence of Erythropoietin Stimulating Agent (ESA) Administrations 
Administration of ESAs is collected with the concomitant medications which are coded using 
WHO-DD Version Sep2017.  The criterion to select proper records is as follows: If the chemical 
subgroup from WHO-DD Version Sep2017 (i.e. TEXT4 for CODE4) takes value “OTHER 
ANTIANEMIC PREPARATIONS”, the medication is classified as ESAs.  
Those cycles where ESAs are administered concurrently will be identified by comparing the start 
and stop dates of each ESA to the start of cycle and end of cycle.  If any of the dates of 
administration of an ESA overlap with any dates between the start of cycle and end of cycle, that 
cycle will be considered as having an ESA administered. Data handling conventions for missing 
start and stop dates are described in Section 6.2.5.   
For the treatment period, the total number ESA administrations is the total number of cycles in 
which there is at least one ESA dose administered. If a patient did not have any ESA use, the 
value of 0 will be assigned to that patient. The number of cycles where ESAs were NOT given is 
calculated as total number of treatment cycles received – total number of cycles where ESAs 
were administered. 
Therefore, any occurrence of an ESA administration during a cycle or the treatment period is 
defined as a binary variable (Yes or No); Yes if total number of cycles with an ESA 
administration ≥ 1 is observed, No for other scenarios. 
5.1.3.7. 
Occurrence of IV Antibiotic Uses 
IV antibiotic administration is collected with concomitant medications which are coded using 
WHO-DD Version Sep2017.  The criteria for identifying an IV antibiotic administration event is 
− If the Therapeutic subgroup from WHO-DD Version Sep2017 (i.e. TEXT2 for CODE2) 
takes value “ANTIBACTERIALS FOR SYSTEMIC USE”, and  
− The route of medication is “intravenous” or the route is “other” with the detailed 
specification as “IVPB”.  
Each IV antibiotic with a unique start date during the treatment period will be defined as a 
separate event. Data handling conventions for missing start and stop dates are described in 
Section 6.2.5.  
Occurrence of an IV antibiotics administration during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of IV antibiotics administrations ≥ 1 is observed, No 
for other scenarios.     
5.1.3.8. 
Occurrence of Infection Serious Adverse Events (SAEs)  
Each infection SAE is captured in the electronic database. The event terms are coded using the 
MedDRA Version 20.1. The criterion for identifying the proper infection SAE records is as 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
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follows: if the system organ class (SOC) from MedDRA takes value “INFECTIONS AND 
INFESTATIONS” and the AE is a serious event. 
Each infection SAE with a unique start date during the treatment period will be defined as 
separate event. Data handling conventions for missing start and stop dates for AEs are described 
in Section 5.2.1.    
Any occurrence of an infection SAE during the treatment period is defined as a binary variable 
(Yes or No); Yes if total number of infection SAEs ≥ 1 is observed, No for other scenarios.  
5.1.3.9. 
Occurrence of Pulmonary Infection SAEs 
Each pulmonary infection SAE is captured in the electronic database. The event terms are coded 
using the MedDRA Version 20.1. The criterion for identifying the  pulmonary infection SAEs 
records is as follows: if the system organ class (SOC) from MedDRA takes value 
“INFECTIONS AND INFESTATIONS”, the PT takes a values from Table 10 and the AE is a 
serious event. 
Table 10 
PT List for Grouping Infection AEs and Pulmonary Infection AEs 
Category 
Preferred terms 
Pulmonary Infection AEs 
Bronchiolitis 
 
Bronchitis 
 
Infectious pleural effusion 
 
Influenza 
 
Lung infection 
 
Pneumonia 
 
Pneumonia bacterial 
 
Pneumonia pneumococcal 
 
Respiratory tract infection 
 
Upper respiratory tract infection 
 
Viral upper respiratory tract infection 
Each pulmonary infection SAE with a unique start date during the treatment period will be 
defined as separate event.  Data handling conventions for missing start and stop dates for AEs 
are described in Section 5.2.1.     
Any occurrence of a pulmonary infection SAE during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of pulmonary infection SAEs ≥ 1 is observed, No for 
other scenarios.  
5.1.3.10. Occurrence of Febrile Neutropenia 
Each febrile neutropenia event is captured in AE data of electronic database, and “FEBRILE 
NEUTROPENIA” is a preferred term which can be used to identify the proper AE records. The 
event terms are coded using the MedDRA Version 20.1.     
Each febrile neutropenia event with a unique start date during the treatment period will be 
defined as a separate event. Data handling conventions for missing start and stop dates for AEs 
are described in Section 5.2.1.    


 
 
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Any occurrence of a febrile neutropenia event during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of febrile neutropenia events ≥ 1 is observed, No for 
other scenarios. 
5.1.3.11. Occurrence of Grade 4 and Grade 3/4 Thrombocytopenia 
Thrombocytopenia events of Grade 4 or Grade 3/4 are defined as any cycle where any platelet 
lab value occurs that meets the CTCAE toxicity grade criteria for ≥ Grade 4 (3) and the value is 
treatment emergent. For the definition of treatment emergent see Section 5.2.4. 
For the treatment period, the total number of thrombocytopenia events is the number of cycles in 
which there is at least one thrombocytopenia event. If a patient did not have any 
thrombocytopenia events, the value of 0 will be assigned to that patient. The number of cycles 
without thrombocytopenia events is calculated as total number of treatment cycles received – 
total number of cycles with a thrombocytopenia event. 
Therefore, any occurrence of a thrombocytopenia event during a cycle or the treatment period is 
defined as a binary variable (Yes or No); Yes if total number of cycles with a thrombocytopenia 
event ≥ 1 is observed, No for other scenarios. 
5.1.3.12. Myelosuppression Endpoints with All data up to End of Cycle 4 
The following myelosuppression endpoints will be derived for a period of interest utilizing all 
available data up to the end of Cycle 4. The period of interest starts from the date of 
randomization/first dose of study drug, whichever is earlier. The end dates of the period depend 
on the status of each patient; for patients who receive ≤ 4 cycles of therapy, the period ends on 
the date of the first dose date of the last cycle + 38 days, and for patients who receive > 4 cycles, 
the period ends on Day 1 of Cycle 5. The derivation of each endpoint will follow the definition 
described in each relevant section. 
− Occurrence of severe (Grade 4) neutropenia (Section 5.1.1.1); 
− Occurrence of RBC transfusions on/after week 5 of study (Section 5.1.2.1); 
− Occurrence of GCSF administrations (Section 5.1.2.2); 
− Occurrence of platelet transfusions (Section 5.1.2.3); 
− Total number of MAHE (Section 5.1.3.1); 
− Number of all-cause hospitalizations (Section 5.1.3.1.1); 
− Number of all-cause dose reductions (Section 5.1.2.4); 
− Number of febrile neutropenias (Section 5.1.3.1); 
− Number of cycles with prolonged severe (Grade 4) neutropenia (duration > 5 days) (Section 
5.1.3.1.2);  
− Number of RBC transfusions on/after 5 weeks (Section 5.1.3.1);  
− Number of platelet transfusions (Section 5.1.3.1); 
− Occurrence of Grade 3 and 4 hematologic toxicities (Section 5.1.3.3); 
− Occurrence of RBC transfusions during the first 4 cycles (Section 5.1.2.1);  
− Number of RBC transfusions during the first 4 cycles (Section 5.1.3.1);  


 
 
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5.1.4. 
Exploratory Efficacy Endpoints  
5.1.4.1. 
FACT-L and FACT-An 
The FACT-L and FACT-An analyses will be documented separately and are not covered in this 
SAP. 
5.1.4.2. 
Grade 2 or Greater Nephrotoxicity 
For any post-baseline creatinine assessment, an event of grade ≥ 2 nephrotoxicity is defined as 
the observed value >1.5 × baseline value, or > 1.5 × Upper Limit of Normal Range (ULN). 
Within a cycle, for each nephrotoxicity event, the occurrence of a creatinine value meeting the 
criteria outlined above is described using a binary variable (Yes or No); Yes, if the designated 
event is observed, No for other scenarios. For the treatment period, the total number of 
nephrotoxicity events where the creatinine value meets the criteria is the number of cycles where 
at least one lab value meets the criteria.  For example, if Cycle 2 has two values that both meet 
criteria, this only counts as one event. If a patient does not have any lab values meeting the 
criteria, the value of 0 will be assigned to that patient.  Unscheduled data and the actual 
assessment date (rather than visit date) will be used for these analyses. 
Any occurrence of a Grade ≥ 2 nephrotoxicity during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of Grade ≥ 2 nephrotoxicity events ≥ 1 is observed, No 
for other scenarios.  
5.1.4.3. 
Occurrence of Alopecia and Mucositis 
Alopecia will be identified by the preferred term of “alopecia”, and mucositis will be identified 
by the high level term ‘stomatitis and ulceration’, or the preferred terms ‘mucosal inflammation’, 
‘mucosal ulceration’, or ‘oesophagitis’ used in MedDRA Version 20.1 coding for AE data, and 
these terms will be used to identify the occurrence of events during the treatment period.  
Separate analyses will be done for each term.  
Any occurrence of an alopecia (or mucositis) event during the treatment period is defined as a 
binary variable (Yes or No); Yes if total number of alopecia (or mucositis) events ≥ 1 is 
observed, No for other scenarios. Total number of events per subject will also be summarized. 
Data handling conventions for missing start/stop dates of AEs are in Section 5.2.1. 
5.1.4.4. 
Neutrophil-lymphocyte Ratio (NLR) and Platelet-lymphocyte Ratio (PLR)  
NLR will be derived using the ANC and ALC, and PLR will be calculated using platelet count 
and ALC.  Both NLR and PLR may have prognostic value in patients with various solid tumors. 
That is, the lower the value, the better the clinical prognosis. If data permit, NLR and PLR will 
be correlated with various anti-tumor efficacy analyses [e.g. ORR, PFS, and etc.]. 
5.2. 
Safety Endpoints  
5.2.1. 
Chemotherapy Exposure Endpoints 
5.2.1.1. 
Duration of Exposure  
Duration of exposure (days) = First dose date of study drug (topotecan or trilaciclib/placebo) 
from the last cycle – first dose date of study drug (topotecan or trilaciclib/placebo) + 21.  


 
 
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5.2.1.2. 
Number of Cycles Received  
Patients are considered to have started a cycle if they have received at least one dose of any study 
drug (topotecan or trilaciclib/placebo).  In addition to the numeric summary for the number of 
cycles, the number of cycles will be categorized as 1, 2, 3, 4, 5 to 10, and > 10.  
5.2.1.3. 
Dose Intensity and Cumulative Dose 
Algorithms for calculating parameters relevant to the dose exposure and intensity are included in 
Table 11.   
Table 11  
Algorithms for Calculating Parameters Relevant to the Dose Exposure and 
Intensity 
Parameter 
Trilaciclib § 
Topotecan^ 
Dosing schedule 
per protocol 
200 mg/m2 IV on 
Days 1 to 5 of a 21-
day cycle 
1.5 mg/m2 IV on Days 
1 to 5 of a 21-day 
cycle 
Dose by cycle  
Total dose 
administered (mg) 
/most recent BSA (m2) 
[(mg/m2)].  
Total dose 
administered 
(mg)/most recent BSA 
(m2) [(mg/m2)].  
Cumulative dose  
Sum of the doses 
administered to a 
patient in the duration 
of exposure [(mg/m2)] 
Sum of the doses 
administered to a 
patient in the duration 
of exposure [(mg/m2)]  
Dose intensity  
Cumulative dose 
(mg/m2) / (duration of 
exposure / 7) 
[(mg/m2/week)] 
Cumulative Dose 
(mg/m2) / (duration of 
exposure / 7) 
[(mg/m2/week)] 
Relative dose 
intensity (%) 
 
 
100 * [Dose intensity 
(mg/m2/week) / (1000 
/3 (mg/m2/week)]  
100 * [Dose intensity 
(mg/m2/week) / (7.5 /3 
(mg/m2/week)]  
Relative Dose (%) 
100 * [Cumulative 
dose (mg/m2) / (1000 
× number of cycles 
(mg/m2)]  
100 * [Cumulative 
dose (mg/m2) / (7.5 × 
number of cycles 
(mg/m2)]  
§ Three different doses (200mg/m2, 240mg/m2, and 280mg/m2) of trilaciclib were evaluated in 
Part 1.  240mg/m2 trilaciclib was the planned dose for all patients in Part 2.  The calculation of 
relevant parameters will be adjusted accordingly based on the example presented in this table.  
^ Four different doses (0.75mg/m2, 1mg/m2, 1.25mg/m2, and 1.5mg/m2) of topotecan were 
evaluated in Part 1.  0.75mg/m2 and 1.5mg/m2 were the planned dose for patients in Part 2.  The 
calculation of relevant parameters for Part 1 will be adjusted accordingly based on the example 
presented in this table. Part 2 dosing amounts were not collected to preserve the blind and these 
parameters will not be calculated for it. 
BSA = body surface area; IV = intravenous. 
 


 
 
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Total number of doses will be calculated and summarized by treatment. 
5.2.1.4. 
Modifications of Study Therapy, Including Cycle (Dose) Delay, Missed Doses, 
Dose Interruptions, and Dose Reductions 
• After Cycle 1, patients need to meet pre-specified laboratory parameter criteria before 
initiating Cycle 2 and each subsequent cycle of chemotherapy. Cycle (dose) delay and its 
associated reasons are collected at the beginning of each cycle in an eCRF page titled 
“Beginning Cycle Assessment”. The reasons for delay will be summarized in the following 
categories: (1) Adverse event, (2) Logistical/Administrative Issues, (3) Hematologic Toxicity 
(which is a sum of those patients who fall into either category 3a or 3b), (3a) ANC < 1.5 x 
109/L, (3b) Platelet Count < 100 x 109/L, (5) Nonhematologic Toxicity and (6) Other. Note 
that categories 3a and 3b are sub-bullets of category (3).  
• Missed doses are identified on the dosing page of each study drug (topotecan or 
trilaciclib/placebo) based on the question “Was the dose missed?”. The missed dose 
information will be obtained for each study drug (topotecan or trilaciclib/placebo). For a 
study drug (topotecan or trilaciclib/placebo), if the last record of response to question “Was 
the dose missed?” is Yes, it will not be considered as a missed dose but instead considered to 
be end of treatment if both criteria below are met: 
o No other study drugs (topotecan or trilaciclib/placebo) are given on the same day, and 
o No study drugs (topotecan or trilaciclib/placebo) are given subsequently. 
The reasons for missed doses will be summarized in the following categories: (1) Adverse 
Event, (2) Logistical/Administrative Issues, and (3) Other. 
• Dose reductions are not permitted for trilaciclib. Dose reductions for topotecan are collected 
on the dosing page; the reasons for reduction will be summarized in the following categories: 
(1) Adverse Event, (2) Change recommendation by SMC, and (3) Other. No more than 2 
dose reductions of topotecan for toxicity in total are allowed for any patient. Toxicity that 
requires dose reduction more than twice will lead to discontinuation of trilaciclib or placebo 
+ topotecan; discontinuations will not be counted as a dose reduction. All dose reductions for 
toxicity are permanent, and no dose increases are allowed when dose reductions are made for 
toxicity. 
• Dose interruptions for all drugs are also captured on the dosing page and will be summarized 
for each study drug (topotecan or trilaciclib/placebo). 
5.2.2. 
Adverse Events  
All AEs will be coded from verbatim text to PTs and grouped by SOC using the MedDRA 
Version 20.1. AEs will be collected from the time of signature of informed consent throughout 
the treatment period and up to 30 days after the last dose of study treatment. AEs are graded by 
investigator according to CTCAE, Version 4.03.  
Any AE that started on or after the first dose of study drugs (topotecan or trilaciclib/placebo) and 
up to the last dose + 30 days will be included as a treatment emergent AE (TEAE). AEs with an 
unknown/not reported onset date will also be included.  


 
 
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Other AE variables include drug-related AEs, AEs leading to study drug (topotecan or 
trilaciclib/placebo) discontinuation or study withdrawal, AEs leading to death, and SAEs.  
AEs with onset/end dates that are partially/completely missing will be imputed as follows: 
(i) For onset date: 
− If only the day part of the AE onset date is missing and occurs in the same month and 
year as the first dose date of study drug (topotecan or trilaciclib/placebo), the date of first 
dose of study drug (topotecan or trilaciclib/placebo) will be used as the onset date of the 
AE. Otherwise, the first day of the month will be used to complete the onset date of the 
AE; 
− If the day and month parts of the AE onset date are missing and occur in the same year as 
the first dose of study drug (topotecan or trilaciclib/placebo), the date of the first dose of 
study drug (topotecan or trilaciclib/placebo) will be used as the onset date of the AE. 
Otherwise, January 1st will be used to complete the onset date of the AE; 
− If the AE onset date is completely missing, the date of the first dose of study drug 
(topotecan or trilaciclib/placebo) will be used as the onset date of the AE. 
(ii) For end date: 
− If only the day part of the AE end date is missing, the last day of the month will be used to 
complete the end date of the AE;  
− If the day and month parts of the AE end date are missing, December 31st will be used to 
complete the end date of the AE; 
− If the AE end date is completely missing and the onset date of the AE occurs after the 
date of the first dose of study drug (topotecan or trilaciclib/placebo), the last date during 
the treatment period + 30 days will be used as the AE end date. If the AE end date is 
completely missing and the onset date of the AE occurs prior to the date of the first dose 
of study drug (topotecan or trilaciclib/placebo) the date of the first dose of study drug 
(topotecan or trilaciclib/placebo) will be used as the AE end date. 
AEs related to hematologic toxicity will be pooled based on the preferred MedDRA Version 
20.1. Table 12 outlines those terms that will be consolidated.  
Table 12 
Preferred Terms to Be Consolidated 
Presented term in the table  Preferred Term 
Neutropenia 
Neutropenia 
 
Neutrophil count decreased 
Febrile neutropenia 
Febrile neutropenia 
Anaemia 
Anaemia 
 
Anaemia macrocytic 
 
Red blood cell count decreased 
 
Hemoglobin decreased 
Thrombocytopenia 
Thrombocytopenia 


 
 
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Presented term in the table  Preferred Term 
 
Platelet count decreased 
Lymphopenia 
Lymphopenia 
 
Lymphocyte count decreased 
Leukopenia 
Leukopenia 
 
White blood cell count decreased 
AEs potentially related to infusion reactions will be pooled based on the PTs of MedDRA 
Version 20.1.  The events described by the PTs listed below will be summarized and presented in 
order of decreasing frequency: Infusion site pain, Infusion site pruritus, Infusion site reaction, 
Infusion site burning, Infusion related reaction, Infusion site irritation, Infusion site redness, 
Allergic reaction, Catheter site itching, Catheter site erythema, Catheter site hematoma, and 
Catheter site pain..   
5.2.3. 
Vital Signs 
Vital signs include pulse rate, respiratory rate, systolic blood pressure (SBP), diastolic blood 
pressure (DBP), weight, height (only measured at screening), and body temperature. Body Mass 
Index (BMI) will be computed as weight (kg)/[height (m)]2, Body Surface Area (BSA) will be 
computed using DuBois-DuBois formula as 0.20247 × [height (m)]0.725 × [weight (kg)]0.425.  
For vital signs, change from baseline to each post-baseline visit and timepoint will be calculated. 
Vitals will be summarized by visit as collected and not windowed. 
The potentially clinically significant findings of vital signs will also be defined based on criteria 
defined in Table 13: 
Table 13 
Potentially Clinically Significant Criteria for Vital Signs 
 Vital Sign Parameter   
 Criterion value   
 Change from baseline  
 SBP   
 ≥180 mmHg   
 Increase ≥40 mmHg   
    
 ≤ 90 mmHg   
 Decrease ≥40 mmHg   
    
    
    
 DBP   
 ≥105 mmHg   
 Increase ≥20 mmHg   
    
 ≤ 50 mmHg   
 Decrease ≥20 mmHg   
 Pulse   
 ≥ 120 bpm   
 Increase ≥40 bpm   
    
  ≤ 50 bpm   
 Decrease ≥40 bpm  
    
    
    
 Weight   
 n/a   
 Change ≥10%   
bpm  = beats per minute 
5.2.4. 
Laboratory 
Blood and urine samples for the determination of clinical chemistry, hematology, and urinalysis 
laboratory variables described in Table 14 will be measured.  


 
 
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Table 14 
Laboratory Assessment 
Lab Category 
Lab tests 
Hematology  
Hemoglobin (HGB), hematocrit, white blood cell (WBC), platelet counts, 
ANC, ALC, Monocyte Absolute, Basophil Absolute, and Eosinophil 
Absolute. 
Chemistry  
albumin, Alkaline Phosphatase (ALP), total bilirubin, calcium, chloride, 
creatinine, glucose, inorganic phosphorus, potassium, total protein, Alanine 
Aminotransferase (ALT), Aspartate Aminotransferase (AST), Lactate 
Dehydrogenase (LDH), sodium, and Blood Urea Nitrogen (BUN). 
Urinalysis  
semiquantitative dipstick: specific gravity, pH, evaluation of glucose, 
protein, bilirubin, ketones, leukocytes, and hemoglobin microscopic 
examination, including RBC, WBC, and casts will be performed, if 
necessary 
Change from baseline in laboratory test results to each assessment will be calculated; for 
hematology parameters, the change from cycle baseline will also be obtained. The urinalysis and 
hematocrit results will not be summarized; they will only be included in listings. 
Clinical laboratory results will be graded according to CTCAE criteria, Version 4.03 which can 
be found in Table A-1 of Appendix.  Any graded abnormality that occurs following the initiation 
of study drug (topotecan or trilaciclib/placebo) and represents at least a 1-grade increase from the 
baseline assessment is defined as treatment emergent. Any assessment for which CTCAE 
toxicity grades are not available, will not be included in any analyses for which toxicity grades 
are required. 
Analysis of Abnormal Hepatic Laboratory Values 
The following categories of abnormal hepatic laboratory values will be evaluated for any 
occurrence among all post baseline assessments.  
• ALT and/or AST >3x ULN, ALP < 2xULN, and Total Bilirubin> 2x ULN 
• AST > 3,5,8,10, and 20x ULN, AST>5x ULN for more than 5 weeks 
• ALT > 3,5,8,10, and 20x ULN, ALT > 5x ULN for more than 5 weeks 
• Total Bilirubin >1.5 or >2x ULN  
5.2.5. 
Electrocardiograms 
Electrocardiogram (ECG) parameters include heart rate, PR interval, and QT, QTcB, QTcF and 
QRS intervals. Change from baseline to each post-baseline visit will be calculated and 
summarized by visit as collected and not windowed. Visits and timepoints only collected for PK 
subjects in Part 1 will be listed but not summarized. 
Potentially clinically significant ECG findings will be identified using the criteria which are 
included in Table 15. ECG results are interpreted as normal, abnormal but not clinically 
significant, or abnormal and clinically significant.  


 
 
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Clinical Study Protocol G1T28-03                                       
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Table 15 
Potentially Clinically Significant Criteria for ECG 
 ECG Parameter   
 Criterion value   
 Heart Rate   
 >120 bpm   
    
  <50 bpm   
 PR Interval   
 ≥ 210ms   
 QRS Interval   
 ≥ 120ms   
    
  ≤ 50ms   
 QT Interval   
 ≥ 500ms   
    
 ≤ 300ms   
 QTcB, QTcF Intervals   
 ≥ 500ms   
    
 ≥ 480ms   
    
 ≥ 450ms   
    
 ≤ 300ms   
    
 Change from baseline ≥ 30 ms  
    
 Change from baseline ≥ 60 ms  
5.2.6. 
Physical Examination 
Physical examination is conducted during screening, on Day 1 of each cycle, and at the post-
treatment visit. Abnormal findings in PE were to be reported as AEs.  These data will not be 
summarized, i.e. they will only be available in listings.  
 
 


 
 
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6. 
ANALYSIS METHODS 
6.1. 
General Principles of Analysis 
6.1.1. 
General Methodology 
In general, all efficacy, safety and PK variables will be summarized using descriptive statistics 
and graphs as appropriate. Continuous variables will be summarized by descriptive statistics 
(sample size (n), mean, standard deviation, minimum, median, and maximum). Categorical 
variables will be summarized in frequency tables (frequencies and percentages).  
Survival estimates will be analyzed with Kaplan-Meier method and summarized with median, 
twenty-fifth and seventy-fifth percentiles, and 95% confidence intervals (CI), if applicable. 
Individual data will be presented in patient listings.  
Analyses will be implemented using SAS® 9.4 or higher (SAS Institute, Cary, North Carolina, 
USA). The International Conference on Harmonization (ICH) numbering convention, i.e. ICH-
E3, will be used for all tables and listings. Upon completion, all SAS programs will be 
validated by an independent programmer within the staff of the third-party vendor doing the 
primary analysis.  The validation process will be used to confirm that statistically valid methods 
have been implemented and that all data manipulations and calculations are accurate.  Checks 
will be made to ensure accuracy, consistency with this plan, consistency within tables, and 
consistency between tables and corresponding data listings. 
All summary tables, listings, and figures (TLFs) will be presented by treatment groups as defined 
in Table 16. 
Table 16 
Treatment Display in TLFs 
Study Part  
Trilaciclib 
Dose 
Topotecan Dose 
Treatment Description in Data 
Display 
Part 1  
200 mg/m2 
1.5 mg/m2 
Cohort 1 
Part 1  
200 mg/m2 
1.25 mg/m2 
Cohort 2 
Part 1 
200 mg/m2 
0.75 mg/m2 
Cohort 3 
Part 1 
240 mg/m2 
0.75 mg/m2 
Cohort 4 & 6 
Part 1 
280 mg/m2 
0.75 mg/m2 
Cohort 5 
Part 1 
240 mg/m2 
1.0 mg/m2 
Cohort 7 
Part 1 
Any 
Any 
Total 
Part 2 
Placebo 
1.5 mg/m2 
Placebo   
Part 2 
240 mg/m2 
0.75 mg/m2 
Trilaciclib 240 mg/m2 and Topotecan 
0.75 mg/m2 
Part 2 
240 mg/m2 
1.5 mg/m2 
Trilaciclib 240 mg/m2 and Topotecan 1.5  
mg/m2 
Part 2 
240 mg/m2 
Any 
Total  
All statistical tests will be presented at a two-sided .20 alpha level unless otherwise specified. 
The primary comparison will be conducted between placebo group (from Part 2A and 2B) and 
Trilaciclib 240 mg/m2 + Topotecan 1.5 mg/m2 group. Where appropriate, model-based point 
estimates, together with their 80% CIs will be presented along with the two-sided p-values for 


 
 
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Clinical Study Protocol G1T28-03                                       
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the tests. P-value will be presented to 4 decimal places, if the p-value <0.0001, the value will be 
presented as “<0.0001”. 
For continuous data, the same number of decimal places as in the raw data will be presented 
when reporting mean, median, minimum and maximum; one more decimal place than in the raw 
data will be presented when reporting standard deviation and standard error (SE).  The derived 
variables will be presented with 1 decimal place. Percentages will be reported with 1 decimal 
place; if the count is 0, no percentage will be presented. Value of percentage less than 1% will be 
presented as “<1%.” Value of percentage less than 100% but ≥ 99.5% will be presented as 
“>99%.” 
6.1.2. 
Handling of Missing Data 
In general, the observed case (OC) data for a visit will consist of the actual observations recorded 
for the visit. If missing, the OC data will remain missing — no missing imputation will be 
performed. Safety analyses will be conducted on the OC data only. However, imputation of 
missing AE and concomitant medication onset and stop dates will be used to determine the status 
of each AE and the prior/concomitant status of each medication. Please refer to Section 5.2.1 for 
the method of imputation of missing AE onset and stop date and Section 6.2.5 for the method of 
imputation of missing concomitant onset and stop dates.  
For demographic and baseline characteristics, each variable will be analyzed and/or summarized 
using the available data. Patients with missing data will be excluded only from analyses for 
which data are not available. 
For the efficacy analyses, missing data will be excluded except for the sensitivity analyses noted 
in Section 6.2.7.1.4. 
6.1.3. 
Visit Windowing 
It is expected that there will be a variation between patients in the actual number of study days 
from the start of administration of study drug (topotecan or trilaciclib/placebo) within each cycle 
− defined as Day 1 − to the dates that the scheduled visits occur. To handle this, for tables and 
figures where data are grouped by visit, assessments will be categorized using visit windows 
based on study days (relative to the Day 1 of each cycle). The visit-window mapping is described 
in Table 17. Visit-based summaries will be based on the windowed visits. All data, whether or 
not within the visit windows, will be presented in patient listings.  
For windowed visits during the treatment cycles, if more than 1 visit occurs during a visit 
window, the visit closest to the scheduled day will be assigned to the windowed visit. If two 
visits are equidistant from the scheduled day, the later visit will be assigned to the windowed 
visit. If there are multiple assessments on the same day, the worst case will be used.  For the 
assigned follow-up visit, the last assessment in the window will be included in the summary. 
For a patient who prematurely discontinues the study, the visit will be slotted accordingly. The 
window for post-treatment visit will be "the first dose date of the last cycle + 38 to last 
assessment date prior to the start of survival follow-up". Day 18 was collected in earlier versions 
of the protocol but will not be summarized as most cycles did not include.


 
 
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Clinical Study Protocol G1T28-03                                       
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Table 17 
Visit Windowing 
 
 
Cycle x 
Post-treatment [d] 
Visit 
CxD1 
CxD5 
CxD10 
CxD12 
CxD15 
EOCx 
 
Scheduled Day [a] 
1 
5[e] 
10 
12 
15[e] 
22 
 
Clinical Chemistry [b] 
Day -3 - 1 
 
 
 
2 to EOC 
 
From first dose date of 
last cycle to first dose 
date of last cycle + 38  
Hematology [c] 
Day -3 - 1 
1 to 7 
8 to 10 
11 to 13 
14 to 17 
18 to EOC 
[a] The scheduled day is relative to the Day 1 of each cycle. 
[b] Clinical chemistry may be obtained up to 72 hours prior to the first dose of each cycle. 
[c] Hematology may be obtained up to 24 hours prior to dosing on Days 1, 3, 10, 12 and 15 of each cycle, at the Post-Treatment Visit, and at 60 days after the 
Post-Treatment Visit. 
[d] 30 ± 3 days after the last dose of study drug (topotecan or trilaciclib/placebo)


 
 
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6.1.4. 
Adjustment for Covariates 
Patient randomization in Part 2 was stratified by ECOG performance status (0 or 1 vs. 2) and 
sensitivity to first-line treatment (sensitive: CR/PR/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 efficacy analyses will use the stratification factors as 
covariates in statistical models.  
6.2. 
Analysis Methods  
6.2.1. 
Patient Disposition 
A summary table will be generated to provide the following by study part, as appropriate: 
• 
Number of patients screened 
• 
Number and percentage of screening failures 
• 
Reason for screening failure 
• 
Number of patients dosed 
• 
Number of patients randomized (Part 2 only) 
• 
Number of patients randomized and not dosed (Part 2 only) 
A separate table will be presented to show the patients included in each analysis set and reason 
for exclusion from an analysis set. 
Patient status at treatment and study completion will be listed and summarized.  The listing will 
include whether patients discontinued from the treatment and the reasons for the discontinuation, 
along with the date of first and last dose and the date of completion or discontinuation from the 
treatment.  The same information will be provided for patients who discontinued from the study.  
The following summaries will be added to the disposition table: 
• 
End of treatment status    
• Reason for study drug (topotecan or trilaciclib/placebo) discontinuation 
• 
Number of patients going into Survival follow-up  
• 
Number and percentage of patients who discontinued the study 
• 
Reason for study discontinuation 
• 
Death and reason for death 
6.2.2. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics, such as age at informed consent date, age groups 
(18-65, >65-75, >75), race, ethnicity, gender, screening vital signs (height, body weight, BMI, 
BSA), ECOG status (0 or 1, 2), sensitivity to first line treatment (sensitive, resistant, or 
unknown), and smoking history (never smoked, former smoker, and current smoker) will be 
summarized and listed.   
6.2.3. 
Disease Characteristics 
Disease characteristics including confirmation of diagnosis using neuroendocrine markers (Yes 
or No) and weight loss in the 6 months prior to randomization (Yes or No; if Yes, ≤5% or >5%), 


 
 
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will be summarized and listed. Family history of cancer and date of initial diagnosis of lung 
cancer will be listed only. 
6.2.4. 
Medical History  
Medical history will be coded to SOC and PT using MedDRA Version 20.1. 
The number and percentage of enrolled patients (Part 1) or randomized patients (Part 2) with any 
past medical history within each SOC and PT will be provided. A patient will only be counted 
once within a particular SOC (PT) even if he/she has multiple conditions/diseases in the same 
SOC (PT). The conditions/diseases from medical history are those conditions/diseases that 
stopped prior to the study entry. 
Surgical history (Yes or No; and if Yes, related to lung cancer) will be summarized and listed. 
Concomitant surgeries will be listed. 
6.2.5. 
Concomitant Medications 
All medication verbatim terms collected will be coded to Anatomical Therapeutic Classification 
(ATC) and PT using the WHO-DD Version Sep2017.  
Prior medications are defined as those taken by the patient prior to the administration of study 
drug (topotecan or trilaciclib/placebo). Concomitant medications are defined as those taken by 
the patient at any time between the date of study drug (topotecan or trilaciclib/placebo) 
administration and study completion/discontinuation. Medication with start date/time being 
partially or completely missing will be assumed to be concomitant if it cannot be definitely 
shown that the medication did not occur during the treatment period.   
Medications with onset/end dates that are partially/completely missing will be imputed as 
follows: 
(i) For onset date: 
− If only the day part of the medication onset date is missing and occurs in the same month 
and year as the first dose date of study drug (topotecan or trilaciclib/placebo), the date of 
first dose of study drug (topotecan or trilaciclib/placebo) will be used as the onset date of 
the medication. Otherwise, the first day of the month will be used to complete the onset 
date of the medication;  
− If the day and month parts of medication onset date are missing and occur in the same 
year as the first dose of study drug (topotecan or trilaciclib/placebo), the date of the first 
dose of study drug (topotecan or trilaciclib/placebo) will be used as the onset date of the 
medication. Otherwise, January 1st will be used to complete the onset date of the 
medication; 
− If the medication onset date is completely missing, the date of the first dose of study drug 
(topotecan or trilaciclib/placebo) will be used as the onset date of the medication. 
(ii) For end date: 
− If only the day part of the medication end date is missing, the last day of the month will be 
used to complete the end date of the medication;  


 
 
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Clinical Study Protocol G1T28-03                                       
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− If the day and month parts of the medication end date are missing, December 31st will be 
used to complete the onset date of the medication; 
− If the medication end date is completely missing and the onset date of the medication 
occurs after the date of the first dose of study drug (topotecan or trilaciclib/placebo), the 
last date during the treatment period will be used as the medication end date. Otherwise, 
the date of the first dose of study drug (topotecan or trilaciclib/placebo) will be used as 
the medication end date.    
Concomitant medications will be summarized by presenting the number and percentage of 
patients by PT and ATC. Patients taking the same medication multiple times will only be 
counted once for that PT or ATC. Each summary will be ordered by descending order of 
incidence of ATC class and PT within each ATC class.  
All prior and concomitant medications will be presented in a patient listing. 
6.2.6. 
Prior and Subsequent Anti-cancer Therapy 
The prior and subsequent anti-cancer therapies, such as prior systemic anti-cancer therapy (Yes 
or No) prior radiotherapy (Yes or No), subsequent systemic anti-cancer therapy (Yes or No), and 
concomitant radiation therapy (Yes or No; Reason) will be summarized and listed. All verbatim 
terms collected of prior and subsequent anti-cancer therapy will be coded to Anatomical 
Therapeutic Classification (ATC) and PT using the WHO-DD Version Sep2017.  
The prior anti-cancer therapy will summarize number of prior lines of therapy and the outcomes 
of those therapies. Subsequent anti-cancer therapy will summarize the number and percentage of 
patients by PT and ATC. Patients taking the same medication multiple times will only be 
counted once for that PT or ATC. Each summary will be ordered by descending order of 
incidence of ATC class and PT within each ATC class.  The data will be presented in a patient 
listing. 
6.2.7. 
Efficacy Analyses 
All the efficacy variables will be summarized using descriptive statistics by cycle or visit, with 
the supportive data provided in patient listings.  Part 1 will be summarized using only descriptive 
statistics. For Part 2, in addition to the descriptive summary, the between treatment comparison 
(trilaciclib 240 mg/m2 + topotecan 1.5 mg/m2 vs placebo + topotecan), will be performed only 
for the primary and secondary endpoints outlined in Section 5.1.1-5.1.3. The comparisons 
between trilaciclib vs. placebo will be built into the multiplicity adjustment described in Section 
6.2.7.1.3, the adjusted one-sided p-values will be reported and be the basis for the study drug 
efficacy conclusion and claim at the significance level of one-sided 0.10. However, for these 
comparisons, all statistical tests will be conducted at a two-sided .20 alpha level unless otherwise 
specified. Where appropriate, model-based point estimates, together with their two-sided 80% 
CIs will be presented along with the two-sided p-value for the test unless otherwise specified. 
Graphical presentation of efficacy results will be appropriately performed as needed. 
Unless otherwise specified, all analyses for the efficacy endpoints will be conducted for the 
treatment period which is defined to be between the start of cycle for Cycle 1 and the end of the 
last cycle. 


 
 
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6.2.7.1. 
Primary and Key Secondary Efficacy Analyses 
6.2.7.1.1. 
Primary Efficacy Analyses 
The primary efficacy endpoint, occurrence of SVN, is a binary response variable (Yes, No). It 
will be summarized using descriptive statistics by treatment group and will be analyzed to 
compare trilaciclib and placebo using modified Poisson regression (Zou, 2004) to account for the 
variable duration of the treatment period for each patient. The model will include baseline ANC 
as a covariate, the stratification factors of ECOG (0 or 1 vs. 2) and sensitivity to first-line 
treatment (sensitive or resistant) and treatment as a fixed effect. The logarithm transformation of 
number of cycles will be included as an offset variable in the modeling. The two-sided p-value, 
adjusted rate ratio (aRR) (trilaciclib vs placebo) and its 80% CIs will be presented.   
For the other primary efficacy endpoint, DSN in Cycle 1 based on Strategy 1 in Section 
5.1.1.2.1, a two-sided p-value will be calculated for the nonparametric analysis of covariance 
(ANCOVA) (Stokes 2012). The nonparametric ANCOVA will include study baseline ANC 
value as covariate, stratification factors of ECOG (0 or 1 vs. 2) and sensitivity to first-line 
treatment (sensitive or resistant), and treatment as a fixed effect. Along with the descriptive 
statistics, the mean difference and Hodges-Lehmann estimate of median difference between the 
two treatment groups, together with its 80% CIs will be provided. 
Additionally, DSN for each cycle will be presented using descriptive statistics.  
6.2.7.1.2. 
Key Secondary Efficacy Analyses 
Occurrence of RBC transfusions on/after 5 weeks on study is a binary variable and will be 
summarized using the same method for occurrence of SVN described in Section 6.2.7.1.1 except 
baseline HGB will be used as a covariate instead of baseline ANC in the modified Poisson 
model. Also, the offset will be the logarithm transformation of duration of treatment period 
divided by 7 (i.e. week) instead of number of cycles. An additional sensitivity analysis will look 
all transfusions during the treatment period, and all transfusions with a subset of subjects 
completing at least 1 cycle. 
Occurrence of GCSF administration is a binary variable and will be summarized using the same 
method for occurrence of SVN described in Section 6.2.7.1.1.  
All-cause dose reductions will be analyzed to compare trilaciclib and placebo using a negative 
binomial regression model to account for the potential over-dispersion. The model includes the 
stratification factors of ECOG (0 or 1 vs. 2) and sensitivity to first-line treatment (sensitive or 
resistant), and treatment as a fixed effect. The logarithm transformation of number of cycles will 
be included as an offset variable in the modeling. The two-sided p-value, aRR (trilaciclib vs 
placebo) and its 80% CIs will be presented. 
The total number of all-cause dose reductions will be summarized descriptively, along with the 
number of cycles, and the event rate per cycle (calculated as the total number of events/total 
number of cycles). The cumulative incidence of events during the treatment period will be 
summarized by cycle. 
Occurrence of platelet transfusion is a binary variable and will be summarized using the same 
method for occurrence of SVN described in Section 6.2.7.1.1 except baseline platelet count will 
be used as a covariate instead of baseline ANC in the modified Poisson model. Also, the offset 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
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will be the logarithm transformation of duration of treatment period divided by 7 (i.e. week) 
instead of number of cycles. 
6.2.7.1.3. 
Key Secondary OS Analysis 
OS will be summarized using Kaplan-Meier method, and the descriptive statistics of median, 
25% and 75% percentiles along with their 95% CIs will be calculated. It will be based on the ITT 
analysis set. The supportive data listings will also be provided. 
In addition to the quartile summary from Kaplan-Meier method, Kaplan-Meier estimates will be 
provided for the survival rates at 3, 6, 9, and 12 months along with their 95% CIs. Additionally, a 
comparison will be conducted between trilaciclib and placebo. The two-sided p-value from a 
Cox proportional hazard model will be presented, the model includes treatment and stratification 
factors as fixed effects. The HR between the two treatment groups, together with its 80% CIs 
will be presented. 
6.2.7.1.4. 
Multiplicity Adjustments 
The clinical trial evaluates the objectives defined in terms of the comparison of Trilaciclib + 
Topotecan 1.5 mg/m2 group to placebo + topotecan group on the primary and key secondary 
myelosuppression efficacy endpoints in Sections 5.1.1 and 5.1.2. The resulting multiplicity 
problem include the following six hypotheses of no effect: 
• Hypothesis 𝐻𝐻1. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo 
+ topotecan group for duration of severe (Grade 4) neutropenia in Cycle 1. 
• Hypothesis 𝐻𝐻2. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo 
+ topotecan group for occurrence of severe (Grade 4) neutropenia. 
• Hypothesis 𝐻𝐻3. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo 
+ topotecan group for all-cause dose reductions in the MAHE composite. 
• Hypothesis 𝐻𝐻4. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo 
+ topotecan group for occurrence of RBC transfusions on/after Week 5 on study. 
• Hypothesis 𝐻𝐻5. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo 
+ topotecan group for occurrence of G-CSF administration. 
• Hypothesis 𝐻𝐻6.Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo 
+ topotecan group for occurrence of platelet transfusions. 
A Hochberg-based gatekeeping procedure will be utilized to control the global familywise error 
rate across the multiple null hypotheses in the strong sense at a 1-sided α=0.10 level. The one-
sided 𝑝𝑝-values for these comparisons will be used for the multiple test procedure, and the raw 
and adjusted 1-sided 𝑝𝑝-values will be provided in the summary.  
Gatekeeping procedure with logical restrictions 
A Hochberg-based gatekeeping procedure satisfies the positive dependence condition given the 
1-sided setting. The procedure is built using the mixture methodology developed in Dmitrienko 
and Tamhane (2011) and accounts for the logical restrictions among the 12 hypotheses displayed 
in Figure 6 by performing multiplicity adjustments in three steps. The logical restrictions can be 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
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achieved by defining the parallel set and serial set for each individual hypothesis based the tree-
structured procedure introduced by Dmitrienko et al (2007).  
• Step 1. The Group 3 versus Group 1 comparisons for Family 1 (hypothesis 𝐻𝐻1) is performed 
using a truncated version of the Hochberg procedure. The truncation parameter γ is set to 0.  
• Step 2. The Group 3 versus Group 1 comparisons for Family 2 (hypothesis 𝐻𝐻2) is performed 
using a truncated version of the Hochberg procedure if 𝐻𝐻1 is significant in Step 1. The 
truncation parameter γ is set to 0.   
• Step 3. The Group 3 versus Group 1 comparisons for Family 3 (hypotheses 𝐻𝐻3, 𝐻𝐻4, 𝐻𝐻5, and 
𝐻𝐻6) are performed using the regular Hochberg test if 𝐻𝐻2 is significant in Step 2. 
Figure 6 
Graphical Display of the Hochberg-based Gatekeeping Procedure 
 
The logical restrictions in the Step 1 and Step 2 contain only one single hypothesis, and the Step 
3 has four hypotheses 𝐻𝐻3, 𝐻𝐻4, 𝐻𝐻5, and 𝐻𝐻6 though the testing procedure can be broadly 
considered as a fixed sequence procedure, its implementation can be performed through the 
framework of Hochberg-based gatekeeping procedure as described in detail below. 
The regular Hochberg test is defined in Dmitrienko et al. (2009) and the truncated Hochberg test 
is defined in Dmitrienko, Tamhane and Wiens (2008). The decision rules used in the regular and 
truncated Hochberg tests will be detailed in the following. In general terms, the truncated version 
of the Hochberg test is defined as a convex combination of the regular Hochberg and Bonferroni 
tests. An important parameter of the truncated Hochberg test is the truncation parameter γ which 
ranges between 0 and 1. If the truncation parameter γ is set to 0, the truncated Hochberg test 
simplifies to the Bonferroni test. On the other hand, if the truncation parameter γ is set to 1, the 
truncated Hochberg test is identical to the regular Hochberg test. The truncated Hochberg test 
satisfies the separability condition (Dmitrienko, Tamhane and Wiens, 2008) if the truncation 
parameter γ is strictly less than 1. This condition ensures that in each step of the testing algorithm 
the error rate can be transferred to the next step provided at least one Trilaciclib + Topotecan 1.5 
H2: Occurrence of 
severe neutropenia 
H1: Duration of severe 
neutropenia in Cycle 1 
Family 1, F1 
One-sided α = 0.10 
H3: All-cause 
Dose reduction 
H4: Occurrence of 
RBC transfusion 
on/after 5 weeks 
on study 
Family 2, F2 
Family 3, F3 
H5: Occurrence of 
G-CSF 
Administration 
H6: Occurrence of 
platelet Transfusion 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
CONFIDENTIAL 
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mg/m2 group versus placebo + topotecan group comparison is significant in the current step 
without inflating the overall type I error rate (Huque, 2016; FDA, 2017). 
Testing algorithm 
This section describes the implementation of the Hochberg-based gatekeeping procedure. The 
testing algorithm relies on the general approach to defining multistage gatekeeping procedures 
based on mixtures of multiple tests proposed in Dmitrienko and Tamhane (2011). 
Decision rules 
The aforementioned 6 hypotheses are grouped into 3 families: 
• Family 1 (𝐹𝐹1) includes the hypotheses 𝐻𝐻1. 
• Family 2 (𝐹𝐹2) includes the hypothesis 𝐻𝐻2. 
• Family 3 (𝐹𝐹3) includes the hypotheses 𝐻𝐻3, 𝐻𝐻4, 𝐻𝐻5, and 𝐻𝐻6. 
Using more compact notation, the families are defined as follows: 
𝐹𝐹1 = {𝐻𝐻𝑖𝑖, 𝑖𝑖∈𝑁𝑁1},  𝐹𝐹2 = {𝐻𝐻𝑖𝑖, 𝑖𝑖∈𝑁𝑁2},  𝐹𝐹3 = {𝐻𝐻𝑖𝑖, 𝑖𝑖∈𝑁𝑁3}. 
where the index sets are defined as 𝑁𝑁1 = {1}, 𝑁𝑁2 = {2}, 𝑁𝑁3 = {3, 4, 5, 6}.  Let 𝑡𝑡𝑖𝑖 and 𝑝𝑝𝑖𝑖 denote 
the test statistic and 1-sided p-values associated with the hypotheses, respectively. Let 𝛼𝛼 denote 
the global familywise error rate, i.e., one-sided 𝛼𝛼= 0.10. 
Consider the closed family associated with Families 1, 2 and 3, i.e., a family of all non-empty 
intersections of the twelve hypotheses. Each intersection will be identified by an index set 
𝐼𝐼⊆𝑁𝑁 = {1, . . . ,6} 
(note that the empty set is excluded). For example, the index vector 𝐼𝐼= {1, 2, 5} corresponds to 
the intersection of the hypotheses 𝐻𝐻1, 𝐻𝐻2, and 𝐻𝐻5. 
To construct the Hochberg-based gatekeeping procedure that controls the global familywise error 
rate in the strong sense at an 𝛼𝛼 level, an 𝛼𝛼-level test needs to be defined for each intersection in 
the closed family. The multiple test and associated 𝑝𝑝-value for an intersection are computed in 
two steps. 
Step 1: Define 𝒑𝒑-values for subset intersections 
Consider an intersection corresponding to the index set 𝐼𝐼⊆𝑁𝑁 and define the index sets 𝐼𝐼𝑘𝑘= 𝐼𝐼∩
𝑁𝑁𝑘𝑘, 𝑘𝑘= 1, 2, 3. The 𝑝𝑝-values for the index sets 𝐼𝐼1, 𝐼𝐼2, and 𝐼𝐼3 are computed as follows: 
Let 𝑛𝑛1 denote the number of hypotheses included in 𝐼𝐼1 and let 𝑚𝑚1 = 𝑛𝑛1. If 𝑛𝑛1 > 0, the truncated 
Hochbergp-value is defined using the ordered 𝑝𝑝-values associated with the hypotheses included 
in the index set 𝐼𝐼1, denoted by  
𝑝𝑝1(1) ≤⋯≤𝑝𝑝1(𝑚𝑚1) 
The truncated Hochberg 𝑝𝑝-value for the index set 𝐼𝐼1 is given by 
𝑝𝑝(𝐼𝐼1) =
min
𝑖𝑖=1,⋯,𝑚𝑚1
𝑝𝑝1(𝑖𝑖)
𝛾𝛾1
𝑚𝑚1 −𝑖𝑖+ 1 + (1 −𝛾𝛾1)
 


 
 
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Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
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Here 𝛾𝛾1 is the pre-specified truncation parameter in Family 1. Choosing a larger value of 𝛾𝛾1 
improves the power of comparisons in Family 1, and 𝛾𝛾1 is set to 0. 
Further, let 𝑛𝑛2 denote the number of hypotheses included in the index set 𝐼𝐼2. If 𝑛𝑛2 > 0, consider 
the hypotheses in the index set 𝐼𝐼2 and remove the hypotheses that are not consistent with the 
logical restrictions defined in Figure 6. Let 𝑚𝑚2 denote the number of hypotheses remaining in the 
index set 𝐼𝐼2 after this logical restriction operation. If 𝑚𝑚2 > 0, let  
𝑝𝑝2(1) ≤⋯≤𝑝𝑝2(𝑚𝑚2) 
denote the ordered 𝑝𝑝-values for the hypotheses remaining in the index set 𝐼𝐼2. The truncated 
Hochberg 𝑝𝑝-value for 𝐼𝐼2 is given by 
𝑝𝑝(𝐼𝐼2) =
min
𝑖𝑖=1,⋯,𝑚𝑚2
𝑝𝑝2(𝑖𝑖)
𝛾𝛾2
𝑚𝑚2 −𝑖𝑖+ 1 + (1 −𝛾𝛾1)
 
where 𝛾𝛾2 is the pre-specified truncation parameter in Family 2, which plays the same role as 𝛾𝛾1 
in Family 1, and 𝛾𝛾2 is set to 0. 
Finally, let 𝑛𝑛3 denote the number of hypotheses included in 𝐼𝐼3. If 𝑛𝑛3 > 0, remove the hypotheses 
that are not consistent with the logical restrictions defined in Figure 6. Let 𝑚𝑚3 denote the number 
of hypotheses remaining in the index set 𝐼𝐼3 after this logical restriction operation. If 𝑚𝑚3 > 0, let  
𝑝𝑝3(1) ≤⋯≤𝑝𝑝3(𝑚𝑚3) 
denote the ordered 𝑝𝑝-values for the hypotheses remaining in the index set 𝐼𝐼3. The Hochberg 𝑝𝑝-
value for 𝐼𝐼3 is given by 
𝑝𝑝(𝐼𝐼3) =
min
𝑖𝑖=1,⋯,𝑚𝑚3
𝑝𝑝3(𝑖𝑖)
1
𝑚𝑚3 −𝑖𝑖+ 1
 
Step 2: Define overall 𝒑𝒑-value 
The overall 𝑝𝑝-value for the intersection corresponding to the index set 𝐼𝐼 is computed by 
combining the 𝑝𝑝-values associated with the index sets 𝐼𝐼1, 𝐼𝐼2, and 𝐼𝐼3. Consider the following three 
scenarios: 
• If 𝑛𝑛1 > 0, the overall 𝑝𝑝-value is found using the following mixing function: 
𝑝𝑝(𝐼𝐼) = min ൬𝑝𝑝(𝐼𝐼1)
𝑏𝑏1
, 𝑝𝑝(𝐼𝐼2)
𝑏𝑏2
, 𝑝𝑝(𝐼𝐼3)
𝑏𝑏3
൰  
where 𝑏𝑏1 = 1,  𝑏𝑏2 = 𝑏𝑏1(1 −𝑓𝑓1 ), 𝑏𝑏3 = 𝑏𝑏2(1 −𝑓𝑓2 ) and 𝑓𝑓1 and 𝑓𝑓2 are computed based on the 
error rate functions of the truncated Hochberg tests used in Families 1 and 2. These quantities are 
defined below. 
• If 𝑛𝑛1 = 0 and 𝑛𝑛2 > 0, the overall 𝑝𝑝-value is given by 
𝑝𝑝(𝐼𝐼) = min ൬𝑝𝑝(𝐼𝐼2)
𝑏𝑏2
, 𝑝𝑝(𝐼𝐼3)
𝑏𝑏3
൰  
where  𝑏𝑏2 = 1, 𝑏𝑏3 = 𝑏𝑏2(1 −𝑓𝑓2 ). 
• If 𝑛𝑛1 = 0, 𝑛𝑛2 = 0 and 𝑛𝑛3 > 0, the overall 𝑝𝑝-value is given by 


 
 
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Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
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𝑝𝑝(𝐼𝐼) = 𝑝𝑝(𝐼𝐼3)
𝑏𝑏3
 
where 𝑏𝑏3 = 1. 
The error rate function of the truncated Hochberg test with the truncation parameter 𝛾𝛾𝑘𝑘 for 
testing an intersection corresponding to the index set 𝐼𝐼𝑘𝑘, 𝑘𝑘= 1, 2, is defined as 
𝑒𝑒𝑘𝑘(𝐼𝐼𝑘𝑘) = 𝑃𝑃[𝑝𝑝(𝐼𝐼𝑘𝑘) ≤𝛼𝛼] 
and 𝑓𝑓𝑘𝑘= 𝑒𝑒𝑘𝑘(𝐼𝐼𝑘𝑘)/𝛼𝛼, 𝑘𝑘= 1, 2. It is shown in Brechenmacher et al. (2011) that 
𝑒𝑒𝑘𝑘(𝐼𝐼𝑘𝑘) = [𝛾𝛾𝑘𝑘+ (1 −𝛾𝛾𝑘𝑘)|𝐼𝐼𝑘𝑘|/𝑛𝑛𝑘𝑘]𝛼𝛼 
if the index set 𝐼𝐼𝑘𝑘 is non-empty and 𝑒𝑒𝑘𝑘(𝐼𝐼𝑘𝑘) = 0 the index set 𝐼𝐼𝑘𝑘 is empty. Here |𝐼𝐼𝑘𝑘| denotes the 
number of hypotheses included in the index set 𝐼𝐼𝑘𝑘.  
As shown in Dmitrienko and Tamhane (2011), the resulting test for the intersection 
corresponding to the index set 𝐼𝐼 is an 𝛼𝛼-level test. This implies that the Hochberg-based 
gatekeeping procedure controls the global familywise error rate in the strong sense at a one-sided 
𝛼𝛼= 0.10. 
Multiplicity-adjusted p-values 
Multiplicity-adjusted 𝑝𝑝-values for the Hochberg-based gatekeeping procedure are computed 
using the closure principle. For each hypothesis, the adjusted 𝑝𝑝-value is defined as the maximum 
over the 𝑝𝑝-values associated with the intersections in the closed family that include the 
hypothesis of interest. For example, the adjusted 𝑝𝑝-value for 𝐻𝐻2 is the maximum over the 𝑝𝑝-
values for intersections containing 𝐻𝐻2. The calculations are performed using the decision matrix 
algorithm, see Dmitrienko and Tamhane (2011).  
Regular and truncated Hochberg tests 
Consider a general problem of testing m null hypotheses denoted by 𝐻𝐻1, . . . , 𝐻𝐻𝑚𝑚. Let 𝑝𝑝1, . . . , 𝑝𝑝𝑚𝑚 
denote the associated raw p-values. Further, let 𝑝𝑝(1) < ⋯< 𝑝𝑝(𝑚𝑚) denote the ordered p-values and 
𝐻𝐻(1) < ⋯< 𝐻𝐻(𝑚𝑚) denote the hypotheses corresponding to the ordered p-values. 
The regular Hochberg test is based on the following testing algorithm: 
• Step 1: If 𝑝𝑝(𝑚𝑚) > 𝛼𝛼, accept 𝐻𝐻(𝑚𝑚) and go to Step 2, otherwise reject all null hypotheses 
and stop. 
• Step 𝑖𝑖= 2, . . . , 𝑚𝑚−1: If 𝑝𝑝(𝑚𝑚−𝑖𝑖+1) > 𝛼𝛼/𝑖𝑖, accept 𝐻𝐻(𝑚𝑚−𝑖𝑖+1) and go to Step 𝑖𝑖+ 1, 
otherwise reject all remaining null hypotheses and stop. 
• Step 𝑚𝑚: If 𝑝𝑝(1) > 𝛼𝛼/𝑚𝑚, accept 𝐻𝐻(1), otherwise reject 𝐻𝐻(1)· 
The truncated Hochberg test with the truncation parameter 𝛾𝛾 is based on the following testing 
algorithm: 
• Step 1: If 𝑝𝑝(𝑚𝑚) > [𝛾𝛾+ (1 −𝛾𝛾)/𝑚𝑚]𝛼𝛼, accept 𝐻𝐻(𝑚𝑚) and go to Step 2, otherwise reject all 
null hypotheses and stop. 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
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• Step 𝑖𝑖= 2, . . . , 𝑚𝑚−1: If 𝑝𝑝(𝑚𝑚−𝑖𝑖+1) > [𝛾𝛾/𝑖𝑖+ (1 −𝛾𝛾)/𝑚𝑚]𝛼𝛼, accept 𝐻𝐻(𝑚𝑚−𝑖𝑖+1) and go to 
Step 𝑖𝑖+ 1, otherwise reject all remaining null hypotheses and stop. 
• Step 𝑚𝑚: If 𝑝𝑝(1) > 𝛼𝛼/𝑚𝑚, accept 𝐻𝐻(1), otherwise reject 𝐻𝐻(1) 
6.2.7.1.5. 
Robustness of Primary and Key Secondary Efficacy Analyses 
A binary response variable (Yes, No) will be analyzed to compare trilaciclib and placebo using 
stratum-adjusted method to account for the baseline ECOG status (0 to 1 vs. 2) and sensitivity to 
first-line treatment (sensitive or resistant) as the stratification factors. The adjusted proportion 
difference (trilaciclib vs placebo) and its 80% CIs will be calculated using Cochran-Mantel-
Haenszel (CMH) weight outlined in Kim et al. 2013. The two-sided p-value will be calculated 
using stratified exact CMH method. Additionally, three sets of sensitivity analysis will be 
conducted to evaluate the robustness of the results from primary or key secondary analyses for a 
binary response variable (Yes, No).  
(i) 
For patients who die during the treatment period without experiencing an event, Yes will 
be assigned to the variable.  
(ii) After the imputation from (i), a worst-comparison analysis will be done to establish a 
stringent boundary of the treatment effect. Patients who die during the treatment period will 
still be set to Yes, and patients who discontinue the study prior to the September 28, 2018 
data cutoff date without experiencing an event will then be imputed. If the patient is from 
the placebo group, No will be assigned to the variables, Yes will be assigned to the 
trilaciclib groups.  
(iii) After the imputation from (i), a tipping-point analysis (Yan et al,. 2009) will be performed 
by assigning the response to the variable for patients who discontinue the study early 
during the treatment period without experiencing an event. 
The tipping-point analysis assumes all possible combinations of numbers of Yes and No for 
the missing responses (defined as patients without an event who have discontinued the 
study prior to the September 28, 2018 data cutoff date) in the trilaciclib and placebo 
groups. For example, let nt be the number of randomized trilaciclib patients with missing 
response and np be the number of randomized placebo patients with missing responses. For 
the trilaciclib patients with missing values, there are nt + 1 possible assumptions for 
number of No (i.e. 0, 1, 2, …, to nt); for the placebo patients with missing values, there are 
np + 1 possible assumptions for number of No.  Therefore, there are total of (nt + 1) × (np + 
1) possible combination of assumptions for number of No and Yes for the trilaciclib and 
placebo patients with missing responses. The un-stratified exact CMH method will be 
performed on the available responses with each of these (nt + 1) × (np + 1) assumptions and 
will be summarized. A figure will be presented with points representing each possible 
combination where the significant p-value ‘tips’ to greater than a one-sided 0.10, which 
would represent a change in the study conclusions. Clinical justification will be provided to 
evaluate whether the assumption is plausible.   
A waterfall plot showing the number of cycles with SVN will be presented. 
DSN for each cycle will be presented using descriptive statistics. The primary analysis on DSN 
defined by Strategy 1 (refer to Section 5.1.1.2.1) will be repeated on DSN defined by Strategy 3 
(refer to Section 5.1.1.2.3). 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
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Each of the analyses will be repeated using two additional distinct data sets to evaluate the 
confounding effect of GCSF administration: inclusion of only those patients or cycles who had 
concurrent GCSF administration; and inclusion of only those patients or cycles who did NOT 
have concurrent GCSF administration.  The “with” and “without” GCSF analyses are subsets of 
the total number of patients or cycles. 
 
DSN, Strategy 2 (refer to Section 5.1.1.2.2) will be summarized using Kaplan-Meier method, 
and the descriptive statistics of median, 25% and 75% percentiles along with their 95% CIs will 
be calculated. Additionally, DSN for each cycle will be presented using descriptive statistics. 
In addition to the summary from Kaplan-Meier method, the two-sided p-value will be obtained 
from the stratified Kaplan-Meier method to account for the stratification factors of ECOG (0 or 1 
vs. 2) and sensitivity to first-line treatment (sensitive or resistant). The hazard ratio (HR) 
between the two treatments (trilaciclib vs placebo), together with its 80% CIs will be calculated 
from a Cox proportional hazard model in which treatment and the stratification factors will be 
included as fixed effects. 
For RBC transfusions, subsets of subjects with baseline HGB <9 g/L and ≥9 g/L will be 
provided, as well as a summary of the number of units transfused. 
The primary and key secondary efficacy endpoints are based on the ITT analysis set, and the 
analysis will be repeated for the mITT analysis set and PP analysis set. 
6.2.7.2. 
Supportive Efficacy Analyses 
6.2.7.2.1. 
Analyses of Total Number of MAHE 
The total number of MAHE in Section 5.1.3.1 will be analyzed to compare trilaciclib and 
placebo using a negative binomial regression model to account for the potential over-dispersion. 
The model includes the stratification factors of ECOG (0 or 1 vs. 2) and sensitivity to first-line 
treatment (sensitive or resistant), and treatment as a fixed effect. The logarithm transformation of 
duration of treatment period divided by 7 (i.e. week) will be included as an offset variable in the 
modeling. The two-sided p-value, aRR (trilaciclib vs placebo) and its 80% CIs will be presented.  
The total number of MAHE will be summarized descriptively, along with the weeks of treatment 
duration, and the event rate per week (calculated as the total number of events/duration of 
treatment period divided by 7 [i.e. week]). The cumulative incidence of events during the 
treatment period will be summarized and presented graphically in three-week intervals. 
The total number of individual MAHE components (specified in Table 4) will be summarized 
similarly, except that DSN > 5 days will be summarized cumulatively by cycle instead of three-
week intervals, and the offset will be the logarithm transformation of number of cycles instead of 
duration of treatment period. 
Time-to-first MAHE endpoints (overall and individually) in Section 5.1.3.1 will be summarized 
similar to DSN, Strategy 2 as described in Section 6.2.7.1.5. A graphical display of cumulative 
incidence will also be presented. 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
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An event chart of the treatment period will also be included, with horizontal bars for each 
subject’s cycle length and time on the x-axis, with points plotted for each of the MAHE 
components. 
For the time (days) to first occurrence of a MAHE event, a graphical display of cumulative 
incidence will be presented. 
6.2.7.2.2. 
Analyses of Objective Response 
The patients in each category of TPR according to the investigator tumor assessment (CR, PR, 
SD, PD, or NE) will be presented in a data listing. The number and percentage of patients in each 
category of BOR (Confirmed CR, Confirmed PR, SD, PD, or NE), ORR, ORRUNCONFIRMED and 
CBR according to the investigator tumor assessment (Confirmed CR, Confirmed PR, SD, PD, or 
NE) will be summarized. Detailed information of deriving tumor relevant responses is provided 
in Section 5.1.3.2.4.    
Similar analyses will be repeated based on the derived responses according to the RECIST 
Version 1.1.  
Estimates of response rate, along with its associated exact 95% two-sided CIs using Clopper-
Pearson method will be computed for ORR and CBR within each treatment group.  
The binary endpoint (Yes, No) of ORR for the two treatments (trilaciclib and placebo) will be 
analyzed to compare trilaciclib and placebo using stratum-adjusted method to account for the 
stratification factors of ECOG (0 or 1 vs. 2) and sensitivity to first-line treatment (sensitive or 
resistant). The adjusted proportion difference (trilaciclib vs placebo) and its 80% CIs will be 
calculated using CMH weight outlined in Kim et al. 2013. The two-sided p-value will be 
calculated using stratified exact CMH method.   
The analyses are based on the response evaluable analysis set. The supportive data listings will 
also be provided. 
Subsets based on subjects with and without dose reductions will also be included. 
A waterfall plot showing the best % change in target lesion sum will also be included. 
6.2.7.2.3. 
Analyses of DOR and PFS 
The analysis method as described in Section 6.2.7.1.3 for OS will be applied to PFS (derived, 
and derived with clinical progression) and DOR (investigator and derived), except DOR will 
exclude the Kaplan-Meier estimates for the survival rates at 3, 6, 9, and 12 months as well as the 
Cox proportional hazard model. 
Spider plot by treatment group of % change in target lesion from baseline for each subject over 
time will be included based on derived assessments. Points will be included for best overall 
response (if CR or PR), new lesions, and end of treatment. 
An event chart of the treatment period will also be included, with horizontal bars for each 
subject’s cycle length and time on the x-axis, with points plotted for start and end of DOR. 
For DOR, the analysis is based on the response evaluable analysis set; for PFS the analysis will 
be based on the ITT. The supportive data listings will also be provided. For the PFS, the derived 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
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endpoint based on only radiologic progression will be considered as the primary, and the derived 
endpoint based on both radiologic and clinical progression will be considered as supportive.  
6.2.7.2.4. 
Analyses of Hematology Lab Values 
For the endpoints specified in Sections 5.1.3.4 and 5.1.3.5, in addition to descriptive statistics 
summary, appropriate graphical display will be provided to facilitate evaluation of trends in the 
change in a given variable over time. Moreover, each of the ANC change over time analysis (i.e. 
observed value at windowed visit and cycle nadir) specified above will be done using three 
distinct data sets to evaluate the confounding effect of GCSF administration: all patients or 
cycles regardless of GCSF administration; inclusion of only those patients or cycles who had 
concurrent GCSF administration; and inclusion of only those patients or cycles who did NOT 
have concurrent GCSF administration.  The “with” and “without” GCSF analyses are subsets of 
the total patient or cycles. 
Figures of mean and 95% CI over time will be provided for ANC (with GCSF subsets also), 
platelet counts, HGB, change from baseline HGB, and ALC. Additionally, jitter scatter plots will 
be provided for mean and 95% CI by cycle for ANC nadir (with GCSF subsets also). 
A Radar plot of grade 3/4 laboratory abnormalities during the treatment period, and during the 
first cycle will be presented. 
6.2.7.2.5. 
Analyses of Other Binary Efficacy Endpoints 
The following binary response variables (Yes, No) will be analyzed using the same method for 
occurrence of SVN except baseline ANC will not be a covariate in the modified Poisson model. 
See Section 6.2.7.1.1: 
• Occurrence of a Grade 3 or 4 hematologic toxicity during the treatment period (refer to 
Section 5.1.3.3); 
• Occurrence of an ESA administration during the treatment period (refer to Section 5.1.3.6); 
• Occurrence of an IV antibiotic administration during the treatment period (refer to Section 
5.1.3.7); The offset in the modified Poisson model will be the logarithm transformation of 
duration of treatment period divided by 7 (i.e. week) instead of number of cycles. 
Additionally, total number of IV antibiotic administrations will be summarized descriptively. 
• Occurrence of an infection SAE during the treatment period (refer to Section 5.1.3.8); The 
offset in the modified Poisson model will be the logarithm transformation of duration of 
treatment period divided by 7 (i.e. week) instead of number of cycles. Additionally, total 
number of infection SAEs will be summarized descriptively. 
• Occurrence of a pulmonary infection SAE during the treatment period (refer to Section 
5.1.3.9). The offset in the modified Poisson model will be the logarithm transformation of 
duration of treatment period divided by 7 (i.e. week) instead of number of cycles. 
Additionally, total number of pulmonary infection SAEs will be summarized descriptively. 
• Occurrence of a Grade 4 and Grade 3 or 4 thrombocytopenia (laboratory values) during the 
treatment period (refer to Section 405.1.3.11); 


 
 
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Clinical Study Protocol G1T28-03                                       
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6.2.7.2.6. 
Analysis of Myelosuppression Endpoints with All data up to End of Cycle 4 
The analyses outlined in Section 5.1.3.12 will be analyzed using the same methods using the 
same methods as the analogous primary, secondary, and supportive efficacy analyses, except 
they will only use data up through the end of Cycle 4. 
For Occurrence of severe (Grade 4) neutropenia see Section 6.2.7.1.1; For Occurrence of RBC 
transfusions on/after week 5 of study, Occurrence of GCSF administrations, Occurrence of 
platelet transfusions, and Occurrence of RBC transfusions during the first 4 cycles see Section 
6.2.7.1.2. 
For Total number of MAHE, Number of all-cause hospitalizations, Number of cycles with all-
cause dose reductions, Number of febrile neutropenia, Number of cycles with prolonged severe 
(Grade 4) neutropenia (duration > 5 days), Number of RBC transfusions on/after 5 weeks, 
Number of platelet transfusions, and Number of RBC transfusions during the first 4 cycles see 
Sections 6.2.7.1.2 and 6.2.7.2.1. 
For Occurrence of Grade 3 and 4 hematologic toxicities see Section 6.2.7.2.5. 
6.2.7.3. 
Exploratory Efficacy Analyses  
For all three exploratory endpoints listed in Sections 5.1.4.2, 5.1.4.3, and 5.1.4.4, the data will 
only be summarized using descriptive statistics, hence, the general rules outlined in Section 6.1.1 
will be followed. Moreover, the supportive data listings will be provided. 
6.2.8. 
Safety Analyses 
All safety analyses will be based on the safety analysis set, as defined in Section 3.1.2.  
Descriptive statistics will be used to summarize the safety outcomes. The continuous safety 
variables will be summarized at each visit including end of each cycle (the last non-missing 
assessment during the cycle), end of treatment (the last non-missing assessment during the 
treatment period), and end of study (the last non-missing assessment during the whole study), if 
applicable. No inferential analyses of safety data are planned unless otherwise specified. 
6.2.8.1. 
Chemotherapy Exposure and Compliance Analyses 
Duration on treatment and number of cycles will be summarized by treatment. Dose intensity for 
each study drug (topotecan or trilaciclib/placebo) will be summarized for patients in Part 1; only 
trilaciclib/placebo will be summarized for Part 2. Dose modifications will be summarized for 
each study drug (topotecan or trilaciclib/placebo). For each study drug, the dosing endpoints 
described in Section 5.2.1 will be summarized by treatment. This includes the following: 
• Number of cycles received; 
• Number of missed doses; 
• Number of dose reductions; 
• Number of dose interruptions;   
• Number of patients with missed dose and its reason; 
• Number of patients with dose reductions and reason; 
• Number of patients with dose interruptions. 
• Number of doses 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
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The number of cycles delayed, the number and percentage of patients experiencing a treatment 
cycle delay, and reason for cycle delay will be summarized by treatment. The study dosing 
records and the derived dosing endpoints will be listed. 
6.2.8.2. 
Adverse Events 
Number and incidence rates of AEs will be summarized by SOC and/or PT for the following 
categories of TEAEs: all AEs, SAEs, AEs leading to death, and AEs leading to study drug 
(topotecan or trilaciclib/placebo) discontinuation or study withdrawal. Patients with more than 
one occurrence of the same SOC (PT) will be counted only once within the SOC (PT) 
categorization.   
AEs will also be summarized similarly by CTCAE grade and relationship to any study drug 
(topotecan or trilaciclib/placebo), and by relationship to each drug. Should a patient experience 
more than one occurrence of the same SOC (PT), the patient’s worst occurrence (worst 
grade/most related causality) will be retained in the tabulation.    
All AEs, including AEs that started prior to the study medication, will be presented in patient 
listings. In addition, separate listings of all SAEs, AEs leading to death, drug-related AEs, AEs 
leading to study drug (topotecan or trilaciclib/placebo) discontinuation or study withdrawal, and 
DLTs will be provided. 
The criteria for identifying infusion related reaction AEs or hematologic toxicity AEs are 
described in Section 5.2.1. A summary table showing incidence of AEs related to infusion and 
related to hematologic toxicity will be presented along with its supportive data listing.     
6.2.8.3. 
Laboratory Evaluations 
For hematology and clinical chemistry labs the observed values and change from baseline will be 
summarized for each visit during the treatment period using descriptive statistics.   
Toxicities for clinical labs will be characterized according to CTCAE, Version 4.03 (Table A-1 
of Appendix when possible), and the frequency and percentage of patients with each CTCAE 
grade for each visit during the treatment period will be described. Moreover, any occurrence of 
grade 3 or grade 4 during the treatment period will be summarized, and shift in grade from 
baseline to the worst post-baseline value will be summarized. Both the scheduled and 
unscheduled assessments will be used to identify the worst post-baseline values. 
Listings of all laboratory data, normal reference ranges, and CTCAE grades (when possible) will 
be provided.    
6.2.8.4. 
Vital Signs 
For vital sign parameters (Systolic Blood Pressure, Diastolic Blood Pressure, Pulse Rate, 
Temperature, and Weight) the observed values and change from baseline will be summarized 
using descriptive statistics at each visit during the treatment period.  
Additionally, the frequency and percentage of patients with any potentially clinically significant 
findings (defined in Table 13) during the treatment period will be presented. A listing of all vital 
sign data will be provided.  


 
 
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Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
CONFIDENTIAL 
      Page 66 of 73 
 
                                                 
 
6.2.8.5. 
Performance Status  
Descriptive statistics will be presented for ECOG score for the observed values and change from 
baseline. A listing of ECOG score for all patients will be provided.   
6.2.8.6. 
Physical Examination 
A listing of physical examination findings for all patients will be provided (where available). 
6.2.8.7. 
ECG 
Descriptive statistics will be presented for each ECG parameter for the observed values and 
change from baseline to post baseline. A listing of all ECG data will be provided.  
The criteria for potentially clinically significant findings are defined in Table 15. The frequency 
and percentage of patients with any potentially clinically significant findings during the 
treatment period will be presented. The supportive data will be provided in patient data listings.  
6.2.9. 
Subgroup Analyses 
The MAHE, OS, and PFS will be examined in the following subgroups: 
− Age group (ages <65; ≥65). 
− Gender (Male; Female). 
− ECOG performance status (0-1; 2). 
− Sensitivity to first treatment (Sensitive; Resistant). 
− Race (Caucasian; non-Caucasian). 
− Region (US; Ex-US). 
− Baseline LDH (≤ ULN; > ULN). 
Descriptive statistics by treatment group will be presented for each subgroup of patients.  
Additional subgroups or endpoints may be identified and explored.  
6.2.10. 
Pharmacokinetic Analysis 
The PK analysis for a subset of patients will be documented separately and is not covered in this 
SAP. 
6.2.11. 
Assess Genetic and/or Expression (RNA/Protein) Biomarkers in Tumors and 
Blood 
A detailed description of the biomarker analysis plan will be documented separately.  In general, 
as data permits, the analyses may include, but not be limited to: 
1. SCLC tumor samples may be assessed for markers of CDK 4/6 dependence and 
independence (including but not limited to PD-L1, PD-1, and others) as defined by IHC 
or qRT-PCR on biological/clinical endpoints.   
2. SCLC tumor samples may be assessed for markers to potentially predict sensitivity to 
trilaciclib treatment. 
3. Peripheral blood samples may be assessed for biomarkers examining the role of trilaciclib 
in the preservation of hematopoietic and immune populations during chemotherapy 
treatment 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
CONFIDENTIAL 
      Page 67 of 73 
 
                                                 
 
4. Peripheral blood samples may be assessed for biomarkers examining the role of trilaciclib 
in anti-tumor immunity 
6.2.12. 
Planned Analysis  
The final myelosuppression analysis will be conducted after all patients have had the opportunity 
to receive at least 12 weeks of treatment. All study data collected through the time of the final 
myelosuppression analysis data cut will be included. This includes, but is not limited to the final 
myelosuppression analysis, interim ORR analysis based on investigator assessment, and interim 
PFS/OS analysis. 
The time of analysis with at least 80% of patients having experienced a progression will be 
considered to be final PFS analysis. Patients will be followed for survival until at least 70% of 
the patients have died, and a final OS analysis will be done then. Additional exploratory analyses 
of OS/PFS may between the final myelosuppression analysis and study completion. Reported 
results, with the exception of the myelosuppression analyses, will be cumulative in nature, 
including all data collected during the entire study; the myelosuppression analyses will be 
complete at the final analysis and no additional data will be expected. 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
CONFIDENTIAL 
      Page 68 of 73 
 
                                                 
 
7. 
CHANGE FROM THE PROTOCOL 
The timing of the final analysis, analysis sets, and endpoints were updated based on scientific advice, 
regulatory guidance, and feedback on other trilaciclib studies. The endpoints and analyses listed below 
are based on the Statistics Section in the Protocol Amendment 5, dated 27 June 2018. The list 
displays the endpoints and analyses which are removed from the initial analysis and are therefore 
not described in the SAP.    
Protocol Section 13.4.1 (Efficacy Endpoints): 
• Hematologic kinetic endpoints: 
o Change and percent change in hematologic parameter values from predose for a 
particular cycle to the end of that cycle 
o Change and percent change in hematologic parameter values from predose for a 
particular cycle to nadir for that cycle 
o Rate of change in hematologic parameter values from predose for a particular cycle to 
nadir for that cycle 
o Change and percent change in hematologic parameter values from nadir for a 
particular cycle to the end of that cycle 
o Rate of change in hematologic parameter values from nadir for a particular cycle to 
the end of that cycle 
o Area under the curve in hematologic parameter values from predose for a particular 
cycle to the end of that cycle 
o Area under the curve in hematologic parameters from predose for a particular cycle to 
nadir for that cycle 
o Area under the curve in hematologic parameter values from nadir for a particular 
cycle to the end of that cycle 
o Time to hematologic parameter value nadir by cycle 
o Time to return to predose hematologic parameter values by cycle 
o Proportion of patients with a return to predose hematologic parameter values by cycle 
• Hematologic toxicity endpoints: 
o Proportion of patients with a hematologic toxicity recovery by cycle. 
o Time to hematologic toxicity recovery by cycle 
• Exploratory efficacy endpoints: 
o Composite hematologic score 
o Composite efficacy score 
Protocol Section 13.4.2.1 (Analysis of Hematologic Parameter Kinetic Endpoints) 
• Additional tabulations for each cycle of treatment in maximum postnadir values. 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
CONFIDENTIAL 
      Page 69 of 73 
 
                                                 
 
• The tabulation of the changes and percent changes from predose to nadir, predose to end of 
cycle, nadir to maximum postnadir, and nadir to end of cycle values for each cycle of 
treatment. 
• Analysis of covariance (ANCOVA) models on hematologic parameter kinetic endpoints 
• Summarization of time to nadir. 
• Descriptive statistics and ANCOVA of area under the curve (AUC) in hematologic 
parameters 
• Repeated-measures model of AUC 
• Summary of proportion of patients return to predose value for each cycle. calculation on 
incidence rate, adjusting for cumulative exposure 
• Analysis of time to return to predose level for each cycle using Kaplan-Meier method. 
• Analysis of Time to return to postnadir predose levels 
Protocol Section 13.4.2.2 (Analysis of Hematologic Toxicity Endpoints)  
• Calculation and analysis of incidence rate of hematologic toxicity, adjusting for cumulative 
exposure 
• Calculation and analysis of toxicity rate relative to cumulative exposure (total number of 
toxicities divided by cumulative exposure).  
• Recurrent events model estimating the incidence of Grade 3 or higher hematologic toxicities 
and testing for the difference between treatment groups. 
• For each hematologic parameter and cycle, the shift summaries of the following: 
o From predose toxicity to maximum on treatment toxicity;  
o from predose toxicity to end of cycle toxicity; 
o from maximum postdose toxicity to end of cycle toxicity. 
Protocol Section 13.4.2.4 (Other Efficacy Endpoints) 
• The number and percent of infections summarized by maximum severity 
• The infection rate: The number of infections occurring during the Treatment divided by 
cumulative exposure. 
Protocol Section 13.6 (Exploratory Analyses) 
• The relationship between hematologic toxicity rates and changes with study drug (topotecan 
or trilaciclib/placebo) exposure 
• The association between composite endpoints and BOR, OS, and PFS 
• The FACT-L and FACT-An analyses analysis in the section is not covered in the SAP 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
CONFIDENTIAL 
      Page 70 of 73 
 
                                                 
 
8. 
REFERENCES 
Brechenmacher T, Xu J, Dmitrienko A, Tamhane AC. A mixture gatekeeping procedure based 
on the Hommel test for clinical trial applications. Journal of biopharmaceutical statistics. 2011; 
21: 748-767. 
 
Dmitrienko A, Wiens BL, Tamhane AC, Wang X. Tree-structured gatekeeping tests in clinical 
trials with hierarchically ordered multiple objectives. Statistics in medicine. 2007; 26: 2465- 
2478. 
 
Dmitrienko A, Tamhane, AC, Wiens B. General multistage gatekeeping procedures. Biometrical 
Journal. 2008; 50, 667-677. 
 
Dmitrienko A, Tamhane, AC, Bretz F. Multiple testing problems in pharmaceutical statistics. 
2009. Chapman and Hall/CRC. 
 
Dmitrienko A, Tamhane AC. Mixtures of multiple testing procedures for gatekeeping 
applications in clinical trials. Statistics in Medicine. 2011; 30, 1473-1488. 
 
Eisenhauer, E., Therasse, P., Bogaerts, J., Schwartz, L.H., Sargent, D., Ford, R., Dancey, J., 
Arbuck, S., Gwyther, S., Mooney, M. and Rubinstein, L., 2009. New response evaluation criteria 
in solid tumours: revised RECIST guideline (version 1.1). European journal of cancer, 45(2), 
228-247.  
 
FDA Center for Biologics Evaluation and Research (CBER). Multiple Endpoints in Clinical 
Trials Guidance for Industry. 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
536750.pdf. Published January 2017. Accessed13 September 2018. 
 
Gerrits CJ, Burris H, Schellens JH, et al. Five days of oral topotecan (Hycamtin), a phase I and 
pharmacological study in adult patients with solid tumours. Eur J Cancer. 1998;34(7):1030-
1035. 
 
Grochow LB, Rowinsky EK, Johnson R, et al. Pharmacokinetics and pharmacodynamics of 
topotecan in patients with advanced cancer. Drug Metab Dispos. 1992;20(5):706 713. 
 
Huque MF. Validity of the Hochberg procedure revisited for clinical trial applications. Statistics 
in medicine. 2016; 35:5-20. 
 
Kim Y, Won S. (2013) Adjusted proportion difference and confidence interval in stratified 
randomized trials. PharmaSUG; Paper SP-04. 
 
Montazeri A, Culine S, Laguerre B, et al. Individual adaptive dosing of topotecan in ovarian 
cancer. Clin Cancer Res. 2002;8:394-399. 
O’Reilly S, Rowinsky EK, Slichenmyer W, et al. Phase I and pharmacologic study of topotecan 
in patients with impaired renal function. J Clin Oncol. Dec 1996a;14(12):3062 3073. 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
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O’Reilly S, Rowinsky E, Slichenmyer W, et al. Phase I and pharmacologic studies of topotecan 
in patients with impaired hepatic function. J Natl Cancer Inst. Jun1996b;88(12):817-824. 
 
Yan X, Lee, S and Li N. Missing data handling methods in medical device clinical trials, Journal of 
Biopharmaceutical Statistics, 2009, 19 (6): 1085 — 1098. 
 
Zou G. A modified Poisson regression approach to prospective studies with binary data. 
American journal of epidemiology. 2004;159(7):702-6.


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
CONFIDENTIAL 
      Page 72 of 73 
 
Table A-1 Clinical Laboratory Parameters CTCAE Criteria 
Parameter 
Grade 
1 
2 
3 
4 
5 
Albumin 
<LLN – 3 g/dL; <LLN – 30 g/L 
<3 – 2 g/dL; <30 – 20 g/L 
<2 g/dL; <20 g/L 
- 
- 
ALP 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
- 
ALT 
>ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
- 
AST 
>ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
- 
Bilirubin 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
- 
Calcium (Hypercalcemia) 
Corrected serum calcium 
of >ULN – 11.5 mg/dL; >ULN 
– 2.9 mmol/L 
Corrected serum calcium 
of >11.5 – 12.5 
mg/dL;  >2.9 – 3.1 mmol/L 
Corrected serum calcium 
of >12.5 – 13.5 
mg/dL; >3.1 – 3.4 mmol/L 
Corrected serum calcium 
of >13.5 mg/dL; >3.4 
mmol/L 
- 
Calcium (Hypocalcemia) 
Corrected serum calcium of 
<LLN – 8.0 mg/dL; <LLN – 
2.0 mmol/L 
Corrected serum calcium of 
<8.0 – 7.0 mg/dL;  <2.0 – 
1.75 mmol/L 
Corrected serum calcium of 
<7.0 – 6.0 mg/dL; <1.75 – 
1.5 mmol/L 
Corrected serum calcium of 
<6.0 mg/dL; <1.5 mmol/L 
- 
CK 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5 x ULN 
>5 x ULN – 10 x ULN 
>10 x ULN 
- 
Creatinine 
>1 – 1.5 x baseline;  >ULN – 
1.5 x ULN 
>1.5 – 3.0 x baseline; >1.5 
– 3.0 x ULN 
>3.0 x baseline; >3.0 – 6.0 
x ULN 
>6.0 x ULN 
- 
GGT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
- 
Glucose (Hyperglycemia) 
Fasting glucose value >ULN – 
160 mg/dL; Fasting glucose 
value >ULN – 8.9 mmol/L 
Fasting glucose value >160 
– 250 mg/dL; Fasting 
glucose value >8.9 – 13.9 
mmol/L 
Fasting glucose value >250 
– 500 mg/dL; Fasting 
glucose value >13.9 – 27.8 
mmol/L 
Fasting glucose value >500 
mg/dL; Fasting glucose 
value >27.8 mmol/L 
- 
Glucose (Hypoglycemia) 
<LLN – 55 mg/dL;  <LLN – 
3.0 mmol/L 
<55 – 40 mg/dL;  <3.0 – 
2.2 mmol/L 
<40 – 30 mg/dL;  <2.2 – 
1.7 mmol/L mmol/L 
<30 mg/dL;  <1.7 mmol/L  
- 
Hemoglobin 
<LLN – 10.0 g/dL; <LLN – 6.2 
mmol/L; <LLN – 100 g/L 
<10.0 – 8.0 g/dL; <6.2 – 
4.9 mmol/L; <100 – 80 g/L 
<8.0 g/dL; <4.9 mmol/L; 
<80 g/L 
- 
- 
Potassium 
(Hyperkalemia) 
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
>7.0 mmol/L 
- 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 2  
Version date: 05Dec2018 
 
CONFIDENTIAL 
      Page 73 of 73 
 
Table A-1 Clinical Laboratory Parameters CTCAE Criteria 
Parameter 
Grade 
1 
2 
3 
4 
5 
Potassium (Hypokalemia) <LLN – 3.0 mmol/L 
- 
<3.0 – 2.5 mmol/L 
<2.5 mmol/L 
- 
Lymphocyte 
<LLN – 800/mm3; <LLN – 0.8 
x 10e9 /L 
<800 – 500/mm3; <0.8 – 
0.5 x 10e9 /L 
<500 – 200/mm3; <0.5 – 
0.2 x 10e9 /L 
<200/mm3; <0.2 x 10e9 /L 
- 
ANC 
<LLN – 1500/mm3; <LLN – 
1.5 x 10e9 /L 
<1500 – 1000/mm3; <1.5 – 
1.0 x 10e9 /L 
<1000 – 500/mm3; <1.0 – 
0.5 x 10e9 /L 
<500/mm3; <0.5 x 10e9 /L 
- 
Phosphates 
<LLN – 2.5 mg/dL; <LLN – 
0.8 mmol/L 
<2.5 – 2.0 mg/dL; <0.8 – 
0.6 mmol/L 
<2.0 – 1.0 mg/dL; 0.6 – 0.3 
mmol/L 
<1.0 mg/dL; <0.3 mmol/L 
- 
Platelet Count 
<LLN – 75,000/mm3; <LLN – 
75.0 x 10e9 /L 
<75,000 – 50,000/mm3; 
<75.0 – 50.0 x 10e9 /L 
<50,000 – 25,000/mm3; 
<50.0 – 25.0 x 10e9 /L 
<25,000/mm3; <25.0 x 10e9 
/L 
- 
Sodium (Hypernatremia) 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
>160 mmol/L 
- 
Sodium (Hyponatremia) 
<LLN – 130 mmol/L 
- 
<130 – 120 mmol/L 
<120 mmol/L 
- 
Urate 
>ULN – 10 mg/dL (0.59 
mmol/L) without physiologic 
consequences 
- 
>ULN – 10 mg/dL (0.59 
mmol/L) with physiologic 
consequences 
>10 mg/dL; >0.59 mmol/L 
- 
White blood cell 
<LLN – 3000/mm3; <LLN – 
3.0 x 10e9 /L 
<3000 – 2000/mm3; <3.0 – 
2.0 x 10e9 /L 
<2000 – 1000/mm3; <2.0 – 
1.0 x 10e9 /L 
<1000/mm3; <1.0 x 10e9 /L 
- 
LLN=lower limit of normal range; ULN=upper limit of normal range. 
 

Prot_000.pdf: 
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. 




G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03 
G1T28 
 
Version: 6.0, dated 27 June 2018  
Page 3 of 114  
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 
 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03 
G1T28 
 
Version: 6.0, dated 27 June 2018  
Page 4 of 114  
G1 Therapeutics CONFIDENTIAL 
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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D'Amico D, Carbone D, Mitsudomi T, et al. High frequency of somatically acquired p53 
mutations in small-cell lung cancer cell lines and tumors. Oncogene. 1992;7:339-346. 
Eckhardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with intravenous 
topotecan as second-line therapy in small-cell lung cancer. J Clin 
Oncol. May 2007;25(15):2086-2092. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247. 
Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by 
PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 
2004 Nov;3(11):1427-1438. 
Gallo JM, Laub PB, Rowinsky EK, Grochow LB, Baker SD. Population pharmacokinetic 
model for topotecan derived from Phase 1 clinical trials. J Clin Oncol. 2000; 18:2459-2467. 
Gerrits CJ, Burris H, Schellens JH, et al. Five days of oral topotecan (Hycamtin), a phase I 
and pharmacological study in adult patients with solid tumours. Eur J Cancer. 
1998;34(7):1030-1035. 
Gouyer V, Gazzeri S, Brambilla E, et al. Loss of heterozygosity at the RB locus correlates 
with loss of RB protein in primary malignant neuro-endocrine lung carcinomas. Int J Cancer. 
1994;58:818-824. 
Grochow LB, Rowinsky EK, Johnson R, et al. Pharmacokinetics and pharmacodynamics of 
topotecan in patients with advanced cancer. Drug Metab Dispos. 1992;20(5):706-713. 


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Version: 6.0, dated 27 June 2018 
 
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Heighway J, Betticher DC. Lung: small cell cancer. Atlas of Genetics and Cytogenetics in 
Oncology and Haematology. June 2004 URL : 
http://atlasgeneticsoncology.org/Tumors/LungSmallCellID5142.html. 
Herben VM, ten Bokkel Huinink WW, Beijnen JH. Clinical pharmacokinetics of topotecan. 
Clin Pharmacokinet. 1996;31(2):85-102. 
McDonnell AM, Nowak AK, Lake RA. Contribution of the immune system to the 
chemotherapeutic response. Semin Immunopathol. 2011 Jul;33(4):353-367. 
Molina JR, Kaufmann SH, Reid JM, et al. Evaluation of lapatinib and topotecan combination 
therapy: tissue culture, murine xenograft, and Phase I clinical trial data. Clinical cancer 
research. 2008;14(23):7900-7908. 
Montazeri A, Culine S, Laguerre B, et al. Individual adaptive dosing of topotecan in ovarian 
cancer. Clin Cancer Res. 2002;8:394-399. 
Mould DR, Nicholas HG, Holford MB, et al. Population pharmacokinetic and adverse event 
analysis of topotecan in patients with solid tumors. Clin Pharmacol Ther. 2002;71:334-348. 
O’Reilly S, Rowinsky EK, Slichenmyer W, et al. Phase I and pharmacologic study of 
topotecan in patients with impaired renal function. J Clin Oncol. Dec 
1996a;14(12):3062-3073. 
O’Reilly S, Rowinsky E, Slichenmyer W, et al. Phase I and pharmacologic studies of 
topotecan in patients with impaired hepatic function. J Natl Cancer Inst. 
Jun1996b;88(12):817-824. 
Peifer M, Fernandez-Cuesta L, Sos ML, et al. Integrative genome analyses identify key 
somatic driver mutations of small-cell lung cancer. Nat Genet. 2012;44:1104-1110. 
Ray-Coquard I, Cropet C, Van Glabbeke M, et al. Lymphopenia as a prognostic factor for 
overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res. 
2009 Jul 1;69(13):5383-5391. 
Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 
as a frequently amplified gene in small-cell lung cancer. Nat Genet.2012;44:1111-1116. 
Saltz L, Sirott M, Young C, et al. Phase 1 clinical and pharmacology study of topotecan 
given daily for 5 consecutive days to patients with advanced solid tumors, with attempt at 
dose intensification using recombinant granulocyte colony-stimulating factor. J Natl. Cancer 
Inst. 1993;85:1499-1507. 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 Update of recommendations for the use 
of white blood cell growth factors: an evidence based clinical practice guideline. J Clin 
Oncol. 2006 Jul 1;24(19):3187-3205. 


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G1T28 
 
Version: 6.0, dated 27 June 2018 
 
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Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth 
factors: American Society of Clinical Oncology clinical practice guideline update. J Clin 
Oncol. 2015 Oct 1; 33(28): 3199-3212. 
Stewart CF, Tagen M, Schwartzberg LS, Blakely LJ, Tauer KW, Smiley LM. Phase I dosage 
finding and pharmacokinetic study of intravenous topotecan and oral erlotinib in adults with 
refractory solid tumors. Cancer Chemother Pharmacol. 2014 Mar;73(3):561-568. 
Tanihara Y, Masuda S, Sato T, Katsura T, Ogawa O, Inui K. Substrate specificity of MATE1 
and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. 
Biochem Pharmacol. Jul 2007; 74(2):359-371. 
van Warmerdam LJC, Verweij J, Schellens JHM, et al. Pharmacokinetics and 
pharmacodynamics of topotecan administered daily for 5 days every 3 weeks. Cancer 
Chemother Pharmacol. 1995;35:237-245. 
von Pawel J, Jotte R, Spigel DR, et al. Randomized phase III trial of amrubicin versus 
topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol. Dec 
2014;32(35):4012-4019.  
Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other 
anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) 
measurement system. J Pain Symptom Manage. 1997 Feb;13(2):63-74.  
Yuan J, Knorr J, Altmannsberger M, et al. Expression of p16 and lack of pRB in primary 
small cell lung cancer. J Pathol. 1999;189:358-362. 
Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer 
chemotherapy. Nat Rev Immunol. 2008 Jan;8(1):59-73. 


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Version: 6.0, dated 27 June 2018 
 
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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 
 
 

SAP_001.pdf: 
  
 
 
 
 
STATISTICAL ANALYSIS PLAN 
- Region 1 - 
 
Study 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   
 
 
 
Sponsor 
G1 Therapeutics 
 
79 T.W. Alexander Drive 
 
4501 Research Commons, Suite 100 
 
Research Triangle Park, NC 27709 
 
 
Name of Test Drug: 
G1T28 
 
 
Protocol Number: 
G1T28-03 
 
 
Phase: 
Phase 1b/2a   
 
 
Analysis Plan Version 
Version 1.0 
 
 
Version Date 
05 December 2018 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03              
Statistical Analysis Plan for Region 1  
Version date: 05Dec2018 
 
 
CONFIDENTIAL 
      Page 2 of 73 
 
                                                 
 
 
 
 
 
APPROVAL SIGNATURES 
 
 
 
AUTHOR: 
  
 
 
 
 
 
 
 
____________________________________________________ 
 
Signature                                                                           Date 
 
Zack Scott, MS 
Manager, Biostatistics 
Pharpoint Research 
 
 
APPROVED BY: 
 
 
 
 
 
 
 
 
 
 
 
 
Signature                                                                           Date 
 
Zhao (Tony) Yang, PhD 
Associate Director of Biostatistics  
G1 Therapeutics Inc 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________ 
 
Signature                                                                           Date 
 
Shannon Morris, M.D. PhD 
VP, Clinical Development 
G1 Therapeutics Inc 
05-Dec-2018 | 09:42 AM ES
05-Dec-2018 | 09:45 AM
05-Dec-2018 | 10:11 AM E


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................9 
2. 
STUDY DETAILS .....................................................................................................10 
2.1. 
Study Objectives .........................................................................................................10 
2.2. 
Study Design ...............................................................................................................11 
2.3. 
Number of Patients .....................................................................................................21 
3. 
ANALYSIS SETS ......................................................................................................22 
3.1. 
Definition of Analysis Sets .........................................................................................22 
3.1.1. 
Intent-to-Treat Analysis Set ........................................................................................22 
3.1.2. 
Modified ITT Analysis Set .........................................................................................22 
3.1.3. 
Safety Analysis Set .....................................................................................................22 
3.1.4. 
Per Protocol (PP) Analysis Set ...................................................................................22 
3.1.5. 
Response Evaluable Analysis Set ...............................................................................22 
3.2. 
Protocol Deviations ....................................................................................................23 
4. 
PROSPECTIVELY DEFINED ANALYSES .............................................................24 
5. 
PRIMARY AND SECONDARY ENDPOINTS ........................................................25 
5.1. 
Efficacy endpoints ......................................................................................................25 
5.1.1. 
Primary Endpoints ......................................................................................................25 
5.1.1.1. 
Occurrence of Severe (Grade 4) Neutropenia ............................................................25 
5.1.1.2. 
Duration of Severe (Grade 4) Neutropenia (DSN) .....................................................26 
5.1.2. 
Key Secondary Endpoints ...........................................................................................28 
5.1.2.1. 
Occurrence of RBC Transfusions ...............................................................................28 
5.1.2.2. 
Occurrence of GCSF Administrations ........................................................................29 
5.1.2.3. 
Occurrence of Platelet Transfusions ...........................................................................29 
5.1.2.4. 
Total Number of Major Adverse Hematologic Event (MAHE) .................................29 
5.1.3. 
Supportive Secondary Efficacy Endpoints .................................................................31 
5.1.3.1. 
Best Overall Response, Duration of Response, Progression-Free Survival, 
and Overall Survival ...................................................................................................31 
5.1.3.2. 
Occurrence of Grade 3 and 4 Hematologic toxicities .................................................37 
5.1.3.3. 
ANC Nadir by Cycle ..................................................................................................38 


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5.1.3.4. 
ANC, Platelet Count, Absolute Lymphocyte Counts (ALC), and 
Hemoglobin Change over Time ..................................................................................38 
5.1.3.5. 
Occurrence of Erythropoietin Stimulating Agent (ESA) Administrations .................38 
5.1.3.6. 
Occurrence of IV Antibiotic Uses ..............................................................................38 
5.1.3.7. 
Occurrence of Infection Serious Adverse Events (SAEs) ..........................................39 
5.1.3.8. 
Occurrence of Pulmonary Infection SAEs .................................................................39 
5.1.3.9. 
Occurrence of Febrile Neutropenia ............................................................................40 
5.1.3.10. 
Occurrence of Grade 4 and Grade 3/4 Thrombocytopenia .........................................40 
5.1.3.11. 
Myelosuppression Endpoints with All data up to End of Cycle 4 ..............................40 
5.1.4. 
Exploratory Efficacy Endpoints .................................................................................41 
5.1.4.1. 
FACT-L and FACT-An ..............................................................................................41 
5.1.4.2. 
Grade 2 or Greater Nephrotoxicity .............................................................................41 
5.1.4.3. 
Occurrence of Alopecia and Mucositis .......................................................................41 
5.1.4.4. 
Neutrophil-lymphocyte Ratio (NLR) and Platelet-lymphocyte Ratio (PLR) .............41 
5.2. 
Safety Endpoints .........................................................................................................42 
5.2.1. 
Chemotherapy Exposure Endpoints ...........................................................................42 
5.2.1.1. 
Duration of Exposure ..................................................................................................42 
5.2.1.2. 
Number of Cycles Received .......................................................................................42 
5.2.1.3. 
Dose Intensity and Cumulative Dose .........................................................................42 
5.2.1.4. 
Modifications of Study Therapy, Including Cycle (Dose) Delay, Missed 
Doses, Dose Interruptions, and Dose Reductions .......................................................43 
5.2.2. 
Adverse Events ...........................................................................................................44 
5.2.3. 
Vital Signs ..................................................................................................................45 
5.2.4. 
Laboratory ...................................................................................................................46 
5.2.5. 
Electrocardiograms .....................................................................................................46 
5.2.6. 
Physical Examination .................................................................................................47 
6. 
ANALYSIS METHODS ............................................................................................48 
6.1. 
General Principles of Analysis ...................................................................................48 
6.1.1. 
General Methodology .................................................................................................48 
6.1.2. 
Handling of Missing Data ...........................................................................................49 
6.1.3. 
Visit Windowing .........................................................................................................49 
6.1.4. 
Adjustment for Covariates ..........................................................................................51 


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6.2. 
Analysis Methods .......................................................................................................51 
6.2.1. 
Patient Disposition ......................................................................................................51 
6.2.2. 
Demographic and Other Baseline Characteristics ......................................................51 
6.2.3. 
Disease Characteristics ...............................................................................................51 
6.2.4. 
Medical History ..........................................................................................................52 
6.2.5. 
Concomitant Medications ...........................................................................................52 
6.2.6. 
Prior and Subsequent Anti-cancer Therapy ................................................................53 
6.2.7. 
Efficacy Analyses .......................................................................................................53 
6.2.7.1. 
Primary and Key Secondary Efficacy Analyses .........................................................54 
6.2.7.2. 
Supportive Efficacy Analyses .....................................................................................62 
6.2.7.3. 
Exploratory Efficacy Analyses ...................................................................................64 
6.2.8. 
Safety Analyses ..........................................................................................................64 
6.2.8.1. 
Chemotherapy Exposure and Compliance Analyses ..................................................65 
6.2.8.2. 
Adverse Events ...........................................................................................................65 
6.2.8.3. 
Laboratory Evaluations ...............................................................................................65 
6.2.8.4. 
Vital Signs ..................................................................................................................66 
6.2.8.5. 
Performance Status .....................................................................................................66 
6.2.8.6. 
Physical Examination .................................................................................................66 
6.2.8.7. 
ECG ............................................................................................................................66 
6.2.9. 
Subgroup Analyses .....................................................................................................66 
6.2.10. 
Pharmacokinetic Analysis ..........................................................................................66 
6.2.11. 
Assess Genetic and/or Expression (RNA/Protein) Biomarkers in Tumors and 
Blood ...........................................................................................................................67 
6.2.12. 
Planned Analysis ........................................................................................................67 
7. 
CHANGE FROM THE PROTOCOL ........................................................................68 
8. 
REFERENCES ...........................................................................................................70 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event 
ALC 
Absolute Lymphocyte Count 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ANCOVA 
Analysis of Covariance 
aRR 
Adjusted Rate Ratio 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under Curve 
β-HCG 
Beta Human Chorionic Gonadotropin  
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BPM 
Beats Per Minute 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CBR 
Clinical Benefit Rate 
CDK 
Cyclin Dependent Kinase 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CSR  
Clinical Study Report 
CT 
Computed Tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
DLT 
Dose-Limiting Toxicity 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
DOR 
Duration of Response 
DSN 
Duration of Severe Neutropenia 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic Case Report Form 
EOI 
End of Infusion 
ESA 
Erythropoietin Stimulating Agent 
FACT 
Functional Assessment of Cancer Therapy 
FACT-AN 
Functional Assessment of Cancer Therapy –Anemia  
FACT-L 
Functional Assessment of Cancer Therapy –Lung  
G1T28 
Trilaciclib 
GCSF 
Granulocyte Colony-Stimulating Factor 


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Abbreviation 
Term 
HGB 
Hemoglobin 
HR 
Hazard Ratio 
ICH 
International Conference on Harmonization 
ITT 
Intent-to-Treat 
IV 
Intravenous 
LD 
Longest Diameter 
LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal Range 
MAHE 
Major Adverse Hematologic Event 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MRI 
Magnetic Resonance Imaging 
Nadir 
The Lowest Point 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NLR 
Neutrophil-Lymphocyte Ratio 
NTL 
Non-Target Lesion 
OC 
Observed Case 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic  
PLR 
Platelet-Lymphocyte Ratio 
PP 
Per Protocol 
PR 
Partial Response 
PRO 
Patient-Reported Outcome 
PT 
Preferred Term 
QOL 
Quality of Life 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumors  
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SCLC 
Small Cell Lung Cancer 
SD 
Stable Disease 
SMC 
Safety Monitoring Committee 
SVN 
Severe Neutropenia 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent AE 
TL 
Target Lesion 
TLFs 
Tables, Listings, and Figures 


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Version date: 05Dec2018 
 
 
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Abbreviation 
Term 
TPR 
Time Point Response 
ULN 
Upper Limit of Normal Range 
WBC 
White Blood Cell 
WHO-DD 
World Health Organization Drug Dictionary 
 


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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the analyses to be performed for 
Study G1T28-03, Phase 1b/2a Study of the Safety, Efficacy, and Pharmacokinetics of trilaciclib 
in Patients with Previously Treated Extensive-Stage Small Cell Lung Cancer (SCLC) Receiving 
Topotecan Chemotherapy.  The SAP is based on the G1T28-03 Protocol Version 6, dated 27 
June 2018.   
Study measurements and assessments, planned statistical methods, and derived variables are 
summarized in this plan.  Planned tables, figures, and listings are specified.  All decisions 
regarding final analyses, as defined in this SAP document, have been made prior to locking the 
database. Any deviations from these guidelines will be documented in the clinical study report 
(CSR).  
The myelosuppression efficacy endpoints and statistical analysis methods described in this SAP 
are reflective of scientific advice obtained in both the US and EU for evaluation of trilaciclib for 
the reduction of chemotherapy-induced myelosuppression.  
Although G1T28-03 does not explicitly state that the trial has been designed to evaluate the 
effects of trilaciclib on chemotherapy-induced myelosuppression, the endpoints of AEs and 
laboratory values used to evaluate safety and tolerability are the same endpoints used to evaluate 
effects on chemotherapy-induced myelosuppression. The data collected for this trial was 
appropriate for the analysis of these myelosuppression endpoints, and the defined endpoints in 
this SAP are consistent with the overall strategy/rationale for Study G1T28-03. 


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Version date: 05Dec2018 
 
 
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2. 
STUDY DETAILS 
2.1. 
Study Objectives 
The primary, secondary, and exploratory objectives of this study are presented in Table 1. 
Table 1 
G1T28-03: Study Objectives 
 
Part 1  
(Phase 1b) 
Parts 2A 
and 2B  
(Phase 2a) 
Primary Objectives 
Assess the DLTs and define the Phase 2 dose of trilaciclib 
administered with topotecan 
X 
 
Assess the safety and tolerability of trilaciclib administered with 
topotecan 
X  
X 
Secondary Objectives 
Assess the PK profile of trilaciclib 
X 
Xa 
Assess the PK profile of topotecan when administered with 
trilaciclib 
X 
Xa 
Assess the hematologic profile (kinetics and 
incidence/duration/frequency of toxicities) of trilaciclib 
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 
Exploratory Objectives 
Assess the incidence of mucositis 
X 
X 
Assess the incidence of alopecia 
X 
X 
Assess the incidence of fatigue 
X 
X 
Assess patient-reported QOL 
X 
X 


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Assess immunologic markers 
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 
  
2.2. 
Study Design 
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 1b/2a study of the 
safety, efficacy, and PK of trilaciclib 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, placebo-controlled 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 
pharmacokinetics (PK) of trilaciclib administered at an initial dose of 200 mg/m2 once daily in 
combination with topotecan on Days 1 to 5 of each 21-day chemotherapy cycle (Figure 1). DLTs 
are defined in Protocol section 6.1.1.1. 
Figure 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  
trilaciclib + 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  
trilaciclib 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 
(topotecan or trilaciclib/placebo). 
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. 


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Trilaciclib Dose Evaluation  
Six patients will initially be enrolled in Part 1 and will receive an initial dose of trilaciclib 
200 mg/m2 in combination with standard topotecan therapy. 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. Trilaciclib dose evaluation criteria are listed below and are presented as a decision tree 
in Figure 2.  
• If there is ≤ 1 DLT in the first cohort of 6 patients during Cycle 1 of Part 1 and the 
trilaciclib PK parameters are as predicted (Protocol 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 trilaciclib 
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 
trilaciclib PK parameters suggest that the trilaciclib dose needs to be escalated or 
de-escalated (see Protocol Section 6.1.1.2), a second cohort of 6 patients will be enrolled 
at the higher or lower predicted trilaciclib dose in combination with topotecan. For 
assessment of data from the second cohort enrolled in Part 1, please see the decision tree 
in Figure 2. 
• If there is > 1 DLT in the first cohort of 6 patients during Cycle 1 of Part 1 and the 
trilaciclib PK parameters suggest that the trilaciclib dose needs to be escalated or 
de-escalated (see Protocol Section 6.1.1.2), a second cohort of 6 patients will be enrolled 
at the modified trilaciclib dose in combination with topotecan. For assessment of data 
from the second cohort enrolled in Part 1, please see the decision tree in Figure 2. 
• If there is > 1 DLT in the first cohort of 6 patients enrolled in Part 1 and the trilaciclib PK 
parameters from these 6 patients are as predicted (Protocol Section 6.1.1.2), the dose of 
trilaciclib should be decreased to 160 mg/m2 and an additional 6 patients should be 
enrolled at the modified trilaciclib dose in combination with topotecan. For assessment of 
data from the second cohort enrolled in Part 1, please see the decision tree in Figure 2.  
• If there is > 1 DLT following a trilaciclib dose of 160 mg/m2 in combination with 
topotecan and the PK parameters from these 6 patients are as predicted (Protocol Section 
6.1.1.2), an additional cohort of 6 patients will be enrolled at a further decreased 
trilaciclib 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 2. 
• If there is > 1 DLT following the second dose reduction of trilaciclib and the PK 
parameters from these 6 patients are as predicted (Protocol 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 safety monitoring committee (SMC) review and 
recommendations for either continued enrollment or permanent closure of the cohort 


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Version date: 05Dec2018 
 
 
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Figure 2 
Trilaciclib Dose Evaluation 
 
 
a      Assess the adjusted trilaciclib dose in the next cohort of 6 patients based on DLTs and PK per the decision tree 
b 
Maximum of 2 trilaciclib 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 SMC composed of the sponsor, medical monitor, and the principal 
investigator(s) to determine the next dose level. If the trilaciclib and/or topotecan dose level for a 
subsequent cohort is adjusted by the SMC, the SMC may also recommend that all patients 
currently receiving trilaciclib in combination with topotecan should have their trilaciclib 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 trilaciclib and topotecan 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. There will be no 
intrapatient dose modifications of trilaciclib in Parts 2A and 2B of the study. 
Each patient will be evaluated for toxicity during each cycle. The toxicity of IV trilaciclib 
administered with topotecan will be assessed by the investigators using National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. 
Topotecan Dose Evaluation 
Since trilaciclib has been shown to inhibit renal transporters for which topotecan is a substrate, 
there is a potential for increasing topotecan exposure when administered after trilaciclib. 
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 trilaciclib and topotecan 
will be assessed on Days 1 and 4 of the first cycle.    
Since myelosuppression is the major toxicity of topotecan and trilaciclib is being developed to 
reduce myelosuppression following cytotoxic chemotherapy, complete blood count (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.   


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Part 2A 
In Part 2A, eligible patients will be randomized (2:1) to receive trilaciclib or placebo 
administered IV once daily with topotecan on Days 1 to 5 of each 21-day chemotherapy cycle 
(Figure 3). In Arm 1, patients will receive the trilaciclib (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 or 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 trilaciclib in Parts 2A of the study. 
Figure 3 
Study Schema: Part 2A 
 
a  
Trilaciclib 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 
Trilaciclib 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 
(topotecan or trilaciclib/placebo). 
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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Part 2B 
Unblinded topotecan PK data in Part 2A suggested differences in the topotecan exposures in 
Arm 1 compared to Arm 2, with the differences being attributed to use of less accurate historical 
controls for topotecan.  In order to accurately assess the impact of trilaciclib on the safety and 
efficacy of topotecan, it is critical that topotecan exposures are similar in the trilaciclib and 
placebo arms.  Therefore, an additional arm of trilaciclib 240 mg/m2 + topotecan 1.5 mg/m2 will 
be investigated in Arm 1 of Part 2B in this study.  In Part 2B, eligible patients will be 
randomized (2:1) to receive trilaciclib or placebo administered IV once daily with topotecan on 
Days 1 to 5 of each 21-day chemotherapy cycle (Figure 4). In Arm 1, patients will receive 
trilaciclib (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 Part 2A, randomization for Part 2B will also be stratified on the basis of 
ECOG performance status (0 or 1 versus 2) and sensitivity to first-line treatment (sensitive: 
CR/PR/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 trilaciclib in Part 2B of the study. 
Figure 4 
Study Schema: Part 2B 
 
a  
Trilaciclib 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 
Trilaciclib 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 
(topotecan or trilaciclib/placebo). 
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 


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Clinical Study Protocol G1T28-03              
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Version date: 05Dec2018 
 
 
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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. 
Criteria for Subsequent Cycles and Study Duration 
In both parts of the study, study drug (topotecan or trilaciclib/placebo) 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, 
whichever occurs first. Treatment cycles will occur consecutively without interruption, except 
when necessary to manage toxicities or for administrative reasons as described below.   
In order to start Cycle 2 and subsequent cycles as scheduled, patients should meet all of the 
following criteria: 
• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L  
• Platelet count ≥ 100 × 109/L 
• Nonhematologic drug-related toxicities (except alopecia) must be ≤ Grade 1 or have 
returned to baseline 
A delay of up to 2 weeks is permitted to allow recovery from any toxicity in order to meet the 
continuation criteria for organ function. If patients meet the criteria for starting the subsequent 
cycle as described above, a delay of up to 1 week is permitted for administrative reasons (eg, 
holiday, vacation, etc.). If the subsequent cycle is delayed, the patient should still complete the 
clinical laboratory assessments and the FACT-L and FACT-An questionnaires on the scheduled 
Day 1, as well as on the actual first dosing day of the next cycle. A patient will be discontinued 
from the study if recovery from any toxicity, in order to meet the continuation criteria for organ 
function, and any delay for administrative reasons requires a total delay of > 2 weeks.  
After discontinuation of study drug (topotecan or trilaciclib/placebo), 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 patient-reported outcome (PRO) scales, CBC 
assessment on Day 22, the Post-Treatment Visit, and the Survival Follow-up Phase of the study.  
The G1T28-03 study will be completed when the Survival Follow-up Phase has been completed, 
or upon sponsor termination of the study. The total study duration is at least 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 trilaciclib 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. 


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Statistical Analysis Plan for Region 1  
Version date: 05Dec2018 
 
 
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The Survival Follow-up Phase of the study will continue until at least 50% of the patients in 
Parts 2A and 2B have died. The study scheduled assessments are presented below: 
 
 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 1  
Version date: 05Dec2018 
 
 
CONFIDENTIAL 
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Table 2 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trilaciclib or 
placeboo 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 1  
Version date: 05Dec2018 
 
 
CONFIDENTIAL 
      Page 19 of 73 
 
                                                 
 
  
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  
 
Topotecan 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
FACT-L 
and 
FACT-Anp 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
AEsq 
X 
X 
 
Prior and Con. 
Medications 
X 
X 
 
Survival 
Follow-upc 
 
 
X 
AE = adverse event; ECG = electrocardiogram; FACT-AN = Functional Assessment of Cancer Therapy – Anemia quality of life instrument; FACT-L = Functional Assessment of Cancer Therapy –
Lung quality of life instrument; PRO = patient reported outcome; Eval. = evaluation; PK = pharmacokinetic 
a 
Trilaciclib + 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 (topotecan or trilaciclib/placebo).  
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 (topotecan or trilaciclib/placebo) 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 (topotecan or 
trilaciclib/placebo), weight loss in the 6 months prior to the first dose of study drug (topotecan or trilaciclib/placebo) (≤ 5% or > 5%), and medications taken within 14 days prior to the first dose 
of study drug (topotecan or trilaciclib/placebo). 
f 
Height will only be measured at the screening visit. Body surface area calculation (based on actual body weight taken prior to study drug (topotecan or trilaciclib/placebo) administration) will be 
completed on Day 1 of each cycle and vital signs obtained immediately before and after trilaciclib 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 Protocol 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 trilaciclib + topotecan. 
h 
Hematology will be obtained (hemoglobin, hematocrit, white blood cells (WBCs) with differential, and platelet counts); see Protocol Section 11.3.2.  Hematology may be obtained up to 24 hours 
prior to first dose of each cycle of trilaciclib + topotecan.  


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 1  
Version date: 05Dec2018 
 
 
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i 
For patients who choose to participate in the optional immunophenotyping portion of the study, peripheral blood will be collected at predose on Day 1 and Day 15 of each cycle; Day 22 of the 
last cycle; and at the Post-Treatment Visit. Immunophenotyping samples may be obtained up to 24 hours prior to first dose of each cycle of trilaciclib + topotecan. 
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 trilaciclib), 1 hour 
(± 10 minutes), and 6.5 hours (± 15 minutes) after start of trilaciclib 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 trilaciclib), 1 hour (± 10 minutes), and between 3.5 to 6.5 hours (± 15 minutes) after start of trilaciclib infusion. 
k 
For female patients of childbearing potential, serum ß-hCG at screening; serum or urine ß-hCG, obtained up to 72 hours prior to each dose of trilaciclib + topotecan chemotherapy in each cycle 
l 
For tumor assessment, all sites of disease (including brain metastases, if present at screening) should be assessed radiologically by CT or MRI at screening and after every even cycle, until the 
occurrence of disease progression. Additional scans may be obtained at the discretion of the investigator, if clinically indicated. If a patient shows a radiological response (CR or PR), a 
confirmatory radiological assessment will be performed at least 4 weeks after the response was first noted. Assessments may be performed within 7 days of starting the subsequent cycle. The 
same method of assessment (CT or MRI) should be used to characterize tumors at screening and at all follow-up assessments. If PET is used, it should also be accompanied by spiral CT or MRI.  
 
l1: At the Post-Treatment Visit, obtain tumor assessment for patients who have not progressed at the time of study drug (topotecan or trilaciclib/placebo) discontinuation (may be performed 
within 4 weeks of treatment discontinuation). For those patients in the survival follow-up who have not progressed at the time of study drug (topotecan or trilaciclib/placebo) 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. 
 
l2: Brain scans with contrast (by CT or MRI) to be obtained with tumor assessment at screening (within 28 days of dosing). 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 (topotecan or trilaciclib/placebo) discontinuation (may be performed within 4 
weeks of treatment discontinuation). For those with brain metastases, brain scans should be done with each tumor assessment.  
m 
Send archived tumor samples to a central pathology laboratory to confirm the diagnosis of SCLC. Available tissue after confirming the diagnosis of SCLC will be banked for assessment of 
relevant DNA, RNA, and protein markers, such as those involved in the CDK4/6 pathway. If central pathology review does not confirm SCLC diagnosis, the patient may be withdrawn from the 
study after consultation between the principal investigator, medical monitor, and sponsor. This should be done as soon as possible after a patient has enrolled in the study. 
n 
Patients enrolled in Part 1 will have trilaciclib and topotecan PK samples collected on Days 1 and 4 (as applicable) of Cycle 1 at the time points specified in Protocol Section 11.3.2. In addition, 
limited PK samples will be collected on Cycle 1 Day 4 in Parts 2A and 2B of the study for trilaciclib population PK analysis. Blood samples will be collected in Parts 2A and 2B of the study at 
the time points specified in Protocol Section 11.3.2. 
o 
Trilaciclib or placebo will be administered as an IV infusion in 250 mL of D5W or sodium chloride solution 0.9% over 30 (± 5) minutes prior to topotecan chemotherapy on Days 1 to 5 of every 
cycle (see Protocol Section 11.3.2). If there is any study drug (topotecan or trilaciclib/placebo) remaining in the trilaciclib 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 interval between doses of trilaciclib on successive days should 
not be greater than 28 hours. The interval between the dose of trilaciclib and the dose of topotecan on a given day should not be greater than 4 hours. Trilaciclib will only be administered with 
topotecan. If administration of topotecan is discontinued, trilaciclib should also be discontinued. Chemotherapy cannot be administered until after completion of the trilaciclib infusion. If the 
second, third, fourth, or fifth dose of trilaciclib in any given cycle is not administered for any reason, do not administer the dose of topotecan on that day (see Protocol Section 11.3.2). After 
discontinuation of study drug (topotecan or trilaciclib/placebo), patients should be strongly encouraged to complete all scheduled assessments through the end of their current 21-day treatment 
cycle, including the patient-reported PRO (scales), CBC assessment on Day 22, the Post-Treatment Visit, and the Survival Follow-up Phase of the study. 
p 
Patient-reported outcomes should be completed at Days 1 and 10 of each cycle and at the Post-Treatment Visit. If a cycle is delayed, the patient should still complete the PRO on the scheduled 
Day 1 of the next cycle, as well as the actual first dosing day of the next cycle of trilaciclib + topotecan. Patient-reported outcomes may be obtained up to 24 hours prior to the first dose of each 
cycle of trilaciclib + topotecan.  
q 
Adverse events will be recorded from the time of informed consent. All AEs should be reported within 30 days of the last dose of study drug (topotecan or trilaciclib/placebo), and followed until 
they are resolved, have returned to baseline, or it is deemed that further recovery is unlikely. 
r 
For patients enrolled in Parts 2A and 2B, randomization is to be done within 3 days prior to the first dose of trilaciclib or placebo + topotecan, following confirmation that the patient is eligible 
for the study. 
s 
Patients with an ANC < 0.5 × 109/L on Day 15 shall be followed (eg, every 24 to72 hours) for recovery (to ensure that duration of ANC < 0.5 × 109/L does not exceed 7 days).


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 1  
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2.3. 
Number of Patients 
Overall, approximately 130 patients will be enrolled in the study. In Part 1, approximately 40 
patients will be enrolled, assuming 9-10 cohorts. Part 1 is open label and no randomization or 
blinding will be required. In Part 2A, approximately 45 patients will be enrolled and randomly 
assigned (2:1) to Arm 1 (trilaciclib (240 mg/m2) + topotecan (0.75 mg/m2)) or Arm 2 (placebo+ 
topotecan (1.5 mg/m2)). In Part 2B, approximately 45 patients will be enrolled and randomly 
assigned (2:1) to Arm 1 (trilaciclib (240 mg/mg2) + topotecan (1.5 mg/m2)) or Arm 2 (placebo + 
topotecan (1.5 mg/m2)).   
The sample size is not determined from a statistical perspective, but rather is based on clinical 
feasibility. Subjects who receive placebo in Part 2A and Part 2B will be combined into a single 
placebo group for the analysis. Thus, approximately 90 patients will be enrolled into Part 2 of the 
study (30 per treatment group). 
With the changes to the protocol detailed in this SAP, the sample size calculation is now based 
on demonstrating the superiority of trilaciclib (240 mg/m2) + topotecan (1.5 mg/m2) vs. placebo+ 
topotecan with respect to at least one of the primary endpoints. 
With the changes, the overall type I error rate is now 0.10 (1-sided) and the type II error rate 
used to compute sample size is 0.10 (corresponding to 90% power).  
To maintain the overall type I error rate, by using the most conservative Bonferroni procedure 
for the 2 primary endpoints, a 1-sided individualized type I error rate 0.10/2=.05 is assigned to 
each outcome variable in the sample size calculation. Assuming a common standard deviation of 
2.5, a true difference in the duration of severe (Grade 4) neutropenia in Cycle 1 of at least 2 days 
between the trilaciclib (240 mg/m2) + topotecan (1.5 mg/m2) group and the placebo+ topotecan 
group requires, 56 evaluable patients (28 per treatment arm in the trilaciclib (240 mg/m2) + 
topotecan (1.5 mg/m2) group and the placebo + topotecan group). This implies that 90 patients 
need to be randomized for all 3 groups assuming a 95% evaluability rate. For occurrence 
endpoints (occurrence of severe (Grade 4) neutropenia, assuming its proportion of 45% for 
placebo + topotecan group, testing for an absolute reduction of 37% to 8% with the trilaciclib 
(240 mg/m2) + topotecan (1.5 mg/m2) group would require a sample size of at least 56 patients 
(29 per treatment arm in the trilaciclib (240 mg/m2) + topotecan (1.5 mg/m2) group and the 
placebo + topotecan group). Assuming a 95% evaluability rate, at least 90 patients for Part 2 of 
the study need to be randomized for all 3 groups to complete the study. Therefore, the final 
adjusted sample size is 90 for Part 2 of the study to account for the evaluation of 2 primary 
endpoints. All calculations were carried out using the POWER procedure in SAS® version 9.4. 
The study will be conducted at up to 60 centers in North America and Europe. 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 1  
Version date: 05Dec2018 
 
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3. 
ANALYSIS SETS 
3.1. 
Definition of Analysis Sets  
Data analyses will be based on the four analysis sets defined below. Analysis sets, including 
exclusions based on key deviations, will be reviewed and approved by G1 Therapeutics prior to 
study unblinding.  
3.1.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat analysis set (ITT) includes all randomized patients in Part 2 and all enrolled 
patients who received at least one dose of study drugs in Part 1. Analyses using the ITT will be 
conducted on the basis of the assigned treatment. The ITT is the primary analysis set for all 
efficacy analysis. 
3.1.2. 
Modified ITT Analysis Set 
The modified ITT (mITT) analysis set is a subset of the ITT analysis set and will only include 
the ITT patients who received at least 1 dose of study drug (topotecan or trilaciclib/placebo). 
Supportive sensitivity analyses will be conducted on the mITT analysis set for primary and key 
secondary efficacy endpoints to evaluate the robustness of the results. Analyses using the mITT 
will be conducted on the basis of the assigned treatment. 
3.1.3. 
Safety Analysis Set 
The safety analysis set includes all enrolled patients who received at least 1 dose of study drug 
(topotecan or trilaciclib/placebo). Analyses using the safety analysis set will be conducted on the 
basis of the actual treatment received. All safety analyses will be assessed using the safety 
population.  
3.1.4. 
Per Protocol (PP) Analysis Set 
The per-protocol (PP) analysis set is a subset of the mITT analysis set. The criteria for inclusion 
in the PP analysis set will be based on study drug (topotecan or trilaciclib/placebo) 
administration and key protocol deviations; the list of patients to be included in this analysis set 
will be finalized and documented prior to unblinding patients in Parts 2 of the study. 
It will include only those patients who have no exclusionary protocol deviations (as described in 
Section 3.2) and who received the treatment to which they were randomized or assigned. For any 
patients who received the wrong treatment during any part of the study, their data will be 
excluded from the PP analysis set. The PP analysis set may be used to analyze selected endpoints 
to test the robustness of results.  
3.1.5. 
Response Evaluable Analysis Set 
The Response Evaluable Analysis Set will include all patients who are in the mITT, have 
measurable disease (target lesions) at the baseline tumor assessment, and either (i) have at least 1 
post-baseline tumor assessment, (ii) have clinical progression as noted by the investigator before 
their first post-baseline tumor scan, or (iii) have died due to disease progression before their first 
post-baseline tumor scan. The response evaluable analysis set will be used for sensitivity 
analyses of tumor response.   


 
 
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3.2. 
Protocol Deviations  
Certain protocol deviations are designated as key in that they may affect the ability to assess the 
safety and efficacy of study drug (topotecan or trilaciclib/placebo). All key protocol deviations 
will be reviewed in a data review meeting to discuss the potential impact on the statistical 
analysis and classify each key deviation as exclusionary or non-exclusionary. This will be 
documented in a note to file prior to database lock and Part 2 unblinding. 
Patients with key deviations determined to impact the analysis will be excluded from the PP 
analysis set. All patients who meet the definition of the ITT/mITT analysis sets will be included 
in the ITT/mITT analysis sets regardless of these deviations. 
If a patient is randomized or assigned to a treatment group, but fails to receive treatment, the 
reason for not receiving treatment will be noted in the CSR. Any such patients who are not 
treated will be excluded from the mITT, safety, response evaluable, and PP analysis sets but will 
be included in the ITT (for Part 2) and in the patient listings for the CSR.   
If the wrong treatment is administered to a patient, and the reason for the incorrect treatment is 
documented, this will be noted in the CSR and the patient’s data included in the Safety Analysis 
Set based on the actual treatment received. 


 
 
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Clinical Study Protocol G1T28-03                                       
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4. 
PROSPECTIVELY DEFINED ANALYSES  
As outlined in the protocol, trilaciclib is an IV Cyclin Dependent Kinase (CDK) 4/6 inhibitor 
being evaluated for its ability to decrease chemotherapy-induced myelosuppression when 
administered in combination with cytotoxic chemotherapy.  Unlike granulocyte-colony 
stimulating factor (GCSF), which stimulates production of neutrophils, and transfusions, which 
only replace red blood cell (RBC) or platelets, trilaciclib is hypothesized to facilitate 
myelopreservation of all hematopoietic lineages including neutrophils, RBC, platelets, 
lymphocytes, etc.  
To capture these two aspects of trilaciclib benefit, the following analyses are prospectively 
proposed in Table 3 and their associated endpoint derivation and analysis methods will be 
detailed in Sections 5.1.1 and 6.2.7.1 with the multiplicity adjustments described in Section 
5.1.1.  
Table 3 
Prospectively Defined Analyses 
Occurrence (proportion of patients) of severe (Grade 4) neutropenia 
Duration of severe (Grade 4) neutropenia in Cycle 1 
Occurrence (proportion of patients) of RBC transfusions on/after 5 weeks 
Occurrence (proportion of patients) of GCSF administration 
Occurrence (proportion of patients) of Platelet transfusion 
Cumulative incidence of major adverse hematologic events (MAHE) which is defined to 
include components as the following: 
• All-cause hospitalizations 
• All-cause dose reductions 
• Febrile neutropenia 
• RBC transfusion on/after 5 weeks 
• Prolonged severe (Grade 4) neutropenia (duration > 5 days) 
• Platelet transfusion 
All-cause hospitalizations in the MAHE composite 
All-cause dose reductions in the MAHE composite 
Febrile neutropenia in the MAHE composite 
RBC transfusions on/after 5 weeks in the MAHE composite 
Prolonged severe (Grade 4) neutropenia in the MAHE composite 
Platelet transfusions in the MAHE composite 
RBC = Red Blood Cell; GCSF = granulocyte-colony stimulating factor; 
 


 
 
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5. 
PRIMARY AND SECONDARY ENDPOINTS  
The following general definitions will be applied to all endpoint derivations unless otherwise 
specified. 
Term 
Definition 
Severe Neutropenia 
(SVN) 
ANC lab value that meets the common terminology criteria for 
adverse events (CTCAE) criteria for ≥ Grade 4 toxicity 
Cycle baseline 
The last non-missing value within the window starting from 3 days 
prior to the date/time of study drug (topotecan or trilaciclib/placebo) 
administration on Day 1 of Cycle 1 and 1 day prior to Day 1 of each 
subsequent cycle (i.e. Cycle 2, Cycle 3, etc.); must be prior to the 
time of study drug (topotecan or trilaciclib/placebo) administration 
Cycle nadir 
The lowest value for a given hematologic parameter that occurs 
between start of cycle and end of cycle and is less than the cycle 
baseline. 
Duration of cycle 
Total number of days from start of cycle to end of cycle, that is, date 
of end of a cycle - date of start of cycle + 1. 
End of cycle* 
Day 1 of the subsequent cycle.  For example, the end of cycle for 
Cycle 1 is Day 1 of Cycle 2. For the last cycle (where no subsequent 
cycle is given), the end of cycle will be defined as Day 38 after the 
first dose of the cycle.  
Start of cycle 
Day 1 of each cycle starts with the administration of study drug(s) 
(topotecan or trilaciclib/placebo) 
Start of study 
Date of enrollment in Part 1 or Date of randomization in Part 2 
Study baseline 
The last non-missing value prior to, or on the date of administration 
of study drug(s) (topotecan or trilaciclib/placebo); must be prior to 
the time of study drug administration 
Change from baseline 
Calculated as the post-baseline value minus the baseline value. If the 
baseline value is missing for a particular endpoint, change from 
baseline will be missing. 
Treatment period 
Total number of days from start of cycle for Cycle 1 and end of 
cycle for the last cycle 
* For various hematologic parameter analyses, the last assessment prior to end of cycle will 
be utilized in the analyses. Situations where this applies will be indicated as such. 
5.1. 
Efficacy endpoints 
5.1.1. 
Primary Endpoints  
5.1.1.1. 
Occurrence of Severe (Grade 4) Neutropenia 
For the treatment period, the total number of SVN events is the number of cycles where at least 
one ANC value is < 0.5 x 109/L.  For example, if Cycle 2 has two ANC values that are both < 0.5 
x 109/L, this only counts as one event. If a patient did not have any SVN events, the value of 0 
will be assigned to that patient. The number of cycles without SVN is calculated as the total 


 
 
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number of cycles received – total number of cycles with SVN. Unscheduled data and the actual 
assessment date (rather than visit date) will be included in the derivation.  
Therefore, any occurrence of an SVN during a cycle or the treatment period is defined as a 
binary variable (Yes or No); Yes, if total number of cycles with SVN ≥ 1 is observed, No for 
other scenarios.    
5.1.1.2. 
Duration of Severe (Grade 4) Neutropenia (DSN)  
There will be three different strategies for assessing DSN in each cycle. All strategies will be 
applied to derive the DSN, with strategy 1 considered as the primary, and strategy 2 and strategy 
3 being supportive sensitivity analyses. The DSN in Cycle 1 is considered the primary endpoint. 
Any unscheduled data and the actual assessment date (rather than visit date) will be included in 
the derivation of each strategy.  
5.1.1.2.1. 
Strategy 1: Without Imputation of Missing ANC Values 
Within each cycle, the DSN (days) is defined as the number of days from the date of first ANC 
value of <0.5×109/L observed between start of cycle and end of cycle, to the date of first ANC 
value ≥ 0.5×109/L that meets the following criteria: (1) occurs after the ANC value of 
<0.5×109/L and (2) no other ANC values <0.5×109/L occur between this day and end of cycle. 
DSN is set to 0 in patients who did not experience SVN in a cycle. Any unscheduled data and the 
actual assessment date (rather than visit date) will be included in the derivation. The following 
rules will be applied in the calculation:    
• For a cycle where the SVN event does not resolve by end of the cycle, DSN will be 
assigned as above except the end date will be the end of cycle.   
• For a cycle where the patient dies, during the SVN event, DSN will be assigned as above 
except the end date will be the date of death. 
• For a cycle where the patient withdraws consent or is lost to follow-up during the SVN 
event, DSN will be assigned as above except the end date will be the date of the last ANC 
assessment prior to the end of study. 
5.1.1.2.2. 
Strategy 2: Without Imputation, Censoring Unresolved SVN 
Within each cycle, DSN (days) is defined as the number of days from the date of first ANC value 
of <0.5 x 109/L observed between start of cycle and end of cycle, to the date of first ANC value ≥ 
0.5 x 109/L that meets the following criteria: (1) occurs after the ANC value of <0.5 x 109/L and 
(2) no other ANC values <0.5 x 109/L occur between this day and end of cycle. The following 
censoring rules will be applied in the calculation:   
• For a cycle where the SVN event does not resolve by end of the cycle, DSN will be 
assigned as above except the end date will be the earlier of end of cycle or date of last 
contact.   
• For a cycle where the patient dies, withdraws consent, or is lost to follow-up during the 
SVN event, DSN will be assigned as above except the end date will be the date of the last 
ANC assessment prior to the end of study.    


 
 
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For the treatment period, the overall DSN (days) is the median value among the DSN (days) 
from all cycles. The following data handling conventions will apply: 
• For those patients where all event duration values are derived from cycles with censored 
data, the median value for that patient will be the median censored value. It will be a 
considered a censored value; 
• For those patients where a subset of event duration values are derived from cycles with 
censored data, the median value for that patient will be estimated using the Kaplan-Meier 
method. It will be considered as an observed value (i.e. no censored value); 
• 
For those patients where the median event duration cannot be derived (e.g. ≤ 2 values), 
the longest event duration amongst all the cycles will be used regardless of censoring, but 
the corresponding censoring flag will be carried over for analysis. 
5.1.1.2.3. 
Strategy 3: With Imputation of Missing ANC Values 
DSN (days) in a cycle is defined as the number of consecutive days with SVN, for patients who 
experienced several episodes of SVN, the number of days for each episode will be summed up. 
DSN is set to 0 in patients who did not experience SVN in a cycle.  
To impute the missing daily ANC value, the following algorithms will be applied in the 
calculation, 
(1) Missing ANC values for Days 1-5 in each cycle will be imputed using linear interpolation, 
any recorded measurement will not be replaced. The missing values for Day 1 and Day 5 
may be potentially imputed with this algorithm. 
Figure 5 
Graphical Demonstration of Linear Interpolation  
Note: The slopes are calculated for each treatment group, where 𝑌𝑌ത1 and 𝑌𝑌ത2 are the 
mean of ANC values at relevant timepoint. For a time interval, e.g. interval of Day 
1 and Day 5 (inclusive), 𝑌𝑌ത1 is the average of the earliest point in the interval and 𝑡𝑡1 
is the average of the earliest day in the interval. Similarly, 𝑌𝑌ത2 is the average of the 
latest point in the interval and 𝑡𝑡2 is the average of the latest day in the interval.  
• If there are at least two assessments within the interval of Day 1 and Day 5 (inclusive), 
calculate the slope between the first available ANC value and last available ANC value: 


 
 
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− If the sign of slope agrees with the sign of slopes calculated from its treatment group, 
the interpolation will be conducted to appropriate schemes as demonstrated in Fig.1 (a) 
and Fig. 1(b); 
− If the sign of slope does not agree with the sign of slopes calculated from its treatment 
group, the interpolation will be done within the patient by using the calculated slope 
from the observed values. 
• If there is only one assessment within the interval of Day 1 and Day 5 (inclusive),  
− If the ANC value is < 0.5×109/L, then the subsequent missing days will be set to this 
value; 
− If ANC value is ≥ 0.5×109/L, SVN cannot be determined, and the data remains missing. 
• If there is no assessment within the interval of Day 1 and Day 5 (inclusive), SVN cannot 
be determined, and the data remains missing.  
(2) A similar algorithm as in (1) will be performed to impute missing ANC values for Days 6-10 
in each cycle using linear interpolation. Day 5 will be used as the earliest date in the 
calculations only if it is recorded; it will be interpolated in this interval. Any other recorded 
measurements will not be replaced.  
(3) Rules of imputation of missing values at Day 11 of a cycle: 
• The ANC before and after the missing day was ≥ 0.5×109/L: the day is ignored as a 
potential day of severe neutropenia. 
• If at either neighboring days the ANCs were < 0.5×109/L, and both are non-missing, then 
the missing day is set to severe neutropenia. 
• If any of the neighboring days were also missing, severe neutropenia cannot be 
determined, and the data remains missing. 
(4) A similar algorithm as in (1) will be performed to impute missing ANC values for Days 12-
15 in each cycle using linear interpolation. Any recorded measurements will not be replaced.  
(5) A similar algorithm as in (1) will be performed to impute missing ANC values between Days 
16 and end of cycle in each cycle using linear interpolation. Day 15 will be used as the 
earliest date in the calculations only if it is recorded; it will be interpolated in this interval. 
Any other recorded measurements will not be replaced.   
(6) For a cycle where the SVN event does not resolve by end of the cycle, the all values between 
the last assessment and the end of cycle are set to SVN.  
(7) For a cycle where the patient dies, during the SVN event, the end date of the SVN is the date 
of death. 
5.1.2. 
Key Secondary Endpoints 
5.1.2.1. 
Occurrence of RBC Transfusions 
Each RBC transfusion with a unique start date on/after 5 weeks on study during the treatment 
period will be defined as a separate event and included in the efficacy analyses. A sensitivity 
analysis including all events occurring during the treatment period will also be performed.  


 
 
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Occurrence of an RBC transfusion during the treatment period is defined as a binary variable 
(Yes or No); Yes if total number of RBC transfusions ≥ 1 is observed, No for other scenarios. 
5.1.2.2. 
Occurrence of GCSF Administrations 
Administration of GCSF is collected with the concomitant medications which are coded using 
World Health Organization Drug Dictionary (WHO-DD Version Sep2017).  The criterion to 
select proper records is as follows: If the chemical subgroup from WHO-DD Version Sep2017 
(i.e. TEXT4 for CODE4) takes value “COLONY STIMULATING FACTOR”, the medication is 
classified as GCSF. 
A cycle where GCSF is administered concurrently will be identified by comparing the start and 
stop dates of each administration of GCSF to the start of cycle and end of cycle.  If any of the 
dates of administration of GCSF overlap with any dates between the start of cycle and end of 
cycle, that cycle will be considered as having GCSF administered. Data handling conventions for 
missing start and stop dates are described in Section 6.2.5. 
For the treatment period, the total number GCSF administrations is the number of cycles in 
which there is at least one GCSF dose administered. If a patient did not have any GCSF use, the 
value of 0 will be assigned to that patient. The number of cycles where GCSF was NOT given is 
calculated as total number of treatment cycles received – total number of cycles where GCSF 
was administered. 
Therefore, any occurrence of a GCSF administration during a cycle or the treatment period is 
defined as a binary variable (Yes or No); Yes if total number of cycles with GCSF administration 
≥ 1 is observed, No for other scenarios.  
5.1.2.3. 
Occurrence of Platelet Transfusions 
Each platelet transfusion with a unique start date during the treatment period will be defined as 
separate event.   
Occurrence of a platelet transfusion during the treatment period is defined as a binary variable 
(Yes or No); Yes if total number of platelet transfusions ≥ 1 is observed, No for other scenarios.   
5.1.2.4. 
Total Number of Major Adverse Hematologic Event (MAHE) 
As a composite measure of trilaciclib effect, MAHE is based on a combination of individual 
components specified in Table 4, which also include details about the derivation or data source 
for each component. For each component of composite MAHE, the number of events is derived 
as the number of episodes with a unique start date during the treatment period between the date 
of the start of Cycle 1 and the end of the last cycle (i.e. last cycle of placebo or trilaciclib plus 
topotecan). A patient without an episode will be assigned a value of 0 for the number of events 
for this component. Then, the total number of MAHE during the treatment period is obtained as 
the summation over all components of composite MAHE during the treatment period.   
Table 4 
Component of MAHE and the Suggested Data Source/Derivation Algorithm 
Seq # 
Component of MAHE Details 
1 
All-cause 
hospitalizations 
Each hospitalization is captured in the AE data of the 
electronic database. Each recorded Preferred Term (PT) 
with a unique start date will be counted as an event, e.g. if 


 
 
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Seq # 
Component of MAHE Details 
a patient is hospitalized and several preferred terms are 
attributed to that hospitalization with the same start date, 
then the event is only counted once. The event terms are 
coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 20.1.  
2 
All-cause dose 
reductions 
Detailed in Section 5.1.2.4.2 
3 
Febrile neutropenia 
Detailed in Section 5.1.3.9 
4 
Prolonged severe 
(Grade 4) neutropenia 
(duration > 5 days) 
Detailed in Section 5.1.1.2.1. Each cycle with a duration 
greater than 5 days will be counted as an event with the 
date of the first grade 4 lab value defined as the start date 
for the time-to-first event analysis. 
5 
RBC transfusion 
on/after 5 weeks 
Detailed in Section 5.1.2.1 
6 
Platelet transfusion 
Detailed in Section 5.1.2.3 
A patient without an episode of MAHE will be assigned a value of 0 for the overall total number 
of MAHE. Additionally, a sensitivity analysis will be done for dose reductions and RBC 
transfusions on/after 5 weeks, that excludes patients who do not start a second cycle of treatment. 
Time to first occurrence of a MAHE will be used as a sensitivity analysis in support of the total 
number of MAHE. It is defined as the first time to observe an event among all the components, 
starting from the date of the start of Cycle 1. Therefore, for a patient with a MAHE, time 
(months) to first occurrence of a MAHE will be the minimum among the 6 potentially derived 
durations (i.e. calculated as (date of first occurrence of a MAHE component event – date of Start 
of Cycle 1 + 1)/30). A patient without any MAHE will be censored at the end of the last cycle 
(i.e. last cycle of placebo or trilaciclib), death, end of study, or date of last contact, whichever is 
earlier.  
5.1.2.4.1. 
All-Cause Hospitalizations 
See Section 5.1.2.4. 
5.1.2.4.2. 
Occurrence of All-Cause Dose Reductions  
Dose (mg/m2) reductions are not permitted for trilaciclib. Dose reductions for topotecan are 
collected on the dosing page.  
No more than 2 dose reductions for toxicity in total are allowed for any patient. All dose 
reductions will be counted as a separate event. For more details see Section 5.2.1.4. 
5.1.2.4.3. 
Prolonged severe (Grade 4) neutropenia (duration > 5 days) 
See Section 5.1.2.4. 


 
 
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5.1.3. 
Supportive Secondary Efficacy Endpoints  
5.1.3.1. 
Best Overall Response, Duration of Response, Progression-Free Survival, and 
Overall Survival 
For tumor assessment, all sites of disease will be assessed radiologically by computed 
tomography (CT) or magnetic resonance imaging (MRI) at screening and every 2 months 
thereafter, until the date of (i) disease progression as defined by RECIST Version 1.1 
(Eisenhauer et al, 2009) or by clinical criteria; or (ii) withdrawal of consent; or (iii) receiving 
subsequent anti-cancer therapy, whichever is earlier. At each tumor assessment visit, the overall 
visit response by RECIST will determined two ways: (1) derived programmatically using the 
information from target lesions (TL), non-target lesions (NTLs) and new lesions as entered into 
the eCRF, and (2) by the investigator and collected in the eCRF.  
For all patients, the RECIST tumor response data will be used to determine each patient’s visit 
response according to RECIST version 1.1 and the best overall response (BOR). 
5.1.3.1.1. 
Target Lesions (TLs) 
Measurable disease is defined as having at least one measurable lesion which is  
• ≥10 mm in the longest diameter (LD) (except lymph nodes which must have short axis ≥15 
mm) with CT or MRI; or  
• ≥10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable); or 
• ≥ 20 mm by chest X-ray. 
Previously irradiated lesions (or lesions treated with loco-regional therapies) may be considered 
measurable if unequivocal growth of the lesion has been demonstrated. A patient can have a 
maximum of 5 measurable lesions representative of all involved organs (maximum of 2 lesions 
per organ, both the lymph node and skin will be considered as a single organ) recorded at 
baseline and these are referred to as target lesions. If more than one baseline scan is recorded, 
then measurements from the one that is closest to start of treatment will be used to define the 
baseline sum of TLs. Table 5 gives definition of TL visit responses. 
Table 5 
Definition of TL Visit Responses 
Visit Reponses 
Description 
Complete 
Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes selected as 
target lesions must have a reduction in short axis to <10mm. 
Partial response 
(PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum of diameters as long as criteria for PD are not met. 
Progressive disease 
(PD) 
A ≥ 20% increase in the sum of diameters of target lesions and an absolute 
increase of ≥ 5mm, taking as reference the smallest sum of diameters (i.e. 
nadir) since treatment started including the baseline sum of diameters. 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD.  
 
 


 
 
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Rounding of TL data 
For calculation of PD and PR for TLs, percentage changes from baseline and previous minimum 
should be rounded to 1 decimal place before assigning a target lesion response. For example 
19.95% should be rounded to 20.0% but 19.94% should be rounded to 19.9%.  
Missing TL data 
If any target lesion measurements are missing, then the target lesion visit response is Not 
Evaluable (NE). The overall visit response will also be NE, unless there is a progression of non-
target lesions or new lesions, in which case the response will be PD.  
TL too small to measure 
If a target lesion becomes too small to measure a value of 5mm will be entered into the database 
and used in TL calculations, unless the radiologist has indicated and entered a smaller value that 
can be reliably measured.  
Lesions that split 
If a TL splits, then the LDs of the split lesions should be summed and reported as the LD for the 
lesion that split. 
Lesions that merge 
If target lesions merge, then the LD of the merged lesion should be recorded for one of the TL 
sizes and the other TL size should be recorded as 0 cm. 
Change in method of assessment of target lesions 
CT, MRI, chest x-ray and clinical examination are the only methods of assessment that can be 
used within a trial, with CT and MRI being the preferred methods and clinical examination and 
chest x-ray only used in special cases. If a change in method of assessment occurs between CT 
and MRI this will be considered acceptable and no adjustment within the programming is 
needed.  
5.1.3.1.2. 
Non-Target Lesions (NTLs) and New Lesions 
The non-target lesion response will be based on the Investigator’s overall assessment of NTLs as 
Table 6: 
Table 6 
Definition of NTLs Visit Responses 
Visit Reponses 
Description 
CR 
Disappearance of all NTLs present at baseline with all lymph nodes non-
pathological in size (<10mm short axis). 
PD 
Unequivocal progression of existing NTLs, which may be due to an important 
progression in one lesion only or in several lesions 
Non-CR/Non-PD 
Persistence of one or more NTLs with no evidence of progression 
NE 
Only relevant when one or some of the NTLs have not been assessed and in the 
Investigator’s opinion, they are not able to provide an evaluable overall NTL 
assessment. 
 


 
 
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New lesions 
New lesions will be identified via a Yes/No tick box. The absence and presence of new lesions at 
each visit should be listed alongside the TL and NTL visit responses. A new lesion indicates 
progression, so the overall visit response will be PD irrespective of the TL and NTL responses. 
5.1.3.1.3. 
Time Point Response (TPR) 
Table 7 defines how the previously defined TL and NTL visit responses will be combined with 
new lesion information to give a TPR. The possible TPRs at a visit are CR, PR, SD, PD, and NE.  
Table 7  
Evaluation of Time Point Response 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/not all evaluated 
No 
PR 
SD 
Non-PD/not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR= partial response, SD = stable disease, PD = progressive disease, NE = not evaluable 
At each visit, patients will be programmatically assigned a RECIST Version 1.1 TPR of CR, PR, 
SD, PD or NE depending on the status of their disease compared to baseline and previous 
assessments as discussed in the Sections 5.1.3.1.1 and 5.1.3.1.2.  
For a scheduled tumor assessment, it is expected that there will be a variation for the actual 
timing of scans among target, non-target, and new lesions. In assigning a date for the derived 
overall assessment at a visit, the earliest date collected at that visit will be used. Within a 
grouped timepoint, if there are multiple assessments on different dates for the same target 
lesions, the last assessment will be used. 
5.1.3.1.4. 
Best Overall Response (BOR) and Duration of Response (DOR) 
BOR will be determined using TPRs up until the last evaluable TPR prior to or on the date of (i) 
disease progression as defined by RECIST Version 1.1 (Eisenhauer et al, 2009) or by clinical 
criteria; or (ii) withdrawal of consent; or (iii) receiving subsequent anti-cancer therapy, 
whichever is earlier. BOR will not be derived for those patients who do not have measurable 
target lesions.   
A patient’s BOR will be determined based on Table 8.  For data-driven scenarios which may not 
be covered by Table 8, the BOR will be reviewed and determined by the medical advisors and 
statisticians prior to unblinding the study.    
For patients who progress and subsequently have a response, the best overall response is only 
derived from assessments up to and including the time of the progression (i.e., it will not include 
the response after the patient has progressed). 


 
 
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There are two ways of assigning BOR for a patient when the minimum interval for confirmation 
of CR and PR is not satisfied or if there are no confirmatory scans for CR and PR: 
• Adding two more response categories as: unconfirmed CR, unconfirmed PR; 
• Assigning BOR as SD, that is, both the unconfirmed CR and unconfirmed PR will be SD. 
Both ways of assigning BOR will be implemented.  
The number and percentage of patients in each category of derived BOR (Confirmed CR, 
Confirmed PR, SD, PD, or NE) will be summarized.  
 
 


 
 
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Clinical Study Protocol G1T28-03                                       
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Table 8  
Best Overall Response When Confirmation of CR and PR are Required [a] 
First 
TPR 
Second TPR 
Best overall response*^ for 
ORR 
Best Overall Response for 
ORRUNCONFIRMED 
CR 
CR 
CR 
CR 
CR 
PR 
SD [b] or PD 
Unconfirmed CR 
CR 
SD 
SD [b] or PD  
Unconfirmed CR 
CR 
PD 
SD [b] or PD  
Unconfirmed CR 
CR 
NE or NA 
SD [c] or NE or NA 
Unconfirmed CR 
PR 
CR 
PR 
Unconfirmed CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD [d] 
Unconfirmed PR 
PR 
PD 
SD [b] or PD 
Unconfirmed PR 
PR 
NE or NA 
SD [c] or NE or NA 
Unconfirmed PR 
NE 
NE 
NE 
NE 
NE 
CR 
SD 
Unconfirmed CR 
NE 
PR 
SD 
Unconfirmed PR 
NE 
SD 
SD 
SD 
NE or NA 
PD 
PD 
PD 
SD 
PD 
SD [b] or PD 
SD [b] or PD 
SD 
CR 
SD 
SD 
SD 
PR 
SD 
SD 
SD 
SD 
SD 
SD 
SD 
NE or NA 
SD [c] or NE or NA 
SD [c] or NE 
PD 
No further 
evaluation 
PD 
PD 
CR = complete response, PR= partial response, SD = stable disease, PD = progressive disease, NE = not evaluable, NA = not 
available. 
a. The minimum interval for confirmation of CR and PR is 4 weeks.  
b.  Best response will be SD if the first time point overall response is after 35 days on study.  Otherwise, the best response will be 
PD. 
c. Best response will be SD if the first time point overall response if after 35 days on study.  Otherwise, the best response will be 
NE. 
d. Best response will be SD provided the criteria for PD have not been met from the first to second assessment. 
* A best overall response of SD can only be made after the subject is on study for a minimum of 35 days (counted from Cycle 1 
Day 1).  If the subject is on study for less than 35 days, any tumor assessment indicating stable disease before this time period 
will have a best response of NE unless PD is identified.  
^Subsequent documentation of a CR may provide confirmation of a previously identified CR even with an intervening NE (e.g., 
CR NE CR). Subsequent documentation of a PR may provide confirmation of a previously identified PR even with an 
intervening NE or SD (e.g., PR NE PR or PR SD PR). However, only one (1) intervening NE or SD will be allowed between PRs 
for confirmation. Note: in the following scenario, PR SD NE PR, the second PR is not a confirmation of the first PR. 
Objective response rate (ORR) will be calculated using two methods: 
Method #1: ORR will be calculated using a strict interpretation of RECIST Version 1.1. 
Objective response will be derived as no/yes (0/1) variable. Patients with a BOR of confirmed 
CR or PR will be assigned ‘Yes’. Patients not having a BOR of confirmed CR or PR will be 
assigned ‘No’. Hence, ORR is defined as the proportion of patients with objective response being 
“Yes”.  


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 1  
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Method #2: ORRUNCONFIRMED will be calculated using all responses regardless of confirmation.  
Objective response will be derived as no/yes (0/1) variable.  Patients with a BOR of confirmed 
CR, confirmed PR, unconfirmed CR or unconfirmed PR will be assigned “Yes”.  All patients 
with other BOR values will be assigned “No”.  Hence, ORRUNCONFIRMED is defined as the 
proportion of patients with objective response being “Yes”.  
Duration of Response (DOR) is the time between first response by RECIST Version 1.1 of CR or 
PR and the first date that progressive disease is documented by RECIST Version 1.1 or death. 
Patients who do not experience PD or death will be censored at the last tumor assessment date.  
Only those patients with confirmed responses will be included in this analysis. Censoring will 
follow the rules outlined below for progression-free survival (PFS) in Section 5.1.3.1.5.  
Clinical benefit rate (CBR) is defined as the proportion of patients with a BOR of confirmed CR, 
confirmed PR, or SD.  
ORR, ORRUNCONFIRMED, DOR and CBR will be calculated using the derived responses and 
investigator responses. 
5.1.3.1.5. 
Progression-free Survival  
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. 
Hence, PFS is defined as the time (months) from date of first dose date of study drug (topotecan 
or trilaciclib/placebo) for patients in Part 1 or date of randomization for patients in Part 2 until 
date of documented disease progression or death due to any cause, whichever comes first. More 
specifically, PFS will be determined using all the assessment data up until the last evaluable visit 
prior to or on the date of (i) disease progression as defined by RECIST Version 1.1 (Eisenhauer 
et al, 2009); or (ii) withdrawal of consent; or (iii) receiving subsequent anti-cancer therapy, 
whichever is earlier. 
PFS will be calculated using derived responses and progression by RECIST Version 1.1 will be 
considered. 
Death, regardless of cause, is always considered as a PD event. The detailed censoring rules for 
the analysis are summarized in Table 9. 
Table 9  
Assignment of Progression or Censoring Based on Radiological Assessment 
Situation 
Date of Progression or Censoring 
Outcome 
No Baseline assessment  
  
Date of first dose of study drug 
(topotecan or trilaciclib/placebo) for 
patients in Part 1 or date of 
randomization for patients in Part 2 
Censored 
No progression - treatment 
not started 
Date of first dose of study drug 
(topotecan or trilaciclib/placebo) for 
patients in Part 1 or date of 
randomization for patients in Part 2 
Censored 


 
 
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Clinical Study Protocol G1T28-03                                       
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Situation 
Date of Progression or Censoring 
Outcome 
No progression  
Date of last adequate radiological 
disease assessment  
Censored 
Treatment discontinuation 
for reasons other than 
disease progression 
Date of last progression assessment 
with no documented progression 
Censored 
New anticancer treatment 
started prior to documented 
disease progression   
Date of last adequate radiologic 
assessment no later than the 
initiation of new anticancer treatment  
Censored 
Disease progression per 
RECIST Version 1.1  
Date of the first reported progression  Progressed 
Death without a PD  
Date of death 
Progressed 
Determination of clinical 
progression per the 
investigator 
Date of the investigator assigned PD   Progressed [a] 
[a] For the primary derivation of PFS, the clinical progression will not be included (i.e. it will 
only be based on radiologic progression), but it will be incorporated as a separate derivation 
of PFS, and its analysis will be considered to be supportive. 
Note: An adequate radiologic assessment is defined as an assessment where the Investigator 
determined radiological response is CR, PR, SD, or PD.  If PD and new anti-cancer therapy 
occur on the same day, will assume that the progression was documented first, e.g. outcome 
is progression and the date is the date of the assessment of progression. 
5.1.3.1.6. 
Overall Survival  
Overall survival is calculated as the time (months) from date of first dose of study drug 
(topotecan or trilaciclib/placebo) for patients in Part 1 or date of randomization for patients in 
Part 2 to the date of death due to any cause. Patients who do not die during the study will be 
censored at the date last known to be alive. Patients lacking data beyond the day of first dose of 
study drug (topotecan or trilaciclib/placebo) for patients in Part 1 or date of randomization for 
patients in Part 2 will have their survival time censored at day of first dose of study drug 
(topotecan or trilaciclib/placebo) for patients in Part 1 or date of randomization for patients in 
Part 2. OS will not be censored if a patient receives other anti-tumor treatments after the study 
drugs (topotecan or trilaciclib/placebo). The analysis of OS will be primarily aimed at showing 
lack of harm from trilaciclib. 
5.1.3.2. 
Occurrence of Grade 3 and 4 Hematologic toxicities  
Hematologic toxicity events are defined as any cycle where any hematologic lab value occurs 
that meets the CTCAE toxicity grade criteria for ≥ Grade 3 and the value is treatment emergent. 
For details on which parameters are included and the definition of treatment emergent see 
Section 5.2.4. 
For the treatment period, the total number of hematologic toxicity events is the number of cycles 
in which there is at least one hematologic toxicity event. If a patient did not have any 
hematologic toxicity events, the value of 0 will be assigned to that patient. The number of cycles 


 
 
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Clinical Study Protocol G1T28-03                                       
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without hematologic toxicity events is calculated as total number of treatment cycles received – 
total number of cycles with a hematologic toxicity event. 
Therefore, any occurrence of a hematologic toxicity event during a cycle or the treatment period 
is defined as a binary variable (Yes or No); Yes if total number of cycles with a hematologic 
toxicity event ≥ 1 is observed, No for other scenarios. 
5.1.3.3. 
ANC Nadir by Cycle 
See table in Section 5 for the definition of cycle nadir. 
5.1.3.4. 
ANC, Platelet Count, Absolute Lymphocyte Counts (ALC), and Hemoglobin 
Change over Time 
For the hematologic parameters consisting of ANC, hemoglobin, platelet count, and ALC, the 
observed lab values in each windowed visit as detailed in Section 6.1.3 will be appropriately 
identified for further analysis.  
5.1.3.5. 
Occurrence of Erythropoietin Stimulating Agent (ESA) Administrations 
Administration of ESAs is collected with the concomitant medications which are coded using 
WHO-DD Version Sep2017.  The criterion to select proper records is as follows: If the chemical 
subgroup from WHO-DD Version Sep2017 (i.e. TEXT4 for CODE4) takes value “OTHER 
ANTIANEMIC PREPARATIONS”, the medication is classified as ESAs.  
Those cycles where ESAs are administered concurrently will be identified by comparing the start 
and stop dates of each ESA to the start of cycle and end of cycle.  If any of the dates of 
administration of an ESA overlap with any dates between the start of cycle and end of cycle, that 
cycle will be considered as having an ESA administered. Data handling conventions for missing 
start and stop dates are described in Section 6.2.5.   
For the treatment period, the total number ESA administrations is the total number of cycles in 
which there is at least one ESA dose administered. If a patient did not have any ESA use, the 
value of 0 will be assigned to that patient. The number of cycles where ESAs were NOT given is 
calculated as total number of treatment cycles received – total number of cycles where ESAs 
were administered. 
Therefore, any occurrence of an ESA administration during a cycle or the treatment period is 
defined as a binary variable (Yes or No); Yes if total number of cycles with an ESA 
administration ≥ 1 is observed, No for other scenarios. 
5.1.3.6. 
Occurrence of IV Antibiotic Uses 
IV antibiotic administration is collected with concomitant medications which are coded using 
WHO-DD Version Sep2017.  The criteria for identifying an IV antibiotic administration event is 
− If the Therapeutic subgroup from WHO-DD Version Sep2017 (i.e. TEXT2 for CODE2) 
takes value “ANTIBACTERIALS FOR SYSTEMIC USE”, and  
− The route of medication is “intravenous” or the route is “other” with the detailed 
specification as “IVPB”.  


 
 
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Clinical Study Protocol G1T28-03                                       
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Each IV antibiotic with a unique start date during the treatment period will be defined as a 
separate event. Data handling conventions for missing start and stop dates are described in 
Section 6.2.5.  
Occurrence of an IV antibiotics administration during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of IV antibiotics administrations ≥ 1 is observed, No 
for other scenarios.     
5.1.3.7. 
Occurrence of Infection Serious Adverse Events (SAEs)  
Each infection SAE is captured in the electronic database. The event terms are coded using the 
MedDRA Version 20.1. The criterion for identifying the proper infection SAE records is as 
follows: if the system organ class (SOC) from MedDRA takes value “INFECTIONS AND 
INFESTATIONS” and the AE is a serious event. 
Each infection SAE with a unique start date during the treatment period will be defined as 
separate event. Data handling conventions for missing start and stop dates for AEs are described 
in Section 5.2.1.    
Any occurrence of an infection SAE during the treatment period is defined as a binary variable 
(Yes or No); Yes if total number of infection SAEs ≥ 1 is observed, No for other scenarios.  
5.1.3.8. 
Occurrence of Pulmonary Infection SAEs 
Each pulmonary infection SAE is captured in the electronic database. The event terms are coded 
using the MedDRA Version 20.1. The criterion for identifying the  pulmonary infection SAEs 
records is as follows: if the system organ class (SOC) from MedDRA takes value 
“INFECTIONS AND INFESTATIONS”, the PT takes a values from Table 10 and the AE is a 
serious event. 
Table 10 
PT List for Grouping Infection AEs and Pulmonary Infection AEs 
Category 
Preferred terms 
Pulmonary Infection AEs 
Bronchiolitis 
 
Bronchitis 
 
Infectious pleural effusion 
 
Influenza 
 
Lung infection 
 
Pneumonia 
 
Pneumonia bacterial 
 
Pneumonia pneumococcal 
 
Respiratory tract infection 
 
Upper respiratory tract infection 
 
Viral upper respiratory tract infection 
Each pulmonary infection SAE with a unique start date during the treatment period will be 
defined as separate event.  Data handling conventions for missing start and stop dates for AEs 
are described in Section 5.2.1.     


 
 
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Clinical Study Protocol G1T28-03                                       
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Any occurrence of a pulmonary infection SAE during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of pulmonary infection SAEs ≥ 1 is observed, No for 
other scenarios.  
5.1.3.9. 
Occurrence of Febrile Neutropenia 
Each febrile neutropenia event is captured in AE data of electronic database, and “FEBRILE 
NEUTROPENIA” is a preferred term which can be used to identify the proper AE records. The 
event terms are coded using the MedDRA Version 20.1.     
Each febrile neutropenia event with a unique start date during the treatment period will be 
defined as a separate event. Data handling conventions for missing start and stop dates for AEs 
are described in Section 5.2.1.    
Any occurrence of a febrile neutropenia event during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of febrile neutropenia events ≥ 1 is observed, No for 
other scenarios. 
5.1.3.10. Occurrence of Grade 4 and Grade 3/4 Thrombocytopenia 
Thrombocytopenia events of Grade 4 or Grade 3/4 are defined as any cycle where any platelet 
lab value occurs that meets the CTCAE toxicity grade criteria for ≥ Grade 4 (3) and the value is 
treatment emergent. For the definition of treatment emergent see Section 5.2.4. 
For the treatment period, the total number of thrombocytopenia events is the number of cycles in 
which there is at least one thrombocytopenia event. If a patient did not have any 
thrombocytopenia events, the value of 0 will be assigned to that patient. The number of cycles 
without thrombocytopenia events is calculated as total number of treatment cycles received – 
total number of cycles with a thrombocytopenia event. 
Therefore, any occurrence of a thrombocytopenia event during a cycle or the treatment period is 
defined as a binary variable (Yes or No); Yes if total number of cycles with a thrombocytopenia 
event ≥ 1 is observed, No for other scenarios. 
5.1.3.11. Myelosuppression Endpoints with All data up to End of Cycle 4 
The following myelosuppression endpoints will be derived for a period of interest utilizing all 
available data up to the end of Cycle 4. The period of interest starts from the date of 
randomization/first dose of study drug, whichever is earlier. The end dates of the period depend 
on the status of each patient; for patients who receive ≤ 4 cycles of therapy, the period ends on 
the date of the first dose date of the last cycle + 38 days, and for patients who receive > 4 cycles, 
the period ends on Day 1 of Cycle 5. The derivation of each endpoint will follow the definition 
described in each relevant section. 
− Occurrence of severe (Grade 4) neutropenia (Section 5.1.1.1); 
− Occurrence of RBC transfusions on/after week 5 of study (Section 5.1.2.1); 
− Occurrence of GCSF administrations (Section 5.1.2.2); 
− Occurrence of platelet transfusions (Section 5.1.2.3); 
− Total number of MAHE (Section 5.1.2.4); 
− Number of all-cause hospitalizations (Section 5.1.2.4.1); 


 
 
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− Number of all-cause dose reductions (Section 5.1.2.4.2); 
− Number of febrile neutropenias (Section 5.1.2.4); 
− Number of cycles with prolonged severe (Grade 4) neutropenia (duration > 5 days) (Section 
5.1.2.4.3);  
− Number of RBC transfusions on/after 5 weeks (Section 5.1.2.4);  
− Number of platelet transfusions (Section 5.1.2.4); 
− Occurrence of Grade 3 and 4 hematologic toxicities (Section 5.1.3.2); 
− Occurrence of RBC transfusions during the first 4 cycles (Section 5.1.2.1);  
− Number of RBC transfusions during the first 4 cycles (Section 5.1.2.4);  
5.1.4. 
Exploratory Efficacy Endpoints  
5.1.4.1. 
FACT-L and FACT-An 
The FACT-L and FACT-An analyses will be documented separately and are not covered in this 
SAP. 
5.1.4.2. 
Grade 2 or Greater Nephrotoxicity 
For any post-baseline creatinine assessment, an event of grade ≥ 2 nephrotoxicity is defined as 
the observed value >1.5 × baseline value, or > 1.5 × Upper Limit of Normal Range (ULN). 
Within a cycle, for each nephrotoxicity event, the occurrence of a creatinine value meeting the 
criteria outlined above is described using a binary variable (Yes or No); Yes, if the designated 
event is observed, No for other scenarios. For the treatment period, the total number of 
nephrotoxicity events where the creatinine value meets the criteria is the number of cycles where 
at least one lab value meets the criteria.  For example, if Cycle 2 has two values that both meet 
criteria, this only counts as one event. If a patient does not have any lab values meeting the 
criteria, the value of 0 will be assigned to that patient.  Unscheduled data and the actual 
assessment date (rather than visit date) will be used for these analyses. 
Any occurrence of a Grade ≥ 2 nephrotoxicity during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of Grade ≥ 2 nephrotoxicity events ≥ 1 is observed, No 
for other scenarios.  
5.1.4.3. 
Occurrence of Alopecia and Mucositis 
Alopecia will be identified by the preferred term of “alopecia”, and mucositis will be identified 
by the high level term ‘stomatitis and ulceration’, or the preferred terms ‘mucosal inflammation’, 
‘mucosal ulceration’, or ‘oesophagitis’ used in MedDRA Version 20.1 coding for AE data, and 
these terms will be used to identify the occurrence of events during the treatment period.  
Separate analyses will be done for each term.  
Any occurrence of an alopecia (or mucositis) event during the treatment period is defined as a 
binary variable (Yes or No); Yes if total number of alopecia (or mucositis) events ≥ 1 is 
observed, No for other scenarios. Total number of events per subject will also be summarized. 
Data handling conventions for missing start/stop dates of AEs are in Section 5.2.1. 
5.1.4.4. 
Neutrophil-lymphocyte Ratio (NLR) and Platelet-lymphocyte Ratio (PLR)  
NLR will be derived using the ANC and ALC, and PLR will be calculated using platelet count 
and ALC.  Both NLR and PLR may have prognostic value in patients with various solid tumors. 


 
 
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Clinical Study Protocol G1T28-03                                       
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That is, the lower the value, the better the clinical prognosis. If data permit, NLR and PLR will 
be correlated with various anti-tumor efficacy analyses [e.g. ORR, PFS, and etc.]. 
5.2. 
Safety Endpoints  
5.2.1. 
Chemotherapy Exposure Endpoints 
5.2.1.1. 
Duration of Exposure  
Duration of exposure (days) = First dose date of study drug (topotecan or trilaciclib/placebo) 
from the last cycle – first dose date of study drug (topotecan or trilaciclib/placebo) + 21.  
5.2.1.2. 
Number of Cycles Received  
Patients are considered to have started a cycle if they have received at least one dose of any study 
drug (topotecan or trilaciclib/placebo).  In addition to the numeric summary for the number of 
cycles, the number of cycles will be categorized as 1, 2, 3, 4, 5 to 10, and > 10.  
5.2.1.3. 
Dose Intensity and Cumulative Dose 
Algorithms for calculating parameters relevant to the dose exposure and intensity are included in 
Table 11.   
Table 11  
Algorithms for Calculating Parameters Relevant to the Dose Exposure and 
Intensity 
Parameter 
Trilaciclib § 
Topotecan^ 
Dosing schedule 
per protocol 
200 mg/m2 IV on 
Days 1 to 5 of a 21-
day cycle 
1.5 mg/m2 IV on Days 
1 to 5 of a 21-day 
cycle 
Dose by cycle  
Total dose 
administered (mg) 
/most recent BSA (m2) 
[(mg/m2)].  
Total dose 
administered 
(mg)/most recent BSA 
(m2) [(mg/m2)].  
Cumulative dose  
Sum of the doses 
administered to a 
patient in the duration 
of exposure [(mg/m2)] 
Sum of the doses 
administered to a 
patient in the duration 
of exposure [(mg/m2)]  
Dose intensity  
Cumulative dose 
(mg/m2) / (duration of 
exposure / 7) 
[(mg/m2/week)] 
Cumulative Dose 
(mg/m2) / (duration of 
exposure / 7) 
[(mg/m2/week)] 
Relative dose 
intensity (%) 
 
 
100 * [Dose intensity 
(mg/m2/week) / (1000 
/3 (mg/m2/week)]  
100 * [Dose intensity 
(mg/m2/week) / (7.5 /3 
(mg/m2/week)]  
Relative Dose (%) 
100 * [Cumulative 
dose (mg/m2) / (1000 
× number of cycles 
(mg/m2)]  
100 * [Cumulative 
dose (mg/m2) / (7.5 × 
number of cycles 
(mg/m2)]  


 
 
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§ Three different doses (200mg/m2, 240mg/m2, and 280mg/m2) of trilaciclib were evaluated in 
Part 1.  240mg/m2 trilaciclib was the planned dose for all patients in Part 2.  The calculation of 
relevant parameters will be adjusted accordingly based on the example presented in this table.  
^ Four different doses (0.75mg/m2, 1mg/m2, 1.25mg/m2, and 1.5mg/m2) of topotecan were 
evaluated in Part 1.  0.75mg/m2 and 1.5mg/m2 were the planned dose for patients in Part 2.  The 
calculation of relevant parameters for Part 1 will be adjusted accordingly based on the example 
presented in this table. Part 2 dosing amounts were not collected to preserve the blind and these 
parameters will not be calculated for it. 
BSA = body surface area; IV = intravenous. 
 
Total number of doses will be calculated and summarized by treatment. 
5.2.1.4. 
Modifications of Study Therapy, Including Cycle (Dose) Delay, Missed Doses, 
Dose Interruptions, and Dose Reductions 
• After Cycle 1, patients need to meet pre-specified laboratory parameter criteria before 
initiating Cycle 2 and each subsequent cycle of chemotherapy. Cycle (dose) delay and its 
associated reasons are collected at the beginning of each cycle in an eCRF page titled 
“Beginning Cycle Assessment”. The reasons for delay will be summarized in the following 
categories: (1) Adverse event, (2) Logistical/Administrative Issues, (3) Hematologic Toxicity 
(which is a sum of those patients who fall into either category 3a or 3b), (3a) ANC < 1.5 x 
109/L, (3b) Platelet Count < 100 x 109/L, (5) Nonhematologic Toxicity and (6) Other. Note 
that categories 3a and 3b are sub-bullets of category (3).  
• Missed doses are identified on the dosing page of each study drug (topotecan or 
trilaciclib/placebo) based on the question “Was the dose missed?”. The missed dose 
information will be obtained for each study drug (topotecan or trilaciclib/placebo). For a 
study drug (topotecan or trilaciclib/placebo), if the last record of response to question “Was 
the dose missed?” is Yes, it will not be considered as a missed dose but instead considered to 
be end of treatment if both criteria below are met: 
o No other study drugs (topotecan or trilaciclib/placebo) are given on the same day, and 
o No study drugs (topotecan or trilaciclib/placebo) are given subsequently. 
The reasons for missed doses will be summarized in the following categories: (1) Adverse 
Event, (2) Logistical/Administrative Issues, and (3) Other. 
• Dose reductions are not permitted for trilaciclib. Dose reductions for topotecan are collected 
on the dosing page; the reasons for reduction will be summarized in the following categories: 
(1) Adverse Event, (2) Change recommendation by SMC, and (3) Other. No more than 2 
dose reductions of topotecan for toxicity in total are allowed for any patient. Toxicity that 
requires dose reduction more than twice will lead to discontinuation of trilaciclib or placebo 
+ topotecan; discontinuations will not be counted as a dose reduction. All dose reductions for 
toxicity are permanent, and no dose increases are allowed when dose reductions are made for 
toxicity. 
• Dose interruptions for all drugs are also captured on the dosing page and will be summarized 
for each study drug (topotecan or trilaciclib/placebo). 


 
 
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5.2.2. 
Adverse Events  
All AEs will be coded from verbatim text to PTs and grouped by SOC using the MedDRA 
Version 20.1. AEs will be collected from the time of signature of informed consent throughout 
the treatment period and up to 30 days after the last dose of study treatment. AEs are graded by 
investigator according to CTCAE, Version 4.03.  
Any AE that started on or after the first dose of study drugs (topotecan or trilaciclib/placebo) and 
up to the last dose + 30 days will be included as a treatment emergent AE (TEAE). AEs with an 
unknown/not reported onset date will also be included.  
Other AE variables include drug-related AEs, AEs leading to study drug (topotecan or 
trilaciclib/placebo) discontinuation or study withdrawal, AEs leading to death, and SAEs.  
AEs with onset/end dates that are partially/completely missing will be imputed as follows: 
(i) For onset date: 
− If only the day part of the AE onset date is missing and occurs in the same month and 
year as the first dose date of study drug (topotecan or trilaciclib/placebo), the date of first 
dose of study drug (topotecan or trilaciclib/placebo) will be used as the onset date of the 
AE. Otherwise, the first day of the month will be used to complete the onset date of the 
AE; 
− If the day and month parts of the AE onset date are missing and occur in the same year as 
the first dose of study drug (topotecan or trilaciclib/placebo), the date of the first dose of 
study drug (topotecan or trilaciclib/placebo) will be used as the onset date of the AE. 
Otherwise, January 1st will be used to complete the onset date of the AE; 
− If the AE onset date is completely missing, the date of the first dose of study drug 
(topotecan or trilaciclib/placebo) will be used as the onset date of the AE. 
(ii) For end date: 
− If only the day part of the AE end date is missing, the last day of the month will be used to 
complete the end date of the AE;  
− If the day and month parts of the AE end date are missing, December 31st will be used to 
complete the end date of the AE; 
− If the AE end date is completely missing and the onset date of the AE occurs after the 
date of the first dose of study drug (topotecan or trilaciclib/placebo), the last date during 
the treatment period + 30 days will be used as the AE end date. If the AE end date is 
completely missing and the onset date of the AE occurs prior to the date of the first dose 
of study drug (topotecan or trilaciclib/placebo) the date of the first dose of study drug 
(topotecan or trilaciclib/placebo) will be used as the AE end date. 
AEs related to hematologic toxicity will be pooled based on the preferred MedDRA Version 
20.1. Table 12 outlines those terms that will be consolidated.  


 
 
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Clinical Study Protocol G1T28-03                                       
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Table 12 
Preferred Terms to Be Consolidated 
Presented term in the table  Preferred Term 
Neutropenia 
Neutropenia 
 
Neutrophil count decreased 
Febrile neutropenia 
Febrile neutropenia 
Anaemia 
Anaemia 
 
Anaemia macrocytic 
 
Red blood cell count decreased 
 
Hemoglobin decreased 
Thrombocytopenia 
Thrombocytopenia 
 
Platelet count decreased 
Lymphopenia 
Lymphopenia 
 
Lymphocyte count decreased 
Leukopenia 
Leukopenia 
 
White blood cell count decreased 
AEs potentially related to infusion reactions will be pooled based on the PTs of MedDRA 
Version 20.1.  The events described by the PTs listed below will be summarized and presented in 
order of decreasing frequency: Infusion site pain, Infusion site pruritus, Infusion site reaction, 
Infusion site burning, Infusion related reaction, Infusion site irritation, Infusion site redness, 
Allergic reaction, Catheter site itching, Catheter site erythema, Catheter site hematoma, and 
Catheter site pain..   
5.2.3. 
Vital Signs 
Vital signs include pulse rate, respiratory rate, systolic blood pressure (SBP), diastolic blood 
pressure (DBP), weight, height (only measured at screening), and body temperature. Body Mass 
Index (BMI) will be computed as weight (kg)/[height (m)]2, Body Surface Area (BSA) will be 
computed using DuBois-DuBois formula as 0.20247 × [height (m)]0.725 × [weight (kg)]0.425.  
For vital signs, change from baseline to each post-baseline visit and timepoint will be calculated. 
Vitals will be summarized by visit as collected and not windowed. 
The potentially clinically significant findings of vital signs will also be defined based on criteria 
defined in Table 13: 
Table 13 
Potentially Clinically Significant Criteria for Vital Signs 
 Vital Sign Parameter   
 Criterion value   
 Change from baseline  
 SBP   
 ≥180 mmHg   
 Increase ≥40 mmHg   
    
 ≤ 90 mmHg   
 Decrease ≥40 mmHg   
    
    
    
 DBP   
 ≥105 mmHg   
 Increase ≥20 mmHg   
    
 ≤ 50 mmHg   
 Decrease ≥20 mmHg   
 Pulse   
 ≥ 120 bpm   
 Increase ≥40 bpm   
    
  ≤ 50 bpm   
 Decrease ≥40 bpm  


 
 
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 Weight   
 n/a   
 Change ≥10%   
bpm  = beats per minute 
5.2.4. 
Laboratory 
Blood and urine samples for the determination of clinical chemistry, hematology, and urinalysis 
laboratory variables described in Table 14 will be measured.  
Table 14 
Laboratory Assessment 
Lab Category 
Lab tests 
Hematology  
Hemoglobin (HGB), hematocrit, white blood cell (WBC), platelet counts, 
ANC, ALC, Monocyte Absolute, Basophil Absolute, and Eosinophil 
Absolute. 
Chemistry  
albumin, Alkaline Phosphatase (ALP), total bilirubin, calcium, chloride, 
creatinine, glucose, inorganic phosphorus, potassium, total protein, Alanine 
Aminotransferase (ALT), Aspartate Aminotransferase (AST), Lactate 
Dehydrogenase (LDH), sodium, and Blood Urea Nitrogen (BUN). 
Urinalysis  
semiquantitative dipstick: specific gravity, pH, evaluation of glucose, 
protein, bilirubin, ketones, leukocytes, and hemoglobin microscopic 
examination, including RBC, WBC, and casts will be performed, if 
necessary 
Change from baseline in laboratory test results to each assessment will be calculated; for 
hematology parameters, the change from cycle baseline will also be obtained. The urinalysis and 
hematocrit results will not be summarized; they will only be included in listings. 
Clinical laboratory results will be graded according to CTCAE criteria, Version 4.03 which can 
be found in Table A-1 of Appendix.  Any graded abnormality that occurs following the initiation 
of study drug (topotecan or trilaciclib/placebo) and represents at least a 1-grade increase from the 
baseline assessment is defined as treatment emergent. Any assessment for which CTCAE 
toxicity grades are not available, will not be included in any analyses for which toxicity grades 
are required. 
Analysis of Abnormal Hepatic Laboratory Values 
The following categories of abnormal hepatic laboratory values will be evaluated for any 
occurrence among all post baseline assessments.  
• ALT and/or AST >3x ULN, ALP < 2xULN, and Total Bilirubin> 2x ULN 
• AST > 3,5,8,10, and 20x ULN, AST>5x ULN for more than 5 weeks 
• ALT > 3,5,8,10, and 20x ULN, ALT > 5x ULN for more than 5 weeks 
• Total Bilirubin >1.5 or >2x ULN  
5.2.5. 
Electrocardiograms 
Electrocardiogram (ECG) parameters include heart rate, PR interval, and QT, QTcB, QTcF and 
QRS intervals. Change from baseline to each post-baseline visit will be calculated and 


 
 
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summarized by visit as collected and not windowed. Visits and timepoints only collected for PK 
subjects in Part 1 will be listed but not summarized. 
Potentially clinically significant ECG findings will be identified using the criteria which are 
included in Table 15. ECG results are interpreted as normal, abnormal but not clinically 
significant, or abnormal and clinically significant.  
Table 15 
Potentially Clinically Significant Criteria for ECG 
 ECG Parameter   
 Criterion value   
 Heart Rate   
 >120 bpm   
    
  <50 bpm   
 PR Interval   
 ≥ 210ms   
 QRS Interval   
 ≥ 120ms   
    
  ≤ 50ms   
 QT Interval   
 ≥ 500ms   
    
 ≤ 300ms   
 QTcB, QTcF Intervals   
 ≥ 500ms   
    
 ≥ 480ms   
    
 ≥ 450ms   
    
 ≤ 300ms   
    
 Change from baseline ≥ 30 ms  
    
 Change from baseline ≥ 60 ms  
5.2.6. 
Physical Examination 
Physical examination is conducted during screening, on Day 1 of each cycle, and at the post-
treatment visit. Abnormal findings in PE were to be reported as AEs.  These data will not be 
summarized, i.e. they will only be available in listings.  
 
 


 
 
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6. 
ANALYSIS METHODS 
6.1. 
General Principles of Analysis 
6.1.1. 
General Methodology 
In general, all efficacy, safety and PK variables will be summarized using descriptive statistics 
and graphs as appropriate. Continuous variables will be summarized by descriptive statistics 
(sample size (n), mean, standard deviation, minimum, median, and maximum). Categorical 
variables will be summarized in frequency tables (frequencies and percentages).  
Survival estimates will be analyzed with Kaplan-Meier method and summarized with median, 
twenty-fifth and seventy-fifth percentiles, and 95% confidence intervals (CI), if applicable. 
Individual data will be presented in patient listings.  
Analyses will be implemented using SAS® 9.4 or higher (SAS Institute, Cary, North Carolina, 
USA). The International Conference on Harmonization (ICH) numbering convention, i.e. ICH-
E3, will be used for all tables and listings. Upon completion, all SAS programs will be 
validated by an independent programmer within the staff of the third-party vendor doing the 
primary analysis.  The validation process will be used to confirm that statistically valid methods 
have been implemented and that all data manipulations and calculations are accurate.  Checks 
will be made to ensure accuracy, consistency with this plan, consistency within tables, and 
consistency between tables and corresponding data listings. 
All summary tables, listings, and figures (TLFs) will be presented by treatment groups as defined 
in Table 16. 
Table 16 
Treatment Display in TLFs 
Study Part  
Trilaciclib 
Dose 
Topotecan Dose 
Treatment Description in Data 
Display 
Part 1  
200 mg/m2 
1.5 mg/m2 
Cohort 1 
Part 1  
200 mg/m2 
1.25 mg/m2 
Cohort 2 
Part 1 
200 mg/m2 
0.75 mg/m2 
Cohort 3 
Part 1 
240 mg/m2 
0.75 mg/m2 
Cohort 4 & 6 
Part 1 
280 mg/m2 
0.75 mg/m2 
Cohort 5 
Part 1 
240 mg/m2 
1.0 mg/m2 
Cohort 7 
Part 1 
Any 
Any 
Total 
Part 2 
Placebo 
1.5 mg/m2 
Placebo   
Part 2 
240 mg/m2 
0.75 mg/m2 
Trilaciclib 240 mg/m2 and Topotecan 
0.75 mg/m2 
Part 2 
240 mg/m2 
1.5 mg/m2 
Trilaciclib 240 mg/m2 and Topotecan 1.5  
mg/m2 
Part 2 
240 mg/m2 
Any 
Total  
All statistical tests will be presented at a two-sided .20 alpha level unless otherwise specified. 
The primary comparison will be conducted between placebo group (from Part 2A and 2B) and 
Trilaciclib 240 mg/m2 + Topotecan 1.5 mg/m2 group. Where appropriate, model-based point 
estimates, together with their 80% CIs will be presented along with the two-sided p-values for 


 
 
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the tests. P-value will be presented to 4 decimal places, if the p-value <0.0001, the value will be 
presented as “<0.0001”. 
For continuous data, the same number of decimal places as in the raw data will be presented 
when reporting mean, median, minimum and maximum; one more decimal place than in the raw 
data will be presented when reporting standard deviation and standard error (SE).  The derived 
variables will be presented with 1 decimal place. Percentages will be reported with 1 decimal 
place; if the count is 0, no percentage will be presented. Value of percentage less than 1% will be 
presented as “<1%.” Value of percentage less than 100% but ≥ 99.5% will be presented as 
“>99%.” 
6.1.2. 
Handling of Missing Data 
In general, the observed case (OC) data for a visit will consist of the actual observations recorded 
for the visit. If missing, the OC data will remain missing — no missing imputation will be 
performed. Safety analyses will be conducted on the OC data only. However, imputation of 
missing AE and concomitant medication onset and stop dates will be used to determine the status 
of each AE and the prior/concomitant status of each medication. Please refer to Section 5.2.1 for 
the method of imputation of missing AE onset and stop date and Section 6.2.5 for the method of 
imputation of missing concomitant onset and stop dates.  
For demographic and baseline characteristics, each variable will be analyzed and/or summarized 
using the available data. Patients with missing data will be excluded only from analyses for 
which data are not available. 
For the efficacy analyses, missing data will be excluded except for the sensitivity analyses noted 
in Section 6.2.7.1.4. 
6.1.3. 
Visit Windowing 
It is expected that there will be a variation between patients in the actual number of study days 
from the start of administration of study drug (topotecan or trilaciclib/placebo) within each cycle 
− defined as Day 1 − to the dates that the scheduled visits occur. To handle this, for tables and 
figures where data are grouped by visit, assessments will be categorized using visit windows 
based on study days (relative to the Day 1 of each cycle). The visit-window mapping is described 
in Table 17. Visit-based summaries will be based on the windowed visits. All data, whether or 
not within the visit windows, will be presented in patient listings.  
For windowed visits during the treatment cycles, if more than 1 visit occurs during a visit 
window, the visit closest to the scheduled day will be assigned to the windowed visit. If two 
visits are equidistant from the scheduled day, the later visit will be assigned to the windowed 
visit. If there are multiple assessments on the same day, the worst case will be used.  For the 
assigned follow-up visit, the last assessment in the window will be included in the summary. 
For a patient who prematurely discontinues the study, the visit will be slotted accordingly. The 
window for post-treatment visit will be "the first dose date of the last cycle + 38 to last 
assessment date prior to the start of survival follow-up". Day 18 was collected in earlier versions 
of the protocol but will not be summarized as most cycles did not include.


 
 
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Table 17 
Visit Windowing 
 
 
Cycle x 
Post-treatment [d] 
Visit 
CxD1 
CxD5 
CxD10 
CxD12 
CxD15 
EOCx 
 
Scheduled Day [a] 
1 
5[e] 
10 
12 
15[e] 
22 
 
Clinical Chemistry [b] 
Day -3 - 1 
 
 
 
2 to EOC 
 
From first dose date of 
last cycle to first dose 
date of last cycle + 38  
Hematology [c] 
Day -3 - 1 
1 to 7 
8 to 10 
11 to 13 
14 to 17 
18 to EOC 
[a] The scheduled day is relative to the Day 1 of each cycle. 
[b] Clinical chemistry may be obtained up to 72 hours prior to the first dose of each cycle. 
[c] Hematology may be obtained up to 24 hours prior to dosing on Days 1, 3, 10, 12 and 15 of each cycle, at the Post-Treatment Visit, and at 60 days after the 
Post-Treatment Visit. 
[d] 30 ± 3 days after the last dose of study drug (topotecan or trilaciclib/placebo)


 
 
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6.1.4. 
Adjustment for Covariates 
Patient randomization in Part 2 was stratified by ECOG performance status (0 or 1 vs. 2) and 
sensitivity to first-line treatment (sensitive: CR/PR/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 efficacy analyses will use the stratification factors as 
covariates in statistical models.  
6.2. 
Analysis Methods  
6.2.1. 
Patient Disposition 
A summary table will be generated to provide the following by study part, as appropriate: 
• 
Number of patients screened 
• 
Number and percentage of screening failures 
• 
Reason for screening failure 
• 
Number of patients dosed 
• 
Number of patients randomized (Part 2 only) 
• 
Number of patients randomized and not dosed (Part 2 only) 
A separate table will be presented to show the patients included in each analysis set and reason 
for exclusion from an analysis set. 
Patient status at treatment and study completion will be listed and summarized.  The listing will 
include whether patients discontinued from the treatment and the reasons for the discontinuation, 
along with the date of first and last dose and the date of completion or discontinuation from the 
treatment.  The same information will be provided for patients who discontinued from the study.  
The following summaries will be added to the disposition table: 
• 
End of treatment status    
• Reason for study drug (topotecan or trilaciclib/placebo) discontinuation 
• 
Number of patients going into Survival follow-up  
• 
Number and percentage of patients who discontinued the study 
• 
Reason for study discontinuation 
• 
Death and reason for death 
6.2.2. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics, such as age at informed consent date, age groups 
(18-65, >65-75, >75), race, ethnicity, gender, screening vital signs (height, body weight, BMI, 
BSA), ECOG status (0 or 1, 2), sensitivity to first line treatment (sensitive, resistant, or 
unknown), and smoking history (never smoked, former smoker, and current smoker) will be 
summarized and listed.   
6.2.3. 
Disease Characteristics 
Disease characteristics including confirmation of diagnosis using neuroendocrine markers (Yes 
or No) and weight loss in the 6 months prior to randomization (Yes or No; if Yes, ≤5% or >5%), 


 
 
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will be summarized and listed. Family history of cancer and date of initial diagnosis of lung 
cancer will be listed only. 
6.2.4. 
Medical History  
Medical history will be coded to SOC and PT using MedDRA Version 20.1. 
The number and percentage of enrolled patients (Part 1) or randomized patients (Part 2) with any 
past medical history within each SOC and PT will be provided. A patient will only be counted 
once within a particular SOC (PT) even if he/she has multiple conditions/diseases in the same 
SOC (PT). The conditions/diseases from medical history are those conditions/diseases that 
stopped prior to the study entry. 
Surgical history (Yes or No; and if Yes, related to lung cancer) will be summarized and listed. 
Concomitant surgeries will be listed. 
6.2.5. 
Concomitant Medications 
All medication verbatim terms collected will be coded to Anatomical Therapeutic Classification 
(ATC) and PT using the WHO-DD Version Sep2017.  
Prior medications are defined as those taken by the patient prior to the administration of study 
drug (topotecan or trilaciclib/placebo). Concomitant medications are defined as those taken by 
the patient at any time between the date of study drug (topotecan or trilaciclib/placebo) 
administration and study completion/discontinuation. Medication with start date/time being 
partially or completely missing will be assumed to be concomitant if it cannot be definitely 
shown that the medication did not occur during the treatment period.   
Medications with onset/end dates that are partially/completely missing will be imputed as 
follows: 
(i) For onset date: 
− If only the day part of the medication onset date is missing and occurs in the same month 
and year as the first dose date of study drug (topotecan or trilaciclib/placebo), the date of 
first dose of study drug (topotecan or trilaciclib/placebo) will be used as the onset date of 
the medication. Otherwise, the first day of the month will be used to complete the onset 
date of the medication;  
− If the day and month parts of medication onset date are missing and occur in the same 
year as the first dose of study drug (topotecan or trilaciclib/placebo), the date of the first 
dose of study drug (topotecan or trilaciclib/placebo) will be used as the onset date of the 
medication. Otherwise, January 1st will be used to complete the onset date of the 
medication; 
− If the medication onset date is completely missing, the date of the first dose of study drug 
(topotecan or trilaciclib/placebo) will be used as the onset date of the medication. 
(ii) For end date: 
− If only the day part of the medication end date is missing, the last day of the month will be 
used to complete the end date of the medication;  


 
 
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− If the day and month parts of the medication end date are missing, December 31st will be 
used to complete the onset date of the medication; 
− If the medication end date is completely missing and the onset date of the medication 
occurs after the date of the first dose of study drug (topotecan or trilaciclib/placebo), the 
last date during the treatment period will be used as the medication end date. Otherwise, 
the date of the first dose of study drug (topotecan or trilaciclib/placebo) will be used as 
the medication end date.    
Concomitant medications will be summarized by presenting the number and percentage of 
patients by PT and ATC. Patients taking the same medication multiple times will only be 
counted once for that PT or ATC. Each summary will be ordered by descending order of 
incidence of ATC class and PT within each ATC class.  
All prior and concomitant medications will be presented in a patient listing. 
6.2.6. 
Prior and Subsequent Anti-cancer Therapy 
The prior and subsequent anti-cancer therapies, such as prior systemic anti-cancer therapy (Yes 
or No) prior radiotherapy (Yes or No), subsequent systemic anti-cancer therapy (Yes or No), and 
concomitant radiation therapy (Yes or No; Reason) will be summarized and listed. All verbatim 
terms collected of prior and subsequent anti-cancer therapy will be coded to Anatomical 
Therapeutic Classification (ATC) and PT using the WHO-DD Version Sep2017.  
The prior anti-cancer therapy will summarize number of prior lines of therapy and the outcomes 
of those therapies. Subsequent anti-cancer therapy will summarize the number and percentage of 
patients by PT and ATC. Patients taking the same medication multiple times will only be 
counted once for that PT or ATC. Each summary will be ordered by descending order of 
incidence of ATC class and PT within each ATC class.  The data will be presented in a patient 
listing. 
6.2.7. 
Efficacy Analyses 
All the efficacy variables will be summarized using descriptive statistics by cycle or visit, with 
the supportive data provided in patient listings.  Part 1 will be summarized using only descriptive 
statistics. For Part 2, in addition to the descriptive summary, the between treatment comparison 
(trilaciclib 240 mg/m2 + topotecan 1.5 mg/m2 vs placebo + topotecan), will be performed only 
for the primary and secondary endpoints outlined in Section 5.1.1-5.1.3. The comparisons 
between trilaciclib vs. placebo will be built into the multiplicity adjustment described in Section 
6.2.7.1.3, the adjusted one-sided p-values will be reported and be the basis for the study drug 
efficacy conclusion and claim at the significance level of one-sided 0.10. However, for these 
comparisons, all statistical tests will be conducted at a two-sided .20 alpha level unless otherwise 
specified. Where appropriate, model-based point estimates, together with their two-sided 80% 
CIs will be presented along with the two-sided p-value for the test unless otherwise specified. 
Graphical presentation of efficacy results will be appropriately performed as needed. 
Unless otherwise specified, all analyses for the efficacy endpoints will be conducted for the 
treatment period which is defined to be between the start of cycle for Cycle 1 and the end of the 
last cycle. 


 
 
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6.2.7.1. 
Primary and Key Secondary Efficacy Analyses 
6.2.7.1.1. 
Primary Efficacy Analyses 
The primary efficacy endpoint, occurrence of SVN, is a binary response variable (Yes, No). It 
will be summarized using descriptive statistics by treatment group and will be analyzed to 
compare trilaciclib and placebo using modified Poisson regression (Zou, 2004) to account for the 
variable duration of the treatment period for each patient. The model will include baseline ANC 
as a covariate, the stratification factors of ECOG (0 or 1 vs. 2) and sensitivity to first-line 
treatment (sensitive or resistant) and treatment as a fixed effect. The logarithm transformation of 
number of cycles will be included as an offset variable in the modeling. The two-sided p-value, 
adjusted rate ratio (aRR) (trilaciclib vs placebo) and its 80% CIs will be presented.   
For the other primary efficacy endpoint, DSN in Cycle 1 based on Strategy 1 in Section 
5.1.1.2.1, a two-sided p-value will be calculated for the nonparametric analysis of covariance 
(ANCOVA) (Stokes 2012). The nonparametric ANCOVA will include study baseline ANC 
value as covariate, stratification factors of ECOG (0 or 1 vs. 2) and sensitivity to first-line 
treatment (sensitive or resistant), and treatment as a fixed effect. Along with the descriptive 
statistics, the mean difference and Hodges-Lehmann estimate of median difference between the 
two treatment groups, together with its 80% CIs will be provided. 
Additionally, DSN for each cycle will be presented using descriptive statistics.  
6.2.7.1.2. 
Key Secondary Efficacy Analyses 
Occurrence of RBC transfusions on/after 5 weeks on study is a binary variable and will be 
summarized using the same method for occurrence of SVN described in Section 6.2.7.1.1 except 
baseline HGB will be used as a covariate instead of baseline ANC in the modified Poisson 
model. Also, the offset will be the logarithm transformation of duration of treatment period 
divided by 7 (i.e. week) instead of number of cycles. An additional sensitivity analysis will look 
all transfusions during the treatment period, and all transfusions with a subset of subjects 
completing at least 1 cycle. 
Occurrence of GCSF administration is a binary variable and will be summarized using the same 
method for occurrence of SVN described in Section 6.2.7.1.1.  
Occurrence of platelet transfusion is a binary variable and will be summarized using the same 
method for occurrence of SVN described in Section 6.2.7.1.1 except baseline platelet count will 
be used as a covariate instead of baseline ANC in the modified Poisson model. Also, the offset 
will be the logarithm transformation of duration of treatment period divided by 7 (i.e. week) 
instead of number of cycles. 
The total number of MAHE in Section 5.1.2.4 will be analyzed to compare trilaciclib and 
placebo using a negative binomial regression model to account for the potential over-dispersion. 
The model includes the stratification factors of ECOG (0 or 1 vs. 2) and sensitivity to first-line 
treatment (sensitive or resistant), and treatment as a fixed effect. The logarithm transformation of 
duration of treatment period divided by 7 (i.e. week) will be included as an offset variable in the 
modeling. The two-sided p-value, aRR (trilaciclib vs placebo) and its 80% CIs will be presented.  
The total number of MAHE will be summarized descriptively, along with the weeks of treatment 
duration, and the event rate per week (calculated as the total number of events/duration of 


 
 
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treatment period divided by 7 [i.e. week]). The cumulative incidence of events during the 
treatment period will be summarized and presented graphically in three-week intervals. 
The total number of individual MAHE components (specified in Table 4) will be summarized 
similarly, except that dose reductions and DSN > 5 days will be summarized cumulatively by 
cycle instead of three-week intervals, and the offset will be the logarithm transformation of 
number of cycles instead of duration of treatment period. 
An event chart of the treatment period will also be included, with horizontal bars for each 
subject’s cycle length and time on the x-axis, with points plotted for each of the MAHE 
components. 
6.2.7.1.3. 
Multiplicity Adjustments 
The clinical trial evaluates the objectives defined in terms of the comparison of Trilaciclib + 
Topotecan 1.5 mg/m2 group to placebo + topotecan group on the primary and key secondary 
myelosuppression efficacy endpoints in Sections 5.1.1 and 5.1.2. The resulting multiplicity 
problem include the following 12 hypotheses of no effect: 
• Hypothesis 𝐻𝐻1. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo 
+ topotecan group for duration of severe (Grade 4) neutropenia in Cycle 1. 
• Hypothesis 𝐻𝐻2. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo 
+ topotecan group for occurrence of severe (Grade 4) neutropenia. 
• Hypothesis 𝐻𝐻3. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo 
+ topotecan group for occurrence of RBC transfusions on/after Week 5 on study. 
• Hypothesis 𝐻𝐻4. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo 
+ topotecan group for occurrence of G-CSF administration. 
• Hypothesis 𝐻𝐻5. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo 
+ topotecan group for occurrence of platelet transfusions. 
• Hypothesis 𝐻𝐻6. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo 
+ topotecan group for the MAHE composite. 
• Hypothesis 𝐻𝐻7. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo 
+ topotecan group for all-cause hospitalizations in the MAHE composite. 
• Hypothesis 𝐻𝐻8. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo 
+ topotecan group for all-cause dose reductions in the MAHE composite. 
• Hypothesis 𝐻𝐻9. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo 
+ topotecan group for febrile neutropenia in the MAHE composite. 
• Hypothesis 𝐻𝐻10. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus 
placebo + topotecan group for RBC transfusions on/after Week 5 in the MAHE 
composite.  
• Hypothesis 𝐻𝐻11. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus 
placebo + topotecan group for platelet transfusions in the MAHE composite.  


 
 
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Clinical Study Protocol G1T28-03                                       
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• Hypothesis 𝐻𝐻12. Comparison of Trilaciclib + Topotecan 1.5 mg/m2 group versus 
placebo + topotecan group for prolonged severe (Grade 4) neutropenia (> 5 days) in 
the MAHE composite. 
A Hochberg-based gatekeeping procedure will be utilized to control the global familywise error 
rate across the multiple null hypotheses in the strong sense at a 1-sided α=0.10 level. The one-
sided 𝑝𝑝-values for these comparisons will be used for the multiple test procedure, and the raw 
and adjusted 1-sided 𝑝𝑝-values will be provided in the summary.  
Gatekeeping procedure with logical restrictions 
A Hochberg-based gatekeeping procedure satisfies the positive dependence condition given the 
1-sided setting. The procedure is built using the mixture methodology developed in Dmitrienko 
and Tamhane (2011) and accounts for the logical restrictions among the 12 hypotheses displayed 
in Figure 6 by performing multiplicity adjustments in three steps. The logical restrictions can be 
achieved by defining the parallel set and serial set for each individual hypothesis based the tree-
structured procedure introduced by Dmitrienko et al (2007).  
• Step 1. The Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo + topotecan group 
comparisons for Family 1 (hypotheses 𝐻𝐻1 and 𝐻𝐻2) are performed using a truncated version of 
the Hochberg procedure. The truncation parameter γ is set to 0.5.  
• Step 2. The Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo + topotecan group 
comparisons for Family 2 (hypotheses 𝐻𝐻3, 𝐻𝐻4, 𝐻𝐻5, and 𝐻𝐻6) are performed using a truncated 
version of the Hochberg procedure if there is at least one significance in Step 1. Specifically, 
the hypotheses 𝐻𝐻3, 𝐻𝐻4, 𝐻𝐻5, and 𝐻𝐻6 depend on the hypotheses 𝐻𝐻1 and 𝐻𝐻2, ie, 𝐻𝐻3, 𝐻𝐻4, 𝐻𝐻5, and 
𝐻𝐻6 are tested only if at least one of the hypotheses 𝐻𝐻1 and 𝐻𝐻2 is rejected. The truncation 
parameter γ is set to 0.5.   
• Step 3. The Trilaciclib + Topotecan 1.5 mg/m2 group versus placebo + topotecan group 
comparisons for Family 3 (hypotheses 𝐻𝐻7, 𝐻𝐻8, 𝐻𝐻9, 𝐻𝐻10, 𝐻𝐻11, and 𝐻𝐻12) are performed using 
the regular Hochberg test if 𝐻𝐻6 is significant in Step 2. 
 
 


 
 
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Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 1  
Version date: 05Dec2018 
 
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Figure 6 
Graphical Display of the Hochberg-based Gatekeeping Procedure 
 
The regular Hochberg test is defined in Dmitrienko et al. (2009) and the truncated Hochberg test 
is defined in Dmitrienko, Tamhane and Wiens (2008). The decision rules used in the regular and 
truncated Hochberg tests will be detailed in the following. In general terms, the truncated version 
of the Hochberg test is defined as a convex combination of the regular Hochberg and Bonferroni 
tests. An important parameter of the truncated Hochberg test is the truncation parameter γ which 
ranges between 0 and 1. If the truncation parameter γ is set to 0, the truncated Hochberg test 
simplifies to the Bonferroni test. On the other hand, if the truncation parameter γ is set to 1, the 
truncated Hochberg test is identical to the regular Hochberg test. The truncated Hochberg test 
satisfies the separability condition (Dmitrienko, Tamhane and Wiens, 2008) if the truncation 
parameter γ is strictly less than 1. This condition ensures that in each step of the testing algorithm 
the error rate can be transferred to the next step provided at least one Trilaciclib + Topotecan 1.5 
mg/m2 group versus placebo + topotecan group comparison is significant in the current step 
without inflating the overall type I error rate (Huque, 2016; FDA, 2017). 
Testing algorithm 
This section describes the implementation of the Hochberg-based gatekeeping procedure. The 
testing algorithm relies on the general approach to defining multistage gatekeeping procedures 
based on mixtures of multiple tests proposed in Dmitrienko and Tamhane (2011). 
Decision rules 
The aforementioned 12 hypotheses are grouped into 3 families: 
• Family 1 (𝐹𝐹1) includes the hypotheses 𝐻𝐻1 and 𝐻𝐻2. 
• Family 2 (𝐹𝐹2) includes the hypothesis 𝐻𝐻3, 𝐻𝐻4, 𝐻𝐻5, and 𝐻𝐻6. 
• Family 3 (𝐹𝐹3) includes the hypotheses 𝐻𝐻7, 𝐻𝐻8, 𝐻𝐻9, 𝐻𝐻10, 𝐻𝐻11, and 𝐻𝐻12. 
H2: Occurrence of severe 
neutropenia 
H1: Duration of severe 
neutropenia in Cycle 1 
Family 1, F1 
One-sided α = 0.10 
H3: Occurrence of 
RBC transfusion 
on/after 5 weeks 
on study 
H8: Dose 
reduction 
H9: Febrile 
neutropenia 
H12: Prolonged 
severe 
neutropenia 
H10: RBC 
transfusion 
on/after 5 weeks 
on study 
H6: MAHE 
H7: 
Hospitalization 
Family 2, F2 
Family 3, F3 
Primary 
Key 
Secondary 
H4: 
Occurrence of 
G-CSF 
Administration 
H5: 
Occurrence of 
platelet 
transfusion 
H11: Platelet 
transfusion  


 
 
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Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 1  
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Using more compact notation, the families are defined as follows: 
𝐹𝐹1 = {𝐻𝐻𝑖𝑖, 𝑖𝑖∈𝑁𝑁1},  𝐹𝐹2 = {𝐻𝐻𝑖𝑖, 𝑖𝑖∈𝑁𝑁2},  𝐹𝐹3 = {𝐻𝐻𝑖𝑖, 𝑖𝑖∈𝑁𝑁3}. 
where the index sets are defined as 𝑁𝑁1 = {1, 2}, 𝑁𝑁2 = {3, 4, 5, 6}, 𝑁𝑁3 = {7, 8, 9, 10, 11 12}. Let 
𝑡𝑡𝑖𝑖 and 𝑝𝑝𝑖𝑖 denote the test statistic and 1-sided p-values associated with the hypotheses, 
respectively. Let 𝛼𝛼 denote the global familywise error rate, i.e., one-sided 𝛼𝛼= 0.10. 
Consider the closed family associated with Families 1, 2 and 3, i.e., a family of all non-empty 
intersections of the twelve hypotheses. Each intersection will be identified by an index set 
𝐼𝐼⊆𝑁𝑁 = {1, . . . ,12} 
(note that the empty set is excluded). For example, the index vector 𝐼𝐼= {1, 2, 5, 8} corresponds 
to the intersection of the hypotheses 𝐻𝐻1, 𝐻𝐻2, 𝐻𝐻5, and 𝐻𝐻8. 
To construct the Hochberg-based gatekeeping procedure that controls the global familywise error 
rate in the strong sense at an 𝛼𝛼 level, an 𝛼𝛼-level test needs to be defined for each intersection in 
the closed family. The multiple test and associated 𝑝𝑝-value for an intersection are computed in 
two steps. 
Step 1: Define 𝒑𝒑-values for subset intersections 
Consider an intersection corresponding to the index set 𝐼𝐼⊆𝑁𝑁 and define the index sets 𝐼𝐼𝑘𝑘= 𝐼𝐼∩
𝑁𝑁𝑘𝑘, 𝑘𝑘= 1, 2, 3. The 𝑝𝑝-values for the index sets 𝐼𝐼1, 𝐼𝐼2, and 𝐼𝐼3 are computed as follows: 
Let 𝑛𝑛1 denote the number of hypotheses included in 𝐼𝐼1 and let 𝑚𝑚1 = 𝑛𝑛1. If 𝑛𝑛1 > 0, the truncated 
Hochbergp-value is defined using the ordered 𝑝𝑝-values associated with the hypotheses included 
in the index set 𝐼𝐼1, denoted by  
𝑝𝑝1(1) ≤⋯≤𝑝𝑝1(𝑚𝑚1) 
The truncated Hochberg 𝑝𝑝-value for the index set 𝐼𝐼1 is given by 
𝑝𝑝(𝐼𝐼1) =
min
𝑖𝑖=1,⋯,𝑚𝑚1
𝑝𝑝1(𝑖𝑖)
𝛾𝛾1
𝑚𝑚1 −𝑖𝑖+ 1 + 1 −𝛾𝛾1
2
 
Here 𝛾𝛾1 is the pre-specified truncation parameter in Family 1. Choosing a larger value of 𝛾𝛾1 
improves the power of comparisons in Family 1, and 𝛾𝛾1 is set to 0.5. 
Further, let 𝑛𝑛2 denote the number of hypotheses included in the index set 𝐼𝐼2. If 𝑛𝑛2 > 0, consider 
the hypotheses in the index set 𝐼𝐼2 and remove the hypotheses that are not consistent with the 
logical restrictions defined in Figure 6. Let 𝑚𝑚2 denote the number of hypotheses remaining in the 
index set 𝐼𝐼2 after this logical restriction operation. If 𝑚𝑚2 > 0, let  
𝑝𝑝2(1) ≤⋯≤𝑝𝑝2(𝑚𝑚2) 
denote the ordered 𝑝𝑝-values for the hypotheses remaining in the index set 𝐼𝐼2. The truncated 
Hochberg 𝑝𝑝-value for 𝐼𝐼2 is given by 
𝑝𝑝(𝐼𝐼2) =
min
𝑖𝑖=1,⋯,𝑚𝑚2
𝑝𝑝2(𝑖𝑖)
𝛾𝛾2
𝑚𝑚2 −𝑖𝑖+ 1 + 1 −𝛾𝛾2
4
 


 
 
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Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 1  
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where 𝛾𝛾2 is the pre-specified truncation parameter in Family 2, which plays the same role as 𝛾𝛾1 
in Family 1, and 𝛾𝛾2 is set to 0.5. 
Finally, let 𝑛𝑛3 denote the number of hypotheses included in 𝐼𝐼3. If 𝑛𝑛3 > 0, remove the hypotheses 
that are not consistent with the logical restrictions defined in Figure 6. Let 𝑚𝑚3 denote the number 
of hypotheses remaining in the index set 𝐼𝐼3 after this logical restriction operation. If 𝑚𝑚3 > 0, let  
𝑝𝑝3(1) ≤⋯≤𝑝𝑝3(𝑚𝑚3) 
denote the ordered 𝑝𝑝-values for the hypotheses remaining in the index set 𝐼𝐼3. The Hochberg 𝑝𝑝-
value for 𝐼𝐼3 is given by 
𝑝𝑝(𝐼𝐼3) =
min
𝑖𝑖=1,⋯,𝑚𝑚3
𝑝𝑝3(𝑖𝑖)
1
𝑚𝑚3 −𝑖𝑖+ 1
 
Step 2: Define overall 𝒑𝒑-value 
The overall 𝑝𝑝-value for the intersection corresponding to the index set 𝐼𝐼 is computed by 
combining the 𝑝𝑝-values associated with the index sets 𝐼𝐼1, 𝐼𝐼2, and 𝐼𝐼3. Consider the following three 
scenarios: 
• If 𝑛𝑛1 > 0, the overall 𝑝𝑝-value is found using the following mixing function: 
𝑝𝑝(𝐼𝐼) = min ൬𝑝𝑝(𝐼𝐼1)
𝑏𝑏1
, 𝑝𝑝(𝐼𝐼2)
𝑏𝑏2
, 𝑝𝑝(𝐼𝐼3)
𝑏𝑏3
൰  
where 𝑏𝑏1 = 1,  𝑏𝑏2 = 𝑏𝑏1(1 −𝑓𝑓1 ), 𝑏𝑏3 = 𝑏𝑏2(1 −𝑓𝑓2 ) and 𝑓𝑓1 and 𝑓𝑓2 are computed based on the 
error rate functions of the truncated Hochberg tests used in Families 1 and 2. These quantities are 
defined below. 
• If 𝑛𝑛1 = 0 and 𝑛𝑛2 > 0, the overall 𝑝𝑝-value is given by 
𝑝𝑝(𝐼𝐼) = min ൬𝑝𝑝(𝐼𝐼2)
𝑏𝑏2
, 𝑝𝑝(𝐼𝐼3)
𝑏𝑏3
൰  
where  𝑏𝑏2 = 1, 𝑏𝑏3 = 𝑏𝑏2(1 −𝑓𝑓2 ). 
• If 𝑛𝑛1 = 0, 𝑛𝑛2 = 0 and 𝑛𝑛3 > 0, the overall 𝑝𝑝-value is given by 
𝑝𝑝(𝐼𝐼) = 𝑝𝑝(𝐼𝐼3)
𝑏𝑏3
 
where 𝑏𝑏3 = 1. 
The error rate function of the truncated Hochberg test with the truncation parameter 𝛾𝛾𝑘𝑘 for 
testing an intersection corresponding to the index set 𝐼𝐼𝑘𝑘, 𝑘𝑘= 1, 2, is defined as 
𝑒𝑒𝑘𝑘(𝐼𝐼𝑘𝑘) = 𝑃𝑃[𝑝𝑝(𝐼𝐼𝑘𝑘) ≤𝛼𝛼] 
and 𝑓𝑓𝑘𝑘= 𝑒𝑒𝑘𝑘(𝐼𝐼𝑘𝑘)/𝛼𝛼, 𝑘𝑘= 1, 2. It is shown in Brechenmacher et al. (2011) that 
𝑒𝑒𝑘𝑘(𝐼𝐼𝑘𝑘) = [𝛾𝛾𝑘𝑘+ (1 −𝛾𝛾𝑘𝑘)|𝐼𝐼𝑘𝑘|/𝑛𝑛𝑘𝑘]𝛼𝛼 
if the index set 𝐼𝐼𝑘𝑘 is non-empty and 𝑒𝑒𝑘𝑘(𝐼𝐼𝑘𝑘) = 0 the index set 𝐼𝐼𝑘𝑘 is empty. Here |𝐼𝐼𝑘𝑘| denotes the 
number of hypotheses included in the index set 𝐼𝐼𝑘𝑘.  


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 1  
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As shown in Dmitrienko and Tamhane (2011), the resulting test for the intersection 
corresponding to the index set 𝐼𝐼 is an 𝛼𝛼-level test. This implies that the Hochberg-based 
gatekeeping procedure controls the global familywise error rate in the strong sense at a one-sided 
𝛼𝛼= 0.10. 
Multiplicity-adjusted p-values 
Multiplicity-adjusted 𝑝𝑝-values for the Hochberg-based gatekeeping procedure are computed 
using the closure principle. For each hypothesis, the adjusted 𝑝𝑝-value is defined as the maximum 
over the 𝑝𝑝-values associated with the intersections in the closed family that include the 
hypothesis of interest. For example, the adjusted 𝑝𝑝-value for 𝐻𝐻2 is the maximum over the 𝑝𝑝-
values for intersections containing 𝐻𝐻2. The calculations are performed using the decision matrix 
algorithm, see Dmitrienko and Tamhane (2011).  
Regular and truncated Hochberg tests 
Consider a general problem of testing m null hypotheses denoted by 𝐻𝐻1, . . . , 𝐻𝐻𝑚𝑚. Let 𝑝𝑝1, . . . , 𝑝𝑝𝑚𝑚 
denote the associated raw p-values. Further, let 𝑝𝑝(1) < ⋯< 𝑝𝑝(𝑚𝑚) denote the ordered p-values and 
𝐻𝐻(1) < ⋯< 𝐻𝐻(𝑚𝑚) denote the hypotheses corresponding to the ordered p-values. 
The regular Hochberg test is based on the following testing algorithm: 
• Step 1: If 𝑝𝑝(𝑚𝑚) > 𝛼𝛼, accept 𝐻𝐻(𝑚𝑚) and go to Step 2, otherwise reject all null hypotheses 
and stop. 
• Step 𝑖𝑖= 2, . . . , 𝑚𝑚−1: If 𝑝𝑝(𝑚𝑚−𝑖𝑖+1) > 𝛼𝛼/𝑖𝑖, accept 𝐻𝐻(𝑚𝑚−𝑖𝑖+1) and go to Step 𝑖𝑖+ 1, 
otherwise reject all remaining null hypotheses and stop. 
• Step 𝑚𝑚: If 𝑝𝑝(1) > 𝛼𝛼/𝑚𝑚, accept 𝐻𝐻(1), otherwise reject 𝐻𝐻(1)· 
The truncated Hochberg test with the truncation parameter 𝛾𝛾 is based on the following testing 
algorithm: 
• Step 1: If 𝑝𝑝(𝑚𝑚) > [𝛾𝛾+ (1 −𝛾𝛾)/𝑚𝑚]𝛼𝛼, accept 𝐻𝐻(𝑚𝑚) and go to Step 2, otherwise reject all 
null hypotheses and stop. 
• Step 𝑖𝑖= 2, . . . , 𝑚𝑚−1: If 𝑝𝑝(𝑚𝑚−𝑖𝑖+1) > [𝛾𝛾/𝑖𝑖+ (1 −𝛾𝛾)/𝑚𝑚]𝛼𝛼, accept 𝐻𝐻(𝑚𝑚−𝑖𝑖+1) and go to 
Step 𝑖𝑖+ 1, otherwise reject all remaining null hypotheses and stop. 
• Step 𝑚𝑚: If 𝑝𝑝(1) > 𝛼𝛼/𝑚𝑚, accept 𝐻𝐻(1), otherwise reject 𝐻𝐻(1) 
6.2.7.1.4. 
Robustness of Primary and Key Secondary Efficacy Analyses 
A binary response variable (Yes, No) will be analyzed to compare trilaciclib and placebo using 
stratum-adjusted method to account for the baseline ECOG status (0 to 1 vs. 2) and sensitivity to 
first-line treatment (sensitive or resistant) as the stratification factors. The adjusted proportion 
difference (trilaciclib vs placebo) and its 80% CIs will be calculated using Cochran-Mantel-
Haenszel (CMH) weight outlined in Kim et al. 2013. The two-sided p-value will be calculated 
using stratified exact CMH method. Additionally, three sets of sensitivity analysis will be 
conducted to evaluate the robustness of the results from primary or key secondary analyses for a 
binary response variable (Yes, No).  


 
 
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Clinical Study Protocol G1T28-03                                       
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(i) 
For patients who die during the treatment period without experiencing an event, Yes will 
be assigned to the variable.  
(ii) After the imputation from (i), a worst-comparison analysis will be done to establish a 
stringent boundary of the treatment effect. Patients who die during the treatment period will 
still be set to Yes, and patients who discontinue the study prior to the September 28, 2018 
data cutoff date without experiencing an event will then be imputed. If the patient is from 
the placebo group, No will be assigned to the variables, Yes will be assigned to the 
trilaciclib groups.  
(iii) After the imputation from (i), a tipping-point analysis (Yan et al,. 2009) will be performed 
by assigning the response to the variable for patients who discontinue the study early 
during the treatment period without experiencing an event. 
The tipping-point analysis assumes all possible combinations of numbers of Yes and No for 
the missing responses (defined as patients without an event who have discontinued the 
study prior to the September 28, 2018 data cutoff date) in the trilaciclib and placebo 
groups. For example, let nt be the number of randomized trilaciclib patients with missing 
response and np be the number of randomized placebo patients with missing responses. For 
the trilaciclib patients with missing values, there are nt + 1 possible assumptions for 
number of No (i.e. 0, 1, 2, …, to nt); for the placebo patients with missing values, there are 
np + 1 possible assumptions for number of No.  Therefore, there are total of (nt + 1) × (np + 
1) possible combination of assumptions for number of No and Yes for the trilaciclib and 
placebo patients with missing responses. The un-stratified exact CMH method will be 
performed on the available responses with each of these (nt + 1) × (np + 1) assumptions and 
will be summarized. A figure will be presented with points representing each possible 
combination where the significant p-value ‘tips’ to greater than a one-sided 0.10, which 
would represent a change in the study conclusions. Clinical justification will be provided to 
evaluate whether the assumption is plausible.   
A waterfall plot showing the number of cycles with SVN will be presented. 
DSN for each cycle will be presented using descriptive statistics. The primary analysis on DSN 
defined by Strategy 1 (refer to Section 5.1.1.2.1) will be repeated on DSN defined by Strategy 3 
(refer to Section 5.1.1.2.3). 
Each of the analyses will be repeated using two additional distinct data sets to evaluate the 
confounding effect of GCSF administration: inclusion of only those patients or cycles who had 
concurrent GCSF administration; and inclusion of only those patients or cycles who did NOT 
have concurrent GCSF administration.  The “with” and “without” GCSF analyses are subsets of 
the total number of patients or cycles. 
 
Time-to-event endpoints will be summarized using Kaplan-Meier method, and the descriptive 
statistics of median, 25% and 75% percentiles along with their 95% CIs will be calculated for 
• Duration of SVN, Strategy 2 (refer to Section 5.1.1.2.2). Additionally, DSN for each 
cycle will be presented using descriptive statistics.  
• Time-to-first MAHE endpoints (overall and individually) in Section 5.1.2.4. 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 1  
Version date: 05Dec2018 
 
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      Page 62 of 73 
 
                                                 
 
In addition to the summary from Kaplan-Meier method, the two-sided p-value will be obtained 
from the stratified Kaplan-Meier method to account for the stratification factors of ECOG (0 or 1 
vs. 2) and sensitivity to first-line treatment (sensitive or resistant). The hazard ratio (HR) 
between the two treatments (trilaciclib vs placebo), together with its 80% CIs will be calculated 
from a Cox proportional hazard model in which treatment and the stratification factors will be 
included as fixed effects. 
For the time (days) to first occurrence of a MAHE event, a graphical display of cumulative 
incidence will be presented. 
The primary and key secondary efficacy endpoints are based on the ITT analysis set, and the 
analysis will be repeated for the mITT analysis set and PP analysis set. 
For RBC transfusions, subsets of subjects with baseline HGB <9 g/L and ≥9 g/L will be 
provided, as well as a summary of the number of units transfused. 
6.2.7.2. 
Supportive Efficacy Analyses 
6.2.7.2.1. 
Analyses of Objective Response 
The patients in each category of TPR according to the investigator tumor assessment (CR, PR, 
SD, PD, or NE) will be presented in a data listing. The number and percentage of patients in each 
category of BOR (Confirmed CR, Confirmed PR, SD, PD, or NE), ORR, ORRUNCONFIRMED and 
CBR according to the investigator tumor assessment (Confirmed CR, Confirmed PR, SD, PD, or 
NE) will be summarized. Detailed information of deriving tumor relevant responses is provided 
in Section 5.1.3.1.    
Similar analyses will be repeated based on the derived responses according to the RECIST 
Version 1.1.  
Estimates of response rate, along with its associated exact 95% two-sided CIs using Clopper-
Pearson method will be computed for ORR and CBR within each treatment group.  
The binary endpoint (Yes, No) of ORR for the two treatments (trilaciclib and placebo) will be 
analyzed to compare trilaciclib and placebo using stratum-adjusted method to account for the 
stratification factors of ECOG (0 or 1 vs. 2) and sensitivity to first-line treatment (sensitive or 
resistant). The adjusted proportion difference (trilaciclib vs placebo) and its 80% CIs will be 
calculated using CMH weight outlined in Kim et al. 2013. The two-sided p-value will be 
calculated using stratified exact CMH method.   
The analyses are based on the response evaluable analysis set. The supportive data listings will 
also be provided. 
Subsets based on subjects with and without dose reductions will also be included. 
A waterfall plot showing the best % change in target lesion sum will also be included. 
6.2.7.2.2. 
Analyses of DOR, PFS, and OS 
DOR (investigator and derived) will be summarized using Kaplan-Meier method, and the 
descriptive statistics of median, 25% and 75% percentiles along with their 95% CIs will be 
calculated. It will be based on the response evaluable analysis set. The supportive data listings 
will also be provided. 


 
 
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PFS (derived, and derived with clinical progression) and OS will be similarly summarized, and 
in addition to the quartile summary from Kaplan-Meier method, Kaplan-Meier estimates will be 
provided for the survival rates at 3, 6, 9, and 12 months along with their 95% CIs. Comparison 
will also be conducted between trilaciclib and placebo. The two-sided p-value from a Cox 
proportional hazard model will be presented, the model includes treatment and stratification 
factors of ECOG (0 or 1 vs. 2) and sensitivity to first-line treatment (sensitive or resistant) as 
fixed effects. The HR between the two treatment groups, together with its 80% CIs will be 
presented. 
Spider plot by treatment group of % change in target lesion from baseline for each subject over 
time will be included based on derived assessments. Points will be included for best overall 
response (if CR or PR), new lesions, and end of treatment. 
An event chart of the treatment period will also be included, with horizontal bars for each 
subject’s cycle length and time on the x-axis, with points plotted for start and end of DOR. 
Both PFS and OS will be based on the ITT analysis set. For the PFS, the derived endpoint based 
on only radiologic progression will be considered as the primary, and the derived endpoint based 
on both radiologic and clinical progression will be considered as supportive. 
6.2.7.2.3. 
Analyses of Hematology Lab Values 
For the endpoints specified in Sections 5.1.3.3 and 5.1.3.4, in addition to descriptive statistics 
summary, appropriate graphical display will be provided to facilitate evaluation of trends in the 
change in a given variable over time. Moreover, each of the ANC change over time analysis (i.e. 
observed value at windowed visit and cycle nadir) specified above will be done using three 
distinct data sets to evaluate the confounding effect of GCSF administration: all patients or 
cycles regardless of GCSF administration; inclusion of only those patients or cycles who had 
concurrent GCSF administration; and inclusion of only those patients or cycles who did NOT 
have concurrent GCSF administration.  The “with” and “without” GCSF analyses are subsets of 
the total patient or cycles. 
Figures of mean and 95% CI over time will be provided for ANC (with GCSF subsets also), 
platelet counts, HGB, change from baseline HGB, and ALC. Additionally, jitter scatter plots will 
be provided for mean and 95% CI by cycle for ANC nadir (with GCSF subsets also). 
A Radar plot of grade 3/4 laboratory abnormalities during the treatment period, and during the 
first cycle will be presented. 
6.2.7.2.4. 
Analyses of Other Binary Efficacy Endpoints 
The following binary response variables (Yes, No) will be analyzed using the same method for 
occurrence of SVN except baseline ANC will not be a covariate in the modified Poisson model. 
See Section 6.2.7.1.1: 
• Occurrence of a Grade 3 or 4 hematologic toxicity during the treatment period (refer to 
Section 5.1.3.2); 
• Occurrence of an ESA administration during the treatment period (refer to Section 5.1.3.5); 
• Occurrence of an IV antibiotic administration during the treatment period (refer to Section 
5.1.3.6); The offset in the modified Poisson model will be the logarithm transformation of 


 
 
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Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 1  
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duration of treatment period divided by 7 (i.e. week) instead of number of cycles. 
Additionally, total number of IV antibiotic administrations will be summarized descriptively. 
• Occurrence of an infection SAE during the treatment period (refer to Section 5.1.3.7); The 
offset in the modified Poisson model will be the logarithm transformation of duration of 
treatment period divided by 7 (i.e. week) instead of number of cycles. Additionally, total 
number of infection SAEs will be summarized descriptively. 
• Occurrence of a pulmonary infection SAE during the treatment period (refer to Section 
5.1.3.8). The offset in the modified Poisson model will be the logarithm transformation of 
duration of treatment period divided by 7 (i.e. week) instead of number of cycles. 
Additionally, total number of pulmonary infection SAEs will be summarized descriptively. 
• Occurrence of a Grade 4 and Grade 3 or 4 thrombocytopenia (laboratory values) during the 
treatment period (refer to Section 405.1.3.10); 
6.2.7.2.5. 
Analysis of Myelosuppression Endpoints with All data up to End of Cycle 4 
The analyses outlined in Section 5.1.3.11 will be analyzed using the same methods using the 
same methods as the analogous primary, secondary, and supportive efficacy analyses, except 
they will only use data up through the end of Cycle 4. 
For Occurrence of severe (Grade 4) neutropenia see Section 6.2.7.1.1; For Occurrence of RBC 
transfusions on/after week 5 of study, Occurrence of GCSF administrations, Occurrence of 
platelet transfusions, and Occurrence of RBC transfusions during the first 4 cycles see Section 
6.2.7.1.2. 
For Total number of MAHE, Number of all-cause hospitalizations, Number of cycles with all-
cause dose reductions, Number of febrile neutropenia, Number of cycles with prolonged severe 
(Grade 4) neutropenia (duration > 5 days), Number of RBC transfusions on/after 5 weeks, 
Number of platelet transfusions, and Number of RBC transfusions during the first 4 cycles see 
Section 6.2.7.1.2. 
For Occurrence of Grade 3 and 4 hematologic toxicities see Section 6.2.7.2.4. 
6.2.7.3. 
Exploratory Efficacy Analyses  
For all three exploratory endpoints listed in Sections 5.1.4.2, 5.1.4.3, and 5.1.4.4, the data will 
only be summarized using descriptive statistics, hence, the general rules outlined in Section 6.1.1 
will be followed. Moreover, the supportive data listings will be provided. 
6.2.8. 
Safety Analyses 
All safety analyses will be based on the safety analysis set, as defined in Section 3.1.2.  
Descriptive statistics will be used to summarize the safety outcomes. The continuous safety 
variables will be summarized at each visit including end of each cycle (the last non-missing 
assessment during the cycle), end of treatment (the last non-missing assessment during the 
treatment period), and end of study (the last non-missing assessment during the whole study), if 
applicable. No inferential analyses of safety data are planned unless otherwise specified. 


 
 
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Clinical Study Protocol G1T28-03                                       
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6.2.8.1. 
Chemotherapy Exposure and Compliance Analyses 
Duration on treatment and number of cycles will be summarized by treatment. Dose intensity for 
each study drug (topotecan or trilaciclib/placebo) will be summarized for patients in Part 1; only 
trilaciclib/placebo will be summarized for Part 2. Dose modifications will be summarized for 
each study drug (topotecan or trilaciclib/placebo). For each study drug, the dosing endpoints 
described in Section 5.2.1 will be summarized by treatment. This includes the following: 
• Number of cycles received; 
• Number of missed doses; 
• Number of dose reductions; 
• Number of dose interruptions;   
• Number of patients with missed dose and its reason; 
• Number of patients with dose reductions and reason; 
• Number of patients with dose interruptions. 
• Number of doses 
The number of cycles delayed, the number and percentage of patients experiencing a treatment 
cycle delay, and reason for cycle delay will be summarized by treatment. The study dosing 
records and the derived dosing endpoints will be listed. 
6.2.8.2. 
Adverse Events 
Number and incidence rates of AEs will be summarized by SOC and/or PT for the following 
categories of TEAEs: all AEs, SAEs, AEs leading to death, and AEs leading to study drug 
(topotecan or trilaciclib/placebo) discontinuation or study withdrawal. Patients with more than 
one occurrence of the same SOC (PT) will be counted only once within the SOC (PT) 
categorization.   
AEs will also be summarized similarly by CTCAE grade and relationship to any study drug 
(topotecan or trilaciclib/placebo), and by relationship to each drug. Should a patient experience 
more than one occurrence of the same SOC (PT), the patient’s worst occurrence (worst 
grade/most related causality) will be retained in the tabulation.    
All AEs, including AEs that started prior to the study medication, will be presented in patient 
listings. In addition, separate listings of all SAEs, AEs leading to death, drug-related AEs, AEs 
leading to study drug (topotecan or trilaciclib/placebo) discontinuation or study withdrawal, and 
DLTs will be provided. 
The criteria for identifying infusion related reaction AEs or hematologic toxicity AEs are 
described in Section 5.2.1. A summary table showing incidence of AEs related to infusion and 
related to hematologic toxicity will be presented along with its supportive data listing.     
6.2.8.3. 
Laboratory Evaluations 
For hematology and clinical chemistry labs the observed values and change from baseline will be 
summarized for each visit during the treatment period using descriptive statistics.   
Toxicities for clinical labs will be characterized according to CTCAE, Version 4.03 (Table A-1 
of Appendix when possible), and the frequency and percentage of patients with each CTCAE 
grade for each visit during the treatment period will be described. Moreover, any occurrence of 


 
 
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Clinical Study Protocol G1T28-03                                       
Statistical Analysis Plan for Region 1  
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grade 3 or grade 4 during the treatment period will be summarized, and shift in grade from 
baseline to the worst post-baseline value will be summarized. Both the scheduled and 
unscheduled assessments will be used to identify the worst post-baseline values. 
Listings of all laboratory data, normal reference ranges, and CTCAE grades (when possible) will 
be provided.    
6.2.8.4. 
Vital Signs 
For vital sign parameters (Systolic Blood Pressure, Diastolic Blood Pressure, Pulse Rate, 
Temperature, and Weight) the observed values and change from baseline will be summarized 
using descriptive statistics at each visit during the treatment period.  
Additionally, the frequency and percentage of patients with any potentially clinically significant 
findings (defined in Table 13) during the treatment period will be presented. A listing of all vital 
sign data will be provided.  
6.2.8.5. 
Performance Status  
Descriptive statistics will be presented for ECOG score for the observed values and change from 
baseline. A listing of ECOG score for all patients will be provided.   
6.2.8.6. 
Physical Examination 
A listing of physical examination findings for all patients will be provided (where available). 
6.2.8.7. 
ECG 
Descriptive statistics will be presented for each ECG parameter for the observed values and 
change from baseline to post baseline. A listing of all ECG data will be provided.  
The criteria for potentially clinically significant findings are defined in Table 15. The frequency 
and percentage of patients with any potentially clinically significant findings during the 
treatment period will be presented. The supportive data will be provided in patient data listings.  
6.2.9. 
Subgroup Analyses 
The MAHE, OS, and PFS will be examined in the following subgroups: 
− Age group (ages <65; ≥65). 
− Gender (Male; Female). 
− ECOG performance status (0-1; 2). 
− Sensitivity to first treatment (Sensitive; Resistant). 
− Race (Caucasian; non-Caucasian). 
− Region (US; Ex-US). 
− Baseline LDH (≤ ULN; > ULN). 
Descriptive statistics by treatment group will be presented for each subgroup of patients.  
Additional subgroups or endpoints may be identified and explored.  
6.2.10. 
Pharmacokinetic Analysis 
The PK analysis for a subset of patients will be documented separately and is not covered in this 
SAP. 


 
 
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Clinical Study Protocol G1T28-03                                       
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6.2.11. 
Assess Genetic and/or Expression (RNA/Protein) Biomarkers in Tumors and 
Blood 
A detailed description of the biomarker analysis plan will be documented separately.  In general, 
as data permits, the analyses may include, but not be limited to: 
1. SCLC tumor samples may be assessed for markers of CDK 4/6 dependence and 
independence (including but not limited to PD-L1, PD-1, and others) as defined by IHC 
or qRT-PCR on biological/clinical endpoints.   
2. SCLC tumor samples may be assessed for markers to potentially predict sensitivity to 
trilaciclib treatment. 
3. Peripheral blood samples may be assessed for biomarkers examining the role of trilaciclib 
in the preservation of hematopoietic and immune populations during chemotherapy 
treatment 
4. Peripheral blood samples may be assessed for biomarkers examining the role of trilaciclib 
in anti-tumor immunity 
6.2.12. 
Planned Analysis  
The final myelosuppression analysis will be conducted after all patients have had the opportunity 
to receive at least 12 weeks of treatment. All study data collected through the time of the final 
myelosuppression analysis data cut will be included. This includes, but is not limited to the final 
myelosuppression analysis, interim ORR analysis based on investigator assessment, and interim 
PFS/OS analysis. 
The time of analysis with at least 80% of patients having experienced a progression will be 
considered to be final PFS analysis. Patients will be followed for survival until at least 70% of 
the patients have died, and a final OS analysis will be done then. Additional exploratory analyses 
of OS/PFS may between the final myelosuppression analysis and study completion. Reported 
results, with the exception of the myelosuppression analyses, will be cumulative in nature, 
including all data collected during the entire study; the myelosuppression analyses will be 
complete at the final analysis and no additional data will be expected. 


 
 
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Clinical Study Protocol G1T28-03                                       
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7. 
CHANGE FROM THE PROTOCOL 
The timing of the final analysis, analysis sets, and endpoints were updated based on scientific advice, 
regulatory guidance, and feedback on other trilaciclib studies. The endpoints and analyses listed below 
are based on the Statistics Section in the Protocol Amendment 5, dated 27 June 2018. The list 
displays the endpoints and analyses which are removed from the initial analysis and are therefore 
not described in the SAP.    
Protocol Section 13.4.1 (Efficacy Endpoints): 
• Hematologic kinetic endpoints: 
o Change and percent change in hematologic parameter values from predose for a 
particular cycle to the end of that cycle 
o Change and percent change in hematologic parameter values from predose for a 
particular cycle to nadir for that cycle 
o Rate of change in hematologic parameter values from predose for a particular cycle to 
nadir for that cycle 
o Change and percent change in hematologic parameter values from nadir for a 
particular cycle to the end of that cycle 
o Rate of change in hematologic parameter values from nadir for a particular cycle to 
the end of that cycle 
o Area under the curve in hematologic parameter values from predose for a particular 
cycle to the end of that cycle 
o Area under the curve in hematologic parameters from predose for a particular cycle to 
nadir for that cycle 
o Area under the curve in hematologic parameter values from nadir for a particular 
cycle to the end of that cycle 
o Time to hematologic parameter value nadir by cycle 
o Time to return to predose hematologic parameter values by cycle 
o Proportion of patients with a return to predose hematologic parameter values by cycle 
• Hematologic toxicity endpoints: 
o Proportion of patients with a hematologic toxicity recovery by cycle. 
o Time to hematologic toxicity recovery by cycle 
• Exploratory efficacy endpoints: 
o Composite hematologic score 
o Composite efficacy score 
Protocol Section 13.4.2.1 (Analysis of Hematologic Parameter Kinetic Endpoints) 
• Additional tabulations for each cycle of treatment in maximum postnadir values. 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-03                                       
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• The tabulation of the changes and percent changes from predose to nadir, predose to end of 
cycle, nadir to maximum postnadir, and nadir to end of cycle values for each cycle of 
treatment. 
• Analysis of covariance (ANCOVA) models on hematologic parameter kinetic endpoints 
• Summarization of time to nadir. 
• Descriptive statistics and ANCOVA of area under the curve (AUC) in hematologic 
parameters 
• Repeated-measures model of AUC 
• Summary of proportion of patients return to predose value for each cycle. calculation on 
incidence rate, adjusting for cumulative exposure 
• Analysis of time to return to predose level for each cycle using Kaplan-Meier method. 
• Analysis of Time to return to postnadir predose levels 
Protocol Section 13.4.2.2 (Analysis of Hematologic Toxicity Endpoints)  
• Calculation and analysis of incidence rate of hematologic toxicity, adjusting for cumulative 
exposure 
• Calculation and analysis of toxicity rate relative to cumulative exposure (total number of 
toxicities divided by cumulative exposure).  
• Recurrent events model estimating the incidence of Grade 3 or higher hematologic toxicities 
and testing for the difference between treatment groups. 
• For each hematologic parameter and cycle, the shift summaries of the following: 
o From predose toxicity to maximum on treatment toxicity;  
o from predose toxicity to end of cycle toxicity; 
o from maximum postdose toxicity to end of cycle toxicity. 
Protocol Section 13.4.2.4 (Other Efficacy Endpoints) 
• The number and percent of infections summarized by maximum severity 
• The infection rate: The number of infections occurring during the Treatment divided by 
cumulative exposure. 
Protocol Section 13.6 (Exploratory Analyses) 
• The relationship between hematologic toxicity rates and changes with study drug (topotecan 
or trilaciclib/placebo) exposure 
• The association between composite endpoints and BOR, OS, and PFS 
• The FACT-L and FACT-An analyses analysis in the section is not covered in the SAP 


 
 
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Clinical Study Protocol G1T28-03                                       
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8. 
REFERENCES 
Brechenmacher T, Xu J, Dmitrienko A, Tamhane AC. A mixture gatekeeping procedure based 
on the Hommel test for clinical trial applications. Journal of biopharmaceutical statistics. 2011; 
21: 748-767. 
 
Dmitrienko A, Wiens BL, Tamhane AC, Wang X. Tree-structured gatekeeping tests in clinical 
trials with hierarchically ordered multiple objectives. Statistics in medicine. 2007; 26: 2465- 
2478. 
 
Dmitrienko A, Tamhane, AC, Wiens B. General multistage gatekeeping procedures. Biometrical 
Journal. 2008; 50, 667-677. 
 
Dmitrienko A, Tamhane, AC, Bretz F. Multiple testing problems in pharmaceutical statistics. 
2009. Chapman and Hall/CRC. 
 
Dmitrienko A, Tamhane AC. Mixtures of multiple testing procedures for gatekeeping 
applications in clinical trials. Statistics in Medicine. 2011; 30, 1473-1488. 
 
Eisenhauer, E., Therasse, P., Bogaerts, J., Schwartz, L.H., Sargent, D., Ford, R., Dancey, J., 
Arbuck, S., Gwyther, S., Mooney, M. and Rubinstein, L., 2009. New response evaluation criteria 
in solid tumours: revised RECIST guideline (version 1.1). European journal of cancer, 45(2), 
228-247.  
 
FDA Center for Biologics Evaluation and Research (CBER). Multiple Endpoints in Clinical 
Trials Guidance for Industry. 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
536750.pdf. Published January 2017. Accessed13 September 2018. 
 
Gerrits CJ, Burris H, Schellens JH, et al. Five days of oral topotecan (Hycamtin), a phase I and 
pharmacological study in adult patients with solid tumours. Eur J Cancer. 1998;34(7):1030-
1035. 
 
Grochow LB, Rowinsky EK, Johnson R, et al. Pharmacokinetics and pharmacodynamics of 
topotecan in patients with advanced cancer. Drug Metab Dispos. 1992;20(5):706 713. 
 
Huque MF. Validity of the Hochberg procedure revisited for clinical trial applications. Statistics 
in medicine. 2016; 35:5-20. 
 
Kim Y, Won S. (2013) Adjusted proportion difference and confidence interval in stratified 
randomized trials. PharmaSUG; Paper SP-04. 
 
Montazeri A, Culine S, Laguerre B, et al. Individual adaptive dosing of topotecan in ovarian 
cancer. Clin Cancer Res. 2002;8:394-399. 
O’Reilly S, Rowinsky EK, Slichenmyer W, et al. Phase I and pharmacologic study of topotecan 
in patients with impaired renal function. J Clin Oncol. Dec 1996a;14(12):3062 3073. 


 
 
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O’Reilly S, Rowinsky E, Slichenmyer W, et al. Phase I and pharmacologic studies of topotecan 
in patients with impaired hepatic function. J Natl Cancer Inst. Jun1996b;88(12):817-824. 
 
Yan X, Lee, S and Li N. Missing data handling methods in medical device clinical trials, Journal of 
Biopharmaceutical Statistics, 2009, 19 (6): 1085 — 1098. 
 
Zou G. A modified Poisson regression approach to prospective studies with binary data. 
American journal of epidemiology. 2004;159(7):702-6.


 
 
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Clinical Study Protocol G1T28-03                                       
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Table A-1 Clinical Laboratory Parameters CTCAE Criteria 
Parameter 
Grade 
1 
2 
3 
4 
5 
Albumin 
<LLN – 3 g/dL; <LLN – 30 g/L 
<3 – 2 g/dL; <30 – 20 g/L 
<2 g/dL; <20 g/L 
- 
- 
ALP 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
- 
ALT 
>ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
- 
AST 
>ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
- 
Bilirubin 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
- 
Calcium (Hypercalcemia) 
Corrected serum calcium 
of >ULN – 11.5 mg/dL; >ULN 
– 2.9 mmol/L 
Corrected serum calcium 
of >11.5 – 12.5 
mg/dL;  >2.9 – 3.1 mmol/L 
Corrected serum calcium 
of >12.5 – 13.5 
mg/dL; >3.1 – 3.4 mmol/L 
Corrected serum calcium 
of >13.5 mg/dL; >3.4 
mmol/L 
- 
Calcium (Hypocalcemia) 
Corrected serum calcium of 
<LLN – 8.0 mg/dL; <LLN – 
2.0 mmol/L 
Corrected serum calcium of 
<8.0 – 7.0 mg/dL;  <2.0 – 
1.75 mmol/L 
Corrected serum calcium of 
<7.0 – 6.0 mg/dL; <1.75 – 
1.5 mmol/L 
Corrected serum calcium of 
<6.0 mg/dL; <1.5 mmol/L 
- 
CK 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5 x ULN 
>5 x ULN – 10 x ULN 
>10 x ULN 
- 
Creatinine 
>1 – 1.5 x baseline;  >ULN – 
1.5 x ULN 
>1.5 – 3.0 x baseline; >1.5 
– 3.0 x ULN 
>3.0 x baseline; >3.0 – 6.0 
x ULN 
>6.0 x ULN 
- 
GGT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
- 
Glucose (Hyperglycemia) 
Fasting glucose value >ULN – 
160 mg/dL; Fasting glucose 
value >ULN – 8.9 mmol/L 
Fasting glucose value >160 
– 250 mg/dL; Fasting 
glucose value >8.9 – 13.9 
mmol/L 
Fasting glucose value >250 
– 500 mg/dL; Fasting 
glucose value >13.9 – 27.8 
mmol/L 
Fasting glucose value >500 
mg/dL; Fasting glucose 
value >27.8 mmol/L 
- 
Glucose (Hypoglycemia) 
<LLN – 55 mg/dL;  <LLN – 
3.0 mmol/L 
<55 – 40 mg/dL;  <3.0 – 
2.2 mmol/L 
<40 – 30 mg/dL;  <2.2 – 
1.7 mmol/L mmol/L 
<30 mg/dL;  <1.7 mmol/L  
- 
Hemoglobin 
<LLN – 10.0 g/dL; <LLN – 6.2 
mmol/L; <LLN – 100 g/L 
<10.0 – 8.0 g/dL; <6.2 – 
4.9 mmol/L; <100 – 80 g/L 
<8.0 g/dL; <4.9 mmol/L; 
<80 g/L 
- 
- 
Potassium 
(Hyperkalemia) 
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
>7.0 mmol/L 
- 


 
 
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Table A-1 Clinical Laboratory Parameters CTCAE Criteria 
Parameter 
Grade 
1 
2 
3 
4 
5 
Potassium (Hypokalemia) <LLN – 3.0 mmol/L 
- 
<3.0 – 2.5 mmol/L 
<2.5 mmol/L 
- 
Lymphocyte 
<LLN – 800/mm3; <LLN – 0.8 
x 10e9 /L 
<800 – 500/mm3; <0.8 – 
0.5 x 10e9 /L 
<500 – 200/mm3; <0.5 – 
0.2 x 10e9 /L 
<200/mm3; <0.2 x 10e9 /L 
- 
ANC 
<LLN – 1500/mm3; <LLN – 
1.5 x 10e9 /L 
<1500 – 1000/mm3; <1.5 – 
1.0 x 10e9 /L 
<1000 – 500/mm3; <1.0 – 
0.5 x 10e9 /L 
<500/mm3; <0.5 x 10e9 /L 
- 
Phosphates 
<LLN – 2.5 mg/dL; <LLN – 
0.8 mmol/L 
<2.5 – 2.0 mg/dL; <0.8 – 
0.6 mmol/L 
<2.0 – 1.0 mg/dL; 0.6 – 0.3 
mmol/L 
<1.0 mg/dL; <0.3 mmol/L 
- 
Platelet Count 
<LLN – 75,000/mm3; <LLN – 
75.0 x 10e9 /L 
<75,000 – 50,000/mm3; 
<75.0 – 50.0 x 10e9 /L 
<50,000 – 25,000/mm3; 
<50.0 – 25.0 x 10e9 /L 
<25,000/mm3; <25.0 x 10e9 
/L 
- 
Sodium (Hypernatremia) 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
>160 mmol/L 
- 
Sodium (Hyponatremia) 
<LLN – 130 mmol/L 
- 
<130 – 120 mmol/L 
<120 mmol/L 
- 
Urate 
>ULN – 10 mg/dL (0.59 
mmol/L) without physiologic 
consequences 
- 
>ULN – 10 mg/dL (0.59 
mmol/L) with physiologic 
consequences 
>10 mg/dL; >0.59 mmol/L 
- 
White blood cell 
<LLN – 3000/mm3; <LLN – 
3.0 x 10e9 /L 
<3000 – 2000/mm3; <3.0 – 
2.0 x 10e9 /L 
<2000 – 1000/mm3; <2.0 – 
1.0 x 10e9 /L 
<1000/mm3; <1.0 x 10e9 /L 
- 
LLN=lower limit of normal range; ULN=upper limit of normal range.