Conditions: Extensive-stage Small-cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 95
Healthy volunteers: no

Brief summary:
A Randomized, double-blind, placebo-controlled, multi-center Phase 3 study evaluating efficacy, safety and pharmacokinetics of Trilaciclib In Extensive-Stage Small Cell Lung Cancer Patients Receiving Carboplatin combined with Etoposide or Topotecan The study consists of 2 parts: Part 1: safety run-in and pharmacokinetics evaluation of 12 ES-SCLC patients (6 each for first line and second/third line ES-SCLC patients); Part 2: randomized, double-blind, placebo-controlled efficacy confirmation study of 80 ES-SCLC patients (stratified by first line and second/third line ES-SCLC, ECOG PS \[0-1 vs 2\] and brain metastases.

The study includes screening period, treatment period, safety follow-up and survival follow-up.

Detailed description:
This is a multi-center Phase 3 clinical trial with an open-label single-arm safety run-in and PK evaluation part and a randomized double-blind, placebo controlled part in patients with ES-SCLC to evaluate the safety, efficacy, and pharmacokinetic profile of Trilaciclib based on completed clinical studies abroad.

The study consists of 2 parts. The first part, safety run-in and PK evaluation, enrolled approximately 12 patients with extensive-stage small-cell lung cancer, 6 patients each with 1st line ES-SCLC and 2nd/3rd line ES-SCLC to receive Trilaciclib in combination with carboplatin and etoposide (EC regimen) or with topotecan, and based on evaluable data from Cycle 1, evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy (prevention of myelosuppression) of Trilaciclib. The second part is a randomized double-blind, placebo-controlled efficacy validation study, and approximately 80 patients with ES-SCLC will be enrolled in Part II, stratified by 1st line vs 2nd/3rd line ES-SCLC, ECOG PS (0-1 vs 2), and presence vs absence of brain metastases, and randomized in a 1:1 ratio to Trilaciclib and placebo, in which patients with 1st line ES-SCLC receive Trilaciclib/placebo combined with EC regimen (Trilaciclib-EC group and placebo-EC group), and patients with 2nd/3rd line ES-SCLC receive Trilaciclib/placebo combined with topotecan (Trilaciclib-TPT group and placeboTPT group), and the efficacy of Trilaciclib (prevention of myelosuppression) will be evaluated with duration of severe neutropenia (DSN) in Cycle 1 as the primary endpoint. The planned dose of Trilaciclib is 240 mg/m2. If the safety data from the first part of the study suggest that the dose of Trilaciclib needs to be adjusted, 12 additional patients (6 patients each for 1st line ES-SCLC and 2nd/3rd line ESSCLC) will be enrolled in the first part of the study to explore the PK and safety of Trilaciclib 200 mg/m2. The study process includes screening period, treatment period, safety followup and survival follow-up.

The end of the study was defined as death in 75% of subjects, or 12 months after the last subject was enrolled, or the sponsor decided to terminate the study, whichever came first.

Arms:
arm 1: 12 patients( 6 patients are first line, 6 patients are second or third line) recieved Trilaciclib(240mg/m\^2) plus chemotherapy. arm 2: 41 patients received trilaciclib(240mg/m\^2) plus chemotherapy arm 3: 42 patients received placebo plus chemotherapy

Interventions: intervention 1: Trilaciclib, carboplatin, etoposide，or Topotecan intervention 2: placebo, carboplatin, etoposide，or Topotecan
Intervention descriptions: intervention 1: Trilaciclib plus carboplatin, etoposide for first line patients ;Trilaciclib plus Topotecan for second or third line patients intervention 2: placebo plus carboplatin, etoposide for first line patients ;placebo plus Topotecan for second or third line patients

Protocol document:
Prot_000.pdf: 
Official Title:         A randomized double-blind, placebo-controlled, multicenter
                             phase 3 study to evaluate the safety, efficacy and
                             pharmacokinetics of trilaciclib in patients with extensive stage
                             small cell lung cancer treated with carboplatin and etoposide
                              or with topotecan
NCT Number:        NCT04902885
Document Date:    Protocol Version 1.4: March 21,2022


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A randomized double-blind, placebo-controlled, multicenter phase 3 study 
to evaluate the safety, efficacy and pharmacokinetics of trilaciclib in 
patients with extensive stage small cell lung cancer treated with carboplatin 
and etoposide or with topotecan 
 
 
 
 
 
Protocol No.: 
 
Version No.: 
 
Version Date: 
 
 
 
Sponsor: 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document is confidential communication document of Jiangsu Simcere Pharmaceutical Co., 
Ltd. Receiving this document means that the recipient agrees that no unpublished information contained 
herein may be published or disclosed without the written consent of Jiangsu Simcere Pharmaceutical 
Co., Ltd., unless such disclosure is required by applicable laws and regulations. In addition, any 
information added to this document is confidential and owned by Jiangsu Simcere Pharmaceutical Co., 
Ltd., and its confidential principle is the same as this document. 
 
 
 
B02B00801-TRILA-301
V1.4
March
 
21,
 
2022
Jiangsu
 
Simcere Pharmaceutical Co., Ltd.


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VERSION HISTORY/REVISION HISTORY 
Version 
No. 
Version Date 
Reason for Amendment Description and Summary of Changes 
1.0 
20201019 
First draft 
1.1 
20210113 
Mainly modified study endpoints and increased exploration of 
population pharmacokinetic profiles 
1.2 
20210119 
Mainly modified some language expressions to be succinct and clear; 
added pharmacokinetic blood sampling points 
1.3 
20210817 
Add two other study secondary endpoints, chemotherapy drug dose 
adjustment recommendations, adjust timepoint and unblinding form of 
the main analysis of Part II, definition of the end of the study, adjust 
other sections and errata 
1 .4 
20220321 
Clarification of safety visit timepoints, full text errata, etc. 
Note: See also Annex Revision Summary for detailed revisions 
 


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 Sponsor Protocol Signature Page 
 
We have read and confirmed this clinical trial protocol. I agree to perform my duties in 
accordance with the laws of China, the Declaration of Helsinki, China 's GCP, and this study 
protocol. 
 
 
Sponsor: Jiangsu Simcere Pharmaceutical Co., Ltd 
Address of Sponsor: No. 699-18, Xuanwu Avenue, Xuanwu District, Nanjing, Jiangsu 
 
 
Authorized signature by sponsor: Wenjie Song Title: Vice President R&D 
Tel.: (021) 68099999-7876 
Address: Building 1, Lane 118, Furonghua Road, Pudong New Area, Shanghai 
 
Signature: Date: 
 
 
 
 
 
 
 


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Principal Investigator Protocol Signature Page 
 
I have read this protocol and agree that it contains all necessary details to conduct the study. 
I will conduct this clinical study in accordance with the ethical principles of the 
Declaration of Helsinki and Good Clinical Practice and applicable regulatory regulations. 
This trial protocol can only be implemented after being reviewed and approved by the 
Ethics Committee and signed with approval comments. This protocol and related information 
are confidential and should not be disclosed to other persons unrelated to this trial or used for 
any purpose other than this study without the written permission of the sponsor. 
Signature confirms approval of the clinical protocol. 
 
 
Study Site: 
 
Investigator Name: 
Tel.: 
 
Signature: Date: 
 
 
 


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Contents 
Contents ..................................................................................................................................... 5 
List of Tables ........................................................................................................................... 10 
Abbreviation ............................................................................................................................ 11 
Protocol Synopsis .................................................................................................................... 13 
1. 
Study Background ........................................................................................................... 29 
1.1. 
Background and rationale .................................................................................... 29 
1.1.1. 
Chemotherapy induced myelosuppression (CIM) is a serious and life-
threatening disease ................................................................................. 29 
1.1.2. 
Current therapies and unmet clinical needs for CIM ............................. 31 
1.1.3. 
Chemotherapy and improving myelosuppression in small cell lung cancer 
in China ................................................................................................. 33 
1.1.4. 
Trilaciclib, a novel prophylactic bone marrow protective agent ........... 37 
1.2. 
Preclinical data .................................................................................................... 37 
1.2.1. 
Pharmacology ........................................................................................ 38 
1.2.2. 
Pharmacokinetics ................................................................................... 39 
1.2.3. 
Toxicology ............................................................................................. 39 
1.3. 
Clinical data ......................................................................................................... 40 
1.3.1. 
Safety data ............................................................................................. 43 
1.3.2. 
Pharmacokinetic data ............................................................................. 44 
1.3.3. 
Efficacy data .......................................................................................... 47 
1.4. 
Risks and benefits ................................................................................................ 50 
2. 
Study objective and study endpoints ............................................................................... 50 
2.1. 
Study objectives ................................................................................................... 50 
2.2. 
Study endpoints ................................................................................................... 51 
3. 
Study design .................................................................................................................... 53 
3.1. 
Overall design ...................................................................................................... 53 
3.2. 
Sample size .......................................................................................................... 54 
3.3. 
Rationale for trial design ..................................................................................... 54 
3.4. 
End of study ......................................................................................................... 55 


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4. 
Study population .............................................................................................................. 56 
4.1. 
Criteria for enrollment ......................................................................................... 56 
4.2. 
Exclusion criteria ................................................................................................. 57 
5. 
Investigations treatment ................................................................................................... 58 
5.1. 
Investigational drug ............................................................................................. 58 
5.2. 
Study treatment regimen ...................................................................................... 58 
5.3. 
Randomization and blinding ................................................................................ 60 
5.3.1. 
Randomization and blinding .................................................................. 60 
5.3.2. 
Unblinding ............................................................................................. 60 
5.4. 
Study treatment modification .............................................................................. 61 
5.4.1. 
Dose modification for trilaciclib/placebo .............................................. 61 
5.4.2. 
Dose modification for chemotherapy agents ......................................... 61 
5.4.2.1. 
Dose modifications based on hematologic toxicities ..................... 61 
5.4.2.2. 
Dose Modifications Based on Nonhematologic Toxicities ............ 63 
5.4.2.2.1. Hepatotoxicity ......................................................................... 63 
5.4.2.2.2. Gastrointestinal side effects ..................................................... 63 
5.4.2.2.3. Hypersensitivity ....................................................................... 63 
5.4.2.3. 
Other toxicities ............................................................................... 64 
5.5. 
Criteria for discontinuation from study treatment or withdrawal ........................ 65 
5.5.1. 
Criteria for discontinuation of study treatment ..................................... 65 
5.5.1.1. 
Dose interruption and termination of trilaciclib ............................. 65 
5.5.2. 
Criteria for early withdrawal ................................................................. 66 
5.5.3. 
Handling of study treatment discontinuation or early withdrawal ........ 66 
5.5.4. 
Criteria for early termination of the study ............................................. 66 
5.6. 
Prior/concomitant medications and therapies ...................................................... 67 
6. 
Pharmacokinetics ............................................................................................................. 68 
6.1. 
Collection, processing and storage of biological samples ................................... 68 
6.1.1. 
PK Blood Sample Collection and Processing........................................ 68 
6.1.1.1. 
PK blood sample collection time .................................................... 68 
6.1.1.1.1. Pharmacokinetic evaluation (Part I) ........................................ 68 


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6.1.1.1.2. Pharmacokinetic evaluation (Part II) ....................................... 69 
6.1.1.2. 
Handling and storage of pk blood samples ..................................... 69 
7. 
Study evaluation .............................................................................................................. 70 
7.1. 
Evaluation of bone marrow protection ................................................................ 70 
7.2. 
Safety evaluation ................................................................................................. 70 
7.2.1. 
Clinical laboratory tests ......................................................................... 70 
7.2.2. 
Physical examination and vital signs ..................................................... 71 
7.2.3. 
12-lead electrocardiogram (ECG) ......................................................... 71 
7.2.4. 
Adverse events ....................................................................................... 71 
7.3. 
Pharmacokinetic evaluation ................................................................................. 72 
7.4. 
Population pharmacokinetic analysis was performed based on the data obtained for 
exploratory analysis to obtain the population pharmacokinetic profile of the 
drug.Antitumor efficacy evaluation ..................................................................... 72 
8. 
Adverse event reporting................................................................................................... 73 
8.1. 
Definitions of adverse event, serious adverse event, and suspected and unexpected 
serious adverse reaction ....................................................................................... 73 
8.2. 
Time period and frequency for collecting adverse event and serious adverse event 
information .......................................................................................................... 76 
8.3. 
Methods for collecting adverse events and serious adverse events ..................... 76 
8.4. 
Follow-up of adverse events and serious adverse events .................................... 76 
8.5. 
Recording and assessment of adverse events and serious adverse events ........... 77 
8.6. 
Regulatory reporting requirements for serious adverse events ........................... 79 
8.7. 
Reporting serious adverse events to sponsor ....................................................... 79 
8.8. 
Pregnancy events ................................................................................................. 79 
8.9. 
Adverse events of special interest (AESIs) ......................................................... 80 
9. 
Study procedures ............................................................................................................. 80 
9.1. 
Test flow table I ................................................................................................... 81 
9.2. 
Test flow table II.................................................................................................. 84 
10. Statistical analysis ........................................................................................................... 88 
10.1. Determination of sample size .............................................................................. 88 


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10.2. Analysis set .......................................................................................................... 88 
10.3. Statistical methods ............................................................................................... 89 
10.3.1. Basic method ......................................................................................... 89 
10.3.2. Summary of study conduct .................................................................... 90 
10.3.3. Treatment group comparability summary ............................................. 90 
10.3.4. Primary efficacy endpoint analysis........................................................ 90 
10.3.5. Secondary efficacy endpoint analyses ................................................... 90 
10.3.6. Safety analysis ....................................................................................... 91 
10.3.7. Pharmacokinetic analysis ...................................................................... 92 
10.3.8. Data analysis time .................................................................................. 92 
10.3.9. Exploratory analyses.............................................................................. 93 
11. Supporting documentation and clinical operations related considerations ..................... 93 
11.1. Management of study drug .................................................................................. 93 
11.1.1. Dosage form, appearance, packaging, and labeling of study drug ........ 93 
11.1.2. Receipt and storage of study drug ......................................................... 93 
11.1.3. Drug administration, distribution and recovery ..................................... 93 
11.2. Data management ................................................................................................ 94 
11.2.1. Data collection ....................................................................................... 94 
11.2.2. Data recording ....................................................................................... 94 
11.2.3. Database lock ......................................................................................... 95 
11.2.4. Data archiving........................................................................................ 95 
11.3. Ethics ................................................................................................................... 96 
11.3.1. Ethics committee ................................................................................... 96 
11.3.2. Ethical conduct of the study .................................................................. 96 
11.3.3. Subject informed consent ...................................................................... 97 
11.3.4. Confidentiality of subject information .................................................. 97 
11.3.5. Research use of samples, specimens, or data ........................................ 98 
11.3.6. Quality assurance and quality control ................................................... 98 
11.3.7. Preservation and confidentiality of data ................................................ 99 
11.4. Protocol amendment .......................................................................................... 100 


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11.5. Protocol deviations ............................................................................................ 100 
11.6. Publication of study results................................................................................ 100 
12. References ..................................................................................................................... 101 
13. Appendices ...................................................................................................................... 106 
Appendix 1 ECOG scoring table ................................................................................... 106 
Appendix 2 List of common CYP3A4 inhibitors or inducers ....................................... 107 
Appendix 3 Pharmacokinetic blood sampling schedule ................................................ 108 


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List of Tables 
Table 1 Summary of Occurrence of Myelosuppression in Asian Patients with Extensive 
Stage Small Cell Lung Cancer Receiving Platinum Combined with Etoposide/Topotecan
 .......................................................................................................................................... 34 
Table 2 Details of Three Clinical Trials of Trilaciclib in Patients with Small Cell Lung 
Cancer ............................................................................................................................... 41 
Table 3 Summary of Trilaciclib Bone Marrow Protection Endpoint Data from Three 
Clinical Trials in SCLC .................................................................................................... 48 
Table 4 Study Treatment Regimen ................................................................................... 59 
Table 5 Dose reductions for carboplatin, etoposide and topotecan .................................. 61 
Table 6 Dose Modification Based on Neutrophil Count and Platelet Count .................... 61 
Table 7 Dose Modification Based on Absolute Trough Neutrophil Count with or without 
Fever ................................................................................................................................. 62 
Table 8 Dose Modification Based on Trough Platelet Values .......................................... 62 
Table 9 Dose Modifications Based on ALT/AST and Bilirubin ....................................... 63 
Table 10 Adverse event severity grade not defined in NCI-CTCAE 5.0 ......................... 77 
Table 11 1st line ES-SCLC Patients Study Procedures (EC Protocol) ............................. 81 
Table 12 2nd/3rd line ES-SCLC Patient Study Flow (Topotecan) ................................... 84 
 


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Abbreviation 
Abbreviation 
Full Name 
AE 
Adverse Event 
ANC 
Absolute Neutrophil Count 
AUC 
Area under concentration-time curve 
CDK4/6 
Cyclin-dependent kinases 4 and 6 
CIA 
Chemotherapy induced anemia 
CIM 
Chemotherapy induced myelosuppression 
CIN 
Neutropenia 
CIT 
Chemotherapy induced thrombocytopenia 
Cmax 
Maximum plasma concentration 
Cyc 
Cyclin 
CYPs 
Cytochromases 
DDI 
Drug-Drug Interaction 
DNA 
Deoxyribonucleotide 
DSN 
Duration of severe neutropenia 
ECOG 
Eastern Cooperative Oncology Group 
ESA 
Erythropoiesis Stimulating Agent 
ES-SCLC 
Extensive stage small cell lung cancer 
FDA 
Food and Drug Administration 
FAS 
Full Analysis Set 
FN 
Febrile neutropenia 
FOB 
Functional Observation Battery 
G-CSF 
Granulocyte colony-stimulating factor 
HRQoL 
Health-related quality of life 
HSC 
Hematopoietic stem cell 
HSPC 
Hematopoietic stem and progenitor cell 
IEC 
Independent Ethics Committee 
ICI 
Immune checkpoint inhibitors 
IWRS 
Interactive web response system 
Kd 
Dissociation constant 
Ki 
Inhibition constant 
MATE 
Multidrug and toxin extrusion 
Min 
Minute 
MOA 
Mechanism of action 
NOEL 
No observed effect level 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PDUFA 
Prescription Drug User Fee Act 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PRO 
Patient Reported Outcomes 
Rb 
Retinoblastoma 


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Abbreviation 
Full Name 
RBC 
Red blood cell 
RES 
Response Assessment Analysis Set 
SAE 
Serious Adverse Event 
SCLC 
Small cell lung cancer 
SS 
Safety Analysis Set 
TEAE 
Treatment-emergent adverse event 
TNBC 
Triple negative breast cancer 
PK/PD 
Pharmacokinetics/Pharmacodynamics 
 
 
 
 


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Protocol Synopsis 
Study title 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase 3 Clinical 
Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Trilaciclib in Patients 
with Extensive Stage Small Cell Lung Cancer Treated with Carboplatin and 
Etoposide or with Topotecan 
STUDY PHASE 
Phase III 
Study objectives 
Part I (Safety Run-in and PK Evaluation Part): 
Primary objective 
• 
To evaluate the pharmacokinetic (PK) profile of Trilaciclib in patients with 
extensive stage small cell lung cancer; 
• 
To evaluate the safety and tolerability of Trilaciclib in patients with extensive 
stage small cell lung cancer; 
• 
To evaluate the effectiveness of Trilaciclib (prevention of chemotherapy-
induced myelosuppression) in patients with extensive stage small cell lung cancer; 
Secondary objectives 
• 
To comprehensively evaluate the myeloprotective effect of Trilaciclib in patients 
with extensive stage small cell lung cancer; 
• 
To evaluate the short-term antitumor efficacy of Trilaciclib in patients with 
extensive stage small cell lung cancer; 
Exploratory objectives: 
• 
To evaluate the long-term antitumor efficacy of Trilaciclib in patients with 
extensive stage small cell lung cancer; 
• 
Population pharmacokinetic profile. 
Part II (randomized, double-blind part): 
Primary objective 
• 
To evaluate the effectiveness of Trilaciclib (prevention of chemotherapy-
induced myelosuppression) in patients with extensive stage small cell lung cancer; 
Secondary objectives 
• 
To comprehensively evaluate the myeloprotective effect of Trilaciclib in patients 
with extensive stage small cell lung cancer; 
• 
To evaluate the safety and tolerability of Trilaciclib in patients with extensive 
stage small cell lung cancer; 
• 
To evaluate the short-term antitumor efficacy of Trilaciclib in patients with 
extensive stage small cell lung cancer; 
Exploratory objectives: 
• 
To evaluate the long-term antitumor efficacy of Trilaciclib in patients with 
extensive stage small cell lung cancer; 


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• 
Population pharmacokinetic profile. 
Study Endpoints 
The following endpoints, not specified, refer to events occurring during 
chemotherapy. 
Part I (Safety Run-in and PK Evaluation Part): 
Primary Endpoint: 
• 
PK profile (Cmax, AUC and other PK parameters); 
• 
Safety and tolerability: adverse events, laboratory abnormalities, etc; 
• 
Duration of severe neutropenia in Cycle 1 (DSN); 
Key Secondary Endpoints: 
• 
Occurrence of severe neutropenia (SN); 
• 
Occurrence of red blood cell transfusion (on/after Week 5); 
• 
Granulocyte colony stimulating factor (G-CSF) use rate; 
• 
Composite endpoint – major adverse hematologic event (Any of the 
following): 
 
All-cause hospitalization; 
 
All-cause dose reductions; 
 
Febrile neutropenia; 
 
SN prolongation (lasting > 5 days); 
 
Red blood cell (RBC) transfusions were performed on/after Week 5. 
Other secondary endpoints: 
• 
Occurrence of Grade 3 and 4 hematological toxicities; 
• 
Absolute neutrophil count trough by cycle; 
• 
Absolute neutrophil count, platelet count, absolute lymphocyte count, and 
hemoglobin over time; 
• 
Erythropoiesis stimulating agent (ESA) utilization rate; 
• 
Rate of recombinant human interleukin-11 use; 
• 
Thrombopoietin (TPO) use rate; 
• 
Occurrence of intravenous or oral antibiotic administration; 
• 
Occurrence of infectious serious adverse events; 
• 
Occurrence of lung infection SAEs: 
• 
Occurrence of febrile neutropenia; 
• 
Occurrence of platelet transfusion; 
• 
Objective tumor response rate (ORR); 
• 
Disease control rate (DCR). 
Exploratory Endpoints: 
• 
Progression-free survival (PFS); 
• 
Overall survival (OS); 


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• 
Population pharmacokinetic profile. 
Part II (randomized, double-blind part): 
Primary Endpoint: 
• 
Duration of severe neutropenia in Cycle 1 (DSN). 
Key Secondary Endpoints: 
• 
Occurrence of severe neutropenia (SN); 
• 
Occurrence of red blood cell transfusion (on/after Week 5); 
• 
Granulocyte colony stimulating factor (G-CSF) use rate; 
• 
Composite endpoint – major adverse hematologic event (Any of the 
following): 
 
All-cause hospitalization; 
 
All-cause dose reductions; 
 
Febrile neutropenia; 
 
SN prolongation (lasting > 5 days); 
 
Red blood cell (RBC) transfusions were performed on/after Week 5. 
Other secondary endpoints: 
• 
Occurrence of Grade 3 and 4 hematological toxicities; 
• 
Absolute neutrophil count trough by cycle; 
• 
Absolute neutrophil count, platelet count, absolute lymphocyte count (ALC), 
and hemoglobin over time; 
• 
Erythropoiesis stimulating agent (ESA) utilization rate; 
• 
Rate of recombinant human interleukin-11 use; 
• 
Thrombopoietin (TPO) use rate; 
• 
Occurrence of intravenous or oral antibiotic administration; 
• 
Occurrence of infectious serious adverse events; 
• 
Occurrence of lung infection SAEs: 
• 
Occurrence of febrile neutropenia; 
• 
Occurrence of platelet transfusion; 
• 
Safety and tolerability: adverse events, laboratory abnormalities, etc.; 
• 
Objective tumor response rate (ORR); 
• 
Disease control rate (DCR). 
Exploratory Endpoints: 
• 
Progression-free survival (PFS); 
• 
Overall survival (OS); 
• 
Population pharmacokinetic profile. 
BACKGROUND 
AND 
Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung 
cancers, and approximately 70% of these patients are in the extensive stage at initial 


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RATIONALE 
diagnosis. Major diagnosis and treatment guidelines at home and abroad (including 
those edited by Chinese Society of Clinical Oncology) recommend platinum-based 
combination with or without PD-L1 antibody as first-line standard treatment for 
SCLC, while topotecan is recommended for second-line chemotherapy. Studies 
have shown that platinum-based combination therapy with etoposide or topotecan is 
associated with significant myelosuppression in extensive stage SCLC (neutropenia 
47% to 92%, leukopenia 8% to 66%, thrombocytopenia 10% to 46%, and anemia 
7% to 34%). In Asian populations (including China, Korea, Japan), the occurrence 
of myelosuppression caused by platinum-based and etoposide chemotherapy was 
similar. Literature have shown that chemotherapy-induced myelosuppression (grade 
3/4 neutropenia 5.6% ~ 93.8%, anemia 2.9% ~ 33.3%, thrombocytopenia 3.2% ~ 
33.3%) is always the main adverse reaction to be urgently addressed in Asian 
populations, including China, South Korea, and Japan, for patients with small cell 
lung cancer treated with carboplatin/cisplatin combined with etoposide effects or 
topotecan. Myelosuppression is an important cause of many adverse events in 
cancer chemotherapy, such as infection, sepsis, bleeding, and fatigue, leading to 
hospitalization or the use of hematopoietic growth factors or the need for red blood 
cell and/or platelet transfusions. In addition, myelosuppression often leads to 
chemotherapy dose reductions or limits in treatment dose intensity, rendering 
patients unable to derive greater benefit from chemotherapy. 
Trilaciclib is a highly potent, selective, reversible CDK4/6 inhibitor in clinical 
development to protect bone marrow by protecting hematopoietic stem and 
progenitor cells (HSPCs) when administered systemically. The proliferation and 
differentiation of HSPCs is very dependent on CDK4/6 activity and is arrested in 
G1 phase of the cell cycle when exposed to appropriate doses of Trilaciclib, thus 
avoiding damage by cytotoxic chemotherapeutic agents of the cell cycle. Therefore, 
for CDK4/6-independent tumors (such as small cell lung cancer, etc.), Trilaciclib 
combined with chemotherapy can protect the bone marrow without antagonizing 
the anti-tumor efficacy of chemotherapy. 
The downstream target of CDK4/6 is the retinoblastoma (Rb) protein, which is 
phosphorylated upon CDK4/6 activation to allow cells to enter S phase. CDK4/6 
inhibitors arrest cells in G1 phase by inhibiting downstream pathways dependent on 
functional Rb protein. It has been shown that SCLC is universally inactivated by 
tumor protein-53 (TP53) and retinoblastoma protein-1 (RB-1), so it is basically 
believed that functional Rb protein is almost absent in SCLC. In addition, two 
recent reports have described the genomic profile of SCLC in detail using next 
generation sequencing methods, including complete exome sequencing, 
transcriptome profiling by RNA sequencing (RNASeq), copy number analysis as 


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well as limited whole genome sequencing to identify translocations. These reports 
confirm the conjecture raised in previous studies based on small numbers of tumor 
samples that inactivation of driver mutations TP53 and RB-1 commonly occurring 
in SCLC. Consistent with these findings, preclinical in vitro and in vivo studies 
have shown that Trilaciclib administered prior to chemotherapy does not attenuate 
the killing of RB-1 inactive tumors, including SCLC. Thus, SCLC can be 
considered CDK4/6-independent due to near universal RB-1 inactivation, which 
makes selective protection of HSPCs without compromising the antitumor efficacy 
of chemotherapy a potentially viable therapeutic strategy. 
Three randomized, double-blind Phase 2 clinical trials in patients with small 
cell lung cancer (SCLC) demonstrated that Trilaciclib administered in combination 
with chemotherapy (including 1st line, 2nd/3rd line) prevented or mitigated 
chemotherapy-induced myelosuppression. The G1T28-05 and G1T28-02 studies 
showed that Trilaciclib administered before first-line chemotherapy (carboplatin 
combined with etoposide) reduced the duration of severe neutropenia in Cycle 1 
from 4 days and 3 days to 0 days, and the occurrence of severe neutropenia from 
49.1% and 42.1% to 1.9% and 5.1%, respectively; the G1T28-03 study results 
showed that the use of Trilaciclib before topotecan reduced the duration of severe 
neutropenia in Cycle 1 from 7 days to 2 days, and the occurrence of severe 
neutropenia from 75.9% to 40.6%. 
Currently, no therapies have been approved for improving myelosuppression 
caused by chemotherapy by protecting HSPCs. Although there are some 
symptomatic treatments for myelosuppression (e.g., blood transfusions, growth 
factors, etc.), there are no available treatments that provide patients with 
comprehensive protection from chemotherapy-induced damage to HSPCs and the 
resulting negative effects. As the first agent designed to reduce chemotherapy-
induced myelosuppression by protecting HSPCs, Trilaciclib showed significant 
ability to prevent or alleviate chemotherapy-mediated myelosuppression in the 
multicellular lineage in patients with extensive stage small cell lung cancer (ES-
SCLC). Based on the clinical data of Trilaciclib, we intend to conduct a clinical trial 
in China that includes an open-label safety run-in and PK evaluation part and a 
randomized double-blind, placebo-controlled efficacy validation part to assess the 
safety, efficacy and pharmacokinetics of Trilaciclib in combination with carboplatin 
and etoposide (EC regimen) or with topotecan in the treatment of extensive-stage 
non-small cell lung cancer. 
Study Design 
This is a multi-center Phase 3 clinical trial with an open-label single-arm 
safety run-in and PK evaluation part and a randomized double-blind, placebo-


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controlled part in patients with ES-SCLC to evaluate the safety, efficacy, and 
pharmacokinetic profile of Trilaciclib based on completed clinical studies abroad. 
The study consists of 2 parts. The first part, safety run-in and PK evaluation, 
enrolled approximately 12 patients with extensive-stage small-cell lung cancer, 6 
patients each with 1st line ES-SCLC and 2nd/3rd line ES-SCLC to receive 
Trilaciclib in combination with carboplatin and etoposide (EC regimen) or with 
topotecan, and based on evaluable data from Cycle 1, evaluated the safety, 
tolerability, pharmacokinetics, and preliminary efficacy (prevention of 
myelosuppression) of Trilaciclib. The second part is a randomized double-blind, 
placebo-controlled efficacy validation study, and approximately 80 patients with 
ES-SCLC will be enrolled in Part II, stratified by 1st line vs 2nd/3rd line ES-SCLC, 
ECOG PS (0-1 vs 2), and presence vs absence of brain metastases, and randomized 
in a 1:1 ratio to Trilaciclib and placebo, in which patients with 1st line ES-SCLC 
receive Trilaciclib/placebo combined with EC regimen (Trilaciclib-EC group and 
placebo-EC group), and patients with 2nd/3rd line ES-SCLC receive 
Trilaciclib/placebo combined with topotecan (Trilaciclib-TPT group and placebo-
TPT group), and the efficacy of Trilaciclib (prevention of myelosuppression) will be 
evaluated with duration of severe neutropenia (DSN) in Cycle 1 as the primary 
endpoint. The planned dose of Trilaciclib is 240 mg/m2. If the safety data from the 
first part of the study suggest that the dose of Trilaciclib needs to be adjusted, 12 
additional patients (6 patients each for 1st line ES-SCLC and 2nd/3rd line ES-
SCLC) will be enrolled in the first part of the study to explore the PK and safety of 
Trilaciclib 200 mg/m2. 
The study process includes screening period, treatment period, safety follow-
up and survival follow-up. 
The end of the study was defined as death in 75% of subjects, or 12 months 
after the last subject was enrolled, or the sponsor decided to terminate the study, 
whichever came first. 
Investigational 
drug 
Investigational product investigated: 
Trilaciclib: Jiangsu Simcere Pharmaceutical Co., Ltd., 300 mg/vial, lyophilized 
powder 
Trilaciclib placebo: The outer packaging box of placebo was designed to be 
consistent with the investigational drug Trilaciclib, and the contents of the box were 
fillers (disks) of the same quality, which did not break the blind by appearance and 
hand after sealing. 
Background Therapy/Chemotherapy: 
Carboplatin: Qilu Pharmaceutical Co., Ltd., 100 mg/10ml/box, solution 


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Etoposide: Jiangsu Hengrui Medicine, 100 mg/5ml/vial, solution 
Topotecan: Jiangsu Aosaikang Pharmaceutical Co., Ltd., 2 mg/vial, solution 
Study treatment 
Chemotherapy: 
Carboplatin - administered on Day 1 of each 21-day cycle at a target AUC of 5 
(maximum dose 750 mg calculated according to Calvert formula) over 30 min by 
intravenous infusion; etoposide - administered on Days 1, 2, and 3 of each 21-day 
cycle at 100 mg/m2 over 60 min by intravenous infusion; topotecan - administered 
on Days 1-5 of each 21-day cycle at 1.25 mg/m2 over 30 min by intravenous 
infusion. 
Trilacicilb or placebo: 
Patients receiving chemotherapy regimen of carboplatin combined etoposide: 
administered at 240 mg/m2 on Days 1, 2 and 3 of each 21-day cycle prior to 
chemotherapy using 5% glucose injection or normal saline 250 mL solution, 30 min 
intravenous drip (try to complete the drip within 30 + 5 min due to PK study). 
Patients whose chemotherapy regimen was topotecan: every 21 days as a 
cycle, on Days 1-5 of each cycle as per 240 mg/m2 was administered before 
chemotherapy and prepared into 250 mL solution with 5% glucose injection or 
normal saline and intravenously infused over 30 min (Because it involved PK 
studies, try to complete the infusion within 30 + 5 min). 
Patients with 1st line ES-SCLC received up to 6 cycles of Trilaciclib or placebo 
combined with carboplatin and etoposide or continued treatment until disease 
progression, intolerability, withdrawal of consent, or investigator termination, 
whichever came first; patients with 2nd/3rd line ES-SCLC received Trilaciclib or 
placebo combined with topotecan until disease progression, intolerability, 
withdrawal of consent, or investigator termination of treatment, whichever came first. 
Notes: 
Trilaciclib or placebo should be administered no more than 28 hours apart 
between infusions for 3 or 5 consecutive days, and no more than 4 hours apart 
between infusions of Trilaciclib and its subsequent chemotherapeutic agents injected 
(with carboplatin and etoposide, or with topotecan). 
Trilaciclib or placebo should be administered in combination with 
chemotherapy, ie, if EC regimen or topotecan is suspended or discontinued, then 
Trilaciclib or placebo should also be suspended or discontinued. Similarly, 
subsequent chemotherapy should not be administered in any cycle if the planned 
administration of Trilaciclib, i.e. Trilaciclib or placebo, has not been completed. 
Prophylactic use of any colony-stimulating factors (including granulocyte 
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erythropoiesis stimulating agent) was not permitted during Cycle 1, but could be used 
therapeutically if febrile neutropenia developed in patients with high-risk infections 
or risk factors indicating poor prognosis (sepsis, age > 65 years, neutrophils < 0.1 × 
109/L, expected neutropenia lasting > 10 days, pneumonia, invasive fungal infections, 
other clinically documented infections, fever requiring hospitalization, previous 
febrile neutropenia, etc.). 
Study 
Population 
Criteria for inclusion 
Patients must meet all of the following inclusion criteria to be enrolled in the study: 
1. 
Age ≥ 18 years, male or female; 
2. 
Histologically or cytologically confirmed extensive stage small cell lung 
cancer (ES-SCLC): 
• 
Patients scheduled to receive carboplatin plus etoposide regimen: no prior 
systemic therapy (eg, chemotherapy or combined with immunotherapy); 
• 
Patients scheduled to receive topotecan regimen: previously received 1/2 lines 
of chemotherapy or combined immunotherapy but not topotecan. 
3. 
Presence of at least one radiation-naïve measurable lesion according to 
RECIST 1.1 criteria; 
4. 
Hemoglobin ≥ 90 g/L; 
5. 
Neutrophil count ≥ 1.5 x 109/L; 
6. 
Platelet count ≥ 100 × 109/L; 
7. 
Creatinine ≤ 15 mg/L or creatinine clearance (CrCl) ≥ 60 mL/min (Cockcroft-
Gault formula); 
8. 
Total bilirubin ≤ 1.5 × upper limit of normal (ULN); 
9. 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × 
ULN or ≤ 5 × ULN (for patients with liver metastases); 
10. Albumin ≥ 30 g/L; 
11. ECOG PS score 0 - 2; 
12. Expected survival time ≥ 3 months; 
13. Contraception: 
Females: All females of childbearing potential must have a negative serum 
pregnancy test at screening and must use reliable contraception from signing of 
informed consent through 3 months after the last dose; 
Male: Female partners of childbearing potential must use reliable contraception 
from signing the informed consent until 3 months after the last dose. 
14. Understand and sign informed consent. 
Exclusion Criteria 
1. 
Symptomatic brain metastases requiring local radiotherapy or hormonal 


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therapy; 
2. 
History of other malignancies, with the following exceptions: (1) clinically 
cured cutaneous basal cell or squamous cell tumors; (2) cured a) cervical 
cancer, b) prostate cancer, c) superficial bladder cancer; or (3) other solid 
tumors with a clinical cure time of more than 3 years; 
3. 
Uncontrolled ischemic heart disease or clinically significant congestive heart 
failure (NYHA Class III or IV); 
4. 
Stroke or cardiovascular or cerebrovascular event within 6 months prior to 
enrollment; 
5. 
Severe active infection; 
6. 
Psychological or other social factors causing insufficient trial compliance; 
7. 
Other uncontrolled serious chronic diseases or conditions that, in the opinion 
of the investigator, would make participation in the trial inappropriate; 
8. 
Known HIV infection, active hepatitis B (defined as positive HBV DNA), and 
hepatitis C (positive HCV RNA); 
9. 
Radiation therapy within 2 weeks prior to enrollment; 
10. Patients who have received cytotoxic drug therapy or investigational drug 
therapy within 4 weeks before enrollment, or non-cytotoxic anti-tumor drug 
therapy within 2 weeks; 
11. Subjects in the first part of the study should not take strong or moderate inducers 
of CYP3A4 concomitantly within 4 weeks before taking the study drug, and 
strong inhibitors of CYP3A4 concomitantly within 2 weeks before taking the 
study drug; 
12. Toxicity from prior anticancer therapy has not recovered to Grade 0 or 1 
(except alopecia); 
13. Hypersensitivity to the study drug (Trilaciclib, etoposide, carboplatin, 
topotecan) or components thereof; 
14. Persons who are unable to act independently due to legal restriction or legal 
sense; 
15. Pregnant or lactating women; 
16. Not suitable for participating in this study in the investigator 's opinion. 
Pharmacokinetic 
evaluation 
In the first part of this study, PK blood samples will be collected at the following time 
points. 
When the chemotherapy regimen is carboplatin combined with etoposide: 
Cycle 1 Day 1: 
Within 0.5 h before the start of the first Trilaciclib infusion, immediately after the end 
of infusion (± 2 min, at the end of administration, excluding the flushing time, the 


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same below), and 0.5 h ± 2 min, 1 h ± 5 min, 2 h ± 5 min, 4 h ± 5 min, 6 h ± 5 min, 
8 h ± 5 min, and 12 h ± 10 min after the end of infusion. 
Cycle 1 Day 2: 
Within 0.5 hours prior to the second Trilaciclib dose (24 hours ± 30 min after the end 
of the first Trilaciclib infusion). 
Cycle 1 Day 3: 
Within 0.5 h before the start of the third Trilaciclib dose, immediately after the end 
of infusion (± 2 min, excluding flushing time), and 0.5 h ± 2 min, 1 h ± 5 min, 2 h ± 
5 min, 4 h ± 5 min, 6 h ± 5 min, 8 h ± 5 min, and 12 h ± 10 min after the end of 
infusion. 
Cycle 1 Day 4: 
24 h ± 30 min after the end of the third Trilaciclib infusion. 
A total of 20 blood sampling points, venous blood is collected to determine the 
concentration of Trilaciclib in blood samples, and pharmacokinetic analysis is 
performed based on the test results. 
When the chemotherapy regimen is topotecan: 
Cycle 1 Day 1: 
Within 0.5 h before the start of the first Trilaciclib dose, immediately after the end of 
infusion (± 2 min, excluding flushing time), and 0.5 h ± 2 min, 1 h ± 5 min, 2 h ± 5 
min, 4 h ± 5 min, 6 h ± 5 min, 8 h ± 5 min, and 12 h ± 10 min after the end of infusion. 
Cycle 1 Day 2: 
Within 0.5 hours prior to the second Trilaciclib dose (24 hours ± 30 min after the end 
of the first Trilaciclib infusion). 
Cycle 1 Day 3: 
Within 0.5 hours prior to the third Trilaciclib dose. 
Cycle 1 Day 4: 
Within 0.5 hours prior to the fourth Trilaciclib dose. 
Cycle 1 Day 5: 
Within 0.5 h before the start of the fifth Trilaciclib dose, immediately after the end of 
infusion (± 2 min, excluding flushing time), and 0.5 h ± 2 min, 1 h ± 5 min, 2 h ± 5 
min, 4 h ± 5 min, 6 h ± 5 min, 8 h ± 5 min, and 12 h ± 10 min after the end of infusion. 
Cycle 1 Day 6: 
24 h ± 30 min after the end of the fifth Trilaciclib infusion. 
A total of 22 blood sampling points, venous blood is collected to determine the 
concentration of Trilaciclib in blood samples, and pharmacokinetic analysis is 
performed based on the test results. 
 
In the second part of this study, PK blood sample collection is planned at the 


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following time points, and the actual blood collection points could be adjusted 
according to the pharmacokinetic study results in the first part. 
For all subjects, venous blood is collected at 4 blood sampling points on Cycle 
1 Day 1 at (excluding flushing time) ± 5 min immediately after the end of 
Trilaciclib/placebo infusion (excluding flushing time), 0.5 h ± 10 min, 5 h ± 1 h after 
the end of infusion and within 1 h before Trilaciclib/placebo administration on Cycle 
1 Day 2 to determine the concentration of Trilaciclib in blood samples, and 
pharmacokinetic analysis is performed according to the test results. 
Safety evaluation 
Safety is evaluated by adverse events (adverse events graded using NCI-CTCAE 
version 5.0), laboratory tests, vital signs, physical examinations, and 
electrocardiograms. 
Efficacy 
evaluation 
Effectiveness refers to prevention of chemotherapy induced bone marrow 
suppression. Efficacy assessments will be based on: dynamic changes in complete 
blood counts; hematological toxicities, including febrile neutropenia and related 
infections; red blood cell and platelet transfusions; hematopoietic growth factor use; 
systemic antibiotic use; dose reduction and discontinuation of chemotherapy. 
The study primarily selected the duration of severe neutropenia (DSN) in Cycle 
1 as the primary endpoint for efficacy evaluation. The overall protective effect of 
Trilaciclib on multilineage of bone marrow will also be comprehensively assessed 
through the evaluation of secondary endpoints, particularly key secondary endpoints 
(including SN occurrence, occurrence of red blood cell transfusions on/after Week 5, 
granulocyte colony-stimulating factor use rate, composite endpoint–major adverse 
hematologic event, etc.). 
Antitumor 
efficacy 
evaluation 
Tumor imaging evaluation was performed according to RECIST1.1. Baseline 
imaging was performed within 21 days prior to the first dose, every 6 ± 1 week after 
the first dose, or more frequently if clinically indicated. Imaging examinations should 
follow calendar days and should not be modified for treatment delays or terminations, 
and subjects who discontinue study drug for unacceptable toxicity or other reasons 
other than disease progression should continue to be followed for tumor assessments 
until disease progression, receipt of new antineoplastic therapy, withdrawal from the 
study, or death, whichever occurs first. 
Efficacy assessments were classified as complete response (CR), partial 
response (PR), stable disease (SD), progressive disease (PD), and not evaluable (NE). 
Confirmation of response according to RECIST 1.1 should be performed no less than 
4 weeks from the date of the first documented partial response (PR) or complete 
response (CR). Imaging assessments for efficacy confirmation may be performed 4 
weeks after response is first observed or at the next scheduled imaging time point. 


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Criteria 
for 
Discontinuation 
of 
Study 
Treatment 
A subject should discontinue study treatment if any of the following occur: 
1. Disease progression, except for subjects who, in the investigator 's judgment, still 
benefit from the study (e.g., pseudoprogression); 
2. To reach the maximum treatment time specified in the protocol; 
3. Subject is pregnant; 
4. Poor compliance of subjects, such as failure to receive medication and 
examinations as required, failure to comply with the restrictions on lifestyle during 
the study, and use of other prohibited concomitant medications, which have a 
significant impact on the evaluation of study drugs; 
5. Initiation of new anticancer therapy; 
6. Occurrence of an adverse event that, in the judgment of the investigator, makes it 
inappropriate to continue treatment with study drug; 
7. The investigator considers that study treatment should be discontinued in the best 
benefit of the subject; 
8. The subject or his/her legal representative (only applicable if the subject is not fully 
capable of civil conduct) requests termination of treatment. 
Subjects who discontinue study treatment should complete the items specified 
in the trial flow chart and continue to be followed up according to the protocol. 
Criteria for early 
withdrawal 
Subjects could withdraw from the study at any time for any reason. The 
investigator may decide whether or not to withdraw a subject from the study based 
on actual clinical circumstances. Criteria for early withdrawal from the study were: 
1. Withdrawal of consent by the subject or his/her legal representative (only 
applicable if the subject himself/herself does not have full civil capacity); 
2. Subject lost to follow-up. 
Subjects who withdrew early were not to undergo any subsequent follow-up and 
assessments. 
Criteria for early 
termination 
of 
the study 
The study may be terminated prematurely at any time if agreed to by the 
investigator and the sponsor in the best benefit of the subject and for reasonable 
medical or ethical reasons. During termination, the sponsor and investigator will 
ensure that adequate consideration is given to protecting the subject 's interests. 
Criteria for early termination of this study were: 
1. Significant safety risk for the study drug in the opinion of regulatory authorities, 
ethics committees, sponsors or investigators; 
2. Identify major defects in the study protocol, or major deviations or human errors 
during the implementation of the study, which seriously affect the quality of the trial 
and make it difficult to achieve the purpose of the study; 
3. The sponsor may terminate the study for any scientific, medical or ethical reason, 


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but shall fully consider the rights, safety and health of the enrolled subjects; 
4. Other reasons that, in the judgment of the sponsor or investigator, make 
continuation of the study inappropriate. 
Sample Size 
A total of approximately 92 subjects are planned to be enrolled, including 
approximately 12 subjects in Part I and 80 subjects in Part II. 
Statistical 
Analysis 
DETERMINATION OF SAMPLE SIZE 
The study consists of 2 parts and a total of approximately 92 ES-SCLC patients 
are planned to be enrolled. The first part (safety run-in and PK evaluation) planned 
to enroll approximately 6 patients each for 1st line ES-SCLC and 2nd/3rd line ES-
SCLC. The second part (efficacy verification) planned to enroll approximately 80 
patients with ES-SCLC, stratified by 1st line vs 2nd/3rd line ES-SCLC, ECOG PS 
(0-1 vs 2), and presence vs absence of brain metastases, to be randomized in a 1:1 
ratio to Trilaciclib versus placebo. 
The sample size for Part I was not based on statistical calculations, but to support 
PK evaluation and safety run-in. In addition, assuming a 5.3% occurrence of severe 
neutropenia, there is an approximately 28% probability of developing at least one 
severe neutropenia in 6 patients; if the occurrenceof severe neutropenia is 40.6%, 
then the probability is 96% to detect at least one subject occurring severe neutropenia. 
The sample size of the second part needs to meet the need to test the efficacy of 
DSNs in Cycle 1 and is calculated by stochastic simulation. An integrated analysis of 
the three overseas pivotal studies of Trilaciclib in SCLC showed an approximately 4-
day reduction in Cycle 1 DSN in the Trilaciclib group compared to the placebo group. 
Taking into account the derivation of DSN in Cycle 1, DSN in Cycle 1 is 0 if the 
subject did not experience any SN during Cycle 1. When there is a large proportion 
of zero-values, i.e., a large proportion of subjects who do not have any SNs in Cycle 
1, DSN in Cycle 1more closely follow a Poisson distribution with a mean of -log 
(proportion of subjects who do not have any SNs in Cycle 1). In the integrated 
analysis, the proportion of subjects who developed SN during Cycle 1 was 6.7% in 
the Trilaciclib group compared to 49.6% in the placebo group. Assuming that the 
proportion of subjects in this study who occurred SN during Cycle 1 was 10% in the 
Trilaciclib group and 45% in the placebo group, the means of Poisson distributions 
were 0.105 and 0.598 for the corresponding Trilaciclib and placebo groups, 
respectively. The stochastic simulation was repeated 10,000 times, each time 
obtaining the DSN in Cycle 1 from a Poiss on distribution and performing 
comparison between groups by Mann-Whitney-Wilcoxon test, 70 subjects (35 per 
group) provided approximately 95% power at the test level of α = 0.05 (2-sided). 


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Assuming a dropout rate of approximately 12%, the sample size for Part II was 80 
subjects (40 per group). 
 
Statistical Analysis 
Part I 
The first part will describe its PK profile and evaluate its safety and tolerability 
based on Cycle 1 data. In addition, preliminary efficacy (prevention of 
myelosuppression) data will be summarized. 
Part II 
The second part is mainly to verify the effectiveness of Trilaciclib treatment 
(prevention of bone marrow suppression). The primary endpoint was duration of 
severe neutropenia (DSN) in Cycle 1. For subjects who experienced at least 1 episode 
of severe neutropenia (SN) in Cycle 1, DSN in Cycle 1 was defined as the number of 
days from the date of the first ANC value < 0.5 x 109/L in Cycle 1 to the date of the 
first ANC value ≥ 0.5 x 109/L. Where the date of the first ANC value ≥ 0.5 x 109/L 
met the following requirements: (1) occurred after the ANC value was < 0.5 x 109/L, 
and (2) there were no other ANC values < 0.5 x 109/L between this date and the end 
of Cycle 1 (otherwise, if this subject entered Cycle 2, it was counted as Day 1 of 
Cycle 2). If the subject did not experience any SN during Cycle 1, DSN in Cycle 1 
was scored as 0. Nonparametric analysis of covariance (Nonparametric ANCOVA) 
will be used to evaluate the efficacy of DSN in Cycle 1. Mean differences between 
treatment groups, standard errors, and their 95% confidence intervals based on 
Satterthwaite t tests were also provided. 
Key secondary efficacy endpoints included SN occurrence, occurrence of red 
blood cell transfusions (on/after Week 5), granulocyte colony-stimulating factor (G-
CSF) use, composite endpoints–major hematological adverse events, etc. Descriptive 
statistics including mean, median, standard deviation and range will be used for 
continuous data while frequency and proportion will be provided for categorical data. 
Differences between groups and their 95% confidence intervals will be estimated. 
Other secondary efficacy endpoints included the occurrence of Grade 3/4 
anemia, trough absolute neutrophil count by cycle, absolute neutrophil count, platelet 
count, absolute lymphocyte count, and hemoglobin over time, occurrence of ESA 
use, occurrence of recombinant human interleukin-11 use, occurrence of 
thrombopoietin (TPO) use, occurrence of intravenous or oral antibiotics, 
occurrence of serious infectious adverse events, occurrence of serious pulmonary 
infection adverse events, occurrence of febrile neutropenia, occurrence of platelet 
transfusions (during chemotherapy), objective tumor response rate (ORR), and 
disease control rate (DCR). Descriptive statistics will be used for summaries. 


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Descriptive statistics for continuous data will include means, medians, standard 
deviations and ranges, and categorical data will provide counts and percentages. 
Safety analysis 
Safety analyses will be based on the Safety Analysis Set. Descriptive analysis 
and summary will be performed for adverse events, laboratory test indicators, vital 
signs and ECG. Occurrence of treatment-emergent adverse events will be provided 
and summarized by severity and relationship to study drug. 
Pharmacokinetic analysis 
The first part of the pharmacokinetic analysis included PK concentration 
analysis and PK parameter analysis. 
PK concentration analysis: PK concentration data will be summarized and listed 
by treatment group according to each scheduled sampling time point as defined in the 
protocol. Mean and median drug concentration-time profiles (linear and semi-log 
plots) are also plotted. Individual PK concentration data from subjects will be plotted 
(linear and semi-log plots) against drug concentration versus time by treatment group 
and analyte according to actual sampling time. Statistical analysis of PK 
concentrations will be based on the PK Analysis Set. 
PK Parameter Analysis: Statistical analysis of PK parameters will be 
summarized descriptively based on the PK Analysis Set. 
Population pharmacokinetic analyses will be exploratory based on the data 
obtained. 
Data Analysis Time 
An analysis will be performed when subjects in Part I have completed Cycle 1 
safety and PK assessments. Based on the Cycle 1 data, their PK profiles are 
characterized and their safety and tolerability are evaluated. In addition, preliminary 
myeloprotective efficacy (prevention of chemotherapy-induced myelosuppression) 
data will be summarized. The data of subjects in Part I may be updated synchronously 
until the end of the study at the time of data analysis in Part II. 
The primary analysis will be performed at the end of Cycle 1 for all randomized 
subjects in Part II. The sponsor 's necessary personnel will be unblinded, but the 
investigators, subjects, and other personnels will remain blinded. The primary 
endpoint for assessing the myeloprotective efficacy of Trilaciclib, duration of severe 
neutropenia (DSN) in Cycle 1, as well as other applicable secondary or exploratory 
endpoints, will be analyzed based on unblinded data. 
The second analysis in Part II will be performed after all randomized subjects 
have completed 6 cycles or end of treatment. 
The final analysis in Part II will be performed at the end of the study. 
 


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1. Study Background 
Trilaciclib (CoselaTM) is a highly selective, reversible CDK4/6 small molecule inhibitor 
with novel chemical structures that transiently stays hematopoietic stem and progenitor cells 
(HSPCs) in the G0/G1 phase in bone marrow. Therefore, for CDK4/6-independent tumors (such 
as small cell lung cancer [SCLC], etc.), Trilaciclib combined with chemotherapy can protect 
the bone marrow without antagonizing the anti-tumor efficacy of chemotherapy. 
Trilaciclib received Breakthrough Therapy Designation from the US Food and Drug 
Administration (FDA) in August 2019 based on its robust and significant myeloprotective 
efficacy demonstrated in 3 clinical trials in SCLC. The sponsor's U.S. partner, G1 Therapeutics, 
has received U.S. FDA marketing approval in February 2021, based on the results of these three 
studies in SCLC, for the use of Trilaciclib in patients with small cell lung cancer treated with a 
platinum-containing combination etoposide regimen or a topotecan-containing regimen to 
reduce the occurrence of chemotherapy-induced myelosuppression. 
The efficacy and safety of Trilaciclib have been confirmed based on three randomized 
controlled clinical trials conducted in SCLC that have been completed overseas. There is no 
evidence that the response to drug treatment in Chinese patients differs from that in overseas 
populations. 
At present, there is no relevant data on the use of Trilaciclib in the Chinese population in 
clinical trials of Trilaciclib, so the safety and efficacy of Trilaciclib in Chinese patients need to 
be further evaluated. A single-arm, open-label safety and PK study and a randomized double-
blind, placebo-controlled study are planned to be conducted in extensive stage small cell lung 
cancer in China in phase I/III clinical trials. 
1.1. 
Background and rationale 
1.1.1. 
Chemotherapy induced myelosuppression (CIM) is a serious and life-
threatening disease 
Chemotherapy-induced myelosuppression (CIM) is a common and important side effect 
during cancer treatment, mainly manifested as neutropenia, anemia and thrombocytopenia. 
Patients with myelosuppression are more likely to experience infections, sepsis, bleeding, and 
reductions in health-related quality of life (HRQoL), frequent hospitalizations, and even death 
[1-4]. In addition, CIM often results in drug dose reduction or delay, and limitations in the dose 
intensity of chemotherapeutic agents may reduce the antitumor efficacy of chemotherapy. 
Chemotherapy induced neutropenia (CIN) is a severe manifestation of CIM, the 
consequences of which depend on the severity and duration of the neutropenia event. In a 


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retrospective analysis of patients with small cell lung cancer (SCLC), non-Hodgkin lymphoma, 
head and neck cancer, or breast cancer, 77.5% were at high risk for febrile neutropenia (FN) 
during chemotherapy, while 18.8% were hospitalized for infection during the first course. For 
patients with Grade 3 or 4 CIN, each additional day of duration was associated with a 28% (95% 
confidence interval [CI]: 7%, 51%) or 30% (95% CI: 10%, 54%) increased risk of infection-
related hospitalization [4]. The results of a study showed that for patients with neutropenia 
requiring hospitalization, in-hospital mortality was estimated to be between 3.4% and 10.5% 
for patients with different tumor types, and the overall mortality was 6.8% [1]. In another 
analysis, the overall in-hospital mortality was 9.5%, with solid tumor mortality ranging from 
3.6% for breast cancer to 13.4% for lung cancer [5]. 
Chemotherapy induced anemia is another serious clinical manifestation of CIM that 
impacts HRQoL, increases the incidence of associated adverse events, and leads to increased 
mortality. Moderate-to-severe anemia is associated with fatigue and dyspnea in patients with 
multiple cancer types. However, SCLC patients tend to be very elderly smokers and have 
cardiopulmonary comorbidities, making anemia a more clinically significant consequence. For 
patients diagnosed with chronic heart failure, hemoglobin levels ≤ 10 g/dL increase the risk of 
death approximately 2-fold [6]. Similarly, in a broader nononcology patient population, patients 
with chronic obstructive pulmonary disease (COPD) who presented with hemoglobin levels 
below 13 g/dL had shorter median overall survival (OS: 49 versus 74 months) compared with 
patients without a diagnosis of anemia [7]. 
The clinical prognosis of chemotherapy-induced thrombocytopenia (CIT) depends on the 
degree and duration of platelet count reduction. Chemotherapy regimens used to treat cancer 
patients with solid tumors have a relatively lower risk of serious long-term thrombocytopenia 
compared to patients with hematologic malignancies, and therefore the risk/consequences of 
bleeding associated with this have received less attention. However, thrombocytopenia can lead 
to some clinically relevant problems in specific patient subpopulations, such as patients with 
brain metastases or those requiring long-term anticoagulant therapy, or in patients requiring 
specific chemotherapy regimens, such as topotecan. At the same time, with the accumulation 
of chemotherapy courses, the severity of CIT will also be aggravated due to the continuous 
suppression of bone marrow by the accumulation of chemotherapy drug doses. Because there 
are limited treatments for CIT, once it occurs, the duration and impact on subsequent 
chemotherapy tend to be more severe than CIN. 


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1.1.2. 
Current therapies and unmet clinical needs for CIM 
The only treatment for severe (Grade 4) neutropenia (SN) is growth factors, but not 
recommended for all patients receiving myelosuppressive chemotherapy. For patients with FN 
risk ≤ 20% [8-9] growth factors are not recommended until the patient experiences an adverse 
event. In addition, these drugs can cause serious side effects, such as bone pain, which in severe 
cases may be intolerable to the patient. For example, in a retrospective pooled analysis, 
approximately 30% of patients treated with pegfilgrastim experienced grade ≥ 2 bone pain [10]. 
There is no effective treatment for patients who cannot tolerate growth factors. 
Chemotherapy induced anemia (CIA) is one of the important manifestations of 
chemotherapy induced myelosuppression. To date, the only treatment for CIA has been 
transfusion or transfusion of erythropoiesis stimulating agents (ESAs), neither of which is a 
perfect intervention. In addition to being a temporary solution to this serious situation, red cell 
transfusion carries the risk of latent infection, immunosuppression, alloimmunization, and 
transfusion reactions. ESAs also have serious side effects, including increased risk of 
myocardial infarction, cerebrovascular accident, and thromboembolism, decreased OS, and 
lead to tumor progression/recurrence. 
Chemotherapy-induced thrombocytopenia (CIT) refers to one of the most common cancer 
treatment complications in which anti-tumor chemotherapeutic drugs exert an inhibitory 
mechanism on the bone marrow, especially on megakaryocytic cells, resulting in platelet counts 
in peripheral blood lower than normal values, and is a common hematological toxicity in 
clinical practice. Treatment of CIT includes platelet transfusions and administration of 
thrombopoietic growth factors, which are mainly recombinant human interleukin 11 and 
recombinant human thrombopoietin [11]. Platelet transfusion is one of the fastest and most 
effective treatments for patients with severe thrombocytopenia. However, platelet transfusion 
may potentially bring about the risk of infection with acquired infectious viral diseases such as 
AIDS and hepatitis C, as well as some complications related to platelet transfusion. Patients 
may also produce platelet antibodies and cause ineffective platelet transfusion or immune 
response after transfusion. Thrombus caused by platelet elevation has always been one of the 
potential risks of application of platelet-stimulating growth factor [12]. Close attention should be 
paid to platelet changes after administration and timely drug withdrawal is required, which also 
limits its application in clinical trials. 
In addition, dose reduction and delay are common clinical measures to cope with CIM. 
These dose modifications limit the relative dose intensity (RDI) of the planned treatment, which 


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may reduce the potential benefit to patients [13-15] and also put pressure on patients, who are 
concerned about worsening their disease if they are not treated as prescribed. 
Thus, despite some targeted clinical interventions for clinically significant CIM, cancer 
patients still suffer from symptoms associated with infection, anemia, and thrombocytopenia, 
transfusion requirements, delayed dosing, and dose reductions; as well as an increased risk of 
long-term complications of myelosuppression and growth factor use (in long-term survivors). 
The continued occurrence of risk events resulting from these CIMs suggests the need for 
additional interventions to improve the current standard of care (SOC). 
Currently, there are no effective therapies that can prevent or mitigate chemotherapy-
induced myelosuppression before chemotherapy occurs. Although growth factors (granulocyte 
colony-stimulating factors [G-CSFs] and erythropoiesis stimulating agent [ESAs]) and blood 
transfusions can be used to treat myelosuppression, these "reactive" interventions are specific 
to a cell lineage, used after chemotherapy has harmed them, and pose risks to patients that are 
inherent to their treatment itself. G-CSF is administered following chemotherapy treatment 
even in the setting of primary prevention (ie, administered during the first cycle of 
chemotherapy and not triggered by the development of adverse events [AEs]) to stimulate 
proliferation of surviving progenitor cells. Chemotherapy still caused irreversible damage to 
the bone marrow. An alternative approach that can replace "reactive" intervention therapies, 
thereby protecting bone marrow from the cytotoxicity of chemotherapy to simultaneously 
protect multiple lineages, is of great clinical benefit. 
This need is particularly acute in patients treated for small cell lung cancer (SCLC), which 
accounts for approximately 15% of all lung cancers, with approximately 70% of patients 
already in the extensive stage at initial diagnosis. Major diagnosis and treatment guidelines at 
home and abroad (including those edited by the Chinese Society of Clinical Oncology) 
recommend platinum-based chemotherapy as the first-line standard treatment for SCLC. 
Studies have shown that platinum-based combination therapy with etoposide or topotecan in 
the treatment of extensive stage small cell lung cancer is highly susceptible to significant 
myelosuppression (neutropenia 47% to 92%, leukopenia 8% to 66%, thrombocytopenia 10% 
to 46% and anemia 7% to 34%) [16-21]. Consistent with the literature findings, the occurrence of 
Grade 4 neutrophils was as high as 52.9%, the occurrence of Grade 3/4 thrombocytopenia was 
36.1%, and the occurrence of Grade 3/4 anemia was 31.9% in the control groups (ie, those 
receiving placebo and chemotherapy) in the three small cell lung cancer trials of Triliciclib, 
which has great room for improvement. 


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1.1.3. 
Chemotherapy and improving myelosuppression in small cell lung cancer in 
China 
The results of epidemiological statistical study of malignant tumors in China in 2015 
showed that 787,000 new cases of lung cancer and 631,000 deaths occurred each year. Small 
cell lung cancer (SCLC), as a histological subtype of lung cancer, accounts for about 15 ~ 25% 
of lung cancer patients, and extensive stage small cell lung cancer (ES-SCLC) accounts for 
about 70% of clinical diagnoses. For ES-SCLC, in line with the major international guidelines 
for diagnosis and treatment, the first-line chemotherapy regimen recommended by the Chinese 
Society of Clinical Oncology is cisplatin/carboplatin combined with etoposide, and the second-
line chemotherapy regimen is topotecan. Literature studies have shown (Table 1) that 
chemotherapy-induced myelosuppression (grade 3/4 neutropenia 15.6% to 93.8%, anemia 0% 
to 33.3%, and thrombocytopenia 0% to 33.3%) [22-39] remains an urgent major adverse reaction 
in Asian populations, including China, South Korea, and Japan, for patients with small cell lung 
cancer receiving carboplatin/cisplatin combined with etoposide effects or topotecan. 
 


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Table 1 Summary of Occurrence of Myelosuppression in Asian Patients with Extensive Stage Small Cell Lung Cancer Receiving Platinum Combined 
with Etoposide/Topotecan 
Investigations 
Study 
Category 
Country 
Treatment group 
N 
Occurrence of Grade 3 or Higher 
Myelosuppression 
Neutropenia 
Anemia 
Thrombocyt
openia 
Shun lu et al, 2015 [29] 
Random 
control 
CHINA 
Endostar (7.5 mg/m2, D1-14) + carboplatin + etoposide (60 
mg/m2, D1-5) 
69 
55.1% 
1.4% 
18.8% 
Carboplatin (AUC = 5, D1) + etoposide (60 mg/m2, D1-5) 
69 
39.1% 
2.9% 
18.8% 
Zhang Shucai et al, 
2007 [31] 
Random 
control 
CHINA 
Carboplatin (300 mg/m2, D1) + etoposide (100 mg, D1-5) 
32 
15.6% 
12.5% 
12.5% 
Ma Jin'an et al, 2006 
[32] 
Retrospectiv
e analysis 
CHINA 
Cisplatin (80 mg/m2 in 3 days) + etoposide (100 mg/m2, D1-3) 
29 
34.5% 
13.8% 
17.2% 
Carboplatin (300 mg/m2, or AUC = 6, D1) + etoposide (120 
mg/m2, D1-3) 
12 
50% 
33.3% 
33.3% 
Ren Li et al 1999 [33] 
Random 
control 
CHINA 
Carboplatin (200 mg/m2, D1) + Cisplatin (20 mg/m2, D1) + 
Etoposide (100 mg/m2, D1-5) 
32 
71.9% 
- 
18.8% 
Carboplatin (300 mg/m2 D1) + etoposide (100 mg/m2 D1-5) 
32 
93.8% 
- 
21.9% 
IMpower133 
(Japanese 
subgroup) 
[27] 
Random 
control 
JAPAN 
Atezolizumab (1200 mg, D1) + carboplatin (AUC = 5, D1) + 
etoposide (100 mg/m2, D1-3) 
20 
70% 
15% 
20% 
Placebo + carboplatin (AUC = 5) + etoposide (100 mg/m2, D1-3) 
20 
68.3% 
9.1% 
18.2% 


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Investigations 
Study 
Category 
Country 
Treatment group 
N 
Occurrence of Grade 3 or Higher 
Myelosuppression 
Neutropenia 
Anemia 
Thrombocyt
openia 
Sun Yan et al., 2016 
Random 
control 
CHINA 
Cisplatin (80 mg/m2, D1) + etoposide (100 mg/m2, D1-3) 
150 
44.0% 
6.7% 
7.3% 
Cheng Ying et al 2019 
[25] 
Random 
control 
CHINA 
Cisplatin (80 mg/m2, D1) + etoposide (100 mg/m2, D1-3) 
111 
73.9% 
15.3% 
10.8% 
Shi Yuankai et al., 
2015 [30] 
Random 
control 
CHINA 
Cisplatin (75 mg/m2, D1) + etoposide (100 mg/m2, D1-3) 
32 
71.9% 
31.3% 
18.8% 
Xiaoqing.L, et al; 2013 
Random 
control 
CHINA 
Cisplatin (75 mg/m2) + etoposide (100 mg/m2, D1-3) 
31 
41.9% 
6.5% 
3.2% 
Yu Haifeng et al. 2010 
[28] 
Retrospectiv
e analysis 
CHINA 
Cisplatin (25 mg/m2, D1-3) + etoposide (100 mg/m2, D1-3) 
19 
31.6% 
15.8% 
0 
Dae Seog Heo, et al.; 
2018 
Random 
control 
Korea 
Cisplatin (70 mg/m2, D1) + etoposide (100 mg/m2, D1-3) 
189 
71.7% 
17.5% 
13.2% 
In-Jae Oh, et al. 2009 
Random 
control 
Korea 
Cisplatin (60 mg/m2) + etoposide (100 mg/m2, D1-3) 
76 
67.5% 
13.0% 
16.9% 
Zhang Liang et al 2019 
[34] 
Retrospectiv
e analysis 
CHINA 
Topotecan, 1.5 mg/m2, D1-5 
42 
66.7% 
23.8% 
26.5% 


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Investigations 
Study 
Category 
Country 
Treatment group 
N 
Occurrence of Grade 3 or Higher 
Myelosuppression 
Neutropenia 
Anemia 
Thrombocyt
openia 
Li Zhihua et al, 2015 
[35] 
Retrospectiv
e analysis 
CHINA 
Topotecan, 0.75 – 1.2 mg/m2, D1-5 
29 
31.00% 
17.20% 
10.30% 
Li Li et al, 2001 [36] 
Prospective 
single arm 
CHINA 
Topotecan, 1.2 mg/m2, D1-5 
40 
30.00% 
0.00% 
7.50% 
Zhu Zhou et al 2013 
[37] 
Retrospectiv
e analysis 
CHINA 
Topotecan, 1.5 mg/m2, D1-5 
22 
40.90% 
- 
- 
Zhao Mingli et al. 
2011 [38] 
Retrospectiv
e analysis 
CHINA 
Topotecan, 1.25-1.5 mg/m2, D1-5 
21 
42.90% 
14.30% 
0 
Inoue A et al, 2015 [39] 
Random 
control 
JAPAN 
Topotecan, 1.0 mg/m2, D1-5 
30 
87% 
30% 
40% 
 


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1.1.4. 
Trilaciclib, a novel prophylactic bone marrow protective agent 
Trilaciclib is a highly potent, selective, and reversible CDK4/6 inhibitor that protects bone 
marrow by protecting hematopoietic stem cells and progenitor cells (HSPCs) when performing 
systemic chemotherapy. The proliferation and differentiation of HSPCs are highly dependent 
on CDK4/6 activity and are arrested in G1 phase of the cell cycle when exposed to appropriate 
doses of trilaciclib, so intravenous administration of trilaciclib before chemotherapy can save 
blood cells from damage by cytotoxic chemotherapeutic drugs of the cell cycle. Therefore, for 
CDK4/6-independent tumors, Trilaciclib combined with chemotherapy can protect the bone 
marrow without antagonizing the anti-tumor efficacy of chemotherapy. 
For SCLC, RB protein, which is a downstream target protein of CDK4/6, has been shown 
to be almost absent in SCLC [37-41]. Detailed description of the genomic profile of SCLC using 
next generation sequencing methods has recently been reported in 2 articles, confirming the 
common occurrence of inactivation of driver mutations TP53 and RB-1 in SCLC [42-43]. 
Consistent with these findings, preclinical in vitro and in vivo studies have shown that exposure 
to Trilaciclib prior to chemotherapy does not attenuate the killing effect of of chemotherapy on 
RB-1 inactive tumors, including SCLC. Therefore, SCLC can be considered CDK4/6-
independent due to near universal RB-1 inactivation, which means that adult SCLC patients 
treated with platinum-based/etoposide regimen can be treated with trilaciclib to prevent CIM. 
Three randomized, double-blind Phase 2 clinical trials in SCLC patients demonstrated that 
Trilaciclib administered in combination with chemotherapy (including 1st and 2nd/3rd lines of 
chemotherapy) prevented or mitigated chemotherapy-induced myelosuppression. Integrated 
analysis of data from the three studies showed that Trilaciclib administered prior to 
chemotherapy reduced the duration of severe neutropenia in Cycle 1 from 4 days to 0 days, 
reduced the occurrence of severe neutropenia by 76% (53.3% to 12.8%, p < 0.0001), reduced 
the occurrence of Grade 3/4 anemia from 31.9% to 20.3% (p = 0.0279), and reduced the 
occurrence of Grade 3/4 thrombocytopenia from 36.1% to 19.5% (p = 0.0067). Based on these 
data, Trilaciclib received Breakthrough Therapy designation in the US in August 2019 and a 
marketing application has been submitted to the US FDA in June 2020 for the indication of the 
use of Trilaciclib in patients with small cell lung cancer receiving platinum-based plus etoposide 
or topotecan-based regimens for the prevention of chemotherapy-induced myelosuppression. 
1.2. 
Preclinical data 
This section provides a brief summary of the preclinical studies of Trilaciclib, which are 
detailed in the Investigator 's Brochure. 


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1.2.1. 
Pharmacology 
In vitro, Trilaciclib (also known as G1T28) demonstrated potent inhibitory activity 
against human CDK4 and CDK6 with half maximal inhibitory concentration (IC50) values of 
1 and 4 nM, respectively, and was highly selective for CDK4 (> 1000-fold selectivity) over 
CDK2. Trilaciclib demonstrated reversible inhibition of CDK4/cyclin D1 with an inhibition 
constant (Ki) of 0.78 nM. 
G1 arrest induced by G1T28 in HSPC was transient and readily reversible in both in 
vitro and in vivo models. In vivo analysis suggests that G1T28 administered in combination 
with myelosuppressive chemotherapy promotes recovery of complete blood count (CBC) and 
improves survival. In addition, animal models have shown that the effect of Trilaciclib in 
preventing myelosuppression persists after 4 cycles of Trilaciclib in combination with 5-
fluorouracil (5-FU), which has a high degree of myelosuppression. Whereas the extent and 
duration of CBC nadir continued to worsen following each cycle of 5-FU alone, this was 
improved by the combination of G1T28 and 5-FU, and after Cycle 4, animals receiving 
G1T28 + 5- FU showed a faster CBC recovery rate compared to 5-FU alone. In line with this, 
G1T28 showed resistance to 5-FU induced DNA damage in HSPC compared to 5-FU alone in 
a single-dose study in all cycles of combination therapy, and this effect persisted. In addition, 
a bone marrow transplantation experiment in mice irradiated with lethal doses showed that 
bone marrow obtained from mice receiving 4 cycles of 5-FU combined with G1T28 was more 
potent in hematopoietic reconstitution after bone marrow transplantation compared with bone 
marrow obtained from mice receiving 4 cycles of 5-FU alone, suggesting that G1T28 
combined with chemotherapy can protect stem cells compared with 5-FU alone. 
In vitro analysis suggests that RB-1 inactivated cells are resistant to CDK4/6 inhibition 
and therefore co-treatment with G1T28 does not protect them from chemotherapy damage. 
Trilaciclib decreased Rb phosphorylation and induced potent G1 cell cycle arrest in a cell 
model with intact and functional retinoblastoma (Rb) protein signaling (CDK 4/6 dependent). 
This effect was transient and reversible, as cells returned to baseline levels and re-entered the 
cell cycle after Trilaciclib washout. In contrast, Trilaciclib did not induce G1 cell cycle arrest 
in cells lacking Rb expression (CDK 4/6-independent mechanism). In combination with 
chemotherapeutic agents, pretreatment with Trilaciclib attenuated chemotherapy-induced 
DNA damage in CDK 4/6-dependent cells and dose-dependently reduced chemotherapy-
induced apoptosis. Thus, G1T28 was well tolerated and did not antagonize the effects of 
chemotherapy in CDK4/6-independent (no RB-1 inactivation) SCLC tumor models. 


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1.2.2. 
Pharmacokinetics 
Pharmacokinetic studies in rats and dogs showed that the plasma half-life values of G1T28 
in rats and dogs were approximately 4 to 5 hours after a single intravenous dose. Exposure 
increased with dose, but not always in proportion with the dose administered. Clearance was 
comparable in each species at all doses tested, indicating linear PK. Following multiple 
intravenous doses, G1T28 did not accumulate in rat and dog plasma and CYP inhibition studies 
in pooled human liver microsomes were performed approximately similarly between 8 exposed males 
and females, and no direct or time-dependent inhibition of CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, or CYP2D6 by trilaciclib was observed. Trilaciclib is unlikely to cause drug-drug 
interactions by inhibiting compound metabolism mediated by CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19, and CYP2D6 at concentrations below 100 µM. 
In vitro inhibition studies using a membrane transporter model system also indicated that 
DDI with Trilaciclib is unlikely to occur through inhibition of BCRP-, BSEP-, OAT1-, OAT3-, 
OATP1B1-, MDR1-, MRP1-, MRP2-, or OATP1B3-mediated transport. Trilaciclib inhibited 
MATE1, MATE2-K, OCT1, and OCT2 in vitro (IC50 values of 0.175, 0.071, 0.6, and 0.152 μM, 
respectively). 
1.2.3. 
Toxicology 
The toxicity of IV and oral G1T28 was assessed in single and repeated dose studies in 
rats and dogs for up to 14 days as well as in a series of in vitro genotoxicity studies. In 
addition, the compatibility of the G1T28 clinical drug product with human blood was assessed 
in vitro. 
There was no evidence that Trilaciclib could adversely affect central nervous system 
function at doses up to 25 mg/kg/day; the minimal clinical signs observed were reversible. 
Although Trilaciclib did inhibit hERG current in vitro at concentrations > 1000 ng/mL, it had 
no effect on heart rhythm or QTc interval in dogs when administered as a single IV dose up to 
45 mg/kg/day (900 mg/m2/day) or as a daily dose up to 15 mg/kg/day (300 mg/m2) for 7 days. 
Trilaciclib administered IV for 7 days was maximally tolerated at 25 mg/kg/day (150 
mg/m2/day) in rats and 15 mg/kg/day (300 mg/m2/day) in dogs, with the primary toxicity 
profile of all cytopenias involving hematopoiesis and reflecting its expected mechanism of 
action. These effects on hematopoiesis were reversible following cessation of dosing. 
Additional effects of Trilaciclib on lung, liver, and endocrine/female reproductive 
systems were also observed. 


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In rats, single very high doses (≥ 75 mg/kg [450 mg/m2] bolus and ≥ 250 mg/kg [1500 
mg/m2] 30-min infusion) were associated with asthma and dyspnea, and necropsy revealed 
dark spots in the lungs. 
The hepatic effects of once-daily Trilaciclib administration included mildly increased 
ALT and AST levels in female rats (50 mg/kg/day) and mildly increased ALT in dogs without 
any concomitant changes in AST, bilirubin, serum protein concentration, or histology. 
Hepatic-related effects were reversible in rats and dogs. In rats, but not dogs, once-daily 
administration of Trilaciclib resulted in changes affecting only the endocrine and/or 
reproductive systems of females, particularly decreased ovarian and uterine weights and 
altered estrous cycles. These effects are reversible and may be secondary to non-specific 
stress. 
Once-daily Trilaciclib administration was associated with occasional swelling or edema 
at the infusion site in dogs, but not rats. In these cases, extravasation of Trilaciclib dosing 
solution may cause irritation; however, there are no nonclinical data to suggest that Trilaciclib 
is a blistering agent. 
Trilaciclib did not demonstrate mutagenic potential in a GLP bacterial reverse mutation 
assay nor did it induce γ-H2AX formation in primary human fibroblasts, suggesting a low risk 
of genotoxicity in cancer patients. 
Triraciclib formulated in glucose 5% (w/v) is well compatible with human blood in vitro 
even at concentrations much higher than those produced during patient treatment. Trilaciclib 
did not cause red blood cell lysis at any concentration tested (up to 2.5 mg/mL). Trilaciclib 
caused flocculation of plasma proteins at concentrations ≥ 2.5 mg/mL, but not at 
concentrations ≤ 0.1 mg/mL. Please refer to the Investigator 's Brochure for more information. 
1.3. 
Clinical data 
This study is intended to enroll patients with extensive stage small cell lung cancer (ES-
SCLC). The following subsections mainly summarize the clinical data of three clinical trials 
of Trilaciclib in ES-SCLC patients in western countries (G1T28-02, G1T28-05, G1T28-03). 
The data of other clinical trials are detailed in the Investigator 's Brochure. The study designs 
for the three clinical trials are shown in Table 2:


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Table 2 Details of Three Clinical Trials of Trilaciclib in Patients with Small Cell Lung Cancer 
 
Trial No./Title 
Enrolled Population 
Study Design 
Study objectives 
G1T28-02 
Phase 
1b/2a 
Safety 
and 
Pharmacokinetic Study of G1T28 (T 
rilaciclib) in Patients with Extensive-
Stage Small Cell Lung Cancer 
(SCLC) Receiving Etoposide and 
Carboplatin Chemotherapy. 
Patients with newly diagnosed extensive 
stage SCLC; 
Part I:19 patients enrolled; 
Part II:77 randomized patients: 
 
Placebo: 38 patients 
 
Trilaciclib: 39 patients 
Part I (Phase 1b/2a): Single-arm open-label 
dose-finding study of Trilaciclib administered 
IV QD on Days 1 through 3 of each 21-day EC 
regimen treatment cycle (Trilaciclib dose 
started at 200 mg/m2 and was escalated or de-
escalated as needed). 
Part II: Trilaciclib or placebo IV QD 1:1 
randomized double-blind. Trilaciclib 240 
mg/m2 or placebo will be administered 
intravenously on Days 1-3 of each cycle prior 
to chemotherapy administration. 
Chemotherapy - carboplatin administered on 
Day 1 of each cycle at a target AUC = 5 
(maximum dose not to exceed 750 mg); 
etoposide 100 mg/m2 administered on Days 1-
3 of each cycle 
Part I: 
 
Evaluate DLTs; 
 
Identify 
the 
recommended 
clinical phase 2 dose; 
 
Safety and tolerability; 
 
Assess PK profile of G1T28, EC 
Part II: 
 
To 
assess 
myeloprotective 
endpoints; 
 
Safety and tolerability; 
 
Assess anti-tumor efficacy 
G1T28-05 
Phase II Clinical Trial of Carboplatin, 
Etoposide, Atislizumab Combined 
with Trilaciclib or Placebo in Newly 
Diagnosed Extensive Stage Non-
Small Cell Lung Cancer 
Patients with newly diagnosed extensive-
stage SCLC; 105 patients randomized 1:1 
Randomized double-blind 1:1 treatment or 
placebo. 
Treatment Arm: Trilaciclib combined with EC 
regimen and atezolizumab administered 
intravenously 
at 
240 
mg/m2 
before 
chemotherapy on Days 1-3 of each cycle of 
Trilaciclib; maintenance with atezolizumab 
alone after Cycle 4; 
Control group: placebo combined with EC 
regimen 
and 
atezolizumab, 
placebo 
administered as Trilaciclib in cycles 1-4; 
 
To assess the myeloprotective 
effect of Trilaciclib in patients 
with extensive stage small cell 
lung cancer treated with EC 
regimen; 
 
Evaluate safety and tolerability; 
 
Evaluate anti-tumor efficacy 


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Trial No./Title 
Enrolled Population 
Study Design 
Study objectives 
afatinib 
monotherapy 
for 
maintenance 
treatment after cycle 4; 
Chemotherapy - carboplatin administered on 
Day 1 of each cycle at a target AUC = 5 
(maximum dose not to exceed 750 mg); 
etoposide 100 mg/m2 administered on Days 1-
3 of each cycle 
G1T28-03 
Phase Ib/IIa Clinical Study to 
Evaluate 
the 
Safety 
and 
Pharmacokinetic Characteristics of 
G1T28 (Trilaciclib) in Patients with 
Previously Treated Extensive-Stage 
Small Cell Lung Cancer Treated with 
Topotecan 
Patients with previously treated (2nd/3rd 
line) extensive stage small cell lung cancer 
were enrolled. 
Part I:32 patients; a total of 90 patients 
were enrolled in Part II. 
Part I: Single-arm, open-label dose-finding 
trial, 
Trilaciclib 
was 
administered 
intravenously on Days 1-5 of each cycle 
before chemotherapy (topotecan) at a starting 
dose of 200 mg/m2, which was increased or 
decreased according to the actual situation. 
Part II was a randomized double-blind trial 
with 2:1 allocation. 
Part IIa: Trilaciclib 240 mg/m2 or placebo 
administered as an intravenous infusion 
before topotecan (0.75 mg/m2) on Days 1-5 of 
each 21-day cycle; 
Part IIb: Trilaciclib 240 mg/m2 or placebo 
administered intravenously before topotecan 
(1.5 mg/m2) on Days 1-5 of each 21-day cycle; 
Part I: 
 
DLTs; 
 
RP2D; 
 
Safety and tolerability 
Part II: 
 
Myeloprotective endpoints; 
 
Anti-tumor efficacy; 
 
PK profiles of Trilaciclib and 
Topotecan 


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1.3.1. 
Safety data 
Exposure: 
Overall, 435 individuals (168 healthy subjects and 267 cancer patients) have been exposed 
to Trilaciclib at various doses and over time: Note that since a small proportion of the same 
patients were included in Study G1T28-02 and Study G1T28-03 and their safety data in each 
study are considered separate patient records, a total of N = 272 cancer patients are reported in 
the Summary of Safety. Cancer patients were treated for a median duration of 4 cycles and 8.8% 
of patients received more than 10 cycles. Trilaciclib has been evaluated at doses between 6 and 
700 mg/m2. The sample size and duration of exposure in these trials provided an adequate safety 
database to assess the safety of Trilaciclib administered as a single agent (in healthy subjects) 
as well as with various chemotherapeutic agents (in cancer patients). 
In the SCLC Safety Analysis Set, patients treated with Trilaciclib prior to chemotherapy 
were more able to receive the recommended dose on time than patients treated with placebo. 
This improvement was reflected in fewer dose reductions and higher relative dose intensity of 
chemotherapy administered in the Trilaciclib + Chemotherapy arm compared to the Placebo + 
Chemotherapy arm. 
The percentage of patients who may discontinue treatment due to treatment-emergent 
adverse events (TEAEs), death, and investigator judgment was lower in patients receiving 
Trilaciclib than in patients receiving placebo. 
Treatment-Emergent Adverse Events: 
In the SCLC Safety Analysis Set, a significantly lower percentage of patients treated with 
Trilaciclib (59.8%) experienced Grade ≥ 3 TEAEs compared with patients treated with placebo 
(83.1%); 
In the SCLC Safety Analysis Set, a significantly lower percentage of patients treated with 
Trilaciclib (44.3%) experienced Grade 3 or 4 hematologic TEAEs compared with patients 
treated with placebo (77.1%); 
In the SCLC Safety Analysis Set, TEAEs that occurred in ≥ 5% of patients treated with 
Trilaciclib and at a ≥ 2% higher occurrence than placebo included fatigue (33.6% and 27.1% in 
the Trilaciclib + Chemotherapy and Placebo + Chemotherapy arms, respectively), pyrexia (13.9% 
and 11.0%), headache (13.1% and 9.3%), hypokalemia (10.7% and 5.9%), infusion-related 
reaction (8.2% and 1.7%), upper abdominal pain (6.6% and 2.5%), peripheral edema (6.6% and 
4.2%), rash (6.6% and 4.2%), and hyperglycemia (5.7% and 3.4%); 
Serious TEAEs were reported in 28.7% of patients receiving Trilaciclib. No preferred term 


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(PT) had a TEAE occurrence of more than 5% in the overall Trilaciclib + Chemotherapy arm, 
and the only serious TEAE with an occurrence of 4% was pneumonia. Only 2 patients 
experienced serious TEAEs related to Trilaciclib (deep vein thrombosis and thrombophlebitis); 
In the SCLC Safety Analysis Set, the percentage of patients who discontinued any study 
drug due to a TEAE was lower in the Trilaciclib + Chemotherapy arm (9.0%) than in the 
Placebo + Chemotherapy arm (11.0%). Among the 12 patients treated with Trilaciclib who 
experienced TEAEs related to Trilaciclib that led to discontinuation of any investigational 
product, only 2 patients had TEAEs related to Trilaciclib only and not to chemotherapy, 1 
patient had a Grade 2 infusion-related reaction and 1 patient had a Grade 2 injection site reaction; 
Grade 5 TEAEs occurred in 2.9% of cancer patients treated with Tralaciclib at any dose in 
any study, none were associated with Trilaciclib, and all were consistent with underlying disease 
and cytotoxic chemotherapy. 
1.3.2. 
Pharmacokinetic data 
Trilaciclib was administered as an intravenous infusion at 100% bioavailability and was 
moderately bound to human plasma proteins (69.6% to 71.7%) and essentially independent of 
concentration (from 0.05 to 20 µg/mL, including treatment-related concentrations). Trilaciclib 
is extensively metabolized in humans mainly by CYP3A4, and the main route of metabolism 
in humans is oxidation (oxidation or N-dealkylation or a combination of both), which is mainly 
excreted in feces (79.1%). 
Following single-dose administration to healthy subjects, Cmax increased in a dose-
proportional manner with AUC slightly greater than dose-proportional over the dose range of 
6-192 mg/m2 (Study G1T28-1-01). At doses of 200 to 700 mg/m2, increases in Cmax were 
approximately dose proportional, while increases in AUC were slightly greater than dose 
proportional (Study G1T28-11). 
Repeated doses of Trilaciclib at doses ranging from 200 to 280 mg/m2 were assessed for 
PK in cancer patients. Trilaciclib did not accumulate following repeated once-daily dosing of 
240 mg/m2 for 4 days, with geometric mean accumulation ratios estimated to be 0.917 (124% 
CV) for Cmax and 1.05 (42.1% CV) for AUC (Study G1T28-03). At 240 mg/m2, concentrations 
of trilaciclib were approximately 1% of Cmax within 24 hours of dosing; therefore, accumulation 
following repeated dosing was expected to be minimal and steady state was achieved by Day 1 
of trilaciclib dosing. 
There were no apparent differences in the PK of Trilaciclib between healthy subjects and 
patients receiving chemotherapy. On Day 1 of treatment, exposure parameters (AUC and Cmax) 


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in cancer patients were similar to healthy subjects receiving the equivalent dose of Trilaciclib. 
Between-subject variability (geometric coefficient of variation [CV]) was moderate in healthy 
subjects (~ 26% to 53% for Cmax and ~ 13% to 26% for AUC) and moderate to high in cancer 
patients (~ 28% to 287% for Cmax and ~ 19% to 75% for AUC) at doses near or equal to the 
recommended therapeutic dose of 240 mg/m2. 
Trilaciclib was primarily metabolized by CYP3A4 as assessed in vitro and demonstrated 
mechanistic, time-dependent inhibition of CYP3A4. Trilaciclib is unlikely to inhibit the activity 
of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, or to induce the activity 
of CYP1A2, CYP2B6, or CYP3A4 at therapeutically relevant concentrations. Trilaciclib 
inhibits OCT2, MATE1, and MATE2-K and is unlikely to inhibit P-gp, BCRP, OATP1B1, 
OATP1B3, OAT1, and OAT3 at clinically relevant concentrations. Based on the in vitro results, 
clinical trials were performed in healthy subjects to detect clinically relevant DDI mediated by 
CYP3A4, MATE, or OCT2. The results showed that the therapeutic dose of Trilaciclib was not 
expected to affect the exposure of co-administered CYP3A substrates and no dose adjustment 
of CYP3A substrates is recommended (Study G1T28-106); no dose adjustment of Trilaciclib is 
required when itraconazole or other CYP3A inhibitors are co-administered (Study G1T28-09 
and Study G1T28-114); no dose adjustment is required when Trilaciclib is co-administered with 
rifampicin or other CYP3A inducers (Study G1T28-106). Trilaciclib increased plasma 
concentrations of metformin by inhibiting OCT2 and/or MATE transporters, but no dose 
adjustment is required when metformin is combined with trilaciclib since the dosing regimen 
of trilaciclib is intermittent and the predicted clinical significance of increased plasma 
concentrations of metformin is modest (Study G1T28-106). Trilaciclib had no effect on the PK 
of etoposide, carboplatin, topotecan, and gemcitabine, nor on the pharmacokinetics of trilaciclib 
(Study G1T28-02, Study G1T28-03, Study G1T28-04, and Study G1T28-05). 
Trilaciclib has a wide therapeutic window. Efficacy E-R analysis showed a flat 
pharmacodynamics-exposure profile. Doses administered between 200 and 280 mg/m2 were 
consistently associated with desirable responsiveness, including myeloprotective efficacy, 
exposure associated with nadir neutrophil (ANC), occurrence of severe neutropenia, and 
occurrence of Grade 3/4 anaemia. Taking into account the difference in drug exposure between 
subjects, the recommended clinical dose is 240 mg/m2, which is the middle of the dose range 
of 200 to 280 mg/m2. Adverse reactions (including headache, phlebitis/thrombophlebitis, and 
injection site reactions) ranged from 28.6% (12/42), 7.1% (3/42), and 11.9% (5/42) in the 
placebo group at cumulative exposure to Trilaciclib of 14.6 to 28.2 µg.h/mL (1/3 higher quartile 


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of exposure), and 11.5% (17/148), 0.7% (1/148), and 3.4% (5/148) in the placebo group, 
respectively. With the exception of 1 case of Grade 3 thrombophlebitis, all adverse events were 
Grade 1 or 2 and were of no practical clinical relevance and no dose adjustment of Trilaciclib 
was required. 
The effect of intrinsic factors on the PK of Trilaciclib was assessed by popPK analysis, 
including a thorough analysis of covariates. Data collected from healthy subjects (Studies 
G1T28-1-01 and G1T28-11) and patients with SCLC or TNBC (Studies G1T28-02, G1T28-03, 
G1T28-05, and G1T28-04) were analyzed combined. The analysis showed no clinically 
meaningful effect of age, sex, weight, and race on Trilaciclib exposure. 
Trilaciclib has not been studied in pediatric patients. The results of the Japanese PK 
bridging study (Study G1T28-17) showed that the safety and tolerability were good at doses 
ranging from 100 to 240 mg/m2 in Japanese subjects, the pharmacokinetic behavior was 
approximately linear, and the AUC and Cmax increased slightly more than dose-proportionally. 
AUC was approximately 30% higher in Japanese subjects compared to non-Japanese subjects, 
while Cmax was 2-fold higher, and AUC at 200 mg/m2 was similar between Japanese and non-
Japanese subjects at 240 mg/m2. At the same dose of 240 mg/m2, the occurrence of adverse 
events was similar between Japanese and non-Japanese subjects, and the safety and tolerability 
of trilaciclib were not significantly different between the two populations. At a single dose of 
240 mg/m2 in Japanese subjects, mean exposure was 4.26 µg.h/mL and was not expected to 
exceed 14.6 to 28.2 µg.h/mL for 3 to 5 consecutive days (1/3 higher quantile of exposure in the 
E-R analysis). Based on the exposure-response relationship from previous studies and the safety 
results from this study, no clinically significant differences in exposure were shown and no dose 
adjustment is recommended for Japanese subjects. 
Less than 2% of the dose of Trilaciclib was excreted unchanged in urine (Study G1T28-1-
01), and approximately 14% of drug-related material was excreted via the kidneys (Study 
G1T28-08). Both studies suggest that renal exclusion is not a major route of exclusion in 
humans. Based on popPK analysis, including 45 patients with mild renal impairment and 16 
patients with moderate renal impairment, mild and moderate renal impairment had no impact 
on Trilaciclib exposure, and no dose adjustment is required for patients with mild or moderate 
renal impairment. Trilaciclib has not been studied in patients with severe renal impairment, end-
stage renal disease, or dialysis. 
Investigations into hepatic impairment are ongoing (Study G1T28-113). Mild hepatic 
impairment had no impact on Trilaciclib exposure based on popPK analysis including 30 


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patients with mild hepatic impairment. No dose adjustment is required in patients with mild 
hepatic impairment. Trilaciclib has not been studied in patients with moderate or severe hepatic 
impairment. 
1.3.3. 
Efficacy data 
Trilaciclib efficacy refers to the prevention of chemotherapy induced bone marrow 
suppression. A summary of myeloprotective endpoint measures for the three clinical trials 
conducted in SCLC patients is presented in Table 3. The trial results showed that Trilaciclib had 
a significant effect in preventing bone marrow suppression, supporting the conduct of a Phase 
3 clinical study based on this data in China to evaluate the safety and efficacy of Trilaciclib in 
Chinese patients. 


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Table 3 Summary of Trilaciclib Bone Marrow Protection Endpoint Data from Three Clinical Trials in SCLC 
Endpoint 
Study G1T28-02 Part II 
Study G1T28-05 
Study G1T28-03 Part II 
Integrated Analysis 
Plac + 
E/C (N = 
38) 
Trila + 
E/C (N = 
39) 
P value 
Plac + 
E/C/A (N 
= 53) 
Trila + 
E/C/A (N 
= 54) 
P value 
Plac + 
TPT 1.5 
mg/m2 (N 
= 29) 
Trila + 
TPT 1.5 
mg/m2 (N 
= 32) 
P value 
Placebo + 
Chemothe
rapy (N = 
119) 
Trilaciclib 
+ 
Chemothe
rapy (N = 
123) 
P value 
Cycle 1 DSN, mean (SD) 
3 (3.9) 
0 (0.5) 
< 0.0001 
4 (4.7) 
0 (1.0) 
< 0.0001 
7 (6.2) 
2 (3.9) 
< 0.0001 
4 (5.1) 
0 (1.8) 
< 0.0001 
Occurrence of severe neutropenia, N 
(%) 
16 (42.1) 
2 (5.1) 
0.0049 26 (49.1) 
1 (1.9) 
< 0.0001 22 (75.9) 13 (40.6) 
0.016 
63 (52.9) 14 (11.4) < 0.0001 
G-CSF use rate, N (%) 
24 (63.2) 4 (10.3) 
0.0003 25 (47.2) 16 (29.6) 
0.0686 19 (65.5) 16 (50.0) 
0.2544 
67 (56.3) 35 (28.5) < 0.0001 
Occurrence of febrile neutropenia TEAEs, 
N (%) 
3 (7.9) 
1 (2.6) 
0.4544 
3 (5.7) 
1 (1.9) 
NE 
5 (17.2) 
2 (6.3) 
NE 
11 (9.2) 
4 (3.3) 
0.0889 
Occurrence of RBC transfusion in Cycle 5 
and beyond, N (%) 
9 (23.7) 
2 (5.1) 
0.0338 11 (20.8) 7 (13.0) 
0.1335 12 (41.4) 10 (31.3) 
0.3222 
31 (26.1) 18 (14.6) 
0.0252 
Number of Red Blood Cell Transfusion 
Events on/after Week 5 (Weekly 
Occurrence) 
0.019 
0.005 
0.0208 
0.026 
0.017 
0.1954 
0.063 
0.026 
0.0302 
0.031 
0.015 
0.0027 
Erythropoiesis StimulatingAgent Use, N 
(%) 
2 (5.3) 
1 (2.6) 
NE 
6 (11.3) 
3 (5.6) 
0.3343 
6 (20.7) 
1 (3.1) 
0.0673 
14 (11.8) 
4 (3.3) 
0.0254 
Number of Erythropoiesis Stimulating 
Agents Used (Events Per Week) 
0.021 
0.016 
0.4368 
0.06 
0.026 
0.2412 
0.143 
0.059 
0.1228 
0.064 
0.016 
0.0359 
Occurrence of Grade 3/4 Decreased 
Hemoglobin Levels, N (%) 
7 (18.4) 
4 (10.3) 
0.1682 15 (28.3) 10 (18.5) 
0.2369 17 (58.6) 12 (37.5) 
0.093 
38 (31.9) 25 (20.3) 
0.0279 
Occurrence of platelet transfusion, N (%) 
0 
2 (5.1) 
NE 
2 (3.8) 
1 (1.9) 
NE 
9 (31.0) 
8 (25.0) 
0.3222 
11 (9.2) 
10 (8.1) 
0.9564 


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Endpoint 
Study G1T28-02 Part II 
Study G1T28-05 
Study G1T28-03 Part II 
Integrated Analysis 
Plac + 
E/C (N = 
38) 
Trila + 
E/C (N = 
39) 
P value 
Plac + 
E/C/A (N 
= 53) 
Trila + 
E/C/A (N 
= 54) 
P value 
Plac + 
TPT 1.5 
mg/m2 (N 
= 29) 
Trila + 
TPT 1.5 
mg/m2 (N 
= 32) 
P value 
Placebo + 
Chemothe
rapy (N = 
119) 
Trilaciclib 
+ 
Chemothe
rapy (N = 
123) 
P value 
Number of platelet transfusions (events 
per week) 
0 
0.008 
0.4539 
0.007 
0.002 
0.7017 
0.063 
0.028 
0.7386 
0.017 
0.011 
0.5169 
Occurrence of Grade 3/4 platelet count 
decreased, N (%) 
5 (13.2) 
4 (10.3) 
0.4572 20 (37.7) 
1 (1.9) 
0.0031 19 (65.5) 21 (65.6) 
0.9306 
43 (36.1) 24 (19.5) 
0.0067 
Occurrence of All Causality 
Chemotherapy Dose Reductions, N (%) 
13 (34.2) 
3 (7.7) 
0.0156 14 (26.4) 
3 (5.6) 
0.0127 
9 (31.0) 
6 (18.8) 
0.204 
36 (30.3) 
11 (8.9) 
< 0.0001 
Number of All Causality Chemotherapy 
Dose Reductions (Events Per Week) 
0.084 
0.022 
0.0189 
0.085 
0.021 
0.0195 
0.116 
0.051 
0.1913 
0.093 
0.028 
< 0.0001 
Occurrence of serious infection TEAEs, N 
(%) 
2 (5.3) 
4 (10.3) 
0.2965 
7 (13.2) 
3 (5.6) 
0.2644 
3 (10.3) 
1 (3.1) 
NE 
12 (10.1) 
8 (6.5) 
0.4152 
Occurrence of intravenous antibiotics, N 
(%) 
8 (21.1) 
8 (20.5) 
0.7154 12 (22.6) 10 (18.5) 
0.8196 
8 (27.6) 
7 (21.9) 
NE 
28 (23.5) 24 (19.5) 
0.6207 
Notes: E-etoposide, C-carboplatin, TPT: topotecan, Trila-Trilaciclib, A-atezolizumab, plac- placebo 
 
 


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1.4. 
Risks and benefits 
In summary, CIM remains an urgent unmet clinical need. Some symptomatic treatments 
for myelosuppression (e.g., blood transfusions, growth factors, etc.) are available, but the 
treatment options are limited, and each therapy carries its own additional risks. Currently, there 
are no effective treatments that can prevent CIM before chemotherapy causes damage, thereby 
improving the overall safety of cancer patients. As the first agent designed to reduce CIM by 
protecting HSPC, Trilaciclib showed a strong ability to prevent or alleviate CIM in patients 
with extensive stage small cell lung cancer (ES-SCLC). The risk-benefit assessments of the 
current data for Trilaciclib support the first clinical study application in China: prophylactic use 
of Trilaciclib to improve CIM in patients with ES-SCLC receiving platinum plus etoposide or 
topotecan. The sponsor will conduct a clinical study including an open-label safety run-in and 
PK evaluation part and a randomized double-blind, placebo-controlled study part to assess the 
safety, efficacy, and pharmacokinetic profile of Trilaciclib in combination with EC or topotecan 
in ES-SCLC to support the marketing of Trilaciclib in China for this indication. 
2. Study objective and study endpoints 
2.1. 
Study objectives 
Part I (Safety Run-in and PK Evaluation Part): 
Primary objective 
• To evaluate the pharmacokinetic (PK) profile of Trilaciclib in patients with extensive stage 
small cell lung cancer; 
• To evaluate the safety and tolerability of Trilaciclib in patients with extensive stage small 
cell lung cancer; 
• To evaluate the effectiveness of Trilaciclib (prevention of chemotherapy-induced 
myelosuppression) in patients with extensive stage small cell lung cancer; 
Secondary objectives 
• To comprehensively evaluate the myeloprotective effect of Trilaciclib in patients with 
extensive stage small cell lung cancer; 
• To evaluate the short-term antitumor efficacy of Trilaciclib in patients with extensive stage 
small cell lung cancer; 
Exploratory objectives: 
• To evaluate the long-term antitumor efficacy of Trilaciclib in patients with extensive stage 
small cell lung cancer; 
• Population pharmacokinetic profile. 


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Part II (randomized, double-blind part): 
Primary objective 
• To evaluate the effectiveness of Trilaciclib (prevention of chemotherapy-induced 
myelosuppression) in patients with extensive stage small cell lung cancer; 
Secondary objectives 
• To comprehensively evaluate the myeloprotective effect of Trilaciclib in patients with 
extensive stage small cell lung cancer; 
• To evaluate the safety and tolerability of Trilaciclib in patients with extensive stage small 
cell lung cancer; 
• To evaluate the short-term antitumor efficacy of Trilaciclib in patients with extensive stage 
small cell lung cancer; 
Exploratory objectives: 
• To evaluate the long-term antitumor efficacy of Trilaciclib in patients with extensive stage 
small cell lung cancer; 
• Population pharmacokinetic profile. 
2.2. 
Study endpoints 
Part I (Safety Run-in and PK Evaluation Part): 
Primary Endpoint: 
• PK profile (Cmax, AUC and other PK parameters); 
• Safety and tolerability: adverse events, laboratory abnormalities, etc.; 
• Duration of severe neutropenia in Cycle 1 (DSN); 
Key Secondary Endpoints: 
• Occurrence of severe neutropenia (SN); 
• Occurrence of red blood cell transfusion (on/after Week 5); 
• Granulocyte colony stimulating factor (G-CSF) use rate; 
• Composite endpoint–major adverse hematologic event (Any of the following): 
 All-cause hospitalization; 
 All-cause chemotherapy dose reductions; 
 Febrile neutropenia; 
 SN prolongation (lasting > 5 days); 
 RBC transfusion on/after Week 5. 
Other secondary endpoints: 
• Occurrence of Grade 3 and 4 hematological toxicities; 


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• Absolute neutrophil count trough by cycle; 
• Absolute neutrophil count, platelet count, absolute lymphocyte count, and hemoglobin over 
time; 
• Erythropoiesis stimulating agent (ESA) use rate; 
• Recombinant human interleukin -11 use rate; 
• Thrombopoietin (TPO) use; 
• Occurrence of intravenous or oral antibiotic administration; 
• Occurrence of infectious serious adverse events; 
• Occurrence of serious adverse events of lung infection; 
• Occurrence of febrile neutropenia; 
• Occurrence of platelet transfusion; 
• Objective tumor response rate (ORR); 
• Disease control rate (DCR). 
Exploratory Endpoints 
• Progression-free survival (PFS); 
• Overall survival (OS); 
• Population pharmacokinetic profile. 
Part II (randomized, double-blind part): 
Primary Endpoint: 
• Duration of severe neutropenia in Cycle 1 (DSN); 
Key Secondary Endpoints: 
• Occurrence of severe neutropenia (SN); 
• Occurrence of red blood cell transfusion (on/after Week 5); 
• Granulocyte colony stimulating factor (G-CSF) use rate; 
• Composite endpoint – major adverse hematologic event (Any of the following): 
 All-cause hospitalization; 
 All-cause chemotherapy dose reductions; 
 Febrile neutropenia; 
 SN prolongation (lasting > 5 days); 
 RBC transfusion on/after Week 5. 
Other secondary endpoints: 
• Occurrence of Grade 3 and 4 hematological toxicities; 


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• Absolute neutrophil count trough by cycle; 
• Absolute neutrophil count, platelet count, absolute lymphocyte count, and hemoglobin over 
time; 
• Erythropoiesis stimulating agent (ESA) use rate; 
• Rate of recombinant human interleukin -11 use; 
• Thrombopoietin (TPO) use; 
• Occurrence of intravenous or oral antibiotic administration; 
• Occurrence of infectious serious adverse events; 
• Occurrence of lung infection SAEs: 
• Occurrence of febrile neutropenia; 
• Occurrence of platelet transfusion; 
• Safety and tolerability: adverse events, laboratory abnormalities, etc.; 
• Objective tumor response rate (ORR); 
• Disease control rate (DCR). 
Exploratory Endpoints 
• Progression-free survival (PFS); 
• Overall survival (OS); 
• Population pharmacokinetic profile. 
3. Study design 
3.1. 
Overall design 
This is a multi-center Phase 3 clinical trial with an open-label single-arm safety run-in and 
PK evaluation part and a randomized double-blind, placebo-controlled part in patients with ES-
SCLC to evaluate the safety, efficacy, and pharmacokinetic profile of Trilaciclib based on 
completed clinical studies abroad. 
The study consists of 2 parts. The first part is safety run-in and PK evaluation, about 12 
patients with extensive stage small cell lung cancer, 6 patients with 1st line ES-SCLC and 6 
patients with 2nd/3rd line ES-SCLC were enrolled and treated with Trilaciclib in combination 
with carboplatin and etoposide or with topotecan, respectively, and based on evaluable data 
from cycle 1, the safety, tolerability, pharmacokinetics, and preliminary efficacy (prevention 
of myelosuppression) of Trilaciclib were evaluated. The second part is a randomized double-
blind, placebo-controlled study enrolling approximately 80 patients with ES-SCLC, stratified 
by 1st line vs 2nd/3rd line ES-SCLC, ECOG PS (0-1 vs 2), and presence vs absence of brain 


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metastases, randomized in a 1:1 ratio to Trilaciclib versus placebo where 1st line ES-SCLC 
patients receive Trilaciclib/placebo in combination with EC regimen (Trilaciclib-EC group 
and placebo-EC group), 2nd/3rd line ES-SCLC patients will receive Trilaciclib or placebo in 
combination with Topotecan (Trilacicli-TPT group and placebo-TPT group), and the efficacy 
of Trilaciclib (prevention of myelosuppression) will be evaluated with duration of severe 
neutropenia (DSN) in Cycle 1 as the primary endpoint. Trilaciclib was administered at a 
planned dose of 240 mg/m2 , and 12 additional patients (6 each for 1st line ES-SCLC and 
2nd/3rd line ES-SCLC) were to be enrolled in Part I to explore the PK and safety of 
Trilaciclib 200 mg/m2 if safety data from Part I of the study suggested that a dose adjustment 
of Trilaciclib was required. 
Patients meeting the inclusion and exclusion criteria will receive the following treatments: 
Patients with first line ES-SCLC: Trilaciclib 240 mg/m2 administered intravenously once 
daily prior to chemotherapy on Days 1 to 3 of each 21-day cycle; carboplatin dose will be 
calculated according to Calvert formula as target AUC = 5 (maximum 750 mg) on Day 1 and 
100 mg/m2 etoposide administered intravenously daily on Days 1-3. Patients will receive up to 
6 cycles or until disease progression, intolerability, withdrawal of consent, or investigator 
termination of treatment, whichever occurs first. 
Patients with 2nd/3rd line ES-SCLC: Trilaciclib 240 mg/m2 IV daily on Days 1 to 5 of 
each 21-day cycle prior to chemotherapy; Topotecan 1.25 mg/m2 on Days 1-5 of each cycle. 
Study drug will be administered until disease progression, intolerability, withdrawal of consent, 
or investigator termination of treatment, whichever occurs first. 
The study process includes screening period, treatment period, safety follow-up and 
survival follow-up. 
3.2. 
Sample size 
The study consists of 2 parts and a total of approximately 92 ES-SCLC patients are planned 
to be enrolled. The first part (safety run-in and PK evaluation) planned to enroll approximately 
6 patients each for 1st line ES-SCLC and 2nd/3rd line ES-SCLC. The second part (efficacy 
verification) planned to enroll approximately 80 ES-SCLC patients (approximately 40 per arm). 
3.3. 
Rationale for trial design 
Trilaciclib has conducted a number of clinical studies in the United States and Europe, all 
clinical trials were conducted according to standard operating procedures of the sponsor and/or 
contract research organization in compliance with Good Clinical Practice for the design, 
conduct, and analysis of clinical trials. All trials were conducted with the approval of the local 


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ethics committee or institutional review board. Among them, three randomized, double-blind 
phase II clinical trials in patients with small cell lung cancer (SCLC) confirmed that Trilaciclib 
administered in combination with chemotherapy (including 1st and 2nd/3rd lines of 
chemotherapy) can prevent or reduce chemotherapy-induced myelosuppression. 
Based on the results of the clinical trials completed overseas, Trilaciclib has clear target of 
action, clear pharmacological action, good safety and tolerability, moderate protein binding rate, 
less DDI, intravenous administration is not affected by dietary absorption, and there is no 
significant difference in PK behavior between cancer subjects and healthy subjects. The 
exposure of Trilaciclib is found to be slightly higher in the Japanese population than in the 
European and American populations. Based on its good safety and tolerability and exposure-
efficacy relationship, it is considered that the exposure difference has no significant clinical 
significance, and dose adjustment is not recommended. Efficacy E-R analysis showed a flat 
pharmacodynamics-exposure profile. Doses administered between 200 and 280 mg/m2 resulted 
in desirable responsiveness, including myeloprotective efficacy (exposure associated with ANC, 
severe neutropenia, and anemia occurrence) and antitumor activity (ORR, PFS, and OS). Taking 
into account the difference in drug exposure between subjects, the recommended clinical dose 
is 240 mg/m2, which is the middle of the dose range of 200 to 280 mg/m2. The E-R analysis of 
safety showed that the higher the exposure, the greater the probability of headache, 
phlebitis/thrombophlebitis, and injection site reactions, but these adverse reactions were of low 
grade and not clinically significant. Chinese and Japanese belong to Asian race, and the safety, 
exposure and efficacy of Trilaciclib in Chinese are expected to be similar to those in Japanese, 
supporting the safety and efficacy of this product in Chinese observed at the dose level of 240 
mg/m2. 
Trilaciclib has demonstrated efficacy and safety. At present, there is no evidence that the 
response of Chinese patients to drug treatment is different from that of overseas populations 
and may bring about safety and effectiveness impact. 
At present, there is no relevant data on the use of Trilaciclib in the Chinese population in 
clinical trials of Trilaciclib. Therefore, in order to further evaluate the safety and efficacy of 
Trilaciclib in Chinese patients, a clinical trial including an open-label safety run-in and PK 
evaluation part and a randomized double-blind, placebo-controlled part is planned to be 
conducted in extensive stage small cell lung cancer in China. 
3.4. 
End of study 
The end of the study is defined as follows: 


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75% of subjects died, or 12 months after the last subject was enrolled, or the sponsor 
decided to terminate the study, whichever came first.  
4. Study population 
The proposed study population is patients with extensive stage small cell lung cancer. 
4.1. 
Criteria for enrollment 
Criteria for enrollment 
Patients must meet all of the following inclusion criteria to be enrolled in the study: 
1. Age ≥ 18 years, male or female; 
2. Histologically or cytologically confirmed extensive stage small cell lung cancer (ES-
SCLC): 
• 
Patients scheduled to receive carboplatin plus etoposide regimen: no prior systemic 
therapy (eg, chemotherapy or combined with immunotherapy); 
• 
Patients scheduled to receive topotecan regimen: previously received 1/2 lines of 
chemotherapy or combined immunotherapy but not topotecan. 
3. Presence of at least one radiation-naïve measurable lesion according to RECIST 1.1 
criteria; 
4. Hemoglobin ≥ 90 g/L; 
5. Neutrophil count ≥ 1.5 × 109/L;  
6. Platelet count ≥ 100 × 109/L;  
7. Creatinine ≤ 15 mg/L or creatinine clearance (CrCl) ≥ 60 mL/min (Cockcroft-Gault 
formula); 
8. Total bilirubin ≤ 1.5 × upper limit of normal (ULN); 
9. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN or 
≤ 5 × ULN (for patients with liver metastases); 
10. Albumin ≥ 30 g/L; 
11. ECOG PS score 0 – 2; 
12. Expected survival time ≥ 3 months; 
13. Contraception: 
Females: All females of childbearing potential must have a negative serum pregnancy 
test at screening and must use reliable contraception from signing of informed consent 
through 3 months after the last dose; 
Male: Female partners of childbearing potential must use reliable contraception from 
signing the informed consent until 3 months after the last dose; 


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14. Understand and sign informed consent. 
4.2. 
Exclusion criteria 
1. Symptomatic brain metastases requiring local radiotherapy or hormonal therapy; 
2. History of other malignancies, with the following exceptions: (1) clinically cured 
cutaneous basal cell or squamous cell tumors; (2) cured a) cervical cancer, b) prostate 
cancer, c) superficial bladder cancer; or (3) other solid tumors with a clinical cure time of 
more than 3 years; 
3. Uncontrolled ischemic heart disease or clinically significant congestive heart failure 
(NYHA Class III or IV); 
4. Stroke or cardiovascular or cerebrovascular event within 6 months prior to enrollment; 
5. Severe active infection; 
6. Psychological or other social factors causing insufficient trial compliance; 
7. Other uncontrolled serious chronic diseases or conditions that, in the opinion of the 
investigator, would make participation in the trial inappropriate; 
8. Known HIV infection, active hepatitis B (defined as positive HBV DNA), and 
hepatitis C (positive HCV RNA); 
9. Radiation therapy within 2 weeks prior to enrollment; 
10. Patients who have received cytotoxic drug therapy or investigational drug therapy 
within 4 weeks before enrollment, or non-cytotoxic anti-tumor drug therapy within 2 
weeks; 
11. Subjects in the first part of the study should not take strong or moderate inducers of 
CYP3A4 concomitantly within 4 weeks before taking the study drug, and strong 
inhibitors of CYP3A4 concomitantly within 2 weeks before taking the study drug;  
12. Toxicity from prior anticancer therapy has not recovered to Grade 0 or 1 (except 
alopecia); 
13. Hypersensitivity to the study drug (Trilaciclib, etoposide, carboplatin, topotecan) or 
components thereof; 
14. Persons who are unable to act independently due to legal restriction or legal sense; 
15. Pregnant or lactating women; 
16. Not suitable for participating in this study in the investigator 's opinion. 


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5. Investigations treatment  
5.1. 
Investigational drug 
The study drug in this trial is: Trilaciclib/placebo, and the chemotherapy drugs for 
combination therapy are carboplatin, etoposide or topotecan. 
Investigational product investigated: 
Trilaciclib: provided by Jiangsu Simcere Pharmaceutical Co., Ltd., 300 mg/vial. 
Trilaciclib is a sterile powder, USP D-mannitol is added as cake formers, and citrate buffer is 
added to maintain the pH of the reconstitution at 4.0 to 5.0. The preparation of the study drug 
for reconstitution and dilution is described in detail in the Pharmacy Manual.  
Trilaciclib placebo: The outer box of the placebo is designed to be consistent with the 
investigational product, Trilaciclib, and the contents of the box are filled with the same quality 
of padding (paper sheets), which will not break blind in appearance or handheld after 
sealing.Placebo was actually used to prepare 250 mL of 5% dextrose in water or saline (0.9% 
sodium chloride) as the vehicle used for Trilaciclib.  
Background Therapy/Chemotherapy: 
Carboplatin: Qilu Pharmaceutical Co., Ltd., 100 mg/10ml/box, solution 
Etoposide: Jiangsu Hengrui Medicine, 100 mg/5ml/vial, solution 
Topotecan: Jiangsu Aosaikang Pharmaceutical Co., Ltd., 2 mg/vial, solution 
The structure and other pharmaceutical properties of chemotherapeutic drugs are detailed 
in the corresponding package inserts. 
5.2. 
Study treatment regimen 
The treatment regimen for this study is as follows: 
Patients with 1st line ES-SCLC were treated with Trilaciclib or placebo in combination 
with carboplatin and etoposide (EC regimen); patients with 2nd/3rd line ES-SCLC were treated 
with Trilaciclib or placebo in combination with topotecan as detailed in Table 4 below:  


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Table 4 Study Treatment Regimen  
Investigational drug 
Usage 
Period of administration 
1st line ES-SCLC 
EC 
Regimen  
Carboplatin 
Target AUC = 5 (maximum dose 750 mg), 
intravenous drip over 30 min on Day 1 of each 
21-day cycle; 
Up to 6 cycles *  
Etoposide 
100 mg/m2, 21 days per cycle, intravenous 
drip over 60 min on days 1-3;  
Up to 6 cycles *  
Trilaciclib/Placebo 
240 mg/m2, 21 days per cycle, 30 min 
intravenous drip before chemotherapy on 
Days 1-3 (try to complete the drip within 30 
+ 5 min due to PK study);  
Up to 6 cycles *  
* OR Progressive disease, intolerable, withdrawal of consent, or investigator discontinuation prior to reaching 
6 cycles, whichever came first 
2nd/3rd line ES-SCLC patients 
Topotecan 
1.25 mg/m2, 21 days per cycle, intravenous 
drip over 30 min on Days 1-5;  
Until 
disease 
progression, 
intolerable, withdrawal of consent, 
or 
investigator 
termination 
of 
treatment, whichever came first  
Trilaciclib/Placebo 
240 mg/m2, 21 days per cycle, administered 
prechemotherapy over 30 min on Days 1-5 
(infusion should be completed within 30 + 5 
min if possible due to PK studies).  
Until 
disease 
progression, 
intolerable, withdrawal of consent, 
or 
investigator 
termination 
of 
treatment, whichever came first  
 
Date of medication visit is based on the first dose of investigational drug 
(Trilaciclib/Placebo) in each cycle (D1). 
Notes: 
Trilaciclib should be administered no more than 28 hours apart between infusions for 3 or 
5 consecutive days, and no more than 4 hours between infusions of Trilaciclib and its 
subsequent injected chemotherapeutic agents (carboplatin or etoposide, or topotecan).  
Trilaciclib should be used in combination with chemotherapy, that is, if EC regimen or 
topotecan is suspended or terminated, then trilaciclib should also be suspended or terminated. 
Similarly, subsequent chemotherapy should not be administered if the planned administration 
of Trilaciclib, i.e. Trilaciclib or placebo, has not been completed in any cycle. 
Prophylactic use of any colony-stimulating factors (including granulocyte colony-
stimulating factor, granulocyte-giant cell colony-stimulating factor, erythropoiesis stimulating 
agent) was not permitted during Cycle 1, but could be used therapeutically if febrile neutropenia 
developed in patients with high-risk infections or risk factors indicating poor prognosis (sepsis, 
age > 65 years, neutrophils < 0.1 × 109/L, expected neutropenia lasting > 10 days, pneumonia, 


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invasive fungal infections, other clinically documented infections, fever requiring 
hospitalization, previous febrile neutropenia, etc.).  
5.3. 
Randomization and blinding 
5.3.1. 
Randomization and blinding 
The first part of the study was divided into open-label studies without randomization and 
blinding. 
The second part of the study was a randomized double-blind study. The investigator will 
enter the Interactive Web Response System (IWRS) after confirming that the subject meets all 
inclusion and exclusion criteria. The IWRS will assign a randomization number that associates 
the subject with a treatment group and assigns a specific treatment to the subject who should 
receive study treatment within 3 days of randomization, including the day of randomization. 
Subjects were randomized to Trilaciclib or placebo in a double-blind 1:1 ratio, stratified by 1st 
line vs 2nd/3rd line ES-SCLC, ECOG PS (0-1 vs 2), and presence vs absence of brain 
metastases. Investigators involved in the trial (including investigators, sponsor personnel, 
contract research organization personnel, central pathology reviewer, biological sample 
analysts, etc., and subjects were blinded to which drug treatment was assigned. The investigator 
obtained the subject 's assigned randomization number based on the information provided by 
the IWRS. 
Specific blinding procedures are described in the Drug Administration Manual. 
5.3.2. 
Unblinding 
Unblinding may be performed in emergency situations. Emergency unblinding should be 
the last category of measures to deal with emergencies associated with the medication and/or 
dose administered to the subject. If unblinding is necessary for safety reasons (e.g., serious 
adverse events, etc.) to treat a subject, it is recommended that the sponsor 's medical monitor 
be contacted prior to unblinding and the investigator unblinding the subject via the IWRS 
system. Once unblinded, the subject discontinued study treatment. The investigator should 
record this event in the original medical records and inform the sponsor 's clinical medical 
director as soon as possible. 
For the purpose of regulatory reporting, the Sponsor PV will unblind the treatment code if 
required by health authorities for all serious, unexpected suspected adverse events considered 
related to the study drug by the investigator or sponsor, etc., but the Sponsor study team remains 
blinded. 
In the second part, when the primary analysis is performed for the primary endpoint, the 


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necessary sponsor personnel will be unblinded and the investigator, subjects and other 
personnel will continue to be blinded; at the final analysis, the study will be unblinded.  
5.4. 
Study treatment modification 
5.4.1. 
Dose modification for trilaciclib/placebo 
Based on previous clinical studies with Trilaciclib and considering that the risk of 
inadequate HSPC stagnation is minimized as much as possible, the dose of Trilaciclib/placebo 
will not be adjusted and remains at 240 mg/m2 in this trial unless safety data in Part I suggest 
that the dose of Trilaciclib/placebo needs to be adjusted.  
Refer to Section 5.5.1.1 for dose interruptions and terminations of Trilaciclib.  
5.4.2. 
Dose modification for chemotherapy agents 
Carboplatin, etoposide, and topotecan should meet neutrophil ≥ 1.5 × 109/L and platelet 
count ≥ 100 × 109/L before dosing on the first day of the second and subsequent cycles, and 
all drug-related nonhematologic toxicities (except alopecia) need to recover to Grade 1 or 
lower or baseline levels. Dose modifications on the first day of the second and subsequent 
cycles are shown in Table 5, and no more than two dose reductions are allowed (concurrent 
carboplatin and etoposide dose reductions are one dose reduction), dose reductions are 
unidirectional permanent, and no dose increases are allowed. Delays in chemotherapy cycles 
of up to 1 week due to operational reasons such as legal holidays and up to 2 weeks due to 
treatment toxicity may be permitted; however, if the investigator believes that a delay of more 
than 2 weeks is beneficial to the subject, dosing may be delayed for more than 2 weeks upon 
request by the investigator and medical review and written approval by the sponsor.  
Table 5 Dose reductions for carboplatin, etoposide and topotecan  
Dose Level 
Etoposide (mg/m2)  
Carboplatin (AUC) 
Topotecan (mg/m2)  
Dose level-1 
Reduce to 75 
Decreased to AUC = 4 
1 
Dose level-2 
Reduce to 50 
Decreased to AUC = 3 
0.8 
Note: Simultaneous dose reduction of carboplatin and etoposide is defined as one dose reduction 
 
5.4.2.1. 
Dose modifications based on hematologic toxicities 
Dose modifications were based on various hematologic toxicities occurring during Cycle 
2 and on Day 1 of subsequent cycles as follows: 
Table 6 Dose Modification Based on Neutrophil Count and Platelet Count  
Neutrophil count < 1.5 x 109/L  
Carboplatin, etoposide and topotecan 


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First occurrence 
Without dose adjustment, G-CSF was used according 
to the 2019 edition of Expert Consensus on Diagnosis 
and Treatment of Neutropenia Caused by Cancer 
Chemotherapy 
Second occurrence 
First Dose Reduction 
Third occurrence 
Second Dose Reduction 
Fourth occurrence 
Drug withdrawn 
Platelet count < 100 x 109/L  
Carboplatin, etoposide and topotecan 
Second occurrence 
First Dose Reduction 
Third occurrence 
Second dose reduction 
Fourth occurrence 
Drug withdrawn 
 
Table 7 Dose Modification Based on Absolute Trough Neutrophil Count with or without 
Fever  
Absolute neutrophil count trough 
Carboplatin, etoposide and topotecan 
Grade 3 or 4 < 7 days (no fever)  
No dose adjustment 
Grade 4 ≥ 7 days (no fever) 
 
First occurrence 
Without dose adjustment, G-CSF was used according 
to the 2019 edition of Expert Consensus on Diagnosis 
and Treatment of Neutropenia Caused by Cancer 
Chemotherapy 
Second occurrence 
First Dose Reduction 
Third occurrence 
Second Dose Reduction 
Fourth occurrence 
Drug withdrawn 
Grade 3/4 (fever) 
 
First occurrence 
Without dose adjustment, G-CSF was used according 
to the 2019 edition of Expert Consensus on Diagnosis 
and Treatment of Neutropenia Caused by Cancer 
Chemotherapy 
Second occurrence 
First Dose Reduction 
Third occurrence 
Second Dose Reduction 
Fourth occurrence 
Drug withdrawn 
 
Table 8 Dose Modification Based on Trough Platelet Values  


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Platelet count 
Carboplatin, etoposide and topotecan 
≥ Grade 3 combined 
bleeding or Grade 4 
  
First occurrence 
No dose adjustment, recombinant human interleukin-11, rhIL-11 
derivatives, recombinant human thrombopoietin or platelet 
transfusions were used according to the 2019 Chinese Expert 
Consensus on Diagnosis and Treatment of Thrombocytopenia 
Associated with Cancer Chemotherapy  
Second occurrence 
First Dose Reduction 
Third occurrence 
Second Dose Reduction 
Fourth occurrence 
Drug withdrawn 
 
5.4.2.2. 
Dose Modifications Based on Nonhematologic Toxicities 
5.4.2.2.1. 
Hepatotoxicity 
Dose modifications were based on hepatotoxicity occurring on the first day of the second 
and subsequent cycles as follows: 
Table 9 Dose Modifications Based on ALT/AST and Bilirubin  
ALT/AST 
 
Bilirubin 
Carboplatin, etoposide and 
topotecan 
Grade 1 
AND/OR 
≤ Grade 2  
No change 
Grade ≥ 2 
a  
First 
occurrence 
Second 
occurrence 
Third 
occurrence 
AND/OR 
Grade ≥ 3 
First occurrence 
Second 
occurrence 
Third occurrence 
 
First Dose Reduction 
Second dose reduction 
Drug withdrawn 
A If liver metastasis is present at baseline and ALT/AST is Grade 2, a 1-grade worsening of the AE grade 
will result in a reduction of the first dose. If combined ALT/AST/combined bilirubin abnormalities occur, 
dose reduction is judged based on more severe cases. 
 
5.4.2.2.2. 
Gastrointestinal side effects 
Antiemetics and antidiarrheals may be used to control nausea, vomiting, and diarrhea. 
Subjects were encouraged to take large oral rehydration fluids. 
5.4.2.2.3. 
Hypersensitivity 
For subjects who experience mild to moderate hypersensitivity reactions and have been 
successfully managed, prophylaxis and bedside vital sign monitoring is recommended for all 


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subsequent doses. 
 
Mild symptoms (eg, mild flushing, rash, itching): complete the infusion. Bedside 
monitoring. No treatment required. 
 
Moderate symptoms (eg, moderate rash, flushing, mild dyspnea, chest discomfort): 
discontinue infusion. Diphenhydramine 25 mg and dexamethasone 10 mg were 
administered intravenously. The infusion was resumed at a low rate (20 mg/h) after 
recovery of symptoms. If no further symptoms appear after 15 min, the rate may be 
increased to full rate until the infusion is complete. If symptoms recur, the infusion must 
be stopped. Subjects should not receive additional chemotherapy during this cycle, but 
may receive doses for subsequent cycles at the investigator 's discretion. 
 
Serious life-threatening symptoms (eg, hypotension requiring vasopressor therapy, 
angioedema, respiratory distress requiring bronchodilator therapy, generalized urticaria): 
discontinue infusion immediately. Diphenhydramine and dexamethasone were 
administered intravenously as described above. Adrenaline or bronchodilators were added 
if needed. Epinephrine is recommended if wheezing is present that is not responsive to 
bronchodilators. Subjects should not receive any further doses of etoposide or 
carboplatin. This event was reported as an adverse event. 
5.4.2.3. 
Other toxicities 
For the first occurrence of any nonhematologic Grade 2 chemotherapy-related toxicity 
(except alopecia), all study treatment 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), treatment 
should be resumed at a reduced dose level following recovery of the toxicity to Grade 1 or 
baseline; for the third occurrence, the dose should be reduced to Dose Level 2. A fourth 
occurrence will lead to discontinuation of carboplatin, etoposide and topotecan treatment. For 
Grade 1 toxicities, the dose should not be reduced. 
For any Grade 3 or 4 chemotherapy-related toxicity not mentioned above, all study 
treatments should be withheld until the toxicity recovers to Grade 1 or baseline. Treatment 
should then be resumed at the first appearance with the first dose reduction and at the second 


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appearance with the second dose reduction. A third occurrence will lead to discontinuation of 
carboplatin, etoposide and topotecan treatment. 
The above chemotherapy drug dose adjustment regimen is recommended by the study. If 
the investigator recommends different treatments in clinical practice, the investigator may select 
the adjustment regimen by referring to the corresponding package insert of chemotherapy drugs 
or clinical routine guidelines. In this case, it is necessary to clearly record the reasons for other 
adjustment regimens in the subject 's case and discuss with the sponsor if necessary. 
5.5. 
Criteria for discontinuation from study treatment or withdrawal 
5.5.1. 
Criteria for discontinuation of study treatment 
A subject should discontinue study treatment if any of the following occur: 
1. Disease progression, except for subjects who, in the investigator 's judgment, still 
benefit from the study (e.g., pseudoprogression); 
2. To reach the maximum treatment time specified in the protocol; 
3. Subject is pregnant; 
4. Poor compliance of subjects, such as failure to receive medication and examinations 
as required, failure to comply with the restrictions on lifestyle during the study, and use of 
other prohibited concomitant medications, which have a significant impact on the 
evaluation of study drugs; 
5. Initiation of new anticancer therapy; 
6. Occurrence of an adverse event that, in the judgment of the investigator, makes it 
inappropriate to continue treatment with study drug; 
7. The investigator considers that study treatment should be discontinued in the best 
benefit of the subject; 
8. The subject or his/her legal representative (only applicable if the subject is not fully 
capable of civil conduct) requests termination of treatment. 
Subjects who discontinue study treatment should complete the items specified in the trial 
flow chart and should be followed up according to the protocol. 
5.5.1.1. 
Dose interruption and termination of trilaciclib 
For adverse events of special interest defined in Protocol Section 8.9, refer to Investigator 
's Brochure Section 6 .2 to determine whether to stop the infusion or interrupt t rilaciclib 
treatment. Adverse events of special interest for which no action was given in the Investigator 
's Brochure were handled as defined below: 


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 
Other Toxicity Events: For severe (Grade 3) other toxicity events, hold Trilaciclib until the 
event recovers to ≤ Grade 1 or baseline, then consider resuming Trilaciclib; if Grade 3 
events recur, permanently discontinue Trilaciclib. Trilaciclib was permanently 
discontinued for life-threatening (Grade 4) other toxicities. 
 
Hepatotoxicity: refer to treatment for "other toxic reactions" above. 
 
Embolic/Thrombotic Events, Venous: if related to the injection site, refer to Chapter 6 .2, 
"Injection site reaction/phlebitis/thrombophlebitis" of the Investigator 's Brochure; if not 
related to the injection site, refer to "Other toxicities" as described above. 
5.5.2. 
Criteria for early withdrawal 
Subjects could withdraw from the study at any time for any reason. The investigator may 
decide whether or not to withdraw a subject from the study based on actual clinical 
circumstances. Criteria for early withdrawal from the study were: 
1. Withdrawal of consent by the subject or his/her legal representative (only applicable if 
the subject himself/herself does not have full civil capacity); 
2. Subject lost to follow-up. 
Subjects who withdrew early were not to undergo any subsequent follow-up and 
assessments. 
5.5.3. 
Handling of study treatment discontinuation or early withdrawal 
When a subject discontinues study treatment or prematurely withdraws, the reason for 
discontinuation/early withdrawal (the primary reason should be provided if there are multiple 
reasons) should be documented in the original medical record and CRF, and unused study drug 
must be counted and returned. When the subject is lost to follow-up, the investigator should 
make every effort to reach out to the subject (telephone, mail/letter, contact relatives and friends 
according to registered information) and record these processes in the relevant documents. 
5.5.4. 
Criteria for early termination of the study 
The study may be terminated prematurely at any time if agreed to by the investigator and 
the sponsor in the best benefit of the subject and for reasonable medical or ethical reasons. 
During termination, the sponsor and investigator will ensure that adequate consideration is 
given to protecting the subject 's interests. 
Criteria for early termination of this study were: 
1. Significant safety risk for the study drug in the opinion of regulatory authorities, ethics 
committees, sponsors or investigators; 
2. Identify major defects in the study protocol, or major deviations or human errors during 


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the implementation of the study, which seriously affect the quality of the trial and make it 
difficult to achieve the purpose of the study; 
3. The sponsor may terminate the study for any scientific, medical or ethical reason, but shall 
fully consider the rights, safety and health of the enrolled subjects; 
4. Other reasons that, in the judgment of the sponsor or investigator, make continuation of the 
study inappropriate. 
5.6. 
Prior/concomitant medications and therapies 
All concomitant medications, including prescription drugs, over-the-counter preparations, 
growth factors, blood products, and parenteral nutrition, were documented during the study 
treatment period and safety follow-up period within 14 days prior to informed consent. 
Documentation will include information on start and stop dates, dose, and reason for use. 
During the study period, no other anticancer therapies other than those specified in this 
protocol, including Chinese herbal medicines with antitumor activity, are allowed before 
disease progression. 
During the study (treatment period and safety follow-up period), participation in other 
interventional investigational product clinical trials is not allowed. 
Extreme care should be taken when etoposide phosphate is used with drugs known to 
inhibit phosphatase activity, such as levamisole hydrochloride. Although carboplatin 
nephrotoxicity is not significant, extra care should be taken when carboplatin is combined with 
aminoglycosides, which increases renal and/or auditory toxicity. Etoposide or any drug 
contraindicated with carboplatin is prohibited and special warnings and precautions in the 
instructions for use of carboplatin and etoposide should be observed. 
Necessary supportive treatments such as antiemetics, antidiarrheals, etc. were permitted. 
Prophylactic use of colony-stimulating factors and hematopoietic growth factors during Cycle 
1 is not permitted (ie, no growth factors should be used prophylactically in principle until the 
actual Cycle 2 Day 1 dose follow-up). However, the use of colony-stimulating factors and 
hematopoietic growth factors in subsequent cycles and, if necessary, therapeutic use in Cycle 1 
may be decided at the discretion of the investigator. 
The PK characteristics of subjects should be evaluated in Part I of the study. In order not 
to affect the metabolism of Trilaciclib, subjects in Part I should not take concomitant strong or 
moderate inducers of CYP3A4 within 4 weeks before administration of the study drug, strong 
inhibitors of CYP3A4 within 2 weeks before administration of the study drug, and strong or 
moderate inducers and strong inhibitors of CYP3A4 before the end of PK blood sampling in 


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Part I. Common inhibitors and inducers of CYP3A4 are detailed in Appendix 2.  
Hematopoietic growth factors, transfusions, or platelet transfusions were prohibited within 
1 week prior to the Screening blood tests. 
Any diagnostic, therapeutic or surgical procedures performed during the study should be 
documented. Documentation will include information on dates, indications for use, procedure 
instructions, and any clinical or pathologic findings. Medications will be coded using the latest 
World Health Organization (WHO) Drug Dictionary version. 
6. Pharmacokinetics 
PK pharmacokinetics will be investigated in this study. 
6.1. 
Collection, processing and storage of biological samples 
6.1.1. 
PK Blood Sample Collection and Processing 
6.1.1.1. 
PK blood sample collection time 
6.1.1.1.1. 
Pharmacokinetic evaluation (Part I) 
In the first part of this study, PK blood samples will be collected at the following time points. 
When chemotherapy regimen is carboplatin combined with etoposide (EC regimen): 
Cycle 1 Day 1: 
Within 0.5 h before the start of the first Trilaciclib infusion, immediately after the end of 
infusion (± 2 min, at the end of administration, excluding the flushing time, the same below), 
and 0.5 h ± 2 min, 1 h ± 5 min, 2 h ± 5 min, 4 h ± 5 min, 6 h ± 5 min, 8 h ± 5 min, and 12 h ± 
10 min after the end of infusion. 
Cycle 1 Day 2: 
Within 0.5 hours prior to the second Trilaciclib dose (24 hours ± 30 min after the end of the 
first Trilaciclib infusion). 
Cycle 1 Day 3: 
Within 0.5 h prior to the start of the third Trilaciclib dose, immediately after the end of infusion 
(± 2 min, excluding flushing time), and 0.5 h ± 2 min, 1 h ± 5 min, 2 h ± 5 min, 4 h ± 5 min, 6 
h ± 5 min, 8 h ± 5 min, and 12 h ± 10 min after the end of infusion. 
Cycle 1 Day 4: 
24 h ± 30 min after the end of the third Trilaciclib infusion. 
A total of 20 blood sampling points, venous blood is collected to determine the concentration 
of Trilaciclib in blood samples, and pharmacokinetic analysis is performed based on the test 
results. 
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Cycle 1 Day 1: 
Within 0.5 h prior to the start of the first Trilaciclib dose, immediately after the end of infusion 
(± 2 min, excluding flushing time), and 0.5 h ± 2 min, 1 h ± 5 min, 2 h ± 5 min, 4 h ± 5 min, 6 
h ± 5 min, 8 h ± 5 min, and 12 h ± 10 min after the end of infusion. 
Cycle 1 Day 2: 
Within 0.5 hours prior to the second Trilaciclib dose (24 hours ± 30 min after the end of the 
first Trilaciclib infusion). 
Cycle 1 Day 3: 
Within 0.5 hours prior to the third Trilaciclib dose. 
Cycle 1 Day 4: 
Within 0.5 hours prior to the fourth Trilaciclib dose. 
Cycle 1 Day 5: 
Within 0.5 h prior to the start of the fifth Trilaciclib dose, immediately after the end of infusion 
(± 2 min, excluding flushing time), and 0.5 h ± 2 min, 1 h ± 5 min, 2 h ± 5 min, 4 h ± 5 min, 6 
h ± 5 min, 8 h ± 5 min, and 12 h ± 10 min after the end of infusion. 
Cycle 1 Day 6: 
24 h ± 30 min after the end of the fifth Trilaciclib infusion. 
A total of 22 blood sampling points, venous blood is collected to determine the concentration 
of Trilaciclib in blood samples, and pharmacokinetic analysis is performed based on the test 
results. 
6.1.1.1.2. 
Pharmacokinetic evaluation (Part II) 
In the second part of this study, PK blood sample collection is planned to be performed at 
the following time points, and the actual blood collection points could be adjusted according to 
the pharmacokinetic study results in the first part. 
In all subjects, venous blood is collected at 4 blood sampling points on Cycle 1 Day 1 
immediately after the end of Trilaciclib/placebo infusion (excluding flushing time) ± 5 min, 0.5 
h ± 10 min, 5 h ± 1 h after the end of infusion, and within 1 h before Trilaciclib/placebo 
administration on Cycle 1 Day 2 to determine the concentration of Trilaciclib in blood samples 
for pharmacokinetic analysis according to the test results. 
6.1.1.2. 
Handling and storage of pk blood samples 
Please refer to the laboratory manual. 


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7. Study evaluation 
7.1. 
Evaluation of bone marrow protection 
Assessment of myeloprotection will be based on the following: dynamic changes in 
complete blood counts; hematological toxicities, including febrile neutropenia and resulting 
infections; red blood cell and platelet transfusions; use of hematopoietic growth factors; 
systemic antibiotic use; dose reduction and discontinuation of chemotherapy. 
Duration of severe neutropenia (DSN) in Cycle 1 was selected as the primary endpoint for 
efficacy evaluation. The overall protective effect of trilaciclib on each bone marrow cell line 
will also be comprehensively assessed through the evaluation of secondary endpoints, 
particularly key secondary endpoints (including SN occurrence, occurrence of red blood cell 
transfusions on/after Week 5, granulocyte colony-stimulating factor use rate, composite 
endpoints-major adverse hematologic event, etc.). 
7.2. 
Safety evaluation 
7.2.1. 
Clinical laboratory tests 
Blood samples for hematology, urinalysis, and blood chemistry will be collected according 
to the trial flow chart and analytical testing will be completed at a local laboratory. 
● 
Blood routine: white blood cell (WBC), red blood cell (RBC), hemoglobin (Hb), platelet 
(PLT), hematocrit (HCT), neutrophil (NEU), eosinophil (EOS), basophil (BAS), monocyte 
(MON), lymphocyte (LYM), etc.; 
● 
Urinalysis: urine protein, urine pH, urine ketone body, urine glucose, urine red blood cells, 
urine white blood cells, etc. Note: 24-hour urine protein quantification is required for 
subjects with urine protein ≥ + +; 
● 
Blood biochemistry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-
glutamyltransferase (γ-GT), lactate dehydrogenase (LDH), cholesterol (TC), triglyceride 
(TG), total bilirubin (TBIL), direct bilirubin (DBIL), total protein (TP), albumin (ALB), 
alkaline phosphatase (ALP), creatine kinase (CK), glucose (GLU), uric acid (UA), blood 
urea nitrogen (BUN)/urea (Urea), creatinine (Cr), sodium (Na), potassium (K), calcium (Ca), 
phosphorus (P), magnesium (Mg) and chloride (Cl); 
● 
Serum pregnancy test (females of childbearing potential only), For female subjects of 
childbearing potential, serum pregnancy test will be performed before the start of 
administration. After negative results of pregnancy test in the screening period, reliable 
contraceptive measures should be started; 
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(hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) and postmenopausal. A 
woman ≥ 50 years of age was considered postmenopausal if she had been amenorrheic for 
12 months prior to the planned date of randomization and had no other medical etiology. A 
woman < 50 years of age is considered postmenopausal if she has been amenorrheic for 12 
months or more after stopping exogenous hormone therapy and has follicle-stimulating 
hormone (FSH) levels in the postmenopausal range. 
● 
Virology: 
Hepatitis B and C screening were performed during the screening period, five items of 
hepatitis B: if hepatitis B surface antigen (HBsAg) was positive or hepatitis B core antibody 
(HBcAb) was positive, HBV-DNA should be added; hepatitis C examination: if hepatitis C 
antibody was positive, HCV-RNA should be added. 
The procedures and timing of these inspections are specified in the Study Flow Chart. 
Additional laboratory tests may be performed if clinically indicated. 
Laboratory test results must be reviewed and confirmed by the investigator or qualified 
designee. 
7.2.2. 
Physical examination and vital signs 
The investigator or other study personnel authorized by the investigator should perform 
physical examinations and determine the subject 's vital signs as specified in the protocol. 
Physical examination included weight, height, general appearance, skin/mucous membranes, 
head, neck, chest, abdomen, joints of spine and limbs, and neurological examination. Height 
was measured at screening only. Further targeted physical examinations may be performed by 
the investigator based on symptoms. Vital signs include temperature, pulse, respiratory rate, 
blood pressure. 
7.2.3. 
12-lead electrocardiogram (ECG) 
Standard 12-lead ECGs, including measurements of heart rate, QRS duration, and PR, 
QT, RR, and QTc intervals (QTc = QT/RR0.33), should be performed using standard 
procedures at the study site. The timing of ECG measurements was specified in the trial flow 
chart. Unscheduled ECGs may be performed if clinically indicated. 
7.2.4. 
Adverse events 
Adverse events were monitored from the time of informed consent through the end of the 
safety follow-up period, initiation of new antineoplastic therapy, or withdrawal from the study, 
whichever came earliest. The investigator should record AEs experienced by each subject and 


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track progress. Adverse events should be graded and documented according to NCI-CTCAE 
version 5.0 throughout the study and during follow-up. 
Details of AE assessment and recording are provided in the relevant sections. 
7.3. 
Pharmacokinetic evaluation 
The first part of the pharmacokinetic analysis included PK concentration analysis and PK 
parameter analysis. 
Pharmacokinetic analysis will be based on PK analysis set (PKS), including all subjects 
who have received at least one dose of study drug and have at least one valid concentration data 
of the tested components after dosing. Non-compartmental methods using WinNonlin Version 
6.3 or higher software were used to calculate pharmacokinetic parameters and descriptive 
summary analyses were provided. 
Single-dose PK parameters: 
Peak drug concentration (Cmax), time to reach maximum concentration (Tmax), terminal 
elimination half-life (T1/2), area under concentration-time curve (AUC, including AUC0-t, 
AUC0- ∞), etc. 
Multiple-dose PK parameters: 
Time to maximum concentration (Tmax), time to maximum concentration at steady state 
(Tss max), maximum drug concentration (Cmax), maximum drug concentration at steady state (Css 
max), minimum plasma concentration at steady state (Css min), area under the concentration-time 
curve (AUC, Including AUC0-t, AUC0-∞, AUCss), terminal elimination half-life (T1/2), 
fluctuation coefficient (DF), accumulation coefficient (RAC), etc. 
7.4. 
Population pharmacokinetic analysis was performed based on the data obtained for 
exploratory analysis to obtain the population pharmacokinetic profile of the 
drug.Antitumor efficacy evaluation 
Tumor imaging evaluation was performed according to RECIST1.1. 
Pre-screening imaging should include at least computed tomography (CT) or magnetic 
resonance imaging (MRI) of the brain, chest, abdomen, and pelvis. Unless contraindicated, IV 
contrast should be used and oral contrast may be used at the investigator 's discretion. 
Baseline imaging was performed within 21 days prior to the first dose, every 6 ± 1 week 
after the first dose, or more frequently if clinically indicated. Imaging examinations should 
follow calendar days and should not be modified for treatment delays or terminations, and 
subjects who discontinue study drug treatment due to intolerable toxicity or for other reasons 
other than disease progression should continue to be followed for tumor assessments until 


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disease progression, receipt of new antineoplastic therapy, withdrawal from the study, or death 
(whichever occurs first), and the sites examined are consistent with the sites examined at 
baseline. 
Efficacy assessments were classified as complete response (CR), partial response (PR), 
stable disease (SD), progressive disease (PD), and not evaluable (NE). Confirmation of 
response according to RECIST 1.1 should be performed no less than 4 weeks from the date of 
the first documented partial response (PR) or complete response (CR). Imaging assessments for 
efficacy confirmation may be performed 4 weeks after response is first observed or at the next 
scheduled imaging time point. 
If there are imaging results meeting the criteria available within 2 1 days prior to the first 
dose, they do not need to be repeated during the screening period. 
For subjects who did not experience disease progression at the time of treatment 
discontinuation, radiographic tumor assessments continued as scheduled until disease 
progression, withdrawal of consent, start of subsequent anticancer therapy, or end of study. 
8. Adverse event reporting 
During this study, the investigator and his/her designated qualified personnel were 
responsible for detecting and recording all events observed during the course of the study that 
met the definition of an adverse event or serious adverse event according to the criteria and 
definitions in this study protocol. Investigators will evaluate adverse events, monitor the 
safety status of subjects and give corresponding protective measures to ensure the safety of 
subjects, and report according to relevant requirements. 
8.1. 
Definitions of adverse event, serious adverse event, and suspected and unexpected 
serious adverse reaction 
An adverse event (AE) is defined as any untoward medical occurrence in a subject 
administered an investigational product and which may manifest as symptoms, signs, disease, 
or laboratory abnormalities, but which do not necessarily have a causal relationship with the 
investigational product. An AE could therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of an investigational product. 
Events meeting the definition of an adverse event include: 
• 
Abnormal laboratory findings (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, electrocardiogram, radiographic scans, vital sign measurements), 
including those that worsened from baseline and were considered clinically significant 


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based on the investigator 's medical and scientific judgment (ie, not related to progression 
of the underlying disease). 
• 
Worsening of a pre-existing condition, including an increase in frequency and/or 
severity of the condition. 
• 
New conditions detected or diagnosed after the start of the study drug (even if they 
may have been present before the start of the study). 
• 
Signs, symptoms, or clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of study treatment 
or concomitant medication. Overdose per se will not be reported as an adverse 
event/serious adverse event unless it is an intentional overdose with possible 
suicidal/self-injurious intent. Such overdoses should be reported regardless of sequelae. 
Events that do not meet the definition of an adverse event include: 
• 
Abnormal laboratory findings or other abnormal safety assessments related to the 
underlying disease. However, if the investigator considers the severity to be greater 
than expected based on the subject 's condition, it should be considered an AE. 
• 
Medical or surgical procedures (eg, endoscopy, appendectomy). Note that the 
condition leading to this procedure was an AE. 
• 
Absence of an untoward medical event (hospitalization for social reasons and/or 
convenience). 
• 
Underlying diseases or conditions present or detected at the start of the study that 
fluctuated daily within the expected range without apparent worsening. 
• 
Pre-existing conditions or signs and/or symptoms not related to the study prior to the 
first dose of study drug. These events will be documented in the medical history section 
of the eCRF. 
• 
Progressive Disease (PD): The expected progression of the disease under study 
occurring during the study is not recorded as an AE or SAE, nor is the sign or symptom 
caused by the expected disease progression recorded as an AE or SAE. If the 
investigator considers disease progression related to the investigational product during 
the study, it should be recorded as AE or reported as SAE; the death caused by disease 
progression during the safety follow-up period of the subject should be reported as 
SAE. 
Definition of Serious Adverse Event 


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Serious Adverse Event (SAE) refers to any untoward medical occurrence such as death, 
life-threatening, permanent or serious disability or incapacity, hospitalization or prolongation 
of hospitalization required by the subject or congenital anomaly or birth defect after the subject 
receives the investigational product. 
• 
Causing death 
• 
Life Threatening 
This refers to an AE in which the subject was already at risk of death at the time of 
the AE, and does not refer to an assumption that the AE, if more severe, could have caused 
death. 
• 
Persistent or significant disability or incapacity 
The AE results may cause serious inconvenience or interference with the subject 's normal 
life and activities. 
• 
Requires hospitalization or prolongation of hospitalization 
The AE caused the subject to be hospitalized for treatment or had already been 
prepared to be discharged, but prolonged hospitalization due to an adverse event; it was 
necessary to be clear that the cause of the condition was due to the adverse event rather 
than admission for elective surgery, non-medical reasons, etc. 
• Congenital anomaly or birth defect 
The offspring of the subject presents with malformation or congenital functional 
defect. 
• Other important medical events 
Medical and scientific judgment must be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening, fatal, or hospitalised, but medical action to prevent one of 
the above situations is also usually considered serious. For example, important treatment 
in the emergency room or allergic bronchospasm at home, cachexia or convulsion without 
hospitalization, drug dependence or addiction. 
When it is unclear whether the SAE is considered, the investigator should discuss with the 
sponsor and the Ethics Committee. 
Definition of suspected and unexpected serious adverse reaction 
Suspected Unexpected Serious Adverse Reaction (SUSAR) refers to a suspected and 
unexpected serious adverse reaction whose nature and severity of clinical manifestations exceed 


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those in the Investigator 's Brochure (IB) of the investigational product, the package insert of 
the marketed drug or the summary of product characteristics. 
8.2. 
Time period and frequency for collecting adverse event and serious adverse event 
information 
AE collection: In this study, AEs will be collected from the time the subject signs the 
informed consent form to the time point specified in the trial flow chart, in which the medical 
events occurred unrelated to the study intervention from the time of signing the informed 
consent form to the first medication should be recorded in the CRF as medical 
history/concomitant diseases, rather than the AE part. 
Investigators were not required to actively collect AEs or SAEs following the subject 's 
safety follow-up period. However, if the investigator learns of any SAE, including death, at any 
time after a participant leaves the study, and considers the event to be reasonably related to the 
study intervention or study participation, the investigator must promptly collect a report. 
8.3. 
Methods for collecting adverse events and serious adverse events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and undirected verbal questioning of the subject is the preferred method to inquire about the 
occurrence of AEs. For example: 
"How do you feel?" 
"Has your health improved or worsened since the last study visit?" 
"Have you taken any new medications since your last study visit? Did you stop taking or 
change any medication you were taking?" 
8.4. 
Follow-up of adverse events and serious adverse events 
Following this initial AE/SAE report, the investigator is required to follow each subject 
for further information at subsequent visits/contacts. All SAEs, AEs related to the study, or 
causing the subject to discontinue study treatment should be followed until the event resolves 
(including return to baseline values), status changes to long-term stabilization, loss to follow-
up, death, or the investigator does not consider continued follow-up or other reasonable 
explanation. The investigator is responsible for performing or arranging for medically indicated 
or sponsor-requested follow-up visits to elucidate as fully as possible the nature and causality 
of the AE or SAE. 
When reporting follow-up information, the investigator should update the information 
with the original electronic report form, print the paper report form and re-sign the name and 


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date. The SAE follow-up report should have the same timelines and procedures as the initial 
report. 
8.5. 
Recording and assessment of adverse events and serious adverse events 
Recording of Adverse Events and Serious Adverse Events 
The investigator is responsible for reviewing all documentation (eg, hospital progress 
notes, laboratory tests, and diagnostic reports) related to the event and recording all relevant 
information on the AE/SAE in the case report form. The investigator will try to determine the 
diagnosis of each event based on signs, symptoms, and/or other clinical information. Whenever 
possible, the diagnosis (rather than individual signs/symptoms) was recorded as an AE/SAE. If 
the diagnosis is unknown, AE names may be temporarily reported as symptoms, signs and 
abnormal examinations, and each symptom, sign and examination should be recorded 
separately; when the diagnosis is confirmed later, the records should be updated. 
In principle, the investigator should not send copies of the subject 's medical records to 
Simcere, and in some cases Simcere may request copies of the medical records for some cases, 
in which case the identification information of all subjects (except subject codes) should be 
obscured (blackened, etc.) before the copies of the medical records are submitted to Simcere. 
During the collection and evaluation of AEs and SAEs, the AE name, start time, stop time 
or outcome, severity, seriousness, concomitant diseases, concomitant medication, event 
description, causality assessment, etc. need to be recorded. 
Severity of Adverse Events and Serious Adverse Events 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 was used 
in this study to evaluate the severity of all adverse events. If there are no AEs defined in NCI-
CTCAE, refer to the following rules for severity: 
Table 10 Adverse event severity grade not defined in NCI-CTCAE 5.0 
Grading 
Rule 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic tests only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate activities of daily living (eg, preparing meals, shopping or buying 
clothes, using the telephone, managing money, etc.). 
Grade 3 
Severe or clinically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL (ability to bathe, dress and undress, eat, go to the toilet, take 
medications, and not bedridden, etc.). 


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Grade 4 
Life-threatening consequences; urgent medical intervention indicated 
Grade 5 
Adverse events leading to death 
 
Degree is a category used to assess the intensity of an event, and both adverse events and 
serious adverse events can be assessed as severe. 
Causality Assessment for Adverse Events and Serious Adverse Events 
Causality assessment is one of the criteria used in determining regulatory reporting 
requirements. The investigator is responsible for assessing the relationship between study 
treatment and the occurrence of each AE/SAE. The investigator judges whether an AE is 
causally related to the drug and will consult the IB or product information for marketed 
products and consider the following: 
• 
Is there a temporally reasonable relationship between the onset of the AE and the 
investigational drug? Is there a time interval between the onset of the AE and the first 
and last dose? 
• 
Whether the symptoms and signs occurred can be caused by the action mechanism 
of the drug itself or the action of metabolic components? 
• 
After dose reduction or discontinuation, the symptoms/signs are relieved or 
improved in the absence of other treatments for AEs? 
• 
Did the symptoms/signs recur or worsen after taking the drug again? 
• 
Can it be explained by the subject 's concomitant diseases, concomitant medication 
or other reasons? 
• 
Whether similar situations have been reported in domestic and international 
literatures? 
Then, a five-point method (definitely related, probably related, possibly related, unlikely 
related, definitely unrelated) was used to provide a causality assessment of the relationship 
between the reported adverse events and the use of the investigational product. 
For each AE/SAE, the investigator must document, review, and provide a causality 
assessment (although information that the investigator may have known was limited in the 
event of an SAE at some time) and update the causality assessment based on follow-up 
information. 


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In this study, SAE reports were classified as "unrelated" in dichotomy if their causality 
assessment was "possibly unrelated" when further assessing whether they met the criteria for 
expedited reporting of suspected unexpected serious adverse reactions. 
8.6. 
Regulatory reporting requirements for serious adverse events 
After the investigator learns of any SAE, whether or not the SAE is related to the 
investigational product and listed in the IB, the investigator should report it in accordance with 
relevant regulatory requirements to meet the legal obligations and ethical responsibilities for 
the safety of subjects and the safety of clinical studies. The Investigator shall properly maintain 
written evidence of all reports above to show that each event received has been properly 
reported. 
The sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to regulatory authorities, ethics committees (IECs), investigational sites, and 
investigators, and will inform local and other regulatory authorities of safety information on 
the investigational product as required and in accordance with sponsor policy. The investigator 
will review investigator safety reports received from the sponsor describing SUSARs or other 
specific safety information and then file them with the IB and notify the Ethics Committee. 
The sponsor will promptly investigate SAEs with the investigator and take necessary 
measures to ensure the safety and rights and interests of the subjects. 
8.7. 
Reporting serious adverse events to sponsor 
The investigator or designee must complete an expedited SAE report within 24 hours of 
becoming aware of the subject 's SAE, including as much detail and useful information as 
possible. Reporting was to be completed within 24 hours even if all information on the SAE 
was not available at that time. The investigator should update the SAE report within 24 hours 
of obtaining additional relevant information. 
The investigator or designee will fill in the relevant information using the Serious Adverse 
Event (SAE) Reporting Form, print it on paper and sign the date and name, and scan it by email 
within 24 hours (i.e. pv@zaiming.com) Sent to Sponsor. 
8.8. 
Pregnancy events 
All subjects participating in this study should use a reliable method of contraception from 
signing the informed consent form to 3 months after the last dose to avoid pregnancy by 
themselves or the female partner of a male subject. However, if any pregnancy occurs in the 
subject (or female partner of a male subject) himself/herself (or the female partner of a male 
subject) after the subject has received at least 1 dose of study drug and up to 3 months after the 


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last dose, the investigator should examine the safety of the subject and fetus and give 
appropriate measures as soon as he/she finds it; and the pregnancy information should be 
recorded on the pregnancy report form and reported to the sponsor within 24 hours of awareness. 
All pregnancies should be followed to outcome until full term (generally 6-8 weeks after 
the expected date of delivery) or premature termination (including spontaneous or elective 
abortion). 
Although pregnancy itself is not considered an AE or SAE, pregnancy complications or 
elective termination of pregnancy will be reported as an AE or SAE. Abnormal pregnancy 
outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic 
pregnancy) were considered SAEs and were reported as SAEs (both Pregnancy Event Report 
Form and Serious Adverse Event (SAE) Report Form were to be completed). 
In principle, any female subject who became pregnant while participating in this study was 
to discontinue study drug immediately. 
8.9. 
Adverse events of special interest (AESIs) 
During this study, the investigator or designee will use the designated report form to email 
the subject within 24 hours of becoming aware of an AESI of Trilaciclib that is ≥Grade 3 
(CTCAE 5.0) (i.e. pv@zaiming.com) Sent to Sponsor. 
 Injection site reaction/phlebitis/thrombophlebitis 
 Acute drug hypersensitivity Reaction 
 Pneumonitis/Interstitial Lung Disease 
 Hepatotoxicity 
 Embolic/Thrombotic Events, Venous 
9. Study procedures 


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9.1. 
Test flow table I 
Table 11 1st line ES-SCLC Patients Study Procedures (EC Protocol) 
 
Screenin
g Period 
Treatment Period a 
(21 days per cycle, 6 cycles) 
Safety Visit b 
Survival 
Follow-up c 
Cycle 1 
Cycle 2 and above 
 
D-21 ~ -
1 
D1 
D2 
D3 
D8 
D10 
D15 
D1 
D2 
D3 
D8 
+ 30 days 
Every 60 days 
Window (Days) 
 
 
 
 
± 1 
± 1 
± 1 
± 3 
 
 
± 1 
± 7 
± 7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Past medical history d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Checked in/out 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (Part II 
only) 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Physical examination 
X 
 
 
 
X 
 
X 
X 
 
 
 
X 
 
Body height e 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
Vital signs 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
Biochemistry f 
X 
 
 
 
X 
 
X 
X 
 
 
X 
X 
 
Hematology g 
X 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
Urine test h 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Serum Pregnancy i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessment j 
X 
Imaging every 6 ± 1 week after first study drug dose 
PK (Part I) k 
 
Part I D1-4 Blood sampling 
 
 
 
 
 
 
PK (Part II) k 
 
Part II Day 1-2 Blood sampling 
 
 
 
 
 
 
Trilaciclib/Placebo l 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
Carboplatin l 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Etoposide l 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
Virology m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Screenin
g Period 
Treatment Period a 
(21 days per cycle, 6 cycles) 
Safety Visit b 
Survival 
Follow-up c 
Cycle 1 
Cycle 2 and above 
 
D-21 ~ -
1 
D1 
D2 
D3 
D8 
D10 
D15 
D1 
D2 
D3 
D8 
+ 30 days 
Every 60 days 
Window (Days) 
 
 
 
 
± 1 
± 1 
± 1 
± 3 
 
 
± 1 
± 7 
± 7 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival and other anti-
tumor conditions 
 
 
 
 
 
 
 
 
 
 
 
 
X 
a. 
Trilaciclib + EC chemotherapy will be administered in 21-day cycles until disease progression, intolerability, or discontinuation of treatment at the investigator 's discretion (eg, 6 cycles 
of chemotherapy have been completed). 
b. 
 Follow-up was performed 30 days (± 7 days) after the last dose, starting a new anticancer therapy (-7 days), or withdrawing from the study (-7 days), whichever came first. 
c. 
Survival follow-up refers to telephone follow-up every 60 days (± 7 days) after the last dose to collect other anti-tumor information until 50% of subjects die. 
d. 
Smoking history, family history and relevant medical history of tumor diagnosis and treatment should be collected for medical history; symptoms, signs, laboratory abnormalities within 4 
weeks before signing the informed consent form, medication history within 14 days before signing the informed consent form, and weight change within 6 months (> or < 5%). Results of 
examinations performed at our hospital within 21 days prior to the first dose (Part I) or randomization (Part II) and meeting the requirements of this protocol prior to signing of informed 
consent (hematology, biochemistry, and urinalysis should be performed within 7 days prior to the first dose of each trial part, pregnancy should be performed within 21 days prior to the 
first dose of each trial part, and virology and pregnancy tests may be performed outside hospital) can be used for screening assessments without the need for the same tests during the 
screening period. Patients who fail the initial screening may not be rescreened (only once) until consultation with the Sponsor 's designated medical representative and approval by the 
Sponsor. 
e. 
Height will be measured only at Screening and weight will be measured pre-dose every cycle except Screening. 
f. 
Biochemistry tests included aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (γ-GT), lactate dehydrogenase (LDH), cholesterol (TC), triglyceride 
(TG), total bilirubin (TBIL), direct bilirubin (DBIL), total protein (TP), albumin (ALB), alkaline phosphatase (ALP), creatine kinase (CK), glucose (GLU), uric acid (UA), blood urea 
nitrogen (BUN)/urea (Urea), creatinine (Cr), sodium (Na), potassium (K), calcium (Ca), phosphorus (P), magnesium (Mg), and chloride (Cl). The first dose was administered within 7 
days after the examination during the screening period, and if the dose was not administered after 7 days of the examination and the investigator assessed that re-judgment was required, 
an additional examination could be performed, starting from Cycle 2, before dosing on Day 1 of each cycle, and on Day 8. 
g. 
Hematology includes: white blood cell (WBC), red blood cell (RBC), hemoglobin (Hb), platelet (PLT), hematocrit (HCT), neutrophil (NEU), eosinophil (EOS), basophil (BAS), 
monocyte (MON), lymphocyte (LYM), etc.; hematology in Cycle 1 is scheduled on Day 1 (within 24 hours before administration), Day 3, Day 8, Day 10, Day 15, and baseline 
hematology should be performed within 24 hours before the first study dose; hematology in other cycles is performed on Days 1 and 8 of each cycle, and the examination on Day 1 of 
each cycle is performed before administration. Subjects were eligible for chemotherapy administration as determined by predose hematology results on Day 1 of each cycle. 
h. 
Urine examination includes: urine protein, urine pH, urine ketone body, urine glucose, urine red blood cells, urine white blood cells and so on. The first dose was administered within 7 
days after the examination during the screening period, and if the dose was not administered after 7 days of the examination and the investigator assessed that re-judgment was required, 
an additional examination could be performed, starting from Cycle 2, before dosing on Day 1 of each cycle, and on Day 8. 
i. 
Women of childbearing potential only. 
j. 
Baseline imaging was performed within 21 days prior to the first dose, every 6 ± 1 weeks after the first dose, or more frequently if clinically indicated. Imaging time should follow 
calendar days and should not be adjusted for treatment delays or terminations, and subjects who discontinue study drug for unacceptable toxicity or other reasons other than disease 
progression should continue to be followed for tumor assessments until disease progression, receipt of new antineoplastic therapy, withdrawal from study, or death, whichever occurs first 
k. 
For Cycle 1 only, blood sampling time points are detailed in Chapter 6 Pharmacokinetics. 


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Screenin
g Period 
Treatment Period a 
(21 days per cycle, 6 cycles) 
Safety Visit b 
Survival 
Follow-up c 
Cycle 1 
Cycle 2 and above 
 
D-21 ~ -
1 
D1 
D2 
D3 
D8 
D10 
D15 
D1 
D2 
D3 
D8 
+ 30 days 
Every 60 days 
Window (Days) 
 
 
 
 
± 1 
± 1 
± 1 
± 3 
 
 
± 1 
± 7 
± 7 
l. 
Chemotherapy: carboplatin - administered on Day 1 of each 21-day cycle with target AUC (Calvert formula) = 5 (maximum dose 750 mg) by intravenous infusion over 30 min; etoposide 
- administered on Days 1, 2, and 3 of each 21-day cycle with 100 mg/m2 by intravenous infusion over 60 min; trilacicilb/placebo: administered every 21 days as 240 mg/m2 before 
chemotherapy on Days 1, 2, and 3 of each 21-day cycle with 5% glucose injection or normal saline prepared into 250 mL solution by intravenous infusion over 30 min (as far as PK 
studies are involved). Subjects in Part I will receive Trilaciclib plus EC regimen and subjects in Part II may receive Trilaciclib or placebo plus EC regimen. Date of medication visit is 
based on the first dose of investigational drug (Trilaciclib/Placebo) in each cycle (D1). 
m. 
Hepatitis B and C screening were performed during the screening period, five items of hepatitis B: if hepatitis B surface antigen (HBsAg) was positive or hepatitis B core antibody 
(HBcAb), HBV-DNA should be added; hepatitis C examination: if hepatitis C antibody was positive, HCV-RNA should be added. 


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9.2. 
Test flow table II 
Table 12 2nd/3rd line ES-SCLC Patient Study Flow (Topotecan) 
 
Screenin
g Period 
Treatment Period a 
(21 days per cycle until disease progression or intolerable) 
Safety Visit b 
Survival 
Follow-up c 
Cycle 1 
Cycle 2 and above 
 
D-21 ~ -
1 
D1 
D2 
D3 
D4 
D5 
D10 
D12 
D15 
D1 
D2 
D3 
D4 
D5 
D10 
+ 30 days 
Every 60 days 
Window 
(Days) 
 
 
 
 
 
 
± 1 
± 1 
± 1 
± 3 
 
 
 
 
± 1 
± 7 
± 7 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past medical 
history d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Checked 
in/out 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizatio
n 
(Part 
II 
only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Physical 
examination 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
Body height e 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Vital signs 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
Biochemistry 
f 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 


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Screenin
g Period 
Treatment Period a 
(21 days per cycle until disease progression or intolerable) 
Safety Visit b 
Survival 
Follow-up c 
Cycle 1 
Cycle 2 and above 
 
D-21 ~ -
1 
D1 
D2 
D3 
D4 
D5 
D10 
D12 
D15 
D1 
D2 
D3 
D4 
D5 
D10 
+ 30 days 
Every 60 days 
Window 
(Days) 
 
 
 
 
 
 
± 1 
± 1 
± 1 
± 3 
 
 
 
 
± 1 
± 7 
± 7 
Hematology g 
X 
X 
 
 
 
X g 
X 
X g 
X g 
X 
 
 
 
 
X 
X 
 
Urine test h 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Serum 
Pregnancy i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor 
assessment j 
X 
Imaging every 6 ± 1 week after first study drug dose 
PK (Part I) k 
 
Day 1-6 blood sampling 
 
 
 
 
 
 
 
 
PK (Part II) k 
 
Day 1-2 blood sampling 
 
 
 
 
 
 
 
 
Trilaciclib/Pl
acebo l 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Topotecan l 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Virology m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival and 
other 
anti-
tumor 
conditions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
a. 
Trilaciclib + Topotecan chemotherapy will be administered in 21-day cycles until disease progression, intolerability, or treatment discontinuation at the investigator 's discretion. 
b. 
Follow-up was performed 30 days (± 7 days) after the last dose, at the start of a new anticancer therapy (-7 days), or at study withdrawal (-7 days), whichever came first. 


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Screenin
g Period 
Treatment Period a 
(21 days per cycle until disease progression or intolerable) 
Safety Visit b 
Survival 
Follow-up c 
Cycle 1 
Cycle 2 and above 
 
D-21 ~ -
1 
D1 
D2 
D3 
D4 
D5 
D10 
D12 
D15 
D1 
D2 
D3 
D4 
D5 
D10 
+ 30 days 
Every 60 days 
Window 
(Days) 
 
 
 
 
 
 
± 1 
± 1 
± 1 
± 3 
 
 
 
 
± 1 
± 7 
± 7 
c. 
Survival follow-up refers to telephone follow-up once at 60 days (± 7 days) after the last dose to collect other anti-tumor information until 50% of subjects die. 
d. 
Smoking history, family history and relevant medical history of tumor diagnosis and treatment should be collected for medical history; symptoms, signs, laboratory abnormalities within 4 
weeks before signing the informed consent form, medication history within 14 days before signing the informed consent form, and weight change within 6 months (> or < 5%). Results of 
examinations performed at our hospital within 21 days prior to the first dose (Part I) or randomization (Part II) and meeting the requirements of this protocol prior to signing of informed 
consent (hematology, biochemistry, and urine tests need to be performed within 7 days prior to the first dose of each trial part, pregnancy tests need to be performed within 21 days prior to 
the first dose of each trial part, and viral and pregnancy tests can be performed outside hospital) can be used for screening assessments without the need for the same tests during the screening 
period. Patients who fail the initial screening may not be rescreened (only once) until consultation with the Sponsor 's designated medical representative and approval by the Sponsor. 
e. 
Height will be measured only at Screening and weight will be measured pre-dose every cycle except Screening. 
f. 
Biochemistry tests included aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (γ-GT), lactate dehydrogenase (LDH), cholesterol (TC), triglyceride 
(TG), total bilirubin (TBIL), direct bilirubin (DBIL), total protein (TP), albumin (ALB), alkaline phosphatase (ALP), creatine kinase (CK), glucose (GLU), uric acid (UA), blood urea 
nitrogen (BUN)/urea (Urea), creatinine (Cr), sodium (Na), potassium (K), calcium (Ca), phosphorus (P), magnesium (Mg), and chloride (Cl). The first dose was administered within 7 days 
after the examination during the screening period, and if the dose was not administered after 7 days of the examination and the investigator assessed that re-judgment was required, an 
additional examination could be performed, starting from Cycle 2, before dosing on Day 1 of each cycle, and on Day 10. 
g. 
Hematology includes: white blood cell (WBC), red blood cell (RBC), hemoglobin (Hb), platelet (PLT), hematocrit (HCT), neutrophil (NEU), eosinophil (EOS), basophil (BAS), monocyte 
(MON), lymphocyte (LYM), etc.; hematology in Cycle 1 is scheduled on Day 1 (within 24 hours before dosing), Day 5, Day 10, Day 12, Day 15, and baseline hematology should be 
performed within 24 hours before the first study dose; hematology in other cycles is performed on Days 1 and 10 of each cycle, and the examination on Day 1 of each cycle is performed 
before dosing. Subjects were eligible for chemotherapy administration as determined by predose hematology results on Day 1 of each cycle. 
h. 
Urine examination includes urine protein, urine pH, urine ketone body, urine glucose, urine red blood cells, urine white blood cells, etc. The first dose is administered within 7 days after the 
examination during the screening period. If the dose is not administered after 7 days of the examination and the investigator considers it necessary to make a re-judgment, an additional test 
may be performed from Cycle 2, before administration on Day 1 of each cycle, and on Day 10. 
i. 
Women of childbearing potential only. 
j. 
Baseline imaging was performed within 21 days prior to the first dose, every 6 ± 1 week after the first dose, or more frequently if clinically indicated. Imaging examinations should follow 
calendar days and should not be modified for treatment delays or terminations, and subjects who discontinue study drug for unacceptable toxicity or other reasons other than disease 
progression should continue to be followed for tumor assessments until disease progression, receipt of new antineoplastic therapy, withdrawal from the study, or death, whichever occurs 
first. 
k. 
For Cycle 1 only, blood sampling time points are detailed in Chapter 6 Pharmacokinetics. 
l. 
Chemotherapy: Topotecan will be administered at 1.25 mg/m2 on Days 1-5 of each 21-day cycle via intravenous drip over 30 min; Trilacicilb/placebo: will be administered at 240 mg/m2 on 
Days 1-5 of each 21-day cycle via intravenous drip over 30 min using 5% glucose injection or normal saline as 250 mL solution before chemotherapy due to PK study. The first of these 
subjects will receive Trilaciclib plus Topotecan and the second will likely receive Trilaciclib or placebo plus Topotecan. Date of medication visit is based on the first dose of investigational 
drug (Trilaciclib/Placebo) in each cycle (D1). 


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Screenin
g Period 
Treatment Period a 
(21 days per cycle until disease progression or intolerable) 
Safety Visit b 
Survival 
Follow-up c 
Cycle 1 
Cycle 2 and above 
 
D-21 ~ -
1 
D1 
D2 
D3 
D4 
D5 
D10 
D12 
D15 
D1 
D2 
D3 
D4 
D5 
D10 
+ 30 days 
Every 60 days 
Window 
(Days) 
 
 
 
 
 
 
± 1 
± 1 
± 1 
± 3 
 
 
 
 
± 1 
± 7 
± 7 
m. 
Hepatitis B and C screening were performed during the screening period, five items of hepatitis B: if hepatitis B surface antigen was positive or hepatitis B core antibody was positive 
(HBcAb), HBV-DNA should be added; hepatitis C examination: if hepatitis C antibody was positive, HCV-RNA should be added. 
 


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10. Statistical analysis 
10.1. Determination of sample size 
The study consists of 2 parts. The first part (safety run-in and PK evaluation) planned to 
enroll approximately 6 patients each for 1st line ES-SCLC and 2nd/3rd line ES-SCLC. The 
second part (efficacy verification) planned to enroll approximately 80 patients with ES-SCLC, 
stratified by 1st line vs 2nd/3rd line ES-SCLC, ECOG PS (0-1 vs 2), and presence vs absence 
of brain metastases, to be randomized in a 1:1 ratio to Trilaciclib versus placebo. 
The sample size for Part I was not based on statistical calculations, but to support PK 
evaluation and safety run-in. In addition, assuming a 5.3% occurrence of severe neutropenia 
(G1T28-02), there is an approximately 28% probability of developing at least one severe 
neutropenia in 6 patients; if the occurrence of severe neutropenia is 40.6% (G1T28-03), then 
the probability is 96% to detect at least one one subject occurring severe neutropenia. 
The sample size of the second part needs to meet the need to test the efficacy of DSNs in 
Cycle 1 and is calculated by stochastic simulation. An integrated analysis of the three overseas 
pivotal studies of Trilaciclib in SCLC showed an approximately 4-day reduction in Cycle 1 
DSN in the Trilaciclib group relative to the placebo group. Taking into account the derivation 
of DSN in Cycle 1, DSN in Cycle 1 is 0 if the subject did not experience any SN during Cycle 
1. When there is a large proportion of zero-values, i.e., a large proportion of subjects who do 
not have any SNs in Cycle 1, the Cycle 1 DSNs more closely follow a Poisson distribution with 
a mean of -log (proportion of subjects who do not have any SNs in Cycle 1). In the integrated 
analysis, the proportion of subjects who developed SN during Cycle 1 was 6.7% in the 
Trilaciclib group compared to 49.6% in the placebo group. Assuming that the proportion of 
subjects in this study who occurred SN during Cycle 1 was 10% in the Trilaciclib group and 
45% in the placebo group, the means of Poisson distributions were 0.105 and 0.598 for the 
corresponding Trilaciclib and placebo groups, respectively. The stochastic simulation was 
repeated 10,000 times, each time obtaining the DSN in Cycle 1 from a Poisson distribution and 
performing comparison between groups by Mann-Whitney-Wilcoxon test, 70 subjects (35 per 
group) provided approximately 95% power at the test level of α = 0.05 (2-sided). Assuming a 
dropout rate of 12%, the sample size for Part II was 80 subjects (40 per group). 
10.2. Analysis set 
Full Analysis Set (FAS): All enrolled subjects who received at least one dose of study drug 
according to the intention-to-treat (ITT) principle. Efficacy analyses will be based on the FAS 


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set unless otherwise specified. The second part, limited to all randomized subjects, will be 
analyzed according to the randomized treatment group. 
Per-Protocol Analysis Set (PPS): Subjects who had major protocol violations and were 
judged to have major impact on the results were excluded from the FAS. The PPS set is a subset 
of the FAS set and the exclusion criteria need to be finalized prior to database lock. The PPS 
may be used for the analysis of individual endpoints. 
 
Response Evaluable Analysis Set (RES): All subjects who took at least one dose of study 
drug, had measurable lesion at baseline, and completed at least one post-treatment tumor 
imaging assessment. This analysis set was used for the analysis of efficacy measures according 
to RECIST assessment of tumors. 
Safety analysis set (SS): All subjects who have received at least one dose of study drug. 
Safety analyses were based on the SS set by actual treatment received. 
PK Analysis Set (PKS): All subjects who received at least one dose of the study drug and 
had at least one valid concentration data of the test components after dosing. Pharmacokinetic 
analyses will be based on the PKS set. 
10.3. Statistical methods 
10.3.1. Basic method 
Part I 
The PK profile will be characterized and safety and tolerability will be evaluated based on 
Cycle 1 data. In addition, preliminary efficacy (prevention of myelosuppression) data will be 
summarized. 
Part II 
It is mainly used to verify the effectiveness of Trilaciclib treatment (prevention of bone 
marrow suppression). The primary endpoint was DSN in Cycle 1. Unless otherwise specified, 
efficacy endpoints will be analyzed in the FAS. Some of these endpoints may be analyzed based 
on the PP. Descriptive statistics for continuous data will include means, medians, standard 
deviations and ranges, and categorical data will provide counts and percentages. Time-to-event 
data will be analyzed using the Kaplan-Meier method. 
Detailed statistical methods, including sensitivity analyses, handling of missing values, etc, 
will be presented in the Statistical Analysis Plan (SAP). 


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10.3.2. Summary of study conduct 
Study enrollment, medications, reasons for discontinuation, and reasons for 
discontinuation will be summarized by treatment group. Major protocol deviations, including 
those for inclusion and exclusion criteria, will be listed and summarized by treatment group. 
10.3.3. Treatment group comparability summary 
For demographics (including age, gender, etc.) and baseline characteristics (including 
baseline conditions, etc.), continuous variables will be summarized using descriptive statistics 
(mean, standard deviation, median, range, etc.) and categorical variables will be summarized 
using counts and proportions, as appropriate. 
Unless otherwise specified, baseline measurements are defined as the last available valid 
measurement prior to the first dose. 
10.3.4. Primary efficacy endpoint analysis 
The primary endpoint was DSN in Cycle 1. For subjects with at least 1 occurrence of 
severe neutropenia (SN) in Cycle 1, Cycle 1 DSN was defined as the number of days from the 
date of the first ANC value < 0.5 x 109/L to the date of the first ANC value ≥ 0.5 x 109/L. Where 
the date of the first ANC value ≥ 0.5 x 109/L met the following requirements: (1) occurred after 
the ANC value was < 0.5 x 109/L, and (2) there were no other ANC values < 0.5 x 109/L between 
this date and the end of Cycle 1 (otherwise, if this subject entered Cycle 2, it was counted as 
Day 1 of Cycle 2). If the subject did not experience any SN during Cycle 1, Cycle 1 DSN was 
scored as 0. 
Nonparametric analysis of covariance (Nonparametric ANCOVA) will be used to evaluate 
the efficacy of Cycle 1 DSN. Mean differences between treatment groups, standard errors, and 
their 95% confidence intervals based on Satterthwaite t tests were also provided. 
Detailed definitions, handling of missing values, and detailed analysis methods for Cycle 
1 DSNs will be provided in the SAP. 
10.3.5. Secondary efficacy endpoint analyses 
Key secondary efficacy endpoints 
Key secondary efficacy endpoints included SN occurrence, occurrence of red blood cell 
transfusion (on/after Week 5), occurrence of use of granulocyte colony-stimulating factor (G-
CSF), composite endpoint - major hematological adverse events, etc. Descriptive statistics will 
be used for summarization. Descriptive statistics for continuous data will include mean, median, 
standard deviation and range. Categorical data will provide counts andpercentages, and the 
differences between groups and their 95% confidence intervals will be estimated. 


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Other secondary efficacy endpoints 
Other secondary efficacy endpoints included the occurrence of grade 3/4 hematologic 
toxicities, trough absolute neutrophil count at each cycle, absolute neutrophil count, platelet 
count, absolute lymphocyte count, and hemoglobin over time, occurrence of ESA use, 
occurrence of recombinant human interleukin-11 use, occurrence of thrombopoietin (TPO) use, 
occurrence of intravenous or oral antibiotics, occurrence of serious infectious adverse events, 
occurrence of serious pulmonary infection adverse events, occurrence of febrile neutropenia, 
occurrence of platelet transfusions (during chemotherapy), objective tumor response rate 
(ORR), and disease control rate (DCR). Descriptive statistics will be used for summaries. 
Descriptive statistics for continuous data will include means, medians, standard deviations, and 
ranges, and categorical data will provide counts and percentages. 
Detailed analysis methods for key secondary efficacy endpoints and other secondary 
efficacy endpoints will be presented in the SAP. 
10.3.6. Safety analysis 
Safety analyses will be based on the Safety Analysis Set. Safety evaluations included 
monitoring of treatment emergent adverse events (TEAEs), physical examinations, vital sign 
measurements, electrocardiograms (ECGs), and clinical laboratory tests (hematology, blood 
chemistry, and urinalysis) throughout the treatment period. 
Descriptive statistics will be used to analyze adverse events, laboratory test indicators, 
vital signs and ECG, and summarized according to the treatment groups actually received. 
Extent of exposure will be summarized as duration of treatment and dose of study drug 
taken during the treatment period. 
According to the vital signs data at baseline and each visit time point, each indicator of 
vital signs at each visit time point and the change from baseline were statistically summarized. 
According to the laboratory test results at baseline and each visit time point, the results of 
laboratory test items completed at each visit time point and the positive and abnormal changes 
from before treatment were statistically summarized. 
Only treatment-emergent adverse events were counted. A TEAE was defined as an 
untoward medical occurrence that emerged during treatment or worsened relative to 
pretreatment. All AEs will be coded according to the International Conference on 
Harmonisation (ICH) Medical Dictionary for Regulatory Activities (MedDRA) and the number 
and incidence will be summarized by System Organ Class (SOC), Preferred Term (PT) and 
investigational product grouping. List the serious adverse events after medication, adverse 


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events leading to drug withdrawal, adverse events leading to dropout and drug-related adverse 
events, and describe the details of each adverse event/adverse reaction in each subject in a 
separate table, including the type, severity, occurrence and duration, outcome of adverse events 
as well as their relationship with the investigational drug and the dose of the drug. 
Concomitant medications will be reported using summary tables. 
10.3.7. Pharmacokinetic analysis 
The first part of the pharmacokinetic analysis included PK concentration analysis and PK 
parameter analysis. 
PK concentration analysis: PK concentration data will be summarized and listed by 
treatment group according to each scheduled sampling time point as defined in the protocol. 
Mean and median drug concentration-time profiles (linear and semi-log plots) are also plotted. 
Individual PK concentration data from subjects will be plotted (linear and semi-log plots) 
against drug concentration versus time by treatment group and analyte according to actual 
sampling time. Statistical analysis of PK concentrations will be based on the PK Analysis Set. 
PK Parameter Analysis: Statistical analysis of PK parameters will be summarized 
descriptively based on the PK Analysis Set. 
Population pharmacokinetic analyses will be exploratory based on the data obtained. 
Detailed analysis methods will be given in the SAP. Population pharmacokinetic analysis 
methods will be presented in an independent population pharmacokinetic analysis plan. 
10.3.8. Data analysis time 
When the subjects in Part I have completed safety and PK assessments in Cycle 1, an 
analysis will be performed to characterize the PK profile and evaluate the safety and tolerability 
based on Cycle 1 data. In addition, preliminary myeloprotective efficacy (prevention of 
chemotherapy-induced myelosuppression) data will be summarized. Data from subjects in Part 
I may be updated synchronously until the end of the study at the time of data analysis in Part II. 
The primary analysis will be performed at the end of Cycle 1 for randomized subjects in 
Part II. The sponsor 's necessary personnel will be unblinded, but the investigator, subject, and 
other personnel will remain blinded. The primary measure of myeloprotective efficacy, duration 
of severe neutropenia (DSN) in Cycle 1, as well as other applicable secondary or exploratory 
endpoints, will be assessed based on unblinded data. 
The second analysis in Part II will be performed after all randomized subjects have 
completed 6 cycles or end of treatment. 
The final analysis of Part II will be performed at the end of the study. 


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10.3.9. Exploratory analyses 
Descriptive statistics will be used to summarize exploratory endpoints, progression-free 
survival (PFS), overall survival (OS), population pharmacokinetic characteristics, etc. Detailed 
analysis methods will be presented in the SAP. 
The analysis methods for population pharmacokinetics will be presented in a separate SAP 
analysis plan for population pharmacokinetics. 
Exploratory analyses may not be included in the clinical study report based on actual 
circumstances. 
11. Supporting documentation and clinical operations related considerations 
11.1. Management of study drug 
11.1.1. Dosage form, appearance, packaging, and labeling of study drug 
Trilaciclib is supplied as a sterile powder in packaging and labeling information according 
to local laws and regulations and is labeled for clinical trial use only. 
Placebo was formulated as the vehicle for Trilaciclib – 250 mL of 5% dextrose in water or 
saline (0.9% sodium chloride) 
Packaging and labeling information for carboplatin, etoposide, and topotecan are detailed 
in the package insert. 
11.1.2. Receipt and storage of study drug 
All study drugs in this study will be supplied uniformly by the sponsor, and the study site 
will receive and manage the study drugs by a designated person. The actual placebo used was 
provided by the study site and reimbursed by the sponsor. The site should maintain and manage 
the study drugs according to the storage conditions provided by the sponsor in strict compliance 
with relevant regulations in Good Clinical Practice. 
All study drug was stored in a secure area until dispensed to subjects and was accessible 
only to authorized personnel. The study drug manager was required to adequately supervise the 
storage environment and the associated temperature/humidity logs were maintained as source 
documents. All study drugs must be used for this study and not diverted. 
The investigator should ensure that all study drugs are used in accordance with this 
protocol. 
11.1.3. Drug administration, distribution and recovery 
Qualified or experienced study team personnel prepared the study drug administration 
according to the instructions for study drug (including investigational and non-investigational 
products) (if applicable) and the drug management manual. Study medication was dispensed at 


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each visit by qualified personnel. They will dispense the study drug according to the quantity 
specified in the process each time. 
Destruction of Study Drug 
To be completed by the sponsor or its authorized unblinded personnel. Ensure that the 
destruction complies with applicable provisions in applicable environmental regulations, unit 
policies, etc., and provide relevant destruction procedures. All destruction should be 
documented. 
11.2. Data management 
11.2.1. Data collection 
According to the study flow chart, at each scheduled visit time point, the investigator will 
record all significant observations in the original medical records and CRFs, at least including 
the following: 
• 
Visit Name and Actual Visit Date in Study Flow Chart 
• 
Subject 's general condition and status, including any significant medical findings 
such as AEs 
• 
Prior/concomitant medications/treatments 
Follow-up visits to subjects by telephone or other means will also be documented in the 
original medical records. 
Information from the original medical records must be transcribed to the appropriate 
section of the CRF in a timely manner. 
Changes to the information in the original medical records and other original documents 
were to be signed and dated by the investigator or his/her designee on the date of change. If 
necessary, make a brief description of the change adjacent to the change. 
11.2.2. Data recording 
The important data of each subject in the clinical trial shall be recorded in the CRF. The 
investigator shall review and agree the completed CRF, and sign the name and date. The 
Investigator 's signature is to document that the Investigator' s assurance of the completeness, 
accuracy, and authenticity of the clinical and laboratory data entries in the case report forms. 
The study was completed using electronic CRFs, which were reviewed and approved/signed by 
an electronic data capture system (EDC). 
Source data refers to clinical findings and observations, laboratory data, and other 
information contained in source documents. Source documents are original records (and 
certified copies of original records), including but not limited to hospital medical records, 


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doctor or office records, doctor or nurse notes, drug distribution and recovery records, 
automated instrument records, and electrocardiograms. The information recorded in the CRF 
should be consistent with the source data recorded in the original records. 
All CRFs must be completed, modified, and replaced by the investigator or other 
authorized personnel. If necessary, manual/system-generated Query forms are hosted on the 
EDC system. The investigator or other authorized personnel must correct the CRF (if applicable) 
and complete Query 's answers. 
If the eCRF needs to be amended after completion, it can be done in 2 ways, but not limited 
to: 
(1) The investigator proactively modifies or answers Query on the EDC system in the EDC 
tool. 
(2) The monitor generates Query for the investigator 's answers. 
11.2.3. Database lock 
The database will be locked when the following conditions are met. 
• 
All data have been collected and stored; 
• 
All medical codes have been checked and confirmed; 
• 
All data queries have been resolved; 
• 
Database quality control passed; 
• 
Source data verification has been completed; 
• 
Third party data reconciliation has been completed (if any); 
• 
Serious adverse event reconciliation has been completed; 
• 
All Investigator signatures have been obtained; 
• 
Analyzable cases have been defined; 
• 
The Statistical Analysis Plan has been signed. 
11.2.4. Data archiving 
After completion of the study, if electronic CRFs are used for the study, the subject 's 
eCRFs will be generated by the EDC system and maintained on a non-rewritable CD for 
archiving by the sponsor and each institution, respectively, for audit and/or inspection. 
The trial data shall be preserved and managed according to GCP requirements, and 
essential documents for clinical trials shall be preserved until 5 years after the investigational 
drug is approved for marketing. 


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11.3. Ethics 
11.3.1. Ethics committee 
The clinical study protocol and its amendment, Investigator 's Brochure, informed consent 
form, study-related subject information (such as advertisement for subject recruitment) and 
other necessary documents should be reviewed by the Ethics Committee. 
Ethics Committee approval must be obtained prior to the start of the study and the date the 
committee met and approved will be indicated in the approval letter to the investigator. 
Any amendment to the protocol must be formally approved or filed by the Ethics 
Committee. 
All serious adverse events will be reported to regulatory authorities in accordance with 
applicable regulatory requirements. 
During the course of the study, the investigator should also promptly report to the Ethics 
Committee any protocol violation that may increase the risk to subjects. 
11.3.2. Ethical conduct of the study 
The study protocol should be reviewed and approved in written form by the Ethics 
Committee of the hospital before implementation. The Ethics Committee should be provided 
with study protocol, protocol amendment, informed consent form and other relevant documents 
such as recruitment advertisement. This clinical trial must comply with the Declaration of 
Helsinki, the Good Clinical Practice (GCP) promulgated by the National Medical Products 
Administration (NMPA) and relevant regulations. Before the start of the trial, approval from 
the hospital ethics committee must be obtained before the start of the study. 
Neither party may unilaterally modify the study protocol without the consent of the study 
sponsor and the investigator. Only to eliminate an immediate and immediate hazard to subjects, 
the investigator may modify or deviate from the study protocol prior to obtaining Ethics 
Committee/Institutional Review Board approval. Meanwhile, the deviations or changes made 
and reasons thereof, as well as proposed protocol amendments shall be submitted to the Ethics 
Committee/Institutional Review Board for review as soon as possible. The investigator must 
explain and document any protocol deviations made. 
During the clinical study, any amendment to this study protocol shall be submitted to the 
Ethics Committee, and other study documents shall be modified accordingly if necessary, and 
submitted and/or approved in accordance with the requirements of the Ethics Committee. The 
Ethics Committee should be informed that the trial has ended after the end of the trial. 


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11.3.3. Subject informed consent 
Informed consent form 
The informed consent form included all elements as defined by ICH, GCP, and regulatory 
requirements and complied with the ethical principles set forth in the Declaration of Helsinki. 
The ICF describes the study drug and study process in detail, and fully explains the risks of the 
study to the subjects. Written documentation of informed consent must be obtained prior to the 
subject performing any study-related procedures. 
The ICF should also state that the subject 's personal identity records must be kept 
confidential, but relevant monitoring, auditing, IEC review and relevant regulatory authorities 
may refer to the subject' s data. 
Informed consent process and documentation 
Informed consent begins before an individual agrees to participate in the clinical study and 
continues throughout the clinical study. The risks and possible benefits of participation will be 
discussed in detail and fully with the subject or his/her legal representative. Subjects will be 
asked to read and review the ICF approved by the Ethics Committee. The investigator will 
explain the clinical study to the subject and answer any questions that the subject may have. 
Subjects were not allowed to participate in the study until informed consent was obtained. 
Subjects may withdraw consent at any time during the course of the clinical study. A copy of 
the informed consent form will be retained by the subject. Even if the enlisted patient refuses 
to participate in the study, his/her rights will be fully protected and the quality of medical care 
will not be compromised. 
11.3.4. Confidentiality of subject information 
Confidentiality of subject information was strictly enforced by the investigator, 
participating investigators, the sponsor, and their agents. Confidentiality covers biological 
samples and genetic testing in addition to the subject 's clinical information. Therefore, the 
study protocol, documentation, data and all other information generated from it will be kept 
strictly confidential. All relevant study or data information will not be divulged to any 
unauthorized third party without prior written approval of the Sponsor. 
Representatives of other authorized representatives of the sponsor, IECs, or 
pharmaceutical companies providing study medication by regulatory authorities may inspect 
all documents and records required to be maintained by the investigator, including, but not 
limited to, medical records and subject medication records. The site should allow access to these 
records. 


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Subject contact information will be securely maintained at each investigational site and 
used internally only during the course of the study. At the end of the study, all records will 
continue to be stored in a secure location for the duration specified by the local IRB and 
regulations. 
11.3.5. Research use of samples, specimens, or data 
PROJECTED USE: Samples and data collected under this protocol will be used for drug 
marketing applications and scientific research related to the drug and will not be used for any 
unrelated purposes. 
Storage: Samples and data will be numbered by the study at the time of storage. Data in 
the computer will also be password protected. Only researchers have access to these samples 
and data. 
11.3.6. Quality assurance and quality control 
To ensure the quality of the trial, the clinical investigation plan was discussed and 
developed jointly by the sponsor and the investigator before the trial was officially started. 
Conduct GCP training for relevant study personnel participating in the trial. 
Each site must manage the study drug according to the requirements of the study protocol 
and relevant regulations of the site, including receipt, storage, dispensing, recovery and 
destruction. 
According to GCP guidelines, necessary steps should be taken during the design and 
conduct of the study to ensure that the data collected are accurate, consistent, complete and 
credible. All observed results and abnormal findings in clinical trials shall be timely verified 
and recorded to ensure the reliability of data. The instruments, equipment, reagents and 
standards used for various inspection items in clinical trials shall have strict quality standards 
and ensure that they work in normal state. 
The investigator entered the information required by the protocol into the eCRF, and the 
monitor verified whether it was completed completely and accurately, and instructed the site 
staff to make necessary corrections and additions. 
Drug regulatory authorities, Independent Ethics Committees (IECs), monitors and/or 
auditors of the sponsor may systematically inspect trial-related activities and documents to 
evaluate whether the trial is conducted according to the requirements of the trial protocol and 
relevant regulations (e.g., Good Laboratory Practice [GLP], Good Manufacturing Practice 
[GMP]), and whether the trial data are recorded in a timely, authentic, accurate, and complete 
manner. 


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Monitoring 
During the study, the monitor designated by the sponsor will regularly contact and visit 
the investigator, and will check various records (eCRFs and other data of the subject) in the trial 
as required, provided that the subject 's privacy is protected in accordance with regulatory 
requirements. The sponsor 's medical monitor will also review the data in the CRF at any time. 
All data in the database will be cleaned by the sponsor. Data quality will be ensured by 
data query and site confirmation. 
AUDIT AND INSPECTION 
The sponsor or its representative may audit the study site. Audits include, but are not 
limited to, study drug supply, completeness of documentation required, informed consent 
process, comparison of eCRFs to source documents. Investigator agrees and participates in 
audits conducted in a reasonable manner at reasonable times. 
Regulatory authorities may inspect the site during or after the trial. The investigator shall 
fully cooperate in and timely contact and inform the sponsor of the examination conducted in a 
reasonable manner at a reasonable time. 
11.3.7. Preservation and confidentiality of data 
To ensure the evaluation and supervision of the clinical study by the CFDA and the sponsor, 
the investigator should agree to retain all study data, including the original documents of 
hospitalization for subjects, informed consent form, case report form, and detailed records of 
drug distribution. Original records and relevant materials will be stored in locked special filing 
cabinets, and clinical study data will be stored for at least 5 years after the investigational drug 
is approved for marketing. Non-investigator and unauthorized personnel should not check, and 
lock the file cabinet in time after use. Original records were electronically stored in a dedicated 
computer and access was set. All data of this clinical study is proprietary to Simcere 
Pharmaceutical. Documentation at the site should not be compromised without prior written 
agreement between the investigator and the sponsor. If the investigator chooses to provide the 
trial documents to the other party or to move them elsewhere, the sponsor must be informed. 
Except as required by the NMPA, the Investigator shall not provide the information in any form 
to any third party without the written consent of the Sponsor. 
• 
Laboratory data information was retrieved as soon as possible after each examination 
and entered into the eCRF truthfully, completely, and timely; 
• 
Specially-assigned person shall be responsible for entering data into electronic 
database, and the electronic database system shall set login name and password; 


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• 
Only the subject code will be shown in the statistical analysis and will be used as the 
unique identifier of subject; 
• 
Subject personal information will be kept confidential as required and will not appear 
in public publications or conference presentations. 
11.4. Protocol amendment 
During the study, the investigator should obtain the sponsor 's consent and approval for 
protocol amendment, and the sponsor should designate relevant personnel to revise the protocol. 
The amended protocol must be submitted to the Ethics Committee for approval. Before 
obtaining approval from the Ethics Committee, the investigator remains in compliance with the 
original study protocol, unless it is intended to avoid immediate hazards to the subject, or the 
protocol amendment involves only changes in study management (e.g., change in telephone 
number, etc.). 
11.5. Protocol deviations 
In the absence of pre-approval and agreement from the sponsor or sponsor 's agent, and in 
compliance with both EC and local regulations, the investigator will try not to violate the 
protocol in its execution unless it is necessary to eliminate an immediate hazard to study 
subjects. When a protocol execution violation is deemed necessary for an individual subject, 
the investigator must contact the sponsor as soon as possible to obtain sponsor review and to 
confirm the impact of the violation on the subject and/or the study. Any significant protocol 
violation that impacts subject eligibility and/or safety must be reviewed and/or approved by the 
EC and regulatory authorities and, where feasible, implemented prior to execution of the 
protocol. 
11.6. Publication of study results 
The study results are the property of the sponsor. If the Investigator intends to publish any 
data and information related to the Study, the Investigator shall provide Company with the 
original or full text of all planned publications (posters, invited presentations or guest 
presentations) at least 30 days prior to submission for publication or other form of publication, 
and submit or publish with the written consent of the Sponsor. 


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[33] Ren L, Hou M, Yi C, Luo D, Qiu M, Xie M, Mei Z. [Comparison between carboplatin and 
cisplatin plus etoposide and carboplatin plus etoposide in the treatment of small cell lung 
cancer.]. Zhongguo Fei Ai Za Zhi. 1999 Dec 25; 2 (2): 87-9. Chinese. 
[34] Zhang Liang, Liu Xianhong, Liu Ying, Bai Lianwei, Cheng Ying. Comparison of efficacy 
and safety of three-drug combination chemotherapy and single-agent topotecan in second-line 
treatment of small cell lung cancer. Chinese Oncology Clinical, 2019 (3): 133-137. 
[35] Li Zhihua, Liu Xiaoqing, Li Jianjie, Gao Red Army, Tang Chuanhao, Li Xiaoyan, Guo 
Wanfeng, Qin Haifeng, Wang Weixia, Qu Lili, Chen Jian. Comparison of efficacy and safety 
of second-line different chemotherapy regimens in the treatment of small cell lung cancer. 
Chinese Journal of Lung Cancer, 2015, 18 (5): 280-288. 
[36] Li Li, Liu Yamin, Yu Xuejun, Wang Yonggang, Zhang Wendong. Clinical study of 
topotecan monotherapy in the treatment of small cell lung cancer. Chinese Oncology Clinical, 
2001, 28 (10): 761-763. 
[37] Zhu Zhou, Ni Bingqiang, Chen Rixin, Xu Yi'an. Comparison of clinical effects of 
irinotecan and topotecan in second-line treatment of small cell lung cancer. Jilin Medical 
Journal, 2013, 26:5367-5369. 
[38] Zhao Mingli, Bi Qing, Ren Hongxuan, Tian Qing, Bao Mingming. Clinical observation of 
irinotecan and topotecan in second-line treatment of 43 cases of small cell lung cancer. Chinese 
Journal of Cancer, 2011, 2:156-158. 
[39] Inoue A, Sugawara S, Yamazaki K, et al. Randomized phase II trial comparing amrubicin 
with topotecan in patients with previously treated small-cell lung cancer: North Japan Lung 
Cancer Study Group Trial 0402. J Clin Oncol. 2008; 26 (33): 5401-5406. 


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[40] D 'Amico D, Carbone D, Mitsudomi T, et al. High frequency of somatically acquired p53 
mutations in small-cell lung cancer cell lines and tumors. Oncogene. 1992; 7:339-346. 
[41] 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 . 
[42] Yuan J, Knorr J, Altmannsberger M, et al. Expression of p16 and lack of pRB in primary 
small cell lung cancer. J Pathol. 1999; 189:358-362. 
[43] Cagle PT, el-Naggar AK, Xu HJ, Hu SX, Benedict WF. Differential retinoblastoma protein 
expression in neuroendocrine tumors of the lung. Potential diagnostic implications. Am J Pathol. 
1997; 150:393-400. 
[44] Gouyer V, Gazzeri S, Brambilla E, et al. Loss of heterozygosity at the RB locus correlates 
with loss of RB protein in primary malignant neuroendocrine lung carcinomas. Int J Cancer. 
1994; 58:818-824. 
[45] 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. 
[46] Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis SOX2 as a 
frequently amplified gene identifies in small-cell lung cancer. Nat Genet.2012; 44:1111-1116. 


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13. Appendices 
Appendix 1 ECOG scoring table 
Attached Table 1 EOCG Scoring Criteria 
Score 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Ambulatory and able to carry out work of a light or sedentary nature, eg, light housework or 
office work, but unable to carry out work of a heavy or sedentary nature. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about 
more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Bedridden, unable to carry on any selfcare. 
5 
Death 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 
 


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Appendix 2 List of common CYP3A4 inhibitors or inducers 
Attached Table 2 List of common CYP3A4 inhibitors or inducers 
CYP 
Enzymes 
Strong inhibitors 
(≥ 5-fold increase in 
AUC) 
Moderate strong inhibitor 
(5-fold > ≥ 2-fold increase 
in AUC) 
Weak inhibitor 
(2-fold > ≥ 1.25-fold increase 
in AUC) 
CYP3A4 
Boceprevir, cobicistat, 
danoprevir, ritonavir, 
elvitegravir, grapefruit 
juice, indinavir, 
itraconazole, 
ketoconazole, lopinavir, 
paritaprevir, obitavir, 
dasabuvir, posaconazole, 
saquinavir, telaprevir, 
tipranavir, telithromycin, 
triamycine, 
voriconazole, 
clarithromycin, edarasib, 
nefazodone, nelfinavir 
Aprepitant, ciprofloxacin, 
conivaptan, crizotinib, 
cyclosporine, diltiazem, 
dronedarone, erythromycin, 
fluconazole, fluvoxamine, 
imatinib, tofepatan, 
verapamil 
Chlorzoxazone, cilostazol, 
cimetidine, clotrimazole, 
fosalopitant, isometrine, 
ivacatropium, lobimide, 
ranitidine, ranolazine, ticagrelor 
 
CYP 
Enzymes 
Strong Inducers 
(≥ 80% decrease in AUC) 
Moderate strong inducer 
(80% > ≥ 50 decrease in 
AUC) 
Weak inducer 
(20% ≤ AUC decreased < 
50%) 
CYP3A4 
Apalutamide, 
carbamazepine, 
enzalutamide, mitotane, 
phenytoin sodium, 
rifampin, St. John 's Wort 
Bosentan, efavirenz, 
etravirine, phenobarbital, 
primidone 
Armodafinil, modafinil, 
rutinamide 
 


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Appendix 3 Pharmacokinetic blood sampling schedule 
PK blood samples will be collected at the following time points during Cycle 1 of Part I of this study. 
Attached Table 3 Blood Collection Schedule -1: Pharmacokinetic Blood Collection Schedule for Trilaciclib (Chemotherapy regimen is carboplatin 
combined with etoposide) 
Date 
D1 
D2 
Time since 
end of 
dosing 
Prior to 
start of 
dosing 
Immediate end 
of installation 
(EOI) 
0.5h 
1h 
2h 
4h 
6h 
8h 
12h 
24h (prior to 2nd dose) * 
Within 
0.5h  
± 2 min 
± 2 
min 
± 5 min 
± 5 min 
± 5 min 
± 5 min 
± 5 min 
± 10 
min 
± 30 min (within 0.5 h 
before 2nd dose) * 
PK blood 
sampling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
  
  
  
  
  
  
  
  
  
  
  
Date 
D3 
D4 
Time since 
end of 
dosing 
Prior to 
start of 
dosing 
Immediate end 
of installation 
(EOI) 
0.5h 
1h 
2h 
4h 
6h 
8h 
12h 
24h 
Within 
0.5h  
± 2 min 
± 2 
min 
± 5 min 
± 5 min 
± 5 min 
± 5 min 
± 5 min 
± 10 min 
± 30 min 


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PK blood 
sampling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
Attached Table 4 Blood Sampling Schedule - 2: Pharmacokinetic Blood Sampling Schedule for Trilaciclib (Topotecan as Chemotherapy Regimen) 
Date 
D1 
D2 
D3 
D4 
Time since 
end of dosing 
Prior 
to start 
of 
dosing 
Immedi
ate end 
of 
installat
ion 
(EOI) 
0.5h 
1h 
2h 
4h 
6h 
8h 
12h 
24 hours 
(before start of 
2nd dose) * 
Before start of 
3rd dose  
Before start of 
4th dose  
Within 
0.5h  
± 2 min 
± 2 
min 
± 5 
min 
± 5 
min 
± 5 
min 
± 5 
min 
± 5 
min 
± 10 
min 
± 30 min 
(within 0.5 h 
before 2nd 
dose) * 
Within 0.5h  
Within 0.5h  
PK blood 
sampling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
  
  
  
  
  
  
  
  
  
  
  
  
  
Date 
D5 
D6 
NA 
NA 


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Time since 
end of dosing 
Prior 
to start 
of 
dosing 
Immedi
ate end 
of 
installat
ion 
(EOI) 
0.5h 
1h 
2h 
4h 
6h 
8h 
12h 
24h 
NA 
NA 
Within 
0.5h  
± 2 min 
± 2 
min 
± 5 
min 
± 5 
min 
± 5 
min 
± 5 
min 
± 5 
min 
± 10 
min 
± 30 min 
NA 
NA 
PK blood 
sampling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
NA 
NA 
*: The blood sampling time on D2 is required to be 24h ± 30 min after the end of D1 administration, and D2 administration is required to be performed within 0.5h 
after blood sampling.


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In Cycle 1 of Part II of this study, PK blood sample collection is planned to be performed at the 
following time points, and the actual blood collection points could be adjusted according to the 
pharmacokinetic study results in Part I. 
Attached Table 5 Blood Collection Schedule - 3: Trilaciclib Pharmacokinetic Blood 
Collection Schedule 
Date 
D1 
D2 
Time since end of 
dosing 
Immediate end of 
installation (EOI) 
0.5h 
5h 
Before 2nd dose 
± 5 min 
± 10 min 
± 1h 
Within 1 h prior to 2nd dose 
PK blood sampling 
√ 
√ 
√ 
√ 
 

SAP_001.pdf: 
 
 
 
 
 
Official Title: 
A randomized double-blind, placebo-controlled, multicenter 
phase 3 study to evaluate the safety, efficacy and 
pharmacokinetics of trilaciclib in patients with extensive stage 
small cell lung cancer treated with carboplatin and etoposide 
or with topotecan 
NCT Number: 
NCT04902885 
Document Date: 
SAP Version 1.0: 16-Feb-2022 
 
 
 


Statistical Analysis Plan (Part II) V1.0 
Confidential 
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Statistical Analysis Plan (SAP) 
(Part II) 
 
 
 
 
 
Protocol: 
A randomized double-blind, placebo-controlled, multicenter 
phase 3 study to evaluate the safety, efficacy and 
pharmacokinetics of trilaciclib in patients with extensive stage 
small cell lung cancer treated with carboplatin and etoposide 
or with topotecan 
Protocol No.: 
B02B00801-TRILA-301 
Sponsor: 
Jiangsu Simcere Pharmaceutical Co., Ltd. 
SAP Author: 
AAAAAAAAAA 
SAP Version: 
V1.0 
SAP Finalized: 
February 16, 2022 
 
 
 
 
Confidentiality Statement 
 
This document is confidential communication document of Jiangsu Simcere Pharmaceutical 
Co., Ltd. Receiving this document means that the recipient agrees that no unpublished information 
contained herein may be published or disclosed without the written consent of Jiangsu Simcere 
Pharmaceutical Co., Ltd., unless such disclosure is required by applicable laws and regulations. In 
addition, any information added to this document is confidential and owned by Jiangsu Simcere 
Pharmaceutical Co., Ltd., and its confidential principle is the same as this document. 
 
 
 


Statistical Analysis Plan (Part II) V1.0 
Confidential 
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CONTENTS 
 
CONTENTS ..................................................................................................................................2 
Abbreviations ........................................................................................................................4 
1. Introduction ..............................................................................................................................6 
2. Study Design ............................................................................................................................6 
2.1. Protocol Synopsis..........................................................................................................6 
2.2. Sample Size Determination...........................................................................................6 
3. Study Conduct ..........................................................................................................................6 
4. Statistical Analysis Methods ....................................................................................................7 
4.1. General Principles .........................................................................................................7 
4.2. Analysis Set ..................................................................................................................7 
4.2.1. Myeloprotection efficacy analysis set ................................................................7 
4.2.2. Antitumor Efficacy Analysis Set .......................................................................8 
4.2.3. Safety Analysis Set ............................................................................................8 
4.2.4. Pharmacokinetic Analysis Set............................................................................8 
4.3. Study Population ...........................................................................................................8 
4.3.1. Subject disposition .............................................................................................8 
4.3.2. Protocol Deviations ............................................................................................8 
4.3.3. Demographic and Baseline Characteristics .......................................................8 
4.3.4. Previous Medical History, Prior Medications, and Non-Drug Therapies ..........9 
4.3.5. Concomitant Medications and Non-Drug Therapies .........................................9 
4.3.6. Subsequent antineoplastic therapy .....................................................................9 
4.4. Efficacy analysis of myeloprotection ............................................................................9 
4.4.1. Primary Efficacy Endpoint ................................................................................9 
4.4.2. Key Secondary Efficacy Endpoints .................................................................12 
4.4.3. Other Secondary Efficacy Endpoints ...............................................................14 
4.5. Anti-tumor efficacy analysis .......................................................................................16 
4.5.1. Objective tumor response rate and disease control rate ...................................16 
4.5.2. Progression Free Survival and Overall Survival Analysis ...............................16 


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4.6. Safety analysis ............................................................................................................17 
4.6.1. Extent of Study Drug Exposure .......................................................................17 
4.6.2. Adverse Events ................................................................................................18 
4.6.3. Clinical Laboratory Tests .................................................................................19 
4.6.4. Vital signs ........................................................................................................19 
4.6.5. ECOG score .....................................................................................................20 
4.6.6. Physical examination .......................................................................................20 
4.6.7. 12 lead ECG .....................................................................................................20 
4.7. Analysis time ..............................................................................................................21 
4.8. Subgroup analysis .......................................................................................................21 
4.9. Sensitivity Analysis ....................................................................................................21 
4.10. 
Pharmacokinetic analysis .................................................................................21 
4.11. 
Handling of Missing Data ................................................................................21 
5. APPENDICES .......................................................................................................................22 
5.1. Appendix 1 Protocol Synopsis ....................................................................................22 
5.2. Appendix 2 Test Flow Sheet .......................................................................................38 
5.3. Appendix 3 Criteria for CTCAE judgment of laboratory parameters ........................45 
5.4. Appendix 4 Window Visits .........................................................................................51 
 


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Abbreviations 
 
 
Abbreviation 
Full Name in Chinese 
AE 
Adverse Events 
ALC 
Absolute lymphocyte count 
ANC 
Absolute neutrophil count 
CDK4/6 
Cyclin-dependent kinases 4 and 6 
CI 
Confidence interval 
CR 
Complete response 
CTCAE 
Criteria for Common Adverse Events 
CYPs 
Cytochromase 
DCR 
Disease control rate 
DSN 
Duration of severe neutropenia 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ESA 
Erythropoietin 
ES-SCLC 
Extensive stage small cell lung cancer 
FAS 
Full Analysis Set 
FN 
Febrile neutropenia 
G-CSF 
Granulocyte colony-stimulating factor 
HSPC 
Hematopoietic stem/progenitor cells 
HGB 
Hemoglobin 
IL-11 
Recombinant human interleukin -11 
IRT 
Interactive response system 
MedDRA 
ICH Medical Dictionary for Regulatory 
Activities 
NE 
Not evaluable 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Disease progression 


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Abbreviation 
Full Name in Chinese 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PKS 
Pharmacokinetic Analysis Set 
PLT 
Platelets 
PPS 
Per-Protocol Analysis Set 
PR 
Partial response 
PT 
Preferred Term 
RBC 
Red blood cell 
RES 
Response Assessment Analysis Set 
RECIST 1.1 
Response Evaluation Criteria in Solid 
Tumors 1.1 
SAE 
Serious Adverse Events 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
SN 
Severe neutropenia 
SOC 
System Organ Class 
SS 
Safety Analysis Set 
TEAEs 
Treatment-emergent adverse event 
TPO 
Thrombopoietin 
WHODrug 
World Health Organization Drug Dictionary 


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1. Introduction 
This Statistical Analysis Plan (SAP) provides planned analyses and corresponding 
statistical methods for Part 2 (randomized, double-blind part) of Protocol B02B00801-TRILA-
301 Version V1.3. 
2. Study Design 
2.1. 
Protocol Synopsis 
Protocol synopsis is provided in Appendix 1, study endpoints are listed in the protocol 
synopsis, and further information is provided in the trial flow chart in Appendix 2. 
2.2. 
Sample Size Determination 
The sample size of the second part of this study needs to meet the need to test the efficacy 
of DSNs in Cycle 1 and is calculated by stochastic simulation. An integrated analysis of the 
three overseas pivotal studies of Trilaciclib in SCLC showed an approximately 4-day reduction 
in Cycle 1 DSN in the Trilaciclib group relative to the placebo group. Taking into account the 
derivation of DSN in Cycle 1, DSN in Cycle 1 is 0 if the subject did not experience any SN 
during Cycle 1. When there is a large proportion of zero-values, i.e., a large proportion of 
subjects who do not have any SNs in Cycle 1, the Cycle 1 DSNs more closely follow a Poisson 
distribution with a mean of -log (proportion of subjects who do not have any SNs in Cycle 1). 
In the integrated analysis, the proportion of subjects who developed SN during Cycle 1 is 6.7% 
in the Trilaciclib group compared to 49.6% in the placebo group. Assuming that the proportion 
of subjects in this study who occurred SN during Cycle 1 is 10% in the Trilaciclib group and 
45% in the placebo group, the means of Poisson distributions is 0.105 and 0.598 for the 
corresponding Trilaciclib and placebo groups, respectively. The stochastic simulation is 
repeated 10,000 times, each time obtaining the DSN in Cycle 1 from a Poisson distribution and 
performing comparison between groups by Mann-Whitney-Wilcoxon test, 70 subjects (35 per 
group) provided approximately 95% power at the test level of α = 0.05 (2-sided). Assuming a 
dropout rate of 12%, the sample size for Part II is 80 subjects (40 per group). 
3. Study Conduct 
The second part of this study is a randomized double-blind, placebo-controlled study 
enrolling approximately 80 patients with ES-SCLC, stratified by 1st line vs 2nd/3rd line ES-
SCLC, ECOG PS (0-1 vs 2), and presence vs absence of brain metastases, randomized in a 1:1 
ratio to Trilaciclib versus placebo where 1st line ES-SCLC patients receive Trilaciclib/placebo 
in combination with EC regimen (Trilaciclib-EC group and placebo-EC group), 2nd/3rd line 
ES-SCLC patients will receive Trilaciclib or placebo in combination with Topotecan (Trilacicli-
TPT group and placebo-TPT group), and the efficacy of Trilaciclib (prevention of 


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Statistical Analysis Plan (Part II) V1.0 
 
 
myelosuppression) will be evaluated with duration of severe neutropenia (DSN) in Cycle 1 as 
the primary endpoint.  
4. Statistical Analysis Methods 
The Part 2 of the study will evaluate the myeloprotective efficacy of Trilaciclib treatment 
(prevention of chemotherapy-induced myelosuppression) based on data from approximately 80 
patients with ES-SCLC, evaluate the safety and tolerability of Trilaciclib in patients with ES-
SCLC, and explore the anti-tumor efficacy. 
4.1. 
General Principles 
Descriptive statistics (mean, standard deviation, median, range, etc.) will be used to 
summarize continuous variables, and counts and proportions will be used to summarize 
categorical variables by treatment group. For time-to-event variables, Kaplan-Meier method 
will be used to estimate the survival function and estimate the median survival time and its 95% 
confidence interval, and survival curves will be provided. 
Unless otherwise specified, the cycle baseline measurement for Cycle 1 is defined as the 
last available valid measurement within 7 days before the start of study medication on Cycle 1 
Day 1; the baseline measurement for subsequent cycles is defined as the last available valid 
measurement within 3 days before the start of study medication on Cycle 1 Day 1. Unless 
otherwise specified, study baseline measurements are defined as the last available valid 
measurement prior to the first dose of study drug. If the last valid measurement coincides with 
the start date of the first study drug administration, the measurement will be considered as 
baseline measurement. Adverse events or concomitant medications that occurred on the day of 
the first dose of study drug are considered postbaseline. 
The start date of each cycle is defined as the first day of the cycle, i.e., the date of the first 
study drug administration of the cycle; the end date of each cycle is defined as the start date of 
the next cycle, or the first day of the cycle +36 days if the next cycle is not entered. 
4.2. 
Analysis Set 
4.2.1. 
Myeloprotection efficacy analysis set 
Full Analysis Set (FAS): All enrolled patients who received at least one dose of study drug 
according to the intention-to-treat (ITT) principle. Randomized subjects will be analysized 
according to the assigned group at randomization. Unless otherwise specified, efficacy analyses 
for myeloprotection will be based on the FAS. 
Per-Protocol Analysis Set (PPS): Patients with major protocol deviations that were judged 
to have a major impact on the results are excluded from the FAS. PPS is a subset of FAS, and 
the classification criteria need to be finalized before database lock library. The PPS may be used 


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for analysis of individual myeloprotective efficacy endpoints. 
4.2.2. 
Antitumor Efficacy Analysis Set 
Response Evaluable Analysis Set (RES): all patients who took at least one dose of study 
drug, had measurable disease at baseline, and completed at least one post-treatment tumor 
imaging assessment. This analysis set will be used for the analysis of anti-tumor efficacy 
endpoints related to tumor RECIST1.1 assessment. 
4.2.3. 
Safety Analysis Set 
Safety analysis set (SS): all patients who have taken at least one dose of study drug. Safety 
analyses will be based on the SS by actual treatment received. 
4.2.4. 
Pharmacokinetic Analysis Set 
PK Analysis Set (PKS): All patients who received at least one dose of the study drug and 
had at least one valid concentration data of the tested components after drug administration. 
Pharmacokinetic analyses will be based on the PKS. 
Patients will be excluded from the PK analysis set if they had major protocol deviations, 
inaccessible or incomplete data, or other circumstances that could affect the pharmacokinetic 
analysis. The list of patients with any major deviation or event significantly affecting PK results 
and reasons for exclusion should be reviewed and confirmed before database lock. 
4.3. 
Study Population 
4.3.1. 
Subject disposition 
The distribution of patients will be summarized based on all screened patients, including 
patient screening, enrolled medication, reason for end of treatment, reason for withdrawal from 
the study and inclusion in each analysis set, and listing will be provided in detail. 
4.3.2. 
Protocol Deviations 
The number and percentage of patients with major protocol deviations (including major 
deviations from inclusion and exclusion criteria) during the trial will be summarized, and the 
reasons for major protocol deviations will be summarized and listed in detail. Patients with 
multiple major protocol deviations in different categories will be counted in each corresponding 
category. 
4.3.3. 
Demographic and Baseline Characteristics 
Demographic and baseline disease characteristics include age at the time of informed 
consent, age group (18-65, > 65-75, > 75), gender, vital signs (weight, height, body surface area) 
at screening, ECOG score, presence of brain metastasis, baseline lactate dehydrogenase (LDH) 
level, family history, allergic history, smoking history, tumor history and history of tumor 
radiotherapy. 


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Descriptive statistics (mean, standard deviation, median, range, etc) will be used to 
summarize continuous variables, and frequency and percentage will be used to summarize 
categorical variables. 
4.3.4. 
Previous Medical History, Prior Medications, and Non-Drug Therapies 
Previous medical history will be coded using the latest version of the Medical Dictionary 
for Regulatory Activities (MedDRA Chinese version 24.0) and summarized by System Organ 
Class (SOC) and Preferred Term (PT). Listing will be provided in detail. 
Prior medications or therapies is defined as any non-study medications or therapies 
administered by the patient from 14 days prior to signing informed consent through the first 
dose of study drug. Patients' prior medications will be coded using the latest version of the 
World Health Organization Drug Dictionary (WHO-DD (March 2021) Chinese version) and 
will be summarized by chemical subgroup and generic drug name. Listing will be provided in 
detail. 
4.3.5. 
Concomitant Medications and Non-Drug Therapies 
Concomitant medications will be coded using the latest version of WHO-DD and 
summarized by chemical subgroup and generic drug name, and the number and percentage of 
patients using concomitant medications will be counted. Concomitant medications and 
concomitant non-drug therapies will be presented in detail in listings. 
The number of cycles with interleukin (IL-11) and thrombopoietin (TPO) administration 
and the weekly event rate will be summarized and tabulated in detail by patient, respectively. 
4.3.6. 
Subsequent antineoplastic therapy 
Subsequent antineoplastic therapy refers to any subsequent non-study oncology agent 
administered after the first dose of study drug. Subsequent anticancer therapies will be coded 
using the most recent version of the World Health Organization Drug Dictionary (WHODrug) 
and summarized by chemical subgroup and generic drug name. The number and percentage of 
subjects with subsequent anticancer therapy will be summarized by treatment group. Listing 
will be provided in detail. 
4.4. 
Efficacy analysis of myeloprotection 
The efficacy analysis of Trilaciclib for myeloprotection in ES-SCLC patients will be based 
primarily on the Full Analysis Set (FAS). If the number of patients differed by more than 10% 
between the PPS and the FAS, efficacy analyses based on the PPS for myeloprotection could 
be performed to support efficacy analyses for the primary and key secondary endpoints. 
4.4.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the duration of severe neutropenia (DSN) during Cycle 


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1. DSN will be assessed by treatment group using two different strategies. Strategy 1 is the 
primary analysis and Strategy 2 is the supportive sensitivity analysis. DSN derivation in each 
strategy will include any unscheduled data and use the actual assessment date (non-visit date). 
4.4.1.1. Strategy 1: Missing ANC values not imputed 
For patients who experienced at least 1 episode of severe neutropenia (SN) within each 
cycle, a DSN is defined as the number of days from the date of the first absolute neutrophil 
count (ANC) value < 0.5 x 10 9/L in that cycle to the date of the first ANC value ≥ 0.5 x 10 
9/L that met the following requirements: (1) occurred after an ANC value < 0.5 x 10 9/L, and 
(2) no other ANC value < 0.5 x 10 9/L occurred between that date and the end of that cycle 
(otherwise the SN event is considered not resolved at the end of that cycle). If a patient does 
not experience any SN during the cycle, DSN will be counted as 0 for that cycle. Exceptions 
will be handled using the following rules: 
 If the SN event is not resolved at the end of the cycle, the DSN will be calculated as 
above, but the end date is the end date of the cycle; 
 If a patient dies during the period of the SN event, the DSN will be calculated as 
described above, but the end date is the date of death; 
 If a patient withdraws consent or is lost to follow-up during the period of the SN 
event, the DSN will be calculated as described above, but the end date will be the 
last ANC assessment date before the end of the study. 
Nonparametric analysis of covariance (Nonparametric ANCOVA) will be used to evaluate 
DSN-based differences in efficacy between the test and placebo groups. The nonparametric 
covariance model will include covariates of baseline ANC study value as a continuous variable, 
and fixed effects of number of lines of treatment (1st line versus 2nd/3rd line), ECOG (0 or 1 
versus 2), brain metastases (yes versus no), and treatment arm (Trilaciclib versus placebo) as 
categorical variables. Stratification will be combined or reduced appropriately if the number of 
patients within a stratum is small. The p-value for the 2-sided test will be calculated from the 
model, and it will be provided the difference in means between the two treatment groups and 
its 95% confidence interval (CI) based on Satterthwaite t-test, as well as the median difference 
between the groups and its 95% confidence interval estimated using Hodges-Lehmann. 
In addition, DSN will be summarized for each cycle by treatment group using descriptive 
statistics. 


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4.4.1.2. Strategy 2: Missing ANC values not imputed, censored handling unresolved SN 
For patients who experienced at least 1 episode of severe neutropenia (SN) within each 
cycle, a DSN is defined as the number of days from the date of the first absolute neutrophil 
count (ANC) value < 0.5 x 10 9/L in that cycle to the date of the first ANC value ≥ 0.5 x 10 9/L 
that meet the following requirements: (1) occurred after an ANC value < 0.5 x 10 9/L, and (2) 
no other ANC value < 0.5 x 10 9/L occurred between that date and the end of that cycle 
(otherwise the SN event is considered not resolved at the end of that cycle). Patients will not be 
included in the analysis if they does not experience any SN during this period. Exceptions will 
be handled using the following rules: 
 If the SN event is not resolved at the end of the cycle, the DSN will be calculated as 
described above, but the end date will be the end date of the cycle or the last contact 
date, whichever occurs first; 
 If a patient dies, withdraws consent, or is lost to follow-up during the period of the 
SN event, the DSN will be calculated as described above, but the end date will be 
the last ANC assessment before the end of the study. 
Overall DSN (days) during treatment is the median DSN value for all cycles and the 
following data handling rules will be applied: 
 If a patient 's SN event duration value is censored for all cycles, the patient' s median 
DSN value will be the median censored value and will be considered censored; 
 If a patient 's partial cycle SN time duration value is a censored value, the Kaplan-
Meier method will be used to estimate the median DSN value for that patient, which 
is the observed value; 
 If a patient 's median DSN value cannot be calculated (eg, has ≤ 2 DSN values), the 
longest DSN value across all cycles (whether censored or not) will be used as the 
median value, but the corresponding censoring flag will be included in the analysis. 
Kaplan-Meier methods will be used to estimate 25%, median, and 75% time (days) of the 
duration of SN and 95% confidence intervals (days) will be provided. Adjusted hazard ratio 
(HR) and its 95% CI between the two treatments (Trilaciclib versus placebo) will be calculated 
from a stratified Cox proportional hazard model with treatment group and randomization 
stratification factors based on Interactive Response Technology (IRT) as fixed effects. 
Stratification will be combined or reduced appropriately if the number of patients within a 
stratum is too small. Two-sided p-values will be calculated from stratified log-rank tests. 


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4.4.2. 
Key Secondary Efficacy Endpoints 
Key secondary efficacy endpoints include the incidence of severe neutropenia (SN), the 
incidence of red blood cell (RBC) transfusions (occured on/after Week 5), granulocyte colony-
stimulating factor (G-CSF) use, and the composite endpoint of major adverse hematologic event 
(MAHE). 
4.4.2.1. Incidence of serious neutropenia events 
The total number of SN events is the total number of cycles with at least one ANC value 
< 0.5 x 10 9/L. For example, two ANC values less than 0.5 x 10 9/L during Cycle 2 are counted 
as only one SN event. If a patient does not experience any SN events, the number of SN events 
for that patient will be counted as zero. Unscheduled data will be included and and actual SN 
assessment date (non-visit date) will be used. Whether a patient experienced a SN event is a 
binary variable (yes or no); 'yes' if ≥ 1 cycles with a SN event is observed; and 'no' otherwise. 
SN events will be summarized by treatment group using descriptive statistics. Part 2 of the 
study will analyze the adjusted rate ratio (aRR) between the two treatment groups based on a 
modified Poisson regression model. The model includes baseline ANC measurement as 
covariate and IRT-based randomization stratification factors including number of lines of 
therapy (1st line versus 2nd/3rd line), ECOG (lines 0-1 versus 2) (not included in the actual 
analysis), and brain metastases (yes versus no), as well as treatment arm as fixed effects. 
Logarithmic transformed values of the number of cycles will be included in the modeling as 
offset variables. P-values, aRR (Trilaciclib versus placebo) and their 95% CIs will be provided 
for the 2-sided tests. In addition, Cochran-Mantel-Haenszel (CMH) weights will be used to 
calculate the adjusted rate difference between the two arms (Trilaciclib versus placebo) and its 
95% CI in Part 2 of the study, and stratified exact CMH method will be used to calculate P 
values under the 2-sided test according to IRT-based randomization stratification factors to test 
the stability of the analysis results. 
4.4.2.2. Incidence of red blood cell transfusion events occured on/after Week 5 
Each red blood cell (RBC) transfusion (including whole blood transfusion and each red 
blood cell component) occured on/after Week 5 is defined as a separate event and included in 
the efficacy analysis. Whether a patient experiences a RBC transfusion event is defined as a 
binary variable (yes or no); "yes" if a total number of RBC transfusion events ≥ 1 is observed, 
otherwise "no". 
The statistical analysis method is similar to that described for SN incidence in Section 
4.4.2.1, except hemoglobin (HGB) baseline measurement will be used as covariate instead of 


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ANC baseline measurement in a modified Poisson regression model. In addition, the offset 
variables will be log-transformed values for duration of treatment (weeks) rather than cycles. 
4.4.2.3. Use rate of granulocyte colony-stimulating factor 
Prophylactic use of any prophylactic colony-stimulating factors (including granulocyte 
colony-stimulating 
factor 
G-CSF, 
granulocyte-giant 
cell 
colony-stimulating 
factor, 
erythropoietin) is not permitted in principle in Cycle 1, but febrile neutropenia with high-risk 
infections or risk factors suggestive of poor prognosis is permitted for therapeutic use. 
Determine if G-CSF is used in this cycle by comparing the start and end dates of each use 
of granulocyte colony-stimulating factor (G-CSF) with the start and end dates of the treatment 
cycle. If the date of G-CSF use lies between the start and end dates of the cycle, the cycle will 
be considered as having G-CSF use. The total number of events with G-CSF use is the total 
number of cycles with at least one GCSF administration. If a patient does not take any G-CSF, 
the number of G-CSF administration events for that patient is zero. Thus, whether a patient 
experiences an event of G-CSF administration is defined as a binary variable (yes or no); "yes" 
if the number of cycles with G-CSF administration is ≥ 1 and "no" otherwise. 
Statistical analysis method is similar to that for SN incidence described in Section 4.4.2.1. 
4.4.2.4. Total occurrence of major adverse hematologic event 
Major adverse hematologic event (MAHEs) are composite endpoints to assess the effect 
of Trilaciclib. MAHE consists of the following 5 component events: 
 
Involved hospitalization 
 
Leading to chemotherapy dose reduction 
 
Febrile neutropenia 
 
Extended SN (greater than 5 days) 
 
RBC transfusion occured on/after Week 5. 
The total number of events for each MAHE component is the sum of the number of events 
that occurred on the date of first study drug administration and before the end of the last 
treatment cycle. The total number of events for MAHEs during treatment is the sum of the 
number of events for each MAHE component. For patients who does not experience any MAHE, 
the total number of MAHE events is 0. 
MAHEs will be coded using the most current version of MedDRA and the total number of 
MAHEs, duration of treatment (weeks), weekly event rates, and cumulative event rates every 3 
weeks will be summarized by number of lines of treatment. According to the actual MAHEs, 
the above summaries will be repeated separately by component events , but for MAHE 
component events leading to chemotherapy dose reduction and SN prolongation, the cumulative 


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event rates will be summarized by cycle rather than every 3 weeks. Part 2 of the study will also 
analyze the adjusted rate ratio between the Trilaciclib and placebo groups using a negative 
binomial regression model. The model includes the three IRT-based randomization 
stratification factors and treatment group as fixed effects, and the log-transformed values of 
treatment duration (weeks) or cycle number as offset variables. Two-sided P values, aRR 
(Trilaciclib versus placebo) and their 95% CIs will be provided. Cumulative incidence of 
MAHEs within specified subgroups will be presented using forest plots.  
Time to first onset (months) for each MAHE component event = (date of first MAHE 
component event – date of first study drug administration + 1)/30.  
For patients who developes MAHEs, the time (months) from the first study drug 
administration (randomization date in Part II) to the first occurrence of MAHEs will be 
summarized and Kaplan-Meier curves will be provided. Time to first MAHE refers to the event 
with the shortest time to first occurrence of the MAHE component; if a patient does not have 
an MAHE, it will be censored at the end date of the last cycle, date of death, end of study, or 
last contact date for that patient, whichever cames first. 
Kaplan-Meier methods will be used to estimate 25%, median, and 75% time (months) to 
first MAHE and provide 95% CIs (months). Part 2 of the study calculates the HR and its 95% 
CI between the two treatments (Trilaciclib versus placebo) from a stratified Cox proportional 
hazards model with treatment group and IRT-based randomization stratification factors as fixed 
effects, and 2-sided P values will be calculated from a stratified log-rank test. 
4.4.3. 
Other Secondary Efficacy Endpoints 
Descriptive statistics will be used to summarize the following additional secondary 
efficacy endpoints. Descriptive statistics for continuous data will include means, medians, 
standard deviations and ranges, and categorical data will provide frequencies and percentages. 
4.4.3.1. Absolute neutrophil count trough values by cycle 
Absolute neutrophil count (ANC) will be summarized by descriptive statistics for cycle 
trough values (which are lower than the ANC value at baseline for that cycle) and changes from 
baseline between the start and end of each cycle. Cycle trough values for ANC will be 
summarized descriptively for Part II of the study to evaluate confounding effects of G-CSF 
administration separately by the presence or absence of G-CSF administration during treatment. 
4.4.3.2. Absolute neutrophil counts, platelet counts, absolute lymphocyte counts, and 
hemoglobin over time  
Hematology parameters, including ANC, platelet count, absolute lymphocyte count (ALC), 
and hemoglobin (HGB) will be summarized by treatment group using descriptive statistics 


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based on laboratory hematology results at baseline and each visit time point. Listing will be 
provided for detials. ANC will be summarized descriptively to evaluate confounding effects of 
G-CSF administration separately according to the presence or absence of G-CSF administration 
during treatment. 
Time-line plots for mean ANC, platelet count, ALC, HGB, and change from baseline in 
HGB (with 95% confidence intervals) will be provided by cycle. 
4.4.3.3. Other dichotomous endpoints 
The total number of events below is the total number of cycles with at least one event. If a 
patient does not experience any of the following events during the treatment period, the number 
of events for that patient is zero. 'Yes' if ≥ 1 of the following events are observed; otherwise 
'No'. 
• Incidence of Grade 3 and 4 Hematologic Toxicities: Grade 3 and 4 hematologic toxicities 
refers to hematology laboratory results with CTCAE Grade 3 or 4. 
• Incidence of platelet transfusion (during chemotherapy) 
• Incidence of febrile neutropenia 
Each of the following events with a unique start date will be defined as a separate event 
during the treatment period. Yes if the total number of the following events observed is ≥ 1, 
otherwise no. 
• Incidence of intravenous or oral antibiotics 
• Incidence of infectious serious adverse events 
• Incidence of serious adverse events of lung infection 
Determine if the following medications is used in that cycle by comparing the start and 
end dates of each use of the following medications with the start and end dates of the treatment 
cycle. The total number of events with the following medications is the total number of cycles 
with at least one dose of the following medication. If a patient did not take the following 
medications during the treatment period, the number of events for that patient is 0. 
• Erythropoiesis-stimulating agent (ESA) Usage 
• Recombinant human interleukin-11 (IL-11) use rate 
• Thrombopoietin (TPO) use 
The total number of events as well as the incidence of the above dichotomous variables 
will be summarized descriptively and tabulated in detail by patient. The statistical analysis 
approach is similar to that described for SN incidence in Section 4.4.2.1, except that baseline 
ANC measurements will not be included as covariates in the modified Poisson regression model. 


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In addition, for comparing the incidence of antibiotic administration, SAEs of infection, and 
SAEs of lung infection between the Trialciclib and placebo groups, the offset variable in the 
modified Poisson regression model will be the log transformed duration of treatment (weeks) 
rather than the number of cycles. 
4.5. 
Anti-tumor efficacy analysis 
4.5.1. 
Objective tumor response rate and disease control rate 
A pooled analysis of objective tumor response rate (ORR) and disease control rate (DCR) 
assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST1.1) 
will be performed based on the Response Evaluation Analysis Set (RES). Based on the 
assessments at each visit, the number and percentage of patients with best response of CR, PR, 
SD, PD and NE will be summarized by treatment group when CR/PR confirmation is not 
required and CR/PR confirmation is required, respectively .  
ORR is calculated based on the number of patients with best response of CR or PR. DCR 
is calculated based on the number of patients with best response of CR, PR, or SD, and 95% 
CIs for ORR and DCR will be calculated using the Clopper-Pearson method. 
ORR as a binary endpoint ("yes"or"no"), CMH weights will be used to analyze the 
difference in adjusted rates between the two treatment arms (Trilaciclib versus placebo) and 
their 95% CIs, and 2-sided P values will be calculated based on the stratified exact CMH method. 
Waterfall plots of best percentage change from baseline in sum of target lesion diameters, 
time line plots of change from baseline, and swimming plots of drug exposure and efficacy 
assessments will be provided for patients based on RES. Supportive data listings will also be 
provided. 
4.5.2. 
Progression Free Survival and Overall Survival Analysis 
Exploratory analyses of progression-free survival (PFS) will be performed based on the 
FAS. PFS is defined as the time from the date of randomization to the first documented 
radiologically disease progression (according to RECIST1.1) or death due to any cause, 
whichever occurs first. In the absence of disease progression and death at the time of analysis, 
PFS will be censored at the date of last tumor assessment; in the absence of a valid postbaseline 
tumor assessment, PFS will be censored at the date of the date of randomization. 
Exploratory analyses of overall survival (OS) will be performed based on the FAS . OS is 
defined as the time from the date of randomization to death of the patient for any cause; for 
patients who have not died at the time of analysis, OS will be censored at the date last known 
to be alive . 
PFS and OS rates at various time points will be estimated using the Kaplan-Meier method, 


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and 95% CI will be provided using Greenwood 's method. The Kaplan-Meier method will also 
be used to estimate 25%, median, and 75% time (months) for PFS and OS, and the Brookmeyer-
Crowley method will be used to calculate the 95% CI and survival curves for PFS and OS will 
be provided. The HR and its 95% CI will be calculated between the two treatment arms 
(Trilaciclib versus placebo) based on a stratified Cox proportional hazards model with treatment 
arm and IRT-based randomization stratification factors as fixed effects. Two-sided P values will 
be calculated from stratified log-rank test. 
4.6. 
Safety analysis 
Safety analyses will be based on SS. Safety evaluations includes adverse events (TEAEs), 
physical examinations, vital sign measurements, electrocardiograms (ECGs), and laboratory 
tests (hematology, blood chemistry, and urinalysis) throughout the treatment period. 
4.6.1. 
Extent of Study Drug Exposure 
Duration of exposure to study drug during the treatment period and number of treatment 
cycles started will be summarized using descriptive statistics. Cumulative actual dose, 
cumulative planned dose, cumulative planned dose for compliance, cumulative planned dose 
for compliance, medication compliance, and relative dose intensity will be summarized for the 
different study drugs (Trilaciclib or chemotherapy drugs), respectively. 
• Duration of chemotherapy exposure (days) = date of first dose of study drug in last cycle – 
date of first dose of study drug + 21 days 
• Number of treatment cycles 
A treatment cycle is considered to be started if the subject receives at least one dose of 
study drug (Trilaciclib/placebo or chemotherapy). Descriptive statistics will be used to 
summarize the number of cycles started and to summarize the counts and percentages of 
subjects by the number of cycles started. 
• Relative dose intensity (%) = (cumulative actual dose administered/cumulative planned 
dose administered) 100%,  
If applicable, the proportion of subjects with dose reductions will be summarized 
separately by study drug. Number of events with dose reductions will be described and the 
number and percentage of subjects will be summarized by number of dose reductions. 
• The dose of Trilaciclib/placebo will not be adjusted in this trial and will remain at 240 
mg/m2 unless safety data in Part 1 suggests that dose adjustment of Trilaciclib/placebo is 
warranted. 
• Carboplatin, etoposide and topology are determined by comparing the actual dose on the 


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respective dosing pages of the current and previous cycles Dose reductions for ticam are 
shown in Table 1 for Cycle 2 and Day 1 of subsequent cycles.  
Table 1 Dose reductions for carboplatin, etoposide and topotecan 
Dose Level 
Etoposide (mg/m2) 
Carboplatin AUC 
Topotecan (mg/m2) 
Dose Level -1 
Reduce to 75 
Decreased to AUC = 4 
1 
Dose Level -2 
Reduce to 50 
Decreased to AUC = 3 
0.8 
No more than two dose reductions are allowed (concurrent carboplatin and etoposide dose 
reductions are one dose reduction), dose reductions are unidirectional permanent, and no dose 
increases are allowed. Delays in chemotherapy cycles of up to 1 week due to operational reasons 
such as legal holidays and up to 2 weeks due to treatment toxicity may be permitted; however; 
If, in the opinion of the investigator, the subject is still benefiting from a dose delay of more 
than 2 weeks, the investigator requests and obtains the sponsor 's medical care Dosing may be 
delayed for greater than 2 weeks following review and written approval. 
The proportion of subjects with treatment cycle delays and reasons for delays will be 
summarized separately by study drug as applicable. Number of cycles delayed will be 
statistically described and the number and percentage of subjects will be summarized by the 
number of cycles delayed. 
4.6.2. 
Adverse Events 
Adverse events will be monitored from the time of informed consent through the end of 
the safety follow-up period, initiation of new antineoplastic therapy, or withdrawal from the 
study, whichever comes first. Adverse events will be graded and recorded according to NCI-
CTCAE version 5.0 throughout the study and during follow-up. 
Only treatment-emergent adverse events (TEAEs) will be summarized. A TEAE is defined 
as any untoward medical occurrence or an adverse event that worsened relative to pretreatment 
state that emerged newly from the first dose of study drug through 30 days after the last dose or 
before the start of new anticancer therapy. AE will be coded according to the International 
Conference on Harmonisation (ICH) Medical Dictionary for Regulatory Activities (MedDRA) 
and the number and incidence will be summarized by System Organ Class (SOC) and Preferred 
Term (PT). Serious adverse events after medication, adverse events leading to dose reduction, 
delay or discontinuation, adverse events leading to dropout, adverse events leading to death, 
adverse events of special interest, drug-related adverse events, etc. will be summarized 
separately, and the details of each adverse event for each patient will listed, including the type, 
severity, occurrence and duration, outcome of adverse events, and the relationship with the 


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study drug. 
For summarizing TEAE, the incidence of adverse events will be calculated based on the 
number of patients with adverse events rather than the number of adverse events. When 
calculating the number and percentage of patients with adverse events, one patient with multiple 
occurrences of the same adverse event will only be counted one. 
4.6.3. 
Clinical Laboratory Tests 
Hematology and blood chemistry test results at baseline and each visit time point and 
corresponding changes from baseline will be summarized descriptively and listing will be 
provided in detail. CTCAE grades for hematology and blood chemistry will be determined 
according to the laboratory parameter CTCAE criteria(see Appendix 3). CTCAE Version 5.0 
will be used for grading. According to CTCAE Version 5.0, CTCAE grading of some items 
requires clinical diagnosis or joint judgment of clinical diagnosis and values, which cannot be 
completely divided by programming, such as hyperglycemia, hypokalemia, hypophosphatemia, 
hyponatremia and hyperuricemia, CTCAE Version 4.03 will be used for grading. Patients' 
changes from baseline CTCAE grade to worst postdose CTCAE grade will be summarized 
using cross-classification tables. Grade 3 or 4 hematology and blood chemistry laboratory 
abnormalities occurring during treatment will also be summarized separately, as appropriate. 
Urinalysis results will be presented in listings only. 
Actual study days for patients may differ from planned study days between the first dose 
of study drug in each cycle and the scheduled visit date. In this case, visit-based summaries will 
categorize assessments based on visit within time window as shown in Appendix 4. 
4.6.4. 
Vital signs 
Descriptive statistical summaries and detailed listings of vital sign and changes from 
baseline at each visit time point will be performed based on vital sign (systolic blood pressure, 
diastolic blood pressure, respiratory rate, pulse, body temperature, weight, etc.) data values at 
baseline and each visit time point. Each vital sign is judged for potential clinical relevance 
according to Table 2 and the number and percentage of patients meeting the criteria will be 
calculated. 
Table 2 Criteria for Vital Signs of Potential Clinical Significance 
Parameter 
Criteria for judgment 
Change from Baseline 
Systolic blood 
pressure (mmHg) 
≥ 180 
Increased ≥ 40 
≤ 90 
Decline ≥ 40 
Diastolic Blood 
Pressure (mmHg) 
≥ 105 
Increased ≥ 20 
≤ 50 
Decrease ≥ 20 


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Pulse (bpm*) 
≥ 120 
Increased ≥ 40 
≤ 50 
Decline ≥ 40 
Weight (kg) 
NA 
≥ 10% increase 
NA 
≥ 10% decrease 
Bpm = beats per minute 
4.6.5. 
ECOG score 
Descriptive statistics and detailed listings of ECOG score at each visit and change from 
baseline will be provided according to ECOG score at baseline and each visit. 
4.6.6. 
Physical examination 
Physical examination findings will be presented in listings at baseline and each visit time 
point. 
4.6.7. 
12 lead ECG 
Descriptive statistics and detailed listings of ECG test results completed at each visit time 
point and changes from baseline will be provided based on ECG test results at baseline and each 
visit time point (heart rate, QRS duration, PR, QT, RR and QTc intervals, etc.). Each ECG 
parameter will be judged for potential clinical relevance according to  Table 3  and the number 
and percentage of patients meeting the criteria will be calculated. 
Table 3 Criteria for ECG Parameters of Potential Clinical Significance 
Parameter 
Criteria for judgment 
Heart Rate (bpm) 
120 
< 50 
PR Interval (msec) 
≥ 210 
RR Interval (msec) 
1200 
< 500 
QRS interval (msec) 
≥ 120 
≤ 50 
QT interval (msec) 
≥ 500 
≤ 300 
QTcB, QTcF Interval (msec) 
≥ 500 
≥ 480 
≥ 450 
≤ 300 
≥ 30 change from baseline 
≥ 60 change from baseline 


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4.7. 
Analysis time 
The primary analysis for Part 2 will be performed at the end of Cycle 1 for all randomized 
subjects. Will be necessary for Sponsor Personnel are unblinded, but the investigator, subject, 
and other personnel will remain blinded. Assessments will be based on unblinded data  Primary 
endpoint of bone marrow protective efficacy of Trilaciclib and other applicable secondary or 
exploratory endpoints. 
The second analysis in Part 2 will be performed after all randomized subjects have 
completed 6 cycles or end of treatment.  
The final analysis in Part 2 will be performed at the end of the study. 
4.8. 
Subgroup analysis 
Designated efficacy and safety endpoints will be analyzed in the following subgroups as 
appropriate by treatment group (Trilaciclib vs. placebo) and other subgroup analyses will be 
performed as needed. 
• Number of lines treated (1 lines vs. 2/3 lines) 
• ECOG (0 or 1 vs. 2) 
• Brain metastases (yes vs. no) 
4.9. 
Sensitivity Analysis 
Sensitivity analyses of myeloprotective endpoints by the presence or absence of concurrent 
G-CSF cycles will be conducted to support the stability of the analysis results based on the FAS 
set. 
The stability of the primary analysis results (Strategy 1) for Cycle 1 DSNs will be checked 
by Strategy 2. Additional sensitivity analyses will be performed as needed. 
4.10. Pharmacokinetic analysis 
The population pharmacokinetic analysis in Part 2 will be exploratory based on the data 
obtained and its analysis plan will be presented in a separate population pharmacokinetic 
analysis plan. 
4.11. Handling of Missing Data 
Every effort should be made to minimize the generation of missing data. Missing data will 
not be imputed unless otherwise specified. For time-to-event endpoints in efficacy, missing data 
will be handled based on statistical analysis model; for response rate in efficacy (such as ORR, 
DCR), missing data will be considered as non-responder and included in the analysis. 
 


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5. APPENDICES 
 
5.1. 
Appendix 1 Protocol Synopsis 
 
 
Title : 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter 
Phase 3 Clinical Study to Evaluate the Safety, Efficacy, and 
Pharmacokinetics of Trilaciclib in Patients with Extensive 
Stage Small Cell Lung Cancer Treated with Carboplatin and 
Etoposide or with Topotecan 
Protocol No. : 
B02B00801-TRILA-301 
Protocol Version 
No.: 
V1.3 
Version Date : 
August 17, 2021 
Sponsor: 
Jiangsu Simcere Pharmaceutical Co., Ltd. 
 
 
Study title 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase 3 Clinical 
Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Trilaciclib in Patients 
with Extensive Stage Small Cell Lung Cancer Treated with Carboplatin and 
Etoposide or with Topotecan 
STUDY PHASE 
Phase III 
Study objectives 
Part I (Safety Run-in and PK Evaluation Part): 
Primary objective 
 
To evaluate the pharmacokinetic (PK) profile of Trilaciclib in patients with 
extensive stage small cell lung cancer; 
 
To evaluate the safety and tolerability of Trilaciclib in patients with extensive 
stage small cell lung cancer; 
 
To evaluate the effectiveness of Trilaciclib (prevention of chemotherapy-
induced myelosuppression) in patients with extensive stage small cell lung cancer; 
Secondary objectives 
 
To comprehensively evaluate the myeloprotective effect of Trilaciclib in 
patients with extensive stage small cell lung cancer; 
 
To evaluate the short-term antitumor efficacy of Trilaciclib in patients with 
extensive stage small cell lung cancer; 
Exploratory objectives: 
 
To evaluate the long-term antitumor efficacy of Trilaciclib in patients with 
extensive stage small cell lung cancer; 
 
Population pharmacokinetic profile. 
Part II (randomized, double-blind part): 


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Primary objective 
 
To evaluate the effectiveness of Trilaciclib (prevention of chemotherapy-
induced myelosuppression) in patients with extensive stage small cell lung cancer; 
Secondary objectives 
 
To comprehensively evaluate the myeloprotective effect of Trilaciclib in 
patients with extensive stage small cell lung cancer; 
 
To evaluate the safety and tolerability of Trilaciclib in patients with extensive 
stage small cell lung cancer; 
 
To evaluate the short-term antitumor efficacy of Trilaciclib in patients with 
extensive stage small cell lung cancer; 
Exploratory objectives: 
 
To evaluate the long-term antitumor efficacy of Trilaciclib in patients with 
extensive stage small cell lung cancer; 
 
Population pharmacokinetic profile. 
Study Endpoints 
The following endpoints, not specified, refer to events occurring during 
chemotherapy. 
Part I (Safety Run-in and PK Evaluation Part): 
Primary Endpoint: 
 
PK profile (Cmax, AUC and other PK parameters); 
 
Safety and tolerability: adverse events, laboratory abnormalities, etc; 
 
Duration of severe neutropenia in Cycle 1 (DSN); 
Key Secondary Endpoints: 
 
Occurrence of severe neutropenia (SN); 
 
Occurrence of red blood cell transfusion (on/after Week 5); 
 
Granulocyte colony stimulating factor (G-CSF) use rate; 
 
Composite endpoint – major adverse hematologic event (Any of the 
following): 
 
All-cause hospitalization; 
 
All-cause dose reductions; 
 
Febrile neutropenia; 
 
SN prolongation (lasting > 5 days); 
 
Red blood cell (RBC) transfusions were performed on/after Week 5. 
Other secondary endpoints: 
 
Occurrence of Grade 3 and 4 hematological toxicities; 
 
Absolute neutrophil count trough by cycle; 
 
Absolute neutrophil count, platelet count, absolute lymphocyte count, and 
hemoglobin over time; 
 
Erythropoiesis stimulating agent (ESA) utilization rate; 


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 
Rate of recombinant human interleukin-11 use; 
 
Thrombopoietin (TPO) use rate; 
 
Occurrence of intravenous or oral antibiotic administration; 
 
Occurrence of infectious serious adverse events; 
 
Occurrence of lung infection SAEs: 
 
Occurrence of febrile neutropenia; 
 
Occurrence of platelet transfusion; 
 
Objective tumor response rate (ORR); 
 
Disease control rate (DCR). 
Exploratory Endpoints: 
 
Progression-free survival (PFS); 
 
Overall survival (OS); 
 
Population pharmacokinetic profile. 
Part II (randomized, double-blind part): 
Primary Endpoint: 
 
Duration of severe neutropenia in Cycle 1 (DSN). 
Key Secondary Endpoints: 
 
Occurrence of severe neutropenia (SN); 
 
Occurrence of red blood cell transfusion (on/after Week 5); 
 
Granulocyte colony stimulating factor (G-CSF) use rate; 
 
Composite endpoint – major adverse hematologic event (Any of the 
following): 
 
All-cause hospitalization; 
 
All-cause dose reductions; 
 
Febrile neutropenia; 
 
SN prolongation (lasting > 5 days); 
 
Red blood cell (RBC) transfusions were performed on/after Week 5. 
Other secondary endpoints: 
 
Occurrence of Grade 3 and 4 hematological toxicities; 
 
Absolute neutrophil count trough by cycle; 
 
Absolute neutrophil count, platelet count, absolute lymphocyte count (ALC), 
and hemoglobin over time; 
 
Erythropoiesis stimulating agent (ESA) utilization rate; 
 
Rate of recombinant human interleukin-11 use; 
 
Thrombopoietin (TPO) use rate; 
 
Occurrence of intravenous or oral antibiotic administration; 
 
Occurrence of infectious serious adverse events; 
 
Occurrence of lung infection SAEs: 


Product: Trilaciclib 
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 
Occurrence of febrile neutropenia; 
 
Occurrence of platelet transfusion; 
 
Safety and tolerability: adverse events, laboratory abnormalities, etc.; 
 
Objective tumor response rate (ORR); 
 
Disease control rate (DCR). 
Exploratory Endpoints: 
 
Progression-free survival (PFS); 
 
Overall survival (OS); 
 
Population pharmacokinetic profile. 
BACKGROUND 
AND 
RATIONALE 
Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung 
cancers, and approximately 70% of these patients are in the extensive stage at initial 
diagnosis. Major diagnosis and treatment guidelines at home and abroad (including 
those edited by Chinese Society of Clinical Oncology) recommend platinum-based 
combination with or without PD-L1 antibody as first-line standard treatment for 
SCLC, while topotecan is recommended for second-line chemotherapy. Studies 
have shown that platinum-based combination therapy with etoposide or topotecan is 
associated with significant myelosuppression in extensive stage SCLC (neutropenia 
47% to 92%, leukopenia 8% to 66%, thrombocytopenia 10% to 46%, and anemia 
7% to 34%). In Asian populations (including China, Korea, Japan), the occurrence 
of myelosuppression caused by platinum-based and etoposide chemotherapy was 
similar. Literature have shown that chemotherapy-induced myelosuppression (grade 
3/4 neutropenia 5.6% ~ 93.8%, anemia 2.9% ~ 33.3%, thrombocytopenia 3.2% ~ 
33.3%) is always the main adverse reaction to be urgently addressed in Asian 
populations, including China, South Korea, and Japan, for patients with small cell 
lung cancer treated with carboplatin/cisplatin combined with etoposide effects or 
topotecan. Myelosuppression is an important cause of many adverse events in 
cancer chemotherapy, such as infection, sepsis, bleeding, and fatigue, leading to 
hospitalization or the use of hematopoietic growth factors or the need for red blood 
cell and/or platelet transfusions. In addition, myelosuppression often leads to 
chemotherapy dose reductions or limits in treatment dose intensity, rendering 
patients unable to derive greater benefit from chemotherapy. 
Trilaciclib is a highly potent, selective, reversible CDK4/6 inhibitor in clinical 
development to protect bone marrow by protecting hematopoietic stem and 
progenitor cells (HSPCs) when administered systemically. The proliferation and 
differentiation of HSPCs is very dependent on CDK4/6 activity and is arrested in 
G1 phase of the cell cycle when exposed to appropriate doses of Trilaciclib, thus 
avoiding damage by cytotoxic chemotherapeutic agents of the cell cycle. Therefore, 
for CDK4/6-independent tumors (such as small cell lung cancer, etc.), Trilaciclib 


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combined with chemotherapy can protect the bone marrow without antagonizing the 
anti-tumor efficacy of chemotherapy. 
The downstream target of CDK4/6 is the retinoblastoma (Rb) protein, which is 
phosphorylated upon CDK4/6 activation to allow cells to enter S phase. CDK4/6 
inhibitors arrest cells in G1 phase by inhibiting downstream pathways dependent on 
functional Rb protein. It has been shown that SCLC is universally inactivated by 
tumor protein-53 (TP53) and retinoblastoma protein-1 (RB-1), so it is basically 
believed that functional Rb protein is almost absent in SCLC. In addition, two 
recent reports have described the genomic profile of SCLC in detail using next 
generation sequencing methods, including complete exome sequencing, 
transcriptome profiling by RNA sequencing (RNASeq), copy number analysis as 
well as limited whole genome sequencing to identify translocations. These reports 
confirm the conjecture raised in previous studies based on small numbers of tumor 
samples that inactivation of driver mutations TP53 and RB-1 commonly occurring 
in SCLC. Consistent with these findings, preclinical in vitro and in vivo studies 
have shown that Trilaciclib administered prior to chemotherapy does not attenuate 
the killing of RB-1 inactive tumors, including SCLC. Thus, SCLC can be 
considered CDK4/6-independent due to near universal RB-1 inactivation, which 
makes selective protection of HSPCs without compromising the antitumor efficacy 
of chemotherapy a potentially viable therapeutic strategy. 
Three randomized, double-blind Phase 2 clinical trials in patients with small 
cell lung cancer (SCLC) demonstrated that Trilaciclib administered in combination 
with chemotherapy (including 1st line, 2nd/3rd line) prevented or mitigated 
chemotherapy-induced myelosuppression. The G1T28-05 and G1T28-02 studies 
showed that Trilaciclib administered before first-line chemotherapy (carboplatin 
combined with etoposide) reduced the duration of severe neutropenia in Cycle 1 
from 4 days and 3 days to 0 days, and the occurrence of severe neutropenia from 
49.1% and 42.1% to 1.9% and 5.1%, respectively; the G1T28-03 study results 
showed that the use of Trilaciclib before topotecan reduced the duration of severe 
neutropenia in Cycle 1 from 7 days to 2 days, and the occurrence of severe 
neutropenia from 75.9% to 40.6%. 
Currently, no therapies have been approved for improving myelosuppression 
caused by chemotherapy by protecting HSPCs. Although there are some 
symptomatic treatments for myelosuppression (e.g., blood transfusions, growth 
factors, etc.), there are no available treatments that provide patients with 
comprehensive protection from chemotherapy-induced damage to HSPCs and the 
resulting negative effects. As the first agent designed to reduce chemotherapy-
induced myelosuppression by protecting HSPCs, Trilaciclib showed significant 


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ability to prevent or alleviate chemotherapy-mediated myelosuppression in the 
multicellular lineage in patients with extensive stage small cell lung cancer (ES-
SCLC). Based on the clinical data of Trilaciclib, we intend to conduct a clinical trial 
in China that includes an open-label safety run-in and PK evaluation part and a 
randomized double-blind, placebo-controlled efficacy validation part to assess the 
safety, efficacy and pharmacokinetics of Trilaciclib in combination with carboplatin 
and etoposide (EC regimen) or with topotecan in the treatment of extensive-stage 
non-small cell lung cancer. 
Study Design 
This is a multi-center Phase 3 clinical trial with an open-label single-arm safety 
run-in and PK evaluation part and a randomized double-blind, placebo-controlled 
part in patients with ES-SCLC to evaluate the safety, efficacy, and pharmacokinetic 
profile of Trilaciclib based on completed clinical studies abroad. 
The study consists of 2 parts. The first part, safety run-in and PK evaluation, 
enrolled approximately 12 patients with extensive-stage small-cell lung cancer, 6 
patients each with 1st line ES-SCLC and 2nd/3rd line ES-SCLC to receive 
Trilaciclib in combination with carboplatin and etoposide (EC regimen) or with 
topotecan, and based on evaluable data from Cycle 1, evaluated the safety, 
tolerability, pharmacokinetics, and preliminary efficacy (prevention of 
myelosuppression) of Trilaciclib. The second part is a randomized double-blind, 
placebo-controlled efficacy validation study, and approximately 80 patients with 
ES-SCLC will be enrolled in Part II, stratified by 1st line vs 2nd/3rd line ES-SCLC, 
ECOG PS (0-1 vs 2), and presence vs absence of brain metastases, and randomized 
in a 1:1 ratio to Trilaciclib and placebo, in which patients with 1st line ES-SCLC 
receive Trilaciclib/placebo combined with EC regimen (Trilaciclib-EC group and 
placebo-EC group), and patients with 2nd/3rd line ES-SCLC receive 
Trilaciclib/placebo combined with topotecan (Trilaciclib-TPT group and placebo-
TPT group), and the efficacy of Trilaciclib (prevention of myelosuppression) will be 
evaluated with duration of severe neutropenia (DSN) in Cycle 1 as the primary 
endpoint. The planned dose of Trilaciclib is 240 mg/m2. If the safety data from the 
first part of the study suggest that the dose of Trilaciclib needs to be adjusted, 12 
additional patients (6 patients each for 1st line ES-SCLC and 2nd/3rd line ES-
SCLC) will be enrolled in the first part of the study to explore the PK and safety of 
Trilaciclib 200 mg/m2. 
The study process includes screening period, treatment period, safety follow-
up and survival follow-up. 
The end of the study is defined as death in 75% of subjects, or 12 months after 
the last subject is enrolled, or the sponsor decided to terminate the study, whichever 
came first. 


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Investigational 
drug 
Investigational product investigated: 
Trilaciclib: Jiangsu Simcere Pharmaceutical Co., Ltd., 300 mg/vial, lyophilized 
powder 
Trilaciclib placebo: The outer packaging box of placebo is designed to be consistent 
with the investigational drug Trilaciclib, and the contents of the box were fillers 
(disks) of the same quality, which did not break the blind by appearance and hand 
after sealing. 
Background Therapy/Chemotherapy: 
Carboplatin: Qilu Pharmaceutical Co., Ltd., 100 mg/10ml/box, solution 
Etoposide: Jiangsu Hengrui Medicine, 100 mg/5ml/vial, solution 
Topotecan: Jiangsu Aosaikang Pharmaceutical Co., Ltd., 2 mg/vial, solution 
Study treatment 
Chemotherapy: 
Carboplatin - administered on Day 1 of each 21-day cycle at a target AUC of 5 
(maximum dose 750 mg calculated according to Calvert formula) over 30 min by 
intravenous infusion; etoposide - administered on Days 1, 2, and 3 of each 21-day 
cycle at 100 mg/m2 over 60 min by intravenous infusion; topotecan - administered 
on Days 1-5 of each 21-day cycle at 1.25 mg/m2 over 30 min by intravenous 
infusion. 
Trilacicilb or placebo: 
Patients receiving chemotherapy regimen of carboplatin combined etoposide: 
administered at 240 mg/m2 on Days 1, 2 and 3 of each 21-day cycle prior to 
chemotherapy using 5% glucose injection or normal saline 250 mL solution, 30 min 
intravenous drip (try to complete the drip within 30 + 5 min due to PK study). 
Patients whose chemotherapy regimen is topotecan: every 21 days as a cycle, 
on Days 1-5 of each cycle as per 240 mg/m2 was administered before chemotherapy 
and prepared into 250 mL solution with 5% glucose injection or normal saline and 
intravenously infused over 30 min (Because it involved PK studies, try to complete 
the infusion within 30+5 min). 
Patients with 1st line ES-SCLC received up to 6 cycles of Trilaciclib or 
placebo combined with carboplatin and etoposide or continued treatment until 
disease progression, intolerability, withdrawal of consent, or investigator 
termination, whichever came first; patients with 2nd/3rd line ES-SCLC received 
Trilaciclib or placebo combined with topotecan until disease progression, 
intolerability, withdrawal of consent, or investigator termination of treatment, 
whichever came first. 
Notes: 
Trilaciclib or placebo should be administered no more than 28 hours apart 
between infusions for 3 or 5 consecutive days, and no more than 4 hours apart 


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between infusions of Trilaciclib and its subsequent chemotherapeutic agents injected 
(with carboplatin and etoposide, or with topotecan). 
Trilaciclib or placebo should be administered in combination with 
chemotherapy, ie, if EC regimen or topotecan is suspended or discontinued, then 
Trilaciclib or placebo should also be suspended or discontinued. Similarly, 
subsequent chemotherapy should not be administered in any cycle if the planned 
administration of Trilaciclib, i.e. Trilaciclib or placebo, has not been completed. 
Prophylactic use of any colony-stimulating factors (including granulocyte 
colony-stimulating factor, granulocyte-giant cell colony-stimulating factor, 
erythropoiesis stimulating agent) is not permitted during Cycle 1, but could be used 
therapeutically if febrile neutropenia developed in patients with high-risk infections 
or risk factors indicating poor prognosis (sepsis, age > 65 years, neutrophils < 0.1 × 
109/L, expected neutropenia lasting > 10 days, pneumonia, invasive fungal infections, 
other clinically documented infections, fever requiring hospitalization, previous 
febrile neutropenia, etc.). 
Study 
Population 
Criteria for inclusion 
Patients must meet all of the following inclusion criteria to be enrolled in the study: 
1. 
Age ≥ 18 years, male or female; 
2. 
Histologically or cytologically confirmed extensive stage small cell lung 
cancer (ES-SCLC): 
 
Patients scheduled to receive carboplatin plus etoposide regimen: no prior 
systemic therapy (eg, chemotherapy or combined with immunotherapy); 
 
Patients scheduled to receive topotecan regimen: previously received 1/2 lines 
of chemotherapy or combined immunotherapy but not topotecan. 
3. 
Presence of at least one radiation-naïve measurable lesion according to 
RECIST 1.1 criteria; 
4. 
Hemoglobin ≥ 90 g/L; 
5. 
Neutrophil count ≥ 1.5 x 109/L; 
6. 
Platelet count ≥ 100 × 109/L; 
7. 
Creatinine ≤ 15 mg/L or creatinine clearance (CrCl) ≥ 60 mL/min (Cockcroft-
Gault formula); 
8. 
Total bilirubin ≤ 1.5 × upper limit of normal (ULN); 
9. 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × 
ULN or ≤ 5 × ULN (for patients with liver metastases); 
10. Albumin ≥ 30 g/L; 
11. ECOG PS score 0 - 2; 
12. Expected survival time ≥ 3 months; 
13. Contraception: 


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Females: All females of childbearing potential must have a negative serum 
pregnancy test at screening and must use reliable contraception from signing of 
informed consent through 3 months after the last dose; 
Male: Female partners of childbearing potential must use reliable contraception 
from signing the informed consent until 3 months after the last dose. 
14. 
Understand and sign informed consent. 
Exclusion Criteria 
1. 
Symptomatic brain metastases requiring local radiotherapy or hormonal 
therapy; 
2. 
History of other malignancies, with the following exceptions: (1) clinically 
cured cutaneous basal cell or squamous cell tumors; (2) cured a) cervical 
cancer, b) prostate cancer, c) superficial bladder cancer; or (3) other solid 
tumors with a clinical cure time of more than 3 years; 
3. 
Uncontrolled ischemic heart disease or clinically significant congestive heart 
failure (NYHA Class III or IV); 
4. 
Stroke or cardiovascular or cerebrovascular event within 6 months prior to 
enrollment; 
5. 
Severe active infection; 
6. 
Psychological or other social factors causing insufficient trial compliance; 
7. 
Other uncontrolled serious chronic diseases or conditions that, in the opinion 
of the investigator, would make participation in the trial inappropriate; 
8. 
Known HIV infection, active hepatitis B (defined as positive HBV DNA), and 
hepatitis C (positive HCV RNA); 
9. 
Radiation therapy within 2 weeks prior to enrollment; 
10. Patients who have received cytotoxic drug therapy or investigational drug 
therapy within 4 weeks before enrollment, or non-cytotoxic anti-tumor drug 
therapy within 2 weeks; 
11. Subjects in the first part of the study should not take strong or moderate inducers 
of CYP3A4 concomitantly within 4 weeks before taking the study drug, and 
strong inhibitors of CYP3A4 concomitantly within 2 weeks before taking the 
study drug; 
12. Toxicity from prior anticancer therapy has not recovered to Grade 0 or 1 
(except alopecia); 
13. Hypersensitivity to the study drug (Trilaciclib, etoposide, carboplatin, 
topotecan) or components thereof; 
14. Persons who are unable to act independently due to legal restriction or legal 
sense; 
15. Pregnant or lactating women; 


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16. Not suitable for participating in this study in the investigator 's opinion. 
Pharmacokinetic 
evaluation 
In the first part of this study, PK blood samples will be collected at the following time 
points. 
When the chemotherapy regimen is carboplatin combined with etoposide: 
Cycle 1 Day 1: 
Within 0.5 h before the start of the first Trilaciclib infusion, immediately after the end 
of infusion (± 2 min, at the end of administration, excluding the flushing time, the 
same below), and 0.5 h ± 2 min, 1 h ± 5 min, 2 h ± 5 min, 4 h ± 5 min, 6 h ± 5 min, 
8 h ± 5 min, and 12 h ± 10 min after the end of infusion. 
Cycle 1 Day 2: 
Within 0.5 hours prior to the second Trilaciclib dose (24 hours ± 30 min after the end 
of the first Trilaciclib infusion). 
Cycle 1 Day 3: 
Within 0.5 h before the start of the third Trilaciclib dose, immediately after the end 
of infusion (± 2 min, excluding flushing time), and 0.5 h ± 2 min, 1 h ± 5 min, 2 h ± 
5 min, 4 h ± 5 min, 6 h ± 5 min, 8 h ± 5 min, and 12 h ± 10 min after the end of 
infusion. 
Cycle 1 Day 4: 
24 h ± 30 min after the end of the third Trilaciclib infusion. 
A total of 20 blood sampling points, venous blood is collected to determine the 
concentration of Trilaciclib in blood samples, and pharmacokinetic analysis is 
performed based on the test results. 
When the chemotherapy regimen is topotecan: 
Cycle 1 Day 1: 
Within 0.5 h before the start of the first Trilaciclib dose, immediately after the end of 
infusion (± 2 min, excluding flushing time), and 0.5 h ± 2 min, 1 h ± 5 min, 2 h ± 5 
min, 4 h ± 5 min, 6 h ± 5 min, 8 h ± 5 min, and 12 h ± 10 min after the end of infusion. 
Cycle 1 Day 2: 
Within 0.5 hours prior to the second Trilaciclib dose (24 hours ± 30 min after the end 
of the first Trilaciclib infusion). 
Cycle 1 Day 3: 
Within 0.5 hours prior to the third Trilaciclib dose. 
Cycle 1 Day 4: 
Within 0.5 hours prior to the fourth Trilaciclib dose. 
Cycle 1 Day 5: 
Within 0.5 h before the start of the fifth Trilaciclib dose, immediately after the end of 


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infusion (± 2 min, excluding flushing time), and 0.5 h ± 2 min, 1 h ± 5 min, 2 h ± 5 
min, 4 h ± 5 min, 6 h ± 5 min, 8 h ± 5 min, and 12 h ± 10 min after the end of infusion. 
Cycle 1 Day 6: 
24 h ± 30 min after the end of the fifth Trilaciclib infusion. 
A total of 22 blood sampling points, venous blood is collected to determine the 
concentration of Trilaciclib in blood samples, and pharmacokinetic analysis is 
performed based on the test results. 
In the second part of this study, PK blood sample collection is planned at the 
following time points, and the actual blood collection points could be adjusted 
according to the pharmacokinetic study results in the first part. 
For all subjects, venous blood is collected at 4 blood sampling points on Cycle 
1 Day 1 at (excluding flushing time) ± 5 min immediately after the end of 
Trilaciclib/placebo infusion (excluding flushing time), 0.5 h ± 10 min, 5 h ± 1 h after 
the end of infusion and within 1 h before Trilaciclib/placebo administration on Cycle 
1 Day 2 to determine the concentration of Trilaciclib in blood samples, and 
pharmacokinetic analysis is performed according to the test results. 
Safety evaluation 
Safety is evaluated by adverse events (adverse events graded using NCI-CTCAE 
version 5.0), laboratory tests, vital signs, physical examinations, and 
electrocardiograms. 
Efficacy 
evaluation 
Effectiveness refers to prevention of chemotherapy induced bone marrow 
suppression. Efficacy assessments will be based on: dynamic changes in complete 
blood counts; hematological toxicities, including febrile neutropenia and related 
infections; red blood cell and platelet transfusions; hematopoietic growth factor use; 
systemic antibiotic use; dose reduction and discontinuation of chemotherapy. 
The study primarily selected the duration of severe neutropenia (DSN) in Cycle 
1 as the primary endpoint for efficacy evaluation. The overall protective effect of 
Trilaciclib on multilineage of bone marrow will also be comprehensively assessed 
through the evaluation of secondary endpoints, particularly key secondary endpoints 
(including SN occurrence, occurrence of red blood cell transfusions on/after Week 5, 
granulocyte colony-stimulating factor use rate, composite endpoint–major adverse 
hematologic event, etc.). 
Antitumor 
efficacy 
evaluation 
Tumor imaging evaluation is performed according to RECIST1.1. Baseline 
imaging is performed within 21 days prior to the first dose, every 6 ± 1 week after 
the first dose, or more frequently if clinically indicated. Imaging examinations should 
follow calendar days and should not be modified for treatment delays or terminations, 
and subjects who discontinue study drug for unacceptable toxicity or other reasons 
other than disease progression should continue to be followed for tumor assessments 
until disease progression, receipt of new antineoplastic therapy, withdrawal from the 


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study, or death, whichever occurs first. 
Efficacy assessments were classified as complete response (CR), partial 
response (PR), stable disease (SD), progressive disease (PD), and not evaluable (NE). 
Confirmation of response according to RECIST 1.1 should be performed no less than 
4 weeks from the date of the first documented partial response (PR) or complete 
response (CR). Imaging assessments for efficacy confirmation may be performed 4 
weeks after response is first observed or at the next scheduled imaging time point. 
Criteria 
for 
Discontinuation 
of 
Study 
Treatment 
A subject should discontinue study treatment if any of the following occur: 
1. Disease progression, except for subjects who, in the investigator 's judgment, still 
benefit from the study (e.g., pseudoprogression); 
2. To reach the maximum treatment time specified in the protocol; 
3. Subject is pregnant; 
4. Poor compliance of subjects, such as failure to receive medication and 
examinations as required, failure to comply with the restrictions on lifestyle during 
the study, and use of other prohibited concomitant medications, which have a 
significant impact on the evaluation of study drugs; 
5. Initiation of new anticancer therapy; 
6. Occurrence of an adverse event that, in the judgment of the investigator, makes it 
inappropriate to continue treatment with study drug; 
7. The investigator considers that study treatment should be discontinued in the best 
benefit of the subject; 
8. The subject or his/her legal representative (only applicable if the subject is not fully 
capable of civil conduct) requests termination of treatment. 
Subjects who discontinue study treatment should complete the items specified 
in the trial flow chart and continue to be followed up according to the protocol. 
Criteria for early 
withdrawal 
Subjects could withdraw from the study at any time for any reason. The 
investigator may decide whether or not to withdraw a subject from the study based 
on actual clinical circumstances. Criteria for early withdrawal from the study were: 
1. Withdrawal of consent by the subject or his/her legal representative (only 
applicable if the subject himself/herself does not have full civil capacity); 
2. Subject lost to follow-up. 
Subjects who withdrew early were not to undergo any subsequent follow-up and 
assessments. 
Criteria for early 
termination 
of 
the study 
The study may be terminated prematurely at any time if agreed to by the 
investigator and the sponsor in the best benefit of the subject and for reasonable 
medical or ethical reasons. During termination, the sponsor and investigator will 
ensure that adequate consideration is given to protecting the subject 's interests. 
Criteria for early termination of this study were: 


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1. Significant safety risk for the study drug in the opinion of regulatory authorities, 
ethics committees, sponsors or investigators; 
2. Identify major defects in the study protocol, or major deviations or human errors 
during the implementation of the study, which seriously affect the quality of the trial 
and make it difficult to achieve the purpose of the study; 
3. The sponsor may terminate the study for any scientific, medical or ethical reason, 
but shall fully consider the rights, safety and health of the enrolled subjects; 
4. Other reasons that, in the judgment of the sponsor or investigator, make 
continuation of the study inappropriate. 
Sample Size 
A total of approximately 92 subjects are planned to be enrolled, including 
approximately 12 subjects in Part I and 80 subjects in Part II. 
Statistical 
Analysis 
DETERMINATION OF SAMPLE SIZE 
The study consists of 2 parts and a total of approximately 92 ES-SCLC patients 
are planned to be enrolled. The first part (safety run-in and PK evaluation) planned 
to enroll approximately 6 patients each for 1st line ES-SCLC and 2nd/3rd line ES-
SCLC. The second part (efficacy verification) planned to enroll approximately 80 
patients with ES-SCLC, stratified by 1st line vs 2nd/3rd line ES-SCLC, ECOG PS 
(0-1 vs 2), and presence vs absence of brain metastases, to be randomized in a 1:1 
ratio to Trilaciclib versus placebo. 
The sample size for Part I is not based on statistical calculations, but to support 
PK evaluation and safety run-in. In addition, assuming a 5.3% occurrence of severe 
neutropenia, there is an approximately 28% probability of developing at least one 
severe neutropenia in 6 patients; if the occurrenceof severe neutropenia is 40.6%, 
then the probability is 96% to detect at least one subject occurring severe neutropenia. 
The sample size of the second part needs to meet the need to test the efficacy of 
DSNs in Cycle 1 and is calculated by stochastic simulation. An integrated analysis of 
the three overseas pivotal studies of Trilaciclib in SCLC showed an approximately 4-
day reduction in Cycle 1 DSN in the Trilaciclib group compared to the placebo group. 
Taking into account the derivation of DSN in Cycle 1, DSN in Cycle 1 is 0 if the 
subject did not experience any SN during Cycle 1. When there is a large proportion 
of zero-values, i.e., a large proportion of subjects who do not have any SNs in Cycle 
1, DSN in Cycle 1more closely follow a Poisson distribution with a mean of -log 
(proportion of subjects who do not have any SNs in Cycle 1). In the integrated 
analysis, the proportion of subjects who developed SN during Cycle 1 is 6.7% in the 
Trilaciclib group compared to 49.6% in the placebo group. Assuming that the 
proportion of subjects in this study who occurred SN during Cycle 1 is 10% in the 
Trilaciclib group and 45% in the placebo group, the means of Poisson distributions 
is 0.105 and 0.598 for the corresponding Trilaciclib and placebo groups, respectively. 


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The stochastic simulation is repeated 10,000 times, each time obtaining the DSN in 
Cycle 1 from a Poiss on distribution and performing comparison between groups by 
Mann-Whitney-Wilcoxon test, 70 subjects (35 per group) provided approximately 
95% power at the test level of α = 0.05 (2-sided). Assuming a dropout rate of 
approximately 12%, the sample size for Part II is 80 subjects (40 per group). 
Statistical Analysis 
Part I 
The first part will describe its PK profile and evaluate its safety and tolerability 
based on Cycle 1 data. In addition, preliminary efficacy (prevention of 
myelosuppression) data will be summarized. 
Part II 
The second part is mainly to verify the effectiveness of Trilaciclib treatment 
(prevention of bone marrow suppression). The primary endpoint is duration of severe 
neutropenia (DSN) in Cycle 1. For subjects who experienced at least 1 episode of 
severe neutropenia (SN) in Cycle 1, DSN in Cycle 1 is defined as the number of days 
from the date of the first ANC value < 0.5 x 109/L in Cycle 1 to the date of the first 
ANC value ≥ 0.5 x 109/L. Where the date of the first ANC value ≥ 0.5 x 109/L met 
the following requirements: (1) occurred after the ANC value is < 0.5 x 109/L, and 
(2) there are no other ANC values < 0.5 x 109/L between this date and the end of 
Cycle 1 (otherwise, if this subject entered Cycle 2, it is counted as Day 1 of Cycle 2). 
If the subject did not experience any SN during Cycle 1, DSN in Cycle 1 is scored as 
0. Nonparametric analysis of covariance (Nonparametric ANCOVA) will be used to 
evaluate the efficacy of DSN in Cycle 1. Mean differences between treatment groups, 
standard errors, and their 95% confidence intervals based on Satterthwaite t tests will 
also be provided. 
Key secondary efficacy endpoints included SN occurrence, occurrence of red 
blood cell transfusions (on/after Week 5), granulocyte colony-stimulating factor (G-
CSF) use, composite endpoints–major hematological adverse events, etc. Descriptive 
statistics including mean, median, standard deviation and range will be used for 
continuous data while frequency and proportion will be provided for categorical data. 
Differences between groups and their 95% confidence intervals will be estimated. 
Other secondary efficacy endpoints included the occurrence of Grade 3/4 
anemia, trough absolute neutrophil count by cycle, absolute neutrophil count, platelet 
count, absolute lymphocyte count, and hemoglobin over time, occurrence of ESA 
use, occurrence of recombinant human interleukin-11 use, occurrence of 
thrombopoietin (TPO) use, occurrence of intravenous or oral antibiotics,  occurrence 
of serious infectious adverse events, occurrence of serious pulmonary infection 
adverse events, occurrence of febrile neutropenia, occurrence of platelet transfusions 


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(during chemotherapy), objective tumor response rate (ORR), and disease control rate 
(DCR). Descriptive statistics will be used for summaries. Descriptive statistics for 
continuous data will include means, medians, standard deviations and ranges, and 
categorical data will provide counts and percentages. 
Safety analysis 
Safety analyses will be based on the Safety Analysis Set. Descriptive analysis 
and summary will be performed for adverse events, laboratory test indicators, vital 
signs and ECG. Occurrence of treatment-emergent adverse events will be provided 
and summarized by severity and relationship to study drug. 
Pharmacokinetic analysis 
The first part of the pharmacokinetic analysis included PK concentration 
analysis and PK parameter analysis. 
PK concentration analysis: PK concentration data will be summarized and listed 
by treatment group according to each scheduled sampling time point as defined in the 
protocol. Mean and median drug concentration-time profiles (linear and semi-log 
plots) are also plotted. Individual PK concentration data from subjects will be plotted 
(linear and semi-log plots) against drug concentration versus time by treatment group 
and analyte according to actual sampling time. Statistical analysis of PK 
concentrations will be based on the PK Analysis Set. 
PK Parameter Analysis: Statistical analysis of PK parameters will be 
summarized descriptively based on the PK Analysis Set. 
Population pharmacokinetic analyses will be exploratory based on the data 
obtained. 
Data Analysis Time 
An analysis will be performed when subjects in Part I have completed Cycle 1 
safety and PK assessments. Based on the Cycle 1 data, their PK profiles are 
characterized and their safety and tolerability are evaluated. In addition, preliminary 
myeloprotective efficacy (prevention of chemotherapy-induced myelosuppression) 
data will be summarized. The data of subjects in Part I may be updated synchronously 
until the end of the study at the time of data analysis in Part II. 
The primary analysis will be performed at the end of Cycle 1 for all randomized 
subjects in Part II. The sponsor 's necessary personnel will be unblinded, but the 
investigators, subjects, and other personnels will remain blinded. The primary 
endpoint for assessing the myeloprotective efficacy of Trilaciclib, duration of severe 
neutropenia (DSN) in Cycle 1, as well as other applicable secondary or exploratory 
endpoints, will be analyzed based on unblinded data. 
The second analysis in Part II will be performed after all randomized subjects 
have completed 6 cycles or end of treatment. 


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The final analysis in Part II will be performed at the end of the study. 
 


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5.2. 
Appendix 2 Test Flow Sheet 
 
Line 1 ES-SCLC Patient Study Flow (EC Protocol) 
 
 
Screenin
g Period 
Treatment Period a 
(21 days per cycle, 6 cycles) 
Safety Visit b 
Survival 
Follow-up c 
Cycle 1 
Cycle 2 and above 
 
D-21 ~ -
1 
D1 
D2 
D3 
D8 
D10 
D15 
D1 
D2 
D3 
D8 
+ 30 days 
Every 60 days 
Window (Days) 
 
 
 
 
± 1 
± 1 
± 1 
± 3 
 
 
± 1 
± 7 
± 7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Past medical history d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Checked in/out 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (Part II 
only) 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Physical examination 
X 
 
 
 
X 
 
X 
X 
 
 
 
X 
 
Body height e 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
Vital signs 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
Biochemistry f 
X 
 
 
 
X 
 
X 
X 
 
 
X 
X 
 
Hematology g 
X 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
Urine test h 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Serum Pregnancy i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessment j 
X 
Imaging every 6 ± 1 week after first study drug dose 
PK (Part I) k 
 
Part I D1-4 Blood sampling 
 
 
 
 
 
 


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Screenin
g Period 
Treatment Period a 
(21 days per cycle, 6 cycles) 
Safety Visit b 
Survival 
Follow-up c 
Cycle 1 
Cycle 2 and above 
 
D-21 ~ -
1 
D1 
D2 
D3 
D8 
D10 
D15 
D1 
D2 
D3 
D8 
+ 30 days 
Every 60 days 
Window (Days) 
 
 
 
 
± 1 
± 1 
± 1 
± 3 
 
 
± 1 
± 7 
± 7 
PK (Part II) k 
 
Part II Day 1-2 Blood sampling 
 
 
 
 
 
 
Trilaciclib/Placebo l 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
Carboplatin l 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Etoposide l 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
Virology m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival and other anti-
tumor conditions 
 
 
 
 
 
 
 
 
 
 
 
 
X 
a. 
Trilaciclib + EC chemotherapy will be administered in 21-day cycles until disease progression, intolerability, or discontinuation of treatment at the investigator 's discretion (eg, 6 cycles 
of chemotherapy have been completed). 
b. 
 Follow-up was performed 30 days (± 7 days) after the last dose, starting a new anticancer therapy (-7 days), or withdrawing from the study (-7 days), whichever came first. 
c. 
Survival follow-up refers to telephone follow-up every 60 days (± 7 days) after the last dose to collect other anti-tumor information until 50% of subjects die. 
d. 
Smoking history, family history and relevant medical history of tumor diagnosis and treatment should be collected for medical history; symptoms, signs, laboratory abnormalities within 4 
weeks before signing the informed consent form, medication history within 14 days before signing the informed consent form, and weight change within 6 months (> or < 5%). Results of 
examinations performed at our hospital within 21 days prior to the first dose (Part I) or randomization (Part II) and meeting the requirements of this protocol prior to signing of informed 
consent (hematology, biochemistry, and urinalysis should be performed within 7 days prior to the first dose of each trial part, pregnancy should be performed within 21 days prior to the 
first dose of each trial part, and virology and pregnancy tests may be performed outside hospital) can be used for screening assessments without the need for the same tests during the 
screening period. Patients who fail the initial screening may not be rescreened (only once) until consultation with the Sponsor 's designated medical representative and approval by the 
Sponsor. 
e. 
Height will be measured only at Screening and weight will be measured pre-dose every cycle except Screening. 
f. 
Biochemistry tests included aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (γ-GT), lactate dehydrogenase (LDH), cholesterol (TC), triglyceride 
(TG), total bilirubin (TBIL), direct bilirubin (DBIL), total protein (TP), albumin (ALB), alkaline phosphatase (ALP), creatine kinase (CK), glucose (GLU), uric acid (UA), blood urea 
nitrogen (BUN)/urea (Urea), creatinine (Cr), sodium (Na), potassium (K), calcium (Ca), phosphorus (P), magnesium (Mg), and chloride (Cl). The first dose was administered within 7 
days after the examination during the screening period, and if the dose was not administered after 7 days of the examination and the investigator assessed that re-judgment was required, 
an additional examination could be performed, starting from Cycle 2, before dosing on Day 1 of each cycle, and on Day 8. 
g. 
Hematology includes: white blood cell (WBC), red blood cell (RBC), hemoglobin (Hb), platelet (PLT), hematocrit (HCT), neutrophil (NEU), eosinophil (EOS), basophil (BAS), 
monocyte (MON), lymphocyte (LYM), etc.; hematology in Cycle 1 is scheduled on Day 1 (within 24 hours before administration), Day 3, Day 8, Day 10, Day 15, and baseline 
hematology should be performed within 24 hours before the first study dose; hematology in other cycles is performed on Days 1 and 8 of each cycle, and the examination on Day 1 of 
each cycle is performed before administration. Subjects were eligible for chemotherapy administration as determined by predose hematology results on Day 1 of each cycle. 


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Screenin
g Period 
Treatment Period a 
(21 days per cycle, 6 cycles) 
Safety Visit b 
Survival 
Follow-up c 
Cycle 1 
Cycle 2 and above 
 
D-21 ~ -
1 
D1 
D2 
D3 
D8 
D10 
D15 
D1 
D2 
D3 
D8 
+ 30 days 
Every 60 days 
Window (Days) 
 
 
 
 
± 1 
± 1 
± 1 
± 3 
 
 
± 1 
± 7 
± 7 
h. 
Urine examination includes: urine protein, urine pH, urine ketone body, urine glucose, urine red blood cells, urine white blood cells and so on. The first dose was administered within 7 
days after the examination during the screening period, and if the dose was not administered after 7 days of the examination and the investigator assessed that re-judgment was required, 
an additional examination could be performed, starting from Cycle 2, before dosing on Day 1 of each cycle, and on Day 8. 
i. 
Women of childbearing potential only. 
j. 
Baseline imaging was performed within 21 days prior to the first dose, every 6 ± 1 weeks after the first dose, or more frequently if clinically indicated. Imaging time should follow 
calendar days and should not be adjusted for treatment delays or terminations, and subjects who discontinue study drug for unacceptable toxicity or other reasons other than disease 
progression should continue to be followed for tumor assessments until disease progression, receipt of new antineoplastic therapy, withdrawal from study, or death, whichever occurs first 
k. 
For Cycle 1 only, blood sampling time points are detailed in Chapter 6 Pharmacokinetics. 
l. 
Chemotherapy: carboplatin - administered on Day 1 of each 21-day cycle with target AUC (Calvert formula) = 5 (maximum dose 750 mg) by intravenous infusion over 30 min; etoposide 
- administered on Days 1, 2, and 3 of each 21-day cycle with 100 mg/m2 by intravenous infusion over 60 min; trilacicilb/placebo: administered every 21 days as 240 mg/m2 before 
chemotherapy on Days 1, 2, and 3 of each 21-day cycle with 5% glucose injection or normal saline prepared into 250 mL solution by intravenous infusion over 30 min (as far as PK 
studies are involved). Subjects in Part I will receive Trilaciclib plus EC regimen and subjects in Part II may receive Trilaciclib or placebo plus EC regimen. Date of medication visit is 
based on the first dose of investigational drug (Trilaciclib/Placebo) in each cycle (D1). 
m. 
Hepatitis B and C screening were performed during the screening period, five items of hepatitis B: if hepatitis B surface antigen (HBsAg) was positive or hepatitis B core antibody 
(HBcAb), HBV-DNA should be added; hepatitis C examination: if hepatitis C antibody was positive, HCV-RNA should be added. 
 
 


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2/3 Line ES-SCLC Patient Study Flow (Topotecan) 
 
 
Screenin
g Period 
Treatment Period a 
(21 days per cycle until disease progression or intolerable) 
Safety Visit b 
Survival 
Follow-up c 
Cycle 1 
Cycle 2 and above 
 
D-21 ~ -
1 
D1 
D2 
D3 
D4 
D5 
D10 
D12 
D15 
D1 
D2 
D3 
D4 
D5 
D10 
+ 30 days 
Every 60 days 
Window 
(Days) 
 
 
 
 
 
 
± 1 
± 1 
± 1 
± 3 
 
 
 
 
± 1 
± 7 
± 7 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past medical 
history d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Checked 
in/out 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizatio
n 
(Part 
II 
only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Physical 
examination 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
Body height e 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Vital signs 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
Biochemistry 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 


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Screenin
g Period 
Treatment Period a 
(21 days per cycle until disease progression or intolerable) 
Safety Visit b 
Survival 
Follow-up c 
Cycle 1 
Cycle 2 and above 
 
D-21 ~ -
1 
D1 
D2 
D3 
D4 
D5 
D10 
D12 
D15 
D1 
D2 
D3 
D4 
D5 
D10 
+ 30 days 
Every 60 days 
Window 
(Days) 
 
 
 
 
 
 
± 1 
± 1 
± 1 
± 3 
 
 
 
 
± 1 
± 7 
± 7 
f 
Hematology g 
X 
X 
 
 
 
X g 
X 
X g 
X g 
X 
 
 
 
 
X 
X 
 
Urine test h 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Serum 
Pregnancy i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor 
assessment j 
X 
Imaging every 6 ± 1 week after first study drug dose 
PK (Part I) k 
 
Day 1-6 blood sampling 
 
 
 
 
 
 
 
 
PK (Part II) k 
 
Day 1-2 blood sampling 
 
 
 
 
 
 
 
 
Trilaciclib/Pl
acebo l 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Topotecan l 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Virology m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival and 
other 
anti-
tumor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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Screenin
g Period 
Treatment Period a 
(21 days per cycle until disease progression or intolerable) 
Safety Visit b 
Survival 
Follow-up c 
Cycle 1 
Cycle 2 and above 
 
D-21 ~ -
1 
D1 
D2 
D3 
D4 
D5 
D10 
D12 
D15 
D1 
D2 
D3 
D4 
D5 
D10 
+ 30 days 
Every 60 days 
Window 
(Days) 
 
 
 
 
 
 
± 1 
± 1 
± 1 
± 3 
 
 
 
 
± 1 
± 7 
± 7 
conditions 
a. 
Trilaciclib + Topotecan chemotherapy will be administered in 21-day cycles until disease progression, intolerability, or treatment discontinuation at the investigator 's discretion. 
b. 
Follow-up was performed 30 days (± 7 days) after the last dose, at the start of a new anticancer therapy (-7 days), or at study withdrawal (-7 days), whichever came first. 
c. 
Survival follow-up refers to telephone follow-up once at 60 days (± 7 days) after the last dose to collect other anti-tumor information until 50% of subjects die. 
d. 
Smoking history, family history and relevant medical history of tumor diagnosis and treatment should be collected for medical history; symptoms, signs, laboratory abnormalities within 4 
weeks before signing the informed consent form, medication history within 14 days before signing the informed consent form, and weight change within 6 months (> or < 5%). Results of 
examinations performed at our hospital within 21 days prior to the first dose (Part I) or randomization (Part II) and meeting the requirements of this protocol prior to signing of informed 
consent (hematology, biochemistry, and urine tests need to be performed within 7 days prior to the first dose of each trial part, pregnancy tests need to be performed within 21 days prior to 
the first dose of each trial part, and viral and pregnancy tests can be performed outside hospital) can be used for screening assessments without the need for the same tests during the screening 
period. Patients who fail the initial screening may not be rescreened (only once) until consultation with the Sponsor 's designated medical representative and approval by the Sponsor. 
e. 
Height will be measured only at Screening and weight will be measured pre-dose every cycle except Screening. 
f. 
Biochemistry tests included aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (γ-GT), lactate dehydrogenase (LDH), cholesterol (TC), triglyceride 
(TG), total bilirubin (TBIL), direct bilirubin (DBIL), total protein (TP), albumin (ALB), alkaline phosphatase (ALP), creatine kinase (CK), glucose (GLU), uric acid (UA), blood urea 
nitrogen (BUN)/urea (Urea), creatinine (Cr), sodium (Na), potassium (K), calcium (Ca), phosphorus (P), magnesium (Mg), and chloride (Cl). The first dose was administered within 7 days 
after the examination during the screening period, and if the dose was not administered after 7 days of the examination and the investigator assessed that re-judgment was required, an 
additional examination could be performed, starting from Cycle 2, before dosing on Day 1 of each cycle, and on Day 10. 
g. 
Hematology includes: white blood cell (WBC), red blood cell (RBC), hemoglobin (Hb), platelet (PLT), hematocrit (HCT), neutrophil (NEU), eosinophil (EOS), basophil (BAS), monocyte 
(MON), lymphocyte (LYM), etc.; hematology in Cycle 1 is scheduled on Day 1 (within 24 hours before dosing), Day 5, Day 10, Day 12, Day 15, and baseline hematology should be 
performed within 24 hours before the first study dose; hematology in other cycles is performed on Days 1 and 10 of each cycle, and the examination on Day 1 of each cycle is performed 
before dosing. Subjects were eligible for chemotherapy administration as determined by predose hematology results on Day 1 of each cycle. 
h. 
Urine examination includes urine protein, urine pH, urine ketone body, urine glucose, urine red blood cells, urine white blood cells, etc. The first dose is administered within 7 days after the 
examination during the screening period. If the dose is not administered after 7 days of the examination and the investigator considers it necessary to make a re-judgment, an additional test 
may be performed from Cycle 2, before administration on Day 1 of each cycle, and on Day 10. 
i. 
Women of childbearing potential only. 
j. 
Baseline imaging was performed within 21 days prior to the first dose, every 6 ± 1 week after the first dose, or more frequently if clinically indicated. Imaging examinations should follow 
calendar days and should not be modified for treatment delays or terminations, and subjects who discontinue study drug for unacceptable toxicity or other reasons other than disease 
progression should continue to be followed for tumor assessments until disease progression, receipt of new antineoplastic therapy, withdrawal from the study, or death, whichever occurs 
first. 
k. 
For Cycle 1 only, blood sampling time points are detailed in Chapter 6 Pharmacokinetics. 
l. 
Chemotherapy: Topotecan will be administered at 1.25 mg/m2 on Days 1-5 of each 21-day cycle via intravenous drip over 30 min; Trilacicilb/placebo: will be administered at 240 mg/m2 on 
Days 1-5 of each 21-day cycle via intravenous drip over 30 min using 5% glucose injection or normal saline as 250 mL solution before chemotherapy due to PK study. The first of these 


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Screenin
g Period 
Treatment Period a 
(21 days per cycle until disease progression or intolerable) 
Safety Visit b 
Survival 
Follow-up c 
Cycle 1 
Cycle 2 and above 
 
D-21 ~ -
1 
D1 
D2 
D3 
D4 
D5 
D10 
D12 
D15 
D1 
D2 
D3 
D4 
D5 
D10 
+ 30 days 
Every 60 days 
Window 
(Days) 
 
 
 
 
 
 
± 1 
± 1 
± 1 
± 3 
 
 
 
 
± 1 
± 7 
± 7 
subjects will receive Trilaciclib plus Topotecan and the second will likely receive Trilaciclib or placebo plus Topotecan. Date of medication visit is based on the first dose of investigational 
drug (Trilaciclib/Placebo) in each cycle (D1). 
m. 
Hepatitis B and C screening were performed during the screening period, five items of hepatitis B: if hepatitis B surface antigen was positive or hepatitis B core antibody was positive 
(HBcAb), HBV-DNA should be added; hepatitis C examination: if hepatitis C antibody was positive, HCV-RNA should be added. 
 
 


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5.3. 
Appendix 3 Criteria for CTCAE judgment of laboratory parameters 
Laboratory parameters will be graded primarily using CTCAE version 5.0. CTCAE grading of some indicators cannot be based on CTCAE 
Version 5.0, requires clinical diagnosis or clinical diagnosis and value determination, and cannot be completely divided by programming, such as 
hyperglycemia, hypokalemia, hypophosphatemia, hyponatremia and hyperuricemia, which will be graded using CTCAE Version 4.03. 
  
  
 
Parameter 
Level 
1 
2 
3 
4 
5 
Albumin 
< lower limit of normal – 3 
g/dL; 
< lower limit of normal – 30 
g/L 
< 3 – 2 g/dL; < 30 – 20 
g/L 
< 2 g/dL; 
< 20 g/L 
Life-threatening; urgent 
intervention indicated 
Death 
ALP 
Alkaline 
phosphatase 
> upper limit of normal - 2.5 
times upper limit of normal 
(normal baseline); 2 to 2.5 
times 
baseline 
(abnormal 
baseline) 
> 2.5 to 5.0 times the upper 
limit of normal (normal 
baseline); > 2.5 to 5.0 times the 
baseline (if abnormal baseline) 
  
> 5.0 to 20.0 times upper limit 
of normal (normal baseline); > 
5.0 to 20.0 times baseline (if 
abnormal baseline) 
  
> 20.0 times upper limit of 
normal 
(normal baseline); 
> 20.0 times baseline if 
baseline is abnormal 
- 
ALT 
Alanine 
Aminotransferas
e 
> upper limit of normal - 3 
times upper limit of normal 
(normal baseline); 1.5 to 3.0 
times baseline (if abnormal 
baseline) 
3 to 5 times the upper limit of 
normal (normal baseline), 
> 3.0 to 5.0 times baseline (if 
baseline is abnormal) 
5 to 20-fold (if baseline is 
normal); > 5 to 20-fold (if 
baseline is abnormal) 
  
> 20 x upper limit of normal 
(if baseline is normal); > 20 
x baseline (if baseline is 
abnormal) 
- 
AST 
Aspartate 
Aminotransferase 
> upper limit of normal - 3 
times normal 
Upper limit (normal baseline); 
baseline 
> 3-5 times upper limit of 
normal 
(normal baseline); 
> 5.0 - 20.0 of upper limit of 
normal 
Fold (normal baseline); > 
baseline 
> 20.0 times upper limit of 
normal 
(normal baseline); 
- 


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Transaminase 
1.5 to 3.0 times (if baseline 
value is abnormal) 
> 3.0 - 5.0 of baseline 
(Abnormal Baseline) 
  
Fol
d 
5.0-20.0 fold (if baseline is 
abnormal) 
  
> 20.0 times baseline if 
baseline is abnormal 
Hypercholesterole
mia 
> upper limit of normal ~ 300 
mg/dL or > upper limit of 
normal ~ 7.75 mmol/L 
  
> 300 - 400 mg/dL 7.75 
- 10.34 mmol/L 
  
Or > 
> 400 - 500 g/dL 10.34 - 
12.92 mmol/L 
  
Or > > 500 mg/dL or > 12.92 
mmol/L 
  
- 
Hypertriglyceride
mia 
150 mg/dL to 300 mg/dL or 
1.71 
mmol/L to 3.42 mmol/L 
  
> 300 mg/dL to 500 mg/dL 
or > 3.42 mmol/L to 5.7 
mmol/L 
  
> 500 mg/dL to 1000 mg/dL 
or > 5.7 mmol/L to 11.4 
mmol/L 
  
Life Threatening 
  
Death 
  
Blood bilirubin 
increased 
  
> upper limit of normal ~ 1.5 
times upper limit of normal 
(normal baseline); > 1 ~ 1.5 
times baseline (abnormal 
baseline) 
  
Greater than 1.5 to 3.0 times 
the upper limit of normal 
(normal baseline); greater than 
1.5 to 3.0 times the baseline 
(abnormal baseline) 
  
Greater than 3.0 to 10 times the
upper limit of normal (normal 
baseline); greater than 3.0 to 10
times the baseline (abnormal 
baseline) 
Greater than 10 times upper 
limit of normal 
(normal baseline); greater 
than 10 times baseline 
(abnormal baseline) 
  
- 
Creatinine 
increased 
  
> upper limit of normal ~ 1.5 
times upper limit of normal 
  
> 1.5 - 3.0 x baseline; > 1.5 - 
3.0 x normal 
Limit 
> 3.0 times baseline value; > 
3.0 ～ 
6.0 x upper limit of normal 
> 6.0 x upper limit of normal 
  
- 
Creatinine 
clearance rate 
(CrCl) 
Creatinine clearance (CrCl) 
less than 60 mL/min/1.73 m2 
  
CrCl 59 
mL/min/1.73 m2 
  
~ 
30 CrCl 29 
mL/min/1.73 m2 
  
~ 
15 CrCl Small in 15 
mL/min/1.73 m2; requiring 
dialysis or renal transplant 
  
Death 


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Hypercalcaemia 
(Corrected for 
albumin) 
  
Corrected serum calcium > 
upper limit of normal ~ 11.5 
mg/dL; > upper limit of 
normal 
Limit: ~ 2.9 mmol/L; 
Ionized calcium 
concentration > upper limit of 
normal ~ 1.5 mmol/L 
Corrected serum calcium > 
11.5 - 12.5 mg/dL; 
> 2.9 - 3.1 mmol/L; calcium 
concentration > 1.5 - 1.6 
mmol/L; symptomatic 
Corrected serum calcium > 12.5
- 13.5 mg/dL; > 3.1 - 3.4
mmol/L; 
calcium
concentration > 1.6 - 1.8 
mmol/L; 
hospitalization 
required 
Corrected serum calcium > 
13.5 mg/dL; > 3.4 mmol/L; 
ionized calcium 
concentration > 1.8 mmol/L; 
life-threatening 
Death 
Hypocalcemia 
(Corrected for 
albumin) 
  
Corrected serum calcium < 
lower limit of normal ~ 8.0 
mg/dL; < lower limit of 
normal ~ 2.0 mmol/L; calcium 
concentration 
< lower limit of normal ~ 1.0 
mmol/L 
  
Corrected serum calcium < 8.0 
- 7.0 mg/dL; < 2.0 - 1.75 
mmol/L; calcium concentration 
< 1.0 
~ 0.9 mmol/L; symptomatic 
  
Corrected serum calcium < 7.0 
- 6.0 mg/dL; < 1.75 - 1.5 
mmol/L; calcium concentration 
< 0.9 
~ 0.8 mmol/L; hospitalization 
required 
  
Corrected serum calcium < 
6.0 mg/dL; < 1.5 mmol/L; 
ionized calcium 
concentration < 0.8 mmol/L; 
life-threatening 
Death 
CK creatine 
phosphokinase 
> upper limit of normal ~ 2.5 
times upper limit of normal 
  
> 2.5 x upper limit of normal 
to 5 x upper limit of normal 
  
> 5 x upper limit of normal to 
10 x upper limit of normal 
  
> 10 x upper limit of normal - 
Gamma glutamyl 
transferase 
(GGT) 
> 1 to 2.5 times the upper limit 
of normal if baseline is normal 
or 2.0 to 2.5 times the baseline 
level if baseline is abnormal 
  
> 2.5 ～ if baseline value is 
normal 
5.0 x upper limit of normal; > 
2.5 to 5.0 x baseline if baseline 
is abnormal 
  
> 5.0 ～ if baseline value is 
normal 
20. times the upper limit of 
normal; if the baseline value is 
abnormal, > 5.0 ~ 20.0 times 
the baseline level 
> 20.0 x upper limit of 
normal if baseline is normal 
or > 20.0 x baseline if 
baseline is abnormal 
- 


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Hyperglycemia 
(CTCAE 4.03) 
Fasting blood glucose greater 
than upper limit of normal - 
160 mg/dL or 
Fasting blood glucose greater 
than upper limit of normal - 
8.9 mol/L 
  
Empty abdominal blood 
glucose greater than 160-250 
mg/dL or fasting plasma 
glucose greater than 8.9-13.9 
mol/L 
  
Empty abdominal blood sugar 
greater than 250-500 
mg/dL or fasting plasma 
glucose greater than 13.9-27.8 
mol/L 
  
Fasting glucose greater than 
500 mg/dL or 27.8 mol/L 
  
- 
Hypoglycemia 
< lower limit of normal ~ 55 
mg/dL; 
< lower limit of normal ~ 3.0 
mmol/L 
< 55 - 40 mg/dL; < 3.0 - 2.2 
mmol/L 
  
< 40-30 mg/dL; < 2.2-1.7 
mmol/L 
  
< 30 mg/dL; 
< 1.7 mmol/L; life-
threatening; seizure 
Death 
Hemoglobin 
Hemoglobin < lower limit of 
normal ~ 10.0 g/dL; 
< lower limit of normal ~ 6.2 
mmol/L; 
< lower limit of normal ~ 100 
g/L 
Hemoglobin < 10.0 - 8.0 g/dL; 
< 6.2 - 4.9 mmol/L; < 100 - 80 
g/L 
  
Hemoglobin < 8.0 g/dL; < 4.9 
mmol/L; < 80 g/L; transfusion 
indicated 
  
Life-threatening; urgent 
treatment required 
Death 
Lipase increased 
> 1.5 x upper limit of normal 
(ULN) 
ULN 
  
> 1.5 - 2.0 x ULN; > 2.0 - 5.0 x 
ULN and asymptomatic 
  
> 2.0 - 5.0 times ULN with 
signs or symptoms; > 5.0 
times ULN but no symptoms 
  
> 5.0 x ULN with signs or 
symptoms 
- 
Hyperkalemia 
> upper limit of normal ~ 5.5 
mmol/L 
> 5.5 - 6.0 mmol/L; 
intervention 
> 6.0 - 7.0 mmol/L; 
hospitalization required 
  
> 7.0 mmol/L; life-
threatening 
Death 
Hypokalemia 
(CTCAE 4.03) 
  
< lower limit of normal (LLN) 
to 3.0 mmol/L 
- 
  
< 3.0 - 2.5 mmol/L 
  
< 2.5 mmol/L 
- 


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Lymphocyte 
count 
  
< lower limit of normal ~ 
800/mm 
3 ; 
< lower limit of normal ~ 0.8 x 
10 
9/L 
  
< 800 - 500/mm 
3 ; < 0.8 - 0.5 
x 10 
9/L 
  
< 500 - 200/mm 
3 ; 
< 0.5 - 0.2 x 10 
9/L 
   
< 200/mm 
3 ; 
< 0.2 x 10 
9/L 
- 
Neutrophil count 
  
< lower limit of normal ~ 
1500/mm 
3 ; 
< lower limit of normal ~ 1.5 x 
10 
9/L 
  
< 1500 - 1000/mm 
3 ; < 1.5 - 
1.0 x 10 
9/L 
  
< 1000 - 500/mm 
3 ; < 1.0 - 0.5 
x 10 
9/L 
  
< 500/mm 
3 ; 
< 0.5 x 10 
9/L 
- 
Hypophosphate
mia (CTCAE 
4.03) 
  
< lower limit of normal ~ 2.5 
mg/dL or < lower limit of 
normal ~ 0.8 mmol/L 
< 2.5 - 2.0 mg/dL or < 0.8 - 
0.6 mmol/L 
< 2.0 - 1.0 mg/dL or < 0.6 - 
0.3 mmol/L 
< 1.0 mg/dL or < 0.3 mmol/L - 
Hypomagnesemia 
  
< lower limit of normal ~ 1.2
mg/dL; < lower limit of normal
~ 0.5 mmol/L 
  
< 1.2 - 0.9 mg/dL; < 0.5 - 0.4 
mmol/L 
  
< 0.9 - 0.7 mg/dL; < 0.4 - 0.3 
mmol/L 
  
< 0.9 - 0.7 mg/dL; 
< 0.4 - 0.3 mmol/L 
  
Death 
Hypermagnesaem
ia 
  
> upper limit of normal ~ 3.0
mg/dL; > upper limit of normal
~ 1.23 mmol/L 
  
- 
> 3.0 - 8.0 mg/dL; 
> 1.23 to 3.30 
mmol/L 
  
> 8.0 mg/dL; > 3.30 mmol/L; 
Life Threatening 
  
Death 
Platelet count 
< lower limit of normal ~
75,000/mm 
3 ; < lower limit of
normal ~ 75.0 x 10 
9/L 
< 75,000 to 50,000/mm 
3 ; 
< 75.0 - 50.0 x 10 
9/L 
  
< 50,000 to 25,000/mm 
3 ; 
< 50.0 - 25.0 x 10 
9/L 
< 25,000/mm 
3 ; 
< 25.0 x 10 
9/L 
  
- 


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Hypernatremia 
> upper limit of normal ~ 150 
mmol/L 
> 150 - 155 mmol/L; 
intervention 
> 155 - 160 mmol/L; 
hospitalization required 
  
> 160 mmol/L; life-
threatening 
Death 
Hyponatremia 
(CTCAE 4.03) 
   
< lower limit of normal ~ 130 
mmol/L 
- 
130 to 120 mmol/L with or 
without symptoms 
  
< 120 mmol/L 
- 
Leucocyte 
< lower limit of normal ~ 
3000/mm 
3 ; 
< lower limit of normal ~ 3.0 x 
10 
9/L 
< 3000 - 2000/mm 
3 ; < 3.0 - 
2.0 x 10 
9/L 
  
< 2000 - 1000/mm 
3 ; < 2.0 - 
1.0 x 10 
9/L 
  
< 1000/mm 
3 ; 
< 1.0 x 10 
9/L 
- 


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5.4. 
Appendix 4 Window Visits 
During the treatment cycle, if more than one visit occurred within a window visit, the visit closest to the scheduled date was selected; if the 
distance between two visits and the scheduled date was the same, the visit occurring later was selected as the window visit; and if multiple visits 
occurred on the same day, the worst case was selected. 
Visit Window - 1L Subject 
 
  
Cycle 1 
Cycle 2 and above 
Safety Visit 
Visits 
D1 
D3 
D8 
D10 
D15 
End 
D1 
D8 
End 
  
Scheduled Date
 
[a] 
1 
3 
8 
10 
15 
22 
1 
8 
22 
30 (+ 3) 
Biochemistry 
-3 to 1 
  
2 to 11 
  
12 to 18 
19 to end of 
cycle 
-3 to 1 
2 to 15 
16 to end 
of cycle 
Date of first dose 
of last cycle to 40 
days after first 
dose 
  
Hematology 
-1 to 1 
2 to 5 
6 to 9 
10 to 12 
13 to 18 
19 to end of 
cycle 
-3 to 1 
2 to 15 
16 to end 
of cycle 
Date of first dose 
of last cycle to 40 
days after first 
dose 
  
[a] Relative to Day 1 of each cycle 


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Visit Window - 2/3L Subject 
 
  
Cycle 1 
Cycle 2 and above 
Safety Visit 
Visits 
D1 
D5 
D10 
D12 
D15 
End 
D1 
D10 
End 
  
Scheduled Date
 [a] 
1 
5 
10 
12 
15 
22 
1 
10 
22 
30 (+ 5) 
Biochemistry 
-3 to 1 
  
  
  
2 to 18 
19 to end of 
cycle 
-3 to 1 
2 to 16 
17 to end 
of cycle 
Date of first dose of 
last cycle to after 
first dose 
42 days 
  
Hematology 
-1 to 1 
2 to 7 
8 to 11 
12 to 13 
14 to 18 
19 to end of 
cycle 
-3 to 1 
2 to 16 
17 to end 
of cycle 
Date of first dose of 
last cycle to after 
first dose 
42 days 
  
[a] Relative to Day 1 of each cycle