Conditions: Small Cell Lung Cancer
Keywords: Small Cell Lung Cancer CDK4/6 Inhibitor Immune Checkpoint Inhibitor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 107
Healthy volunteers: no

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

The study was a randomized, double-blinded, placebo-controlled design. Approximately, 100 patients were randomized to trilaciclib + E/P/A or placebo + E/P/A in the study.

Detailed description:
The posted results represent the final results from Study G1T28-05, a Phase 2 study of carboplatin, etoposide, and atezolizumab with or without trilaciclib (G1T28) in patients with untreated extensive-stage small cell lung cancer (SCLC).

The final myelopreservation efficacy results are from database lock 1 (data cut-off \[DCO\] 17 Aug 2018). The final anti-tumor efficacy data (BOR, DOR, PFS) are from a second database lock 2 (DCO 28 June 2019) that occurred to support the trilaciclib New Drug Application (NDA). Final overall survival and safety data are reported from the final study database lock (DCO 11 Dec 2020, last patient last visit date of 29 October 2020).

Please note the last patient last visit date description above which is recorded as the study completion date. Following the last patient last visit, the final database lock occurred a few weeks later which accounts for the discrepancy between the study completion date and the reported assessment time frames.

Arms:
arm 1: Induction: Patients received trilaciclib 240 mg/m² administered intravenously (IV) once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was administered on Day 1 of each 21-day cycle using the Calvert formula with a target area under the concentration-time curve (AUC) = 5 milligrams per milliliter per minute (mg/mL/min) to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle.

Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or discontinuation by the patient or investigator. arm 2: Induction: Patients received placebo administered IV once daily prior to E/P/A on Days 1, 2 and 3 of each 21-day E/P/A therapy cycle (up to 4 cycles in total). Etoposide 100 mg/m² was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. Carboplatin was be administered on Day 1 of each 21-day cycle using the Calvert formula with a target AUC = 5 mg/mL/min to calculate the dose. Atezolizumab 1200 mg was administered as an IV infusion on Day 1 of each 21-day cycle.

Maintenance: Following the induction phase, patients received maintenance atezolizumab at a dose of 1200 mg on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or discontinuation by the patient or investigator.

Interventions: intervention 1: Trilaciclib intervention 2: Placebo intervention 3: Carboplatin intervention 4: Etoposide intervention 5: Atezolizumab
Intervention descriptions: intervention 1: Trilaciclib IV intervention 2: Placebo IV intervention 3: Carboplatin IV intervention 4: Etoposide IV intervention 5: Atezolizumab IV

Protocol document:
Prot_000.pdf: 
G1 Therapeutics CONFIDENTIAL 
 
 
 
 
 
Phase 2 Study of Carboplatin, Etoposide, and Atezolizumab With or Without 
Trilaciclib (G1T28) in Patients with Untreated Extensive-Stage Small Cell Lung Cancer 
 
Clinical Study Protocol G1T28-05  
EudraCT # 2017-000358-20 
 
 
Original Protocol Issue Date: 14 February 2017 
Amendment 1 Protocol Issue Date: 02 May 2017 
Amendment 2 Protocol Issue Date:  14 September 2018 
Version: 3.0 
 
Investigational Phase: 2 
 
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 G1T28-05 
Trilaciclib (G1T28) 
 
Version: 3.0, dated 14 September 2018 
 
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PROTOCOL SIGNATURE PAGE 
Clinical Study Protocol G1T28-05: Phase 2 Study of Carboplatin, Etoposide, and 
Atezolizumab With or Without Trilaciclib (G1T28) in Patients with Untreated Extensive 
Stage Small Cell Lung Cancer 
Original Protocol (Version 1.0) Issue Date: 14 February 2017 
Version: 2.0 (Amendment 1) dated 02 May 2017 
Version: 3.0 (Amendment 2) dated 14 September 2018 
By signing below, the investigator agrees to adhere to the protocol as outlined. 
Principal Investigator: 
 
 
Principal Investigator Signature 
Date 
Principal Investigator Name 
Institution 
 
 
 
 
 
 
 


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Clinical Study Protocol G1T28-05 
Trilaciclib (G1T28) 
 
Version: 3.0, dated 14 September 2018 
 
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1. 
TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ........................................................................................................................... 2 
PROTOCOL SIGNATURE PAGE ........................................................................................................................ 3 
1. 
TABLE OF CONTENTS ............................................................................................................................... 4 
1.1. 
List of In-Text Tables ....................................................................................................................... 7 
1.2. 
List of In-Text Figures ...................................................................................................................... 7 
2. 
LIST OF ABBREVIATIONS ........................................................................................................................ 8 
3. 
SYNOPSIS .................................................................................................................................................. 13 
4. 
INTRODUCTION ....................................................................................................................................... 26 
4.1. 
Background ..................................................................................................................................... 26 
4.2. 
Study Rationale ............................................................................................................................... 27 
4.3. 
Summary of Clinical Data ............................................................................................................... 28 
4.3.1. 
Trilaciclib ...................................................................................................................... 28 
4.3.2. 
Atezolizumab ................................................................................................................ 31 
4.4. 
Summary of Nonclinical Data ......................................................................................................... 31 
4.4.1. 
Pharmacology Studies ................................................................................................... 32 
4.4.2. 
Pharmacokinetic Studies ............................................................................................... 33 
4.4.3. 
Toxicity and Safety Studies........................................................................................... 34 
4.4.4. 
Potential Risks ............................................................................................................... 34 
4.5. 
Study and Dose Rationale ............................................................................................................... 42 
4.6. 
Risk/Benefit Assessment ................................................................................................................. 43 
5. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................... 44 
6. 
INVESTIGATIONAL PLAN ...................................................................................................................... 47 
6.1. 
Overall Study Design and Plan ....................................................................................................... 47 
6.1.1. 
Criteria for Subsequent Cycles and Study Duration ...................................................... 48 
6.1.2. 
Safety Assessments ....................................................................................................... 50 
6.1.3. 
Data Monitoring Committee ......................................................................................... 50 
6.1.4. 
Tumor Assessment ........................................................................................................ 50 
7. 
STUDY POPULATION .............................................................................................................................. 52 
7.1. 
Selection of Patients ........................................................................................................................ 52 
7.1.1. 
Inclusion Criteria ........................................................................................................... 52 
7.1.2. 
Exclusion Criteria.......................................................................................................... 54 
8. 
TREATMENTS ........................................................................................................................................... 56 
8.1. 
Treatments Administered ................................................................................................................ 56 
8.2. 
Investigational Products .................................................................................................................. 57 
8.2.1. 
Identity .......................................................................................................................... 57 
8.2.2. 
Packaging and Labeling ................................................................................................ 57 
8.2.3. 
Storage .......................................................................................................................... 58 
8.2.4. 
Procedure for Dispensing .............................................................................................. 58 
8.2.5. 
Investigational Product Accountability ......................................................................... 58 
8.3. 
Method of Assigning Patients to Treatment Groups ....................................................................... 59 
8.4. 
Dose, Dosing Regimen, and Route ................................................................................................. 59 
8.4.1. 
Trilaciclib ...................................................................................................................... 59 
8.4.2. 
Placebo .......................................................................................................................... 59 
8.4.3. 
Etoposide and Carboplatin ............................................................................................ 60 
8.4.4. 
Atezolizumab ................................................................................................................ 61 


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Trilaciclib (G1T28) 
 
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8.4.5. 
Dose Modifications ....................................................................................................... 61 
8.5. 
Randomization and Blinding........................................................................................................... 68 
8.6. 
Prior and Concomitant Medications and Procedures ...................................................................... 69 
8.7. 
Transfusions .................................................................................................................................... 70 
8.8. 
Prophylactic Cranial Irradiation ...................................................................................................... 71 
8.9. 
Treatment Compliance .................................................................................................................... 71 
9. 
STUDY FLOWCHART .............................................................................................................................. 72 
10. SCHEDULE OF STUDY PROCEDURES ................................................................................................. 76 
10.1. 
Screening......................................................................................................................................... 76 
10.2. 
Enrollment....................................................................................................................................... 76 
10.3. 
Induction Part of the Study ............................................................................................................. 77 
10.3.1. 
Induction Cycle 1 .......................................................................................................... 77 
10.3.2. 
Induction Cycle 2 .......................................................................................................... 78 
10.3.3. 
Induction Cycles 3 and 4 ............................................................................................... 80 
10.3.4. 
Atezolizumab Administration While Trilaciclib or Placebo + E/P Is 
Held ............................................................................................................................... 81 
10.4. 
Last Induction Cycle – Day 22........................................................................................................ 81 
10.5. 
Maintenance Part of the Study ........................................................................................................ 82 
10.5.1. 
Maintenance Cycle 1 and Odd Cycles .......................................................................... 82 
10.5.2. 
Maintenance Cycle 2 and Even Cycles ......................................................................... 82 
10.6. 
Post-Treatment Visits ...................................................................................................................... 83 
10.7. 
Survival Follow-up Phase ............................................................................................................... 84 
10.8. 
Study Drug Discontinuation ............................................................................................................ 84 
10.9. 
Unscheduled Visits ......................................................................................................................... 85 
11. STUDY ASSESSMENTS ........................................................................................................................... 86 
11.1. 
Tumor Response ............................................................................................................................. 86 
11.1.1. 
Tumor Assessments ...................................................................................................... 86 
11.1.2. 
Tumor Lesions: Identification and Follow-up ............................................................... 86 
11.1.3. 
Definitions of Tumor Response and Disease Progression ............................................. 88 
11.1.4. 
Treatment Beyond Disease Progression Per RECIST Version 1.1 ............................... 89 
11.2. 
Pharmacokinetic Assessments ........................................................................................................ 90 
11.3. 
Anti-atezolizumab Therapeutic Antibodies Assessment ................................................................. 93 
11.4. 
Safety Assessments ......................................................................................................................... 93 
11.4.1. 
Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest .............................................................................................................. 94 
11.4.2. 
Clinical Laboratory Assessments ................................................................................ 100 
11.4.3. 
Demographics and Vital Signs .................................................................................... 101 
11.4.4. 
Physical Examination .................................................................................................. 101 
11.4.5. 
Electrocardiogram Assessments .................................................................................. 102 
11.4.6. 
Concomitant Medications ........................................................................................... 102 
11.5. 
Patient Reported Outcomes ........................................................................................................... 102 
11.6. 
Immunologic Markers ................................................................................................................... 102 
11.7. 
Appropriateness of Measurements ................................................................................................ 103 
12. STUDY TERMINATION OR STUDY DRUG DISCONTINUATION ................................................... 104 
12.1. 
Study Termination......................................................................................................................... 104 
12.2. 
Site Termination ............................................................................................................................ 104 
12.3. 
Discontinuation of Study Drug ..................................................................................................... 104 
12.4. 
Withdrawal of Patients from the Study ......................................................................................... 105 
13. STATISTICS ............................................................................................................................................. 106 
13.1. 
Sample Size and Power ................................................................................................................. 106 
13.2. 
General Considerations ................................................................................................................. 107 


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Version: 3.0, dated 14 September 2018 
 
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13.2.1. 
Analysis Sets ............................................................................................................... 107 
13.2.2. 
Timing of Analyses ..................................................................................................... 108 
13.2.3. 
General Considerations for Data Analysis .................................................................. 108 
13.3. 
Baseline and Demographic Characteristics ................................................................................... 109 
13.4. 
Prior and Subsequent Anticancer Therapies ................................................................................. 109 
13.5. 
Efficacy Analyses ......................................................................................................................... 109 
13.5.1. 
Primary Myelosuppression Efficacy Endpoints .......................................................... 110 
13.5.2. 
Key Secondary Efficacy Endpoints ............................................................................. 110 
13.5.3. 
Multiplicity Adjustment for the Primary and Key Secondary 
Myelosuppression Efficacy Endpoints ........................................................................ 111 
13.5.4. 
Analysis of Supportive Secondary Efficacy Endpoints (Antitumor 
and Myelosuppression) ............................................................................................... 115 
 
 
13.6. 
Safety Analyses ............................................................................................................................. 116 
13.7. 
Pharmacokinetic Analysis ............................................................................................................. 117 
 
 
14. QUALITY CONTROL AND QUALITY ASSURANCE ......................................................................... 119 
15. ETHICS AND PROTECTION OF HUMAN PATIENTS ........................................................................ 120 
15.1. 
Ethical Conduct Statement ............................................................................................................ 120 
15.2. 
Institutional Review Board/Independent Ethics Committee ......................................................... 120 
15.3. 
Informed Consent .......................................................................................................................... 120 
15.4. 
Patient Confidentiality .................................................................................................................. 120 
15.5. 
Adherence to the Protocol ............................................................................................................. 121 
15.6. 
Protocol Amendments ................................................................................................................... 121 
15.7. 
Patient Compliance ....................................................................................................................... 121 
15.8. 
Study Discontinuation ................................................................................................................... 121 
16. DATA HANDLING AND RECORD KEEPING ...................................................................................... 122 
16.1. 
Data Collection and Retrieval ....................................................................................................... 122 
16.2. 
Data Monitoring Committee ......................................................................................................... 122 
16.3. 
Investigator Reporting Requirements............................................................................................ 122 
16.4. 
Records Retention ......................................................................................................................... 122 
16.5. 
Study Monitoring .......................................................................................................................... 123 
16.6. 
Audits and Inspections .................................................................................................................. 123 
17. PUBLICATION POLICY ......................................................................................................................... 124 
18. REFERENCES .......................................................................................................................................... 125 
19. APPENDICES ........................................................................................................................................... 129 
 
 


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Trilaciclib (G1T28) 
 
Version: 3.0, dated 14 September 2018 
 
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1.1. 
List of In-Text Tables 
Table 4-1 
Important Identified Risks for Atezolizumab ................................................................ 36 
Table 4-2 
Potential Risks for Atezolizumab .................................................................................. 39 
Table 5-1 
G1T28-05: Study Objectives and Endpoints ................................................................. 44 
Table 8-1 
Etoposide and Carboplatin Dose Reductions ................................................................ 62 
Table 8-2 
Etoposide and Carboplatin Dose Adjustments Based on Lack of 
Recovery of Absolute Neutrophil or Platelet Counts on the First 
Day of Induction Cycle 2 and Each Successive Cycle .................................................. 63 
Table 8-3 
Etoposide and Carboplatin Dose Adjustments Based on Absolute 
Neutrophil Count Nadir With or Without Fever ........................................................... 64 
Table 8-4 
Etoposide and Carboplatin Dose Adjustment Based on Platelet 
Nadir ............................................................................................................................. 65 
Table 8-5 
Etoposide and Carboplatin Reduction for Hepatic Toxicity.......................................... 66 
Table 9-1 
Schedule of Assessments .............................................................................................. 73 
Table 11-1 
Evaluation of Overall Response at Each Time Point .................................................... 89 
Table 11-2 
Day 1 of Induction Cycles 1 and 3 Blood Sampling Scheme 
Based on Predicted Administration Times of Trilaciclib/Placebo, 
Carboplatin, and Etoposide ........................................................................................... 91 
Table 11-3 
Pharmacokinetic Parameters ......................................................................................... 93 
 
 
1.2. 
List of In-Text Figures 
Figure 6-1 
Study Schema ................................................................................................................ 48 
Figure 13-1 
Graphical Display of the Hochberg-based Gatekeeping 
Procedure for Region 1 ............................................................................................... 113 
Figure 13-2 
Graphical Display of the Hochberg-based Gatekeeping 
Procedure for Region 2 ............................................................................................... 114 
 


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Trilaciclib (G1T28) 
 
Version: 3.0, dated 14 September 2018 
 
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2. 
LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
ADA 
antidrug antibodies 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse events of special interest  
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
ARR 
adjusted relative risk 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
ATA 
anti-atezolizumab therapeutic antibodies 
ATC 
Anatomical Therapeutic Classification 
ATIN 
acute tubulo-interstitial nephritis 
AUC 
area under the concentration-time curve 
AUC0-t 
area under the plasma concentration-time curve from 0 to t hours after dosing 
AUC0-∞ 
area under the concentration time curve from time zero extrapolated to infinity 
AUCEOC 
area under the concentration-time curve from predose to end of cycle 
AUCNadir 
area under the concentration-time curve from predose to nadir 
AUCNEOC 
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 
CD3 
cluster of differentiation 3 
CD137 
cluster of differentiation 137 
CDK2/4/6 
cyclin-dependent kinase 2/4/6 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL 
clearance 


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Trilaciclib (G1T28) 
 
Version: 3.0, dated 14 September 2018 
 
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Abbreviation 
Definition 
Cmax 
maximum concentration 
Cmin 
minimum concentration 
CR 
complete response 
CT 
computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
D5W 
dextrose 5% in water 
DDI 
drug-drug interaction 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic case report form 
EdU 
5-ethynyl-2'-deoxyuridine 
EEG 
electroencephalogram 
EOI 
end of infusion 
E/P 
etoposide and carboplatin 
E/P/A 
etoposide, carboplatin, and atezolizumab 
ESA 
erythropoietin stimulating agent 
 
 
 
 
 
 
FDA 
Food and Drug Administration 
FDG-PET 
positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose 
FSH 
follicle-stimulating hormone  
G1 
gap 1 phase of the cell cycle 
G2 
gap 2 phase of the cell cycle 
G1T28 
trilaciclib; formerly G1T28-1 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GFR 
glomerular filtration rate 
GLP 
Good Laboratory Practice 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HBV 
hepatitis B virus 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 


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Trilaciclib (G1T28) 
 
Version: 3.0, dated 14 September 2018 
 
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Abbreviation 
Definition 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HSC 
hematopoietic stem cell 
HSPC 
hematopoietic stem and progenitor cell 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFNγ 
interferon-gamma 
IHC 
immunohistochemistry 
IL-2 
interleukin-2 
irAE 
immune-related adverse event 
irCR 
immune-related complete response 
irPD 
immune-related disease progression 
irPFS 
immune-related progression-free survival 
irPR 
immune-related partial response 
IRB 
institutional review board 
IRR 
infusion-related reaction 
irRECIST 
immune-related Response Evaluation Criteria in Solid Tumors 
irSD 
immune-related stable disease 
ITT 
intent-to-treat 
IV 
intravenous 
IWRS 
interactive web-response system 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LS 
least squares 
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 
mITT 
modified intent-to-treat  
MOA 
mechanism of action 
MRI 
magnetic resonance imaging 
MRP1 or 2 
multidrug resistance protein 1 or 2 
mUC 
metastatic urothelial carcinoma 
NCI 
National Cancer Institute 
NCI-H69 
human small cell lung cancer cell line 


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Abbreviation 
Definition 
NE 
not evaluable 
NSCLC 
non-small cell lung cancer 
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 
ORR 
objective response rate 
OS 
overall survival 
PCI 
prophylactic cranial irradiation 
PD 
PD-1 
 
PD-L1 
progressive disease 
programmed cell death protein 1 
programmed death-ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PR 
partial response 
 
 
 
 
qRT-PCR 
quantitative reverse transcriptase-polymerase chain reaction 
Rb 
retinoblastoma protein 
RB-1 
retinoblastoma gene 
RBC 
red blood cell(s) 
RCC 
renal cell carcinoma 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
RH 
relative humidity 
RNA 
ribonucleic acid 
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 
SMQs 
standardised MedDRA queries 
SOC 
system organ class 
StD 
standard deviation 
t1/2 
terminal half-life 
T3 
tri-iodothyronine 
T4 
thyroxine 


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Version: 3.0, dated 14 September 2018 
 
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Abbreviation 
Definition 
TEAE 
treatment-emergent adverse event 
Tmax 
time to reach Cmax  
TOP 
trilaciclib, oxaliplatin/anti-PD-L1 combination 
TNF 
tumor necrosis factor 
TSH 
thyroid-stimulating hormone 
UC 
urothelial carcinoma 
UGT1A1 
uridine disphosphate glucuronosyltransferase 1 family, polypeptide A1 
ULN 
upper limit of normal 
Vz 
volume of distribution in the terminal elimination phase 
WHO-DD 
World Health Organization Drug Dictionary 
WBC 
white blood cell 
WHO 
World Health Organization 
 
 
 


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3. 
SYNOPSIS 
Title 
Phase 2 Study of Carboplatin, Etoposide, and Atezolizumab With or 
Without Trilaciclib (G1T28) in Patients with Untreated Extensive-Stage 
Small Cell Lung Cancer 
Study Rationale 
Small cell lung cancer (SCLC) accounts for approximately 15% of all 
lung cancer cases worldwide and more than two-thirds of patients present 
with extensive-stage disease. Although response rates to first-line 
chemotherapy in extensive-stage SCLC are in the range of 50% to 60%, 
the median duration of response is short (approximately 4 months), with a 
median survival of 8 to 10 months and 2-year survival rates of less than 
10%. Increasing evidence suggests that immune responses against SCLC 
cells make immunotherapy a viable therapeutic approach in this disease. 
Furthermore, there is evidence that certain chemotherapeutic regimens 
may augment the immunotherapeutic response in SCLC, in part by 
releasing neoantigens and educating the immune system against the 
surviving cancer cells.   
Atezolizumab (Tecentriq®), is a monoclonal antibody that binds to 
programmed death-ligand 1 (PD-L1), inhibiting its interaction with the 
programmed cell death protein 1 (PD-1) receptor and releasing the 
PD-L1/PD-1 mediated inhibition of the immune response. Atezolizumab 
is an immunotherapy indicated for the treatment of locally advanced or 
metastatic urothelial carcinoma (approved in the United States in 
May 2016) and metastatic non-small cell lung cancer (NSCLC) (approved 
in the United States in October 2016). Etoposide and carboplatin (E/P) is a 
standard SCLC treatment and is currently under investigation with 
atezolizumab for the treatment of SCLC. 
The major drawback to platinum-based chemotherapeutic regimens used 
in SCLC treatment is dose-limiting myelosuppression, which may 
antagonize the intended effects of the immunotherapy by reducing both 
the number and function of lymphocytes. Therefore, an approach to 
maintain immune system function while administering cytotoxic 
chemotherapy is needed to fully realize the therapeutic potential of 
immunotherapies.    
Trilaciclib (G1T28) is a highly potent, selective, and reversible 
cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in development to 
preserve bone marrow and immune system function (including lymphoid 
progenitors and lymphocytes) from damage by chemotherapy, allowing 
faster hematopoietic recovery, preserving long-term bone marrow 
function, and enhancing the antitumor activity of chemotherapy. 
Trilaciclib is administered intravenously prior to every dose of 
chemotherapy in every cycle, eg, on Days 1 to 3 prior to E/P 
administration in 21-day cycles, for extensive-stage SCLC. This pulsatile 
dosing around chemotherapy administration allows preservation of the 
bone marrow and immune system without adding to the 
chemotherapy-induced myelosuppression caused by chronic inhibition of 
CDK4/6 in the bone marrow. 
To evaluate the effect of trilaciclib in combination with chemotherapy and 


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an immune checkpoint inhibitor, immunocompetent MC38 tumor-bearing 
mice were treated with trilaciclib, oxaliplatin, or anti-PD-L1 alone or in 
combination, and tumor size was measured during and after treatment for 
100 days. The addition of trilaciclib to an oxaliplatin/anti-PD-L1 
combination (TOP) treatment significantly improved the overall response 
rate, complete response rate, and median overall survival (OS) compared 
to oxaliplatin/anti-PD-L1 combination (93% vs 46%; 79% vs 38%; not 
reached at 100 days vs 59 days, respectively). Taken together, this 
demonstrates that trilaciclib, which has been shown to preserve immune 
function during chemotherapy, enhances the antitumor activity of 
chemotherapy/anti-PD-L1 combination therapy.   
In summary, nonclinical data demonstrate that trilaciclib administration 
with chemotherapy preserves bone marrow and immune system function 
from damage by chemotherapy and enhances the antitumor activity of 
chemotherapy/anti-PD-L1 combination therapy. Additionally, preliminary 
clinical data suggest that lymphocyte numbers are relatively unchanged 
when trilaciclib is used in combination with chemotherapy. Preserving 
adaptive immunity with trilaciclib may enhance the efficacy of 
chemotherapy combined with immune checkpoint inhibitors, supporting 
clinical testing of the novel combination of etoposide, carboplatin, and 
atezolizumab (E/P/A) therapy and trilaciclib. 
Clinical Phase 
2 
Indication 
Treatment of SCLC 




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E/P/A) cycles, patients will proceed to the maintenance part of the study 
and receive atezolizumab every 21 days. Study drug refers to trilaciclib or 
placebo + E/P/A during the induction part and atezolizumab during the 
maintenance part. Treatment in both parts will continue until disease 
progression, unacceptable toxicity, withdrawal of consent, or 
discontinuation by investigator. Following disease progression per 
RECIST v1.1, if the patient appears to be deriving clinical benefit, the 
investigator believes it is in the best interest of the patient, and the patient 
has provided re-consent, study drug administration may be continued until 
loss of clinical benefit. The study includes 3 phases: Screening Phase, 
Treatment Phase (induction part + maintenance part), and Survival 
Follow-up Phase. The Treatment Phase begins on the day of first dose 
with study treatment and completes after the last Post-Treatment Visit.   
Randomization will be stratified by Eastern Cooperative Oncology Group 
(ECOG) performance status (0 to 1 versus 2) and presence of brain 
metastases (yes versus no).  
Criteria for Subsequent Cycles and Study Duration 
Study drug administration will continue for up to 
4 chemotherapy-containing (trilaciclib or placebo + E/P/A) cycles during 
the induction part of the study and atezolizumab will be administered 
every 21 days during the maintenance part of the study. Study drug 
administration will continue until disease progression per RECIST v1.1, 
unacceptable toxicity, withdrawal of consent, or discontinuation by 
investigator, whichever occurs first. However, if the patient appears to be 
deriving clinical benefit, the investigator believes it is in the best interest 
of the patient, and the patient has provided re-consent, study drug 
administration may be continued until loss of clinical benefit. Treatment 
cycles will occur consecutively without interruption, except when 
necessary to manage toxicities or for administrative reasons as described 
below.  
In order to start Induction Cycle 2 and subsequent cycles as scheduled 
during the induction part, patients must have an absolute neutrophil count 
(ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and nonhematologic 
drug-related toxicities (except alopecia) must be ≤ Grade 1 or have 
returned to baseline. A delay of > 9 weeks for recovery from any toxicity 
related to trilaciclib or placebo + E/P in order to meet the continuation 
criteria will result in discontinuation of trilaciclib or placebo + E/P. A 
delay of > 15 weeks for recovery and management of immune-related 
toxicities attributed to atezolizumab (12 weeks for recovery to ≤ Grade 1 
and up to an additional 3 weeks for steroid taper of oral prednisone or 
equivalent to ≤ 10 mg/day) will result in discontinuation of atezolizumab. 
If patients meet the criteria for starting the subsequent cycle, a delay of up 
to 2 weeks is permitted for administrative reasons (eg, holiday, vacation, 
etc.); however, a total delay of more than 9 weeks for trilaciclib or 
placebo + E/P, or 15 weeks for atezolizumab must be discussed with the 
medical monitor. If the subsequent cycle is delayed, the patient should 
still complete the clinical laboratory assessments, the Functional 
Assessment of Cancer Therapy–Lung quality of life instrument 
(FACT-L), and the Functional Assessment of Cancer Therapy–Anemia 
quality of life instrument (FACT-An) questionnaires on the scheduled 


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Day 1, as well as on the actual first dosing day of the next cycle.  
Atezolizumab has been associated with risks such as the following: 
infusion-related reactions (IRRs); immune-related hepatitis, pneumonitis, 
colitis, pancreatitis; diabetes mellitus; hypothyroidism; hyperthyroidism; 
adrenal insufficiency; Guillain-Barré syndrome; myasthenic syndrome or 
myasthenia gravis; hypophysitis; and meningoencephalitis. In addition, 
systemic immune activation is a potential risk associated with 
atezolizumab when given in combination with other immunomodulating 
agents. Refer to the Atezolizumab Guidance for the Investigator 
(Appendix 1) for a detailed description of anticipated safety risks for 
atezolizumab and their management. 
Management of immune-related adverse events (irAEs) attributed to 
atezolizumab may include administration of immunosuppressant 
medications like corticosteroids, etc.; delay of a scheduled dose; or 
discontinuation of therapy. No dose reductions will be allowed for 
atezolizumab. Atezolizumab dosing will be held in the event of any irAEs 
attributed to atezolizumab until the event has improved to ≤ Grade 1. See 
the Atezolizumab Guidance for the Investigator (Appendix 1). 
Other irAEs attributed to atezolizumab not listed above should be 
assessed by the investigator and discussed with the medical monitor to 
determine if atezolizumab should be held or discontinued. If the irAE 
does not improve to ≤ Grade 1 within 12 weeks, treatment will be 
permanently discontinued.  
Discontinuation or interruption of trilaciclib or placebo + E/P does not 
preclude continuation of atezolizumab and vice versa. For instance, if an 
adverse event (AE) is attributed to trilaciclib or placebo, etoposide, or 
carboplatin (eg, hematologic toxicity) during the induction part of the 
study, then atezolizumab will be continued while the trilaciclib or placebo 
+ E/P are held. While the trilaciclib or placebo + E/P are held, the patient 
will continue to receive atezolizumab, be monitored for safety, and will 
begin the next trilaciclib or placebo + E/P/A-containing induction cycle 
after the toxicity resolves. If the AE is immune related and attributed to 
atezolizumab; then trilaciclib or placebo + E/P will be continued for up to 
4 cycles while the atezolizumab is held. After discontinuation of all study 
drugs, patients should be strongly encouraged to complete all scheduled 
assessments through the end of their current 21-day treatment cycle, 
 complete blood count (CBC) assessment on 
Day 22; all Post-Treatment Visits; and the Survival Follow-up Phase of 
the study, which is to continue until at least 70% of the patients on the 
study have died. The G1T28-05 study will be completed when the 
Survival Follow-up Phase has been completed, or upon sponsor 
termination of the study. 
Tumor Assessment 
Tumor assessments using radiologic imaging will be performed after 
every even cycle for the first 9 months of the study (ie, approximately 
every 6 weeks) and after every third cycle (ie, approximately every 
9 weeks) thereafter while receiving study drug. Tumor assessments will 
include tumor response based on RECIST v1.1 and irRECIST. For tumor 
assessment, all sites of disease should be assessed radiologically by 
computed tomography (CT) or magnetic resonance imaging (MRI) at 


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screening and every scheduled tumor assessment until the occurrence of 
disease progression. CT or MRI scans obtained as standard of care prior to 
informed consent will not need to be repeated if performed within 14 days 
prior to dosing. Brain scans performed as standard of care 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 prior to 
starting the subsequent cycle. Additional scans may be obtained at the 
discretion of the investigator, if clinically indicated. If a patient shows a 
radiological response (complete response [CR] or partial response [PR]), a 
confirmatory radiological assessment will be performed at least 4 weeks 
after the response was first noted. For patients who have a confirmed CR, 
it is strongly recommended that they receive prophylactic cranial 
irradiation (PCI) after completion of chemotherapy (ie, induction). 
Patients with a confirmed PR should also consider PCI after completion 
of chemotherapy (ie, induction) based on the investigator’s judgment. 
Following the completion of the induction part, PCI may be administered 
concurrently with atezolizumab during the maintenance part. For those 
patients who have not progressed at the time of study drug 
discontinuation, tumor assessments to include all sites of disease will be 
assessed radiologically by CT or MRI, as performed at screening, every 
2 months (approximately 60 ± 7 days) until the occurrence of progressive 
disease or study completion. The same method of assessment (CT or 
MRI) should be used to characterize tumors at screening and at all 
follow-up assessments. If positron emission tomography (PET) is used, it 
should also be accompanied by spiral CT or MRI.    
Safety Assessments 
Safety assessments will include monitoring of AEs (including SAEs, 
irAEs, and AEs of special interest [AESI]), vital signs measurements, 
physical examinations, electrocardiograms (ECGs), performance status, 
clinical laboratory studies, and IRRs. Safety surveillance reporting of AEs 
commences at the time of informed consent. AEs will be collected 
through 30 days after the last dose of study drug; SAEs and AESI will be 
collected through 90 days after the last dose of study drug.  
An independent data monitoring committee (DMC) will monitor 
accumulating safety and disposition data after approximately 12 patients 
have been enrolled and have completed at least 1 cycle to assess the initial 
safety data from the 2 groups, and then approximately every 4 months 
during the Treatment Phase 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.    
Treatment Duration  
Study drug administration will continue for each patient until disease 
progression per RECIST v1.1, unacceptable toxicity, withdrawal of 
consent, or discontinuation by investigator, whichever occurs first. 
However, if the patient appears to be deriving clinical benefit, the 
investigator believes it is in the best interest of the patient, and the patient 
has provided re-consent, study drug administration may be continued until 
loss of clinical benefit.   
Study drug refers to trilaciclib or placebo + E/P/A during the induction 
part and atezolizumab during the maintenance part. 


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Study Duration 
The total study duration is at least 36 months, assuming 12 months of 
accrual and 24 months follow-up. 
The Survival Follow-up Phase will continue until at least 70% of the 
randomized patients have died. 
Approximate Number of 
Patients 
Approximately 100 patients will be randomly assigned to 1 of 2 groups as 
follows: trilaciclib administered intravenously (IV) with E/P/A therapy 
during induction followed by atezolizumab maintenance (Group 1) or 
placebo administered IV with E/P/A therapy during induction followed by 
atezolizumab maintenance (Group 2). 
Number of Study 
Centers 
Up to 60 centers in North America and Europe 
Diagnosis and Main 
Criteria for Inclusion 
For a patient to be eligible for participation in this study, all of the 
following criteria must apply. 
1. Age ≥ 18 years  
2. Unequivocally confirmed diagnosis of SCLC by histology or 
cytology, preferably including the presence of neuroendocrine 
features by immunohistochemistry 
3. Extensive-stage SCLC 
4. At least 1 target lesion that is measurable by RECIST v1.1 
(Eisenhauer 2009) 
5. Hemoglobin ≥ 9.0 g/dL 
6. ANC ≥ 1.5 × 109/L 
7. Platelet count ≥ 100 × 109/L 
8. Creatinine ≤ 1.5 mg/dL or glomerular filtration rate (GFR) of 
≥ 60 mL/minute 
9. Total bilirubin ≤ 1.5 × ULN; < 3 × ULN if the patient has 
documented Gilbert’s disease 
10. Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤ 2.5 × ULN; ≤ 5 × ULN in the presence of liver metastases 
11. ECOG performance status of 0 to 2 
12. Predicted life expectancy of ≥ 3 months 
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. Females must be either 
postmenopausal, surgically sterile, or agree to use 2 forms of 
highly effective contraception during the study and for 
6 months following discontinuation of study treatment  
i. Postmenopausal is defined as (1) at least 60 years of age, 
(2) medically confirmed ovarian failure, or (3) younger 
than 60 years of age and have had cessation of regular 
menses for at least 12 consecutive months with no 


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alternative pathological or physiological cause, and/or 
serum levels of estradiol and follicle stimulating hormone 
within the laboratory’s reference range for postmenopausal 
females 
ii. Acceptable surgical sterilization techniques are complete 
or partial hysterectomy, bilateral tubal ligation with 
surgery at least 6 months prior to dosing, or bilateral 
oophorectomy with surgery at least 2 months prior to 
dosing  
iii. Highly effective methods of contraception are those that 
result in a low failure rate (ie, less than 1% per year) when 
used consistently and correctly. These include the 
following: 
1. Established use of oral, injected or implanted 
hormonal methods of contraception (stable dose at 
least 3 months prior to dosing)  
2. Placement of an intrauterine device or intrauterine 
system  
3. Barrier methods of contraception: condom or 
occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/suppository. 
Barrier methods alone (without spermicide) are not 
acceptable methods. Likewise, spermicide alone is 
not an acceptable method 
4. Male sterilization (with the appropriate 
post-vasectomy documentation of the absence of 
sperm in the ejaculate). For female patients on the 
study, the vasectomized male partner should be the 
sole partner for that patient   
5. True abstinence, when this is in line with the 
preferred and usual lifestyle of the subject. Periodic 
abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not 
acceptable methods of contraception   
b. 
For males: Males must be surgically sterile or have a female 
partner who is either postmenopausal, surgically sterile, or 
using 2 forms of highly effective contraception as noted 
above. Acceptable surgical sterilization techniques are 
vasectomy with surgery at least 6 months prior to dosing. 
Males must also refrain from sperm donation during the study 
and for 6 months following discontinuation of treatment 
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. Limited-stage SCLC 
2. Prior chemotherapy for limited or extensive-stage SCLC 
3. Prior treatment with immunotherapies including but not limited to 
cluster of differentiation 137 (CD137) agonists or immune 
checkpoint blockade therapies (such as anti-program cell death 
protein 1 [PD-1], or anti-programmed death ligand 1 [PD-L1], 
CTLA4 therapeutic antibodies) 
4. Presence of symptomatic brain metastases requiring immediate 
treatment with radiation therapy or steroids 
5. Malignancies other than SCLC within 3 years prior to 
randomization, with the exception of those with a negligible risk of 
metastasis or death treated with expected curative outcome 
6. History of idiopathic pulmonary fibrosis, organizing pneumonia, 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest CT scan (history of 
radiation pneumonitis in the radiation field [fibrosis] is permitted) 
7. Active, known, or suspected autoimmune disease that has required 
systemic treatment in the past 2 years (ie, with use of disease 
modifying agents, corticosteroids, or immunosuppressive drugs). 
Exceptions include vitiligo, controlled asthma, Type I diabetes, 
Graves’ disease, Hashimoto’s disease, or with medical monitor 
approval. Stable replacement therapy (eg, thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) for well-controlled disease is not 
considered a form of systemic treatment 
8. 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) 
9. Known history of stroke or cerebrovascular accident within 
6 months prior to enrollment 
10. Serious active infection at the time of enrollment 
11. Psychiatric illness/social situations that would limit study 
compliance 
12. Other uncontrolled serious chronic disease or conditions that in the 
investigator’s opinion could affect compliance or follow-up in the 
protocol 
13. Known human immunodeficiency virus (HIV), known active 
Hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive or 
HBV DNA detected) or Hepatitis C (eg, hepatitis C virus [HCV] 
RNA [qualitative] is detected) 
14. Radiotherapy to any site within 2 weeks prior to enrollment  
15. Receipt of any investigational medication within 4 weeks prior to 
enrollment 
16. Administration of a live attenuated vaccine within 4 weeks before 


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enrollment or anticipation that such a live attenuated vaccine will 
be required during the study 
17. Influenza vaccination should be given during influenza season 
only (approximately October to March). Patients must not receive 
live, attenuated influenza vaccine (eg, FluMist) within 4 weeks 
prior to enrollment, at any time during the study, and at least 
5 months after the last dose of atezolizumab 
18. Patients with a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalents) or other 
immunosuppressive medications (including but not limited to 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-tumor necrosis factor [TNF] agents) within 14 days of study 
drug administration. Inhaled or topical steroids and adrenal 
replacement doses > 10 mg daily prednisone equivalents are 
permitted in the absence of active autoimmune disease. 
19. Hypersensitivity to any of the components of the formulation of 
etoposide or etoposide phosphate 
20. Hypersensitivity to carboplatin or other platinum-containing 
compounds, or mannitol  
21. History of severe allergic, anaphylactic, or other hypersensitivity 
reactions to chimeric or humanized antibodies or fusion proteins 
22. Known hypersensitivity to Chinese hamster ovary cell products or 
other recombinant human antibodies 
23. Legal incapacity or limited legal capacity  
24. Pregnant or lactating women 
Chemotherapy 
Treatment 
Carboplatin dose calculated using the Calvert formula with a target area 
under the concentration-time curve (AUC) = 5 (maximum dose of 
750 mg) administered IV over 30 minutes on Day 1, and 
100 mg/m2 etoposide administered IV over 60 minutes daily on Days 1, 2, 
and 3 of 21-day cycles. 
Investigational 
Medicinal Products and 
Administration 
Trilaciclib 240 mg/m2 in 250 mL of dextrose 5% in water (D5W) or in 
sodium chloride solution 0.9%, administered as an IV infusion over 
approximately 30 minutes once daily on Days 1 to 3 of each 21-day cycle 
prior to the dose(s) of chemotherapy. 
Atezolizumab 1200 mg in 250 mL sodium chloride solution 0.9% will be 
administered as an IV infusion on Day 1 of each 21-day cycle in both the 
induction and maintenance parts. During the induction part, atezolizumab 
should be administered following the completion of trilaciclib or placebo, 
carboplatin, and etoposide. Atezolizumab should be infused over 
60 minutes for the first administration and, if tolerated, all subsequent 
infusions may be delivered over 30 minutes.  
There will be no intrapatient dose modifications of trilaciclib or 
atezolizumab in the study. 




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Statistical Analysis 
The intent-to-treat (ITT) population includes all randomized patients and 
will be the primary analysis set for efficacy and 
. 
ITT analyses will be conducted on the basis of the assigned treatment. The 
safety analysis set includes all patients who received at least 1 dose of 
study drug and will be used for the analysis of safety endpoints. The 
safety analysis set analyses will be conducted on the basis of the actual 
treatment received. The PK analysis set will include all dosed patients in 
the PK portion of the study with evaluable PK data. 
Data will be summarized by treatment group. Treatment differences 
between treatment groups will be calculated as trilaciclib + E/P/A therapy 
versus placebo + E/P/A therapy. 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.  
Study G1T28-05 was originally designed as a Phase 2 clinical study to 
investigate if myelopreservation, ie, preservation of hematopoietic stem 
and progenitor cell (HSPC) and immune system function during 
chemotherapy, by trilaciclib could provide survival benefit to patients 
receiving a combination of cytotoxic chemotherapy and an immune 
checkpoint inhibitor. Recent results from a clinical study in 
treatment-naive extensive-stage SCLC patients (Study G1T28-02) who 
received trilaciclib or placebo in combination with etoposide/carboplatin, 
provided compelling evidence that trilaciclib resulted in a clinically 
meaningful decrease in myelosuppression across 3 lineages: neutrophils, 
RBC, and lymphocytes. Hence, the primary analysis in this Study 
G1T28-05, where the chemotherapy backbone of etoposide and 
carboplatin is the same as Study G1T28-02, is being modified to assess 
primary and key secondary myelosuppression efficacy endpoints. This 
allows for an earlier assessment of trilaciclib’s mechanism of action 
(MOA) and efficacy, with OS retained as a secondary endpoint. This 
change in endpoints does not alter the assessments or protocol-defined 
patient care. 
The primary endpoints include (i) duration of severe (Grade 4) 
neutropenia in Cycle 1 and (ii) occurrence of severe (Grade 4) 
neutropenia. Occurrence will be displayed as the proportion of patients 
with an event for each study arm. 
Duration of severe (Grade 4) neutropenia in Cycle 1 will be analyzed with 
nonparametric analysis of covariance (ANCOVA) (Stokes 2012), while 
the occurrence of severe (Grade 4) neutropenia will be analyzed using 
modified Poisson regression (ie, Poisson regression with a robust error 
variance) (Zou 2004),. Unless otherwise specified, these endpoints will be 
evaluated for the induction treatment period, which is defined as the 
duration between the date of randomization and the end of the last cycle in 
the protocol-defined induction phase (ie, last cycle of placebo or trilaciclib 
plus E/P/A).  There are multiple key secondary  endpoints. To 
accommodate the primary and key secondary endpoints, 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=0.025 level.  


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These analyses will be conducted based on the ITT analysis set. The 
stratification factors of ECOG performance status (0 to 1 versus 2) and 
presence of brain metastases (yes versus no) will be accounted for in the 
statistical analyses. Appropriate sensitivity analyses for the primary and 
key secondary endpoints will be conducted to evaluate the robustness of 
the results. 
Other secondary endpoints including antitumor activity as assessed by 
objective response and PFS (as assessed by RECIST version 1.1) and OS 
will be evaluated. 
Summaries of safety data will be performed using the safety analysis set. 
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. Absolute values and changes 
from baseline in vital signs, ECG results, 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 
National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), Version 4.03. Shifts in toxicity grades from 
baseline will be summarized.  
Pharmacokinetic results will be analyzed and reported for the PK analysis 
set, separately for each analyte. Plasma concentration-time data will be 
tabulated descriptively and graphically by treatment group. 
Pharmacokinetic parameters will be calculated using noncompartmental 
methods based on the plasma concentration-time data. Pharmacokinetic 
parameters will be summarized descriptively.  
Rationale for Number of 
Patients 
The sample size calculation is based on demonstrating the superiority of 
trilaciclib + E/P/A versus placebo + E/P/A for the primary endpoints. To 
maintain the overall type I error rate using the most conservative 
Bonferroni procedure for the 2 primary endpoints, a 1-sided 
individualized type I error rate 0.025/2 = 0.0125 is assigned to each 
outcome variable in the sample size calculation. Assuming a 95% 
evaluability rate, at least 106 patients need to be enrolled to complete the 
study.  


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4. 
INTRODUCTION 
4.1. 
Background 
Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancer cases 
worldwide and more than two-thirds of patients present with extensive-stage disease. 
Although response rates to first-line chemotherapy in extensive-stage SCLC are in the range 
of 50% to 60%, the median duration of response is short (approximately 4 months), with a 
median survival of 8 to 10 months and 2-year survival rates of less than 10% (Jemal 2009; 
Eckardt 2006; Noda 2002; Hanna 2006; Socinski 2009; Hermes 2008; Schmittel 2006; 
Lyman 2006). Increasing evidence suggests that immune responses against SCLC cells make 
immunotherapy a viable therapeutic approach in this disease (Horn 2016). Furthermore, there 
is evidence that certain chemotherapeutic regimens may augment the immunotherapeutic 
response in SCLC, in part by releasing neoantigens and educating the immune system against 
the surviving cancer cells.   
Atezolizumab (Tecentriq®), is a monoclonal antibody that binds to programmed death-ligand 
1 (PD-L1), inhibiting its interaction with the programmed cell death protein 1 (PD-1) 
receptor and releasing the PD-L1/PD-1 mediated inhibition of the immune response. 
Atezolizumab is an immunotherapy indicated for the treatment of locally advanced or 
metastatic urothelial carcinoma (UC) (approved in the United States in May 2016) and 
metastatic non-small cell lung cancer (NSCLC) (approved in the United States in 
October 2016). Etoposide and carboplatin (E/P) is a standard SCLC treatment and is 
currently under investigation with atezolizumab for the treatment of SCLC. 
The major drawback to platinum-based chemotherapeutic regimens used in SCLC treatment 
is dose-limiting myelosuppression, which may antagonize the intended effects of the 
immunotherapy by reducing both the number and function of lymphocytes. Therefore, an 
approach to maintain immune system function while administering cytotoxic chemotherapy 
is needed to fully realize the therapeutic potential of immunotherapies.    
Trilaciclib is a highly potent, selective, and reversible cyclin-dependent kinase 4/6 (CDK4/6) 
inhibitor in development to preserve bone marrow and immune system function (including 
lymphoid progenitors and lymphocytes) from damage by chemotherapy, allowing faster 
hematopoietic recovery, preserving long-term bone marrow function, and enhancing the 
antitumor activity of chemotherapy. Trilaciclib is administered intravenously prior to every 
dose of chemotherapy in every cycle, eg, on Days 1 to 3 prior to E/P administration in 21-day 
cycles, for extensive-stage SCLC. This pulsatile dosing around chemotherapy administration 
allows preservation of the bone marrow and immune system without adding to the 
chemotherapy-induced myelosuppression caused by chronic inhibition of CDK4/6 in the 
bone marrow. Preserving adaptive immunity with trilaciclib may enhance the efficacy of 
chemotherapy combined with immune checkpoint inhibitors, supporting clinical testing of 
the novel combination of etoposide, carboplatin, and atezolizumab (E/P/A) therapy and 
trilaciclib.  


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4.2. 
Study Rationale 
Nonclinical studies in mice have shown that trilaciclib causes a “priming” effect on bone 
marrow and immune cells. Specifically, trilaciclib administration causes a transient gap 1 
(G1) cell cycle arrest in bone marrow progenitors and lymphocytes (B cells and thymocytes), 
thus protecting them from cytotoxic chemotherapy damage. The transient G1 cell cycle arrest 
is followed by a brief increased rate of proliferation up to 72 hours following trilaciclib 
administration before returning to a baseline proliferative rate within 1 week, as 
demonstrated by assessing 5-ethynyl-2'-deoxyuridine (EdU) incorporation in specific cell 
populations. In addition, trilaciclib can protect T lymphocyte numbers and functionality post 
chemotherapy treatment. In a well-established 5-fluorouracil (5-FU) treatment murine model, 
T lymphocyte populations recovered faster in mice that received up to 4 cycles of 
trilaciclib + 5-FU, compared to 5-FU alone. Splenocytes derived from mice that received 
trilaciclib + 5-FU and stimulated ex vivo with anti-cluster of differentiation 3 (CD3) and 
anti-CD28 antibodies demonstrated normal levels of interferon-gamma (IFNγ) and 
interleukin 2 (IL-2) release, while stimulated splenocytes from mice treated with 5-FU alone 
demonstrated a decreased release of both cytokines. Taken together, these data suggest that 
trilaciclib-mediated preservation of lymphocyte numbers and function, along with the 
transient increase in proliferation of lymphocytes and other immune cells coinciding with 
chemotherapy-associated neoantigen release, could allow for maximal priming of the 
immune system to generate an efficacious adaptive immune response. 
Chemotherapy-induced lymphopenia is a well-known phenomenon, yet has not been well 
studied in the past. Chemotherapy-associated late bone marrow toxicity results from 
therapy-induced damage and premature exhaustion of hematopoietic stem cells (HSCs). 
Cytotoxics can cause direct damage to activated HSCs, but also induce functional attrition of 
HSCs indirectly through a process of proliferative exhaustion. This HSC intrinsic damage 
leads to a reduction of long-term multilineage reconstitution potential as well as 
myeloid-biased differentiation, resulting in lymphopenia. Nonclinical data demonstrate that 
trilaciclib administered prior to chemotherapy for multiple cycles can lead to a lasting 
protection of HSC function, thereby ameliorating the long-term toxicity associated with serial 
exposure to chemotherapy agents (ie, “exhaustion”), and preservation from myeloid-biased 
differentiation.   
Chemotherapy-induced lymphopenia could potentially decrease the efficacy of immune 
checkpoint inhibitors when administered with chemotherapy. As a clinical biomarker of 
immune system function, baseline lymphocyte counts from patients with SCLC who received 
first-line E/P (N = 134) or second-line topotecan therapy (N = 78) were evaluated via a 
retrospective chart review and in data from 2 ongoing SCLC clinical trials testing the 
combination of trilaciclib with these chemotherapy regimens (first line, E/P, NCT02499770; 
and second line, topotecan, NCT02514447). Baseline lymphocyte counts from patients with 
SCLC were lower at the start of second-line treatment compared to the start of first-line 
treatment (1116 versus 1481/μL, respectively; p = 0.0002), demonstrating persistent 
lymphopenia months after first-line chemotherapy. In the ongoing trilaciclib SCLC studies, 
lymphocyte counts have remained relatively unchanged through repeated cycles of both first- 
and second-line chemotherapy, demonstrating preservation of this important cell population.   


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Currently, there are no approved treatments to decrease myelosuppression across multiple 
lineages by preserving hematopoietic stem and progenitor cell (HSPC) function. Although 
some therapies may help to address issues once they have occurred (eg, transfusions, growth 
factors, etc), there are no available options that provide patients with a means to effectively 
preserve HSPC and immune system function from chemotherapy-induced damage and the 
resultant negative impact. For this reason, patients receiving myelosuppressive chemotherapy 
often experience clinically significant consequences, such as severe neutropenia and risk of 
infections, anemia requiring red blood cell (RBC) transfusions, dose reductions, etc. Thus, 
myelosuppression continues to be a serious side effect of chemotherapy for patients with 
SCLC who have significant side effects from treatment, short time to progression, and poor 
overall survival (OS). This population would benefit from a therapeutic option that 
minimizes the myelosuppressive impact of treatment by reducing the frequency of severe 
cytopenias, preserving immune system function, and maintaining long-term bone marrow 
function. Minimizing myelosuppression should, ideally, lead to decreased 
chemotherapy-induced morbidity and mortality, facilitation of optimal standard of care 
chemotherapy regimens, and enhanced antitumor activity. 
To evaluate the effect of trilaciclib in combination with chemotherapy and an immune 
checkpoint inhibitor, immunocompetent MC38 tumor-bearing mice were treated with 
trilaciclib, oxaliplatin, or anti-PD-L1 alone or in combination, and tumor size was measured 
during and post treatment for 100 days. The addition of trilaciclib to an oxaliplatin/anti-PD-
L1 combination (TOP) treatment significantly improved the overall response rate, complete 
response rate, and median OS compared to oxaliplatin/anti-PD-L1 combination (93% vs 
46%; 79% vs 38%; not reached at 100 days vs 59 days, respectively). Taken together, this 
demonstrates that trilaciclib, which has been shown to preserve immune function during 
chemotherapy, enhances the antitumor activity of chemotherapy/anti-PD-L1 combination 
therapy.   
In summary, nonclinical data demonstrate that trilaciclib administration with chemotherapy 
preserves bone marrow and immune system function from damage by chemotherapy. 
Additionally, clinical data from Study G1T28-02 (Section 4.3.1), where patients received 
trilaciclib or placebo in combination with etoposide/carboplatin, provides compelling 
evidence that trilaciclib decreases myelosuppression across 3 lineages (neutrophils, RBC, and 
lymphocytes), and suggests that trilaciclib contributes to a more functional activated immune 
system as compared with placebo. It is this difference that is hypothesized to translate into 
potentially improved efficacy (eg, OS) when chemotherapy is combined with checkpoint 
inhibitors.  
4.3. 
Summary of Clinical Data   
4.3.1. 
Trilaciclib 
A brief summary of the clinical data with trilaciclib is provided in the following sections. 
Detailed information is presented in the trilaciclib Investigator’s Brochure (IB). 
Study G1T28-1-01 was a Phase 1a, safety, PK, and pharmacodynamic study of trilaciclib.  
Forty-five healthy male and female subjects were enrolled into 7 dose cohorts where 
trilaciclib was administered intravenous (IV) as a 30-minute infusion (randomized, 


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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 (TEAEs) 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 TEAEs were mild in intensity; 13 subjects 
experienced a total of 19 TEAEs 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 TEAEs 
resulting in withdrawal from the study. All TEAEs 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 trilaciclib, 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 trilaciclib 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 trilaciclib. The elimination 
kinetics of trilaciclib appeared to follow a 3-compartment model. The geometric mean 
half-life (t1/2) was 12.9 to 14.7 hours for the 48 to 192 mg/m2 dose levels. The interpatient 
variability (%CV) of the PK parameters at the 192 mg/m2 dose level was low (< 15%). The 
PK of trilaciclib suggests that drug accumulation following repeated administration is 
unlikely to occur. Urinary excretion appears to be a minor route of elimination for unchanged 
trilaciclib. 
Trilaciclib showed positive pharmacodynamic effects in 2 assays. Dose-dependent inhibition 
of ex vivo whole blood stimulation occurred following a single IV infusion of trilaciclib 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 trilaciclib 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.  
Trilaciclib is also being tested in 2 ongoing Phase 1b/2a studies (G1T28-02 and G1T28-03). 
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E/P therapy for patients with newly diagnosed extensive-stage SCLC. Study G1T28-03 is 
designed to assess the safety and PK of trilaciclib in combination with topotecan for patients 
with previously treated extensive-stage SCLC. The safety profiles observed to date in 
G1T28-02 and G1T28-03 are consistent with the general safety profile of patients undergoing 
chemotherapy treatment; no new safety signals have been identified as of the trilaciclib IB 
data cutoff date of 20 May 2016.   
In G1T28-02, a total of 19 patients were treated in the dose exploration Part 1, and 
75 patients were treated in the placebo-controlled, double-blinded, randomized Part 2.  
(Please see the current version of the trilaciclib IB for detailed information on Part 1 
patients.) The unblinded randomized results from Part 2 provide proof-of-concept evidence 
of the myelopreservation benefits of trilaciclib combined with E/P compared with placebo + 
E/P. The trilaciclib arm was favored across all neutrophil-related endpoints, including the 
proportion of patients with Grade 4 absolute neutrophil count (ANC) values (16/37 [43.2%] 
for placebo versus 2/38 [5.3%] for trilaciclib: p-value = 0.0001) and dose reductions due to 
neutropenia (10/37 [32.4%] for placebo versus 2/38 [5.3%] for trilaciclib: p-value = 0.0033). 
In alignment with the reduction of Grade 4 ANC events, the proportion of patients who 
received granulocyte colony-stimulating factor (G-CSF) was also significantly lower in the 
trilaciclib group (4/38 [10.5%]) than in the placebo group (24/37 [64.9%]: p-value < 0.0001). 
RBC endpoints also favored trilaciclib versus placebo, eg, 2/35 (5.7%) of patients enrolled on 
the trilaciclib arm received an RBC transfusion on/after Week 5 versus 8/37 (21.6%) of 
patients in the placebo arm. In addition, mean lymphocyte counts over time in the trilaciclib 
arm were greater than those observed in the placebo arm, and the recovery to baseline after 
each chemotherapy-induced lymphocyte nadir was faster in the trilaciclib arm compared with 
the placebo arm. Consistent with the faster recovery of lymphocyte counts, E/P + trilaciclib, 
as compared to E/P + placebo, not only increased the total number of circulating CD8+ cells 
during treatment, but also resulted in a larger population of activated CD8+ T cells, and 
fewer regulatory T cells; both of which are consistent with a more robust immune response 
which could correlate with improved antitumor responses. In Part 2, almost all patients 
reported at least 1 TEAE, and almost all patients reported TEAEs related to etoposide or 
carboplatin. Approximately half the patients reported TEAEs related to trilaciclib, but none 
were ≥ Grade 3, which suggests that trilaciclib is not associated with severe toxicity. There 
were notably fewer high-grade (≥ Grade 3 and ≥ Grade 4) TEAEs reported during treatment 
with trilaciclib compared with placebo, an observation primarily driven by a significant 
decrease in the number of hematologic high-grade TEAEs reported in the trilaciclib arm. 
Fatigue, nausea, thrombocytopenia, and anemia were the most frequent TEAEs in the 
trilaciclib group. Neutropenia, anemia, alopecia, and thrombocytopenia were the most 
frequent TEAEs in the placebo group.   
In G1T28-03, the majority of patients (92.9%; 13 of 14) reported TEAEs, with the most 
common (ie, reported by > 50% of patients) being thrombocytopenia, neutropenia, anemia, 
and leukopenia.  TEAEs considered related to trilaciclib per investigator assessment were 
reported by 4 patients (28.6%). The majority of patients (85.7%) reported at least 1 Grade 3, 
4, or 5 TEAE; those reported by more than 1 patient included thrombocytopenia, leukopenia, 
neutropenia, anemia, neutrophil count decreased, pneumonia, and dyspnea. The majority of 
the Grade 3, 4, or 5 TEAEs have been reported by patients in Cohorts 1 and 2, likely due to 
the supratherapeutic levels of topotecan observed in these patients, which may be responsible 
for the higher number of hematology-related TEAEs in Cohorts 1 and 2. Over one-half of 


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patients (64.3%) reported an SAE, all of which were considered unlikely or not related to 
trilaciclib and did not meet DLT criteria. One patient died during participation in the study 
due to an SAE of disease progression that was considered unrelated to trilaciclib by the 
investigator.    
The PK assessments of trilaciclib in the ongoing studies support the findings from the study 
in healthy male and female subjects (GT128-01). Clearance was observed to be high, with 
little or no drug accumulation during 3 or 4 days of dosing, except at the trilaciclib 
280 mg/m2 dose level tested in Study G1T28-03.    
4.3.2. 
Atezolizumab 
Atezolizumab (Tecentriq®) has been evaluated in several clinical indications. At this time, 
atezolizumab is approved for patients with UC and NSCLC, for which safety data is 
available and briefly summarized below. Further details are provided in the Atezolizumab 
Guidance for the Investigator (Appendix 1) and atezolizumab prescribing information 
(Appendix 2).   
Adverse Reactions 
The most common adverse reactions (rate ≥ 20%) in patients with UC included fatigue 
(52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia 
(21%), and constipation (21%). 
The most common adverse reactions (rate ≥ 20%) in patients with NSCLC included fatigue 
(46%), decreased appetite (35%), dyspnea (32%), cough (30%), nausea (22%), 
musculoskeletal pain (22%), and constipation (20%). 
Serious Adverse Reactions 
Based on pooled data from atezolizumab single-agent studies in patients with UC, NSCLC, 
and other indications (N = 1978), with additional safety data as of 10 May 2016 across 
patients who have received atezolizumab single agent or in combination with 
chemotherapy/targeted therapy (N = 6053) (where applicable), the serious adverse drug 
reactions (ADRs) occurring in > 1% of patients included the following: dyspnea (3.0%, 60 of 
1978 patients), pyrexia (2.4%, 48 of 1978 patients), back pain (1.2%, 23 of 1978 patients), 
pneumonitis (fatal outcome expected for reporting purposes) (1.2%, 24 of 6053 patients), and 
abdominal pain (1.1%, 22 of 1978 patients). 
Potential risks and adverse events of special interest (AESI) identified for atezolizumab are 
described in Section 4.4.4.2, and full details can be found in the Atezolizumab Guidance for 
the Investigator (Appendix 1), atezolizumab prescribing information (Appendix 2), and 
atezolizumab AESI list (Appendix 3). 
4.4. 
Summary of Nonclinical Data 
A brief summary of the trilaciclib nonclinical data is provided in the following sections. 
Detailed information is presented in the trilaciclib IB.  


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Nonclinical data related to atezolizumab is provided in the prescribing information 
(Appendix 2).   
4.4.1. 
Pharmacology Studies 
Trilaciclib 
 
Through a structure-based design approach to optimize potency, selectivity, and drug 
metabolism and PK properties, G1 Therapeutics, Inc. identified trilaciclib as a highly potent 
inhibitor of CDK4 and CDK6 (half maximal inhibitory concentration [IC50] values of 0.8 and 
6 nM, respectively) that is highly selective for CDK4 versus cyclin-dependent kinase 
2 (CDK2) (> 2000-fold selectivity). 
The trilaciclib-induced G1 arrest of HSPCs has been shown to be transient and readily 
reversible in both in vitro and in vivo models. In vivo analysis has demonstrated that 
coadministration of trilaciclib with myelosuppressive chemotherapy leads to improved CBC 
recovery of all blood lineages and increased survival. In addition, administration of trilaciclib 
with every cycle of the highly myelosuppressive chemotherapy 5-FU for a total of 4 cycles 
demonstrated that the reduction in chemotherapy-induced myelosuppression persisted 
following Cycle 4. While the extent and duration of nadir in CBCs worsened after each cycle 
of 5-FU administered alone, coadministration of trilaciclib with 5-FU ameliorated this 
worsening effect and the animals that received trilaciclib + 5-FU demonstrated a faster rate of 
recovery of CBCs compared with the 5-FU alone group following Cycle 4. In accordance 
with the single-dose study, trilaciclib administration with all cycles of 5-FU maintained the 
protective effect against 5-FU-induced DNA damage in HSPCs over multiple cycles, leading 
to an effect that persisted and was greater following multiple cycles of trilaciclib + 5-FU 
compared with 5-FU alone. In addition, bone marrow obtained from mice that received 
4 cycles of trilaciclib 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 trilaciclib administered with chemotherapy can preserve stem 
cell function. 
Retinoblastoma (Rb) is the direct downstream target of CDK4/6 and its expression is 
required for CDK4/6-dependent cells. Importantly, cancers that delete Rb do not require 
CDK4/6 activity for cell cycle progression (Fry 2004); therefore, loss of Rb is a hallmark 
identifier of CDK4/6 independence. Since inactivation of the retinoblastoma gene (RB-1) is 
an obligate event in SCLC development (D’Amico 1992; Heighway 2004; Yuan 1999; 
Cagle 1997; Gouyer 1994, Peifer 2012; Rudin 2012), this tumor type is highly resistant to 
CDK4/6 inhibitors and coadministration of CDK4/6 inhibitors with DNA damaging 
chemotherapeutic agents such as those used in SCLC are not expected to antagonize the 
efficacy of such agents. In vitro analysis has shown that RB-1 inactive cells are resistant to 
CDK4/6 inhibition and therefore are not protected from chemotherapy when cotreated with 
trilaciclib. To expand these findings in vivo, trilaciclib was tested alone and in combination 
with topotecan or an E/P combination regimen in a cell-based xenograft SCLC model (H69) 
in immune-deficient mice. Trilaciclib administered alone or 30 minutes before E/P or 
topotecan was well tolerated, with no additive weight loss or toxicity. Single agent trilaciclib 
was inactive towards NCI-H69 SCLC tumors and combination with an E/P regimen did not 


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result in additive efficacy, nor did it antagonize the intended effects of E/P. Combination of 
trilaciclib and topotecan was superior to topotecan alone during dosing and the addition of 
trilaciclib extended the statistically significant (p < 0.05) antitumor effect of topotecan after 
dosing. Thus, trilaciclib was well tolerated and did not antagonize the effects of 
chemotherapy in a CDK4/6-independent (RB-1 inactive) SCLC tumor model.  
Atezolizumab 
A summary of the pharmacology studies of atezolizumab is provided in the prescribing 
information (Appendix 2). 
4.4.2. 
Pharmacokinetic Studies 
Trilaciclib 
 
Pharmacokinetic (PK) studies in rats and dogs showed that the relationship between dose 
level and plasma exposure to trilaciclib was generally similar between males and females and 
did not change with repeated daily dosing. Exposure to trilaciclib increased with dose level, 
but not always proportionally. Plasma half-life values for trilaciclib after IV administration 
were approximately 4 hours in rats and dogs. 
In vitro analyses of direct and time-dependent inhibition suggest that drug interactions based 
on inhibition of cytochrome P40 (CYP)1A2-, 2B6-, 2C8-, 2C9-, 2C19-, and 2D6-mediated 
metabolic pathways are unlikely at concentrations of trilaciclib below 100 µM 
(44,600 ng/ml). Drug interactions based on trilaciclib mechanism-based inhibition of 
CYP3A4-mediated metabolic pathways are possible. Additionally, in vitro induction studies 
of the 3 major inducible CYP enzymes (CYP1A2, CYP3A4, and CYP2B6) in human 
hepatocytes suggest that trilaciclib -mediated induction is unlikely.   
While etoposide is a CYP3A4 substrate, there are no specific label warnings regarding 
coadministration with CYP3A4 inhibitors. This may in part be due to the relatively equal 
contributions of renal and hepatic clearance to the total clearance of etoposide. In addition, 
administration of oral ketoconazole, a potent CYP3A4 and uridine disphosphate 
glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) inhibitor, with oral etoposide 
for 3 of every 5-week cycles resulted in an increase of the median AUC of oral etoposide of 
only 20% and did not alter its toxicity profile (Yong 2007). In the present Study G1T28-05, 
IV trilaciclib will be administered prior to IV etoposide on Days 1 to 3 of 21-day cycles in 
patients with adequate renal function. In the Phase 1b dose-finding portion of Part 1 of the 
G1T28-02 study in patients with newly diagnosed SCLC, where the same doses of etoposide 
of carboplatin were used as in this study, PK of etoposide, carboplatin, and trilaciclib were 
assessed on Days 1 and 3 of the first cycle. The PK of etoposide and carboplatin was 
consistent with historical data, indicating the lack of a drug-drug interaction between 
trilaciclib and etoposide or carboplatin.  
In vitro inhibition studies with membrane transporter model systems also suggest trilaciclib is 
unlikely to cause a drug-drug interaction (DDI) based on inhibition of breast cancer 
resistance protein (BCRP)-, bile salt export pump (BSEP)-, organic anion transporter 
1 (OAT1)-, organic anion transporter 3 (OAT3)-, organic anion transporting polypeptide 1B1 


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(OATP1B1)-, p-glycoprotein (MDR1)-, multidrug resistance protein 1 (MRP1)-, multidrug 
resistance protein 2 (MRP2)-, organic cation transporter 1 (OCT1)-, or organic anion 
transporting polypeptide 1B3 (OATP1B3)-mediated transport. Trilaciclib is a potent inhibitor 
of multidrug and toxin extrusion 1 (MATE1), multidrug and toxin extrusion 2-K 
(MATE2-K), and organic cation transporter 2 (OCT2) (IC50 values were 0.175, 0.071, and 
0.152 µM, respectively), and therefore, may be a cause of a DDI if coadministered with 
substrates of these transporters.      
Carboplatin has been reported (Yonezawa 2006) to not be a substrate for OCT2, MATE1, or 
MATE2. Etoposide has not been reported to be a substrate for any of these 3 transporters, 
and by structure is not expected to be a substrate. Based upon these data, a clinically 
significant alteration of carboplatin or etoposide PK due to trilaciclib inhibition of OCT2, 
MATE1, or MATE2-K is not expected, and none was detected in the G1T28-02 study in 
patients with newly diagnosed SCLC. 
Atezolizumab 
A summary of the PK studies of atezolizumab is provided in the prescribing information 
(Appendix 2).   
4.4.3. 
Toxicity and Safety Studies 
Trilaciclib 
 
The toxicity of IV and oral trilaciclib was evaluated in single- and repeat-dose studies of up 
to 14 days duration in rats and dogs and in a battery of in vitro genotoxicity studies. In 
addition, the compatibility of trilaciclib clinical drug product with human blood was 
evaluated in vitro. 
For further information, please refer to the trilaciclib IB. 
Atezolizumab 
A summary of the toxicity and safety studies of atezolizumab is provided in the Guidance to 
the Investigator (Appendix 1) and prescribing information (Appendix 2).   
4.4.4. 
Potential Risks 
4.4.4.1. 
Trilaciclib 
 
When administered IV daily for 7 days, trilaciclib was tolerated in rats at up to 50 mg/kg 
(approximately 300 mg/m2) and in dogs at up to 15 mg/kg (approximately 300 mg/m2), with 
toxicity characterized chiefly by reduced hematopoiesis that involved all cell lineages and 
was a reflection of the drug’s intended pharmacodynamic activity. The magnitude and/or 
duration of effect differed among cell lineages, but were dose related in all lineages. Effects 
on hematopoiesis were readily monitored by peripheral blood cell counts and were reversible 
when dosing stopped. Clinically significant leukopenia occurred in rats and dogs given IV 


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trilaciclib for 7 days at ≥ 150 and 300 mg/m2, respectively, and it led to morbidity and 
mortality in dogs given daily doses for 6 days at 900 mg/m2. 
In addition to the intended effects on hematopoiesis, animal studies with trilaciclib suggest 
that potential side effects in human patients might include the following: 
• Pulmonary macrophage accumulation: In rats, daily oral doses of trilaciclib for 14 days at 
≥ 5 mg/kg (≥ 30 mg/m2) resulted in minimal to mild accumulation of foamy macrophages 
in alveoli. The magnitude of this finding increased with dose level, but it was not 
associated with any discernable change in the rate or character of respiration. 
Macrophage accumulation showed evidence of resolving within 3 weeks after dosing 
stopped. Pulmonary macrophage accumulation was also seen in dogs given daily IV 
doses of trilaciclib by 30-minute infusion at 45 mg/kg (900 mg/m2) for 5 days, at which 
point dosing was stopped due to toxicity. The DLT in these dogs was considered to be 
severe immunocompromise secondary to inhibition of myelopoiesis and lymphopoiesis; 
ie, an extension of the primary pharmacodynamic activity of trilaciclib. 
• Increased heart rate: In dogs, single IV doses of trilaciclib at ≥ 15 mg/kg (≥ 300 mg/m2) 
produced increases in heart rate that were relatively mild (30 to 60 beats per minute 
[bpm]) and resolved within a few hours. 
• Effects on liver: Daily IV doses of trilaciclib in rats at ≥ 10 mg/kg/day (≥ 60 mg/m2/day) 
and in dogs at ≥ 15 mg/kg/day (approximately 300 mg/m2/day) resulted in slightly 
increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
levels. Liver-related effects in both species were reversible within 2 weeks after the last 
dose. There were no effects on liver in rats given daily oral doses for 14 days at up to 
30 mg/kg (180 mg/m2). 
• Local irritation at the infusion site: Dogs given daily doses of trilaciclib for 7 days had 
occasional episodes of swelling/edema at the infusion site. This was considered likely to 
be due to leakage or accidental injection of dosing solution into the perivenous tissue. 
The profile of TEAEs reported in the trilaciclib clinical development program are consistent 
with the underlying patient population with SCLC undergoing chemotherapy. There are no 
consistent patterns of TEAEs that can be considered attributable to trilaciclib. In addition, 
there have been no new risks identified and the preclinical risks have not been linked to 
clinical observations.    
4.4.4.2. 
Atezolizumab 
Per Section 5, Warnings and Precautions in the prescribing information for atezolizumab 
(Appendix 2), the important identified risks for atezolizumab are described in Table 4-1. A 
summary of potential risks for atezolizumab is provided in the Atezolizumab Guidance for 
the Investigator (Section 1.4, Appendix 1), the prescribing information (Appendix 2), and in 
Table 4-2. A list of AESI identified for atezolizumab is provided in Appendix 3. Please refer 
to the Atezolizumab Guidance for the Investigator (Appendix 1) and the full atezolizumab 
prescribing information (Appendix 2) for important dose management information specific to 
adverse reactions. 


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Table 4-1 
Important Identified Risks for Atezolizumab 
Identified Risk 
Description of Risk 
Immune-related pneumonitis 
Pneumonitis occurred in 3.1% (68/2160) of patients who received 
atezolizumab. The majority of patients experienced only mild to 
moderate events. Of the 68 patients, 64% (36/56) of the All 
NSCLC group and 75% (9/12) of the All UC group experienced 
events with a maximum severity of Grade 1 or 2. One event was 
fatal in the All NSCLC group (considered unrelated to 
atezolizumab), and no events were fatal in the All UC group. The 
median time to onset was 3.5 months (range: 3 days to 
20.5 months). The median duration was 1.5 months (range: 0 days 
to 15.1 + months; + denotes a censored value). Pneumonitis led to 
discontinuation of atezolizumab in 10 (0.5%) patients. 
Pneumonitis requiring the use of corticosteroids occurred in 1.6% 
(34/2160) of patients receiving atezolizumab. As expected, 
pneumonitis events occurred more frequently in the NSCLC 
patient population, most likely due to higher baseline incidence, 
higher prevalence of other risk factors, and atezolizumab-induced 
immunologic response to the tumor. 
Immune-related hepatitis 
Cases of hepatitis, some leading to fatal outcomes, have been 
observed in clinical trials with atezolizumab. Most of the hepatic 
events identified were non-serious elevations of liver enzymes. 
Hepatitis occurred in 0.3% (7/2160) of patients who received 
atezolizumab. The median time to onset was 1.1 months (range: 
9 days to 7.9 months). The median duration was 1 month (range: 9 
days to 1.9+ months; + denotes a censored value). Hepatitis led to 
discontinuation of atezolizumab in 2 (< 0.1%) patients. Hepatitis 
requiring the use of corticosteroids occurred in 0.2% (5/2160) of 
patients receiving atezolizumab. All of these events resolved with 
the exception of 1 case of Grade 1 hepatitis, which was resolving 
at the time of data cutoff. Additionally, 1 patient (< 0.1%) 
experienced hepatic failure (with fatal outcome, considered 
unrelated to study therapy). 
Immune-related colitis 
Cases of diarrhea or colitis have been observed in clinical trials 
with atezolizumab. Colitis occurred in 1.1% (23/2160) of patients 
who received atezolizumab. The median time to onset was 
4 months (range: 15 days to 15.2 months). The median duration 
was 1.4 months (range: 3 days to 17.8+ months; + denotes a 
censored value). Colitis led to the discontinuation of atezolizumab 
in 5 (0.2%) patients. Colitis requiring the use of corticosteroids 
occurred in 0.5% (10/2160) of patients receiving atezolizumab. 
Immune-related pancreatitis 
Pancreatitis and elevations in serum amylase and lipase occurred 
in 0.5% (10/2160) of patients who received atezolizumab. Most 
events identified were non-serious elevations in lipase or amylase. 
A total of 4 (0.2%) patients experienced pancreatitis, including 
1 patient with acute pancreatitis.  The median time to onset was 
5.5 months (range: 9 days to 16.9 months). The median duration 
was 19 days (range: 3 days to 11.2+ months; + denotes a censored 
value). Pancreatitis requiring the use of corticosteroids occurred in 
< 0.1% (2/2160) of patients receiving atezolizumab. 


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Immune-related diabetes mellitus 
Diabetes mellitus occurred in 0.3% (7/2160) of patients who 
received atezolizumab (4 reports of diabetes mellitus, 2 reports of 
type 1 diabetes mellitus and 1 report of type 2 diabetes mellitus). 
Of these 7 patients, 2 developed serious events and 5 developed 
events that were considered non-serious. Two cases resolved, 
1 case resolved with sequelae, and 4 were not resolved by the time 
of the clinical cutoff. The time to onset ranged from 3 days to 6.5 
months. Diabetes mellitus led to the discontinuation of 
atezolizumab in 1 (< 0.1%) patient. 
Immune-related hypothyroidism 
Hypothyroidism occurred in 4.7% (101/2160) of patients who 
received atezolizumab. The median time to onset was 5.5 months 
(range: 15 days to 31.3 months). Events have generally been mild, 
and patients who received treatment with thyroid replacement 
were able to continue on study treatment. A total of 19 patients 
experienced adverse events that appear in both the hypothyroidism 
and hyperthyroidism standardised MedDRA queries (SMQs). 
These 19 patients are therefore duplicated in the data presented on 
hypothyroidism and hyperthyroidism. The vast majority of the 
duplicated patients were reported to have experienced blood 
thyroid stimulating hormone increased. Because primary 
hypothyroidism is more prevalent than hyperthyroidism in patients 
treated with both atezolizumab and other drugs in this class, it is 
probable that the majority of patients that appear in both searches 
actually developed hypothyroidism. 
Immune-related hyperthyroidism 
Hyperthyroidism occurred in 1.7% (36/2160) of patients who 
received atezolizumab. The median time to onset was 3.5 months 
(range: 21 days to 31.3 months). No severe events were identified. 
Please see immune-related hypothyroidism above for patients 
duplicated in the data presented on hypothyroidism and 
hyperthyroidism. 
Immune-related adrenal insufficiency 
Adrenal insufficiency occurred in 0.3% (7/2160) of patients who 
received atezolizumab. The median time to onset was 5.7 months 
(range: 3 days to 19 months). Adrenal insufficiency requiring the 
use of corticosteroids occurred in 0.3% (6/2160) of patients 
receiving atezolizumab. 
Immune-related hypophysitis 
Hypophysitis occurred in < 0.1% (1/2160) of patients who 
received atezolizumab. The time to onset for this patient was 
13.7 months. 
Immune-related Guillain-Barré 
syndrome 
Guillain-Barré syndrome and demyelinating polyneuropathy 
occurred in 0.2% (5/2160) of patients who received atezolizumab. 
The median time to onset was 7 months (range: 18 days to 
8.1 months). The median duration was 4.6 months (0+ day to 8.3+ 
months). Guillain-Barré syndrome led to discontinuation of 
atezolizumab in 1 patient (< 0.1%). Guillain-Barré syndrome 
requiring the use of corticosteroids occurred in < 0.1% (2/2160) of 
patients receiving atezolizumab 
Immune-related myasthenic 
syndrome/myasthenia gravis 
Myasthenic syndrome/myasthenia gravis, which may be life 
threatening, were observed in patients receiving atezolizumab. 
Patients should be monitored for symptoms of motor and sensory 
neuropathy. Four cases of myasthenia gravis or myasthenic 


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syndrome have been reported from across the entire development 
program as of 07 July 2016. The first case concerned a 64-year-
old male patient receiving atezolizumab monotherapy for renal 
cell carcinoma (RCC) in the Study PCD4989g (GO27831). The 
patient was positive for acetylcholine receptor binding antibodies 
and acetylcholine receptor modulating antibodies. The event was 
considered serious, and the patient was treated with corticosteroids 
and discontinued from the study. A second case of myasthenia 
gravis was received concerning a 64-year-old male patient 
receiving atezolizumab in combination with ipilimumab in Study 
GO29322. The event was considered serious, and the patient was 
treated with corticosteroids and mycophenolate and discontinued 
from the study. The third case concerned a 56-year-old male who 
developed bilateral ptosis while receiving atezolizumab 
monotherapy for urothelial bladder cancer in the expanded access 
program ML29725. The patient was positive for acetylcholine 
receptor antibodies, acetylcholine receptor modulating antibodies 
and striated muscles antibodies and was diagnosed with 
myasthenia gravis. The event was considered serious and the 
patient was treated with corticosteroids and discontinued from 
atezolizumab. The fourth case concerned a 67-year-old female 
patient receiving atezolizumab in combination with cobimetinib in 
Study GP28363. The patient developed ptosis, an acetylcholine 
receptor antibody test was negative and the results of the nerve 
conduction studies were normal. The patient was diagnosed with 
myasthenia gravis and treated with pyridostigmine, and 
atezolizumab and cobimetinib were discontinued. 
Immune-related meningoencephalitis 
Meningitis occurred in 0.1% (3/2160) of patients who received 
atezolizumab. The time to onset ranged from 15 to 16 days. All 
3 patients required the use of corticosteroids and discontinued 
atezolizumab. Encephalitis occurred in < 0.1% (2/2160) of 
patients. The time to onset was 14 and 16 days. Encephalitis led to 
discontinuation of atezolizumab in 1 (< 0.1%) patient. 
Encephalitis requiring the use of corticosteroids occurred in 
< 0.1% (1/2160) of patients receiving atezolizumab 
Immune-related myocarditis 
Although no cases were identified from the pooled 2160 patients 
who received single agent atezolizumab, 2 cases of myocarditis, 
including a life-threatening case, have been reported from across 
the entire development program as of 20 February 2017. The time 
to onset ranged from 18 to 33 days. The first case concerned a 
59-year-old female patient with follicular lymphoma receiving 
atezolizumab in combination with bendamustine and 
obinutuzumab in Study BO29563. Her cardiac biopsy revealed 
T-cell infiltration. The second case concerned a 69-year-old male 
patient with RCC receiving atezolizumab in combination with 
bevacizumab in Study WO29637. He developed clinical 
sign/symptoms including chest pressure, and positive diagnostic 
test results including abnormal electrocardiogram (ECG) and 
increased cardiac enzymes. Both patients discontinued 
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Immune-related nephritis 
Immune-related nephritis is a relatively rare complication of 
checkpoint inhibitor therapy with the most common reported 
underlying pathology being acute tubulo-interstitial nephritis 
(ATIN). The most common presentation is an asymptomatic 
increase in creatinine levels. In the absence of alternative 
etiologies (eg, prerenal and postrenal causes, and concomitant 
medications), immune-related nephritis is defined as renal 
dysfunction requiring steroids treatment and/or confirmed by 
biopsy 
Infusion-related reactions 
Infusion-related reactions are known to occur with the 
administration of monoclonal antibodies. The signs and symptoms 
of infusion-related reactions share considerable overlap with 
several very common atezolizumab adverse drug reactions 
(ADRs) including influenza-like illness, pyrexia, and rash. The 
identified reactions occurred within 24 hours of atezolizumab 
administration and were generally mild to moderate in severity, 
and only 10 patients (0.5%) out of the 2160 pooled UC and 
NSCLC patients developed SAEs. Twenty-four (1.1%) of 
2160 patients were reported to have experienced the event of 
infusion reaction (with 2 serious events). Across all 2160 patients, 
16 patients (0.7%) were reported to have hypersensitivity (with 
4 serious events), and none were reported to have experienced 
anaphylactic or anaphylactoid reactions. 
Notes: The cutoff dates for the following studies are 31 March 2016 for Study PCD4989g, 07 January 2015 for FIR, 
01 December 2015 for POPLAR, 01 December 2015 for BIRCH, 07 July 2016 for OAK, and 04 July 2016 for 
IMvigor 210. 
 
Table 4-2 
Potential Risks for Atezolizumab 
Potential Risk 
Description of Risk 
Anti-drug antibodies (ADA) 
Cynomolgus Monkey Studies: After a single intravenous (IV) 
administration of atezolizumab to cynomolgus monkeys, antidrug 
antibodies (ADAs) were detected in 12 of 12 animals (100%) at 
Day 14; 11 of 12 animals remained ADA positive after Day 14 
until the end of the study. Fifty of 56 animals (89%) given 
atezolizumab tested positive for ADA following 9 weekly doses. 
While ADAs affected the pharmacokinetics of some animals, 
average exposure for ADA -positive and ADA-negative animals 
was similar. 
Clinical Studies: ADAs have been observed in the clinical trials 
to date for atezolizumab; however, at doses of 10 mg/kg and 
above, they do not appear to affect exposure. The incidence of 
serious adverse events (SAEs) was increased in ADA-positive 
patients (40.5%) compared with ADA-negative patients (34%), 
but no specific trend in either MedDRA system organ class (SOC) 
or individual adverse event preferred term (PT) was identified in 
ADA-positive patients. In all safety-evaluable patients with 
available post-treatment ADA status (n = 2007), the incidence of 
hypersensitivity events and infusion-related reactions was low and 
numerically higher in ADA- positive than ADA-negative patients. 
Hypersensitivity events were reported in 24 patients (1.2%): 


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9 ADA-negative (0.7%) and 15 ADA- positive (1.9%) patients. 
Infusion-related reactions occurred in 25 patients (1.2%): 
14 ADA-negative (1.1%) and 11 ADA-positive (1.4%) patients. 
The incidences of all grade AEs, Grade 5 AEs, AEs leading to 
treatment discontinuation, AEs leading to dose interruption, and 
adverse events of special interest (AESIs) were similar 
irrespective of post-baseline ADA status (negative or positive). 
Numerical differences were observed in Grade 3/4 AEs (40.7% in 
ADA-negative vs. 47.0% in ADA-positive patients), but no 
individual PT could be identified to explain this difference. 
Embryofetal toxicity 
Several nonclinical studies have demonstrated that the PD-L1/ 
PD-1 signaling pathway is critical in establishing and maintaining 
maternal/fetal tolerance, which is essential for embryo-fetal 
survival during gestation (Guleria et al. 2005; Habicht et al. 2007; 
D’Addio et al. 2011). Inhibition of the PD-L1/PD-1 pathway has 
not been reported to result in teratogenic effects, and syngeneic 
homozygous knockout fetuses (PD-L1 or PD-1 knockouts) 
develop normally and have not shown skeletal or visceral defects. 
Administration of atezolizumab is expected to have an adverse 
effect on pregnancy via modulation of maternal/fetal tolerance, 
and poses a risk to the human fetus, including embryo-lethality via 
an increased risk of immune- mediated rejection. 
No reproductive or teratogenicity studies in animals have been 
conducted with atezolizumab. There are no clinical studies of 
atezolizumab in pregnant women. Atezolizumab is not 
recommended during pregnancy unless the potential benefit for 
the mother outweighs the potential risk to the fetus. 
Immune-related myositis 
Immune-related myositis occurred in 0.2% (4/2160) of metastatic 
urothelial carcinoma (mUC) and NSCLC patients who received 
single-agent atezolizumab. Patients may experience weakness, 
tenderness and aching of the muscles. Four cases containing 7 
events were identified, including 3 cases of polymyalgia 
rheumatica from studies IMvigor 210, FIR and OAK, and 1 case 
of dermatomyositis from BIRCH. Atezolizumab treatment was not 
changed for all polymyalgia rheumatica events and was 
interrupted for the dermatomyositis events. The dermatomyositis 
events had features consistent with cancer associated myositis, and 
there was insufficient evidence to support the attribution of a 
causal relationship between myositis and atezolizumab. Myositis 
is an ADR for other immune checkpoint inhibitors. Myositis 
remains a potential risk for atezolizumab and will continue to be 
monitored by routine pharmacovigilance 
Immune-related ocular inflammatory 
toxicity 
Ocular inflammatory toxicity events occurred in 0.5% (10/2160) 
of mUC and NSCLC patients who received single-agent 
atezolizumab. Most of the ocular events identified were 
nonserious, with Grade 1 or 2 in severity. Four events were 
considered relate to atezolizumab and led to treatment 
discontinuation, including 1 serious retinopathy, 1 serious optic 
neuritis, 1 nonserious optic neuritis, all from Study OAK, and 
1 nonserious episcleritis from Study BIRCH. However, these 
cases either had clear alternate explanations, including cataract 


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surgery prior to event, lung cancer paraneoplastic related 
neuropathy, previous brain radiotherapy or had very limited 
information reported for assessment. Two cases of uveitis, from 
Study FIR and OAK, were both considered not related to study 
treatment. Based on the totality of the data to date, the evidence 
does not support a definitive causal association between 
Atezolizumab and ocular inflammatory toxicity. Based on the 
totality of the data to date, the evidence does not support a 
definitive causal association between atezolizumab and ocular 
inflammatory toxicity. 
The etiology of uveitis or optic neuritis may include 
autoimmunity, demyelinating disorders, inflammation, infections, 
drug or toxic reasons, trauma, or the underlying malignancy (Guly 
and Forrester 2010, Kale 2016). Immune-related ocular 
inflammatory toxicity is considered an important risk for 
atezolizumab, and it will continue to be monitored by routine 
pharmacovigilance. 
Immune-related severe cutaneous 
reactions 
Severe cutaneous adverse reactions occurred in 0.6% (13/2160) of 
mUC and NSCLC patients who received single-agent 
atezolizumab.  Most of the cutaneous events identified were 
nonserious; however, 1 patient (< 0.1%) experienced a serious 
case of bullous dermatitis from Study OAK that resolved 
following treatment with corticosteroids. Across the clinical 
development program, isolated severe skin toxicities including 
lichenoid drug reaction, pemphigoid, Stevens-Johnson syndrome 
(localized to the eye) and toxic epidermal necrolysis have been 
reported; however, causality to atezolizumab could not be 
confirmed. Severe cutaneous adverse reactions have been 
observed in patients treated with other immune checkpoint 
inhibitors and are an important potential risk for atezolizumab. It 
will continue to be monitored by routine pharmacovigilance. 
Immune-related vasculitis 
Nonclinical studies demonstrated dose-dependent evidence of 
arteritis/periarteritis in cynomolgus monkeys treated with 
atezolizumab. Vasculitis occurred in 0.2% (5/2160) of mUC and 
NSCLC patients who received single-agent atezolizumab. One 
serious event of Henoch-Schonlein purpura nephritis was reported 
that is also represented in the information for immune-related 
nephritis due to the overlap in PTs in the search strategies. Three 
cases of polymyalgia rheumatica from studies IMvigor 210, FIR 
and OAK were reported and are described in the information for 
immune-related myositis, due to similar overlapped terms in the 
search strategies. One case of nonserious injection site vasculitis 
was reported from Study BIRCH. Currently, no causal relationship 
with atezolizumab has been established. Immune-related vasculitis 
is considered an important potential risk of atezolizumab and it 
will continue to be monitored by routine pharmacovigilance 


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Description of Risk 
Autoimmune hemolytic anemia 
Autoimmune hemolytic anemia event is a rare condition and a 
known ADR for products similar in class (rare to uncommon 0.1% 
to ≤ 1%). An analysis was done of the Roche global safety 
database with a cut-off date 05 January 2017, which identified 
5 patients with evidence of autoimmune hemolytic anemia 
reported in atezolizumab-treated patients. All cases had possible 
alternate etiologies including concomitant medications, suspected 
infection, and concurrent therapy with an additional 
immunomodulating agent. Autoimmune hemolytic anemia is 
considered an important potential risk of atezolizumab and it will 
continue to be monitored by routine pharmacovigilance. 
Clinical cutoff dates: GO27831: 31 March 2016, GO28625: 07 January 2015, GO28753: 01 December 2015, GO28754: 
01 December 2015, GO29293: 04 July 2016, GO28915: 07 July 2016. 
ADA status cutoff dates: GO27831: 02 December 2014, GO28625: 07 January 2015, GO28753: 08 May 2015, 
GO28754: 28 May 2015, GO29293: 04 July 2016, GO28915: 07 July 2016 
 
Other AESI that are being monitored for atezolizumab include immune-related myositis, 
immune-related nephritis, immune-related uveitis, immune-related myopathies, and 
rhabdomyolysis. A list of AESI identified for atezolizumab is provided in Appendix 3. 
Other safety events of interest that are currently being monitored in the atezolizumab clinical 
program include the following: immune-related myopathies, including rhabdomyolysis.  
Reports of myopathies, including rhabdomyolysis, have been observed across the clinical 
development program of atezolizumab. Patients who present with signs or symptoms of 
muscular pain should be assessed for inflammatory causes of muscle pain. Management of 
these patients should be along institutional guidelines. 
4.5. 
Study and Dose Rationale 
In a Phase 1a, safety, PK, and pharmacodynamic study of trilaciclib (Study G1T28-1-01),   
45 healthy male and female subjects were enrolled into 7 dose cohorts where trilaciclib 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). Trilaciclib was well tolerated, with no DLTs or 
SAEs reported. Pharmacodynamic analysis 24 hours following administration of trilaciclib 
192 mg/m2 demonstrated a significant decrease 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 trilaciclib 200 mg/m2 (rounded up from the BED of 
192 mg/m2) was selected as the starting dose for the subsequent Phase 1b/2a SCLC studies 
(G1T28-02 [administered prior to etoposide and carboplatin] and G1T28-03 [administered 
prior to topotecan]). Based on the Phase 1b results from these 2 studies, trilaciclib 240 mg/m2 
was chosen as the recommended Phase 2 dose. In the G1T28-02 study, there was no impact 
of trilaciclib on etoposide or carboplatin PK. Based on the PK and safety from the G1T28-02 
study, the lack of predicted drug-drug interactions and nonoverlapping toxicities between 
atezolizumab and trilaciclib, etoposide, and carboplatin, the evaluation of this 4-drug 
combination is reasonable. The goals of the present study are to assess the safety, tolerability, 
and efficacy of combining trilaciclib 240 mg/m2 with E/P/A therapy.   


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4.6. 
Risk/Benefit Assessment 
Trilaciclib is being developed to reduce chemotherapy-induced myelosuppression, which is a 
significant issue. Nonclinical data demonstrate that trilaciclib administration with 
chemotherapy preserves bone marrow and immune system function from damage by 
chemotherapy. In addition, preliminary clinical data suggest that lymphocyte numbers are 
relatively unchanged when trilaciclib is used in combination with chemotherapy. Preserving 
adaptive immunity with trilaciclib may enhance the efficacy of chemotherapy combined with 
immune checkpoint inhibitors, supporting clinical testing of the novel combination of E/P/A 
therapy and trilaciclib.  
Given the paucity of hematologic toxicities associated with atezolizumab (Section 6.1 of the 
atezolizumab package insert), the addition of atezolizumab to E/P chemotherapy is not 
predicted to influence the underlying myelosuppression profile of E/P. Multiple studies of 
chemotherapy administered in combination with checkpoint inhibitors suggest that the 
addition of a checkpoint inhibitor to a myelosuppressive chemotherapy backbone, does not 
result in any new safety signals and does not result in a clinically relevant exacerbation of the 
chemotherapy-induced myelosuppression (Ghandi 2018; Langer 2016; Rizvi 2016; 
Jotte 2018). Therefore, the potential myelopreservation benefit from the addition of trilaciclib 
to E/P can be evaluated in a setting that also includes atezolizumab. 
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 4.5, the BED of IV trilaciclib is 192 mg/m2 and 
a dose of 200 mg/m2 was used as the initial starting dose for administration on Days 1 to 3 of 
every 21-day cycle in the G1T28-02 study.  However, based on clinical data from G1T28-02 
and G1T28-03, the recommended Phase 2 dose of trilaciclib is 240 mg/m2. Therefore, 
trilaciclib 240 mg/m2 administered on Days 1 to 3 of every 21-day cycle of E/P/A therapy 
will be used in the present study.  
In conclusion, the possible benefits of combining trilaciclib at a dose of 240 mg/m2 with 
E/P/A therapy to preserve bone marrow and immune system function from damage by 
chemotherapy and potentially increase the activity of the E/P/A combination regimen 
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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design and Plan 
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 2 study of the 
efficacy and safety of E/P/A with trilaciclib or placebo therapy for patients with newly 
diagnosed extensive-stage SCLC. Approximately 100 patients will be randomly assigned 
(1:1 fashion) to trilaciclib 240 mg/m2 or placebo administered IV on Days 1 to 3 with E/P/A 
therapy for up to four 21-day cycles (induction part) (Figure 6-1). Randomization will be 
stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 to 1 versus 
2) and presence of brain metastases (yes versus no). Following the completion of up to 
4 chemotherapy-containing (trilaciclib or placebo + E/P/A) cycles, patients will proceed to 
the maintenance part of the study and receive atezolizumab every 21 days. Study drug refers 
to trilaciclib or placebo + E/P/A during the induction part and atezolizumab during the 
maintenance part. Treatment in both parts will continue until disease progression, 
unacceptable toxicity, withdrawal of consent, or discontinuation by investigator. Following 
disease progression per RECIST v1.1, if the patient appears to be deriving clinical benefit, 
the investigator believes it is in the best interest of the patient, and the patient has provided 
re-consent, study drug administration may be continued until loss of clinical benefit. The 
study includes 3 phases: Screening Phase, Treatment Phase (induction part + maintenance 
part), and Survival Follow-up Phase. The Treatment Phase begins on the day of first dose 
with study treatment and completes after the last Post Treatment Visit.   


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Figure 6-1 
Study Schema 
 
CR = complete response; E/P/A = etoposide, carboplatin, and atezolizumab; irRECIST = immune-related RECIST; 
PR = partial response; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1; SD = stable disease 
a  
Randomization will be stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 to 1 versus 2) 
and presence of brain metastases (yes versus no). 
b 
During the induction part of the study, trilaciclib or placebo + E/P/A therapy will continue for up to four 21-day cycles 
or until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator. Tumors should be 
assessed after every even cycle (ie, approximately every 6 weeks) using RECIST, Version 1.1. Following disease 
progression per RECIST v1.1, if the patient appears to be deriving clinical benefit, the investigator believes it is in the 
best interest of the patient, and the patient has provided re-consent, study drug administration may be continued until 
loss of clinical benefit (see Section 11.1.4). Assessments should be performed within 7 days of starting the subsequent 
cycle. 
c 
Following induction, patients will proceed to the maintenance part of the study and receive atezolizumab every 21 days 
until disease progression per RECIST, Version 1.1, unacceptable toxicity, or discontinuation by the patient or 
investigator. Tumors should be assessed after every even cycle for the first 9 months of the study (ie, approximately 
every 6 weeks) and after every third cycle (ie, approximately every 9 weeks) thereafter while receiving study drug. 
Following disease progression per RECIST v1.1, if the patient appears to be deriving clinical benefit, the investigator 
believes it is in the best interest of the patient, and the patient has provided re-consent, study drug administration may 
be continued until loss of clinical benefit (see Section 11.1.4). 
d 
All patients will return to the study center for post-treatment visits at 30 (+ 3) and 90 (+7) days after the last dose of 
study drug. 
e 
The Survival Follow-up Phase will continue until at least 70% of the patients randomized in the study have died. 
 
 
The initial diagnosis of SCLC should be made based on standard pathological examination, 
preferably including immunohistochemical staining for neuroendocrine features. Archived 
tumor samples should be available for banking for assessment of relevant DNA, ribonucleic 
acid (RNA), and protein markers, such as PD-L1 or those involved in the CDK4/6 pathway. 
Tumor samples may be banked for up to 10 years. 
6.1.1. 
Criteria for Subsequent Cycles and Study Duration 
Study drug administration will continue for up to 4 chemotherapy-containing (trilaciclib or 
placebo + E/P/A) cycles during the induction part of the study and atezolizumab will be 
administered every 21 days during the maintenance part of the study. Study drug 
administration will continue until disease progression per Response Evaluation Criteria in 
Solid Tumors, Version 1.1 (RECIST v1.1), unacceptable toxicity, withdrawal of consent, or 
discontinuation by investigator, whichever occurs first. However, if the patient appears to be 
deriving clinical benefit, the investigator believes it is in the best interest of the patient, and 
the patient has provided re-consent, study drug administration may be continued until loss of 




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The Survival Follow-up Phase will continue until at least 70% of the randomized patients 
have died. 
6.1.2. 
Safety Assessments 
Safety assessments will include monitoring of AEs (including SAEs, irAEs and AESI), vital 
signs measurements, physical examinations, ECGs, performance status, clinical laboratory 
studies, and IRRs as described in Section 11.4. Safety surveillance reporting of AEs 
commences at the time of informed consent. AEs will be collected through 30 days after the 
last dose of study drug; SAEs and AESI will be collected through 90 days after the last dose 
of study drug. 
6.1.3. 
Data Monitoring Committee 
An independent data monitoring committee (DMC) will monitor accumulating safety and 
disposition data after approximately 12 patients have been enrolled and have completed at 
least 1 cycle to assess the initial safety data from the 2 groups, and then approximately every 
4 months during the Treatment Phase of the study, depending upon the enrollment rate. 
Details of the DMC, including objectives, composition, scope, and frequency, will be 
described in a DMC charter. 
6.1.4. 
Tumor Assessment 
Tumor assessments using radiologic imaging will be performed after every even cycle (ie, 
approximately every 6 weeks) for the first 9 months of the study and after every third cycle 
(ie, approximately every 9 weeks) thereafter while receiving study drug. Tumor assessments 
will include tumor response based on RECIST v1.1 and irRECIST. For tumor assessment, all 
sites of disease should be assessed radiologically by computed tomography (CT) or magnetic 
resonance imaging (MRI) at screening and every scheduled tumor assessment until the 
occurrence of disease progression. CT or MRI scans obtained as standard of care prior to 
informed consent will not need to be repeated if performed within 14 days prior to dosing. 
Brain scans performed as standard of care 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 prior to starting the subsequent cycle. Additional scans may be obtained at the 
discretion of the investigator, if clinically indicated. If a patient shows a radiological 
response (CR or PR), a confirmatory radiological assessment will be performed at least 
4 weeks after the response was first noted. For patients who have a confirmed CR, it is 
strongly recommended that they receive prophylactic cranial irradiation (PCI) after 
completion of chemotherapy (ie, induction). Patients with a confirmed PR should also 
consider PCI after completion of chemotherapy (ie, induction) based on the investigator’s 
judgment (see Section 8.8). Following the completion of the induction part, PCI may be 
administered concurrently with atezolizumab during the maintenance part. For those patients 
who have not progressed at the time of study drug discontinuation, tumor assessments to 
include all sites of disease, will be assessed radiologically by CT or MRI, as performed at 
screening, every 2 months (approximately 60 ± 7 days) until the occurrence of progressive 
disease or study completion. The same method of assessment (CT or MRI) should be used to 
characterize tumors at screening and at all follow-up assessments. If positron emission 


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tomography (PET) is used, it should also be accompanied by spiral CT or MRI. Tumor 
assessment is further described in Section 11.1. 


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7. 
STUDY POPULATION  
7.1. 
Selection of Patients 
Overall, approximately 100 patients will be randomly assigned (1:1 ratio) to 1 of 2 groups as 
follows: trilaciclib administered IV with E/P/A therapy followed by atezolizumab 
maintenance (Group 1) or placebo administered IV with E/P/A therapy followed by 
atezolizumab maintenance (Group 2). 
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. Extensive-stage SCLC 
4. At least 1 target lesion that is measurable by RECIST v1.1 (Eisenhauer 2009) 
5. Hemoglobin ≥ 9.0 g/dL 
6. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
7. Platelet count ≥ 100 × 109/L 
8. Creatinine ≤ 1.5 mg/dL or glomerular filtration rate (GFR) of ≥ 60 mL/minute 
9. Total bilirubin ≤ 1.5 × ULN; < 3 × ULN if the patient has documented Gilbert’s disease 
10. AST and ALT ≤ 2.5 × ULN; ≤ 5 × ULN in the presence of liver metastases 
11. ECOG performance status of 0 to 2 
12. Predicted life expectancy of ≥ 3 months 
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. Females 
must be either postmenopausal, surgically sterile, or agree to use 2 forms of 
highly effective contraception during the study and for 6 months following 
discontinuation of study treatment  


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i. 
Postmenopausal is defined as (1) at least 60 years of age, (2) medically 
confirmed ovarian failure, or (3) younger than 60 years of age and have had 
cessation of regular menses for at least 12 consecutive months with no 
alternative pathological or physiological cause and/or serum levels of 
estradiol and follicle stimulating hormone within the laboratory’s reference 
range for postmenopausal females 
ii. 
Acceptable surgical sterilization techniques are complete or 
partial hysterectomy, bilateral tubal ligation with surgery at least 6 months 
prior to dosing, or bilateral oophorectomy with surgery at least 2 months 
prior to dosing  
iii. 
Highly effective methods of contraception are those that result in a low 
failure rate (ie, less than 1% per year) when used consistently and correctly. 
These include the following: 
1. Established use of oral, injected or implanted hormonal 
methods of contraception (stable dose at least 3 months prior to 
dosing)  
2. Placement of an intrauterine device or intrauterine system  
3. Barrier methods of contraception: condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository. Barrier methods alone 
(without spermicide) are not acceptable methods. Likewise, 
spermicide alone is not an acceptable method 
4. Male sterilization (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate). For 
female patients on the study, the vasectomized male partner 
should be the sole partner for that patient  
5. True abstinence, when this is in line with the preferred and 
usual lifestyle of the patient. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception   
 
b. For males: Males must be surgically sterile or have a female partner who is either 
postmenopausal, surgically sterile, or using 2 forms of highly effective 
contraception as noted above. Acceptable surgical sterilization techniques are 
vasectomy with surgery at least 6 months prior to dosing. Males must also refrain 
from sperm donation during the study and for 6 months following discontinuation 
of treatment 
 
14. Able to understand and sign an informed consent 
 


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7.1.2. 
Exclusion Criteria 
A patient will not be eligible for participation in this study if any of the following criteria 
apply. 
1. Limited-stage SCLC 
2. Prior chemotherapy for limited or extensive-stage SCLC 
3. Prior treatment with immunotherapies including but not limited to cluster of 
differentiation 137 (CD137) agonists or immune checkpoint blockade therapies (such as  
anti-PD-1, anti-PD-L1, CTLA4 therapeutic antibodies) 
4. Presence of symptomatic brain metastases requiring immediate treatment with radiation 
therapy or steroids 
5. Malignancies other than SCLC within 3 years prior to randomization, with the exception 
of those with a negligible risk of metastasis or death treated with expected curative 
outcome 
6. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced 
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening 
chest CT scan (history of radiation pneumonitis in the radiation field [fibrosis] is 
permitted) 
7. Active, known, or suspected autoimmune disease that has required systemic treatment in 
the past 2 years (ie, with use of disease modifying agents, corticosteroids, or 
immunosuppressive drugs). Exceptions include vitiligo, controlled asthma, type I 
diabetes, Graves’ disease, Hashimoto’s disease, or with medical monitor approval. Stable 
replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) for well-controlled disease is not 
considered a form of systemic treatment. 
8. 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) 
9. Known history of stroke or cerebrovascular accident within 6 months prior to enrollment 
10. Serious active infection at the time of enrollment 
11. Psychiatric illness/social situations that would limit study compliance 
12. Other uncontrolled serious chronic disease or conditions that in the investigator’s opinion 
could affect compliance or follow-up in the protocol 
13. Known human immunodeficiency virus (HIV), known active Hepatitis B (eg, HBsAg 
reactive or HBV DNA detected) or Hepatitis C (eg, HCV RNA [qualitative] is detected)  


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14. Radiotherapy to any site within 2 weeks prior to enrollment  
15. Receipt of any investigational medication within 4 weeks prior to enrollment 
16. Administration of a live attenuated vaccine within 4 weeks before enrollment or 
anticipation that such a live attenuated vaccine will be required during the study 
17. Influenza vaccination should be given during influenza season only (approximately 
October to March). Patients must not receive live, attenuated influenza vaccine (eg, 
FluMist) within 4 weeks prior to enrollment, at any time during the study, and at least 
5 months after the last dose of atezolizumab 
18. Patients with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalents) or other immunosuppressive medications 
(including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, 
and anti-tumor necrosis factor [TNF] agents) within 14 days of study drug administration. 
Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone 
equivalents are permitted in the absence of active autoimmune disease. 
19. Hypersensitivity to any of the components of the formulation of etoposide or etoposide 
phosphate 
20. Hypersensitivity to carboplatin or other platinum-containing compounds, or mannitol 
21. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
22. Known hypersensitivity to Chinese hamster ovary cell products or other recombinant 
human antibodies  
23. Legal incapacity or limited legal capacity  
24. Pregnant or lactating women 
Patients may withdraw from study drug or from the study at their own discretion (or at the 
discretion of the investigator) for any reason at any time (see Section 12.3 and 12.4).  


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8. 
TREATMENTS 
8.1. 
Treatments Administered 
In the induction part of the study, patients will receive trilaciclib 240 mg/m2 or placebo 
administered IV once daily on Days 1 to 3 of each 21-day E/P/A therapy cycle (up to 
4 cycles in total). In the maintenance part of the study, patients will receive atezolizumab 
every 21 days.  
Patients will receive E/P/A therapy in 21-day cycles during the induction part of the study. 
The carboplatin dose will be calculated using the Calvert formula with a target AUC = 5 
(maximum 750 mg) IV over 30 minutes on Day 1, and 100 mg/m2 etoposide will be 
administered IV over 60 minutes daily on Days 1, 2, and 3 of each 21-day cycle. 
Atezolizumab 1200 mg in 250 mL sodium chloride solution 0.9% will be administered as an 
IV infusion on Day 1 of each 21-day cycle in both the induction and maintenance parts. 
Atezolizumab should be infused over 60 minutes for the first administration and, if tolerated, 
all subsequent infusions may be delivered over 30 minutes. Atezolizumab should be 
administered following the completion of administration of trilaciclib or placebo, etoposide, 
and carboplatin.  
There will be no intrapatient dose modifications of trilaciclib or atezolizumab during the 
study. Dose modifications allowed for E/P are described in Section 8.4.5. 
The interval between doses of trilaciclib or placebo on successive days should not be 
greater than 28 hours. The interval between the dose of trilaciclib or placebo and the 
first dose of chemotherapy on a given day (etoposide or carboplatin) should not be 
greater than 4 hours.  
Trilaciclib or placebo will only be administered with E/P therapy. If administration of 
E/P therapy is held or discontinued, trilaciclib or placebo will also be held or 
discontinued.  
Chemotherapy cannot be administered until after completion of the trilaciclib or 
placebo infusion. If the second or third dose of trilaciclib or placebo in any given cycle 
is not administered for any reason, do not administer the dose of etoposide 
chemotherapy on that day, since this could potentially exacerbate myelosuppression 
(see Section 4.5). 
In both parts of the study, study drug administration will continue until disease progression 
per RECIST v1.1, unacceptable toxicity, withdrawal of consent, or discontinuation by 
investigator. Following disease progression per RECIST v1.1, if the patient appears to be 
deriving clinical benefit, the investigator believes it is in the best interest of the patient, and 
the patient has provided re-consent, study drug administration may be continued until loss of 
clinical benefit (see Section 11.1.4). Treatment cycles will occur consecutively without 
interruption, except when necessary to manage toxicities or for up to a 2-week delay for 
administrative reasons; however, a total delay of more than 9 weeks for trilaciclib or placebo 
+E/P, or 15 weeks for atezolizumab must be discussed with the medical monitor. If the 
subsequent cycle is delayed, the patient should still complete the clinical laboratory 


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assessments 
 on the scheduled Day 1, as well 
as on the actual first dosing day of the next cycle.  
Patients should meet the requirements outlined in Section 6.1.1 before initiation of Cycle 2 
and each subsequent induction cycle of therapy.  
8.2. 
Investigational Products 
Study drug refers to trilaciclib or placebo + E/P/A during the induction part and atezolizumab 
during the maintenance part. 
8.2.1. 
Identity 
8.2.1.1. 
Trilaciclib 
Trilaciclib is supplied as a single-use, sterile powder with 300 mg trilaciclib in each 30-mL 
flint glass vial. D-mannitol, USP is added as a cake forming agent and citrate buffer is added 
to maintain the reconstituted pH at 4.0 to 5.0. The process for reconstitution of study drug is 
detailed in the Pharmacy Manual. 
8.2.1.2. 
Placebo 
The placebo formulation of 250 mL of dextrose 5% in water (D5W) or sodium chloride 
solution 0.9% will be prepared by the pharmacist/designee on site.  
8.2.1.3. 
Etoposide and Carboplatin 
Descriptions of the formulations of commercially-available etoposide and carboplatin can be 
found in the respective current prescribing information (see Appendix 4).  
8.2.1.4. 
Atezolizumab 
A description of the formulation of atezolizumab can be found in the current prescribing 
information (see Appendix 2). 
8.2.2. 
Packaging and Labeling 
8.2.2.1. 
Trilaciclib 
Trilaciclib Sterile Powder, 300 mg per vial is manufactured and packaged by 
 
. 
Individual vials of trilaciclib will be labeled and supplied to the unblinded 
pharmacist/designee who will inventory the contents and document them according to the 
drug accountability requirements (Section 8.2.5). 
8.2.2.2. 
Placebo 
The placebo formulation of 250 mL of D5W or sodium chloride solution 0.9% will be 
prepared by the pharmacist/designee on site, and labeled with the randomization number. 


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8.2.2.3. 
Etoposide and Carboplatin 
Descriptions of the packaging and labeling of commercially-available carboplatin and 
etoposide can be found in the respective current prescribing information (see Appendix 4).  
8.2.2.4. 
Atezolizumab 
A description of the packaging and labeling of atezolizumab can be found in the current 
prescribing information (see Appendix 2). 
8.2.3. 
Storage 
8.2.3.1. 
Trilaciclib 
Study drugs will be stored 
under applicable storage conditions at the 
site and only the pharmacist/designee and designated personnel will have access to the study 
drugs. Storage conditions of trilaciclib are detailed in the pharmacy manual. 
8.2.3.2. 
Placebo 
The placebo formulation of 250 mL of D5W or sodium chloride solution 0.9% will be stored 
identically to trilaciclib to protect the integrity of the blind. 
8.2.3.3. 
Etoposide and Carboplatin 
Information regarding the storage of commercially-available carboplatin and etoposide can 
be found in the respective current prescribing information (see Appendix 4). 
8.2.3.4. 
Atezolizumab 
Information regarding the storage of atezolizumab can be found in the current prescribing 
information (see Appendix 2). 
8.2.4. 
Procedure for Dispensing  
Dispensing instructions, including instructions for masking the trilaciclib or placebo infusion 
bags and tubing will be provided in the Pharmacy Manual and will be maintained in the 
pharmacy records.  
8.2.5. 
Investigational Product Accountability 
The pharmacist/designee will verify the integrity of the clinical trial supplies (storage 
conditions, correct amount received, condition of shipment, kit numbers, etc.) according to 
the investigative site’s standard operating procedures (SOPs). 
At a minimum, the following data will be tracked on the drug accountability log at the site 
pharmacy: 
• Date received 
• Lot number 


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• 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. 
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. Patients meeting all inclusion and exclusion criteria will be 
randomized 1:1 to receive trilaciclib or placebo with E/P/A therapy during the induction part 
as described in Section 8.5.  Each enrolled patient will be assigned a unique randomization 
number by an interactive web-response system (IWRS); this number will be unique and will 
not be reused. 
8.4. 
Dose, Dosing Regimen, and Route 
8.4.1. 
Trilaciclib  
Trilaciclib 240 mg/m2 diluted in 250 mL of D5W or sodium chloride solution 0.9% is to be 
administered by IV infusion over approximately 30 minutes. If there is any study drug 
remaining in the infusion bag at the end of the 30 minutes, the infusion should be continued 
at the same rate until the entire contents of the bag have been administered to ensure patients 
receive the full dose. Details regarding the reconstitution and dilution of trilaciclib vials are 
detailed in the Pharmacy Manual. 
The interval between doses of trilaciclib on successive days should not be greater than 
28 hours. Trilaciclib will only be administered with E/P therapy. If administration of 
E/P therapy is held or discontinued, trilaciclib will also be held or discontinued. 
8.4.2. 
Placebo 
The placebo formulation of 250 mL of D5W or sodium chloride solution 0.9% will be 
administered over approximately 30 minutes. If there is any volume remaining in the infusion 
bag at the end of the 30 minutes, the infusion should be continued at the same rate until the 
entire contents of the bag have been administered to ensure patients receive the full dose. 
The interval between doses of placebo on successive days should not be greater than 
28 hours. Placebo will only be administered with E/P therapy. If administration of 
E/P therapy is held or discontinued, placebo will also be held or discontinued. 


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8.4.3. 
Etoposide and Carboplatin 
Etoposide and carboplatin will be administered IV in accordance with the prescribing 
information (see Appendix 4) and according to the study site’s standard practice.  
Needles or IV administration sets containing aluminum parts that may come in contact with 
carboplatin should not be used for the preparation or administration of the drug. Aluminum 
can react with carboplatin causing precipitate formation and loss of potency. 
The interval between the dose of trilaciclib or placebo and the first dose of 
chemotherapy on a given day (etoposide or carboplatin) should not be greater than 
4 hours. 
Chemotherapy cannot be administered until after completion of the trilaciclib or 
placebo infusion. If the second or third dose of trilaciclib in any given cycle is not 
administered for any reason, do not administer the dose of etoposide chemotherapy on 
that day, since this could potentially exacerbate myelosuppression (see Section 4.5).    
8.4.3.1. 
Carboplatin 
The carboplatin dose will be calculated using the Calvert formula with a target AUC = 5 on 
Day 1 of each 21-day cycle and administered as an IV infusion over 30 to 60 minutes (per 
institutional standard of care). The Calvert formula is as follows: 
Total carboplatin dose (mg) = (target AUC) × (GFR + 25)  
Because the estimated GFR may be based on serum creatinine measurements obtained using 
standardized isotope dilution mass spectrometry, the dose of carboplatin should be capped 
at 750 mg to avoid potential toxicity due to overdosing. The cap dose of 750 mg for 
carboplatin is based on a GFR estimate that is capped at 125 mL/min for patients with normal 
renal function (ie, maximum carboplatin dose = target AUC of 5 mg•min/mL × 150 mL/min 
= 750 mg). 
The weight used for calculation of GFR using the Cockcroft-Gault equation should be the 
actual body weight (and not ideal body weight). 
Refer to the carboplatin prescribing information (see Appendix 4) for details regarding 
preparation, administration, instructions and precautions. Premedications may be provided 
per local standard of care. 
8.4.3.2. 
Etoposide 
Etoposide 100 mg/m2 will be administered as an IV infusion over 60 minutes on Days 1, 2, 
and 3 of each 21-day cycle. 
Refer to the etoposide prescribing information (see Appendix 4) for details regarding 
preparation, administration, instructions, and precautions. 


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8.4.4. 
Atezolizumab 
Atezolizumab 1200 mg will be administered as an IV infusion on Day 1 of each 21-day 
cycle. The first dose should be administered over 60 minutes and, if it is tolerated, 
subsequent doses may be administered over 30 minutes. For the first 4 cycles, ie, during the 
induction part, atezolizumab should be administered following the administration of 
trilaciclib or placebo, etoposide and carboplatin. 
Refer to the atezolizumab prescribing information (see Appendix 2) for details regarding 
preparation, administration, instructions, and precautions. 
8.4.5. 
Dose Modifications 
8.4.5.1. 
Trilaciclib 
To ensure the greatest level of safety when trilaciclib is coadministered with 
chemotherapeutic agents, the magnitude and duration of trilaciclib-induced HSPC arrest was 
simulated using a PK/pharmacodynamic model and verified by performing bone marrow cell 
cycle analysis before or after administration of trilaciclib IV at 192 mg/m2 to different groups 
of human subjects in the Phase 1a Study G1T28-1-01. Trilaciclib 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 4.3.1). 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. However, higher doses of trilaciclib (240 and 280 mg/m2) 
have been tested in patients with SCLC. Based on the Phase 1b results from these subsequent 
Phase 1b/2a SCLC studies (G1T28-02 [administered prior to etoposide and carboplatin] and 
G1T28-03 [administered prior to topotecan]), trilaciclib 240 mg/m2 was chosen as the 
recommended Phase 2 dose. Therefore, to minimize this risk of an insufficient HSPC 
arrest, the dose of trilaciclib will not be modified and will remain at 240 mg/m2 
throughout the study. 
8.4.5.2. 
Modification of Etoposide and Carboplatin Dosing 
Patients should meet the laboratory parameter requirements outlined in Section 10.3.2 before 
initiation of Cycle 2 and each subsequent cycle of E/P therapy. All nonhematologic 
drug-related toxicities (except alopecia) should have resolved to Grade 1 or baseline before 
initiation of the next cycle of E/P therapy. 
Dose adjustments are to be made according to the organ system showing the greatest degree 
of drug-related toxicity. Toxicities will be graded using NCI CTCAE, Version 4.03. Initiation 
of the next cycle of trilaciclib or placebo + E/P therapy may be delayed by no more than 
9 weeks to allow recovery from toxicity due to the chemotherapy agents. A treatment delay 
of > 9 weeks due to trilaciclib or placebo + E/P toxicity will lead to discontinuation of 
trilaciclib or placebo + E/P therapy. 
No more than 2 dose reductions of E/P in total are allowed for any patient. Simultaneous 
reduction in the doses of etoposide and carboplatin will count as 1 dose reduction. Toxicity 


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that requires dose reduction more than twice will lead to discontinuation of trilaciclib or 
placebo + E/P therapy. Under this circumstance, administration of trilaciclib or placebo 
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 
Etoposide and Carboplatin Dose Reductions 
Dose level 
Etoposide (mg/m2) 
Carboplatin (AUC) 
Dose level -1 (first dose reduction) 
Reduce to 75 mg/m2 
Reduce to AUC = 4 
Dose level -2 (second dose reduction) 
Reduce to 50 mg/m2 
Reduce to AUC = 3 
AUC = area under the concentration-time curve 
 
Dose Modifications for Hematologic Toxicity 
First Day of Induction Cycle 2 and Beyond 
In order to start Induction Cycle 2 and subsequent induction cycles as scheduled, on Day 1 of 
the cycle, patients must have an ANC ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and 
nonhematologic drug-related toxicities (except alopecia) must be ≤ Grade 1 or have returned 
to baseline. The dose adjustments in Table 8-2 are based on the ANC and platelet counts on 
the first day of treatment for Cycle 2 and each subsequent induction cycle. 


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Table 8-2 
Etoposide and Carboplatin Dose Adjustments Based on Lack of Recovery 
of Absolute Neutrophil or Platelet Counts on the First Day of Induction 
Cycle 2 and Each Successive Cycle 
Absolute Neutrophil Count 
< 1.5 × 109/L 
 
Etoposide 
 
Carboplatin 
First episode 
No change. Use G-CSF with subsequent 
cycles. Refer to the American Society of 
Clinical Oncology (ASCO) guidelines 
(Smith 2015). 
No change. Use G-CSF with 
subsequent cycles. Refer to ASCO 
guidelines (Smith 2015). 
 
Second episode 
 
First dose reduction 
 
First dose reduction 
 
Third episode 
 
Second dose reduction 
 
Second dose reduction 
 
Fourth episode 
 
Discontinue drug 
 
Discontinue drug 
Platelet Count < 100 x 109/L 
 
Etoposide 
 
Carboplatin 
First episode 
First dose reduction 
 
First dose reduction 
 
Second episode 
 
Second dose reduction 
 
Second dose reduction 
 
Third episode 
 
Discontinue drug 
 
Discontinue drug 
G-CSF = granulocyte colony-stimulating factor 
 
Neutrophils 
The dose adjustments in Table 8-3 are based on the ANC nadir with or without fever during 
the preceding treatment cycle. 


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Table 8-3 
Etoposide and Carboplatin Dose Adjustments Based on Absolute 
Neutrophil Count Nadir With or Without Fever 
ANC Nadir 
 
Etoposide 
 
Carboplatin 
Grade 3a (without fever) 
No Change 
No change 
Grade 4b for ≥ 7 days  
(without fever) 
 
 
 
 
 
 
First episode 
No change. Use G-CSF with subsequent 
cycles. Refer to the ASCO guidelines 
(Smith 2015). 
No change. Use G-CSF with 
subsequent cycles.  Refer to ASCO 
guidelines (Smith 2015). 
 
Second episode 
 
First dose reduction 
 
First dose reduction 
 
Third episode 
 
Second dose reduction 
 
Second dose reduction 
 
Fourth episode 
 
Discontinue drug 
 
Discontinue drug 
Grade 3/4 with fever 
 
 
First episode 
No change. Use G-CSF with subsequent 
cycles. Refer to the ASCO guidelines 
(Smith 2015). 
No change. Use G-CSF with 
subsequent cycles. Refer to ASCO 
guidelines (Smith 2015). 
Second episode 
First dose reduction 
First dose reduction 
 
Third episode 
 
Second dose reduction 
 
Second dose reduction 
Fourth episode 
Discontinue drug 
Discontinue drug 
ANC = absolute neutrophil count; G-CSF = granulocyte colony-stimulating factor 
a 
Grade 3 ANC: 500 to < 1000/mm3 
b 
Grade 4 ANC: < 500/mm3 
 
Platelets 
The dose adjustments in Table 8-4 are based on the platelet nadir during the preceding 
treatment cycle. 


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Table 8-4 
Etoposide and Carboplatin Dose Adjustment Based on Platelet Nadir 
Platelet Count Nadir 
Etoposide 
Carboplatin 
Grade 4a or ≥ Grade 3b with bleeding 
First episode 
First dose reduction 
First dose reduction 
 
Second episode 
 
Second dose reduction 
 
Second dose reduction 
 
Third episode 
 
Discontinue drug 
 
Discontinue drug 
a 
Grade 4 platelet count: <25,000/mm3 
b 
Grade 3 platelet count:  25,000 to < 50,000/mm3 
 
Colony Stimulating Factors    
Patients will not receive colony stimulating factors (CSFs; eg, granulocyte colony 
stimulating factor [G-CSF]; granulocyte-macrophage colony-stimulating factor 
[GM-CSF]) or erythropoiesis stimulating agents (ESAs) during Induction Cycle 1 (ie, 
prior to the actual Cycle 2 Day 1 dosing visit).  
Although CSFs should not be routinely used as adjunctive treatment with antibiotic therapy 
for patients with fever and neutropenia in any cycle, they may be considered in patients with 
fever and neutropenia who are at high risk for infection-associated complications or who 
have prognostic factors predictive of poor clinical outcomes (including in Induction Cycle 1 
if necessary). Subsequent use after Induction Cycle 1 will be based on toxicities as outlined 
above. Please also refer to the ASCO guidelines (Smith 2015) for neutropenia.  
When indicated, as outlined above in Table 8-2 and Table 8-3, either filgrastim or 
pegfilgrastim may be used per the prescribing information. In the event a patient has a 
neutropenic event requiring G-CSF in the subsequent cycle, then filgrastim or pegfilgrastim 
should not be initiated until at least 24 hours after dosing of the next subsequent cycle is 
complete (ie, no earlier than Day 4 of the next subsequent cycle). Filgrastim or pegfilgrastim 
should not be used to increase low neutrophil counts mid-cycle or prior to the start of the 
subsequent cycle.   
For a hemoglobin level < 9.0 g/dL or symptomatic anemia when indicated, epoetin alfa or 
darbepoetin alfa may be used to treat patients per the prescribing information. 
8.4.5.2.1. 
Dose Modifications for Nonhematologic Toxicity 
Hepatic Toxicity 
The following dose adjustments for etoposide and carboplatin are based on serum AST/ALT 
and bilirubin levels (Table 8-5) during the preceding treatment cycle. 


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


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Other Toxicities 
For the first occurrence of any nonhematologic Grade 2 chemotherapy-related toxicity 
(except alopecia), trilaciclib or placebo + E/P 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, E/P should be resumed at 
dose level -1; for the third occurrence, the E/P doses should be reduced to dose level -2. A 
fourth occurrence will result in discontinuation of trilaciclib or placebo + E/P therapy. No 
dose reduction should be made for Grade 1 toxicities. 
For any Grade 3 or 4 chemotherapy-related toxicities not mentioned above, trilaciclib or 
placebo + E/P 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 trilaciclib or 
placebo + E/P therapy. 
8.4.5.3. 
Atezolizumab 
A list of the AESI for atezolizumab is provided in Appendix 3 and these should be reported 
using the same process and timeline as SAE reporting (see Section 11.4.1.10).  
No dose reductions will be allowed for atezolizumab during the study. Management of irAEs 
may include administration of corticosteroids, delay of a scheduled dose, or discontinuation 
of therapy. Please refer to the Atezolizumab Guidance for the Investigator (Appendix 1) and 
the full atezolizumab prescribing information (Appendix 2) for guidance on the management 
of irAEs. 
Atezolizumab has been associated with risks such as the following: IRRs; immune-related 
hepatitis, pneumonitis, colitis, pancreatitis; diabetes mellitus; hypothyroidism; 
hyperthyroidism; adrenal insufficiency; Guillain-Barré syndrome; myasthenic syndrome or 
myasthenia gravis; hypophysitis; and meningoencephalitis. In addition, systemic immune 
activation is a potential risk associated with atezolizumab when given in combination with 
other immunomodulating agents. Refer to the Atezolizumab Guidance for the Investigator 
(Appendix 1) for a detailed description of anticipated safety risks for atezolizumab and their 
management. 
For patients enrolled with baseline AST and ALT ≥ 3 x ULN in the presence of liver 
metastases, if further increase in AST and ALT occurs, atezolizumab should be held until the 
patient is discussed with the medical monitor.   
Systemic immune activation is a rare condition characterized by an excessive immune 
response. Given the mechanism of action of atezolizumab, systemic immune activation is 
considered a potential risk when given in combination with other immunomodulating agents.  
Systemic immune activation should be included in the differential diagnosis for patients who, 
in the absence of an alternative etiology, develop a sepsis-like syndrome after administration 
of atezolizumab, and the initial evaluation should include the following: 


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• CBC with peripheral smear 
• Prothrombin time, partial thromboplastin time, fibrinogen, and D-dimer 
• Ferritin 
• Triglycerides 
• AST, ALT, and total bilirubin 
• Lactate dehydrogenase 
• Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
 
Other irAEs attributed to atezolizumab not listed above should be assessed by the 
investigator and discussed with the medical monitor to determine if atezolizumab should be 
held or discontinued.  
If corticosteroids have been initiated as part of the irAE management, they must be tapered 
over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent before atezolizumab can be 
resumed. If the delay for re-starting atezolizumab is > 15 weeks for recovery from 
immune-related toxicities attributed to atezolizumab (12 weeks for recovery to ≤ Grade 1 and 
up to an additional 3 weeks for steroid taper of oral prednisone or equivalent to 
≤ 10 mg/day), atezolizumab will be permanently discontinued. 
Discontinuation or interruption of trilaciclib or placebo + E/P does not preclude 
continuation of atezolizumab and vice versa. For instance, if an AE is attributed to 
trilaciclib or placebo, etoposide, or carboplatin (eg, hematologic toxicity) during the 
induction part of the study, then atezolizumab will be continued while the trilaciclib or 
placebo + E/P are held. While the trilaciclib or placebo + E/P are held, the patient will 
continue to receive atezolizumab, be monitored for safety (see Section 10.3.4), and will 
begin the next trilaciclib or placebo + E/P/A-containing induction cycle after the 
toxicity resolves. If the AE is immune related and attributed to atezolizumab; then 
trilaciclib or placebo + E/P will be continued for up to 4 induction cycles while the 
atezolizumab is held.  
8.5. 
Randomization and Blinding 
The study is randomized and blinded. Patients meeting all inclusion and exclusion criteria 
will be randomized 1:1 to receive trilaciclib or placebo with E/P/A therapy by an IWRS 
according to a randomization schedule generated by an unblinded statistician. Randomization 
will be stratified by ECOG performance status (0 to 1 versus 2) and presence of brain 
metastases (yes versus no). 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 


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obtain the treatment assignment details from the IWRS. Any unplanned unblinding must be 
communicated to the project manager and study statistician for documentation in the study 
files and the clinical study report.   
8.6. 
Prior and Concomitant Medications and Procedures 
All concomitant medications including prescription medications, over-the-counter 
preparations, growth factors, blood products, and parenteral nutrition taken during the 
14 days before the date of enrollment, during the study treatment, and through 30 days after 
the last dose of study drug will be documented. Documentation will include information 
regarding start and stop dates, dose(s), and reasons for the medication use.   
Administration of other concomitant nonprotocol anticancer therapies prior to progression is 
not permitted while on this study. 
Administration of other concomitant investigational agents for any indication is not permitted 
while on this study. 
Palliative radiation therapy or surgery is allowed to control disease symptoms but not to aid 
in the response of the tumor and patients requiring palliative radiation may continue 
receiving study drug administration if they meet the requirements described in 
Section 11.1.4. However, for patients who have not had disease progression, the requirement 
for palliative radiation therapy or surgery will be regarded as disease progression.  
Caution should be exercised when administering etoposide phosphate with drugs that are 
known to inhibit phosphatase activities (eg, levamisole hydrochloride). Although carboplatin 
has limited nephrotoxic potential, caution should be exercised when administering 
carboplatin with aminoglycosides, which has resulted in increased renal and/or audiologic 
toxicity. Any medication that is contraindicated when using etoposide or carboplatin is not 
permitted, and special warnings and precautions for use of carboplatin and etoposide should 
be observed.  
Necessary supportive care such as antiemetics, antidiarrheals, etc., per the standard of care at 
the study center will be permitted. Administration of hematopoietic growth factors in 
Induction Cycle 1 will not be permitted (ie, no growth factors should be used prior to 
the actual Induction Cycle 2 Day 1 dosing visit; Section 8.4.5.2). However, hematopoietic 
growth factors may be utilized in subsequent cycles at the investigator’s discretion as stated 
in Section 8.4.5.2. To reduce potential immune system interactions, the use of 
dexamethasone as an antiemetic should be minimized where possible.  
For the purposes of this trial, concomitant medications like bisphosphonates and denosumab, 
which are used to prevent skeletal-related events in patients with bony metastases, are 
allowed as long as the patient has been on stable doses for at least 4 weeks. 
Trilaciclib is a time-dependent inhibitor of CYP3A4 and is a substrate for CYP3A4. 
Trilaciclib 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 trilaciclib (Section 4.4.2).  


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• 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. 
 
Trilaciclib 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 4.4.2). 
Cytochrome P450 enzymes, as well as conjugation/glucuronidation reactions, are not 
involved in the metabolism of atezolizumab. No drug interaction studies for atezolizumab 
have been conducted. There are no known interactions with other medicinal products or other 
form of interactions (Section 1.10 of the Atezolizumab Guidance for the Investigator, 
Appendix 1).  
Atezolizumab should not be given to patients with a condition requiring systemic treatment 
with either corticosteroids (> 10 mg daily prednisone equivalents) or other 
immunosuppressive medications (including but not limited to cyclophosphamide, 
azathioprine, methotrexate, thalidomide, and anti-TNF agents) within 14 days of 
atezolizumab administration. Inhaled or topical steroids and adrenal replacement doses 
> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune 
disease.  
Any diagnostic, therapeutic, or surgical procedures performed during the study period will be 
documented. Documentation will include information regarding the date(s), indication(s), 
description of the procedure(s), and any clinical or pathological findings.  
Medications will be coded using the most recent World Health Organization (WHO) Drug 
Dictionary version. 
8.7. 
Transfusions 
Platelets should be transfused at a threshold of ≤ 10,000/µL. Platelets should also be 
transfused in any patient who is bleeding with a platelet count < 50,000/µL (100,000/µL for 
central nervous system or ocular bleeding). Please also refer to the American Society of 
Clinical Oncology (ASCO) guidelines (Schiffer 2001). 
Patients with hemoglobin < 8.0 g/dL or with symptomatic anemia can be treated with RBC 
transfusions at the investigators discretion.  


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8.8. 
Prophylactic Cranial Irradiation  
Prophylactic cranial irradiation for patients without detectable brain metastases has been 
shown to decrease the frequency of subsequent intracranial relapse and improve survival for 
patients with SCLC (Aupérin A 1999; Slotman 2007). Therefore, patients with a confirmed 
CR are strongly encouraged to receive PCI after completion of induction chemotherapy. 
Patients with a confirmed PR should also consider PCI after completion of induction 
chemotherapy based on the investigator’s judgment. Following the completion of the 
induction part, PCI may be administered concurrently with atezolizumab during the 
maintenance part.   
8.9. 
Treatment Compliance 
The investigator or designee will dispense the study drugs, via an unblinded 
pharmacist/designee, only for use by patients enrolled in the study as described in this 
protocol. The study drugs are 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 drugs 
administered in the clinic. The clinical study site will maintain records of study drugs 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 trilaciclib or placebo, etoposide, 
carboplatin, and atezolizumab 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.  
The timing and number of samples collected for PK, immunologic markers and 
anti-atezolizumab antibody testing may be altered based on emerging data without requiring 
an amendment if the blood volume/day or overall does not increase and the patient is not 
required to have additional clinic visits or prolongation of a clinic visit, ie, the risk-benefit 
profile for the patient does not worsen. The investigators and institutional review boards 
(IRBs) or Independent Ethics Committees (IECs) will be notified if the frequency is reduced. 




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Screen-
ing  
Enroll 
Induction (21-day cycles)a 
Last 
Induc
-tion 
Cycle 
Maintenance  
(21-day cycles)b 
Post-Treatment 
Visitsc 
Survival 
Follow-
upd 
Induction Cycles 1 and 3 
Induction Cycles 2 and 4 
Maintenance 
Cycle 1 and 
Odd Cycles 
Maintenance  
Cycle 2 and 
Even Cycles 
Cycle Day  
-14  
-3 to 1 
1 
2 
3 
8 
15 
1 
2 
3 
8 
15 
22 
1 
1 
30 (+3) 
90 (+7) 
 
Atezolizumab PKr 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
Immunologic 
Markers 
 
 
Xs 
 
 
 
 
 
 
 
 
 
 
Xs 
 
 
Xs 
 
Anti-atezolizumab 
Antibody Testingt 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
AEsu 
Xu 
Xu 
Xu 
 
Con. Medications 
X 
X 
 
 
Survival 
Follow-upd 
 
 
X 
AE = adverse event; Eval. = evaluation; 
 
; irRECIST = immune-related RECIST; 
; PK = pharmacokinetics; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors, Version 
1.1; T3 = tri-iodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone 
a 
During the induction part, study drug administration (trilaciclib or placebo plus E/P/A) will continue for up to four 21-day cycles or until disease progression per RECIST v1.1, unacceptable 
toxicity, withdrawal of consent, or discontinuation by investigator, whichever occurs first. Following disease progression per RECIST v1.1, if the patient appears to be deriving clinical benefit, 
the investigator believes it is in the best interest of the patient, and the patient has provided re-consent, study drug administration may be continued until loss of clinical benefit.  
b 
During the maintenance part, study drug administration (atezolizumab) will continue in 21-day cycles until disease progression per RECIST v1.1, unacceptable toxicity, withdrawal of consent, or 
discontinuation by investigator, whichever occurs first. Following disease progression per RECIST v1.1, if the patient appears to be deriving clinical benefit, the investigator believes it is in the 
best interest of the patient, and the patient has provided re-consent, study drug administration may be continued until loss of clinical benefit. 
c 
Patients will return to the study center for post-treatment visits at 30 (+3) and 90 (+7) days after the last dose of study drug.  
d 
Monthly phone calls will be made to each patient that is in the Survival Follow-up Phase. Patients will be followed for survival until at least 70% of the patients have died. Any anticancer 
therapies used will be collected.  
e 
Informed consent may be obtained up to 28 days prior to the first study treatment administration. 
f 
Including medical, surgical, radiation history, smoking history, family history, documentation of tumor diagnosis, baseline signs and symptoms within 4 weeks prior to randomization, weight 
loss in the 6 months prior to randomization (≤ 5% or > 5%), and medications taken within 14 days of enrollment. 
g 
Height will only be measured at the screening visit. Weight will only be measured at the screening visit and on Day 1 of each cycle. Body surface area calculation (based on actual body weight) 
will be completed on Day 1 of each cycle and vital signs obtained within 15 minutes before and after trilaciclib or placebo and E/P/A infusions. Vitals only need to be taken before the trilaciclib 
or placebo infusion, between each subsequent infusion, and after the last infusion on Days 1 and 3.  
h 
Clinical chemistry (albumin, alkaline phosphatase, total bilirubin, calcium, chloride, creatinine, glucose, inorganic phosphorus, potassium, total protein, ALT, AST, lactate dehydrogenase [LDH], 
sodium, and blood urea nitrogen [BUN], amylase, lipase) and urine analysis may be obtained up to 72 hours prior to the first dose of each cycle of trilaciclib or placebo + E/P/A therapy 
(induction part) or atezolizumab (maintenance part).  
i 
Hematology will be obtained (hemoglobin, white blood cells (WBC) with differential, and platelet counts). Hematology may be obtained up to 24 hours prior to first dose of each cycle of 
trilaciclib/placebo + E/P/A therapy (induction part) or atezolizumab (maintenance part). 
j 
For female patients of childbearing potential: serum ß-hCG at enrollment; and serum or urine ß-hCG obtained at the post-treatment visits.   




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10. 
SCHEDULE OF STUDY PROCEDURES 
Study procedures are summarized across all study visits within the schedule of assessments 
(Table 9-1).  
10.1. 
Screening 
Patients should be screened no more than 14 days before the first dose of study treatment is 
administered. Written informed consent must be obtained from each patient before the 
initiation of any screening procedures. Informed consent and brain scans may be obtained up 
to 28 days prior to the first study treatment administration. After a patient has given informed 
consent, eligibility will be determined by a review of the inclusion/exclusion criteria and 
completion of all screening procedures outlined in Table 9-1 and listed below.  
• Collection of demographics 
• Collection of medical history 
• ECOG performance status evaluation 
• Physical examination 
• Height, weight, and vital signs measurements 
• ECG 
• Clinical chemistry, hematology, and urinalysis tests   
• Thyroid-stimulating hormone (TSH), free thyroxine (T4), and free tri-iodothyronine (T3) 
tests 
• Tumor assessment (by CT scan or MRI; see details in Section 11.1.1); CT or MRI scans 
obtained prior to informed consent will not need to be repeated if performed within 
14 days prior to dosing.  
• Brain scan with contrast (by MRI or CT); brain MRI or CT scans obtained prior to 
informed consent will not need to be repeated if performed within 28 days prior to 
dosing.  
Monitoring of AEs and concomitant medications will commence at the time of informed 
consent. AEs and concomitant medications will be collected through 30 days after the last 
dose of study drug; SAEs and AESI will be collected through 90 days after the last dose of 
study drug. 
10.2. 
Enrollment  
Eligibility will be determined prior to enrollment, randomization, and the start of study 
treatment. Females of childbearing potential will have a serum pregnancy test. Eligible 
patients will be instructed on all protocol requirements, including any restrictions on 
concomitant medication usage. 
Randomization will be performed within 3 days of the first dose of trilaciclib or 
placebo + E/P/A therapy, following confirmation that the patient is eligible for the study. 
Study drug refers to trilaciclib or placebo + E/P/A during the induction part and atezolizumab 
during the maintenance part. 




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• Plasma PK samples (postdose samples for measurement of trilaciclib, etoposide, and 
carboplatin concentrations for patients in the PK subgroup; and for measurement of 
atezolizumab concentrations for all patients as described in Section 11.2) 
 
Induction Cycle 1 Days 2, 3, 8, and 15 
All procedures and assessments to be conducted during Induction Cycle 1 Days 2, 3, 8, and 
15 are outlined in Table 9-1. The DMC may recommend decreasing the frequency of 
hematological evaluations based on accumulating data. The investigators and institutional 
review boards (IRBs) or Independent Ethics Committees (IECs) will be notified if the 
frequency is reduced. 
On Day 2 of Induction Cycle 1, study treatments (trilaciclib or placebo + etoposide) will be 
administered (as described in Section 8.1). 
On Day 3 of Induction Cycle 1, study treatments (trilaciclib or placebo + etoposide) will be 
administered (as described in Section 8.1). The following additional assessments will be 
performed: 
• Vital signs (obtained within 15 minutes before and after trilaciclib or placebo and 
etoposide infusions; only needed once between infusions; and after the last infusion on 
Days 1 and 3) 
10.3.2. 
Induction Cycle 2 
Adverse events and concomitant medications will be monitored throughout the study. AEs 
and concomitant medications will be collected through 30 days after the last dose of study 
drug; SAEs and AESI will be collected through 90 days after the last dose of study drug. 
Induction Cycle 2 Day 1 
Patients will return to the study center on Induction Cycle 2 Day 1. The following procedures 
will be performed and results reviewed before study drug administration: 
• ECOG performance status evaluation 
• Physical examination 
• Weight and vital signs measurements 
• 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). The clinical chemistry and hematology results 
should be reviewed before dosing. 
• TSH, free T4, and free T3 tests 
• FACT-L and FACT-An Questionnaires 
• Plasma PK sample (predose atezolizumab sample) 
• 
) 


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Vital signs should be obtained within 15 minutes before and after trilaciclib or placebo, 
etoposide, and carboplatin infusions; only once between infusions; and after the last infusion 
on Days 1 and 3. 
In order to start Induction Cycle 2 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 9 weeks is permitted to allow 
recovery from any toxicity related to trilaciclib or placebo, carboplatin, or etoposide in order 
to meet the continuation criteria. A delay of up to 15 weeks is permitted to allow recovery 
and management from immune-related toxicities attributed to atezolizumab (12 weeks for 
recovery to ≤ Grade 1 and up to an additional 3 weeks for steroid taper of oral prednisone or 
equivalent to ≤ 10 mg/day). If the patient meets the criteria for starting the subsequent cycle 
as stated in protocol Section 6.1.1, a delay of up to 2 weeks is permitted for administrative 
reasons (eg, holiday, vacation, etc.); however, a total delay of more than 9 weeks for 
trilaciclib or placebo + E/P, or 15 weeks for atezolizumab must be discussed with the medical 
monitor. If a cycle is delayed, the patient should still complete the clinical laboratory 
assessments and the FACT-L and FACT-An questionnaires on the scheduled Day 1 of the 
next cycle, as well as the actual first dosing day of the next cycle of trilaciclib or placebo + 
E/P/A chemotherapy.  
A delay of > 9 weeks for recovery from any toxicity related to trilaciclib or placebo + E/P in 
order to meet the continuation criteria will result in discontinuation of trilaciclib or placebo + 
E/P. A delay of > 15 weeks for recovery and management of immune-related toxicities 
attributed to atezolizumab (12 weeks for recovery to ≤ Grade 1 and up to an additional 
3 weeks for steroid taper of oral prednisone or equivalent to ≤ 10 mg/day) will result in 
discontinuation of atezolizumab (see Section 8.4.5.3).  
For patients who are eligible to initiate Induction Cycle 2, study treatments (trilaciclib or 
placebo + etoposide + carboplatin + atezolizumab) will be administered as described in 
Section 8.1.  
Postdose assessments on Induction Cycle 2 Day 1 are as follows: 
• Vital signs (obtained within 15 minutes before and after trilaciclib or placebo, etoposide, 
carboplatin, and atezolizumab infusions; only needed once between infusions; and after 
the last infusion on Days 1 and 3) 
• Plasma PK sample (postdose sample for measurement of atezolizumab concentration as 
described in Section 11.2, for all patients) 
Induction Cycle 2 Days 2, 3, 8, and 15 
All procedures and assessments to be conducted during Induction Cycle 2 Days 2, 3, 8, and 
15 are outlined in Table 9-1. The DMC may recommend decreasing the frequency of 
hematological evaluations based on accumulating data. The investigators and IRBs will be 
notified if the frequency is reduced. 


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On Day 2 of Induction Cycle 2, study treatments (trilaciclib or placebo + etoposide) will be 
administered (as described in Section 8.1). 
On Day 3 of Induction Cycle 2, study treatments (trilaciclib or placebo + etoposide) will be 
administered (as described in Section 8.1). The following additional assessments will be 
performed: 
• Vital signs (obtained within 15 minutes before and after trilaciclib or placebo, etoposide, 
and atezolizumab infusions; only needed once between infusions; and after the last 
infusion on Days 1 and 3) 
For tumor assessment, all sites of disease should be assessed radiologically by CT or MRI at 
screening and after every even cycle for the first 9 months of the study (ie, approximately 
every 6 weeks) and after every third cycle (ie, approximately every 9 weeks) thereafter, 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. The same method of assessment (CT or MRI) should be used to characterize 
tumors at screening and at all follow-up assessments. 
10.3.3. 
Induction Cycles 3 and 4 
Procedures and assessments to be performed during Induction Cycle 3 are similar to 
Induction Cycle 1 (see Section 10.3.1 and Table 9-1).  
Procedures and assessments to be performed during Induction Cycle 4 are similar to 
Induction Cycle 2 (see Section 10.3.2 and Table 9-1).  
In order to start Induction Cycles 3 and 4 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 9 weeks is 
permitted to allow recovery from any toxicity related to trilaciclib or placebo, carboplatin, or 
etoposide in order to meet the continuation criteria. A delay of up to 15 weeks is permitted to 
allow recovery and management from immune-related toxicities attributed to atezolizumab 
(12 weeks for recovery to ≤ Grade 1 and up to an additional 3 weeks for steroid taper of oral 
prednisone or equivalent to ≤ 10 mg/day). If the patient meets the criteria for starting the 
subsequent cycle as stated in protocol Section 6.1.1, a delay of up to 2 weeks is permitted for 
administrative reasons (eg, holiday, vacation, etc.); however, a total delay of more than 
9 weeks for trilaciclib or placebo + E/P, or 15 weeks for atezolizumab must be discussed 
with the medical monitor. If a cycle is delayed, the patient should still complete the clinical 
laboratory assessments and the FACT-L and FACT-An questionnaires on the scheduled Day 
1 of the next cycle, as well as the actual first dosing day of the next cycle. 
A delay of > 9 weeks for recovery from any toxicity related to trilaciclib or placebo + E/P in 
order to meet the continuation criteria will result in discontinuation of trilaciclib or placebo + 
E/P. A delay of > 15 weeks for recovery and management of immune-related toxicities 


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attributed to atezolizumab (12 weeks for recovery to ≤ Grade 1 and up to an additional 
3 weeks for steroid taper of oral prednisone or equivalent to ≤ 10 mg/day) will result in 
discontinuation of atezolizumab (see Section 8.4.5.3).  
10.3.4. 
Atezolizumab Administration While Trilaciclib or Placebo + E/P Is Held 
During the induction part, interruption or delay of trilaciclib or placebo + E/P does not 
preclude continuation of atezolizumab and vice versa. If the AE is immune related and 
attributed to atezolizumab, then trilaciclib or placebo + E/P will be continued for up to 
4 cycles while atezolizumab is held. If an AE is attributed to trilaciclib or placebo, etoposide, 
or carboplatin (eg, hematologic toxicity) during the induction part of the study, then 
atezolizumab will be continued every 21 days while trilaciclib or placebo + E/P are held. 
During the period in which trilaciclib or placebo + E/P are held and atezolizumab is 
continued, patients should be monitored as follows prior to administering atezolizumab every 
21 days:    
• 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). The clinical chemistry and hematology results 
should be reviewed before dosing. 
• FACT-L and FACT-An Questionnaires 
10.4. 
Last Induction Cycle – Day 22 
On Day 22 of the last induction cycle, patients will return to the clinic for ECG assessment 
and collection of a blood sample for hematology tests. 
• If the patient continues directly into maintenance without interruption, then the 
hematology and ECG assessments will be performed as part of the Day 1 assessments 
in the first cycle of atezolizumab maintenance.   
• If atezolizumab is held or discontinued for any reason after the last cycle of 
trilaciclib/placebo with carboplatin and etoposide, the patient should return to the 
clinic at the end (eg, Day 22) of this last induction cycle for hematology and ECG 
assessments. 
Adverse events and concomitant medications will be monitored throughout the study. AEs 
and concomitant medications will be collected through 30 days after the last dose of study 
drug; SAEs and AESI will be collected through 90 days after the last dose of study drug. 
For patients who have a confirmed CR, it is strongly recommended that they receive PCI 
after completion of chemotherapy. Patients with a confirmed partial response should also 
consider PCI after completion of chemotherapy based on the investigator’s judgment. 


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10.5. 
Maintenance Part of the Study 
Following induction, patients will proceed to the maintenance part of the study and receive 
atezolizumab every 21 days. Treatment in the maintenance part of the study will continue 
until disease progression, unacceptable toxicity, withdrawal of consent, or discontinuation by 
investigator. Following disease progression per RECIST v1.1, if the patient appears to be 
deriving clinical benefit, the investigator believes it is in the best interest of the patient, and 
the patient has provided re-consent, study drug administration may be continued until loss of 
clinical benefit. 
10.5.1. 
Maintenance Cycle 1 and Odd Cycles 
Adverse events and concomitant medications will be monitored throughout the study. AEs 
and concomitant medications will be collected through 30 days after the last dose of study 
drug; SAEs and AESI will be collected through 90 days after the last dose of study drug.  
Maintenance Cycle 1 and Odd Cycles – Day 1 
Patients will return to the study center on study Day 1 of Maintenance Cycle 1 and odd 
cycles in the maintenance part of the study. The following procedures will be performed and 
results reviewed before study drug administration: 
• ECOG performance status evaluation 
• Physical examination 
• Weight and vital signs measurements 
• Clinical chemistry, hematology, and urinalysis tests (note: clinical chemistry and 
urinalysis tests may be obtained up to 72 hours prior to the first dose of each cycle of 
study treatments, and hematology tests may be obtained up to 24 hours prior to the first 
dose of each cycle of study treatments). The clinical chemistry and hematology results 
should be reviewed before dosing. 
• FACT-L and FACT-An Questionnaires 
• Immunologic marker blood sample collection (predose) (Cycle 1 and 5, only) 
The timing for critical assessments/procedures is outlined in Table 9-1.  
For patients who continue to meet the continuation criteria as described in Section 6.1.1, 
atezolizumab will be administered (as described in Section 8.1) and all Day 1 postdose 
procedures outlined in Table 9-1 will be completed. Postdose assessments on Day 1 are as 
follows: 
• Vital signs (obtained within 15 minutes before and after atezolizumab infusion) 
10.5.2. 
Maintenance Cycle 2 and Even Cycles 
Adverse events and concomitant medications will be monitored throughout the study. AEs 
and concomitant medications will be collected through 30 days after the last dose of study 
drug; SAEs and AESI will be collected through 90 days after the last dose of study drug.  




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• Pregnancy test 
• Tumor assessment (obtain tumor assessment by CT scan or MRI for patients who have 
not progressed at the time of study drug discontinuation [every 2 months (approximately 
60 ± 7 days) until the occurrence of progressive disease or study completion]; see details 
in Section 11.1.1) after every even cycle for the first 9 months of the study and after 
every third cycle thereafter 
• 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]) 
• 
 
• Plasma PK sample for measurement of atezolizumab concentration (30 [+3] and 90 [+7] 
days after the last dose of study drug) 
• 
 
• Immunologic markers blood sample collection (90 [+7] days after the last dose of study 
drug, only) 
AEs and concomitant medications will be collected through 30 days after the last dose of 
study drug; SAEs and AESI will be collected through 90 days after the last dose of study 
drug. 
After completing the post-treatment visits, 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 70% of the patients 
randomized to 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.   
The following information will be collected monthly for all patients: 
• Survival status 
• Details of any anticancer treatment   
10.8. 
Study Drug Discontinuation 
After discontinuation of study drug, patients should be strongly encouraged to complete all 
scheduled assessments through the end of their current 21-day treatment cycle, 
 
 CBC assessment on Day 22; the Post-Treatment 
Visits; and the Survival Follow-up Phase of the study, which is to continue until at least 70% 
of randomized patients 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. 


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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. 
Tumor Response 
Efficacy evaluation will be based on tumor response using RECIST v1.1, including objective 
response rate (ORR), PFS, and OS. Additionally, tumor response and immune-related 
progression-free survival (irPFS) will be assessed using irRECIST. 
11.1.1. 
Tumor Assessments 
For tumor assessment, all sites of disease should be assessed radiologically by CT or MRI at 
screening and after every even cycle for the first 9 months of the study (ie, approximately 
every 6 weeks) and after every third cycle (ie, approximately every 9 weeks) thereafter while 
receiving study drug, until the occurrence of disease progression (see Table 9-1). CT or MRI 
scans obtained prior to informed consent will not need to be repeated if performed within 14 
days prior to dosing. Brain scans performed as standard of care 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 prior to starting the subsequent cycle. Additional scans may be 
obtained at the discretion of the investigator, if clinically indicated. If a patient shows a 
radiological response (CR or PR), a confirmatory radiological assessment will be performed 
at least 4 weeks after the response was first noted. For patients who have a confirmed CR, it 
is strongly recommended that they receive PCI after completion of chemotherapy. Patients 
with a confirmed PR should also consider PCI after completion of chemotherapy based on 
the investigator’s judgment (see Section 8.8). Following the completion of the induction part, 
PCI may be administered concurrently with atezolizumab during the maintenance part. For 
those patients who have not progressed at the time of study drug discontinuation, tumor 
assessments, including all sites of disease, will be assessed radiologically by CT or MRI, as 
performed at screening, every 2 months (approximately 60 ± 7 days) until the occurrence of 
progressive disease or study completion. 
The same method of assessment (CT or MRI) should be used to characterize tumors at 
screening and at all follow-up assessments. If PET is used, it should also be accompanied by 
spiral CT or MRI. 
Investigators should follow the RECIST v1.1 guidelines (Eisenhauer 2009) for tumor 
assessments.  
11.1.2. 
Tumor Lesions: Identification and Follow-up 
11.1.2.1. 
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) 


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Measurable lymph nodes must be ≥ 15 mm on the short axis by CT or MRI (with a scan slice 
thickness of no greater than 5 mm); only the short axis is to be measured at baseline and 
follow-up. 
Lytic bone lesions or mixed lytic-blastic lesions with a soft tissue component meeting the 
definition of measurability above can be considered measurable lesions. Cystic lesions 
representing cystic metastases that meet the definition of measurability described above can 
be considered measurable lesions. If present, noncystic lesions should be selected as target 
lesions for this study. 
A tumor lesion that has been previously irradiated may be considered measurable if 
unequivocal growth of the lesion has been demonstrated.  
Target lesions: At baseline, up to 5 measurable tumor lesions/lymph nodes (with a 
maximum of 2 lesions per organ) should be identified as target lesions that will be followed 
to quantitate the status of disease during the study. Lesions with the longest diameter, that are 
representative of all involved organs, and for which reproducible repeated measurements can 
be obtained should be selected as the target lesions.  
At baseline and each follow-up time point (see Table 9-1), each target lesion should be 
measured and the overall tumor burden will be calculated as the sum of the diameters of the 
target lesions (longest diameter [LD] for tumor lesions and short axis for lymph nodes) and 
documented in the eCRF. If a target lesion fragments into multiple smaller lesions, the LDs 
of all fragmented portions are added to the sum of the diameters. If multiple lesions coalesce, 
the LD of the coalesced lesion will be included in the sum of the diameters. 
11.1.2.2. 
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.  
11.1.2.3. 
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 v1.1 guidelines (Eisenhauer 
2009), new lesions include the following: 
• A lesion in an anatomical location that was not scanned at baseline 


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• 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. 
11.1.3. 
Definitions of Tumor Response and Disease Progression 
The determination of SCLC tumor response and progression will be based on the 
RECIST v1.1 criteria (Eisenhauer 2009). The definitions for tumor response per the 
RECIST v1.1 criteria are as follows: 
11.1.3.1. 
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. 
11.1.3.2. 
 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.  


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11.1.3.3. 
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 11-1 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 11.1.3.1 
and 11.1.3.2.  
Table 11-1 
Evaluation of Overall Response at Each Time Point 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/not evaluated 
No 
PR 
SD 
Non-PD/not evaluated 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR= partial response, SD = stable disease, PD = progressive disease, NE = not evaluable 
Source: (Eisenhauer 2009) 
 
11.1.4. 
Treatment Beyond Disease Progression Per RECIST Version 1.1 
Evidence indicates some patients treated with immunotherapy may derive clinical benefit 
after initial evidence of apparent disease progression (Wolchok et al 2013; Nishino 2013). 
Therefore, study drug administration may be continued until loss of clinical benefit, provided 
the patient appears to be deriving clinical benefit, the investigator believes it is in the best 
interest of the patient to continue and the patient has provided re-consent. Study drug 
administration refers to trilaciclib or placebo + E/P/A during the induction part or 
atezolizumab during the maintenance part. Treatment past disease progression per 
RECIST v1.1 should only be considered if a patient is clinically stable and has the following:  
• Evidence of clinical benefit as assessed by the investigator 
• Absence of symptoms and signs (including worsening of laboratory values; eg, new or 
worsening hypercalcemia) indicating unequivocal progression of disease 
• No decline in ECOG performance status that can be attributed to disease progression 
• Absence of tumor growth at critical anatomical sites (eg, leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions 
• All patients continuing treatment beyond progression must sign a separate written 
consent to acknowledge deferring alternative potential treatment options in favor of 
continuing study treatment at the time of initial apparent progression. 
 
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. Decisions to 


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continue treatment beyond initial progression per RECIST v1.1 may be discussed with the 
medical monitor and should be documented in the study records.  
Patients with radiographic disease progression confirmed at a subsequent tumor assessment 
may be considered for continued study treatment at the discretion of the investigator if they 
continue to meet the criteria above and have evidence of clinical benefit. 
Immune-related disease progression (irPD) must be confirmed with worsening of disease 
bulk on the next tumor assessment, performed at least 4 weeks after the disease progression 
by RECIST v 1.1 was first noted. If the criteria of worsening disease bulk are met on 
2 consecutive scans, the patient is determined to have confirmed irPD. If following an initial 
progression, the patient has a subsequent immune-related response (immune-related CR, PR 
or SD; determined from baseline), then the original progression is not confirmed and the 
patient may continue to receive study treatment and any subsequent progression must be 
confirmed on the next consecutive tumor assessment.  
Confirmation of progression due to worsening disease bulk is defined as an additional 20% 
or greater increase in tumor burden volume from the time of initial RECIST v1.1 defined 
progression (including all target lesions and new measurable lesions) or an unequivocal 
further increase in nontarget lesions. In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. New lesions are considered 
measurable at the time of initial progression if the longest diameter is at least 10 mm (except 
for pathological lymph nodes, which must have a short axis of at least 15 mm). Any new 
lesion considered nonmeasurable at the time of initial progression may become measurable 
and therefore included in the tumor burden measurement if the longest diameter increases to 
at least 10 mm (except for pathological lymph nodes, which must have an increase in short 
axis to at least 15 mm). 
For statistical analyses that include the investigator-assessed progression date, subjects who 
continue treatment beyond initial investigator-assessed, RECIST v1.1-defined progression 
will be considered to have investigator-assessed progressive disease at the time of the initial 
progression event. For patients who continue on treatment beyond RECIST v1.1-defined 
progression and have confirmed irPD, the date of the previous irPD will be recorded as the 
irPFS date.  
11.2. 
Pharmacokinetic Assessments  
In a subgroup of at least 5 patients in each treatment group of the study, blood samples will 
be collected for the measurement of trilaciclib, etoposide, and carboplatin concentrations in 
plasma at the time points outlined below and in Table 9-1. The sites identified to participate 
in the trilaciclib, etoposide, and carboplatin PK substudy will be based on the site’s ability to 
complete all PK assessments. Sites will be identified during the site selection process. All 
patients in each treatment group will have blood samples collected for the measurement of 
atezolizumab plasma concentrations. 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 trilaciclib, etoposide, carboplatin, and atezolizumab using validated 


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methods. Any remaining samples may be stored long term (up to 10 years) for the future 
analysis of trilaciclib drug metabolites. 
Day 1 of Induction Cycles 1 and 3 
Blood samples will be collected at the following time points on Day 1 of Induction Cycles 1 
and 3 for all patients enrolled in the PK subgroup of the study: predose (0 hour; prior to 
dosing of trilaciclib or placebo) and at 0.5 (end of infusion [EOI] of trilaciclib or placebo), 
1 (EOI of carboplatin), 2 (EOI of etoposide), 4, 6, and 24 (prior to trilaciclib or placebo dose 
on Day 2) hours. The EOI sample for trilaciclib or placebo should be drawn 2 to 5 minutes 
prior to the EOI. The EOI samples for trilaciclib or placebo, carboplatin, and etoposide must 
be drawn after completing infusion of the drugs and the actual times at which the samples 
were drawn should be documented. A ± 5-minute time window will be allowed for samples 
collected between the following time points: predose to 2 hours after the end of trilaciclib or 
placebo infusion. A ± 10-minute time window will be allowed for samples collected between 
the following time points: 4 to 6 hours after the end of trilaciclib or placebo infusion. A 
± 1-hour time window will be allowed for the 24-hour time point. The actual time of blood 
sample collection should be documented in the eCRF. The Induction Cycle 1 Day 1 sampling 
scheme is summarized in Table 11-2.    
Table 11-2 
Day 1 of Induction Cycles 1 and 3 Blood Sampling Scheme Based on 
Predicted Administration Times of Trilaciclib/Placebo, Carboplatin, and 
Etoposide 
Sample 
1 
2 
3 
4 
5 
6 
7 
Sample  
Time (h) from 
start of trilaciclib/ 
placebo infusion 
0 
(Predosea) 
0.5b 
(Trilaciclib
/Placebo 
EOIc) 
1.0 
(Carbo 
EOIc) 
2.0 
(Etop 
EOIc) 
4.0d 
6.0 e 
24f 
(prior to 
trilaciclib 
dose on 
Day 2) 
Carbo = carboplatin; EOI = end of infusion; Etop = etoposide; h = hour 
Times are approximate. For simplicity, assumptions were based on 0.5 hour infusion of trilaciclib/placebo. Actual times will 
be recorded and may vary from those listed here. 
a 
Predose is defined as prior to initiation of trilaciclib/placebo administration. 
b 
The EOI sample for trilaciclib should be drawn 2 to 5 minutes prior to the EOI. 
c 
Trilaciclib/placebo – 30-minute infusion; carboplatin infusion = 30 minutes; etoposide infusion = 60 minutes 
d 
Sample #5 to be collected 4 hours from the start of trilaciclib/placebo infusion (eg, 3.5 hours from trilaciclib/placebo 
EOI) 
e 
Sample #6 to be collected 5 hours from the start of trilaciclib/placebo infusion (eg, 4.5 hours from trilaciclib/placebo 
EOI) 
f 
Sample #7 to be collected prior to initiation of trilaciclib/placebo Day 2 dose 
 
If it is necessary to slow the infusion rate of any of the study drugs at a given visit for a 
particular patient, the collection time of any subsequent PK sample(s) should be adjusted 
accordingly to ensure that the sample is collected at the actual EOI (trilaciclib/placebo, 
carboplatin, and/or etoposide). Please continue to use the sample labels with the scheduled 
time; however, ensure that actual time of sample collection is recorded appropriately on the 
eCRF. 


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Day 1 of Induction Cycles 1, 2, 3, and 4; Maintenance Cycles 4, 8, 12, and Every Eighth 
Cycle Thereafter; and at 30 and 90 Days After the Last Dose of Study Drug  
Blood samples will be collected at the following time points relative to atezolizumab infusion 
to determine the minimum and maximum observed serum atezolizumab concentration: 
predose and 30 minutes after the end of the atezolizumab infusion. 
Pharmacokinetic Parameters 
Pharmacokinetic parameters to be derived from trilaciclib, etoposide, carboplatin, and 
atezolizumab plasma concentration-time data are presented in Table 11-3. 




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The toxicity of trilaciclib administered IV with chemotherapy will be assessed by the 
investigators using the NCI CTCAE, Version 4.03. 
11.4.1. 
Adverse Events, Serious Adverse Events, and Adverse Events of Special 
Interest  
11.4.1.1. 
Definition of Adverse Event 
An AE is defined as any untoward medical occurrence in a patient administered a medicinal 
product that does not necessarily have a causal relationship with this treatment. An AE can, 
therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the study (investigational) product. 
An abnormal laboratory value is not an AE unless it is considered to be clinically significant. 
Adverse events include the following: 
• All suspected adverse drug reactions (ADRs) 
• All reactions from medication overdose, abuse, withdrawal, sensitivity, or toxicity 
• Apparently unrelated illnesses, including the worsening of a pre-existing illness (see 
pre-existing conditions below) 
• Injury or accidents (Note that if a medical condition is known to have caused the injury or 
accident [eg, a fall secondary to dizziness], the medical condition [dizziness] and the 
accident [fall] should be reported as 2 separate AEs). The outcome of the accident (eg, 
hip fracture secondary to the fall) should be recorded under comments. 
• Abnormalities in physiological testing or physical examination (findings that require 
clinical intervention or further investigation beyond ordering a repeat [confirmatory] test) 
• Laboratory abnormalities that are clinically significant and require clinical intervention or 
further investigation (beyond ordering a repeat [confirmatory] test) unless they are 
associated with an already reported clinical event. Laboratory abnormalities associated 
with a clinical event (eg, elevated liver enzymes in a patient with jaundice) should be 
described under comments on the report of the clinical event rather than listed as a 
separate AE. 
An AE does not include: 
• Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion); 
the condition that leads to the procedure will be an AE 
• Pre-existing diseases or conditions present or detected at the start of the study that do not 
worsen 
• Situations where an untoward medical occurrence has not occurred (eg, hospitalization 
for elective surgery, social, and/or convenience admissions) 
• Overdose of either study drug or concomitant medication without any signs or symptoms 
• Disease progression 


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An unexpected AE is any AE that is not identified in nature, severity, or frequency in the 
current IB or product information. 
• An unexpected ADR is an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (eg, IB for an unapproved 
investigational medicinal product). All noxious and unintended responses to a medicinal 
product related to any dose should be considered ADRs. The phrase “responses to a 
medicinal product” means that a causal relationship between a medicinal product and an 
AE is at least a reasonable possibility, ie, the relationship cannot be ruled out. All serious 
and unexpected ADRs will have expedited reporting to the regulatory agencies following 
the 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. 
11.4.1.2. 
Definition of Serious Adverse Event 
The ICH topic E2A on Clinical Safety Data Management, Definitions and Standards for 
Expedited Reporting defines an SAE as any untoward medical occurrence that at any dose:  
• Results in death 
• Is life threatening 
NOTE: The term "life threatening" in the definition of "serious" refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe.  
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
(see Section 11.4.1.10) is appropriate in other situations, such as important medical events 
that may not be immediately life threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes listed 
in the definition above. These should also usually be considered serious. Examples of such 
events are intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 


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To ensure there is no confusion or misunderstanding of the difference between the terms 
“serious” and “severe”, the following note of clarification is provided: 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
“serious,” which is based on patient/event outcome or action criteria usually associated with 
events that pose a threat to a patient’s life or functioning. Seriousness (not severity) serves as 
a guide for defining regulatory reporting obligations. 
11.4.1.3. 
Definition of Adverse Events of Special Interest 
Adverse events of special interest for atezolizumab are defined in Appendix 3. 
11.4.1.4. 
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 5). 
11.4.1.5. 
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. Investigators should use their knowledge of the patient, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to determine 
whether or not an AE is considered to be related to the study drug. The following guidance 
should be taken into consideration when determining causality: 
• Temporal relationship of event onset to the initiation of study drug 
• Course of the event, considering especially the effects of dose reduction, discontinuation 
of study drug, or reintroduction of study drug (as applicable) 
• Known association of the event with the study drug or with similar treatments 
• Known association of the event with the disease under study 
• Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event 
The following terms for assessment of the causality to study drug or study procedures are to 
be used: 
• Unrelated: There is not a temporal relationship to study drug administration (eg, too 
early, too late, or study drug not taken), or there is a reasonable causal relationship 
between another drug, concurrent disease, or circumstance and the AE. 
• 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. 


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• 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. 
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy. 
11.4.1.6. 
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 
11.4.1.7. 
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. AEs will 
be collected through 30 days after the last dose of study drug; SAEs and AESI will be 
collected through 90 days after the last dose of study drug. 
11.4.1.8. 
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 11.4.1.2) 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”). 


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• 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 
11.4.1.9. 
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). 
11.4.1.10. 
Reporting of Serious Adverse Events and Adverse Events of Special Interest 
The reporting period for SAEs and AESI (see Appendix 3) begins from the time of informed 
consent through 90 days after the last dose of study treatment (safety follow-up phone call). 
Any SAE that is thought to be related to the study drug or any AESI that occurs after the 
reporting period must be reported within 24 hours of discovery of the SAE or AESI. 
All SAEs and AESI must be entered into the eCRF and the initial SAE or AESI form should 
be completed and sent to the safety team within 24 hours of first knowledge of the event by 
the study personnel. 
 
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. 
11.4.1.11. 
Follow-up of Adverse Events 
All AEs (both serious and nonserious) will be followed up in accordance with good medical 
practice until resolution, return to baseline, or it is deemed that further recovery is unlikely. 
All measures required for AE management and the ultimate outcome of the AE will be 
recorded in the source document and reported to the sponsor. 
All unresolved AEs should be followed by the investigator until the events are resolved, the 
patient is lost to follow-up, or the AE is otherwise explained, or further recovery is not 
deemed to be feasible. At the last scheduled visit, the investigator should instruct each patient 
to report any subsequent event(s) that the patient, or the patient’s personal physician, believes 
might reasonably be related to participation in this study.  
Prior to the conclusion of the study at the site, the investigator should notify the medical 
monitor of any death or AE occurring at any time after a patient has discontinued or 
terminated study participation that may reasonably be related to the study drug.  


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After study conclusion, the investigator should notify G1 Therapeutics of any death or SAE 
they are aware of occurring at any time after a patient has discontinued or terminated study 
participation that may reasonably be related to the study drug. G1 Therapeutics should also 
be notified if the investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a patient that has participated in 
this study. 
11.4.1.12. 
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. The sponsor or its representative 
will report all unexpected SAEs to the Competent Authority, the Medicine Evaluation Board, 
and the Competent Authorities in other Member States, as applicable in an expedited time 
frame. 
All SAEs must be entered into the SAE form 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. 
G1 Therapeutics, or their designee, and their collaborators are responsible for submitting 
reports of AEs associated with the use of the study drug that are both serious and unexpected 
to the FDA and European National Competent Authorities, the Medicine Evaluation Board, 


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and the Competent Authorities in other Member States, if applicable, in an expedited time 
frame in compliance with current legislation. Unexpected SAEs 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. 
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. 
11.4.1.13. 
Handling of Overdoses and Toxicity 
No information on treatment of overdose of trilaciclib is currently available. General 
supportive measures should be used as appropriate. 
11.4.1.14. 
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. Follow-up and documentation must occur even if the patient 
withdraws from the study or the study is completed. 
No information is currently available regarding the effects of trilaciclib on fertility, gestation, 
or subsequent child development. 
Atezolizumab can cause fetal harm when administered during pregnancy. Animal studies 
have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of 
immune-related rejection of the developing fetus resulting in fetal death. 
The avoidance of pregnancy or fathering a child (including sperm donation) is suggested for 
6 months following the discontinuation of study drug. 
11.4.2. 
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, WBCs with differential and platelet counts) 


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• Chemistry (albumin, alkaline phosphatase [ALP], total bilirubin, calcium, chloride, 
creatinine, glucose, inorganic phosphorus, potassium, total protein, ALT, AST, LDH, 
amylase, lipase, sodium, and BUN) 
• TSH, free T4, and free T3 
• Urinalysis (semiquantitative dipstick: specific gravity, pH, evaluation of glucose, protein, 
bilirubin, ketones, leukocytes, and hemoglobin; and a microscopic examination, 
including RBC, WBC, and casts will be performed, if necessary) 
If the subsequent cycle is delayed, the patient should still complete the clinical laboratory 
assessments on the scheduled Day 1, as well as on the actual first dosing day of the next 
cycle.  
Laboratory parameters will be analyzed by a local certified laboratory and a report of the 
laboratory values will be sent to the study center. Laboratory parameters for which clinically 
significant values are noted will be re-measured on the appropriate clinical follow-up 
arranged by the investigator. Any laboratory value that remains abnormal at the end of the 
study and that is considered clinically significant 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 5). 
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. 
11.4.3. 
Demographics and Vital Signs 
The following will be collected: 
• Height in centimeters (cm) 
• Body weight in kilogram (kg) 
• Body temperature (Celsius) 
• Systolic and diastolic blood pressure, pulse rate, respiration rate, and pulse oximetry will 
be measured with the patient. Blood pressure should be assessed after 5 minutes of rest. 
11.4.4. 
Physical Examination 
Full physical examination evaluations at screening should include general appearance, skin, 
neck, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and 
neurological examinations. Subsequent physical exams should include body systems as 
appropriate. 
Information about the physical examination must be present in the source documentation at 
the study site. The result of the physical examination prior to the start of study drug must be 
included in the relevant eCRF. Clinically relevant findings made after the start of study drug, 
which meet the definition of an AE, must be recorded on the AE eCRF. 


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11.4.5. 
Electrocardiogram Assessments 
Standard 12-lead ECGs will be performed as outlined in Table 9-1. Patients should rest for 
5 minutes prior to each ECG assessment.  
Any ECG with a QTc value of > 500 should be repeated every 5 minutes for a total of 
3 ECGs to confirm this finding. The QTc value should also be confirmed via manual read.  
The investigator or qualified designee should review the ECGs for any abnormalities as 
compared with predose ECGs. 
11.4.6. 
Concomitant Medications 
Review of concomitant medications will occur at the times outlined in Table 9-1. See 
Section 8.6 for more information on concomitant medications. 
11.5. 
Patient Reported Outcomes 
The FACT-L and FACT-An instruments will be administered to the patients by a designated 
trained study site staff member. The instruments will be administered in the clinic for the 
baseline assessment (on or within 1 day prior to initiation of study treatment), at Day 1 of 
each cycle, and at the Post-Treatment visit. If the subsequent cycle is delayed, the patient 
should still complete the PRO on the scheduled Day 1, as well as on the actual first dosing 
day of the next cycle. Where possible, the same staff member will administer the instrument 
at each site. 
Both the FACT-L and FACT-An contain a core general questionnaire that measures physical, 
social/family, emotional, and functional well-being. The FACT-L has an additional lung 
cancer subscale (FACT-L) (Cella 1995). The FACT-An has an additional subscale that 
measures the impact of fatigue and other anemia-related symptoms on patients with cancer 
(FACT-An) (Yellen 1997). The core general questionnaire is the same for both instruments; 
as such, at each assessment, the core questionnaire will be administered once along with the 
lung and anemia subscales.   
11.6. 
Immunologic Markers 
The addition of trilaciclib to standard chemotherapy could provide clinical benefit to patients 
with CDK4/6-independent cancers through the reduction of myelosuppression-related side 
effects and improved chemotherapy activity. There are at least 2 potential mechanisms by 
which trilaciclib may improve chemotherapy activity: maintaining dose intensity and 
maintaining immune system function through repeated cycles of chemotherapy. In addition 
to the common side effects that result from myelosuppression, chemotherapy-induced 
immunosuppression may limit response rates and survival due to an inability of the damaged 
host immune system to effectively mount a response against the cancer. The impact of 
chemotherapy on the host immune system has been shown to be a double-edged sword, 
where the specific chemotherapeutic agent and dosing regimen (low dose versus standard 
dosing) dictate the impact on the immune system. Chemotherapeutic agents may elicit part of 
their antitumor efficacy by modulating the immune system to enhance antigen presentation, 
uptake, and processing; prime the immune response through immunodepletion; inhibit 


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regulatory cells; and stimulate immune effector cells (Zitvogel 2008; McDonnell 2011; 
Bracci 2014). Conversely, immunosuppression from direct cytotoxicity to the bone marrow 
and immune system over repeated cycles of chemotherapy may counterbalance the positive 
immunostimulatory effects of chemotherapy. Preclinical mouse models have shown that 
chemotherapeutic response is more robust in tumors transplanted into immunocompetent 
mice compared to immunodeficient mice, suggesting that the loss of immune system function 
is detrimental to the overall efficacy of the chemotherapy (Apetoh 2007; Casares 2005). In 
support of these data, severe lymphopenia (< 1000 cells/µL) in patients with breast cancer, 
advanced soft tissue sarcoma, and non-Hodgkin lymphoma has been shown to negatively 
affect PFS and OS (Ray-Coquard 2009).  
Since immune reprogramming is now believed to be an important mechanism of 
chemotherapy response, therapeutic approaches to maintain bone marrow health and immune 
system function should enhance this activity. The effect of trilaciclib in combination with 
chemotherapy and a checkpoint inhibitor was evaluated in MC38 tumor-bearing mice treated 
with trilaciclib, oxaliplatin, or anti-PD-L1 alone or in combination. Tumor size was measured 
during and post treatment for 100 days. The addition of trilaciclib to an oxaliplatin/ 
anti-PD-L1 combination (TOP) treatment significantly improved the overall response rate, 
complete response rate, and median OS compared to oxaliplatin/anti-PD-L1 combination 
(93% vs 46%; 79% vs 38%; not reached at 100 days vs 59 days, respectively). Taken 
together, this demonstrates that trilaciclib, which has been shown to preserve immune 
function during chemotherapy, enhances the antitumor activity of chemotherapy/anti-PD-L1 
combination therapy. 
Therefore, to evaluate the impact of trilaciclib administration on chemotherapy-induced 
changes of the immune system, peripheral blood immune subsets will be characterized in 
patients enrolled into the study. Immunophenotypic changes will be compared between 
patients receiving E/P/A therapy plus placebo or trilaciclib. To assess these changes, 
peripheral blood will be collected at predose on Day 1 of Induction Cycle 1, Day 1 of 
Maintenance Cycle 1 (first cycle of maintenance part), Day 1 of Maintenance Cycle 5, and at 
the post-treatment visit at 90 (+7) days after the last dose of study drug. 
11.7. 
Appropriateness of Measurements 
The measures of efficacy, PK, and safety evaluated in this study are based on the mechanism 
and activity of trilaciclib, standard types of assessments typically performed in patients with 
SCLC, and prior clinical observations derived from patients receiving trilaciclib + E/P/A 
therapy. The measurement of tumor response based on the RECIST v1.1 (Eisenhauer 2009) 
is standard. The PK and safety measures included in this study are also standard.  


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12. 
STUDY TERMINATION OR STUDY DRUG 
DISCONTINUATION 
12.1. 
Study Termination 
The entire study may be terminated in the event of any of the following: 
• Occurrence of AEs unknown to date with respect of their nature, severity, and duration, 
or the unexpected incidence of known AEs 
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of patients 
• Cancellation of the drug development program 
• Sponsor decision for other reasons  
 
12.2. 
Site Termination 
A study site will be closed if there is evidence of fraud, other unethical conduct, or 
significant regulatory noncompliance to the protocol or to Good Clinical Practice (GCP), or 
if insufficient patients have been enrolled to meet the site objectives. 
12.3. 
Discontinuation of Study Drug 
Study drug will be discontinued if any of the following events occur during the study: 
• A patient suffers an AE that, in the judgment of the investigator, sponsor, or medical 
monitor, presents an unacceptable risk to the patient (see Section 8.4.5) 
• 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 and the physician determines 
the patient is not deriving clinical benefit as defined in Section 11.1.4. 
 
Discontinuation or interruption of trilaciclib or placebo + E/P does not preclude continuation 
of atezolizumab and vice versa. For instance, if an AE is attributed to trilaciclib or placebo, 
etoposide, or carboplatin (eg, hematologic toxicity) during the induction part; then 
atezolizumab will be continued while the trilaciclib or placebo + E/P are held. While the 
trilaciclib or placebo + E/P are held, the patient will continue to receive atezolizumab, be 
monitored for safety, and will begin the next trilaciclib or placebo + E/P/A-containing 
induction cycle after the toxicity resolves. If the AE is immune related and attributed to 
atezolizumab; then trilaciclib or placebo + E/P will be continued for up to 4 cycles while the 
atezolizumab is held.  


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After discontinuation of all study drugs, patients should be strongly encouraged to complete 
all scheduled assessments through the end of their current 21-day treatment cycle, 
 
 CBC assessment on Day 22; all Post-Treatment Visits; 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 every 2 months (approximately 
60 ± 7 days) until the occurrence of progressive disease or study completion.  
The investigator will document the reason for study drug discontinuation on the applicable 
eCRF page.   
When discontinuation is due to a SAE or a Grade 3 or 4 toxicity considered to be related to 
study medication, the investigator should follow the event until resolution, return to baseline, 
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) 
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 separate statistical 
analysis plans (SAPs); due to discrepancies between regional regulatory requirements, details 
of the analyses will be specific to the endpoints in each region and will be defined in detail in 
the respective regional SAP prior to unblinding. Hence, details of the methods are not fully 
described in this protocol. For any differences in analyses between the protocol and SAP, the 
plan as outlined in the SAP will supersede the protocol.   
While this Study G1T28-05 was originally designed to evaluate OS as the primary efficacy 
endpoint comparing trilaciclib + E/P/A to placebo + E/P/A, recent clinical results from Study 
G1T28-02 in patients with treatment-naive extensive-stage SCLC comparing trilaciclib plus 
E/P to placebo + E/P, provided compelling evidence that trilaciclib decreased 
myelosuppression across 3 lineages: neutrophils, RBC, and lymphocytes and achieved a 
meaningful level of myelopreservation. Critical hematologic myelosuppression endpoints 
were identified from that study and will be applied across the trilaciclib program. Hence, 
Study G1T28-05, where the chemotherapy backbone of etoposide and carboplatin and the 
patient population is the same as Study G1T28-02, is being modified to broaden the analysis 
of trilaciclib benefit to include multiple primary and key secondary endpoints related to 
myelosuppression, while retaining OS as a secondary endpoint. This amendment changes the 
primary endpoint of Study G1T28-05 from OS to primary and key secondary endpoints 
measuring clinically meaningful reductions in myelosuppression. This revision does not alter 
the ability of G1T28-05 to fulfill its original goal, but rather these changes facilitate the 
sponsor’s ability to confirm the benefit of trilaciclib for treatment of myelosuppression in a 
second randomized, double-blinded, placebo-controlled study in first line SCLC. The same 
myelopreservation mechanism of action (MOA) of trilaciclib that is associated with 
improvement in myelosuppression is also hypothesized to potentially impact antitumor 
efficacy, such as OS. Therefore, changing the primary endpoint to myelosuppression allows 
for an earlier assessment of trilaciclib MOA and efficacy, with OS retained as a later 
manifestation of its effect. Although the primary endpoint for the G1T28-05 protocol was 
designed to be OS, the data collection for the myelosuppression analyses has been consistent 
with the data collection in the other trilaciclib clinical studies evaluating myelosuppression as 
a primary endpoint. As such, the data for this revised primary analysis has been collected 
throughout the study. This change in endpoints also does not alter the assessments or 
protocol-defined patient care.  
At the time of performing the primary and secondary myelosuppression analyses, all patients 
will have completed the randomized induction treatment part of the study and will have 
discontinued trilaciclib or placebo.  However, patients may still be in the atezolizumab 
monotherapy maintenance part of the study or being followed for survival. This will ensure 
that this amendment will not incur any potential operational bias for the PFS/OS analysis 
results. 
13.1. 
Sample Size and Power 
The initial sample size calculations were based on a primary endpoint of OS where a sample 
size of 100 (1:1 treatment allocation ratio between the two groups of placebo + E/P/A and 


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trilaciclib + E/P/A) provided 80% power to detect a hazard ratio of 0.6 using an overall type 
1 error probability of 0.1 (1-sided).  With the change in endpoints outlined in this 
amendment, the sample size calculation is now based on demonstrating the superiority of 
trilaciclib + E/P/A versus placebo + E/P/A with respect to at least one of the primary 
endpoints. 
 
With this amendment, the overall type I error rate is now 0.025 (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 0.025/2 = 
0.0125 is assigned to each outcome variable in the sample size calculation. Assuming a 
common standard deviation (StD) of 2.5, a true difference in the duration of severe (Grade 4) 
neutropenia in Cycle 1 of at least 2 days between the treatment groups (trilaciclib + E/P/A 
versus placebo + E/P/A) requires, 82 evaluable patients (41 per treatment arm). This implies 
that 88 patients need to be randomized assuming a 95% evaluability rate. For occurrence 
endpoints (occurrence of severe (Grade 4) neutropenia, assuming its proportion of 45% for 
placebo + E/P/A, testing for an absolute reduction of 34% to 11% with trilaciclib + E/P/A 
would require a sample size of at least 100 patients (50 per treatment arm). Assuming a 95% 
evaluability rate, at least 106 patients need to be enrolled to complete the study. Therefore, 
the final adjusted sample size is 106 to account for the evaluation of 2 primary endpoints. 
 
All calculations were carried out using the POWER procedure in SAS® version 9.4. 
13.2. 
General Considerations 
13.2.1. 
Analysis Sets 
The intent-to-treat (ITT) analysis set includes all randomized patients. Analyses using the 
ITT will be conducted on the basis of the assigned treatment. All efficacy analyses will be 
assessed using the ITT and the ITT is the primary analysis set for analysis. A 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. Supportive sensitivity analyses will be conducted 
based 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. 
The safety analysis set includes all enrolled patients who received at least 1 dose of study 
drug. The safety analysis set analyses will be conducted on the basis of the actual treatment 
received. All safety analyses will be assessed using the safety analysis set. 
A per-protocol (PP) analysis set is a subset of the mITT analysis set and may also be used to 
analyze select endpoints; it will be based on study drug exposure (compliance and/or time on 
study drug) and major protocol deviations, which will be fully defined and documented 
before unblinding. The criteria for inclusion in the PP analysis set will be finalized and 
documented prior to unblinding patients in the study. 


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The response evaluable analysis set will include all patients who are in the mITT and have at 
least 1 postbaseline tumor assessment, or have clinical progression as noted by the 
investigator before their first postbaseline tumor scan or have died due to disease progression 
before their first postbaseline tumor scan. The response evaluable analysis set will be used 
for analyses of tumor response. 
The PK set will include all dosed patients in Part 1 with evaluable PK data. 
13.2.2. 
Timing of Analyses 
13.2.2.1. 
DMC Reviews 
A DMC will monitor accumulating safety data according to a charter that defines its roles 
and responsibilities. The DMC will perform reviews after approximately 12 patients have 
been enrolled and have completed at least 1 cycle to assess the initial safety data from the 
2 groups, and then approximately every 4 months during the Treatment Phase, 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 Analysis 
The final analysis will be conducted after all patients have had the opportunity to receive at 
least 12 weeks of treatment (ie, randomized induction treatment part of the study).  All study 
data collected through the time of the final analysis data cut, will be included in the final 
analysis. This includes, but is not limited to, the final myelosuppression analysis, final ORR 
analysis, and interim PFS/OS analyses.  
At the time of the final analysis, the sponsor will be unblinded; however, investigators and 
patients will remain blinded. 
13.2.2.3. 
End of Study Analysis 
Patients will be followed for survival until at least 70% of the patients have died at which 
time an end of study analysis for OS and PFS will be done. 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. Additional PFS/OS analyses may be done 
with the timing to occur between the first interim PFS/OS efficacy analysis and the end of 
study PFS/OS analysis. 
13.2.3. 
General Considerations for Data Analysis 
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Data will be summarized descriptively by treatment group. Treatment differences between 
treatment groups will be calculated as trilaciclib + E/P/A therapy versus placebo + E/P/A 
therapy. 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, 25% and 75% percentiles, and standard 
error. All data will be listed for all patients. All CIs will be 95%, unless stated otherwise. 
For the primary and key secondary endpoints, a multiple testing procedure will be used to 
control the overall familywise error rate at α = 0.025 (one-sided) for the comparisons of 
trilaciclib + E/P/A to placebo + E/P/A (See Section 13.5.4).   
All other statistical tests will be conducted at a 2-sided significance level of 0.05 unless 
otherwise specified (trilaciclib + E/P/A versus placebo + E/P/A). Where appropriate, 
model-based point estimates, together with their 95% CIs will be presented along with the 
2-sided p-value for each test. 
The effects of covariates and withdrawal from study treatment due to reasons other than 
death, disease progression, and toxicity will be assessed to determine the impact on the 
general applicability of results from this study. Further details of the analysis, including the 
handling of missing data, impact of variable chemotherapy dose exposure including dose 
reductions, transformations, and other data handling procedures will be provided in the SAP. 
 
13.3. 
Baseline and Demographic Characteristics 
Demographics and baseline characteristics will be summarized descriptively by treatment 
and overall.  
13.4. 
Prior and Subsequent Anticancer Therapies 
All prior and subsequent anticancer therapy verbatim terms will be coded to Anatomical 
Therapeutic Classification (ATC) and PT using the World Health Organization Drug 
Dictionary (WHO-DD Version Sep2017). The number and percentage of randomized 
patients receiving subsequent anticancer therapy will be provided by systemic anticancer 
therapy. All subsequent anticancer therapies will be presented in a patient listing. 
 
13.5. 
Efficacy Analyses 
Unless otherwise specified, all the myelosuppression efficacy analyses will be based on the 
ITT. Unless otherwise specified, all primary and key secondary efficacy endpoints will be 
evaluated and derived for the induction treatment period between the date of randomization 
and the end of the last cycle in the protocol-defined induction phase (ie, last cycle of placebo 
or trilaciclib plus E/P/A). 
 


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13.5.1. 
Primary Myelosuppression Efficacy Endpoints 
The primary myelosuppression efficacy endpoints are defined as follows: 
  
All Regions 
Duration of severe (Grade 4) neutropenia in Cycle 1 
Occurrence of severe (Grade 4) neutropenia 
 
13.5.1.1. 
Methods of Analysis for Primary Myelosuppression Efficacy Endpoints 
A 2-sided p-value will be calculated for the DSN in Cycle 1 using nonparametric analysis of 
covariance (ANCOVA) (Stokes 2012). The nonparametric ANCOVA will include study 
baseline ANC value as covariate, stratification factors of ECOG performance status (0 to 1 
versus 2) and presence of brain metastases (yes versus no), and treatment as a fixed effect. 
Along with the descriptive statistics, the Hodges-Lehmann estimate of median difference 
between the 2 treatment groups, together with its 95% CIs will be provided. 
The occurrence of severe (Grade 4) neutropenia is a binary response variable (yes versus no) 
and will be analysed to compare trilaciclib and placebo using modified Poisson regression 
(Zou 2004) to account for the variable duration of the induction treatment period for each 
patient. The model will include baseline value as covariate, the stratification factors of 
ECOG performance status (0 to 1 versus 2) and presence of brain metastases (yes versus no), 
and treatment as a fixed effect. The 1-sided p-value adjusted relative risk (aRR) (trilaciclib vs 
placebo) and its 95% CIs will be presented.   
 
A detailed description of the analysis methods will be provided in the SAPs. 
 
13.5.2. 
Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are defined in the table below.  
 
Region 1 
Region 2 
Occurrence of RBC transfusions on/after Week 5 
(proportion of patients) 
Overall survival (will not be factored into 
multiplicity adjustment) 
Occurrence of G-CSF administration (proportion of 
patients) 
All-cause dose reductions (number of events) 
Composite MAHE composed of the following 
5 components (number of events for all 
components): 
• All-cause hospitalizations  
• All-cause dose reductions  
• Febrile neutropenia 
• RBC transfusions on/after Week 5 
 
 
• Prolonged severe (Grade 4) neutropenia 
 
(> 5 days) 
Occurrence of RBC transfusions on/after Week 5 
(proportion of patients) 
Occurrence of G-CSF administration (proportion of 
patients) 
 


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13.5.2.1. 
Methods of Analysis for OS 
Although OS is a key secondary endpoint in Region 2, OS will be analyzed with a 
descriptive intention and will not be factored into multiplicity adjustment as described in 
Section 13.5.3. That is, no formal statistical testing will be planned. The analysis of OS will 
be primarily aimed at showing lack of harm from trilaciclib.  
OS will be calculated as the time (months) from the date of randomization 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 date of randomization will have their 
survival time censored at the date of randomization. OS will not be censored if a patient 
receives subsequent anticancer treatments after discontinuation of the study drugs. 
 
13.5.2.2. 
Methods of Analysis for Key Secondary Myelosuppression Endpoints 
A binary response variable (yes versus no) for the key secondary endpoints will be analyzed 
to compare trilaciclib and placebo using modified Poisson regression (Zou 2004) as outlined 
in Section 13.5.1.1.   
The total number of MAHE will be analyzed to compare trilaciclib and placebo using a 
negative binomial regression model to account for the variable duration of the induction 
treatment period for each patient. The model includes stratification factors of ECOG 
performance status (0 to 1 versus 2) and presence of brain metastases (yes versus no), and 
treatment as a fixed effect. The 1-sided p-value adjusted relative risk (aRR) (trilaciclib vs 
placebo) and its 95% CIs will be presented. The cumulative incidence of events will be 
presented graphically.   
A more detailed description of the analysis methods will be provided in the SAPs.  
13.5.3. 
Multiplicity Adjustment for the Primary and Key Secondary 
Myelosuppression Efficacy Endpoints 
To accommodate the primary and key secondary myelosuppression efficacy endpoints, 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=0.025 
level. The one-sided p-values for these comparisons will be used for the multiple test 
procedure. The general testing strategy is described below for Region 1 (Section 
13.5.3.1) and Region 2 (Section 13.5.3.2) with more detailed information provided in the 
respective SAPs.  
13.5.3.1. 
Multiplicity Adjustments in Region 1 
The multiplicity problem includes the following 10 hypotheses of no effect: 
• Hypothesis H1. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
duration of severe (Grade 4) neutropenia in Cycle 1. 
• Hypothesis H2. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
occurrence of severe (Grade 4) neutropenia. 


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• Hypothesis H3. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
occurrence of RBC transfusions on/after Week 5 on study. 
• Hypothesis H4. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
occurrence of G-CSF administration. 
• Hypothesis H5. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for the 
MAHE composite. 
• Hypothesis H6. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
all-cause hospitalizations in the MAHE composite. 
• Hypothesis H7. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
all-cause dose reductions in the MAHE composite. 
• Hypothesis H8. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
febrile neutropenia in the MAHE composite. 
• Hypothesis H9. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
RBC transfusions on/after Week 5 in the MAHE composite.  
• Hypothesis H10. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
prolonged severe (Grade 4) neutropenia (> 5 days) in the MAHE composite. 
These 10 hypotheses can be grouped into 3 families: 
• Family 1 (F1) includes the hypotheses H1 and H2. 
• Family 2 (F2) includes the hypothesis H3, H4, and H5. 
• Family 3 (F3) includes the hypotheses H6, H7, H8, H9, and H10. 
The 1-sided p-values for these 10 comparisons will be used for the multiple testing 
procedure. 
A Hochberg-based gatekeeping procedure will be utilized to control the global familywise 
error rate across the 10 null hypotheses in the strong sense at a 1-sided α=0.025 level, and it 
satisfies the positive dependence condition at 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 10 hypotheses displayed in Figure 13-1 by performing 
multiplicity adjustments in three steps:  
• Step 1. The trilaciclib vs placebo comparisons for Family 1 (hypotheses H1 and H2) 
are performed using a truncated version of the Hochberg procedure. The truncation 
parameter γ is set to 0.5.  
• Step 2. The trilaciclib vs placebo comparisons for Family 2 (hypotheses H3, H4, and 
H5) are performed using a truncated version of the Hochberg procedure if there is at 
least one significance in Step 1. Specifically, the hypotheses H3, H4, and H5 depend 
on the hypotheses H1 and H2, ie, H3, H4, and H5 are tested only if at least one of the 
hypotheses H1 and H2 is rejected. The truncation parameter γ is set to 0.5.  


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• Step 3. The trilaciclib vs placebo comparisons for Family 3 (hypotheses H6, H7, H8, 
H9, and H10) are performed using the regular Hochberg test if H5 is significant in 
Step 2. 
Figure 13-1 
Graphical Display of the Hochberg-based Gatekeeping Procedure for 
Region 1 
 
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 SAPs. 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 vs placebo comparison is significant in the current step 
without inflating the overall type I error rate (Huque, 2016; FDA, 2017). 
13.5.3.2. 
Multiplicity Adjustments in Region 2 
The multiplicity problem includes the following 5 hypotheses of no effect: 
• Hypothesis H1. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
duration of severe (Grade 4) neutropenia in Cycle 1. 
• Hypothesis H2. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
occurrence of severe (Grade 4) neutropenia. 


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• Hypothesis H3. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for the 
number of all-cause dose reductions. 
• Hypothesis H4. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
occurrence of RBC transfusions on/after Week 5 on study.  
• 
Hypothesis H5. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
occurrence of G-CSF administration. 
These 5 hypotheses can be grouped into 3 families: 
• Family 1 (F1) includes the hypothesis H1. 
• Family 2 (F2) includes the hypothesis H2. 
• 
Family 3 (F3) includes the hypotheses H3, H4, and H5. 
Figure 13-2 
Graphical Display of the Hochberg-based Gatekeeping Procedure for 
Region 2 
 
Though the testing procedure can be broadly considered as a fixed sequence procedure with 
the third family consisting of three hypotheses H3, H4, and H5, its implementation can be 
performed through a similar Hochberg-based gatekeeping procedure as described in 
Section 13.5.3.1. Hence, the multiplicity adjustments will be performed in three steps as 
demonstrated in Figure 13-2:  
• Step 1. The trilaciclib vs placebo comparisons for Family 1 (hypothesis H1) is 
performed using a truncated version of the Hochberg procedure. The truncation 
parameter γ is set to 0.  
• Step 2. The trilaciclib vs placebo comparisons for Family 2 (hypothesis H2) is 
performed using a truncated version of the Hochberg procedure if H1 is significant in 
Step 1. The truncation parameter γ is set to 0.  


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• 
Step 3. The trilaciclib vs placebo comparisons for Family 3 (hypotheses H3, H4, and 
H5) are performed using the regular Hochberg test if H2 is significant in Step 2. 
Based on the proposed testing strategy in Figure 13-2, the study can be potentially claimed to 
be positive if at least both H1 and H2 are statistically significant. 
13.5.4. 
Analysis of Supportive Secondary Efficacy Endpoints (Antitumor and 
Myelosuppression) 
The detailed derivation for these endpoints along with their analysis methods will be 
included in the SAPs.   
For Region 1 only, OS will be considered as a supportive secondary endpoint and will be 
analyzed according to Section 13.5.2.1. 
For Region 2 only, the composite MAHE endpoint will be considered a supportive 
secondary efficacy endpoint to be analyzed as described above (Section 13.5.3). 
All the remaining endpoints are relevant to both Regions. 
Anti-tumor activity per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as 
assessed by the investigator will include the following:   
• Objective response (CR or PR) 
• Best overall response (BOR) 
• Duration of objective response (DOR) 
• Progression-free survival (PFS) 
At each tumor assessment visit, an overall time point response by RECIST v1.1 will be 
determined programmatically using the information from target lesions, NTLs, and new 
lesions collected in the eCRF. BOR will be determined using visit responses until the last 
evaluable overall visit response prior to or on the date of (i) radiographic disease progression; 
(ii) withdrawal of consent to obtain scans; (iii) death; (iv) lost to follow-up; or (v) initiation 
of subsequent anticancer therapy, whichever is earlier.   
Duration of Objective Response (DOR) is the time between first objective response of CR or 
PR and the first date that progressive disease is objectively documented or death, whichever 
comes first. Patients who do not experience objective CR or PR will not be included in the 
analysis.  For patients with objective response of CR or PR but (i) withdrawal of consent to 
obtain scans; (ii) lost to follow up; (iii) initiation of subsequent anticancer therapy, or (iv) 
death, the DOR of this patient will be censored at the earliest date among these four. 
PFS is defined as the time (number of months) from date of randomization until date of 
documented radiologic disease progression per RECIST version 1.1 or death due to any 
cause, whichever comes first. More specifically, PFS will be determined using all data until 
the last evaluable visit prior to or on the date of (i) radiographic disease progression per 
RECIST version 1.1; (ii) withdrawal of consent to obtain scans; or (iii) initiation of 








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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
An eCRF must be completed for each patient enrolled. Each completed eCRF, as well as 
records for those patients who discontinue the study, will require a signature by the principal 
investigator at the study site. If a patient withdraws from the study, the reason must be noted 
on the eCRF, and if a patient is withdrawn from the study because of a treatment-limiting 
AE, thorough efforts should be made to clearly document the outcome. The investigator 
should ensure the accuracy, completeness, legibility, and timeliness of the data reported to 
the sponsor in the eCRFs and in all required reports. 
Accurate and reliable data collection will be assured by verification and cross-check of the 
eCRFs against the investigator’s records by the study monitor (source document 
verification), and the maintenance of a drug-dispensing log by the investigator.  
A comprehensive validation check program will verify the data and discrepancy reports will 
be generated accordingly for resolution by the investigator. As patients complete the study 
(or withdraw) and their signed eCRFs become available for review, a comparison check will 
be run to identify and resolve any discrepancies in the data base.  


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15. 
ETHICS AND PROTECTION OF HUMAN PATIENTS 
15.1. 
Ethical Conduct Statement 
The investigator will ensure that this study is conducted in full conformance with the 
principles of the Declaration of Helsinki (as amended in Tokyo, Venice, Hong Kong, and 
South Africa) or with the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the individual. The investigator will 
ensure adherence to the basic principles of GCP as outlined in the current version of 21 CFR, 
subchapter D, Part 312, Responsibilities of Sponsors and Investigators, part 50, Protection of 
Human Subjects, and Part 56, Institutional Review Boards, and ICH E6 GCP. The 
investigator will follow all national, state, and local laws of the pertinent regulatory 
authorities. 
15.2. 
Institutional Review Board/Independent Ethics Committee 
The protocol and all associated amendments and consent/assent materials will be reviewed 
and approved by the investigative site’s local or a central IRB or IEC. 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/IEC, 
including regulatory agency/competent authority, prior to initiating the study. Approval must 
be obtained in writing via a letter identifying the protocol, the date of the IRB/IEC meeting, 
and the date of approval. Any modifications made to the protocol after receipt of the 
IRB/IEC approval must also be submitted by the investigator to the IRB/IEC in accordance 
with local procedures and regulatory requirements. Any updates to the protocol should 
receive IRB/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/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/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 (both nonsubstantial and substantial amendments) must be 
submitted to the appropriate IRB/IEC for information in accordance with local requirements. 
Approval must be received 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, etc.), except for those changes which 
would decrease risk to the patient. 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/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 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/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/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, X-ray, signed informed 
consent forms, consultant letters, and patient screening and randomization 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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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. 
Ghandi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in 
metastatic non–small-cell lung cancer. N Engl J Med 2018;378: 2078-2092. 
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. 
Guleria I, Khosroshahi A, Ansari MJ, et al. A critical role for the programmed death ligand 1 
in fetomaternal tolerance. J Exp Med. 2005;202:231-237. 
Guly CM, Forrester JV. Investigation and management of uveitis. BMJ. 2010;341:821-826. 
Habicht A, Dada S, Jurewicz M, et al. A link between PD-L1 and T regulatory cells in 
fetomaternal tolerance. J Immunol. 2007;179:5211-19. 
Hanna N, Bunn PA, Jr, Langer C, et al. Randomized phase III trial comparing 
irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated 
extensive-stage disease small-cell lung cancer. J Clin Oncol 2006;24: 2038-2043. 
Heighway J, Betticher DC. Lung: small cell cancer. Atlas of Genetics and Cytogenetics in 
Oncology and Haematology. June 2004 URL : 
http://atlasgeneticsoncology.org/Tumors/LungSmallCellID5142.html. 
Hermes A, Bergman B, Bremnes R, et al. Irinotecan plus carboplatin versus oral etoposide 
plus carboplatin in extensive small-cell lung cancer: a randomized phase III trial. J Clin 
Oncol 2008;26: 4261-4267. 
Horn L, Reck M, Spigel DR. The future of immunotherapy in the treatment of small cell lung 
cancer. Oncologist. 2016 Aug;21(8):910-921. 
Huque MF. Validity of the Hochberg procedure revisited for clinical trial applications. 
Statistics in medicine. 2016; 35: 5-20. 
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J 
Clin 2009 Jul-Aug;59(4):225-49. 
Jotte RM, Cappuzzo F, Vynnychenko I, et al. IMpower131: Primary PFS and safety analysis 
of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel 
vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. J Clin Oncol 
2018;36 (suppl; abstr LBA9000). 
Kale N. Optic neuritis as an early sign of multiple sclerosis. Eye Brain. 2016; 8:195-202. 


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Trilaciclib (G1T28) 
 
Version: 3.0, dated 14 September 2018 
 
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Langer CJ, Gadgeel SM, Borghael H, et al. Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, 
phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 2016; 17(11):1497-
1508. 
Lyman GH. Chemotherapy dose intensity and quality cancer care. Oncology (Williston Park) 
2006;20(14 Suppl 9):16-25. 
McDonnell AM, Nowak AK, Lake RA. Contribution of the immune system to the 
chemotherapeutic response. Semin Immunopathol. 2011 Jul;33(4):353-367. 
FDA Center for Biologics Evaluation and Research (CBER). Multiple Endpoints in Clinical 
Trials Guidance for Industry.  https://www.fda.gov/downloads/drugs/guidancecompliance 
regulatoryinformation/guidances/ucm536750.pdf. Published January 2017. Accessed 
13 September 2018. 
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a 
common language for tumor response to immunotherapy: immune-related response criteria 
using unidimensional measurements. Clin Cancer Res. 2013 Jul 15;19(14)3936-3943. 
Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide 
plus cisplatin for extensive small cell-lung cancer. N Engl J Med 2002;346: 85-91. 
Peifer M, Fernandez-Cuesta L, Sos ML, et al. Integrative genome analyses identify key 
somatic driver mutations of small-cell lung cancer. Nat Genet. 2012;44:1104-1110. 
Ray-Coquard I, Cropet C, Van Glabbeke M, et al. Lymphopenia as a prognostic factor for 
overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res. 
2009 Jul 1;69(13):5383-5391. 
Rizvi NA, Hellmann MD, Brahmer JR, et al. Nivolumab in combination with platinum‐based 
doublet chemotherapy for first-line treatment of advanced non–small-cell lung cancer. J Clin 
Oncol. 2016; 34:2969-2979. 
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. 
Schiffer CA, Anderson KC, Bennett CL, et al. Platelet transfusion for patients with cancer: 
clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 
2001;19(5):1519-1538. 
Schmittel A, Sebastian M, Fischer von Weikersthal L, et al. A German multicenter, 
randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as 
first-line therapy for extensive-disease small-cell lung cancer. Ann Oncol 
2011;22:1798-1804. 
Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive 
small-cell lung cancer. N Engl J Med. 2007 Aug 16;357(7):664-672. 




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19. 
APPENDICES 
APPENDIX 1: Atezolizumab Guidance for the Investigator 
APPENDIX 2: Package Insert for Atezolizumab 
Tecentriq® (atezolizumab) injection package insert link: 
https://www.gene.com/download/pdf/tecentriq_prescribing.pdf 
APPENDIX 3: Atezolizumab Adverse Events of Special Interest  
APPENDIX 4: Package Inserts for Chemotherapy Agents 
Etopophos® (etoposide phosphate) package insert link: 
http://packageinserts.bms.com/pi/pi_etopophos.pdf   
Etoposide concentrate for solution for infusion 20 mg/mL. Summary of Product 
Characteristics July 2015 link:  
https://www.medicines.org.uk/emc/medicine/30539 
Paraplatin® (carboplatin) package insert link: 
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-
4180b_03_05_Carboplatin%20label%201-9-04%20FDA.pdf 
Carboplatin 10 mg/mL concentrate for infusion. Summary of Product Characteristics. 
April 2016 link: http://www.medicines.org.uk/emcmobile/medicine/25716 
APPENDIX 5: 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 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
– Region 2–
Study Title: 
Phase 2 Study of Carboplatin, Etoposide, and Atezolizumab With 
or Without Trilaciclib (G1T28) in Patients with Untreated 
Extensive Stage Small Cell Lung Cancer 
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: 
G1T28-05 
Phase: 
Phase 2   
Analysis Plan Version 
Version 1.0 
Version Date 
01 November 2018 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-05            
Statistical Analysis Plan for Region 2 
Version date: 01Nov2018 
 
CONFIDENTIAL 
      Page 2 of 66 
 
                                                 
 
 
 
 
 
APPROVAL SIGNATURES 
 
 
 
AUTHOR: 
  
 
 
 
 
 
 
 
 
Signature                                                                           Date 
 
 
  
 
 
 
APPROVED BY: 
 
 
 
 
 
 
 
 
 
Signature                                                                           Date 
 
 
  
G1 Therapeutics Inc 
 
 
 
 
 
 
 
 
 
 
Signature                                                                           Date 
 
 
 
G1 Therapeutics Inc 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-05            
Statistical Analysis Plan for Region 2 
Version date: 01Nov2018 
 
CONFIDENTIAL 
      Page 3 of 66 
 
                                                 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY DETAILS .......................................................................................................9 
2.1. 
Study Objectives ...........................................................................................................9 
2.2. 
Study Design .................................................................................................................9 
2.3. 
Number of Patients .....................................................................................................15 
3. 
ANALYSIS SETS ......................................................................................................16 
3.1. 
Definition of Analysis Sets .........................................................................................16 
3.1.1. 
Intent-to-Treat Analysis Set ........................................................................................16 
3.1.2. 
Modified ITT Analysis Set .........................................................................................16 
3.1.3. 
Safety Analysis Set .....................................................................................................16 
3.1.4. 
Per Protocol (PP) Analysis Set ...................................................................................16 
3.1.5. 
Response Evaluable Analysis Set ...............................................................................16 
3.1.6. 
Pharmacokinetics (PK) Analysis Set ..........................................................................16 
3.2. 
Protocol Deviations ....................................................................................................17 
4. 
PROSPECTIVELY DEFINED ANALYSES.............................................................18 
5. 
PRIMARY AND SECONDARY ENDPOINTS ........................................................19 
5.1. 
Efficacy Endpoints ......................................................................................................20 
5.1.1. 
Primary Endpoints ......................................................................................................20 
5.1.1.1. 
Occurrence of Severe (Grade 4) Neutropenia ............................................................20 
5.1.1.2. 
Duration of Severe (Grade 4) Neutropenia (DSN) .....................................................20 
5.1.2. 
Key Secondary Endpoints ...........................................................................................23 
5.1.2.1. 
Occurrence of RBC Transfusions ...............................................................................23 
5.1.2.2. 
Occurrence of GCSF Administrations ........................................................................23 
5.1.2.3. 
All-Cause Dose Reductions ........................................................................................23 
5.1.2.4. 
Overall Survival ..........................................................................................................24 
5.1.3. 
Supportive Secondary Endpoints ................................................................................24 
5.1.3.1. 
Total Number of Major Adverse Hematologic Events (MAHE) ...............................24 
5.1.3.2. 
Best Overall Response, Duration of Response, and Progression-Free 
Survival .......................................................................................................................25 
5.1.3.3. 
Occurrence of Grade 3 and 4 Hematologic Toxicities ...............................................31 


 
 
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5.1.3.4. 
ANC Nadir by Cycle ..................................................................................................31 
5.1.3.5. 
ANC, Platelet Count, Absolute Lymphocyte Counts (ALC), and 
Hemoglobin Change over Time ..................................................................................31 
5.1.3.6. 
Occurrence of Erythropoiesis Stimulating Agent (ESA) Administrations .................31 
5.1.3.7. 
Occurrence of IV Antibiotic Uses ..............................................................................32 
5.1.3.8. 
Occurrence of Infection Serious Adverse Events (SAEs) and Pulmonary 
Infection SAEs ............................................................................................................32 
5.1.3.9. 
Occurrence of Pulmonary Infection SAEs .................................................................32 
5.1.3.10. 
Occurrence Febrile Neutropenia .................................................................................33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2. 
Safety Endpoints .........................................................................................................35 
5.2.1. 
Chemotherapy Exposure Endpoints ...........................................................................35 
5.2.1.1. 
Duration of Exposure ..................................................................................................35 
5.2.1.2. 
Number of Cycles Received .......................................................................................35 
5.2.1.3. 
Dose Intensity and Cumulative Dose .........................................................................35 
5.2.1.4. 
Modifications of Study Therapy, Including Cycle (Dose) Delay, Missed 
Doses, Dose Interruptions, and Dose Reductions. ......................................................36 
5.2.2. 
Adverse Events (AEs) .................................................................................................37 
5.2.3. 
Vital Signs ..................................................................................................................39 
5.2.4. 
Laboratory ...................................................................................................................39 
5.2.5. 
Electrocardiograms .....................................................................................................40 
5.2.6. 
Physical Examination .................................................................................................41 
6. 
ANALYSIS METHODS ............................................................................................42 
6.1. 
General Principles of Analysis ...................................................................................42 
6.1.1. 
General Methodology .................................................................................................42 
6.1.2. 
Handling of Missing Data ...........................................................................................42 


 
 
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Statistical Analysis Plan for Region 2 
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6.1.3. 
Visit Windowing .........................................................................................................43 
6.1.4. 
Adjustment for Covariates ..........................................................................................45 
6.2. 
Analysis Methods .......................................................................................................45 
6.2.1. 
Patient Disposition ......................................................................................................45 
6.2.2. 
Demographic and Other Baseline Characteristics ......................................................45 
6.2.3. 
Disease Characteristics ...............................................................................................45 
6.2.4. 
Medical/Surgical History ............................................................................................46 
6.2.5. 
Concomitant Medications ...........................................................................................46 
6.2.6. 
Radiotherapy and Subsequent Anti-Cancer Therapy .................................................47 
6.2.7. 
Efficacy Analyses .......................................................................................................47 
6.2.7.1 
Primary and Key Secondary Efficacy Analyses .........................................................47 
6.2.7.2 
Supportive Secondary Efficacy Analyses ...................................................................55 
6.2.7.3 
Exploratory Efficacy Analyses ...................................................................................57 
6.2.8. 
Safety Analyses ..........................................................................................................57 
6.2.8.1. 
Chemotherapy Exposure and Compliance Analyses ..................................................57 
6.2.8.2. 
Adverse Events ...........................................................................................................58 
6.2.8.3. 
Laboratory Evaluations ...............................................................................................58 
6.2.8.4. 
Vital Signs ..................................................................................................................59 
6.2.8.5. 
Performance Status .....................................................................................................59 
6.2.8.6. 
Physical Examination .................................................................................................59 
6.2.8.7. 
ECG ............................................................................................................................59 
6.2.9. 
Subgroup Analyses .....................................................................................................59 
6.2.10. 
Pharmacokinetic Analysis ..........................................................................................60 
6.2.11. 
Evaluate Genetic and/or Expression (RNA/Protein) Biomarkers in Tumors 
and Blood ....................................................................................................................60 
 
 
 
6.2.13. 
Planned Analysis ........................................................................................................60 
7. 
CHANGE FROM THE PROTOCOL ........................................................................61 
8. 
REFERENCES ...........................................................................................................62 
 


 
 
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Statistical Analysis Plan for Region 2 
Version date: 01Nov2018 
 
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      Page 6 of 66 
 
                                                 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event 
ALC 
Absolute Lymphocyte Count 
ALP 
Alkaline Phosphatase 
ALC 
Absolute Lymphocyte Count 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
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 
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 
DMC 
Data Monitoring Committee 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic Case Report Form 
E/P/A 
Etoposide, Carboplatin, and Atezolizumab 
EOI 
End of Infusion 
ESA 
Erythropoietin Stimulating Agent 
 
 
 
  
 
  
G1T28 
Trilaciclib 
GCSF 
Granulocyte Colony-Stimulating Factor 
HR 
Hazard Ratio 
ICH 
International Conference on Harmonization 


 
 
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Statistical Analysis Plan for Region 2 
Version date: 01Nov2018 
 
CONFIDENTIAL 
      Page 7 of 66 
 
                                                 
 
Abbreviation 
Term 
irRECIST 
immune-related Response Evaluation Criteria in Solid Tumors 
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 
NE 
Not Evaluable 
NLR 
Neutrophil-Lymphocyte Ratio 
NTL 
Non-Target Lesion 
OC 
Observed Case 
ORR 
Objective Response Rate 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PFS2 
Progression-Free Survival 2 
PK 
Pharmacokinetic  
PLR 
Platelet-Lymphocyte Ratio 
PP 
Per Protocol 
PR 
Partial Response 
 
 
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 
SOC 
System Organ Class 
SVN 
Severe Neutropenia 
TEAE 
Treatment Emergent AE 
TL 
Target Lesion 
TLFs 
Tables, Listings, and Figures 
TPR 
Time Point Response 
ULN 
Upper Limit of Normal Range 
WBC 
White Blood Cell 
WHO-DD 
World Health Organization Drug Dictionary 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-05            
Statistical Analysis Plan for Region 2 
Version date: 01Nov2018 
 
CONFIDENTIAL 
      Page 8 of 66 
 
                                                 
 
1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the analyses to be performed 
following the completion of Study G1T28-05, Phase 2 Study of Carboplatin, Etoposide, and 
Atezolizumab With or Without Trilaciclib (G1T28) in Patients with Untreated Extensive Stage 
Small Cell Lung Cancer. The SAP is based on the G1T28-05 Protocol Version 3, dated 14 
September 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).  


 
 
G1 Therapeutics, Inc. 
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2. 
STUDY DETAILS 
2.1. 
Study Objectives 
The primary, secondary, and exploratory objectives of this study as defined in the study protocol 
are presented in Table 1. 
Table 1  
G1T28-05: Study Objectives 
Primary Objective 
Evaluate potential of trilaciclib, compared with placebo, to reduce chemotherapy-induced myelosuppression 
in patients with SCLC undergoing treatment with E/P/A 
Key Secondary Objectives 
Evaluate potential of trilaciclib, compared with placebo, to reduce chemotherapy-induced myelosuppression 
and its consequences in patients with SCLC undergoing treatment with E/P/A 
Supportive Secondary Objectives 
Evaluate potential of trilaciclib, compared with placebo, to reduce chemotherapy-induced myelosuppression 
and its consequences in patients with SCLC undergoing treatment with E/P/A 
Evaluate the antitumor activity of trilaciclib or placebo administered in combination with E/P/A to patients 
with SCLC 
Determine the safety and tolerability of trilaciclib or placebo administered in combination with E/P/A in 
patients with SCLC 
Evaluate potential of trilaciclib to reduce chemotherapy-induced myelosuppression by assessing effects on 
multiple lineages and current standard of care interventions to treat myelosuppression (neutrophils, RBC, 
platelets, lymphocytes) 
Describe the PK of trilaciclib, carboplatin, and etoposide in a subset of patients; and atezolizumab in all 
patients 
 
 
 
 
 
 
 
  
  
 
E/P/A = etoposide + carboplatin + atezolizumab; irRECIST = immune-related RECIST; ORR = objective response rate; 
OS = overall survival; PK = pharmacokinetics; PFS = progression-free survival; 
; RBC = red 
blood cell; SCLC = small cell lung cancer 
 
2.2. 
Study Design 
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 2 study of the 
efficacy and safety of (etoposide, carboplatin, and atezolizumab) E/P/A with trilaciclib or 
placebo therapy for patients with newly diagnosed extensive-stage SCLC. Approximately 100 
patients will be randomly assigned (1:1 fashion) to trilaciclib 240 mg/m2 or placebo administered 
IV on Days 1 to 3 with E/P/A therapy for up to four 21-day cycles (induction part). 
Randomization will be stratified by Eastern Cooperative Oncology Group (ECOG) performance 
status (0 to 1 versus 2) and presence of brain metastases (yes versus no). Following the 
completion of up to 4 chemotherapy-containing (trilaciclib or placebo + E/P/A) cycles, patients 
will proceed to the maintenance part of the study and receive atezolizumab monotherapy on Day 


 
 
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1 of every 21-day cycles. Study drug refers to trilaciclib or placebo + E/P/A during the induction 
part and atezolizumab during the maintenance part. Treatment in both parts will continue until 
disease progression, unacceptable toxicity, withdrawal of consent, or discontinuation by 
investigator. Following disease progression per Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1), if the patient appears to be deriving clinical benefit, the investigator 
believes it is in the best interest of the patient, and the patient has provided re-consent, study 
drug administration may be continued until loss of clinical benefit. The study includes 3 phases: 
Screening Phase, Treatment Phase (induction part + maintenance part), and Survival Follow-up 
Phase. The Treatment Phase begins on the day of first dose with study treatment and completes 
after the last Post Treatment Visit.  
An independent data monitoring committee (DMC) will perform interim reviews of 
accumulating safety and disposition data approximately every 4 months during the Treatment 
Phase of the study, depending upon the enrollment rate. The first DMC meeting 
will occur after approximately the first 20 patients have been enrolled and completed at least 1 
cycle. Details of the DMC, including objectives, composition, scope, and frequency, will be 
described in a DMC charter.  
 
Criteria for Subsequent Cycles and Study Duration 
Study drug administration will continue for up to 4 chemotherapy-containing (trilaciclib or 
placebo + E/P/A) cycles during the induction part of the study and atezolizumab monotherapy 
will be administered on Day 1 of every 21-day cycle during the maintenance part of the study. 
Study drug administration will continue until disease progression per RECIST v1.1, 
unacceptable toxicity, withdrawal of consent, or discontinuation by investigator, whichever 
occurs first. However, if the patient appears to be deriving clinical benefit, the investigator 
believes it is in the best interest of the patient, and the patient has provided re-consent, study 
drug administration may be continued until loss of clinical benefit (see Section 11.1.4). 
Treatment cycles will occur consecutively without interruption, except when necessary to 
manage toxicities or for administrative reasons as described below. 
Criteria for Starting Cycle 2 and subsequent cycles in the induction part up to 
Induction Cycle 4  
Patients must 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 > 9 weeks for recovery from any toxicity related to trilaciclib or placebo + etoposide 
and carboplatin (E/P) in order to meet the continuation criteria will result in discontinuation of 
trilaciclib or placebo + E/P. A delay of > 15 weeks for recovery and management of immune-
related toxicities attributed to atezolizumab (12 weeks for recovery to ≤ Grade 1 and up to an 
additional 3 weeks for steroid taper of oral prednisone or equivalent to  10 mg/day) will result 
in discontinuation of atezolizumab. If patients meet the criteria for starting the subsequent cycle, 
a delay of up to 2 weeks is permitted for administrative reasons (eg, holiday, vacation, etc.); 


 
 
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however, a total delay of more than 9 weeks for trilaciclib or placebo + E/P, or 15 weeks for 
atezolizumab must be discussed with the medical monitor. 
 
 
 
 
 
Discontinuation or interruption of trilaciclib or placebo + E/P does not preclude continuation of 
atezolizumab and vice versa. For instance, if an AE is attributed to trilaciclib or placebo, 
etoposide, or carboplatin (eg, hematologic toxicity) during the induction part of the study; then 
atezolizumab may be continued while the trilaciclib or placebo + E/P are held. While the 
trilaciclib or placebo + E/P are held, the patient will continue to receive atezolizumab, be 
monitored for safety, and will begin the next trilaciclib or placebo + E/P/A-containing induction 
cycle after the toxicity resolves. If the AE is immune related and attributed to atezolizumab; then 
trilaciclib or placebo + E/P may be continued for up to 4 cycles while the atezolizumab is held.  
After discontinuation of all study drugs, patients should be strongly encouraged to complete all 
scheduled assessments through the end of their current 21-day treatment cycle, 
 
; CBC assessment on Day 22; all Post-Treatment Visits; 
and the Survival Follow-up Phase of the study, which is to continue until at least 70% of the 
patients on the study have died. The G1T28-05 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 36 months, assuming 12 months of accrual and 24 
months follow-up. 
• The Survival Follow-up Phase will continue until at least 70% of the randomized patients 
have died.  
The study scheduled assessments are presented in Table 2 below: 
 


 
 
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Table 2  
Schedule of Assessments 
  
Screen-
ing  
Enroll 
Induction (21-day cycles)a 
Last 
Induc
-tion 
Cycle 
Maintenance  
(21-day cycles)b 
Post-Treatment 
Visitsc 
Survival 
Follow-
upd 
Induction Cycles 1 and 3 
Induction Cycles 2 and 4 
Maintenance 
Cycle 1 and 
Odd Cycles 
Maintenance  
Cycle 2 and 
Even Cycles 
Cycle Day  
-14  
-3 to 1 
1 
2 
3 
8 
15 
1 
2 
3 
8 
15 
22 
1 
1 
30 (+3) 
90 (+7) 
 
Informed Consente 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Eval. 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance Status 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
Physical Exam 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
Height, Weight & 
Vital Signsg 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Clinical Chemistry 
X 
 
Xh 
 
 
 
 
Xh 
 
 
 
 
 
Xh 
Xh 
X 
X 
 
TSH, free T4, and 
free T3 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
Hematology 
X 
 
Xi 
 
X 
X 
X 
Xi 
 
X 
X 
X 
X 
Xi 
Xi 
X 
X 
 
Urinalysis 
X 
 
Xh 
 
 
 
 
Xh 
 
 
 
 
 
Xh 
Xh 
X 
X 
 
Pregnancy testj 
 
Xj 
 
 
 
 
 
 
 
 
 
  
 
 
 
X 
X 
 
Randomizationk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Assessmentl 
Xl2 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Xl1,l2 
Xl1,l2 
Xl1 
Archived Tumor 
Samplem 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trilaciclib or 
Placebon 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Carboplatin 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Etoposide 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Atezolizumab 
 
 
Xo 
 
 
 
 
Xo 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PKq (Trilaciclib, 
Etoposide, 
Carboplatin) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Screen-
ing  
Enroll 
Induction (21-day cycles)a 
Last 
Induc
-tion 
Cycle 
Maintenance  
(21-day cycles)b 
Post-Treatment 
Visitsc 
Survival 
Follow-
upd 
Induction Cycles 1 and 3 
Induction Cycles 2 and 4 
Maintenance 
Cycle 1 and 
Odd Cycles 
Maintenance  
Cycle 2 and 
Even Cycles 
Cycle Day  
-14  
-3 to 1 
1 
2 
3 
8 
15 
1 
2 
3 
8 
15 
22 
1 
1 
30 (+3) 
90 (+7) 
 
Atezolizumab PKr 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
Immunologic 
Markers 
 
 
Xs 
 
 
 
 
 
 
 
 
 
 
Xs 
 
 
Xs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEsu 
Xu 
Xu 
Xu 
 
Con. Medications 
X 
X 
 
 
Survival Follow-upd 
 
 
X 
AE = adverse event; Eval. = evaluation; 
 
 irRECIST = immune-related RECIST; 
; PK = pharmacokinetics; RECIST v1.1 = Response Evaluation 
Criteria in Solid Tumors, Version 1.1; T3 = tri-iodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone 
a 
During the induction part, study drug administration (trilaciclib or placebo plus E/P/A) will continue for up to four 21-day cycles or until disease progression per 
RECIST v1.1, unacceptable toxicity, withdrawal of consent, or discontinuation by investigator, whichever occurs first. Following disease progression per RECIST v1.1, if the 
patient appears to be deriving clinical benefit, the investigator believes it is in the best interest of the patient, and the patient has provided re consent, study drug administration may 
be continued until loss of clinical benefit.  
b 
During the maintenance part, study drug administration (atezolizumab) will continue in 21-day cycles until disease progression per RECIST v1.1, unacceptable toxicity, 
withdrawal of consent, or discontinuation by investigator, whichever occurs first. Following disease progression per RECIST v1.1, if the patient appears to be deriving clinical 
benefit, the investigator believes it is in the best interest of the patient, and the patient has provided re consent, study drug administration may be continued until loss of clinical 
benefit. 
c 
Patients will return to the study center for post-treatment visits at 30 (+3) and 90 (+7) days after the last dose of study drug.  
d 
Monthly phone calls will be made to each patient that is in the Survival Follow-up Phase. Patients will be followed for survival until at least 70% of the patients have 
died. Any anticancer therapies used will be collected.  
e 
Informed consent may be obtained up to 28 days prior to the first study treatment administration. 
f 
Including medical, surgical, radiation history, smoking history, family history, documentation of tumor diagnosis, baseline signs and symptoms within 4 weeks prior to 
randomization, weight loss in the 6 months prior to randomization (≤ 5% or > 5%), and medications taken within 14 days of enrollment. 
g 
Height will only be measured at the screening visit. Weight will only be measured at the screening visit and on Day 1 of each cycle. Body surface area calculation (based 
on actual body weight) will be completed on Day 1 of each cycle and vital signs obtained within 15 minutes before and after trilaciclib or placebo and E/P/A infusions. Vitals only 
need to be taken before the trilaciclib or placebo infusion, between each subsequent infusion, and after the last infusion on Days 1 and 3.  
h 
Clinical chemistry (albumin, alkaline phosphatase, total bilirubin, calcium, chloride, creatinine, glucose, inorganic phosphorus, potassium, total protein, ALT, AST, 
lactate dehydrogenase [LDH], sodium, and blood urea nitrogen [BUN], amylase, lipase) and urine analysis may be obtained up to 72 hours prior to the first dose of each cycle of 
trilaciclib or placebo + E/P/A therapy (induction part) or atezolizumab (maintenance part).  
i 
Hematology will be obtained (hemoglobin, white blood cells (WBC) with differential, and platelet counts). Hematology may be obtained up to 24 hours prior to first 
dose of each cycle of trilaciclib/placebo + E/P/A therapy (induction part) or atezolizumab (maintenance part). 
j 
For female patients of childbearing potential: serum ß-hCG at enrollment; and serum or urine ß-hCG obtained at the post-treatment visits.   
k 
Randomization is to be done within 3 days prior to first dose of trilaciclib or placebo + E/P/A therapy, following confirmation that the patient is eligible for the study. 


 
 
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l 
For tumor assessment, all sites of disease should be assessed radiologically by CT or MRI at screening and after every even cycle for 9 months of the study (ie, 
approximately every 6 weeks) and after every third cycle (ie, approximately every 9 weeks) thereafter while receiving study drug, until the occurrence of disease progression. 
Additional scans may be obtained at the discretion of the investigator, if clinically indicated. If a patient shows a radiological response (CR or PR), a confirmatory radiological 
assessment will be performed at least 4 weeks after the response was first noted. Assessments should be performed within 7 days of starting the subsequent cycle. The same 
method of assessment (CT or MRI) should be used to characterize tumors at screening and at all follow-up assessments. If positron emission tomography is used, it should also be 
accompanied by spiral CT or MRI.  
 
l1: At the post-treatment visits at 30 (+3) and 90 (+7) days after the last dose of study drug, obtain tumor assessment for patients who have not progressed at the time of 
study drug discontinuation (may be performed within 4 weeks). For those patients in the survival follow-up who have not progressed at the time of study drug discontinuation, 
tumor assessments, including all sites of disease, will be assessed radiologically by CT or MRI, as performed at screening, every 2 months (approximately 60 ± 7 days) until the 
occurrence of progressive disease or study completion. 
 
l2: Brain scans with contrast (by CT or MRI) to be obtained with tumor assessment at screening (within 28 days of dosing). Patients without the presence of brain 
metastases at screening should also have a brain scan at the end of the induction part. Patients with brain metastases at screening should have brain scans with every scheduled 
tumor assessment.  
m 
Archived tumor samples should be available for banking for assessment of relevant DNA, ribonucleic acid (RNA), and protein markers, such as PD-L1 or those involved 
in the CDK4/6 pathway. Tumor samples may be banked for up to 10 years. 
n 
Trilaciclib or placebo will be administered as an IV infusion in 250 mL of D5W or sodium chloride solution 0.9% over approximately 30 minutes prior to E/P 
chemotherapy on Days 1 to 3 of every induction cycle. If there is any volume remaining in the trilaciclib or placebo infusion bag at the end of the 30 minutes, the infusion should 
be continued at the same rate until the entire contents of the bag have been administered to ensure patients receive the full dose. The interval between doses of trilaciclib or placebo 
on successive days should not be greater than 28 hours. The interval between the dose of trilaciclib or placebo and the first dose of chemotherapy on a given day (etoposide or 
carboplatin) should not be greater than 4 hours. Trilaciclib or placebo will only be administered with chemotherapy. If administration of E/P chemotherapy is discontinued, 
trilaciclib or placebo should also be discontinued. Chemotherapy cannot be administered until after completion of the trilaciclib or placebo infusion. If the second or third dose of 
trilaciclib in any given cycle is not administered for any reason, do not administer the dose of etoposide or carboplatin chemotherapy on that day. After discontinuation of study 
drug, patients should be strongly encouraged to complete all scheduled assessments through the end of their current 21-day treatment cycle, 
 
 CBC assessment on Day 22; the Post-Treatment Visits; and the Survival Follow-up Phase of the study. 
o 
During the induction part, atezolizumab should be administered following the administration of trilaciclib or placebo, etoposide, and carboplatin. 
p 
 
 
 
q 
At least 5 patients enrolled in each treatment group will have trilaciclib, etoposide, and carboplatin PK samples collected on Day 1 of Induction Cycles 1 and 3 at the 
time points specified.  
r 
Blood samples will be collected from all patients predose and 30 minutes after the end of atezolizumab infusion to determine the minimum and maximum observed 
serum atezolizumab concentration on Day 1 of Induction Cycles 1, 2, 3, and 4; Maintenance Cycles 4, 8, 12, and every eighth cycle thereafter; and at 30 (+3) and 90 (+7) days after 
the last dose of study drug.  
s 
Peripheral blood samples will be collected at predose on Day 1 of Induction Cycle 1, Day 1 of Maintenance Cycle 1 (first cycle of maintenance part), Day 1 of 
Maintenance Cycle 5, and at the post treatment visit at 90 (+7) days after the last dose of study drug. 
t 
 
  
u 
Adverse events will be recorded from the time of informed consent. AEs will be collected through 30 days after the last dose of study drug; SAEs and AESI will be 
collected through 90 days after the last dose of study drug. All AEs should be followed until they are resolved, have returned to baseline, or it is deemed that further recovery is 
unlikely.  
 


 
 
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2.3. 
Number of Patients 
Overall, approximately 100 patients will be enrolled in the study. The 100 patients will be 
randomly assigned (1:1 fashion) to trilaciclib 240 mg/m2 or placebo administered IV on Days 1 
to 3 with E/P/A therapy for up to four 21-day cycles (induction part). 
The initial sample size calculations were based on a primary endpoint of OS where a sample size 
of 100 (1:1 treatment allocation ratio between the two groups of placebo + E/P/A and trilaciclib 
+ E/P/A) provided 80% power to detect a hazard ratio of 0.6 using an overall type 1 error 
probability of 0.1 (1-sided).  With the change in endpoints outlined in amendment 2, the sample 
size calculation is now based on demonstrating the superiority of trilaciclib + E/P/A versus 
placebo + E/P/A with respect to at least one of the primary endpoints. With this amendment, the 
overall type I error rate is now 0.025 (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 0.025/2 = 0.0125 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 treatment groups (trilaciclib + E/P/A versus placebo + E/P/A) requires 
82 evaluable patients (41 per treatment arm). This implies that 88 patients need to be randomized 
assuming a 95% evaluability rate. For occurrence endpoints (occurrence of severe (Grade 4) 
neutropenia, assuming its proportion of 45% for placebo + E/P/A, testing for an absolute 
reduction of 34% to 11% with trilaciclib + E/P/A would require a sample size of at least 100 
patients (50 per treatment arm). Assuming a 95% evaluability rate, at least 106 patients need to 
be enrolled to complete the study. Therefore, the final adjusted sample size is 106 to account for 
the evaluation of 2 primary endpoints. 
All calculations were carried out using the POWER procedure in SAS® version 9.4. 


 
 
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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 
the study unblinding. 
3.1.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set includes all randomized patients. 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 
A 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 (etoposide, carboplatin, atezolizumab, or 
trilaciclib). 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 
(etoposide, carboplatin, atezolizumab, or trilaciclib). 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 analysis set.  
3.1.4. 
Per Protocol (PP) Analysis Set 
The per-protocol (PP) analysis set is a subset of the mITT analysis set and may also be used to 
analyze select endpoints. The criteria for inclusion in the PP analysis set will be based on study 
drug administration and major protocol deviations, and it will be finalized and documented prior 
to unblinding patients in the study. 
It will include only those patients who have no key protocol deviations (as described in Section 
3.2) and who received the treatment to which they were randomized. For any patients who 
received the wrong treatment during any part of the study, their data will be excluded from the 
PP analysis set. PP analysis set may be used to analyze selected endpoints to test the robustness 
of results. 
3.1.5. 
Response Evaluable Analysis Set 
The Response Evaluable Analysis Set will include all patients who are in the mITT and (1) have 
at least 1 post-baseline tumor assessment, (2) discontinued treatment because of clinical 
progression, or (3) died due to disease progression before their first postbaseline tumor scan. The 
response evaluable analysis set will be used for analyses of tumor response. 
3.1.6. 
Pharmacokinetics (PK) Analysis Set 
The PK Analysis Set will not be used for any analyses described in this SAP.  Rather the PK 
analyses and the PK Analysis Set will be described in a separate document. 


 
 
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3.2. 
Protocol Deviations  
Certain protocol deviations are key in that they may affect the ability to assess the safety and 
efficacy of study drug. Patients with key deviations 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 set regardless of these deviations. 
The criteria for inclusion in the PP set will be finalized and documented prior to unblinding 
patients for the study. 
If a patient is randomized, 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 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. All major protocol deviations will be reviewed in a 
data review meeting to classify protocol deviations as non-key or key, and to discuss the 
potential impact on statistical analysis. This will be documented in a note to file prior to database 
lock and unblinding.  
    






 
 
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5.1. 
Efficacy Endpoints 
Unless otherwise specified, all primary and key secondary efficacy endpoints will be evaluated 
and derived for the induction treatment period. 
5.1.1. 
Primary Endpoints 
5.1.1.1. 
Occurrence of Severe (Grade 4) Neutropenia 
For the induction treatment period, the total number of SVN events is the number of induction 
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 induction cycles 
without SVN is calculated as total number of induction cycles received – total number of 
induction 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 an induction cycle or the induction treatment period 
is defined as a binary variable (Yes or No); Yes, if total number of induction 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 for this 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. 


 
 
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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. If no SVN 
occurs, then the cycle is not used in this analysis. 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.    
For the induction 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 
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) Rules of imputation of missing values at Day 2 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. 


 
 
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(2) Missing ANC values for Days 3-8 in each cycle will be imputed using linear 
interpolation, any recorded measurement will not be replaced. The missing values for 
Day 3 and Day 8 may be potentially imputed with this algorithm. 
Figure 1 Graphical Demonstration of Linear Interpolation 
 
Note: The slopes are calculated for each treatment group, where 𝑌̅1 and 𝑌̅2 are the 
mean of ANC values at relevant timepoint. For a time interval, e.g. interval of Day 
1 and Day 8 (inclusive), 𝑌̅1 is the average of the earliest point in the interval and 𝑡1 
is the average of the earliest day in the interval. Similarly, 𝑌̅2 is the average of the 
latest point in the interval and 𝑡2 is the average of the latest day in the interval.  
• If there are at least two assessments within the interval of Day 3 and Day 8 (inclusive), 
calculate the slope between the first available ANC value and last available ANC value: 
− 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 3 and Day 8 (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 3 and Day 8 (inclusive), SVN cannot 
be determined, and the data remains missing.  
(3) A similar algorithm as in (1) will be performed to impute missing ANC values for Days 
9-15 in each cycle using linear interpolation. Day 8 will be used as the earliest date in the 


 
 
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calculations only if it is recorded; it will be interpolated in this interval. Any other 
recorded measurements will not be replaced.  
(4) 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.   
(5) For a cycle where the SVN event does not resolve by end of the cycle, all values between 
the last assessment and the end of cycle are set to SVN.  
(6) 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 induction 
treatment period will be defined as a separate event and included in the efficacy analyses. A 
sensitivity analysis including all events occurring during the entire induction treatment period 
will also be performed. 
Occurrence of an RBC transfusion during the induction treatment period is defined as a binary 
variable (Yes or No); Yes if total number of RBC transfusion ≥ 1 is observed, No for other 
scenarios.   
5.1.2.2. 
Occurrence of GCSF Administrations 
Administration of GCSF is collected throughout the induction treatment period. Those cycles 
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 induction treatment period, the total number GCSF administrations is the number of 
induction 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 induction cycles 
where GCSF was NOT given is calculated as total number of induction cycles received – total 
number of induction cycles where GCSF was administered. 
Therefore, any occurrence of a GCSF administration during an induction cycle or the induction 
treatment period is defined as a binary variable (Yes or No); Yes if total number of induction 
cycles with GCSF administration ≥ 1 is observed, No for other scenarios.    
5.1.2.3. 
All-Cause Dose Reductions  
Dose reductions are not permitted for trilaciclib or atezolizumab. Dose reductions for E/P are 
derived from changes in the protocol-specified dose on the dosing page and correspond to the 
reductions for toxicity specified in the protocol.  










 
 
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grouped timepoint, if there are multiple assessments on different dates for the same target 
lesions, the last assessment will be used.  
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; or (ii) withdrawal of consent; or (iii) 
receiving subsequent anti-cancer therapy, whichever is earlier.   
A patient’s BOR will be determined based on Table 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 locking the database.    
For patients who are treated beyond progression and subsequently have a response, the best 
overall response is only derived from assessments up to and including the time of the initial 
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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where ESAs were NOT given is calculated as total number of induction cycles received – total 
number of induction cycles where ESAs were administered. 
Therefore, any occurrence of an ESA administration during the induction treatment period is 
defined as a binary variable (Yes or No); Yes if total number of induction cycles with 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 
World Health Organization Drug Dictionary (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 induction 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 induction treatment period is defined 
as a binary variable (Yes or No); Yes if total number of IV antibiotics administration ≥ 1 is 
observed, No for other scenarios.     
5.1.3.8. 
Occurrence of Infection Serious Adverse Events (SAEs) and Pulmonary 
Infection 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 induction treatment period will be defined 
as separate event. Data handling conventions for missing start and stop dates for AEs are 
described in Section 5.2.2.    
Any occurrence of an infection SAE during the induction treatment period is defined as a binary 
variable (Yes or No); Yes if total number of infection SAE events ≥ 1 is observed, No for other 
scenarios.  
5.1.3.9. 
Occurrence of Pulmonary Infection 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 pulmonary infection SAE 
records is as follows: if the SOC from MedDRA takes value “INFECTIONS AND 
INFESTATIONS”, the PT takes values from Table 10, and the AE is a serious event. 
 
 




 
 
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5.2. 
Safety Endpoints  
5.2.1. 
Chemotherapy Exposure Endpoints 
5.2.1.1. 
Duration of Exposure 
Duration of exposure will be calculated for the overall treatment period as well as separately for 
the induction treatment period and the maintenance treatment period. Note that Duration of 
exposure will be different than Duration of the treatment period defined elsewhere, and it will 
only apply to exposure summaries. 
Induction period duration of exposure (days) = Day 1 of last induction cycle – Cycle 1 Day 1 of 
induction phase + 21. 
Maintenance period duration of exposure (days) = Day 1 of the last maintenance cycle – Cycle 1 
Day 1 of maintenance phase + 21. 
Overall period duration of exposure (days) = Day 1 of the last cycle (either maintenance or 
induction) – Cycle 1 Day 1 of induction phase + 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 (carboplatin, etoposide, atezolizumab or trilaciclib).  In addition to the numeric summary 
for the number of cycles, the number of cycles for the induction treatment period will be 
categorized as 1, 2, 3 or 4. The number of cycles in the maintenance period will be categorized 
as:  1, 2, 3, 4, 5, 6, and > 6.  
5.2.1.3. 
Dose Intensity and Cumulative Dose 
Algorithms for calculating parameters relevant to the dose exposure and intensity are included in 
Table 12.  All doses, including unscheduled doses, will be used in the applicable parameter 
calculations. For trilaciclib/placebo, etoposide, and carboplatin, these drug specific calculations 
will be for induction period exposure only. For atezolizumab they will be for induction, 
maintenance, and overall exposure periods. 




 
 
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answers “Yes”), this will be counted as a delay. Reason for delay is not collected. Delays 
will be calculated over the induction, maintenance, and overall periods. 
• Missed doses are identified on the dosing page of each study drug based on the question 
“Was the dose given?”. The missed dose information will be obtained for each study 
drug. For a study drug, if the last record of response to question “Was the dose given?” is 
No, 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 are given on the same day, and 
o No study drugs are given subsequently. 
The reasons for missed doses will be summarized in the following categories: (1) 
Hematological toxicity, (2) Non-hematological toxicity, and (3) Other.  
• Dose reductions are not permitted for trilaciclib or atezolizumab.  
• Dose reductions for carboplatin and etoposide are determined by comparing the actual 
dose on the respective drug administration pages between the current cycle and the 
previous cycle. A window of 10% around both etoposide and carboplatin doses will be 
used to check for dose reductions. They occur in the following order: 
o 1st Reduction: Etoposide dose reduced from 100 mg/m2 to 75 mg/m2, Carboplatin 
dose reduced from AUC 5 to AUC 4. 
o 2nd Reduction: Etoposide dose reduced to 50 mg/m2, Carboplatin dose reduced to 
AUC 3. 
No more than 2 dose reductions of E/P in total are allowed for any patient. Toxicity that 
requires dose reduction more than twice will lead to discontinuation of trilaciclib or 
placebo + E/P therapy; 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. 
5.2.2. 
Adverse Events (AEs) 
All AEs will be coded from verbatim text to PTs and grouped by SOC using the MedDRA 
Version 20.1. AEs will be collected from the time of signature of informed consent throughout 
the treatment period and up to 30 days after the last dose of study treatment. SAEs and AESI will 
be collected through 90 days after the last dose of study drug. AEs are graded by investigator 
according to CTCAE, Version 4.03.  
For the induction treatment period, TEAE analyses will include all AE’s that started on or after 
the first dose of study drugs and up to the date of first dose of atezolizumab in the maintenance 
period. If the subject did not enter the maintenance period, then AEs up to the first dose of the 
last cycle in the induction period + 36 days (inclusive) will be considered TEAE.  












 
 
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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 5.2.2 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 6.2.7.1.5. 
6.1.3. 
Visit Windowing 
It is expected that there will be a variation between patients in the actual number of study days 
from the start of administration of study drug within each cycle − defined as Day 1 − to the dates 
that the scheduled visits 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 18. 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. 
Only induction treatment cycles will have windowed visits. For maintenance treatment cycles, 
nominal visits will be used as all assessments are scheduled for Day 1 of each cycle. 
 
 




 
 
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Clinical Study Protocol G1T28-05                                     
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6.1.4. 
Adjustment for Covariates 
Patient randomization was stratified by ECOG performance status (0 or 1 vs. 2) and presence of 
brain metastases (Yes vs. No). 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 treatment group: 
• 
Number of patients screened 
• 
Number and percentage of screening failures 
• 
Reason for screening failure 
• 
Number of patients dosed 
• 
Number of patients randomized 
• 
Number of patients randomized and not dosed 
A separate table will be presented to show the patients included in each analysis set and reason 
for exclusion from an analysis set. 
Patient status at treatment and study completion will be listed and summarized.  The listing will 
include whether patients discontinued from the treatment and the reasons for the discontinuation, 
along with the date of first and last dose and the date of completion or discontinuation from the 
treatment.  The same information will be provided for patients who discontinued from the study.  
The following summaries will be added to the disposition table: 
• 
End of treatment status (discontinued/ongoing for each study drug)   
• 
Reason for study drug discontinuation (for each study drug) 
• 
Number of patients going into Survival follow-up  
• 
Number of patients continuing into Maintenance period  
• 
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), gender, race, ethnicity, country, screening vital signs (body weight, height, 
BMI, BSA), ECOG status, presence of brain metastases, and smoking history (never smoker, 
former smoker and current smoker), will be summarized and listed.   
6.2.3. 
Disease Characteristics 
Disease characteristics including diagnosis confirmation by neuroendocrine markers, stage at 
diagnosis, site from which diagnostic sample was obtained, and baseline LDH will be 
summarized and listed. Date of SCLC diagnosis, and date of extensive stage diagnosis will be 
listed only. 


 
 
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6.2.4. 
Medical/Surgical History  
Medical history will be coded to SOC and PT using MedDRA Version 20.1. 
The number and percentage of randomized patients with any past medical/surgical history within 
each SOC and PT will be provided by treatment group. A patient will only be counted once 
within a particular SOC (PT) even if he/she has multiple conditions/diseases in the same SOC 
(PT). The conditions/diseases from medical history are those conditions/diseases that stopped 
prior to the study entry. 
6.2.5. 
Concomitant Medications 
All medication verbatim terms collected will be coded to Anatomical Therapeutic Classification 
(ATC) and PT using the WHO-DD Version Sep2017.  
Prior medications are defined as those taken by the patient prior to the administration of study 
drug. Concomitant medications are defined as those taken by the patient at any time between the 
date of study drug administration and study completion/discontinuation. Medication with start 
date being partially or completely missing will be assumed to be concomitant if it cannot be 
definitely shown that the medication did not occur during the treatment period.   
Medications with onset/end dates that are partially/completely missing will be imputed as 
follows: 
(i) For onset date: 
− If only the day part of the medication onset date is missing and occurs in the same month and 
year as the first dose date of study drug, the date of first dose of study drug will be used as 
the onset date of the medication. Otherwise, the first day of the month will be used to 
complete the onset date of the medication;  
− If the day and month parts of medication onset date are missing and occur in the same year as 
the first dose of study drug, the date of the first dose of study drug will be used as the onset 
date of the medication. Otherwise, January 1st will be used to complete the onset date of the 
medication; 
− If the medication onset date is completely missing, the date of the first dose of study drug 
will be used as the onset date of the medication. 
(ii) For end date: 
− If only the day part of the medication end date is missing, the last day of the month will be 
used to complete the end date of the medication;  
− 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, the last date during the treatment period will be 
used as the medication end date. Otherwise, the date of the first dose of study drug will be 
used as the medication end date.    
Concomitant medications will be summarized by presenting the number and percentage of 
patients by PT and ATC. Patients taking the same medication multiple times will only be 
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.  


 
 
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Clinical Study Protocol G1T28-05                                     
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All prior and concomitant medications will be presented in a patient listing. 
6.2.6. 
Radiotherapy and Subsequent Anti-Cancer Therapy 
The prior and subsequent radiotherapy (Yes or No), site and reason will be summarized by 
treatment group and listed.  
All verbatim terms collected of subsequent anti-cancer therapy will be coded to Anatomical 
Therapeutic Classification (ATC) and PT using the WHO-DD Version Sep2017.  
The subsequent anti-cancer therapy 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. Additionally, anti-cancer therapies will 
be grouped into lines of treatment and the number of subsequent lines of therapy will be 
summarized categorically. Best response to treatment will also be summarized. The data will be 
presented in a patient listing. All subsequent anti-cancer therapies will be presented in a patient 
listing. 
6.2.7. 
Efficacy Analyses 
All the efficacy variables will be summarized using descriptive statistics by cycle or visit, with 
the supportive data provided in patient listings.  Data will be summarized using descriptive 
statistics and the between treatment comparison (trilaciclib vs placebo), will be performed only 
for the primary and secondary endpoints outlined in Sections 5.1.1 – 5.1.3. The comparisons 
between trilaciclib vs. placebo will be built into the multiplicity adjustment described in Section 
6.2.7.1.4, 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 0.025. However, for these 
comparisons, all statistical tests will be conducted at a two-sided .05 alpha level unless otherwise 
specified. Where appropriate, model-based point estimates, together with their two-sided 95% 
CIs will be presented along with the two-sided p-value for the test unless otherwise specified.  
Graphical presentation of efficacy results will be performed as needed. 
Unless otherwise specified, all analyses for the efficacy endpoints will be conducted for the 
induction treatment period which is defined to be between the date of randomization and the end 
of the last induction cycle.  
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 induction 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 brain 
metastases (Yes vs. No), and treatment as a fixed effect. The logarithm transformation of number 
of induction 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 95% 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, treatment difference will be evaluated using a nonparametric analysis of covariance 


 
 
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Clinical Study Protocol G1T28-05                                     
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(ANCOVA) (Stokes 2012). The nonparametric ANCOVA will include study baseline ANC 
value as covariate, stratification factors of ECOG (0 or 1 vs. 2) and brain metastases (Yes vs. 
No), and treatment as a fixed effect. A two-sided p-value will be generated from this model. 
Along with the descriptive statistics, the mean difference and Hodges-Lehmann estimate of 
median difference between the two treatment groups, together with its 95% 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 induction treatment 
period divided by 7 (i.e. week) instead of number of induction cycles, and. An additional 
sensitivity analysis will look all transfusions during the induction 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 brain metastases (Yes vs. No), and treatment as 
a fixed effect. The logarithm transformation of number of induction cycles will be included as an 
offset variable in the modeling. The two-sided p-value, aRR (trilaciclib vs placebo) and its 95% 
CIs will be presented. 
The total number of all-cause dose reductions will be summarized descriptively, along with the 
number of induction cycles, and the event rate per cycle (calculated as the total number of 
events/total number of induction cycles). The cumulative incidence of events during the 
induction treatment period will be summarized and presented graphically by cycle. 
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 GC only. 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 95% 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 + 
E/P/A versus placebo + E/P/A on the primary and key secondary myelosuppression efficacy 
endpoints in Sections 5.1.1 and 5.1.2.  


 
 
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Clinical Study Protocol G1T28-05                                     
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The multiplicity problem includes the following 5 hypotheses of no effect: 
• Hypothesis 𝐻1. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
duration of severe (Grade 4) neutropenia in Cycle 1. 
• Hypothesis 𝐻2. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
occurrence of severe (Grade 4) neutropenia. 
• Hypothesis 𝐻3. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
all-cause dose reductions in the MAHE composite. 
• Hypothesis 𝐻4. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
occurrence of RBC transfusions on/after Week 5 on study. 
• Hypothesis 𝐻5. Comparison of trilaciclib + E/P/A versus placebo + E/P/A for 
occurrence of G-CSF administration. 
These 5 hypotheses can be grouped into 3 families: 
• Family 1 (𝐹1) includes the hypothesis 𝐻1. 
• Family 2 (𝐹2) includes the hypothesis 𝐻2. 
• Family 3 (𝐹3) includes the hypotheses 𝐻3, 𝐻4, and 𝐻5. 
The 1-sided p-values for these 5 comparisons will be used for the multiple testing procedure. 
A Hochberg-based gatekeeping procedure will be utilized to control the global familywise error 
rate across the 5 null hypotheses in the strong sense at a 1-sided α=0.025 level, and it satisfies the 
positive dependence condition at 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 5 hypotheses displayed in  
 


 
 
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Clinical Study Protocol G1T28-05                                     
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Figure 2 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 vs placebo comparisons for Family 1 (hypothesis 𝐻1) are 
performed using a truncated version of the Hochberg procedure. The truncation 
parameter γ is set to 0.  
• Step 2. The trilaciclib vs placebo comparisons for Family 2 (hypothesis 𝐻2) are 
performed using a truncated version of the Hochberg procedure if 𝐻1 is significant in 
Step 1. The truncation parameter γ is set to 0.  
• Step 3. The trilaciclib vs placebo comparisons for Family 3 (hypotheses 𝐻3, 𝐻4, and 𝐻5) 
are performed using the regular Hochberg test if 𝐻2 is significant in Step 2. 
 
 




 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-05                                     
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• Family 2 (𝐹2) includes the hypothesis 𝐻2. 
• Family 3 (𝐹3) includes the hypotheses 𝐻3, 𝐻4, and 𝐻5. 
Using more compact notation, the families are defined as follows: 
𝐹1 = {𝐻𝑖, 𝑖∈𝑁1},  𝐹2 = {𝐻𝑖, 𝑖∈𝑁2},  𝐹3 = {𝐻𝑖, 𝑖∈𝑁3}. 
where the index sets are defined as 𝑁1 = {1}, 𝑁2 = {2}, 𝑁3 = {3,4,5}. Let 𝑡𝑖 and 𝑝𝑖 denote the 
test statistic and 1-sided p-values associated with the hypotheses, respectively. Let 𝛼 denote the 
global familywise error rate, i.e., one-sided 𝛼= 0.025. 
Consider the closed family associated with Families 1, 2 and 3, i.e., a family of all non-empty 
intersections of the five hypotheses. Each intersection will be identified by an index set 
𝐼⊆𝑁 = {1, . . . ,5} 
(note that the empty set is excluded). For example, the index vector 𝐼= {1, 2, 5} corresponds to 
the intersection of the hypotheses 𝐻1, 𝐻2, and 𝐻5. 
To construct the Hochberg-based gatekeeping procedure that controls the global familywise error 
rate in the strong sense at an 𝛼 level, an 𝛼-level test needs to be defined for each intersection in 
the closed family. The multiple test and associated 𝑝-value for an intersection are computed in 
two steps. 
Step 1: Define 𝒑-values for subset intersections 
Consider an intersection corresponding to the index set 𝐼⊆𝑁 and define the index sets 𝐼𝑘= 𝐼∩
𝑁𝑘, 𝑘= 1, 2, 3. The 𝑝-values for the index sets 𝐼1, 𝐼2, and 𝐼3 are computed as follows: 
Let 𝑛1 denote the number of hypotheses included in 𝐼1 and let 𝑚1 = 𝑛1. If 𝑛1 > 0, the truncated 
Hochbergp-value is defined using the ordered 𝑝-values associated with the hypotheses included 
in the index set 𝐼1, denoted by  
𝑝1(1) ≤⋯≤𝑝1(𝑚1) 
The truncated Hochberg 𝑝-value for the index set 𝐼1 is given by 
𝑝(𝐼1) =
min
𝑖=1,⋯,𝑚1
𝑝1(𝑖)
𝛾1
𝑚1 −𝑖+ 1 + (1 −𝛾1)
 
Here 𝛾1 is the pre-specified truncation parameter in Family 1. Choosing a larger value of 𝛾1 
improves the power of comparisons in Family 1, and 𝛾1 is set to 0.5. 
Further, let 𝑛2 denote the number of hypotheses included in the index set 𝐼2. If 𝑛2 > 0, consider 
the hypotheses in the index set 𝐼2 and remove the hypotheses that are not consistent with the 
logical restrictions defined in  
 


 
 
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Clinical Study Protocol G1T28-05                                     
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Figure 2. Let 𝑚2 denote the number of hypotheses remaining in the index set 𝐼2 after this logical 
restriction operation. If 𝑚2 > 0, let  
𝑝2(1) ≤⋯≤𝑝2(𝑚2) 
denote the ordered 𝑝-values for the hypotheses remaining in the index set 𝐼2. The truncated 
Hochberg 𝑝-value for 𝐼2 is given by 
𝑝(𝐼2) =
min
𝑖=1,⋯,𝑚2
𝑝2(𝑖)
𝛾2
𝑚2 −𝑖+ 1 + (1 −𝛾2)
 
where 𝛾2 is the pre-specified truncation parameter in Family 2, which plays the same role as 𝛾1 
in Family 1, and 𝛾2 is set to 0.5. 
Finally, let 𝑛3 denote the number of hypotheses included in 𝐼3. If 𝑛3 > 0, remove the hypotheses 
that are not consistent with the logical restrictions defined in  
 


 
 
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Clinical Study Protocol G1T28-05                                     
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Figure 2. Let 𝑚3 denote the number of hypotheses remaining in the index set 𝐼3 after this logical 
restriction operation. If 𝑚3 > 0, let  
𝑝3(1) ≤⋯≤𝑝3(𝑚3) 
denote the ordered 𝑝-values for the hypotheses remaining in the index set 𝐼3. The Hochberg 𝑝-
value for 𝐼3 is given by 
𝑝(𝐼3) =
min
𝑖=1,⋯,𝑚3
𝑝3(𝑖)
1
𝑚3 −𝑖+ 1
 
Step 2: Define overall 𝒑-value 
The overall 𝑝-value for the intersection corresponding to the index set 𝐼 is computed by 
combining the 𝑝-values associated with the index sets 𝐼1, 𝐼2, and 𝐼3. Consider the following three 
scenarios: 
• If 𝑛1 > 0, the overall 𝑝-value is found using the following mixing function: 
𝑝(𝐼) = min (𝑝(𝐼1)
𝑏1
, 𝑝(𝐼2)
𝑏2
, 𝑝(𝐼3)
𝑏3
)  
where 𝑏1 = 1,  𝑏2 = 𝑏1(1 −𝑓1 ), 𝑏3 = 𝑏2(1 −𝑓2 ) and 𝑓1 and 𝑓2 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 𝑛1 = 0 and 𝑛2 > 0, the overall 𝑝-value is given by 
𝑝(𝐼) = min (𝑝(𝐼2)
𝑏2
, 𝑝(𝐼3)
𝑏3
)  
where  𝑏2 = 1, 𝑏3 = 𝑏2(1 −𝑓2 ). 
• If 𝑛1 = 0, 𝑛2 = 0 and 𝑛3 > 0, the overall 𝑝-value is given by 
𝑝(𝐼) = 𝑝(𝐼3)
𝑏3
 
where 𝑏3 = 1. 
The error rate function of the truncated Hochberg test with the truncation parameter 𝛾𝑘 for 
testing an intersection corresponding to the index set 𝐼𝑘, 𝑘= 1, 2, is defined as 
𝑒𝑘(𝐼𝑘) = 𝑃[𝑝(𝐼𝑘) ≤𝛼] 
and 𝑓𝑘= 𝑒𝑘(𝐼𝑘)/𝛼, 𝑘= 1, 2. It is shown in Brechenmacher et al. (2011) that 
𝑒𝑘(𝐼𝑘) = [𝛾𝑘+ (1 −𝛾𝑘)|𝐼𝑘|/𝑛𝑘]𝛼 
if the index set 𝐼𝑘 is non-empty and 𝑒𝑘(𝐼𝑘) = 0 the index set 𝐼𝑘 is empty. Here |𝐼𝑘| denotes the 
number of hypotheses included in the index set 𝐼𝑘.  
As shown in Dmitrienko and Tamhane (2011), the resulting test for the intersection 
corresponding to the index set 𝐼 is an 𝛼-level test. This implies that the Hochberg-based 


 
 
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Clinical Study Protocol G1T28-05                                     
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gatekeeping procedure controls the global familywise error rate in the strong sense at a one-sided 
𝛼= 0.025. 
Multiplicity-adjusted p-values 
Multiplicity-adjusted 𝑝-values for the Hochberg-based gatekeeping procedure are computed 
using the closure principle. For each hypothesis, the adjusted 𝑝-value is defined as the maximum 
over the 𝑝-values associated with the intersections in the closed family that include the 
hypothesis of interest. For example, the adjusted 𝑝-value for 𝐻2 is the maximum over the 𝑝-
values for intersections containing 𝐻2. 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 𝐻1, . . . , 𝐻𝑚. Let 𝑝1, . . . , 𝑝𝑚 
denote the associated raw p-values. Further, let 𝑝(1) < ⋯< 𝑝(𝑚) denote the ordered p-values and 
𝐻(1) < ⋯< 𝐻(𝑚) denote the hypotheses corresponding to the ordered p-values. 
The regular Hochberg test is based on the following testing algorithm: 
• Step 1: If 𝑝(𝑚) > 𝛼, accept 𝐻(𝑚) and go to Step 2, otherwise reject all null hypotheses 
and stop. 
• Step 𝑖= 2, . . . , 𝑚−1: If 𝑝(𝑚−𝑖+1) > 𝛼/𝑖, accept 𝐻(𝑚−𝑖+1) and go to Step 𝑖+ 1, 
otherwise reject all remaining null hypotheses and stop. 
• Step 𝑚: If 𝑝(1) > 𝛼/𝑚, accept 𝐻(1), otherwise reject 𝐻(1)· 
The truncated Hochberg test with the truncation parameter 𝛾 is based on the following testing 
algorithm: 
• Step 1: If 𝑝(𝑚) > [𝛾+ (1 −𝛾)/𝑚]𝛼, accept 𝐻(𝑚) and go to Step 2, otherwise reject all 
null hypotheses and stop. 
• Step 𝑖= 2, . . . , 𝑚−1: If 𝑝(𝑚−𝑖+1) > [𝛾/𝑖+ (1 −𝛾)/𝑚]𝛼, accept 𝐻(𝑚−𝑖+1) and go to 
Step 𝑖+ 1, otherwise reject all remaining null hypotheses and stop. 
• Step 𝑚: If 𝑝(1) > 𝛼/𝑚, accept 𝐻(1), otherwise reject 𝐻(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 ECOG (0 or 1 vs. 2) and brain metastases (Yes vs. No) 
as the stratification factor. The adjusted proportion difference (trilaciclib vs placebo) and its 95% 
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 induction treatment period (up to 30 days after last dose in 
induction period) without experiencing an event, Yes will be assigned to the variable.  


 
 
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Clinical Study Protocol G1T28-05                                     
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(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 induction treatment 
period will still be set to Yes, and patients who do not complete 4 induction cycles and do 
not experience 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 group. 
(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 do not complete 4 induction 
cycles and do not experience 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 less than 4 induction 
cycles) in the trilaciclib and placebo groups. For example, let nt be the number of 
randomized trilaciclib patients with missing response and nc 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 nc + 1 possible assumptions for number of 
No.  Therefore, there are total of (nt + 1) × (nc + 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) × (nc + 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 0.025, 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 induction cycles with SVN will be presented. 
DSN for each induction cycle will be presented using descriptive statistics. The primary analysis 
on DSN defined by Strategy 1 (refer to Section 6.2.7.1.1) 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. 
DSN, Strategy 2 (refer to Section 5.1.1.2.2) endpoint 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. The hazard ratio 
(HR) between the two treatments (trilaciclib vs placebo), together with its 95% 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. 


 
 
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Clinical Study Protocol G1T28-05                                     
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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 Secondary 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 brain metastases (Yes 
vs. No), and treatment as a fixed effect. The logarithm transformation of duration of induction 
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 95% CIs will be presented. 
The total number of MAHE will be summarized descriptively, along with the weeks of induction 
treatment duration, and the event rate per week (calculated as the total number of events/duration 
of induction treatment period divided by 7 [i.e. week]). The cumulative incidence of events 
during the induction 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 induction cycles 
divided instead of duration of induction 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. 
 
An event chart of the induction 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. 
6.2.7.2.2 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.  


 
 
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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. The adjusted proportion difference (trilaciclib vs placebo) and its 95% 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 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 induction 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.  
6.2.7.2.4 Analyses of Hematology Lab Values 
For the endpoints specified in Section 5.1.3.4 and 5.1.3.5, in addition to descriptive statistics 
summary, graphical displays 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 number 
of patients 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 induction period, and during the first 
induction 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: 


 
 
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• Occurrence of a Grade 3 or 4 hematologic toxicity during the induction treatment period 
(refer to Section 5.1.3.3); 
• Occurrence of an ESA administration during the induction treatment period (refer to Section 
5.1.3.6); 
• Occurrence of an IV antibiotic administration during the induction treatment period (refer to 
Section 5.1.3.7); The offset in the modified Poisson model will be the logarithm 
transformation of duration of induction treatment period divided by 7 (i.e. week) instead of 
number of induction cycles. Additionally, total number of IV antibiotic administrations will 
be summarized descriptively. 
• Occurrence of an infection SAE during the induction treatment period (refer to Section 
5.1.3.8); The offset in the modified Poisson model will be the logarithm transformation of 
duration of induction treatment period divided by 7 (i.e. week) instead of number of 
induction cycles. Additionally, total number of infection SAEs will be summarized 
descriptively. 
• Occurrence of a pulmonary infection SAE during the induction treatment period (refer to 
Section 5.1.3.9); The offset in the modified Poisson model will be the logarithm 
transformation of duration of induction treatment period divided by 7 (i.e. week) instead of 
number of induction cycles. Additionally, total number of pulmonary infection SAEs will be 
summarized descriptively. 
 
  
 
 
 
 
 
6.2.8. 
Safety Analyses 
All safety analyses will be based on the safety analysis set, as defined in Section 3.1.3.  
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 
applicable 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 
modifications will be summarized for each study drug (trilaciclib, carboplatin, etoposide, or 
atezolizumab). For each study drug, the dosing endpoints described in Section 5.2.1 will be 
summarized for the induction treatment period. Atezolizumab specifics summaries will be 
summarized by maintenance and overall treatment periods as well. This includes the following: 
• Number of cycles received; 


 
 
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• 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; 
• Number of patients with dose interruptions. 
The number of cycles delayed and the number and percentage of patients experiencing a 
treatment 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, atezolizumab AESIs, AEs leading to death, and AEs 
leading to study drug discontinuation or study withdrawal. Patients with more than one 
occurrence of the same SOC (PT) will be counted only once within the SOC (PT) categorization. 
AEs and SAEs will be summarized for the induction, maintenance, and overall treatment periods, 
the rest will be summarized for the overall treatment period only. 
AEs will also be summarized similarly by CTCAE grade and relationship to any study drug 
(trilaciclib, carboplatin, etoposide, or atezolizumab), 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. Those related 
to any study drug or atezolizumab will be summarized for the induction, maintenance, and 
overall treatment periods, the rest will be summarized for the overall treatment period only. 
All AEs, including AEs that started prior to the study medication, will be presented in patient 
listings. In addition, separate listings of all SAEs, atezolizumab AESIs, AEs leading to death, 
drug-related AEs, and AEs leading to study drug discontinuation or study withdrawal will be 
provided. 
The criteria for identifying infusion related reaction AEs or hematologic toxicity AEs are 
described in Section 5.2.2. A summary table showing the incidence of each category of AEs 
related to infusion and related to hematologic toxicity will be presented along with its supportive 
data listing. These will be summarized for the overall treatment period only. 
6.2.8.3. 
Laboratory Evaluations 
For hematology and clinical chemistry labs, the observed values and change from baseline will 
be summarized by cycle visit 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 overall 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. 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-05                                     
Statistical Analysis Plan for Region 2 
Version date: 01Nov2018 
 
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Listings of all laboratory data with 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 14) during the overall 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 screening physical examination dates 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 16. The frequency 
and percentage of patients with any potentially clinically significant findings during the 
induction treatment period will be presented. The supportive data will be provided in patient data 
listings.  
6.2.9. 
Subgroup Analyses 
The MAHE will be examined in the following subgroups: 
− Age group (ages <65; >65). 
− Gender (Male; Female). 
− Brain metastases (Yes; No). 
− ECOG performance status (0-1; 2). 
− 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. 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-05                                     
Statistical Analysis Plan for Region 2 
Version date: 01Nov2018 
 
CONFIDENTIAL 
      Page 62 of 66 
 
                                                 
 
6.2.11. 
Evaluate 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 
 
 
 
 
 
 
 
6.2.13. 
Planned Analysis  
The final myelosuppression analysis will be conducted after all patients have had the opportunity 
to receive at least 12 weeks of treatment (ie, randomized induction treatment part of the study). 
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 when 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 at which time an end of study analysis for OS will be conducted. Reported 
results, except 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 
myelosuppression analysis and no additional data will be expected. Additional PFS/OS analyses 
may be done with the timing to occur between the final myelosuppression analysis and study 
completion. 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-05                                     
Statistical Analysis Plan for Region 2 
Version date: 01Nov2018 
 
CONFIDENTIAL 
      Page 63 of 66 
 
                                                 
 
7. 
CHANGE FROM THE PROTOCOL 
The endpoints and analyses listed below are based on the Statistics Section in the Protocol 
Amendment 2, dated 14 September 2018. The list displays the changes from the initial analysis 
indicated in the protocol.  
 
 
 
 
 
 
 
  
 
 
 
 
 
 


 
 
G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-05                                     
Statistical Analysis Plan for Region 2 
Version date: 01Nov2018 
 
CONFIDENTIAL 
      Page 64 of 66 
 
                                                 
 
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. 
European Medicines Agency. Guideline on the evaluation of anticancer medicinal products in 
man. (2012). https://www.ema.europa.eu/documents/scientific-guideline/guideline-evaluation-
anticancer-medicinal-products-man_en-0.pdf. Accessed 19 October 2018.  
  
FDA Center for Biologics Evaluation and Research (CBER). Multiple Endpoints in Clinical 
Trials Guidance for Industry. https://www.fda.gov/downloads/drugs/guidancecompliance 
regulatoryinformation/guidances/ucm536750.pdf. Published January 2017. Accessed 
13 September 2018. 
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  
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.