Clinical trial NCT04863248
Conditions: Metastatic Non-Small Cell Lung Cancer NSCLC Lung Cancer
Keywords: Trilaciclib Lung Cancer Non-Small Cell Lung Cancer PRESERVE 4 CDK 4/6 Inhibitor cyclin-dependent kinase 4/6 inhibitor Preserve NSCLC solid tumors chemotherapy metastatic myeloprotection advanced stage 4 lung docetaxel COSELA G1T28
Sponsor: G1 Therapeutics, Inc.
Start date: 2021-04-30; Completion date: 2022-02-02
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled, global, multicenter, Phase 2 trial evaluating the effect of trilaciclib on overall survival when administered prior to docetaxel in patients with metastatic NSCLC treated in the 2nd or 3rd line setting.

Detailed description:
Patients must have documented disease progression during or after one or two lines of systemic therapy for recurrent or metastatic NSCLC. Prior treatment must have included, either in the same line or as separate lines of therapy: 1) a maximum of 1 line of platinum-containing chemotherapy for recurrent/metastatic disease and 2) a maximum of 1 line of a locally approved/authorized programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) monoclonal antibody (mAb) containing regimen for recurrent/metastatic disease.

Patients will be randomly assigned (1:1) to receive trilaciclib or placebo intravenously (IV) prior to docetaxel on Day 1 of each 21-day cycle.

The study will include a screening phase, a treatment phase and a survival follow-up phase. The patient may continue to receive treatment on study until disease progression, unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the trial, whichever occurs first.

This study was terminated by the Sponsor for non-safety reasons. At the time of study termination, 10 patients had been screened, 7 were randomized, and 2 of the 7 had discontinued from the study. In addition, it was decided that there would be no statistical analyses of the efficacy or safety data due to the limited number of patients treated (N=7).

Arms: arm 1: Patients will receive trilaciclib administered IV prior to docetaxel administered IV on Day 1 of each 21-day cycle. arm 2: Patients will receive placebo administered IV prior to docetaxel administered IV on Day 1 of each 21-day cycle.
Interventions: intervention 1: Trilaciclib intervention 2: Placebo intervention 3: Docetaxel
Intervention descriptions: intervention 1: Trilaciclib administered IV over 30 minutes prior to docetaxel IV on Day 1 of each 21-day cycle. intervention 2: Placebo administered IV over 30 minutes prior to docetaxel IV on Day 1 of each 21-day cycle. intervention 3: Docetaxel administered IV on Day 1 of each 21-day cycle.

Protocol documents:
Prot_SAP_001.pdf: 
 
 
 
Protocol Title: A Phase 2 Randomized, Double-blind, Clinical Trial of Trilaciclib versus 
Placebo in Patients with Metastatic Non-Small Cell Lung Cancer (NSCLC) 
Treated with Docetaxel in the 2nd/3rd Line Setting (PRESERVE 4)  
Protocol Number: G1T28-210 
Compound: Trilaciclib for Injection, 300 mg/vial 
Study Phase: 2 
Study Name: PRESERVE 4 
Sponsor Name: G1 Therapeutics, Inc. 
Legal Registered Address:  G1 Therapeutics, Inc. 
700 Park Offices Dr. Suite 200 
PO Box 110341  
Research Triangle Park, NC 27709 
 
Regulatory Agency Identifier Numbers:  IND: 154630 
EudraCT: 2021-000186-32 
 
Approval Date: 20 May 2021 (Version 2.0) 
Original Protocol: 01 Feb 2021 (Version 1.0) 
 
 
This document contains confidential and/or trade secret information that is disclosed only in connection 
with the licensing and/or registration of products for G1 Therapeutics, Inc. This document should not be 
disclosed or used, in whole or in part, for any other purpose without the prior written consent of 
G1 Therapeutics, Inc. 
1




 
  
INVESTIGATOR’S AGREEMENT 
 
Clinical Study Protocol G1T28-210: A Phase 2 Randomized, Double-blind, Clinical Trial of 
Trilaciclib versus Placebo in Patients with Metastatic Non-Small Cell Lung Cancer 
(NSCLC) Treated with Docetaxel in the 2nd/3rd Line Setting (PRESERVE 4)  
 
Protocol Amendment 1 (Version 2.0) Issue Date: 20 May 2021 
Original Protocol (Version 1.0) Issue Date: 01 Feb 2021  
 
I have read the G1T28-210 protocol and agree to conduct the study as outlined. I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol.  
 
 
 
 
 
 
Principal Investigator Signature 
 
Date 
 
 
 
 
 
 
 
 
Principal Investigator Name 
 
Institution 
 
 
 
3


1. 
SYNOPSIS 
Name of Sponsor/Company: G1 Therapeutics, Inc. 
Name of Investigational Product: Trilaciclib for Injection, 300 mg/vial 
Name of Active Ingredient: Trilaciclib dihydrochloride (hereafter referred to as trilaciclib) (G1T28) 
Protocol Number: G1T28-210 
Phase: 2 
Country: Worldwide 
Title of Study:  
A Phase 2 Randomized, Double-blind, Clinical Trial of Trilaciclib versus Placebo in Patients with 
Metastatic Non-Small Cell Lung Cancer (NSCLC) Treated with Docetaxel in the 2nd/3rd Line Setting 
(PRESERVE 4) 
Study center(s): Approximately 60 centers 
Study period:  
Estimated date first patient enrolled: 2Q2021 
Estimated date last patient completed: 1Q2024 
Objectives:  
Primary: 
To assess the effect of trilaciclib administered prior to docetaxel compared with placebo administered 
prior to docetaxel on overall survival (OS) in patients with metastatic NSCLC receiving docetaxel in 
the 2nd or 3rd line. 
Study Design: 
This is a randomized, double-blind, placebo-controlled, global, multicenter, Phase 2 trial evaluating the 
effect of trilaciclib compared with placebo on OS in metastatic NSCLC patients receiving docetaxel in 
the 2nd or 3rd line setting. Patients must have documented disease progression during or after one or two 
lines of systemic therapy for recurrent or metastatic NSCLC. Prior treatment must have included, 
either in the same line or as separate lines of therapy: 1) a maximum of 1 line of platinum-containing 
chemotherapy for recurrent/metastatic disease and 2) a maximum of 1 line of a locally 
approved/authorized programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) 
monoclonal antibody (mAb) containing regimen for recurrent/metastatic disease. Patients will be 
randomly assigned (1:1) to receive trilaciclib or placebo intravenously (IV) prior to docetaxel on Day 1 
of each 21-day cycle. There will be 2 stratification factors for randomization: Country and Eastern 
Cooperative Oncology Group (ECOG) performance status (0-1 versus 2). Within each country, patient 
randomization will be stratified by ECOG performance status (0-1 versus 2).  
Study drugs will be administered as follows: 
• 
Trilaciclib (240 mg/m2) or placebo – administered as a 30-minute IV infusion no more than 
4 hours prior to chemotherapy on each day chemotherapy is administered.  
• 
Docetaxel 75 mg/m2 – IV, Day 1 
The study will include 3 study phases: Screening Phase, Treatment Phase, and Survival Follow-up 
Phase. The Treatment Phase begins on the day of randomization for the first patient and completes at 
the Post-Treatment visit for the last patient. The first Survival Follow-up assessment should occur ~2 
months after the last dose of study drug. 
The patient may continue to receive treatment on study until disease progression, unacceptable 
toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the trial, whichever 
4


occurs first. Treatment cycles will occur consecutively without interruption, except when necessary to 
manage toxicities or for administrative reasons.  
Upon discontinuation of study treatment, patients will be followed for survival, i.e., patients or their 
caregivers will be contacted approximately every 2 months until the end of the study (or death) to 
record their status (alive or dead) as well as details of any subsequent systemic anti-cancer therapy 
initiated. 
Methodology:  
Sample Size Justification: 
The sample size is determined to support the primary objective of the study. That is, to evaluate the 
effect of trilaciclib compared to placebo on the OS of patients with metastatic NSCLC receiving 
docetaxel in the 2nd/3rd line setting. A total of 104 deaths will be required to achieve 85% power to 
detect a hazard ratio (HR) of 0.55 in OS at a 2-sided significance level of 0.05. A HR of 0.55 
corresponds to a median OS of 16.5 months for the trilaciclib group assuming a median OS of 
9.1 months for the placebo group (Garon, 2014). With a 12-month enrollment period and a 30-month 
study duration (after the first patient is randomized), a total of 146 patients are required for 
randomization at a 1:1 ratio to trilaciclib or placebo. This sample size has taken into consideration an 
interim analysis for OS at the information fraction of 0.70 using the O'Brien-Fleming method for α-
spending to ensure strong control of Type I error rate at 1-sided 0.025 between the interim and the final 
analysis for OS. In the sample size calculation, it is also assumed that about 5% of patients are lost-to-
follow-up during the 30--month study duration. 
Number of patients (planned):  
Approximately 146 patients with NSCLC are planned in this study. 
Diagnosis and main criteria for inclusion:  
Patients ≥18 years of age at the time of signing the informed consent with histologically or 
cytologically-confirmed metastatic NSCLC. Patients of any histology appropriate for treatment with 
docetaxel in the 2nd/3rd line will be eligible. Patients must have documented disease progression during 
or after treatment with platinum-based chemotherapy and a locally approved/authorized PD-1/PD-L1 
inhibitor. Patients should not have been previously treated with docetaxel or with therapy targeted to 
driver mutations. Measurable or non-measurable disease per Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 is permitted as is ECOG performance status of 0 to 2. At the time of providing 
informed consent, a formalin-fixed paraffin-embedded (FFPE) tumor specimen (from archival or fresh 
biopsy) with an associated pathology report documenting NSCLC must be available to send to 
Sponsor, within the timeframe specified, for planned retrospective biomarker analyses.  
Investigational product, dosage and mode of administration:  
On Day 1 of each 21-day cycle, a dose of trilaciclib 240 mg/m2 diluted in 250 mL of dextrose 5% in 
water or sodium chloride solution 0.9% will be administered as a 30-minute IV infusion no more than 
4 hours prior to docetaxel administration. 
Duration of treatment:  
Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, 
discontinuation by Investigator, or the end of the trial, whichever occurs first. 
Reference therapy, dosage and mode of administration:  
On Day 1 of each 21-day cycle, a dose of placebo (250 mL of dextrose 5% in water or sodium chloride 
solution 0.9%) will be administered by IV infusion over approximately 30 minutes no more than 4 
hours prior to docetaxel administration.  
5


On Day 1 of each 21-day cycle, docetaxel will be administered IV in accordance with the prescribing 
information and institutional guidelines.  
Criteria for evaluation: 
Efficacy: 
Antitumor efficacy will be assessed by OS, PFS, objective response rate (ORR), and duration of 
objective response (DOR). Tumor response criteria will be based on RECIST v1.1.  
Myelopreservation efficacy will be assessed based on hematology assessments, myelosuppression-
related adverse event (AE) details, dose reductions/delays and supportive care interventions (including 
transfusions).  
Safety: 
Safety will be evaluated by monitoring AEs, clinical laboratory test results (hematology, clinical 
chemistry), vital sign measurements (blood pressure, heart rate, and body temperature), 12-lead safety 
electrocardiogram (ECG) results, dose intensity, and physical examination findings. 
PROs: 
Patient-reported outcomes (PROs) will be assessed using the European Organisation for Research and 
Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-LC13 with supplemental weight loss item 
(EORTC IL118), Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-Fatigue), 
Patient Global Impression of Change (PGIC), Patient Global Impression of Severity (PGIS), and 5-
level EQ-5D (EQ-5D-5L).  
Pharmacodynamics: 
Pharmacodynamics will be assessed using peripheral blood to evaluate potential markers of response 
and resistance, including immune effects. 
Statistical methods: 
Data will be summarized by treatment group. The descriptive summary for the categorical variables 
will include counts and percentages. The descriptive summary for the continuous variables will include 
means, standard deviations, medians, 25% and 75% percentiles, and minimum and maximum values.  
Stratification factors and factors used in statistical models: 
There are two stratification factors for randomization: country and ECOG performance status (0-1 
versus 2). Within each country, patient randomization will be stratified by ECOG performance status 
(0-1 versus 2). A randomization schema will be in place to ensure the best possible balance of 
treatment assignment within each stratum produced by these stratification factors. Countries will be 
grouped into the factor of “region” with 3 components: United States (US), Europe, and Asia. The 
factor “region” will be used instead of “country” in the statistical analysis models to account for 
regional differences in clinical practice.  
Analysis population 
The intent-to-treat (ITT) population includes all randomized patients. Analyses for the ITT population 
will be conducted based on the randomly assigned treatment regardless of whether the patient received 
study treatment or was compliant with the protocol. Unless otherwise specified, the ITT population is 
the primary population for all efficacy analyses. 
The response evaluable (RE) population will include patients in the ITT population who have a 
measurable lesion (target lesions) at the baseline tumor assessment, and either (i) have at least 
1 post-dose tumor assessment, or (ii) do not have post-dose tumor assessment but have clinical 
progression as noted by the Investigator, or (iii) have died due to disease progression before their first 
post-dose tumor scan. RE population will be the primary analysis set to evaluate tumor response and 
the data will be analyzed based on the randomly assigned treatment.  
6


The safety population includes all randomized patients who received at least one dose of study drug. 
Analyses conducted on the safety population will be based on the actual treatment received. All safety 
analyses will be conducted using the safety population. 
The pharmacokinetic (PK) population will include all patients who received at least one dose of study 
drug and had evaluable PK data. 
Statistical analysis methods for primary and secondary endpoints 
Analysis for Primary Endpoint 
The primary endpoint OS is defined as the time (months) from the date of randomization to the date of 
death for patients who died in the study due to any cause, and the time to the last contact date known to 
be alive for those who survived as of the data cutoff date for the interim OS analysis or as of the date 
for the final database lock (censored cases). Patients lacking data beyond the date of randomization 
will have their survival time censored at the date of randomization. The targeted number of deaths for 
the final analysis is 104 and the analysis for OS is event-driven.  
Treatment effect on OS will be primarily evaluated using a stratified log-rank test controlling for the 
stratification factors of region (US, Europe, or Asia), and ECOG performance status (0-1 versus 2). 
Unless otherwise specified, ECOG status information as entered in the Interactive Web Response 
System (IWRS) at the time of randomization will be used as the factor for this and all other stratified 
analyses. The magnitude of the treatment effect, HR (trilaciclib versus placebo), will be estimated 
using a Cox proportional hazard model with the same factors as included in the stratified log-rank test. 
Additionally, the Kaplan-Meier plots will be generated, and the median, 25% and 75% percentile of 
OS will be estimated using the Kaplan-Meier method with their corresponding 95% confidence 
interval calculated based on the method by Brookmeyer and Crowley (1982) for each treatment group. 
The analyses for OS will be performed on the ITT population. 
Interim Analysis for OS 
An interim analysis of OS will be conducted at the 70% information fraction, that is, when 73 deaths 
are observed. The timing of the interim analysis is estimated to be approximately 19 months after the 
first patient is randomized in the study. To perform the interim analysis, the database will be locked. If 
the interim OS analysis result by the stratified log-rank test is positive as determined by the 
pre-specified statistical criterion, the study will be stopped for success and the results from the interim 
OS analyses are considered to be final. If the interim OS analysis result does not meet the criterion of 
success, the study will continue until a total of 104 deaths are observed. At that time, the study 
database will be locked to perform the final OS analysis. It is estimated that it will take approximately 
30 months after the first patient is randomized in the study to reach the total targeted number of deaths 
in this study. 
Analysis for secondary anti-tumor efficacy endpoints 
PFS 
PFS is defined as the time (months) from date of randomization until date of documented radiologic 
disease progression (PD) per RECIST v1.1 or death due to any cause, whichever comes first. For 
patients who do not experience PD or are alive at time of performing the analysis, PFS will be 
calculated per censoring rules detailed in the Statistical Analysis Plan (SAP).  
Per literature, the expected median PFS for patients receiving docetaxel is 3 months (Garon, 2014). 
Assuming trilaciclib can achieve a treatment effect of HR of 0.60, it is estimated that at the time of 
performing the OS interim analysis, 86% of patients would have a radiographic-determined disease 
progression or died. Therefore, the analysis for PFS will be conducted at the time when the OS interim 
analysis is conducted since the PFS events are considered mature. Treatment effect on PFS will be 
evaluated using the stratified log-rank test controlling for the two stratification factors. A Cox 
proportional hazard model with the same terms as in the stratified log-rank test will be used to estimate 
the HR between the 2 treatment groups (trilaciclib versus placebo) for PFS along with its 95% 
7


confidence interval. In addition, the Kaplan-Meier plots will be produced, and the median, 25% and 
75% percentile of PFS will be estimated using the Kaplan-Meier method with their corresponding 95% 
confidence interval calculated based on the method by Brookmeyer and Crowley (1982) for each 
treatment group. PFS will be analyzed on the ITT population. 
Tumor Response 
Objective response is defined as achieving either complete response (CR) or partial response (PR) per 
RECIST v1.1. The ORR along with its exact 95% two-sided confidence interval using the Clopper-
Pearson method will be computed for each treatment group. The treatment effect on ORR will be 
evaluated using a stratified Cochran–Mantel–Haenszel (CMH) method to account for the two 
stratification factors. The adjusted proportion difference (trilaciclib minus placebo) and its 95% 
confidence intervals will be calculated using CMH weight. ORR will be analyzed on the Response 
Evaluable patient population. 
DOR is the time (months) between the date achieving first objective response (CR or PR), confirmed at 
the next tumor scan, and the date of documented disease progression per RECIST v1.1 or death, 
whichever comes first. Patients who do not experience objective CR or PR will not be included in the 
analysis. For patients with objective response who do not reach radiographically determined PD or die 
at the time of analysis, censored time will be calculated following the rules detailed in Section 
12.4.6.2.2. The median, 25% and 75% percentile of DOR will be estimated using the Kaplan-Meier 
method with their corresponding 95% confidence interval calculated based on the method by 
Brookmeyer and Crowley (1982) for each treatment group.  
Analysis for safety endpoints 
Safety and tolerability will be assessed by AEs, dose modifications, laboratory tests, vital signs, and 
ECG. Safety data will be summarized using descriptive statistics by treatment group based on the 
safety population. AEs are defined as those events occurring or worsening after treatment has begun on 
this study. AE data will be coded to system organ class (SOC) and preferred term (PT) using the latest 
version of Medical Dictionary for Regulatory Activities (MedDRA). The severity (toxicity grades 1-5) 
will be summarized by SOC, PT and CTCAE grade, as appropriate. In the tabulation of severity and 
causality for an AE, if the same AE occurs on multiple occasions, the highest grade and strongest 
relationship to study drug will be used. Concomitant medications, as well as prior and subsequent 
anticancer therapies, will be coded to Anatomical Therapeutic Classification (ATC) using the World 
Health Organization-Drug Dictionary (WHO-DD) and summarized by treatment group. 
For laboratory assessments, vital signs, and ECG intervals, observed values and changes from baseline 
will be summarized by treatment group. For serum chemistry AEs will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0 by 
Investigators. AEs overall, AEs related to each study drug, AEs leading to study drug discontinuation 
or dose modifications, and trilaciclib AEs of special interests (AESIs) will be summarized by SOC, PT 
and CTCAE grade, as appropriate. For laboratory assessments, vital signs, and ECG intervals, 
observed values and changes from baseline will be summarized by treatment group. For serum 
chemistry and hematology laboratory parameters, clinical labs will be characterized according to 
CTCAE toxicity grade from 1 to 5, v5.0 when possible, and the number and percentage of patients 
within each CTCAE grade will be summarized for the overall treatment period as well as for each 
cycle. Safety data collected through scheduled or unscheduled visits will all be included in the safety 
evaluation.  
Pharmacokinetic/Pharmacodynamic Analyses 
Analyses may be performed to examine the relationship(s) between exposure to trilaciclib and 
pharmacodynamic endpoints or other efficacy and safety endpoints. 
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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................9 
3. 
LIST OF ABBREVIATIONS .....................................................................................15 
4. 
INTRODUCTION ......................................................................................................21 
4.1. 
Lung Cancer ................................................................................................................21 
4.2. 
Study Rationale ...........................................................................................................22 
4.2.1. 
Rationale for Improving Anti-tumor Efficacy with Trilaciclib ..................................23 
4.2.2. 
Rationale for Immunogenicity of NSCLC Tumor Type and Docetaxel 
Chemotherapy .............................................................................................................25 
4.2.3. 
Rationale for Immune Mechanism of Trilaciclib .......................................................26 
4.2.4. 
Rationale for Trilaciclib following Progression on Immunotherapy ..........................26 
4.2.5. 
Rationale for Myelopreservation ................................................................................27 
4.2.6. 
Rationale for Combination with Docetaxel ................................................................27 
4.2.7. 
Summary of Nonclinical Data ....................................................................................28 
4.2.7.1. 
Pharmacology Studies ................................................................................................28 
4.2.7.2. 
Pharmacokinetic Studies .............................................................................................30 
4.2.8. 
Summary of Clinical Data ..........................................................................................31 
4.2.8.1. 
Trilaciclib ....................................................................................................................31 
4.2.8.2. 
Trilaciclib Risks ..........................................................................................................35 
4.2.8.3. 
Docetaxel ....................................................................................................................37 
4.3. 
Benefit/Risk Assessment ............................................................................................37 
5. 
OBJECTIVES AND ENDPOINTS ............................................................................39 
6. 
INVESTIGATIONAL PLAN .....................................................................................42 
6.1. 
Overall Study Design ..................................................................................................42 
6.2. 
Rationale for Primary and Secondary Endpoints ........................................................43 
6.2.1. 
Anti-tumor Efficacy ....................................................................................................43 
6.2.2. 
Myelopreservation Efficacy ........................................................................................43 
6.2.3. 
Patient-Reported Outcomes ........................................................................................43 
9


6.2.4. 
Safety ..........................................................................................................................44 
6.3. 
Rationale for Dose and Schedule of Study Treatment ................................................44 
6.3.1. 
Trilaciclib ....................................................................................................................44 
6.3.2. 
Docetaxel ....................................................................................................................45 
6.4. 
Rationale for Supportive Care Interventions ..............................................................45 
6.5. 
Rationale for Patient Population .................................................................................45 
6.6. 
Rationale for Stratification Factors .............................................................................45 
7. 
STUDY POPULATION .............................................................................................47 
7.1. 
Inclusion Criteria ........................................................................................................47 
7.2. 
Exclusion Criteria .......................................................................................................48 
8. 
SCHEDULE OF ASSESSMENTS .............................................................................50 
9. 
STUDY TREATMENT ..............................................................................................54 
9.1. 
Study Drugs Administered .........................................................................................54 
9.1.1. 
Dose, Dosing Regimen, and Route .............................................................................54 
9.1.1.1. 
Trilaciclib/Placebo ......................................................................................................54 
9.1.1.2. 
Docetaxel ....................................................................................................................55 
9.1.2. 
Preparation, Handling, Storage, and Accountability ..................................................56 
9.1.3. 
Treatment Compliance ................................................................................................56 
9.2. 
Criteria for Starting Each Cycle .................................................................................56 
9.3. 
Toxicity Management and Dose Modifications .........................................................57 
9.3.1. 
Dose reduction ............................................................................................................57 
9.3.2. 
Safety Criteria for Adjustment or Stopping Doses .....................................................59 
9.3.3. 
Recommended Actions with Trilaciclib/Placebo for Adverse Events of 
Special Interest ............................................................................................................61 
9.3.4. 
Hy’s Law Management ...............................................................................................62 
9.4. 
Supportive Care Interventions ....................................................................................63 
9.4.1. 
Colony Stimulating Factor Usage ...............................................................................63 
9.4.2. 
Erythropoiesis-Stimulating Agent Usage ...................................................................64 
9.4.3. 
Transfusions ................................................................................................................64 
9.5. 
Prior/Concomitant Medications and Procedures ........................................................64 
9.6. 
Measures to Minimize Bias: Randomization and Blinding ........................................65 
9.7. 
Intervention after End of Study Treatment .................................................................66 
10


10. 
DISCONTINUATION OF STUDY INTERVENTION AND PATIENT 
DISCONTINUATION/WITHDRAWAL ..................................................................67 
10.1. 
Discontinuation of Study Treatment ...........................................................................67 
10.2. 
Discontinuation/Withdrawal from the Study ..............................................................67 
10.3. 
Lost to Follow-Up .......................................................................................................68 
10.4. 
Study and Site Start and Closure ................................................................................68 
11. 
STUDY ASSESSMENTS ..........................................................................................70 
11.1. 
Screening Assessments ...............................................................................................70 
11.1.1. 
Randomization ............................................................................................................70 
11.1.2. 
Demographics .............................................................................................................70 
11.1.3. 
Medical History and NSCLC Cancer Disease History ...............................................70 
11.2. 
Anti-tumor Efficacy Assessments ..............................................................................71 
11.2.1. 
Anti-tumor Efficacy Assessment ................................................................................71 
11.2.2. 
Myelopreservation Assessments .................................................................................72 
11.3. 
Safety Assessments .....................................................................................................72 
11.3.1. 
Vital Signs ..................................................................................................................72 
11.3.2. 
Physical Examination .................................................................................................72 
11.3.3. 
ECOG Performance Status .........................................................................................72 
11.3.4. 
Electrocardiogram .......................................................................................................73 
11.3.5. 
Clinical Safety Laboratory Assessments ....................................................................73 
11.3.6. 
Adverse and Serious Adverse Events .........................................................................74 
11.3.6.1. 
Time Period and Frequency for Collecting Adverse and Serious Adverse 
Event Information .......................................................................................................74 
11.3.6.2. 
Method of Detecting Adverse and Serious Adverse Events .......................................75 
11.3.6.3. 
Follow-up of Adverse and Serious Adverse Events ...................................................75 
11.3.6.4. 
Regulatory Reporting Requirements for Serious Adverse Events .............................75 
11.3.6.5. 
Pregnancy ...................................................................................................................75 
11.4. 
Patient-Reported Outcomes ........................................................................................76 
11.4.1. 
EORTC QLQ-C30 and EORTC QLQ-LC13 .............................................................76 
11.4.2. 
FACIT-Fatigue ...........................................................................................................76 
11.4.3. 
Patient Global Impression of Change and Patient Global Impression of 
Severity .......................................................................................................................77 
11.4.4. 
5-Level EQ-5D ...........................................................................................................77 
11


11.5. 
Pharmacokinetics ........................................................................................................77 
11.6. 
Biomarkers ..................................................................................................................78 
11.6.1. 
Rationale for Archival Tumor Collection ...................................................................78 
11.6.2. 
Description of CDK4/6 Signature ..............................................................................78 
11.7. 
Immunologic and Hematologic Markers ....................................................................79 
11.8. 
Data Monitoring Committee .......................................................................................79 
11.10. 
Survival Follow-up Phase ...........................................................................................80 
12. 
STATISTICAL CONSIDERATIONS .......................................................................81 
12.1. 
Sample Size Determination ........................................................................................81 
12.2. 
Analysis Population ....................................................................................................81 
12.3. 
Timing of Planned Analysis .......................................................................................81 
12.3.1. 
First Planned Analysis – Interim Analysis for Overall Survival and Analyses 
for Progression Free Survival, Tumor Responses and Myelosuppression 
Endpoints ....................................................................................................................81 
12.3.2. 
Second Planed Analysis – Final Analysis for Overall Survival and Safety 
Data Analyses .............................................................................................................82 
12.4. 
Statistical Analysis Methods .......................................................................................82 
12.4.1. 
General Considerations ...............................................................................................82 
12.4.2. 
Patient Disposition ......................................................................................................83 
12.4.3. 
Demographic and Baseline Characteristics ................................................................83 
12.4.4. 
Prior and Subsequent Anticancer Therapies ...............................................................83 
12.4.5. 
Study Drug Exposure, Modification and Dose Intensity ............................................83 
12.4.6. 
Efficacy Analyses .......................................................................................................84 
12.4.6.1. 
Analyses of Primary Efficacy Endpoint – Overall Survival .......................................84 
12.4.6.2. 
Analysis for Secondary Anti-tumor Efficacy Endpoints ............................................85 
12.4.6.3. 
Analysis for Myelosuppression Endpoints .................................................................87 
12.4.6.4. 
Subgroup Analysis for Primary Efficacy Endpoint ....................................................88 
12.4.7. 
PRO Analyses .............................................................................................................88 
12.4.8. 
Safety Analyses ..........................................................................................................88 
12.4.8.1. 
Adverse Events ...........................................................................................................88 
12.4.8.2. 
Other Safety Endpoints ...............................................................................................89 
 
 ..................................................................................................89 
12.4.10. 
Pharmacokinetic Analyses ..........................................................................................89 
12


12.4.11. 
Pharmacokinetic/Pharmacodynamic Analyses ...........................................................90 
13. 
ETHICS ......................................................................................................................91 
13.1. 
Ethics Review .............................................................................................................91 
13.2. 
Ethical Conduct of the Study ......................................................................................91 
13.3. 
Written Informed Consent ..........................................................................................91 
14. 
DATA HANDLING AND RECORDKEEPING .......................................................92 
14.1. 
Data Protection ...........................................................................................................92 
14.2. 
Data Quality Assurance ..............................................................................................92 
14.3. 
Dissemination of Clinical Study Data ........................................................................93 
14.4. 
Source Documents ......................................................................................................93 
14.5. 
Audits and Inspections ................................................................................................93 
15. 
PUBLICATION POLICY ..........................................................................................94 
16. 
REFERENCES ...........................................................................................................95 
17. 
APPENDICES ..........................................................................................................105 
17.1. 
Clinical Laboratory Tests .........................................................................................105 
17.2. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .........................................................................................106 
17.2.1. 
Definition of AE .......................................................................................................106 
17.2.2. 
Definition of SAE .....................................................................................................107 
17.2.3. 
Recording and Follow-Up of AE and/or SAE ..........................................................108 
17.2.4. 
Reporting of SAEs ....................................................................................................110 
17.3. 
Contraceptive Guidance and Collection of Pregnancy Information .........................111 
17.4. 
Definitions of Tumor Response and Disease Progression (per RECIST v1.1) ........114 
 
LIST OF TABLES 
Table 1: 
Abbreviations ..............................................................................................................15 
Table 2: 
Integrated Analysis for Myelopreservation Efficacy in SCLC 
(Studies G1T28-02, G1T28-03, and G1T28-05) ........................................................32 
Table 3: 
G1T28-04: Summary of Overall Survival and Progression-Free Survival 
(ITT Analysis Set) ......................................................................................................33 
Table 4: 
G1T28-04: Tumor Response According to PD-L1 Status ..........................................34 
Table 5: 
Objectives and Endpoints ...........................................................................................39 
Table 6: 
Schedule of Assessments ............................................................................................51 
13


Table 7: 
Study Drugs ................................................................................................................54 
Table 8: 
Recommended Chemotherapy Dose Modifications ...................................................57 
Table 9: 
Recommended Dose Modification for Drug-Related Hematologic Toxicity .............59 
Table 10: Recommended Actions with Trilaciclib/Placebo Following AESIs ..........................61 
Table 11: Patient Risk Factors for Poor Clinical Outcomes Resulting from Febrile 
Neutropenia or Infection .............................................................................................64 
Table 12: ECOG Performance Status .........................................................................................73 
Table 13: Thresholds for Claiming Statistical Superiority (Trilaciclib versus Placebo) 
at Interim or Final Analysis for Overall Survival .......................................................85 
Table 14: Protocol-Specified Safety Laboratory Assessments .................................................105 
 
LIST OF FIGURES 
Figure 1: 
Trilaciclib Transiently Arrests Normal Cells to Prevent 
Chemotherapy-Induced Myelosuppression and Improve Anti-Tumor 
Efficacy .......................................................................................................................23 
Figure 2: 
G1T28-04: Overall Survival – Kaplan-Meier Curve (ITT Analysis Set) ...................24 
Figure 3: 
The Addition of Trilaciclib to Chemotherapy/Immune Checkpoint Inhibitor 
Treatment Enhances Efficacy Through T Cell Activation .........................................29 
Figure 4: 
Study Design ...............................................................................................................42 
 
  
14


3. 
LIST OF ABBREVIATIONS  
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations  
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
AE 
adverse event 
AESI 
adverse event of special interest 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
aPTT 
activated partial thromboplastin time 
aRR 
adjusted relative risk 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
AUC 
area under the concentration-time curve 
BCRP 
breast cancer resistance protein  
BED 
biologically effective dose 
β-hCG 
beta human chorionic gonadotropin  
BICR 
blinded independent central review 
BMI 
body mass index 
BOR 
best overall response 
BSA 
body surface area 
BSEP 
bile salt export pump  
CAP 
College of American Pathologists 
CBC 
complete blood count 
CD 
cluster of differentiation 
CDK 
cyclin-dependent kinase  
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIM 
chemotherapy-induced myelosuppression 
15


Abbreviation 
Definition 
CMH 
Cochran-Mantel-Haenszel 
CNS 
central nervous system 
CPS 
combined positive score 
CR 
complete response 
CT 
computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte associated protein 4 
CYP 
cytochrome P450 
D5W 
dextrose 5% in water 
DC 
dendritic cell 
DCAF 
d-type cyclin activating features 
DDI 
drug-drug interaction 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DOR 
duration of objective response 
DSN 
duration of sever neutropenia 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EMA 
European Medicines Agency 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality of Life 
Core Questionnaire 
EORTC QLQ-LC13 
European Organisation for Research and Treatment of Cancer Quality of Life 
Lung Cancer Module 
EORTC IL118 
European Organisation for Research and Treatment of Cancer Quality of Life 
Lung Cancer Module with supplemental weight loss item  
EOT 
End of Treatment 
E/P 
etoposide plus carboplatin 
E/P/A 
cisplatin, etoposide and atezolizumab 
ES-SCLC 
extensive stage SCLC 
EQ-5D-5L 
5-level EQ-5D 
16


Abbreviation 
Definition 
EQ-VAS 
EQ visual analogue scale 
ER 
estrogen receptor 
ESA 
erythropoiesis stimulating agent 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy - Fatigue 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FN 
febrile neutropenia 
FSH 
follicle stimulating hormone 
G1 
gap 1 phase of the cell cycle 
G2 
gap 2 phase of the cell cycle 
G1T28 
trilaciclib; formerly G1T28-1 
GC 
gemcitabine and carboplatin 
GC therapy 
gemcitabine and carboplatin on Days 1 and 8 of 21-day cycles 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GI 
gastrointestinal 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRT 
hormone replacement therapy 
HSPC 
hematopoietic stem and progenitor cell 
IB 
Investigator’s Brochure 
IC 
tumor-infiltrating immune cells 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICI 
immune checkpoint inhibitors 
IEC 
independent ethics committee  
17


Abbreviation 
Definition 
IFN 
interferon 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
INR 
International Normalized Ratio 
IP 
intraperitoneal 
IRB 
institutional review board 
ISH 
in situ hybridization 
ITT 
intent-to-treat 
IV 
intravenous 
IWRS 
Interactive Web Response System 
Ki 
inhibition constant 
LFT 
liver function test 
M 
mitosis 
mAb 
monoclonal antibody 
MATE1 or 2-K 
multidrug and toxin extrusion 1 or 2-K  
MDR1 
p-glycoprotein  
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
major histocompatibility complex 
MOA 
mechanism of action 
MRI 
magnetic resonance imaging 
MRP1 or 2 
multidrug resistance protein 1 or 2 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
not evaluable 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
OAT1 or 3 
organic anion transporter 1 or 3  
OATP1B1 or 1B3 
organic anion transporting polypeptide 1B1 or 1B3  
OCT1 or 2  
organic cation transporter 1 or 2 
ORR 
objective response rate 
OS 
overall survival 
18


Abbreviation 
Definition 
PCS 
potentially clinically significant 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 
PDX 
patient derived xenografts 
PFS 
progression-free survival 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PK 
pharmacokinetic(s) 
PR 
partial response 
PRO 
patient-reported outcome 
PSA 
prostate-specific antigen 
PT 
preferred term 
PTFE 
polytetrafluorethylene 
PVG 
pharmacovigilance 
QTcF 
QT corrected using Fridericia’s formula 
Rb 
retinoblastoma protein 
RB 
retinoblastoma gene 
RBC 
red blood cell 
RE 
Response Evaluable 
RECIST 
Response Evaluation Criteria in Solid Tumors  
ROS1 
c-ROS oncogene 1 
RP2D 
recommended Phase 2 dose 
S 
synthesis phase of the cell cycle 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCLC 
small cell lung cancer 
SD 
stable disease 
SOC 
system organ class 
SN 
severe neutropenia 
SUSAR 
suspected unexpected serious adverse reactions 
19


Abbreviation 
Definition 
TCR 
T cell receptor 
TEAE 
treatment-emergent adverse event 
TIM3 
T-cell immunoglobulin and mucin domain 3 
TNBC 
triple-negative breast cancer 
Treg 
regulatory T cells 
TTCD-fatigue 
Time to confirmed deterioration of fatigue 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog scale 
WHO-DD 
World Health Organization Drug Dictionary 
20


4. 
INTRODUCTION 
4.1. 
Lung Cancer  
Worldwide, there were more than 2 million cases of lung cancer and 1.75 million lung cancer 
related deaths in 2018 (WHO, 2020). The American Cancer Society estimates that in 2020, 
~135,000 of those lung cancer deaths will occur in the US alone 
(American Cancer Society, 2020). Approximately 84% of these patients will be diagnosed with 
non-small cell lung cancer (NSCLC) and almost 70% will present with locally advanced or 
metastatic disease (ASCO, 2020; Little, 2007). Historically, treatment in the metastatic setting 
has been driven almost exclusively by the use of systemic chemotherapy. However, in the last 
ten to twenty years, a greater understanding of the pathways that dictate tumor response and the 
advent of multiple targeted therapies has changed the landscape of treatment options 
significantly. Lung tumors are routinely tested for the presence of specific driver mutations 
(e.g., epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], BRAF, and 
cROS- oncogene 1 [ROS1]), that predict a favorable response to targeted tyrosine kinase 
inhibitors (Kalemkerian, 2018). As many as 50% to 64% of patients have been identified as 
having a targetable genetic alteration and those that receive treatment have better outcomes 
(Kris, 2014; Barlesi, 2016).  
For those patients without a targetable genetic alteration, treatment options have also changed 
considerably. Though systemic therapy remains an important component of treatment in this 
context, the advent of immunotherapy has significantly improved outcomes for this patient 
population. Multiple randomized trials, in both squamous and non-squamous histologies, have 
established that overall survival (OS) is improved with the addition of programmed cell death 
protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) inhibitors (Spigel, 2019; Reck, 2016; 
Gandhi, 2018; Paz-Ares, 2018). Those with high levels of PD-L1 expression typically receive 
pembrolizumab or atezolizumab monotherapy in the first line followed by platinum-based 
chemotherapy in order to maximize treatment response and minimize toxicity. Those with a 
higher burden of disease requiring more aggressive initial treatment or with lower levels of 
PD-L1 expression typically receive immunotherapy in combination with a platinum-based 
chemotherapy doublet.  
Despite these improvements in the therapy for metastatic NSCLC, the majority of patients 
ultimately progress during or after treatment with immunotherapy and platinum-based 
chemotherapy. Management of this pretreated patient population is challenging and treatment 
options are limited to single agent chemotherapies such as docetaxel, pemetrexed (for those with 
non-squamous histology), and gemcitabine (Shepherd, 2000; Fossella, 2010; Gridelli, 2004; 
Hanna, 2004; Anderson, 2000). The clinical trials that established these treatment options 
predated immunotherapies and robust data for individual agents is often lacking. The high-level 
evidence that does exist demonstrates a limited impact of 2nd line therapy on treatment outcomes. 
For example, in a study where 1,253 patients were treated with docetaxel plus or minus the 
VEGFR2 inhibitor ramucirumab following progression on platinum-based- chemotherapy, 
survival was significantly improved with the addition of ramucirumab, but the clinical benefit 
was only 1.5 months (hazard ratio [HR] 0.86, p=0.023) (Garon, 2014).  
In contrast, the large Phase 3 studies evaluating the addition of immunotherapy in the first line 
consistently demonstrated large treatment effects (HRs ~0.5-0.6) that were both statistically 
21


significant and highly clinically meaningful (Spigel, 2019; Reck, 2016; Gandhi, 2018; 
Paz-Ares, 2018). In an effort to translate these early successes to later lines of therapy, numerous 
ongoing Phase 3 studies are evaluating the continuation of PD-1/PD-L1 inhibitors (following 
progression on the same) in combination with kinase inhibitors hypothesized to synergistically 
illicit an ongoing immune response. However, the mechanisms of immune checkpoint inhibitor 
(ICI) resistance are complex and include genetic, epigenetic, and cellular signaling alterations 
that dysregulate neoantigen presentation/processing and disrupt cytotoxic T cells activity as well 
as mechanisms in which non-cancerous stromal or immune cells promote growth and resistance 
to ICIs (Liu, 2019; Barrueto, 2020; Jenkins, 2018; Fares, 2019; Borcherding, 2018; Gidel, 2018). 
Novel therapies, whose mechanisms broadly target these ICI mechanisms of resistance, 
including CDK4/6 inhibition, could be particularly valuable following disease progression on 
currently clinically available immunotherapies.  
In addition to the need for therapies that more effectively extend overall survival, patients treated 
in the metastatic setting are particularly vulnerable to the chemotherapy-induced 
myelosuppression (CIM) and health-related quality of life impacts associated with extensive 
systemic therapy. CIM is a significant issue in cancer treatment; patients with myelosuppression 
are more likely to experience infections, sepsis, bleeding, and fatigue, often leading to the need 
for hospitalizations, hematopoietic growth factor support, transfusions (red blood cells [RBCs] 
and/or platelets) and even death (Caggiano, 2005; Gustinetti, 2016; Bodey, 1966; Li, 2016). 
Moreover, CIM commonly leads to dose reductions and delays, which limit therapeutic dose 
intensity and can compromise the anti-tumor efficacy benefits of chemotherapy. Furthermore, 
existing supportive care interventions for CIM are generally used after the onset of symptoms, 
only address the deficiency of a single blood cell lineage and carry their own set of risks and 
limitations. Introducing a therapy that can protect the hematopoietic stem and progenitor cells 
(HSPCs) of the host from CIM has the potential to maximize the anti-tumor activity of the 
chemotherapy while minimizing the consequences to the patient of chemotherapy-induced 
cellular damage. 
In summary, though immunotherapy has markedly improved the treatment of metastatic NSCLC, 
options following disease progression on these therapies remain limited. An alternative therapy 
that extends the duration of OS without significant additive toxicity, while concurrently 
decreasing myelosuppression and improving quality of life, would be a welcome addition in this 
heavily pretreated and often clinically fragile patient population. Therefore, further evaluation of 
trilaciclib in this area of high unmet medical need is warranted. 
4.2. 
Study Rationale 
Trilaciclib is a highly potent and selective, reversible, cyclin-dependent kinase (CDK) 4/6 
inhibitor that preserves HSPCs as well as immune system function during chemotherapy 
(myelopreservation) in addition to directly enhancing anti-tumor immunity (anti-cancer efficacy) 
(Figure 1). Both HSPC and lymphocyte proliferation are dependent on CDK4/6 activity 
(Kozar, 2004; Malumbres, 2004; Ramsey, 2007; Horsley, 2008) and become arrested in the 
gap 1 (G1) phase of the cell cycle upon exposure to trilaciclib (He, 2017). This trilaciclib-induced 
transient cell cycle arrest has been demonstrated to provide resistance to chemotherapy-induced 
cell damage by preventing HSPCs from proliferating in the presence of cytotoxic chemotherapy 
and favorably altering the tumor immune microenvironment through transient T-cell inhibition 
22


when combined with chemotherapy and ICIs (He, 2017; Bisi, 2016; Lai, 2020). In February 
2021, the FDA approved trilaciclib (COSELA™) as a treatment to decrease the incidence of 
chemotherapy-induced myelosuppression in adult patients when administered prior to a 
platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage 
small cell lung cancer (ES-SCLC). 
Figure 1: 
Trilaciclib Transiently Arrests Normal Cells to Prevent 
Chemotherapy-Induced Myelosuppression and Improve Anti-Tumor 
Efficacy 
4.2.1. 
Rationale for Improving Anti-tumor Efficacy with Trilaciclib 
The use of trilaciclib for patients with triple-negative breast cancer (TNBC) was evaluated in 
Study G1T28-04, a global, multicenter, randomized, open-label, Phase 2 clinical trial to evaluate 
the safety, efficacy, and pharmacokinetics (PK) of trilaciclib administered prior to 
gemcitabine/carboplatin (GC) therapy for patients with locally advanced unresectable/metastatic 
TNBC who had previously been treated with 0 to 2 lines of therapy in the metastatic setting. 
Patients were randomized 1:1:1 to one of two different trilaciclib + GC treatment regimens or 
GC alone. Based on its mechanism of action (MOA), it was hypothesized that trilaciclib 
administered before chemotherapy could protect the bone marrow from the cytotoxic effects of 
chemotherapy, while also enhancing immune activity in patients with TNBC, thus potentially 
improving both safety and anti-tumor activity.  
The G1T28-04 study was the first evaluation of trilaciclib in a tumor type other than small cell 
lung cancer (SCLC), where trilaciclib development has focused on myelopreservation benefits 
(Section 4.2.8.1). Three randomized, double-blind, Phase 2 clinical trials (G1T28-02, G1T28-03 
and G1T28-05) evaluating trilaciclib/placebo administered prior to chemotherapy in patients 
23


with SCLC have demonstrated in a variety of clinical settings (first-, second-, third-line SCLC 
treated with several different classes of chemotherapy) that trilaciclib can prevent 
chemotherapy -induced myelosuppression as measured by multiple endpoints (Section 4.2.8.1; 
Table 2; Weiss, 2019; Hart, 2019; Daniel, 2019). While the benefit in chemotherapy-induced 
myelosuppression in these studies was striking, these myelopreservation benefits were observed 
in the setting of only minor improvements in progression-free survival (PFS) and OS as 
evidenced by HRs <1.0 in almost all clinical settings for trilaciclib compared with placebo. 
In contrast to the previously observed SCLC results, the addition of trilaciclib to chemotherapy 
for patients with TNBC in G1T28-04 did not result in statistically significant improvements in 
myelosuppression endpoints, but instead resulted in a substantial improvement in anti-tumor 
efficacy as measured by OS (median OS duration in control: 12.6 months versus not evaluable or 
17.8 months in the two trilaciclib groups, HR: 0.31 [p=0.0016] and HR: 0.40 [p=0.0004], 
respectively; Figure 2) and by PFS (median PFS in control 5.7 months versus 9.4 months or 
7.3 months in the two trilaciclib groups HR: 0.65 and 0.57, respectively; not statistically 
significant) (O’Shaughnessy, 2020; Tan, 2019). The clinically meaningful anti-tumor efficacy 
results observed in G1T28-04 were noted across both of the trilaciclib treatment groups and in 
the context of a control group with survival reflective of published literature.  
Figure 2: 
G1T28-04: Overall Survival – Kaplan-Meier Curve (ITT Analysis Set) 
 
CI=confidence interval; HR=hazard ratio; ITT=intent-to-treat; NR=not reached. 
Group 1: GC administered on Days 1 and 8 of 21-day cycles; Group 2: Trilaciclib and GC administered on Days 1 
and 8 of 21-day cycles; Group 3: Trilaciclib administered on Days 1, 2, 8, and 9 and GC administered on Days 2 
and 9 of 21-day cycles 
Note: The HR and its 95% CI comparing Group 1 and 2 and Group 1 and 3 were calculated using the Cox regression 
model with treatment and stratification factors of number of prior lines of therapy (0 versus 1 or 2) and liver 
involvement. 
Note: P-values comparing Group 1 and 2 and Group 1 and 3 were calculated using the stratified log-rank test to 
account for the number of prior lines of therapy (0 versus 1 or 2) and liver involvement as the stratification factors.  
Note: data generated from final database. 
24


The impact on OS was consistent across subgroups, including predictors of immune response. 
Approximately 57.6% of the available tumor samples in G1T28-04 were considered PD-L1 
positive (Ventana SP142 assay), and though larger in the PD-L1 positive population, the benefit 
of adding trilaciclib extended to both PD-L1 positive and negative cohorts (Table 4).  
The translation of these anti-tumor efficacy findings to other tumor types is predicted to be 
primarily driven by the tumor type, chemotherapy type and host, i.e., (1) the tumor must be 
sufficiently immunogenic and sensitive to the host cytolytic efforts as to see improvement in 
anti-tumor endpoints like OS, (2) the chemotherapy should promote immune activation, and (3) 
the host must be able to mount an effective cytolytic response against the tumor. In the SCLC 
trials, the addition of trilaciclib to the standard of care therapies provided modest improvement, 
to neutral effects, on measures of anti-tumor efficacy including objective response rate (ORR), 
PFS and OS. These results are not surprising considering that SCLC is one of the most 
aggressive solid tumors and is not particularly immunogenic or sensitive to immune modulation 
(Wang, 2019).  
In contrast, NSCLC has been extensively documented as sensitive to immune modulation with 
multiple established immunotherapy treatment options in the early lines of treatment for 
metastatic NSCLC (Spigel, 2019; Wang, 2019; Reck, 2016; Gandhi, 2018; Paz-Ares, 2018). This 
highly responsive NSCLC immune milieu and the novel trilaciclib immune activating effects 
described below provide a strong rationale to evaluate the efficacy of trilaciclib in patients with 
previously treated NSCLC.  
4.2.2. 
Rationale for Immunogenicity of NSCLC Tumor Type and Docetaxel 
Chemotherapy  
While NSCLC has been recognized as having an immunosuppressive tumor microenvironment 
through high numbers of regulatory T cells (Treg) directly inhibiting T-cell proliferation 
(Woo, 2001; Woo, 2002), tumor-infiltrating cluster of differentiation (CD)8+ T cells with 
increased PD-1 expression (Zhang, 2010), and downregulation of major histocompatibility 
complex (MHC) class I/tumor antigen expression (Korkolopoulou, 1996), results from numerous 
trials evaluating immunotherapeutic agents, including immune checkpoint inhibitors, have 
demonstrated the efficacy of this approach in NSCLC (Spigel, 2019; Reck, 2016; Gandhi, 2018; 
Paz-Ares, 2018). 
A number of immune correlates of clinical outcome in patients with NSCLC have been identified 
providing clinical evidence for immune system involvement in NSCLC. High levels of 
infiltrating CD8+, CD4+, CD3+ T cells as well as higher densities of mature dendritic cells (DCs) 
have been associated with improved survival (Wing, 2008; Chen, 2012). Conversely, the number 
of Treg cells as well as PD-L1 expression in NSCLC tumors have been shown to be independent 
predictors of reduced survival or unfavorable prognosis in patients with NSCLC, respectively 
(Petersen, 2006; Shimizu, 2010; Mu, 2011). 
In addition to the inherent immunogenicity associated with NSCLC, docetaxel has demonstrated 
an ability to enhance the sensitivity of tumors to immune-mediated cell death (Hodge, 2013). In 
particular, immune modulating effects on the tumor stroma have been noted (Opzoomer, 2019). 
In vivo, docetaxel has been shown to induce selective cell death in myeloid-derived suppressor 
cells known to contribute to immune suppression while simultaneously promoting differentiation 
of this cell type towards a pro-inflammatory phenotype (Kodumudi, 2010). Lastly, docetaxel has 
25


been shown to decrease Treg cells in patients with non-small cell lung cancer (Li, 2014). Taken 
together, these data suggest docetaxel may lead to immune activation in NSCLC and further the 
potential benefit of trilaciclib. 
4.2.3. 
Rationale for Immune Mechanism of Trilaciclib 
In the G1T28-05 study evaluating trilaciclib prior to cisplatin, etoposide, and atezolizumab 
(E/P/A) in patients with ES-SCLC, flow cytometry and T cell receptor (TCR) 
immunosequencing data revealed that patients receiving trilaciclib had an increased ratio of total 
and activated CD8+ T cells to Tregs and increased peripheral T-cell clonal expansion suggesting 
enhanced T-cell activation. Furthermore, there was significant enhancement in newly detected 
expanded clones among patients receiving trilaciclib compared with placebo, which was stronger 
among patients with an anti-tumor response to E/P/A, suggesting that trilaciclib may enhance 
tumor antigen presentation, a phenomenon that has been observed in preclinical studies with 
other CDK4/6 inhibitors (Daniel, 2020).  
These observations are consistent with those from the G1T28-02 Phase 2 study of patients with 
ES-SCLC receiving trilaciclib prior to etoposide plus carboplatin (E/P). In G1T28-02, a higher 
proportion of activated or effector CD8+ and CD4+ T cells was observed in patients receiving 
trilaciclib compared with placebo. In addition, high levels of T-cell clonal expansion were 
associated with improved PFS and numerically longer median OS. Taken together, the data 
suggest that the addition of trilaciclib at least preserves, if not enhances, T-cell function during 
treatment with E/P or E/P/A (Lai 2020). 
Lastly, to evaluate the effect of trilaciclib on T cell activation in G1T28-04, peripheral blood was 
collected and the TCR was evaluated. Simpson clonality decreased over time in patients that 
received trilaciclib in addition to GC when compared to GC alone. Furthermore, when patients 
were stratified above or below median Simpson clonality at baseline, there was an improvement 
among patients receiving trilaciclib. In addition to a decrease in Simpson clonality, responders 
receiving trilaciclib prior to GC had more newly detected expanded T-cell clones compared with 
responders receiving GC alone. These data suggest trilaciclib enhances anti-tumor immunity 
through T cell activation leading to an anti-tumor response (O’Shaughnessy, 2020).  
Taken together these data from clinical trials evaluating trilaciclib in a variety of clinical 
contexts, suggest that trilaciclib has a consistent positive impact on anti-tumor immune 
modulation. Further, there appear to be several immune based mechanisms through which this 
effect can be mediated including neoantigen presentation and T cell activation and function. 
4.2.4. 
Rationale for Trilaciclib following Progression on Immunotherapy 
Interestingly, many of the mechanisms to overcome ICI-induced resistance have been associated 
with the immune activating effects of CDK4/6 inhibition, including increasing antigen 
presentation (MHC class I), enhancing T cell clonality and tumor infiltration, inhibiting 
regulatory T cell proliferation, decreasing T cell exhaustion markers (PD-1, cytotoxic 
T-lymphocyte associated protein 4 [CTLA-4], and T-cell immunoglobulin and mucin domain 3 
[TIM3]), stabilizing expression of PD-L1 on tumor cells, promoting dendritic cell migration, and 
increasing T effector cell function through high interferon [IFN] gamma production 
(Chaikovsky and Sage, 2018; Deng, 2018; Goel, 2017; Schaer, 2018; Lai, 2020; Bonelli, 2019; 
Teh and Aplin, 2019).  
26


Multiple ongoing trials in this setting, i.e., following disease progression on platinum-based 
chemotherapy and immunotherapy, are evaluating additional checkpoint inhibitor therapy, but in 
combination with a partner hypothesized to promote an ongoing immune response. However, as 
described above, multiple mechanisms of resistance can develop following treatment with 
immunotherapy and novel agents that exploit multiple or alternative pathways may be preferred. 
In addition to documented anti-tumor immune modulating effects alone and in combination with 
checkpoint inhibitors, trilaciclib has translated these effects to improved survival in the TNBC 
setting and belongs to a class of agents with a diverse repertoire of immune-modulating effects. 
Overall, these data suggest that patients may benefit from trilaciclib after progressing on ICI 
treatment. 
4.2.5. 
Rationale for Myelopreservation 
Trilaciclib has shown well-documented improvement in myelosuppression outcomes that could 
provide a substantial benefit to patients receiving docetaxel. In the REVEL trial, 39% of patients 
receiving docetaxel alone experienced grade 3 or greater neutropenia with 10% experiencing 
febrile neutropenia (FN) (Garon, 2014). In addition, 6% of patients experienced Grade 3 or 
greater anemia. Patients treated for SCLC with trilaciclib had marked reductions in the 
occurrence of these endpoints, required less supportive care, and experienced enhanced quality 
of life (Table 2). 
4.2.6. 
Rationale for Combination with Docetaxel 
Following progression on chemotherapy and immunotherapy, single-agent chemotherapy is the 
most common standard of care. As there is limited high-quality data for any specific agent in the 
modern era, several options can be utilized. However, single-agent docetaxel, with activity in 
both squamous and non-squamous histologies, is commonly utilized in clinical practice and as 
the reference standard in metastatic NSCLC clinical trials.  
Ramucirumab in combination with docetaxel is also approved for the treatment of metastatic 
NSCLC following disease progression on or after platinum-based chemotherapy. This approval 
was based on a Phase 3 study that revealed a 1.5-month improvement in survival with the 
addition of ramucirumab. However, the rate of grade 3 or greater treatment-emergent adverse 
events increased from 71% to 79%. Furthermore, this small benefit occurred prior to the 
widespread use of immunotherapy. It is unclear if the same benefit would be seen in patients 
treated with today’s standard of care. As a result, National Comprehensive Cancer Network 
(NCCN) guidelines list both the combination and docetaxel alone as potential treatment options 
in this clinical setting and utilization is at the discretion of the individual provider. Because there 
are no mature data available evaluating the combination of trilaciclib and a taxane containing 
regimen, the risks of also incorporating ramucirumab were felt to outweigh the small associated 
benefits.  
Trilaciclib has been successfully combined at the recommended Phase 2 dose with most major 
chemotherapy classes other than microtubule inhibitors. In three randomized, controlled, Phase 2 
studies in SCLC patients, the combination resulted in consistent improvements in chemotherapy-
induced myelosuppression across multiple lineages. Even in the TNBC trial where the addition 
of trilaciclib to gemcitabine/carboplatin did not improve neutropenia-based myelopreservation 
endpoints, rates of adverse events were comparable despite patients on trilaciclib receiving 
almost double the number of chemotherapy cycles. There is no evidence to suggest that a 
27


different result would be expected from the combination of trilaciclib with taxane based 
chemotherapy.  
Preclinical in vivo studies evaluating trilaciclib in combination with paclitaxel or docetaxel 
utilizing a clinically relevant dose administration schedule support the safety of this combination. 
In addition, there are at least 4 clinical studies combining chronically dosed oral CDK4/6 
inhibitors (palbociclib, ribociclib) with taxane-based chemotherapy. Two of those studies have 
reported acceptable early safety results in combination with standard clinical doses of paclitaxel 
and docetaxel (Lewis, 2018; Clark, 2019). In both of these studies, patients received multiple 
doses of oral CDK4/6 inhibitors (known to cause neutropenia). In contrast, trilaciclib is an IV 
CDK4/6 inhibitor dosed only prior to chemotherapy. Finally, trilaciclib is being evaluated in an 
ongoing Phase 2 study in combination with paclitaxel in the neoadjuvant breast cancer setting. 
4.2.7. 
Summary of Nonclinical Data 
A summary of the trilaciclib nonclinical data is presented in the trilaciclib Investigator’s 
Brochure (IB).  
Nonclinical data related to docetaxel are provided in the local prescribing information. 
4.2.7.1. 
Pharmacology Studies 
Through a structure-based design approach to optimize potency, selectivity, and drug 
metabolism and PK properties, G1 Therapeutics, Inc. identified trilaciclib as a highly potent 
inhibitor of CDK4 and CDK6 (half maximal inhibitory concentration [IC50] values of 1 nM and 
4 nM, respectively) that is highly selective for CDK4/Cyclin D1 versus cyclin-dependent kinase 
2 (CDK2)/Cyclin E (>2500-fold selectivity). Trilaciclib also demonstrated reversible inhibition 
of CDK4/Cyclin D1, with an inhibition constant (Ki) value of 0.78 nM. 
The trilaciclib-induced G1 arrest of HSPCs has been shown to be transient and readily reversible 
in both in vitro and in vivo models. In vivo analysis has demonstrated that trilaciclib administered 
prior to myelosuppressive chemotherapy leads to improved complete blood count (CBC) 
recovery of all blood lineages and increased survival. Specifically, in a model using the 
chemotherapy 5-fluorouracil (5-FU) that is highly myelosuppressive in mice, the extent and 
duration of nadir in CBCs worsened after each cycle of 5-FU administered alone. Trilaciclib 
administered prior to 5-FU ameliorated this worsening effect and the animals that received 
trilaciclib + 5-FU demonstrated a faster rate of recovery of CBCs compared with the 5-FU alone 
group following Cycle 4 (He, 2017).  
Preclinical data has also shown that trilaciclib enhances immune activation and promotes anti-
tumor immunity by differentially arresting cytotoxic and regulatory T-cell subsets followed by a 
faster recovery in cytotoxic T lymphocytes than in regulatory T cells in tumors. Specifically, the 
addition of trilaciclib to various chemotherapy/ICI treatment combinations resulted in enhanced 
tumor growth delay and durability of the antitumor response. Trilaciclib favorably modulated the 
proliferation of T-cell subsets in the tumor microenvironment, consistent with an enhanced 
cytotoxic T-cell response (Figure 3; Lai, 2020). This differential alteration of cell cycle kinetics 
between cytotoxic T lymphocytes and regulatory T cells results in a higher proportion of 
cytotoxic T lymphocytes than regulatory T cells, enhancement of T-cell activation, and a 
decrease in regulatory T cell-mediated immunosuppressive functions 
(Chaikovsky and Sage, 2018; Deng, 2018; Goel, 2017; Schaer, 2018). Together, these events 
28


promote the cytotoxic T lymphocyte-mediated clearance of tumor cells. Therefore, these data 
support the hypothesis that trilaciclib-mediated transient proliferative arrest of T cells (protecting 
them from chemotherapy-induced damage), followed by activation of cytotoxic T lymphocytes 
in the context of fewer regulatory T cells led to the anti-tumor response observed.  
Figure 3: 
The Addition of Trilaciclib to Chemotherapy/Immune Checkpoint Inhibitor 
Treatment Enhances Efficacy Through T Cell Activation 
 
 
(Upper right and upper left) Addition of trilaciclib to oxaliplatin and αPD-L1/ αPD-1combination therapy led to 
enhanced anti-tumor activity and durability of response in the MC38 tumor model (n=10–15 per treatment group). 
(Lower left) Transient G1 arrest led to changes in the proportion of intra-tumor T-cell subsets favoring effector T-
cell function as measured by the ratio of CD8+ T cells to Tregs (% CD8+ T cells / % Tregs) in the CD45+ population 
(n=5–8 tumors analyzed per treatment group and time point). (Lower right) Trilaciclib in combination with 
chemotherapy and ICI enhanced the gene signature of cytotoxic anti-tumor response. T-cell repertoire analyses of 
MC38 tumors from OP- or TOP-treated mice (n=5 per treatment group) on day 17, presented as median clonality 
score and TIL fraction (right panel). Error bars denote standard error, and dotted lines represent the median value for 
TIL fraction and clonality score. *p<0.05.  
 
However, as a consequence of trilaciclib’s MOA, there is a hypothetical risk that administration 
of trilaciclib prior to chemotherapy could decrease chemotherapy efficacy by pausing 
CDK4/6-dependent tumor cells in G1 in the presence of chemotherapy; nonclinical data suggest 
this risk is not clinically significant. To understand why trilaciclib should not antagonize 
chemotherapy treatment, the baseline proliferation rates of HSPCs, bone marrow, and patient 
derived xenografts (PDX) were examined using flow cytometric analysis of the cell cycle. A bar 
graph depicting mean percentage of cells in synthesis phase of the cell cycle (S)/gap 2 phase of 
the cell cycle (G2)/mitosis (M) demonstrates that there are a higher proportion of cells cycling in 
tumor cells when compared to bone marrow/HSPCs. Specifically, <4% of human HSPCs are 
cycling, while in breast tumors an average of ~40% of cells were cycling (Sorrentino, 2018). 
29


These results illustrate why tumor cells are more susceptible to chemotherapy-induced damage 
compared to HSPCs, since chemotherapy treatment is predominantly effective in the S/G2/M 
phases of the cell cycle. 
To evaluate the impact of trilaciclib on chemotherapy anti-tumor efficacy in CDK4/6 dependent 
tumors, two different models were treated with chemotherapy and trilaciclib. MCF7 
tumor-bearing mice, a well-established estrogen receptor (ER)+ CDK4/6 dependent breast 
cancer model, were treated with docetaxel (IV, 5 mg/kg) ± trilaciclib once weekly for three 
doses. Although weekly trilaciclib treatment caused some tumor growth inhibition, administering 
trilaciclib with docetaxel did not alter the effects of chemotherapy. Next, MDA-MB231 
tumor-bearing mice were treated with daily trilaciclib (intraperitoneal [IP], 100 mg/kg) for 
28 days to confirm CDK4/6 dependence. Continuous treatment with trilaciclib caused stable 
disease in MDA-MB231 tumor-bearing mice. MDA-MB231 tumor-bearing mice were then 
treated with eribulin (IV, 0.5 mg/kg) ± trilaciclib once weekly for three doses. Similar to the 
MCF7 model, the addition of trilaciclib to eribulin treatment did not impact chemotherapy 
efficacy (Sorrentino, 2018). These experiments demonstrate that transient CDK4/6 inhibition 
prior to chemotherapy (eribulin, docetaxel) does not antagonize the intended anti-tumor effects 
of the chemotherapy in these CDK4/6-dependent tumor models. 
While there is emerging preclinical data demonstrating the efficacy of CDK4/6 inhibitors in 
combination with targeted therapy in NSCLC subpopulations (Freed, 2019; Gopalan, 2018; 
Haines, 2018; Knudsen, 2017), single agent efficacy has shown minimal benefit in the clinic 
(Goldman, 2020; Edelman, 2019; Gopalan, 2018; Patnaik, 2016). Furthermore, the available 
nonclinical in vivo data indicate combining chemotherapy with trilaciclib does not diminish the 
antitumor intended effects of the chemotherapy (data not shown, internal G1 data) as loss of 
CDK4/6 pathway function is correlated with increased tumor proliferation and improved tumor 
response to chemotherapy in a variety of cancer types (Socinski, 2009; Herschkowitz, 2008; 
Ertel, 2010; Witkiewicz, 2012). Lastly, applying a DNA signature analysis algorithm to the 
cBioportal dataset to characterize NSCLC tumors as CDK4/6 dependent, independent or 
indeterminate, only 7.4% of EGFR WT NSCLC lung tumor would be classified as CDK4/6 
dependent (Gao, 2013; Cerami, 2012). Overall, preclinical and clinical data suggest that there is 
minimal risk that trilaciclib administered prior to docetaxel will induce a G1 arrest in the tumor 
cell with resultant antagonism of the intended efficacy effect of the chemotherapy. 
4.2.7.2. 
Pharmacokinetic Studies 
In vitro analyses of direct and time-dependent inhibition suggest that drug interactions based on 
inhibition of cytochrome P450 (CYP)1A2-, 2B6-, 2C8-, 2C9-, 2C19-, and 2D6-mediated 
metabolic pathways are unlikely at clinical doses, however, the studies do suggest that drug 
interactions based on trilaciclib-mediated inhibition of CYP3A4-mediated metabolic pathways 
are possible (see Section 4.2.8.1.1). Additionally, in vitro induction studies of the 3 major 
inducible CYP enzymes (CYP1A2, CYP3A4, and CYP2B6) in human hepatocytes suggest that 
trilaciclib-mediated induction is unlikely.  
In vitro inhibition studies with membrane transporter model systems also suggest trilaciclib is 
unlikely to cause a drug-drug interaction (DDI) based on inhibition of breast cancer resistance 
protein (BCRP)-, bile salt export pump (BSEP)-, organic anion transporter 1 (OAT1)-, organic 
anion transporter 3 (OAT3)-, organic anion transporting polypeptide 1B1 (OATP1B1)-, p 
30


glycoprotein (MDR1)-, multidrug resistance protein 1 (MRP1)-, multidrug resistance protein 2 
(MRP2)-, or organic anion transporting polypeptide 1B3 (OATP1B3)-mediated transport. 
However, in vitro, trilaciclib is a potent inhibitor of multidrug and toxin extrusion 1 (MATE1), 
multidrug and toxin extrusion 2-K (MATE2-K), organic cation transporter 1 (OCT1), and 
organic cation transporter 2 (OCT2). See Section 4.2.8.1.1 for clinical evaluation. 
4.2.8. 
Summary of Clinical Data 
4.2.8.1. 
Trilaciclib 
A brief summary of the clinical data is provided in the following sections. Detailed information 
is presented in the trilaciclib IB. 
The safety and efficacy of administering trilaciclib prior to chemotherapy was tested in one 
completed and one ongoing Phase 1b/2 study (G1T28-02 and G1T28-03) and one ongoing and 
one completed Phase 2 study (G1T28-05 and G1T28-04) in patients with SCLC or TNBC. The 
Phase 2 portions of Studies G1T28-02, G1T28-03, and Study G1T28-05 were randomized, 
double-blind, and placebo-controlled. Study G1T28-04 was randomized and included a control 
arm but was not double-blinded. 
• Study G1T28-02 examined once-daily IV administration of either trilaciclib or 
placebo on Days 1 to 3 of each 21-day E/P chemotherapy cycle in patients with 
treatment naïve extensive-stage SCLC.  
• Study G1T28-03 examined once-daily IV administration of trilaciclib or placebo on 
Days 1 to 5 of each 21-day topotecan chemotherapy cycle in patients with previously 
treated extensive-stage SCLC.  
• Study G1T28-05 examined once-daily IV administration of trilaciclib or placebo on 
Days 1 to 3 for a maximum of four 21-day cycles of E/P and atezolizumab, followed 
by monotherapy atezolizumab, in patients with treatment naïve extensive-stage 
SCLC.  
• Study G1T28-04 examined once-daily IV administration of trilaciclib prior to 
gemcitabine and carboplatin in patients with metastatic TNBC who had received 0 to 
2 lines of previous therapy in the metastatic setting. Patients received 1) GC therapy 
only on Days 1 and 8 of a 21-day cycle, 2) trilaciclib and GC once daily on Days 1 
and 8 of each 21-day cycle, OR 3) trilaciclib on Days 1, 2, 8 and 9 with GC on 
Days 2 and 9 of each 21-day cycle (further noted as Group 1, 2, or 3, respectively).  
At the recommended phase 2 dose (RP2D) of 240 mg/m2, across all three SCLC studies, 
trilaciclib administered prior to chemotherapy statistically significantly reduced the duration of 
severe neutropenia (DSN) in Cycle 1 and occurrence of severe neutropenia (SN) (primary 
endpoints) compared with placebo. An integrated data analysis of the three SCLC studies 
(G1T28-02, G1T28-03, and G1T28-05) for 8 of the most relevant myelosuppression endpoints 
(neutrophils, RBCs and platelets) demonstrated statistically significant, and clinically 
meaningful, improvements for trilaciclib over available therapies in 6 of 8 endpoints across 
multiple lineages. Importantly, these myelopreservation benefits come with an overall improved 
safety profile compared with available therapy, as evidenced by reduced high grade 
treatment-emergent AEs across all SCLC studies, and no detriment to anti-tumor efficacy results. 
31


Table 2: 
Integrated Analysis for Myelopreservation Efficacy in SCLC 
(Studies G1T28-02, G1T28-03, and G1T28-05) 
Placebo 
+Chemo 
Trilaciclib 
+Chemo 
2-sided p-value 
ITT Set  
119 
123 
 
Neutrophils 
DSN [days] in Cycle 1 – Mean (SD)a 
4 (5.1) 
0 (1.8) 
<0.0001 
Occurrence of SN (Yes, %)b 
64 (52.9)  
14 (11.4)  
<0.0001 
RBCs 
Occurrence of Grade 3/4 hemoglobin decreased 
(anemia) (Yes, %)b 
38 (31.9) 
25 (20.3) 
0.0279 
Occurrence of RBC transfusion on/after 5 weeks 
(Yes, %)b 
31 (26.1) 
18 (14.6) 
0.0252 
Cumulative incidence of RBC transfusion on/after 5 
weeks - Event rate (per 100 weeks) c 
 3.1 
1.5 
0.0027 
Platelets 
Occurrence of Grade 3/4 platelet count decreased 
(thrombocytopenia) (Yes, %) b 
43 (36.1) 
24 (19.5) 
0.0067 
Occurrence of platelet transfusion (Yes, %)b 
11 (9.2) 
10 (8.1) 
0.9564 
Cumulative incidence of platelet transfusion - Event 
rate (per 100 weeks)c 
1.7 
1.1 
0.5169 
ANC=absolute neutrophil count; Chemo=chemotherapy; DSN=duration of severe (Grade 4) neutropenia; 
ECOG=Eastern Cooperative Group; ITT=intent to treat; SN=severe (Grade 4) neutropenia which is defined as ANC 
< 500/mm3; RBC=red blood cells, SCLC=small cell lung cancer; SD=standard deviation. 
Chemo=etoposide + platinum in G1T28-02, etoposide + platinum + atezolizumab in G1T28-05, and topotecan in 
G1T28-03. Standard supportive care interventions were allowed for all arms.  
a. p-value was obtained from a nonparametric analysis of covariance (ANCOVA).  
b. p-value was obtained from a modified Poisson model. 
c. p-value was obtained from a negative binomial model. All three models contained fixed effect of treatment, 
ECOG performance status (0-1 versus 2), Presence of brain metastases (Y/N), and study (G1T28-02, G1T28-03, or 
G1T28-05). Corresponding baseline assessment was also included as a covariate. 
Results from the TNBC Study G1T28-04 demonstrated that although the addition of trilaciclib to 
GC did not statistically significantly improve chemotherapy-induced myelosuppression as 
measured by the neutrophil-based endpoints of DSN in Cycle 1 and occurrence of SN, there were 
trends toward improvement in RBC and platelet-based measures. In addition, antitumor efficacy 
results demonstrated- a clinically meaningful improvement in PFS and OS (Figure 2; Table 3). 
This meaningful antitumor efficacy was observed in both trilaciclib- groups compared with the 
control group and was also consistent across subgroups, including predictors of immune 
response. Approximately 57.6% of the available tumor samples in G1T28-04 were considered 
PD-L1 positive (Ventana SP142 assay), and though larger in the PD-L1 positive population, the 
benefit of adding trilaciclib extended to both PD-L1 positive and negative cohorts (Table 4). 
32


Table 3: 
G1T28-04: Summary of Overall Survival and Progression-Free Survival 
(ITT Analysis Set) 
Category 
Group 1 
GC (Day 1+8) 
(N=34) 
Group 2  
GC + 
Trilaciclib 
(Day 1+8) 
(N=33) 
Group 3  
GC + 
Trilaciclib 
(Day 1/2+8/9) 
(N=35) 
Groups 2+3 
(N=68) 
Overall survival (months) (95% CI)a, d 
 
 
 
25% 
5.8 (2.8, 9.7) 
9.4 (3.4, 19.6) 
8.8 (6.0, 15.3) 
8.8 (6.0, 14.0) 
Median 
12.6 (6.3, 15.6) 
NR (10.2, NR) 
17.8 (12.9, 32.7) 
19.8 (14.0, NR) 
75% 
17.8 (12.8, 25.0) 
NR (NR, NR) 
32.7 (19.8, NR) 
NE (32.7, NR) 
Comparison (treatment group versus Group 1) 
 
 
 
Adjusted HR (SE)b 
NA 
0.31 (0.111) 
0.40 (0.125) 
0.37 (0.101) 
95% CIb 
NA 
0.15, 0.63 
0.22, 0.74 
0.21, 0.63 
2-sided p-valuec 
NA 
0.0016 
0.0004 
<0.0001 
Progression-free survival (months) (95% CI)a, d 
25% 
2.2 (1.2, 5.4) 
5.3 (1.2, 7.9) 
6.2 (1.2, 7.1) 
5.9 (2.1, 6.5) 
Median 
5.7 (3.3, 9.9) 
9.4 (6.1, 11.9) 
7.3 (6.2, 13.9) 
9.0 (6.4, 11.3) 
75% 
9.9 (8.3,18.8) 
13.0 (9.7, 24.1) 
13.9 (9.0, NR) 
13.9 (10.9,15.6) 
Comparison (Treatment Group versus Group 1) 
Adjusted HR (SE)b 
NA 
0.62 (0.209) 
0.63 (0.212) 
0.62 (0.180) 
95% CIb 
NA 
0.32-1.20 
0.32, 1.22 
0.36, 1.10 
2-sided p-valuec 
NA 
0.2099 
0.1816 
0.1291 
CI=confidence interval; GC=gemcitabine and carboplatin; HR=hazard ratio; ITT=intent-to-treat; N=total number of 
patients in each treatment group; NA=not applicable; NR=not reached; SE=standard error. 
a Calculated using the Kaplan-Meier method 
b The HR and its 95% CI were calculated using the Cox regression model controlling for stratification factors of the 
number of prior lines of therapy (0 versus 1 or 2) and liver involvement. 
c P-value was calculated using the stratified log-rank test controlling for the two stratification factors. 
d OS reported from final database; PFS reported from earlier data cutoff on 15 May 2020.  
33


Table 4: 
G1T28-04: Tumor Response According to PD-L1 Status 
 
PD-L1 Positive 
PD-L1 Negative 
 
Group 
1 
Group 2 
Group 3 
Group 
2+ 3 
Group 
1 
Group 2 
Group 3 
Group 
2+ 3 
Patients analyzed 
17 
16 
16 
32 
10 
10 
16 
26 
Median PFS, 
months (95% 
CI)a 
5.4 
(3.3-
NR) 
7.9 (6.1-
NR) 
10.9 (6.2-
NR) 
9.7 (6.2-
15.5) 
9.2 (8.3-
NR) 
11.9 
(8.8-NR) 
9.0 (6.4-
NR) 
9.4 (6.5-
14.6) 
p-value 
- 
0.492 
0.075 
0.149 
- 
0.376 
0.488 
0.943 
HR (95% 
CI) 
- 
0.74 
(0.3-1.7) 
0.41 (0.2-
1.1) 
0.57 
(0.3-1.2) 
- 
0.60 
(0.2-1.9) 
1.47 
(0.5-4.3) 
0.97 
(0.4-2.5) 
Median OS, 
months (95% 
CI)a 
10.5 
(6.3-
18.8) 
20.1 
(10.2-
NR) 
32.7 
(15.3-
NR) 
32.7 
(17.7-
NR) 
13.9 
(12.6-
NR) 
NR (9.4-
NR) 
17.8 
(12.9-
NR) 
17.8 
(13.1-
NR) 
p-value 
- 
0.037 
0.01 
0.004 
- 
0.077 
0.198 
0.093 
HR (95% 
CI) 
- 
0.38 
(0.2-1.0) 
0.30 (0.1-
0.8) 
0.34 
(0.2-0.7) 
- 
0.35 
(0.1-1.2) 
0.55 
(0.2-1.4) 
0.48 
(0.2-1.2) 
HR=hazard ratio; NR=not reached; OS=overall survival; PD-L1=programmed death ligand-1; PFS=progression-free 
survival 
Group 1: chemotherapy on Days 1 and 8; Group 2: trilaciclib and chemotherapy on Days 1 and 8; Group 3: 
trilaciclib along on Days 1 and 8 with chemotherapy on Days 2 and 9. HR and p-values are comparisons between 
Group 2 and Group 1, Group 3 and Group 1, and between combined Groups 2 and 3 and Group 1. 
a OS reported from final database; PFS reported from earlier data cutoff on 15 May 2020.  
As mentioned in Section 4.2.7, there is a hypothetical risk that administration of trilaciclib prior 
to chemotherapy could decrease chemotherapy efficacy by pausing CDK4/6-dependent tumor 
cells in the G1 phase of the cell cycle in the presence of chemotherapy. This hypothetical risk is 
countered by the results observed in Study G1T28-04 which suggested that the addition of 
trilaciclib improves the anti-tumor efficacy of GC regardless of the CDK4/6 status of the TNBC 
tumor. Although TNBC tumors are predominantly classified as CDK4/6 independent (i.e., their 
replication is not sensitive to CDK4/6 inhibition), there is a small subset of patients whose 
tumors are classified as either CDK4/6 indeterminate or CDK4/6 dependent. When the TNBC 
population enrolled in Study G1T28-04 is divided into these subsets, evaluation of the anti-tumor 
efficacy in patients whose tumors are classified as CDK4/6 indeterminate or CDK4/6 dependent 
suggests that trilaciclib does not antagonize the anti-tumor effects of GC. Specifically, PFS and 
OS did not decrease when trilaciclib was added to GC in the most CDK4/6-dependent population 
(see the trilaciclib IB). 
4.2.8.1.1. Pharmacokinetics 
A clinical DDI study using the index CYP3A substrate midazolam indicated that trilaciclib had 
no impact on CYP3A activity. Two clinical DDI studies using a strong CYP3A inhibitor 
itraconazole were also conducted. No clinically significant changes in exposure were observed 
for trilaciclib when co-administered with itraconazole.  
Clinical data from the evaluation of trilaciclib administered prior to topotecan (Study G1T28-03) 
suggests that drugs that are substrates of MATE1 and MATE2 do not pose a clinically relevant 
34


risk of DDIs when administered concomitantly with trilaciclib. In an additional clinical DDI 
assessment, trilaciclib increased metformin (MATE1, MATE-2K and OCT2 substrate) exposure 
by 65%, in healthy subjects, compared with administration of metformin alone.  
Avoid concomitant use of trilaciclib with certain OCT2, MATE1, and MATE-2K substrates 
(e.g., dofetilide, dalfampridine) where minimal concentration changes may lead to serious or life-
threatening toxicities.  Refer to the prescribing information for these concomitant medications 
for assessing the benefit and risk of concomitant use with trilaciclib. 
Docetaxel has not been reported to be a substrate for MATE1 or MATE2 (Nieuweboer, 2015), 
and is not believed to be a substrate for OCT2. As such, a clinically significant alteration of 
docetaxel PK due to trilaciclib inhibition of OCT2, MATE1, or MATE2-K is not expected.  
Study G1T28-11 was a single ascending dose study, with both placebo and positive control 
groups, with the objective to evaluate potential effects of trilaciclib on ECG parameters, 
including concentration-QTc (C-QTc) analysis. Trilaciclib transiently increased heart rate by 
approximately 10 beats per minute. At the clinical dose of 240 mg/m2, trilaciclib did not have a 
clinically relevant effect on QTc (i.e., >10 msec).  
4.2.8.2. 
Trilaciclib Risks 
Reproductive/embryo-fetal effects are an important potential risk of trilaciclib. Both nonclinical 
toxicology studies with trilaciclib, and clinical studies with other compounds with a similar 
MOA, report effects on either the reproductive system or embryo/fetus. Since this clinical study 
will focus on trilaciclib administered prior to cytotoxic chemotherapy (which carries its own risk 
of reproductive/embryo-fetal toxicity), the risks specific to trilaciclib are consistent with those 
experienced with chemotherapy. In addition, female patients will be monitored for pregnancy 
and eligibility criteria describing specific birth control methods are incorporated. Dose 
discontinuation recommendations for female patients who become pregnant while receiving 
trilaciclib are also provided in the protocol (Section 11.3.6.5). Detailed information regarding all 
important identified and important potential risks of trilaciclib administration can be found in the 
trilaciclib IB. 
Adverse events of special interest (AESIs) identified for trilaciclib are described below. Rates 
reported below reflect those observed in the integrated safety summary from the four Phase 2 
oncology studies conducted with trilaciclib to date (G1T28-02 [database lock: 05 May 2019], 
G1T28-03 [data cutoff: 31 May 2019], G1T28-05 [data cutoff: 28 June 2019], and G1T28-04 
[data cutoff: 28 June 2019]). Some AESIs have been infrequently reported (or not reported) in 
the trilaciclib clinical program to date but are considered to be potential class effects of CDK4/6 
inhibitors. However, as trilaciclib is given IV and only when chemotherapy is administered, the 
safety profile of trilaciclib appears to be different from that of the oral, chronically dosed 
members of its pharmacologic class. All patients will be monitored for these events and dose 
modification and discontinuation guidelines are provided in Section 9 and Section 10. 
Trilaciclib AESIs: 
1. Injection Site Reaction/Phlebitis/Thrombophlebitis: Infusion of trilaciclib may result 
in local irritation manifesting as erythema, pain, and swelling; and in a subset of patients, 
the irritation may cause phlebitis/thrombophlebitis. Injection site reactions have been 
observed in approximately 15 to 20% of patients receiving trilaciclib and the events have 
35


been Grade 1 or 2. Phlebitis/thrombophlebitis has been noted in approximately 5 to 10% 
of patients receiving trilaciclib and the events were primarily Grade 1 or 2. Supportive 
care interventions such as slowing the infusion rate, flushing the infusion line with a 
minimum of 20 mL normal saline or 5% dextrose (D5W), rotating IV catheter sites, and 
removing the IV (when given peripherally) following each trilaciclib infusion can 
decrease the frequency and severity of these events. In addition, if symptoms are 
observed with normal saline as diluent/flush, use of D5W as an alternative may decrease 
the symptoms. Central access may also be considered. 
2. Acute Drug Hypersensitivity Reaction: Trilaciclib administration may cause acute drug 
hypersensitivity reaction characterized by symptoms like angioedema, pruritis, and 
urticaria. These events have been reported in approximately 6% of patients receiving 
trilaciclib compared with approximately 3% in patients receiving placebo and were 
classified as Grade 1 and 2. Only one case of Grade 2 anaphylaxis was observed, which 
occurred 4 days after the preceding dose of trilaciclib, resolved on the same day, was not 
serious, and did not result in discontinuation of treatment.  
3. Pneumonitis/Interstitial Lung Disease: A rare (1 to 3%) but serious class effect (<1% 
fatal) that is associated with the use of oral CDK4/6 inhibitors. Symptoms include 
hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams in patients in 
whom infectious, neoplastic, or other causes have been excluded. The only case of 
pneumonitis reported in patients who received trilaciclib was observed in a patient in 
whom trilaciclib had been discontinued for two months and who had been receiving 
atezolizumab (known to cause pneumonitis) as monotherapy. The pneumonitis event was 
Grade 3 and considered by the Investigator to be related to atezolizumab.  
4. Hepatotoxicity: Both nonclinical toxicology studies with trilaciclib, and clinical studies 
with other compounds with a similar MOA, report reversible elevations in transaminases 
with continuous dosing. There has been only 1 instance of Grade 4 alanine 
aminotransferase (ALT) increase in a patient receiving trilaciclib, no Grade 4 aspartate 
aminotransferase (AST) increases, and no cases of Hy’s law reported in patients 
receiving trilaciclib. However, generally low grade and transient increases in AST, ALT, 
or bilirubin have been observed in a small number of patients (~ 5%) receiving trilaciclib 
prior to chemotherapy. Patients with mild hepatic impairment have been treated with 
trilaciclib without a clinically significant increase in exposure or the frequency/severity 
of AEs. Studies evaluating the PK of trilaciclib in patients with hepatic impairment are 
ongoing. 
5. Embolic and Thrombotic Events, Venous: The CDK4/6 inhibitor abemaciclib has been 
associated with an increased risk for venous thromboembolism when combined with 
endocrine therapy in patients with breast cancer. This same risk has not been reported for 
the other approved oral CDK4/6 inhibitors (ribociclib and palbociclib); therefore, it is not 
clear if this is a class effect. Approximately 3% of cancer patients that received trilaciclib 
prior to chemotherapy experienced a venous thromboembolic event and half of those 
events (3/6) were Grade 3 or 4. No Grade 5 events were reported. Approximately 2% of 
patients receiving chemotherapy alone or with placebo reported an embolic or thrombotic 
event, 1 of 3 such events was Grade 3.  
36


4.2.8.3. 
Docetaxel 
Docetaxel is commonly used in the treatment of metastatic NSCLC (NCCN, 2020) and is 
approved by the US FDA and the European Medicines Agency for this indication 
(Taxotere®, 2020; Taxotere, 2005). Per Warnings and Precautions in the prescribing information 
for docetaxel, the following are important risks related to docetaxel use: 
• Acute myeloid leukemia, myelodysplasia or other second primary malignancies 
• Cutaneous reactions including erythema, edema and desquamation 
• Neurologic reactions including paresthesia, dysesthesia, and pain  
• Cystoid macular edema 
• Asthenia 
• Fetal harm 
• Alcohol content (in a dose of Taxotere injection) 
• Tumor lysis syndrome 
• Neutropenia 
• Serious gastrointestinal complications (ex. enterocolitis) 
• Hypersensitivity reactions 
• Fluid retention 
• Respiratory disorders (ex. acute respiratory distress syndrome, interstitial lung disease, 
pulmonary fibrosis, respiratory failure) 
• Severe adverse reactions in patients with liver impairment 
4.3. 
Benefit/Risk Assessment 
Trilaciclib (CDK4/6 inhibitor) is being evaluated for anti-tumor efficacy, specifically OS, 
following disease progression on both immunotherapy and platinum-based chemotherapy, a 
clinical setting where treatment options are limited and outcomes are suboptimal. In addition to 
facilitating host immune function, trilaciclib can also provide benefit by making chemotherapy 
safer and allowing patients to receive the standard of care doses and schedule. These effects have 
been shown in other trilaciclib clinical trials to improve the patient experience and are provided 
in the context of minimal toxicity (low grade injection site reactions/phlebitis/thrombophlebitis). 
As stated in Section 4.2.8, the dose of 240 mg/m2 trilaciclib established in the SCLC and TNBC 
studies (G1T28-04) will be administered prior to a commonly used chemotherapy regimen of 
docetaxel. The clinically meaningful anti-tumor efficacy results observed in G1T28-04 were 
noted across multiple endpoints, with OS, PFS, and ORR endpoints all showing numerical 
improvement with the addition of trilaciclib to GC compared with GC alone.  
Studies to date with trilaciclib have demonstrated a manageable safety profile (see Section 4.2.8). 
Trilaciclib is not expected to have significant overlapping toxicity with docetaxel. In fact, 
37


trilaciclib is expected to have a favorable impact on specific docetaxel complications such as 
myelosuppression and potentially on gastrointestinal (GI) related side effects.  
As described in Section 4.2.9.1 and 4.2.8.1, there is a hypothetical risk that administration of 
trilaciclib prior to chemotherapy could decrease chemotherapy efficacy by pausing CDK4/6-
dependent tumor cells in G1 in the presence of chemotherapy. However, at this time there is no 
nonclinical (Section 4.2.7) or clinical (Section 4.2.8) evidence to support this theoretical risk. In 
addition, since sensitivity to CDK4/6 inhibitors is a surrogate marker for CDK4/6 dependence, 
and the oral, chronically-dosed CDK4/6 inhibitors have shown minimal anti-tumor activity in 
solid tumors other than ER+ breast cancer (Baghdadi, 2019; Goldman, 2014; Goldman, 2018; 
Gopalan, 2014; Infante, 2016; Karasic, 2018; Rose, 2018), these results suggest that the majority 
of solid tumor cancers are not CDK4/6 dependent and not susceptible to this hypothetical risk.  
Given the potential benefit to patients with previously treated metastatic NSCLC from the 
addition of trilaciclib to docetaxel and the limited potential for significant trilaciclib-related 
toxicity, the benefit/risk assessment is positive for this combination.  
A COVID-19 risk assessment has been performed, documented, and will be provided as a 
separate document. 
38








6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is a randomized, double-blind, placebo-controlled, global, multicenter, Phase 2 trial 
evaluating the effect of trilaciclib compared with placebo on OS in patients with metastatic 
NSCLC receiving docetaxel in the 2nd or 3rd line setting. Patients must have documented disease 
progression during or after 1 or 2 lines of systemic therapy for recurrent or metastatic NSCLC. 
Prior treatment must have included, either in the same line or as separate lines of therapy: 1) a 
maximum of 1 line of platinum-containing chemotherapy in the recurrent/metastatic setting and 
2) a maximum of 1 line of a locally approved/authorized PD-1/PD-L1 monoclonal antibody 
(mAb) containing regimen in the recurrent/metastatic setting.  
Approximately 146 patients will be randomly assigned (1:1) to receive trilaciclib or placebo by 
IV prior to docetaxel on Day 1 of each 21-day cycle. There will be 2 stratification factors for 
randomization: Country, and ECOG performance status (0-1 versus 2). Within each country, 
patient randomization will be stratified by ECOG performance status (0-1 versus 2).  
Study drugs administered are as follows: 
• Trilaciclib (240 mg/m2) or placebo – administered as a 30-minute IV infusion no more 
than 4 hours prior to chemotherapy on each day chemotherapy is administered 
(Section 9.1.1).  
• Docetaxel 75 mg/m2 –IV, Day 1 
The study will include 3 study phases: Screening Phase, Treatment Phase, and Survival 
Follow-up Phase (Figure 4). The Treatment Phase begins on the day of randomization for the 
first patient and completes at the Post-Treatment Visit for the last patient. The first Survival 
Follow-up assessment should occur approximately 2 months after the last dose of study drug.  
Figure 4: 
Study Design 
 
D=day; PD=progressive disease, WD=withdraw, DC=discontinue 
Criteria which patients must meet in order to receive study drug on Day 1 are provided in 
Section 9.2. Treatment cycles will occur consecutively without interruption, except when 
necessary to manage toxicities or for administrative reasons. Study drug administration will 
continue until disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) 
v1.1 or clinical progression as determined by the Investigator, unacceptable toxicity, withdrawal 
of consent, discontinuation by Investigator, or the end of the trial, whichever occurs first. 
42






6.3.2. 
Docetaxel 
The dose and schedule of docetaxel is described in Section 9.1.1.2. This is consistent with 
standard of care as established in clinical trials (Shepherd, 2000; Garon, 2014), and the approved 
labeling for this product (NCCN, 2020; Taxotere, 2020; Taxotere, 2005). 
6.4. 
Rationale for Supportive Care Interventions  
Per NCCN guidelines docetaxel, as utilized in NSCLC, is considered an intermediate risk 
regimen with a risk of FN between 10 and 20%. At this level of risk, guidelines do not require 
routine prophylactic granulocyte colony-stimulating factor (G-CSF) in Cycle 1 (NCCN, 2020b). 
Therefore, in order to facilitate an unbiased evaluation of trilaciclib effects on the hematologic 
and pharmacodynamic endpoints, primary prophylactic G-CSF will be prohibited in Cycle 1; 
however therapeutic G-CSF (administered in response to a neutropenic event) in Cycle 1 and 
secondary prophylactic G-CSF beginning in Cycle 2 and for all subsequent cycles (i.e., after a 
precipitating event in a prior cycle of therapy) will be allowed per growth factor/neutropenia 
management guidelines in Section 9.4 and Investigator discretion (Aapro, 2010; Smith, 2015).  
Erythropoiesis-stimulating agent (ESA) administration and RBC or platelet transfusions will be 
allowed per Investigator discretion based on guidelines detailed in Section 9.4.2 and 
Section 9.4.3. While these interventions may confound analysis of the myelosuppression 
endpoints, allowing physicians to provide appropriate supportive care to patients will facilitate 
patient safety.  
6.5. 
Rationale for Patient Population 
Though immunotherapy has markedly improved the treatment of metastatic NSCLC, options 
following disease progression remain limited. An alternative therapy that extends the duration of 
OS without significant additive toxicity, while concurrently decreasing myelosuppression and 
improving quality of life, would be a welcome addition in this heavily pretreated and often 
clinically fragile patient population. Therefore, further evaluation of trilaciclib in this area of 
high unmet medical need is warranted. 
6.6. 
Rationale for Stratification Factors  
As outlined in Section 6.1, randomization will be stratified by country and ECOG performance 
status. Within each country, patient randomization will be stratified by ECOG performance 
status (0-1 versus 2). These factors were chosen because they are predicted to have an impact on 
the primary endpoint of overall survival, and in some cases the secondary myelopreservation 
endpoints, such that if there is an imbalance in these factors, interpretation of the results of the 
study could be compromised. 
Country was chosen as a stratification factor to account for the geographic differences in patient 
populations, treatment practice patterns and access to supportive care and subsequent anti-cancer 
therapy; all of which could influence the primary and secondary endpoint outcomes.  
Performance status is an established indicator of survival and treatment tolerance. Those with 
ECOG performance status of 2 typically have shorter survival times and greater toxicity with 
subsequent therapeutic interventions (Sweeney, 2001; Jang, 2014). However, this group in 
particular may derive benefit from the myelopreservation and limited toxicity seen with 
45


trilaciclib and has few well-tolerated alternative options. As such, these patients will be eligible 
but stratified by ECOG performance status (0-1 versus 2) in order to minimize any impact on 
survival outcomes. 
46


7. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
a protocol waiver or exemption, is not permitted. 
7.1. 
Inclusion Criteria 
Patient eligibility should be reviewed and documented by an appropriately qualified member of 
the investigator study team before patients are included in the study. Patients must meet all of the 
following inclusion criteria to be eligible for enrollment into the study: 
1. Age ≥18 years of age at the time of signing the informed consent. 
2. Histologically or cytologically confirmed metastatic NSCLC (squamous or 
nonsquamous) with no known actionable driver mutations (ex. EGFR, ROS1, ALK).  
o Patients must have had documented disease progression during or after 1 or 
2 lines of systemic treatment for recurrent or metastatic disease.  
o Two components of treatment must have been received in the same line or as 
separate lines of therapy: (i) a maximum of 1 line of platinum-containing 
chemotherapy regimen for recurrent/metastatic disease, and (ii) a maximum of 1 line 
of a locally approved/authorized PD-1/PD-L1 mAb containing regimen for 
recurrent/metastatic disease. 
o Maintenance therapy following platinum doublet-based chemotherapy is not 
considered as a separate line of therapy. Maintenance therapy is defined as 
therapy given within 42 days after the last dose of platinum-based chemotherapy 
in patients with ongoing clinical benefit (complete response [CR], partial response 
[PR] or stable disease [SD]).  
3. Measurable or non-measurable disease per RECIST v1.1 
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2  
5. A formalin-fixed paraffin-embedded (FFPE) tumor specimen (from archival or fresh 
biopsy) with an associated pathology report documenting NSCLC must be available to 
send to the Sponsor, within the specified timeframe, for planned retrospective biomarker 
analyses (see Section 11.6.1).  
6. Adequate organ function defined by the following laboratory values: 
a) Hemoglobin ≥9.0 g/dL in the absence of RBC transfusion or ESA administration 
within 14 days prior to first dose of trilaciclib/placebo 
b) Absolute neutrophil count (ANC) ≥1.5 × 109/L 
c) Platelet count ≥100 × 109/L 
d) Total bilirubin ≤ upper limit of normal (ULN) 
e) AST/ALT <1.5 × ULN if alkaline phosphatase >2.5 × ULN 
f) If alkaline phosphatase <2.5 × ULN then AST, ALT <2.5 x ULN in the absence 
of liver metastasis or <5 × ULN in the presence of liver metastasis  
47


g) Estimated glomerular filtration rate ≥30 mL/minute/1.73m2 
7. Resolution of nonhematologic toxicities per National Cancer Institute Common 
Terminology Criteria Version 5.0 (NCI-CTCAE) from prior therapy or surgical 
procedures to ≤ Grade 1 or baseline (except alopecia). 
8. Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. Please 
see Section 17.3 for detailed instructions on methods of contraception requirements. 
9. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol.  
7.2. 
Exclusion Criteria  
A patient will not be eligible for participation in this study if any of the following criteria apply:  
1. Prior therapy with docetaxel. 
2. Any contraindication to the administration of docetaxel at the discretion of the 
investigator. 
3. Mixed NSCLC/SCLC, or lung tumors whose predominant histology is sarcomatoid, 
or neuroendocrine.  
4. Any chemotherapy, immunotherapy, biologic, investigational, or hormonal therapy 
for cancer treatment (except for adjuvant hormonal therapy for breast cancer or 
prostate cancer defined as M0 disease or prostate-specific antigen (PSA) 
persistence/recurrence without metastatic disease) within 3 weeks prior to the first 
dose of trilaciclib/placebo.  
5. Any radiotherapy within 2 weeks prior to the first dose of trilaciclib/placebo. 
6. Presence of central nervous system (CNS) metastases requiring immediate treatment 
with radiation therapy or steroids (i.e., patient must be off steroids administered for 
brain metastases for at least 14 days prior to the first dose of trilaciclib/placebo).  
7. Presence of leptomeningeal disease. 
8. Significant third-space fluid retention (ex. ascites or pleural effusion) not amenable to 
required repeat drainage. 
9. QT corrected using Fridericia’s formula (QTcF) interval >480 msec at screening 
(confirmed on repeat). For patients with ventricular pacemakers, QTcF >500 msec. 
10. Symptomatic peripheral neuropathy (≥ Grade 2 NCI-CTCAE v5.0) 
11. History of interstitial lung disease (ILD) 
12. Clinically significant (i.e., active) cardiovascular disease at the time of signing the 
informed consent; for example cerebrovascular accidents (≤ 6 months before the first 
dose of trilaciclib/placebo), myocardial infarction (≤ 6 months before the first dose of 
trilaciclib/placebo), unstable angina, serious cardiac arrythmia requiring medication, 
48


or uncontrolled symptomatic congestive heart failure [Class II or higher as defined by 
the New York Heart Association [NYHA] functional classification system])  
13. Known serious active infection including but not limited to human immunodeficiency 
virus (HIV) (e.g., viral load indicative of HIV, HIV 1/2 antibodies), Hepatitis B (e.g., 
HBsAg reactive or HBV DNA detected), Hepatitis C (e.g., HCV RNA [quantitative] 
is detected) or tuberculosis   
14. Prior allogeneic or autologous hematopoietic stem cell or bone marrow 
transplantation  
15. Receipt of any low-dose systemic chemotherapeutic agent (e.g., low-dose 
methotrexate for rheumatoid arthritis) administered for a nononcologic purpose 
within 3 weeks prior to the first dose of trilaciclib/placebo.  
16. Receipt of any live attenuated vaccines within 4 weeks prior to first dose of study 
treatment or anticipation that such a vaccine will be required during the study 
treatment period. 
17. Known hypersensitivity to docetaxel or to other drugs formulated with polysorbate 
80 or any excipients of trilaciclib 
18. Pregnant or lactating women  
19. Legal incapacity or limited legal capacity  
20. Other uncontrolled serious chronic disease or psychiatric condition that in the 
Investigator’s opinion could affect patient safety, compliance, or follow-up in the 
protocol 
21. Concurrent participation in any other interventional clinical trial. 
49


8. 
SCHEDULE OF ASSESSMENTS 
The procedures and assessments to be performed during the study are outlined in Table 6. The 
timing and number of samples collected for biomarker testing may be altered based on emerging 
data without requiring an amendment if the blood volume per day or overall does not increase 
and the patient is not required to have additional clinic visits or prolongation of a clinic visit, 
i.e., the risk-benefit profile for the patient does not worsen.  
When there are multiple procedures at the same or overlapping time points, order of events 
should be: patient reported outcome measures, ECGs, vitals, blood draw. Unscheduled 
assessments and visits to manage patient safety may occur at the Investigator’s discretion. Study 
procedures performed at unscheduled visits should be recorded in the appropriate electronic case 
report form (eCRF). 
 
50


Table 6: 
Schedule of Assessments 
Assessment 
Screening 
Rand 
21 Day Treatment [Cycles] 
Post-
Treatment 
Visit 
Survival 
Follow-
Up 
Details 
Provided in 
Section 
Cycle 1 
Cycle 2 
and 
beyond 
Day 
-28 to -1 
-3 to -
1 
1 
5 
(±1 day) 
9 
(±1 day) 
13 
(±1 day) 
17 
(±1 day) 
1a 
30 ±7d 
post-last 
dose 
Every 2 
months 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Section 13.3 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Section 11.1.2 
Medical History 
and NSCLC 
History 
X 
 
 
 
 
 
 
 
 
 
Section 11.1.3 
Eligibility 
Evaluation and 
Randomization 
X 
X 
 
 
 
 
 
 
 
 
Section 
11.1.1, 
Section 7.1, 
and Section 
7.2 
Archived Tumor 
Sample 
X 
 
 
 
 
 
 
 
 
 
Section 11.6.1 
ECOG 
Performance Status 
X 
 
X 
 
 
 
 
X 
X 
 
Section 11.3.3 
Complete physical 
exam, including 
height and weight 
X 
 
 
 
 
 
 
 
 
 
Section 11.3.2 
Brief physical 
exam, including 
weight 
 
 
X 
 
 
 
 
X 
X 
 
Section 11.3.2 
Vital Signs 
X 
 
X 
 
 
 
 
X 
X 
 
Section 11.3.1 
12-lead 
Electrocardiogram 
X 
 
X 
 
 
 
 
X 
[C2 only] 
 
 
Section 11.3.4 
51


Assessment 
Screening 
Rand 
21 Day Treatment [Cycles] 
Post-
Treatment 
Visit 
Survival 
Follow-
Up 
Details 
Provided in 
Section 
Cycle 1 
Cycle 2 
and 
beyond 
Day 
-28 to -1 
-3 to -
1 
1 
5 
(±1 day) 
9 
(±1 day) 
13 
(±1 day) 
17 
(±1 day) 
1a 
30 ±7d 
post-last 
dose 
Every 2 
months 
 
Clinical Chemistry 
X 
 
X 
 
 
 
 
X 
X 
 
Section 11.3.5 
Hematology 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Section 11.3.5 
Pregnancy Test 
(WOCBP) 
 
X 
X 
 
 
 
 
X 
X 
 
Section 11.3.5 
Tumor Assessment 
by RECIST v1.1 
X 
 
X  
(every 6 weeks from C1D1) 
X 
 
Section 11.2.1 
Trilaciclib or 
Placebo 
 
 
X 
 
 
 
 
X 
 
 
Section 
9.1.1.1.1  
Docetaxel 
 
 
X 
 
 
 
 
X 
 
 
Section 
9.1.1.2 
EORTC QLQ-C30, 
EORTC 
QLQ-LC13 with 
supplemental 
weight loss item 
(EORTC IL118), 
FACIT-Fatigue, 
PGIS, and EQ-5D-
5L 
 
 
X 
 
 
X 
 
X 
X 
 
Section 11.4 
PGIC 
 
 
 
 
 
X 
 
X 
X 
 
Section 11.4 
Blood Sample for 
PK 
 
 
X 
 
 
 
 
 
 
 
Section 11.5 
52


Assessment 
Screening 
Rand 
21 Day Treatment [Cycles] 
Post-
Treatment 
Visit 
Survival 
Follow-
Up 
Details 
Provided in 
Section 
Cycle 1 
Cycle 2 
and 
beyond 
Day 
-28 to -1 
-3 to -
1 
1 
5 
(±1 day) 
9 
(±1 day) 
13 
(±1 day) 
17 
(±1 day) 
1a 
30 ±7d 
post-last 
dose 
Every 2 
months 
 
Blood Sample for 
Immunologic and 
Hematologic 
Markers 
 
 
 
X 
 
 
X 
 
 
X 
[C2, C3, C5 
only] 
 
 
Section 11.7 
Survival Contact 
and Subsequent 
Anti-cancer 
Therapies 
 
 
 
 
 
 
 
 
 
X 
Section 11.10 
AEs 
 
 
X 
 
Section 11.3.6 
Concomitant 
Medications 
X 
X 
X 
 
Section 11.1.3 
AE=adverse event; β-hCG=beta human chorionic gonadotropin; ECOG=Eastern Cooperative Oncology Group; EORTC QLQ-C30=European Organisation for 
Research and Treatment of Cancer Quality of Life Core Questionnaire; EORTC QLQ-LC13=European Organisation for Research and Treatment of Cancer 
Quality of Life Lung Cancer Module; EORTC IL118=European Organisation for Research and Treatment of Cancer Quality of Life Lung Cancer Module with 
supplemental weight loss item; EQ-5D-5L=5-level EQ-5D; FACIT-Fatigue=Functional Assessment of Chronic Illness Therapy – Fatigue; NSCLC=non-small 
cell lung cancer; PGIC=Patient Global Impression of Change; PGIS=Patient Global Impression of Severity; PK=pharmacokinetic; Rand=randomization; 
RECIST=Response Evaluation Criteria in Solid Tumors; WOCBP=women of childbearing potential. 
a There should be no more than 5 weeks (for toxicity and/or administrative reasons) between doses of chemotherapy; however dosing delays >5 weeks may be 
permitted on a case by-case basis with the documented approval of the Investigator and Medical Monitor. 
 
53


9. 
STUDY TREATMENT 
9.1. 
Study Drugs Administered 
Study drugs are defined as any investigational agent(s), marketed product(s), or placebo 
intended to be administered to a study patient according to the study protocol. Study drugs 
used in this protocol are described in Table 7. 
Table 7: 
Study Drugs 
 
Study Drugs 
Product Name: 
Trilaciclib 
Placebo 
Docetaxel 
Type 
Investigational 
product 
Placebo 
Chemotherapy 
Dosage Formulation: 
Single-use, sterile 
powder to be 
reconstituted with 
250 mL of dextrose 
5% in water (D5W) or 
normal saline (sodium 
chloride solution 
0.9%) per the 
Pharmacy Manual 
250 mL of dextrose 
5% in water (D5W) or 
normal saline (sodium 
chloride solution 
0.9%) 
Description of the 
formulation is 
provided in the current 
prescribing 
information 
(Taxotere, 2020; 
Taxotere, 2005) 
Unit Dose Strength(s) 
300 mg/20 mL 
N/A 
See current 
prescribing 
information 
Dosage Level(s) 
240 mg/m2 
N/A – administered on 
Day 1 to match 
trilaciclib 
75 mg/m2 
Route of 
Administration 
IV 
IV 
IV 
Infusion Time 
30 minutes 
30 minutes 
1 hour or per 
Institutional Standards 
IV=intravenous; N/A=not applicable. 
9.1.1. 
Dose, Dosing Regimen, and Route 
9.1.1.1. 
Trilaciclib/Placebo 
Trilaciclib for Injection, 300 mg/vial (also referred to as “Trilaciclib Sterile Powder for 
concentrate for solution for IV infusion, 300 mg/vial”) is supplied as a sterile, preservative-
free, yellow, lyophilized cake in a single-dose vial (300 mg/20 mL). 
Trilaciclib must be reconstituted and further diluted prior to IV infusion as outlined in the 
Pharmacy Manual. Aseptic technique must be used for reconstitution and dilution. BSA 
should be calculated as per institutional practice. Actual body weight (not “adjusted” body 
weight) should be utilized for dose calculations. If there is a change in body weight ≥10% 
relative to the weight at the time of the last dose calculation, dose should be recalculated. 
Recalculation of dose more frequently per local institutional guidelines is permitted. Dose 
54


recalculation to adjust for changes in body weight will not be considered a dose reduction 
and will be made at the discretion of the Investigator. 
The placebo, either 250 mL of dextrose 5% in water (D5W) or sodium chloride solution 
0.9%, will be administered by IV infusion over approximately 30 minutes by peripheral or 
central access. 
9.1.1.1.1. Administration of Trilaciclib/Placebo 
• Administer diluted trilaciclib solution or placebo as a 30-minute IV infusion 
completed within 4 hours prior to the start chemotherapy. Do not administer 
trilaciclib/placebo as a bolus.  
• Trilaciclib/placebo is always administered first. Results from hematology labs should 
be reviewed prior to administration of trilaciclib/placebo. If administration of 
docetaxel therapy is delayed or discontinued, trilaciclib/placebo will also be delayed 
or discontinued. 
• Diluted trilaciclib/placebo solution must be administered with an infusion set, 
including an in-line filter (0.2 or 0.22 micron). Compatible in-line filters include 
polyethylene sulfone, polyvinylidene fluoride, and cellulose acetate.  
• Do not administer diluted trilaciclib/placebo solution with a polytetrafluorethylene 
(PTFE) in-line filter. PTFE in-line filters are not compatible with diluted 
trilaciclib/placebo solution. 
• Do not co-administer other drugs through the same infusion line.  
• Do not co-administer other drugs through a central access device unless the device 
supports co-administration of incompatible drugs.  
Upon completion of infusion of diluted trilaciclib/placebo solution, the infusion line/cannula 
must be flushed with at least 20 mL sterile D5W or 0.9% normal saline. 
The infusion rate may be decreased to manage an infusion-related AE; for example, if a 
patient experiences a burning sensation during infusion, the duration of infusion may be 
increased to 45 minutes (or longer if clinically indicated) to alleviate the symptoms.  
9.1.1.2. 
Docetaxel 
Docetaxel will be administered IV in accordance with the prescribing information/summary 
of product characteristics (Taxotere, 2020; Taxotere, 2005) and according to the study site’s 
standard practice. Protocol-specified doses of docetaxel will be administered IV in 
accordance with institutional guidelines and the recommended instructions below. Deviation 
from the recommendations provided in this protocol in order to follow institutional 
guidelines must receive prior approval from the Medical Monitor or Sponsor. 
Actual body weight (not ideal body weight) should be utilized for dose calculations. At a 
minimum, if there is a change in body weight of >10% relative to the weight at the time of 
the last dose calculation, doses should be recalculated. Recalculation of the dose more 
frequently per local institutional guidelines is permitted. Dose recalculation to adjust for 
changes in body weight will not be considered a dose reduction.  
55


Trilaciclib/placebo is always administered first, followed by docetaxel. Administer diluted 
trilaciclib solution or placebo as a 30-minute IV infusion to be completed within 4 hours 
prior to the start chemotherapy. Docetaxel may be administered immediately following 
trilaciclib/placebo, but not until the completion of the trilaciclib/placebo infusion. If 
administration of trilaciclib/placebo is delayed or discontinued, docetaxel will also be 
delayed or discontinued. Likewise, if docetaxel is delayed or discontinued, trilaciclib/placebo 
will also be delayed or discontinued. 
9.1.2. 
Preparation, Handling, Storage, and Accountability 
The Investigator or institution is responsible for study drug accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). The 
Investigator/institution may assign some or all of the Investigator’s/institution’s duties for 
investigational product(s) accountability to an appropriate pharmacist or another appropriate 
individual who is under the supervision of the Investigator/institution. 
Further guidance and information are provided in the Pharmacy Manual. 
9.1.3. 
Treatment Compliance 
The Investigator or designee will dispense the study drugs, via an unblinded 
Pharmacist/Designee, only for use by patients enrolled in the study as described in this 
protocol. The study drugs are not to be used for reasons other than those described in this 
protocol. The clinical study site will maintain records of study drugs’ receipt, preparation, 
and dispensing, including the applicable lot numbers; patient’s height, body weight, and body 
surface area; date and time of the start and end of each trilaciclib or placebo and docetaxel 
infusion; and total drug administered in milligrams. Any discrepancy between the calculated 
dose and dose administered and the reason for the discrepancy (e.g., interruption of infusion 
without restarting) will be recorded on eCRF and in the source documents. 
9.2. 
Criteria for Starting Each Cycle 
Patients must meet all the following minimum criteria to receive study treatment on Day 1 
for Cycle 1 and each subsequent cycle:  
• ANC ≥1.5 × 109/L,  
• Platelet count ≥100 × 109/L 
• Total bilirubin ≤ upper limit of normal (ULN)  
• AST/ALT ≤ 1.5 × ULN if alkaline phosphatase >2.5 × ULN 
• Other nonhematologic drug-related toxicities (excluding alopecia) must be ≤ Grade 1 
or have returned to baseline.  
For dose delays due to toxicity, the patient should be followed (at least) weekly, including 
CBCs if the AE is hematologic, to monitor the toxicity until treatment criteria described 
above are met or until they discontinue treatment (e.g., if more than 5 weeks elapse from the 
last chemotherapy dose). If the Day 1 dose is delayed, any assessments completed as part of 
the planned Day 1 visit will be captured in the eCRF as unscheduled visits. The PRO 
questionnaires should be completed on both the planned Day 1 visit and on the actual Day 1 
of the cycle (i.e., when criteria are met to proceed with Day 1 treatment).  
56


There should be no more than 5 weeks (for toxicity and/or administrative reasons) between 
doses of chemotherapy; however dosing delays >5 weeks may be permitted on a case by-case 
basis with the documented approval of the Investigator and Medical Monitor. 
In both the trilaciclib and placebo arms, study drug administration will continue until 
progressive disease per RECIST v1.1 or clinical progression as determined by the 
Investigator, unacceptable toxicity, withdrawal of consent, Investigator decision, or the end 
of the study. 
9.3. 
Toxicity Management and Dose Modifications 
The dose of trilaciclib will not be modified and will remain at 240 mg/m2 throughout the 
study. If administration of docetaxel therapy is discontinued, trilaciclib will also be 
discontinued.  
The dose of docetaxel can be reduced when necessary as described below. The recommended 
dose modification procedures for hematologic toxicities are described in Table 9. If a 
subsequent cycle is delayed for toxicity, the patient should still complete the clinical 
laboratory assessments on the scheduled Day 1 (entered as an Unscheduled assessment in 
EDC) as well as on the actual first dosing day of that cycle. If the delay is secondary to 
hematologic toxicity, weekly repeat hematology assessments should continue until the 
finding meets criteria for resumption of dosing. 
Non-hematologic toxicities should be managed as per standard of care for docetaxel. 
Recommendation for management of trilaciclib/placebo AESIs are provided in Table 10. 
Recommendations for hepatobiliary toxicity management are in Section 9.3.4. All 
recommendations are intended as a minimum guideline for toxicity management and are not 
a replacement for independent medical judgement tailored to specific circumstances with an 
individual patient. Please also refer to the individual package insert/summary of product 
characteristics (Taxotere, 2020; Taxotere, 2005) for additional information and 
recommendations. 
9.3.1. 
Dose reduction 
Recommended dose levels for reduction of docetaxel dose are described in Table 8. 
Chemotherapy dose reductions for hematologic toxicities should be based on values obtained 
within 24 hours prior to Day 1 of a given cycle. All dose reductions for an individual patient 
are permanent; and the dose, which has been reduced for toxicity, must not be re-escalated. 
Up to a maximum of 2 dose reductions will be allowed per patient. If a third dose reduction 
is required per the modifications below, the patient should discontinue study treatment. 
Table 8: 
Recommended Chemotherapy Dose Modifications 
 
Docetaxel 
Starting Dose 
75 mg/m2 
Dose Level -1 
60 mg/m2  
Dose Level -2 
50 mg/m2  
No dose modification is permitted for trilaciclib. 
Note that dose modifications (specifically dose reductions/discontinuations) are 
recommended for those events considered related to drug (i.e., toxicities) such that 
57


decreasing the dose or stopping the drug will lead to improved patient safety. If an event is 
not thought to be related to study drug by the Investigator, dose reduction/discontinuation is 
not required since decreasing the dose or stopping the drug would not be expected to alter the 
risk of the event occurring again; rather the Investigator should consider if treatment should 
be delayed until the event recovers to ≤Grade 1 or baseline before resumption of treatment. 
Decreased neutrophil, platelet counts or hemoglobin values that occur in isolation (e.g., at 
nadir) that do not result in a dosing delay, FN, serious adverse event (SAE) or other 
consequence, do not require dose modification. 
If drug-related toxicity requires discontinuation of docetaxel or trilaciclib then the patient 
must permanently discontinue all study drugs and should complete the Post-Treatment Visit 
and enter Survival Follow-up.
58


9.3.2. 
Safety Criteria for Adjustment or Stopping Doses 
Table 9: 
Recommended Dose Modification for Drug-Related Hematologic Toxicity 
 
 
Action Taken 
Event, CTCAE 
Grade or Lab Value 
Frequency 
Trilaciclib 
Docetaxel 
Toxicity Management 
ANC  
<1.5 x 109/L 
(≥Grade 2) 
1st occurrence 
Hold drug until ANC criteria for 
dosing reached. No change in 
dose. 
Hold drug until ANC criteria 
for dosing reached. No change 
in dose. 
Administer prophylactic 
G-CSF with each 
subsequent cycle of 
chemotherapy. 
2nd occurrence 
Hold drug until ANC criteria for 
dosing reached. No change in 
dose. 
Hold drug until ANC criteria 
for dosing reached.  
Reduce dose of docetaxel by 
one dose level and resume 
dosing. 
3rd occurrence 
Hold drug until ANC criteria for 
dosing reached. No change in 
dose. 
Hold drug until ANC criteria 
for dosing reached.  
Reduce dose of docetaxel by 
one more dose level and 
resume dosing. 
4th occurrence 
Permanently discontinue 
 
Febrile neutropenia 
(Grade 3 or 4) 
OR 
Grade 4 Neutropenia 
lasting >7 days 
 
 
1st occurrence 
Hold drug until ANC criteria for 
dosing reached. No change in 
dose. 
Hold drug until ANC criteria 
for dosing reached. Reduce 
dose of docetaxel by one dose 
level and resume dosing. 
Administer prophylactic 
G-CSF with each 
subsequent cycle of 
chemotherapy. 
2nd occurrence 
Hold drug until ANC criteria for 
dosing reached. No change in 
dose. 
Hold drug until ANC criteria 
for dosing reached. Reduce 
dose of docetaxel by one more 
dose level and resume dosing. 
3rd occurrence 
Permanently discontinue 
 
Platelets 
 <100 - 75 x 109/L 
(Grade 1) 
 
Any occurrence 
Hold drug until platelet criteria 
for dosing reached. No change in 
dose. 
Hold drug until platelet criteria 
for dosing reached. No change 
in dose.  
Monitor for signs and 
symptoms of bleeding. 
Consider treatment as 
clinically indicated 
59


 
 
Action Taken 
Event, CTCAE 
Grade or Lab Value 
Frequency 
Trilaciclib 
Docetaxel 
Toxicity Management 
Platelets  
<75 - 50 x109/L 
(Grade 2) 
1st Occurrence 
Hold drug until platelet criteria 
for dosing reached. No change in 
dose. 
Hold drug until platelet criteria 
for dosing reached. No change 
in dose. 
Monitor for signs and 
symptoms of bleeding. 
Consider treatment as 
clinically indicated 
2nd Occurrence 
Hold drug until platelet criteria 
for dosing reached. No change in 
dose. 
Hold drug until platelet criteria 
for dosing reached.  
Reduce dose of docetaxel by 
one dose level and resume 
dosing. 
3rd Occurrence 
Hold drug until platelet criteria 
for dosing reached. No change in 
dose. 
Hold drug until platelet criteria 
for dosing reached.  
Reduce dose of docetaxel by 
one dose level and resume 
dosing. 
4th Occurrence 
Permanently discontinue 
Platelets  
<50 x 109/L 
(≥Grade 3) 
OR 
Symptomatic 
thrombocytopenia 
(severe or medically 
significant bleeding) 
1st occurrence 
Hold drug until platelet criteria 
for dosing reached. No change in 
dose. 
Hold drug until platelet criteria 
for dosing reached. Reduce 
dose of docetaxel by one dose 
level and resume dosing. 
Monitor for signs and 
symptoms of bleeding. 
Consider treatment as 
clinically indicated 
2nd occurrence 
Hold drug until platelet criteria 
for dosing reached. No change in 
dose. 
Hold drug until platelet criteria 
for dosing reached. Reduce 
dose of docetaxel by one more 
dose level and resume dosing. 
3rd occurrence 
Permanently discontinue 
ANC=absolute neutrophil count; CTCAE=Common Terminology Criteria for Adverse Events; G-CSF=granulocyte colony-stimulating factor. 
 
60


9.3.3. 
Recommended Actions with Trilaciclib/Placebo for Adverse Events of Special 
Interest  
Suggested actions to be taken with trilaciclib/placebo following AESI are provided in Table 10. 
Table 10: 
Recommended Actions with Trilaciclib/Placebo Following AESIs 
AESI 
Severity  
Recommended Action 
Injection site 
reactions including 
phlebitis and 
thrombophlebitis 
Grade 1: Tenderness with or 
without symptoms (e.g. warmth, 
erythema, itching) 
Interrupt or slow infusion of trilaciclib. If 
0.9% normal saline is being used as a 
diluent/flush, consider changing to 5% 
dextrose as appropriate for subsequent 
infusions. 
Grade 2: Pain; lipodystrophy; 
edema; phlebitis 
Interrupt infusion of trilaciclib. If pain not 
severe, follow instructions for Grade 1. 
Otherwise, stop infusion in extremity and 
rotate site of infusion to site in alternative 
extremity. If 0.9% normal saline is being 
used as a diluent/flush, consider changing 
to 5% dextrose as appropriate for 
subsequent infusions. Central access may 
also be considered. 
Grade 3: Ulceration or necrosis; 
severe tissue damage; operative 
intervention indicated.  
Grade 4: Life threatening 
consequences; urgent interventions 
indicated. 
Stop infusion and permanently discontinue 
trilaciclib. 
Acute drug 
hypersensitivity 
reactions  
Grade 2: Moderate; minimal, local 
or noninvasive intervention 
indicated; limiting Activities of 
Daily Living 
Stop infusion and hold trilaciclib until 
recovery to Grade ≤1 or baseline, then 
consider resuming trilaciclib. If Grade 2 
recurs, permanently discontinue trilaciclib. 
Grade 3: Severe or medically 
significant but 
not immediately life-threatening; 
hospitalization or prolongation of 
hospitalization indicated; 
disabling; limiting self-care ADL 
OR 
Grade 4: Life-threatening 
consequences; urgent intervention 
indicated 
Permanently discontinue trilaciclib. 
61


AESI 
Severity  
Recommended Action 
ILD/pneumonitis 
Grade 2 (symptomatic) 
Hold trilaciclib until recovery to Grade ≤1 
or baseline, then consider resuming 
trilaciclib. 
If Grade 2 recurs, permanently discontinue 
trilaciclib. 
Grades 3: Severe symptoms; 
limiting self-care ADL; oxygen 
indicated  
OR  
Grade 4: Life-threatening 
respiratory compromise; urgent 
intervention indicated (e.g., 
tracheotomy or intubation) 
Permanently discontinue trilaciclib. 
Other toxicities 
Grade 3: Severe or medically 
significant but not immediately 
life-threatening; hospitalization or 
prolongation of hospitalization 
indicated; disabling; limiting self-
care ADL. 
Hold trilacicib until recovery to Grade ≤1 
or baseline, then consider resuming 
trilaciclib.  
If Grade 3 recurs, permanently discontinue 
trilaciclib.  
Grade 4: Life-threatening 
consequences; urgent intervention 
indicated. 
Permanently discontinue trilaciclib 
AESI=adverse event of special interest; ILD=interstitial lung disease 
9.3.4. 
Hy’s Law Management 
Abnormal values in AST and/or ALT concurrent with abnormal elevations in total bilirubin that 
meet the criteria outlined below in the absence of other causes of liver injury are considered 
potential cases of drug-induced liver injury (potential Hy’s Law cases) and should always be 
considered important medical events.  
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions. Patients who 
present with the following laboratory abnormalities should be evaluated further to determine the 
etiology of the abnormal laboratory values: 
• Baseline AST or ALT and total bilirubin values are within the normal range and the 
patient subsequently presents with AST or ALT ≥3 × ULN concurrent with a total 
bilirubin ≥2 × ULN with no evidence of hemolysis and an alkaline phosphatase ≤2 × 
ULN or not available. 
• Preexisting ALT OR AST OR total bilirubin values above the upper limit of normal, 
and the patient subsequently presents with:  
- 
AST or ALT ≥2 times the baseline values and ≥3 × ULN, or ≥8 × ULN 
(whichever is smaller)  
62


- 
Concurrent with total bilirubin increased by one time the baseline value OR ≥3 × 
ULN (whichever is smaller). 
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history and physical assessment. In addition to repeating AST 
and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, direct and 
indirect bilirubin, gamma-glutamyl transferase, prothrombin time (PT)/International Normalized 
Ratio (INR), and alkaline phosphatase. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen, recreational drug and supplement consumption, family 
history, occupational exposure, sexual history, travel history, history of contact with a jaundiced 
patient, surgery, blood transfusion, history of liver or allergic disease, and work exposure, should 
be collected. Further testing for acute hepatitis A, B, or C infection and liver imaging (e.g., 
biliary tract) may be warranted.  
All cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for liver function test (LFT) abnormalities identified at the time should be considered 
potential Hy’s Law cases irrespective of availability of all the results of the investigations 
performed to determine etiology of the abnormal LFTs. Such potential Hy’s Law cases should be 
promptly reported as SAE via the EDC. 
9.4. 
Supportive Care Interventions 
9.4.1. 
Colony Stimulating Factor Usage 
Use of prophylactic colony stimulating factors (e.g., G-CSF; granulocyte-macrophage colony-
stimulating factor [GM-CSF]) during Cycle 1 (i.e., prior to the actual Cycle 2 Day 1 dosing visit) 
is not allowed. In subsequent cycles (Cycle 2 and beyond), prophylactic colony- -stimulating 
factors are allowed as outlined in regional guidelines or consensus (e.g., American Society of 
Clinical Oncology [ASCO], European Society for Medical Oncology [ESMO], Chinese Anti-
Cancer Association) and package inserts/summary of product characteristics.  
If in any cycle (including Cycle 1), a patient experiences severe neutropenia (Grade 4) or FN and 
is at high risk for infection associated- complications or has prognostic factors that are predictive 
of poor clinical outcomes (Table 11), therapeutic G-CSF/GM-CSF may be used to treat the 
severe neutropenia or FN event per regional guidelines and package inserts.  
Short-acting G-CSF products (i.e., Neupogen or biosimilars) may be administered starting 24 to 
48 hours after chemotherapy and must be stopped 48 hours prior to study drug administration in 
the next cycle. Similarly, Neulasta (or biosimilars) or other long half-life G-CSF products (ex. 
macapegfilgrastim) may be administered 24 to 48 hours after chemotherapy but due to its 
prolonged half-life should not be repeated within that cycle. Biosimilars must be approved for 
use by the national regulatory authority (ex. FDA, European Commission, or the China National 
Medical Products Administration [NMPA]). 
63


Table 11: 
Patient Risk Factors for Poor Clinical Outcomes Resulting from Febrile 
Neutropenia or Infection 
Risk Factor 
Sepsis syndrome 
Age >65 years 
Profound neutropenia (absolute neutrophil count <0.1 × 109/L) 
Neutropenia expected to last >10 days 
Pneumonia 
Invasive fungal infection 
Other clinically documented infections 
Hospitalization at time of fever 
Prior episode of febrile neutropenia 
ASCO=American Society of Clinical Oncology  
Source: Table recreated from Table 2 of the ASCO guidelines (Smith, 2015; Smith, 2006). 
9.4.2. 
Erythropoiesis-Stimulating Agent Usage 
If a patient experiences a hemoglobin level <10.0 g/dL or symptomatic anemia during study 
treatment, ESAs may be used per the current prescribing information (Bohlius, 2019) 
(Procrit®, 2017; Aranesp®, 2011). 
9.4.3. 
Transfusions 
Red Blood Cells 
Based on the NCCN Clinical Practice Guidelines in Oncology for Hematopoietic Growth Factors 
Version 2.2020 and the AABB Clinical Practice Guidelines, the following RBC transfusion 
thresholds are recommended (Carson, 2016; Goel, 2018); however, the patient’s clinical situation 
should always be the primary guiding factor when deciding to transfuse. 
• Transfusion is not indicated until the hemoglobin level is ≤7 g/dL for hospitalized 
adult patients who are hemodynamically stable. 
• An RBC transfusion threshold of ≤8 g/dL is recommended for patients undergoing 
orthopedic surgery, cardiac surgery, and those with preexisting cardiovascular 
disease.  
• Patients with symptomatic anemia should be transfused per the Investigator discretion 
regardless of hemoglobin levels. 
Platelets 
Platelet transfusion is recommended at a threshold of ≤10 × 109/L. Platelets should also be 
transfused in any patient who is bleeding with a platelet count <50 × 109/L (100 × 109/L for 
central nervous system or ocular bleeding) (Kaufman, 2015; Schiffer, 2017). 
9.5. 
Prior/Concomitant Medications and Procedures 
All concomitant medications including prescription medications, over-the-counter preparations, 
growth factors, and blood products from informed consent through 30 days after the last dose of 
study treatment (Post-Treatment Visit) will be documented, where possible. During the study, 
64


prescription, and commercially available products, including traditional Chinese medications, 
with known or suspected immunomodulatory properties should be used with caution or avoided 
entirely. 
Avoid concomitant use of trilaciclib with certain OCT2, MATE1, and MATE-2K substrates 
(e.g., dofetilide, dalfampridine) where minimal concentration changes may lead to serious or life-
threatening toxicities. Refer to the prescribing information for these concomitant medications for 
assessing the benefit and risk of concomitant use of trilaciclib (Section 4.2.8.1.1). 
Docetaxel is a CYP3A4 substrate. Concomitant use of docetaxel and drugs that inhibit CYP3A4 
may increase exposure to docetaxel and should be avoided. In patients receiving treatment with 
docetaxel, close monitoring for toxicity and a docetaxel dose reduction should be considered if 
systemic administration of a potent CYP3A4 inhibitor cannot be avoided.  
Any medication that is contraindicated when using docetaxel is not permitted, and special 
warnings and precautions for use of docetaxel should be observed.  
Administration of other concomitant investigational agents for any indication or any live 
attenuated vaccines is not permitted while on this study. Necessary supportive care (antiemetics, 
antidiarrheals, chemotherapy premedication, etc.) per the standard of care at the study center will 
be permitted. See Section 9.4 for guidance on the use of growth factors (colony-stimulating 
factors and ESAs) during the study. 
Administration of other systemic concomitant non-protocol anticancer therapies prior to 
progression is not permitted while on this study, with the exception of adjuvant endocrine 
therapy for breast cancer or prostate cancer defined as M0 disease or PSA persistence/recurrence 
without metastatic disease. This includes any low-dose systemic chemotherapeutic agent given 
for a nononcologic purpose (e.g., low-dose methotrexate for rheumatoid arthritis). Palliative 
treatment of a symptomatic lesion(s) is permitted to control disease symptoms but not to aid in 
the response of the tumor. If the lesion(s) treated is being followed for evaluation by RECIST 
(target or nontarget lesion), then “not evaluable” should be reported in electronic data capture 
(EDC) for this lesion at subsequent disease assessments following palliative treatment. Patients 
requiring palliative therapy may continue receiving study drug until documented disease 
progression (radiographic or clinical) if, in the Investigator’s opinion, the patient is continuing to 
receive clinical benefit and they meet the requirements described in Section 9.2. However, for 
patients who have not had disease progression at the time of the need for palliative radiation 
therapy or surgery, the requirement for intervention will be regarded as disease progression in 
the study’s analyses and will be entered as such in the EDC.  
Any diagnostic, therapeutic, or surgical procedures performed during the study period will be 
documented. Documentation will include information regarding the date(s), indication(s), 
description of the procedure(s), and any clinical or pathological findings, if available.  
9.6. 
Measures to Minimize Bias: Randomization and Blinding 
The study will be randomized and double-blind. Patients meeting all inclusion and exclusion 
criteria will be randomized 1:1 by an Interactive Web Response System (IWRS) according to a 
randomization schedule generated by an unblinded external statistician. Each patient will be 
assigned a unique randomization number, which will not be reused. A patient who is randomized 
and discontinues from the study, even if no study drug was administered, will not be replaced. If 
65


a patient does not receive the correct study treatment for their allocated treatment arm, the reason 
must be clearly documented in the eCRF. The patient will remain on study and continue to 
receive the same study treatment, all data will be collected, and follow up will continue as 
described in the Schedule of Assessments. 
There will be 2 stratification factors for randomization: country and ECOG performance status 
(0-1 versus 2). Within each country, patient randomization will be stratified by ECOG 
performance status (0-1 versus 2).  
Each site will have an unblinded Pharmacist/Designee, who will have access to the treatment 
assignment. Because the active drug product trilaciclib has a faint yellow color when 
reconstituted and diluted, additional procedures will be implemented to ensure the blind is 
maintained for the patient, Investigator, Research Nurse, Study Coordinator, and other blinded 
site personnel. Details regarding the preparation and administration of trilaciclib/placebo in a 
manner to maintain the blind will be included in the Pharmacy Manual. 
The patients, Investigators, other site staff involved in the clinical care of the patients, and the 
Sponsor or Designees involved in the conduct of the study will not be aware of the treatment 
group to which a particular patient has been randomized. If an Investigator determines that a 
patient’s assignment should be unblinded for reasons of safety, this should be discussed with the 
study Medical Monitor prior to unblinding, unless an urgent and immediate intervention is 
required that precludes this discussion. If unblinding of the treatment assignment is necessary, 
the Investigator or Designee will obtain the treatment assignment details from the IWRS. 
Unblinding of personnel should be limited to the minimum needed for mitigation of safety 
concern. Following unblinding, patient continuation on study will be determined on a case by 
case basis. Any unplanned unblinding must be communicated to the Project Manager, Study 
Statistician, and Sponsor for documentation in the study files and the clinical study report. 
If the blinding code is broken, the date and reason for unblinding must be fully documented in 
source documents and entered on the eCRF. However, every effort should be made by the site 
staff to ensure that the treatment arm in which the unblinded patient is assigned is not 
communicated to any sponsor personnel or designee involved in the conduct of the trial. 
9.7. 
Intervention after End of Study Treatment 
Following completion of study treatment on the study, patients will receive treatment as 
determined by their healthcare provider. During Survival Follow-up, the patient (or legally 
authorized representative where allowed by local regulation) will be contacted to record their 
status (alive or dead) as well as details of any subsequent systemic anti-cancer therapy initiated 
(see Section 11.10). 
66


10. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PATIENT DISCONTINUATION/WITHDRAWAL  
10.1. 
Discontinuation of Study Treatment 
Study drugs will be discontinued if any of the following events occur during the study: 
• A patient suffers an AE that, in the judgment of the Investigator, Sponsor, or Medical 
Monitor, presents an unacceptable risk to the patient 
• General or specific changes in the patient’s condition (e.g., a significant intercurrent 
illness or complication) that, in the judgment of the Investigator, are unacceptable for 
further administration of study drug 
• Occurrence of pregnancy during the study 
• Significant noncompliance with protocol requirements 
• The Sponsor or legal representative of the Sponsor requests the patient to withdraw 
• Patient has documented disease progression (radiographic or clinical progression). See 
Section 9.5 for details regarding palliative therapy.  
• If total time between chemotherapy treatments exceeds a total of >5 weeks, unless agreed 
to by the treating Investigator and Medical Monitor. 
• Where permanent discontinuation of all study drugs is indicated in the toxicity 
management recommendations 
At the time of study drug discontinuation, a Post-Treatment Visit should be completed with 
assessments performed as shown in the Schedule of Assessments (Table 6). The Investigator or 
Designee will document the reason for study drug discontinuation on the applicable eCRF. When 
discontinuation is due to a SAE or a Grade 3 or 4 toxicity considered to be related to study 
medication, the Investigator should follow the event until resolution, return to baseline, or it is 
deemed that further recovery is unlikely. Data on these events should be collected on the AE 
eCRF. In the event a patient discontinues due to pregnancy, the Investigator or designee should 
notify the Medical Monitor by telephone within 24 hours of pregnancy confirmation (see 
Section 17.3). 
For those patients who have not progressed clinically or radiologically at the time of study drug 
discontinuation, every effort should be made to continue radiological tumor assessments every 
12 weeks (±7 days) during survival follow-up, utilizing the same imaging modality as used at 
Screening as outlined in the Schedule of Assessments (Table 6), until progressive disease, 
initiation of subsequent anti-cancer therapy, withdrawal of consent, or study completion, 
whichever occurs first. Results of these scans should be assessed by RECIST v1.1 and data 
entered in EDC in the corresponding tumor assessment forms.  
10.2. 
Discontinuation/Withdrawal from the Study 
A patient may withdraw from the study at any time at his/her own request or may be withdrawn 
at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. At the time of discontinuing from the study, if patient has not already 
67


discontinued study intervention, a Post-Treatment Visit should be completed with assessments 
performed as shown in the Schedule of Assessments (Table 6).  
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the Investigator or designee must document this in the site study records. 
If a patient withdraws consent for further study procedures, the site should clarify if the patient 
(or legally authorized representative where allowed by local regulation) remains open to survival 
contact and associated data collection. Public records may be used to verify survival status if 
permitted by institutional or country guidelines. 
10.3. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
In general, a patient is considered lost to follow-up after there are at least 3 documented attempts 
to contact the patient. It is recommended that 1 attempt is via certified letter to the patient. 
10.4. 
Study and Site Start and Closure  
The overall study begins when the first patient signs the informed consent form. The overall 
study ends when the last patient completes the last study-related phone-call or visit, discontinues 
from the trial or is lost to follow-up (i.e., the subject is unable to be contacted by the 
investigator).  
A study site is considered eligible to start participation in the study once all regulatory approvals 
are in place, site agreement contract is fully executed, and any other required documents are in 
place as required by Sponsor.  
The end of study is event driven. That is, the study will continue until the targeted number of 
deaths is observed. There is an interim analysis for OS planned when approximately 73 patients 
have died. If the interim results demonstrate a statistically significant effect of trilaciclib over 
placebo for OS based on pre-specified criterion, the study will be stopped early due to success. 
Otherwise, the study will continue and be considered complete when the targeted number of 
deaths have occurred for the final OS analysis (approximately 104 deaths), or upon sponsor 
termination of the study. 
The Sponsor’s designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected, a study-site closure visit has been performed, and the site has closed all 
regulatory activities with the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC). 
The Investigator may be requested to initiate study-site closure at any time, provided there is 
reasonable cause and sufficient notice is given in advance of the intended termination. Should 
68


this occur with patients receiving study drug, the patients will transition to receive standard of 
care treatment by their healthcare provider outside of this study. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or Good Clinical 
Practice (GCP) guidelines 
• Inadequate recruitment of patients by the Investigator 
• Discontinuation of further development of trilaciclib 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the patient and 
should assure appropriate patient therapy and/or follow-up. 
69


11. 
STUDY ASSESSMENTS  
Study procedures and their timing are summarized in the Schedule of Assessments (Table 6). 
Adherence to the study design requirements, including those specified in the Schedule of 
Assessments, is essential and required for study conduct. Immediate safety concerns should be 
discussed with the study Medical Monitor upon occurrence or awareness to determine if the 
patient should continue or discontinue study intervention. 
The Investigator or Designee will maintain a screening log to record details of all patients 
screened and to confirm eligibility or record reasons for screening failure, as applicable.  
Procedures conducted as part of the patient’s routine clinical management (e.g., hematology, 
clinical chemistry) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and are performed 
within 28 days prior to Cycle 1 Day 1.  
11.1. 
Screening Assessments 
The following information for screening failures should be recorded into appropriate eCRFs: 
patient ID, demographic data, and reason for failing the screening process. Patients may only be 
rescreened one time at the discretion of the Investigator. For abnormal laboratory values, a 
second test to confirm the first is permitted.  
11.1.1. 
Randomization 
Eligibility should be determined prior to randomization and the start of study treatment. All 
eligible patients will be randomly allocated according to the randomization schedule and will 
receive a unique randomization number. Once a randomization number is assigned to a patient, it 
can never be re-assigned to another patient.  
Eligible patients will be instructed on all protocol requirements, including any restrictions on 
concomitant medication usage. 
Randomization will be performed via IWRS and can be completed up to 3 days prior to the first 
dose of trilaciclib or placebo + docetaxel therapy, following confirmation that the patient is 
eligible for the study. Patients can also be randomized and receive Cycle 1 Day 1 on the same 
day. When required by institutional procedures, randomization will be allowed up to 7 days prior 
to dosing without a protocol deviation. Screening procedures must be completed prior to 
randomization and the screening window remains 28 days. 
11.1.2. 
Demographics 
Age, gender, race, and ethnicity will be collected during the Screening period. 
11.1.3. 
Medical History and NSCLC Cancer Disease History 
Medical and surgical history, including past and current conditions, will be collected. 
Concomitant medications taken from informed consent through 30 days after the last dose of 
study treatment will be recorded. Prior medications (those taken within 14 days of informed 
consent will also be recorded. 
70


Documentation of NSCLC history, including date of diagnosis and histologic type, as well as 
prior therapy (ex. surgery, radiation, systemic chemotherapy, immunotherapy) for NSCLC will 
also be recorded. PD-L1 status will be collected and recorded where available. 
11.2. 
Anti-tumor Efficacy Assessments 
11.2.1. 
Anti-tumor Efficacy Assessment 
Tumor assessment will be performed at the timepoints specified in the Schedule of Assessments 
(Table 6) relative to Cycle 1 Day 1, regardless of drug (cycle) delays.  
Baseline imaging should include computed tomography (CT) or magnetic resonance imaging 
(MRI) of the chest, abdomen, pelvis, and brain. IV contrast should be used unless 
contraindicated. Any CT or MRI obtained as standard of care prior to signing the informed 
consent will not need to be repeated as long as those imaging tests were obtained within 28 days 
prior to Cycle 1 Day 1.  
After baseline tumor assessments (Screening assessment within 28 days prior to Cycle 1 Day 1), 
evaluation of tumor response per RECIST v1.1 will be performed every 6 weeks following Cycle 
1 Day 1 (±7 days) during study drug administration (including imaging of the chest, abdomen, 
and pelvis [and brain if metastasis present at Screening or if symptoms develop]), with additional 
scans performed as clinically indicated. Post-baseline tumor assessments should use the same 
imaging modality as at Screening. IV contrast should be used unless contraindicated. Tumor 
assessments will continue until disease progression, withdrawal of consent, initiation of 
subsequent anti-cancer therapy, or the end of study, whichever occurs first. 
For those patients who have not progressed clinically or radiologically at the time of study drug 
discontinuation, every effort should be made to continue radiological tumor assessments every 
12 weeks (±7 days) during survival follow-up, utilizing the same imaging modality as used at 
Screening, until the occurrence of progressive disease, withdrawal of consent, initiation of 
subsequent anticancer therapy, or study completion.  
Tumor response criteria will be based on RECIST v1.1 (Eisenhauer, 2009) as cited in 
Section 17.4. A partial or complete response should be confirmed by a repeat scan at the next 
scheduled tumor assessment per RECIST v1.1.  
During the course of this study, scans may be collected and sent/uploaded to the Sponsor or 
Designee for storage. Centralized storage is intended for possible blinded independent central 
review (BICR) of disease assessments. At the discretion of the Sponsor, BICR of all scans by 
RECIST v1.1 may be conducted retrospectively. The blinded review will include all patients 
with available images. However, the raw images for patients enrolled in China cannot be stored 
outside of China and therefore these images will be stored in the server in China for central 
imaging review if approved by the related authority. If needed, guidelines for imaging collection 
and storage will be provided in a separate document. The clinical management of patients will be 
based solely upon the results of the assessment conducted by the Investigator based on 
RECIST v1.1 per protocol. 
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11.2.2. 
Myelopreservation Assessments 
The myelopreservation effects of trilaciclib administered prior to docetaxel compared with 
placebo administered prior to docetaxel will be evaluated based on the following: kinetics of 
changes in CBCs (including DSN in Cycle 1 and rate of SN); hematologic toxicities, including 
FN; RBC and platelet transfusions; hematopoietic growth factor utilization; infections and 
systemic antibiotic use. All of these variables will be assessed as described in the safety 
assessments (monitoring of AEs, clinical laboratory assessments, and concomitant medications).  
11.3. 
Safety Assessments  
Unless specified otherwise, safety assessments should be conducted prior to study drug 
administration. 
11.3.1. 
Vital Signs 
The following will be collected per the Schedule of Assessments (Table 6) 15 minutes (+/- 10 
minutes) before and after the trilaciclib/placebo infusion: 
• Body temperature, pulse rate, blood pressure (diastolic and systolic) 
11.3.2. 
Physical Examination 
Full physical examination at Screening should include general appearance, height in centimeters, 
body weight in kilograms, skin, neck, eyes, ears, nose, throat, lungs, heart, abdomen, lymph 
nodes, extremities, and neurological examinations. Subsequent physical exams should include 
body systems as determined by provider (e.g., brief physical exam) and weight.  
Information about the physical examination must be present in the source documentation at the 
study site. Clinically relevant findings observed prior to the start of study drug, should be 
recorded as medical history. Clinically relevant findings observed after the start of study drug, 
which meet the definition of an AE, must be recorded on the AE eCRF. 
Assessments may be performed by a physician, registered nurse, or other qualified health care 
provider.  
11.3.3. 
ECOG Performance Status 
The Investigator or qualified designee will assess ECOG performance status during the 
Screening Period to assess for eligibility according to the inclusion and exclusion criteria 
(Table 12) as well as to monitor performance throughout the study (Table 6).  
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Table 12: 
ECOG Performance Status 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light housework, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry out any selfcare. Totally confined to bed or chair 
5 
Dead 
ECOG=Eastern Cooperative Oncology Group  
Source: Oken, 1982. 
11.3.4. 
Electrocardiogram 
Single standard 12-lead ECGs will be performed as outlined in the Schedule of Assessments 
(Table 6) on Day 1 of Cycles 1 and 2 at the following timepoints: predose (any time prior to 
trilaciclib/placebo on the day of dosing) and at the end of trilaciclib/placebo infusion (within 30 
minutes following the infusion but prior to initiation of docetaxel infusion). Additional ECGs 
may be performed as clinically indicated at any time during the study.  
All 12-lead ECGs will be obtained after the patient has been resting for at least 5 minutes and 
shall be recorded at 25 mm/sec. All ECGs for an individual patient shall be recorded with the 
patient in the same physical position.  
Any ECG with a QTc value of >500 msec shall have the QTc value confirmed via manual read. 
A repeat ECG in triplicate (over approximate 5-minute period) should also be obtained for 
confirmation. The Investigator or qualified designee should review the ECGs for any 
abnormalities as compared with the baseline ECG. Following confirmation, the Investigator 
should evaluate for any other potential causes of the prolongation (e.g., concomitant 
medications) and determine the appropriate clinical course.  
11.3.5. 
Clinical Safety Laboratory Assessments 
Hematology, clinical chemistry, and serum or urine pregnancy test will be performed at the site’s 
local certified laboratory per the schedule outlined in the Schedule of Assessments (Table 6). 
Clinical laboratory samples may be collected from patients at a different location than the 
Investigator’s clinic following approval by the Medical Monitor. A list of clinical laboratory tests 
to be performed is provided in Section 17.1. Hematology may be obtained up to 24 hours and 
serum chemistry may be obtained up to 72 hours prior to each time point on Schedule of 
Assessments but must be reviewed before dosing. Laboratory toxicities will be assessed using 
the NCI-CTCAE, v5.0. 
For women of childbearing potential, pregnancy tests will be performed as follows: serum beta 
human chorionic gonadotropin (ß-hCG) at Screening (must be performed during window 
allowing randomization in IWRS and negative results should be available prior to 
73


randomization) and serum or urine ß-hCG prior to the start of each cycle thereafter, as well at the 
post-treatment visit.  
An abnormal laboratory value is not an AE unless it is considered to be clinically significant. 
Whether a clinically significant laboratory value is also an adverse event will be determined by 
the investigator. Laboratory parameters for which clinically significant values are noted will be 
re-measured on the appropriate clinical follow-up arranged by the Investigator. Any laboratory 
value that remains abnormal at the end of the study and that is considered clinically significant 
should be followed according to accepted medical standards for up to 30 days or until the values 
return to normal or baseline or are no longer considered clinically significant by the Investigator. 
If such values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified, and the Medical Monitor notified.  
If a subsequent cycle is delayed for toxicity, the patient should still complete the clinical 
laboratory assessments on the scheduled Day 1 (entered as an Unscheduled assessment in EDC) 
as well as on the actual first dosing day of that cycle. If the delay is secondary to hematologic 
toxicity, weekly repeat hematology assessments should continue until the finding meets criteria 
for resumption of dosing (see Section 9.3.2; Table 9). 
11.3.6. 
Adverse and Serious Adverse Events 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up, as applicable, AEs that are serious, considered related to the study drugs or study procedures, 
or that caused the patient to discontinue the study or study drugs (see Section 10.1). Patients 
should be encouraged to report AEs freely or in response to general, nondirected questioning. 
Adverse events (serious and non-serious) should be reported on the appropriate page of the 
eCRF. Toxicity will be assessed by Investigators using NCI-CTCAE v5.0. 
11.3.6.1. Time Period and Frequency for Collecting Adverse and Serious Adverse Event 
Information 
AEs will be collected starting from the first dose of study drug through the Post-Treatment Visit. 
Any SAE occurring between the date the patient signs informed consent and the first dose of any 
study drug, and which the Investigator feels is related to a study specific procedure (i.e., would 
not have occurred unless the patient was on the study), should also be reported. Any AEs that 
occur between the date of signing informed consent and the first dose of study drug should be 
recorded as Medical History. 
All SAEs will be recorded and reported to G1 Therapeutics, Inc. Pharmacovigilance (PVG) or 
designee immediately and should not exceed 24 hours after becoming aware of the event, as 
indicated in Section 17.2.  
Investigators are not obligated to actively seek AE or SAE information after 30 days following 
the last dose of study drugs on this study. However, if the Investigator learns of any SAE, 
including a death, at any time after a patient has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, the 
Investigator or designee must promptly notify G1 Therapeutics, Inc. PVG or designee. 
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11.3.6.2. Method of Detecting Adverse and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 17.2. 
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the patient is the preferred method to inquire about AE 
occurrences. 
11.3.6.3. Follow-up of Adverse and Serious Adverse Events 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All AEs (both serious and nonserious) will be followed in accordance 
with good medical practice until resolution, return to baseline, or it is deemed that further 
recovery is unlikely. All measures required for AE management and the ultimate outcome of the 
AE will be recorded in the source document and reported to G1 Therapeutics, Inc. 
All SAEs will be followed until resolution, stabilization, the event is otherwise explained, or the 
patient is lost to follow-up (as defined in Section 10.3). Further information on follow-up 
procedures is provided in Section 17.2. 
11.3.6.4. Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification of G1 Therapeutics, Inc. PVG or designee by the Investigator (or designee) 
of a SAE is essential so that legal obligations and ethical responsibilities towards the safety of 
patients and the safety of a study intervention under clinical investigation are met. 
G1 Therapeutics, Inc. has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical investigation. G1 
Therapeutics, Inc. will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Central IRB/IEC, and Investigators. For all studies, except 
those utilizing medical devices, Investigator safety reports must be prepared for suspected 
unexpected serious adverse reactions (SUSAR) according to local regulatory requirements and 
G1 Therapeutics, Inc. policy and forwarded to Investigators, as necessary. 
An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from G1 Therapeutics, Inc. or designee 
will review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
11.3.6.5. Pregnancy 
Details of all pregnancies in female patients and female partners of male patients will be 
collected after the start of study intervention and until 30 and 120 days respectively, after the last 
dose of study drug. 
If a pregnancy is reported, the Investigator or designee should inform G1 Therapeutics, Inc. PVG 
or designee within 24 hours of learning of the pregnancy and should follow the procedures 
outlined in Section 17.3. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
75


11.4. 
Patient-Reported Outcomes 
The PRO items below will be self-administered by patients, overseen by a designated study site 
staff member. PRO questionnaires should be completed on Days 1 and 13 of Cycle 1 and Day 1 
of each subsequent cycle and at the Post-Treatment Visit, except for the Patient Global 
Impression of Change (PGIC) which is not administered on Day 1 of Cycle 1, per the schedule 
outlined in the Schedule of Assessments (Table 6).  
The PRO questionnaires should be completed on both the planned Day 1 visit and on the actual 
Day 1 of the cycle (i.e., when dosing is delayed and criteria are then met to proceed with Day 1 
treatment). PRO questionnaires may be administered up to 1 calendar day prior to each dosing 
day and are to be completed on the same day a blood sample is collected for hematology 
assessment. Questionnaires administered on Cycle 1 Day 13 may be obtained ±1 day of 
scheduled visit. Questionnaires should be completed before treatment administration, and where 
possible before any laboratory tests or other procedures that are performed that day. 
11.4.1. 
EORTC QLQ-C30 and EORTC QLQ-LC13 
The EORTC QLQ-C30 and QLQ-LC13 are validated instruments that will be administered on 
the days outlined in the Schedule of Assessments (Table 6).  
The EORTC quality of life questionnaire (QLQ) is an integrated system for assessing the health-
related quality of life (QoL) of cancer patients participating in international clinical trials 
(Aaronson, 1993). The core questionnaire, the QLQ-C30, includes 30 items that address 
symptoms and functional impacts that are applicable across cancer populations. The QLQ-C30 
yields 15 domains assessing global health status, symptoms (e.g., fatigue, nausea and vomiting), 
and function (e.g., physical functioning, emotional functioning). Each domain is scored on a 
0-100 scale. The detailed scoring algorithm is included in the scoring manual (Fayers, 2001).  
The EORTC QLQ-LC13 is a supplemental module that was designed for use among a wide 
range of lung cancer patients varying in disease stage and treatment modality (Bergman, 1994). 
The QLQ-LC13 incorporates one multi-item scale to assess dyspnea, and a series of single items 
assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and 
hemoptysis. Domains are scored on a 0-100 scale. The open-ended item assessing location of 
pain and the item asking about the use and effect of pain medications will not be included in the 
QLQ-LC13 version to be administered in this trial, as it is not used in the scoring of the measure. 
A supplemental item from the EORTC Item Library addressing weight loss (“Has weight loss 
been a problem for you?”) will be added to the QLQ-LC13. This version of the QLQ-LC13 has 
been titled the EORTC IL118 by the EORTC. The scoring algorithm is described in the scoring 
manual (Fayers, 2001). 
11.4.2. 
FACIT-Fatigue 
The is FACIT-Fatigue (Yellen, 1997) is a 13-item measure that measures the severity of fatigue 
(e.g., “I feel fatigued,” “I feel tired”) and the impact of fatigue on functioning (e.g., “I have 
trouble starting things because I am tired,” “I need to sleep during the day”). Patients rate their 
experiences over the “past 7 days” using a 0-4 verbal rating scale (“Not at all” to “Very Much”). 
The FACIT-Fatigue is scored as a sum of all 13 of the item responses; the scale range is from 0-
76


52. After appropriate reverse scoring of 11 items, lower scores on the FACIT-F indicate greater 
levels of fatigue. 
11.4.3. 
Patient Global Impression of Change and Patient Global Impression of Severity 
The PGIC and Patient Global Impression of Severity (PGIS) items will be self-administered on 
the days outlined in the Schedule of Assessments (Table 6). The PGIC item will ask the patient 
to rate the change in their fatigue since taking study drug on a 7-point scale ranging from -3 
(very much worse) to 3 (very much better). The PGIS item, will ask the patient to rate the overall 
severity of their fatigue over the past week on a 5-point scale ranging from 0 (none) to 4 
(severe).  
11.4.4. 
5-Level EQ-5D 
The EQ-5D-5Lwill be provided to patients for self-administration on the days outlined in the 
Schedule of Assessments (Table 6). The 5-level EQ-5D (EQ-5D-5L) is a standardized instrument 
by which treatment effects can be assessed by measuring health status at different points in time, 
e.g., before and after treatment, and then investigating the gains (or losses) in reported health 
status. The EQ-5D-5L consists of the EQ-5D descriptive system and the EQ visual analogue 
scale (EQ-VAS). For the EQ-5D, respondents will rate their health on each of 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension has 5 
levels: no problems, slight problems, moderate problems, severe problems, and extreme 
problems. The patient will be asked to indicate his/her health state by ticking the box next to the 
most appropriate statement in each of the five dimensions. This decision results in a 1-digit 
number that expresses the level selected for that dimension. The digits for the five dimensions 
can be combined into a 5-digit number that describes the patient’s health state. The EQ-VAS 
records the patient’s self-rated health on a vertical visual analogue scale, where the endpoints are 
labelled “The best health you can imagine” and “The worst health you can imagine”. The VAS 
can be used as a quantitative measure of health outcome that reflect the patient’s own judgement.  
11.5. 
Pharmacokinetics 
Blood samples for PK analysis will be collected as indicated in the Schedule of Assessments 
(Table 6) from all patients. Three blood samples for PK analysis of trilaciclib will be collected: 
on Cycle 1 Day 1 at the end of trilaciclib/placebo infusion (sample can be taken up to 15 minutes 
prior to the end of infusion), at 30 minutes post the end of trilaciclib/placebo infusion (±15 
minutes) and at 4-6 hours post the end of the trilaciclib/placebo infusion.  
Three samples will also be collected for PK analysis of docetaxel: on Cycle 1 Day 1 at the end of 
docetaxel infusion (sample can be taken up to 15 minutes prior to end of infusion), 2 hours after 
end of docetaxel infusion (±30 minutes) and at 4-6 hours post the end of the docetaxel infusion. 
The actual date and time of each blood sample collection, the scheduled timepoint of collection, 
and the time of dose administration prior to the pharmacokinetic sample will be recorded. Details 
of PK blood sample collection including volume to be collected, timing of samples, processing, 
storage, and shipping procedures are provided in the Laboratory Manual. Blood samples for PK 
analysis may be collected from patients at a different location than Investigator’s clinic. 
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11.6. 
Biomarkers  
11.6.1. 
Rationale for Archival Tumor Collection 
Because trilaciclib maintains G1 arrest in CDK4/6 dependent cells, there is a hypothetical risk 
that trilaciclib could antagonize the anti-tumor efficacy of cytotoxic chemotherapy by 
maintaining a G1 cell cycle arrest of CDK4/6 dependent tumor cells during chemotherapy. While 
the currently available nonclinical and clinical data indicate that this risk remains hypothetical 
and does not influence the overall benefit/risk assessment for combining trilaciclib with 
chemotherapy, this study will evaluate in a retrospective fashion the relationship between 
CDK4/6 status and measures of anti-tumor efficacy; the planned statistical analyses are described 
in Section 12.4.9.  
To support these analyses, prior to signing the informed consent, a FFPE archival tumor 
specimen with an associated pathology report documenting NSCLC (recurrent/metastatic 
preferred) for each patient must be confirmed to be available to send to a central storage facility 
for planned retrospective biomarker analyses. Tumor tissue must consist of a fixed paraffin-
embedded block (100 microns preferred; 75 microns (minimum) unless otherwise approved by 
the Medical Monitor. If a block is not available, 20 or more (15 minimum) freshly cut unstained 
slides are an acceptable alternative. If archival tissue is not available, a fresh biopsy must be 
obtained. Acceptable samples include core needle biopsies, tumor tissue - excisional or 
incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. Fine-
needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavage 
samples are not acceptable. Additional guidance is provided in the Laboratory Manual.  
In addition to CDK4/6 status as described below, tumor PD-L1 status (positive or negative) will 
be determined and anti-tumor efficacy endpoints by PD-L1 status will be evaluated. Any 
remaining tumor tissue following the described analyses will be banked and may be analyzed for 
relevant DNA, ribonucleic acid (RNA), or protein biomarkers and their role in cancer, including 
to better understand immune-related mechanisms.  
Note: No tumor tissue will be archived for study centers in China. 
11.6.2. 
Description of CDK4/6 Signature 
In order to characterize this hypothetical risk in a tumor type without a clear CDK4/6 response 
phenotype, archival tumor tissue will be collected from patients’ most recent biopsy (NSCLC 
primary or metastatic site) and subjected to a genetic signature analysis based on published 
literature in an effort to characterize patient tumors into one of the following three groups 
(Gong, 2017; Shapiro, 2017):  
• CDK4/6 independent 
• CDK4/6 dependent 
• CDK4/6 indeterminate 
The evaluation of the relationship between CDK4/6 status and anti-tumor outcomes may be 
performed when the final OS analysis is performed, that is, when the predicted death events are 
observed. The use of mature OS data, in addition to the ORR and PFS data, will allow for a more 
robust interpretation of the relationship between CDK4/6 status and anti-tumor outcomes without 
78


the complication of trying to draw conclusions with inadequate information (i.e., immature anti-
tumor efficacy data).  
This timing is considered to be appropriate since all currently available data indicate that if there 
is a risk, it is not clinically relevant; therefore, waiting until mature OS data does not pose a 
significant hazard to the enrolled patients, particularly since the percentage of patients at risk for 
a potential negative outcome (i.e., who have CDK4/6 dependent tumors) is predicted to be <10% 
(Section 4.2.7).  
11.7. 
Immunologic and Hematologic Markers 
Blood samples for biomarker analysis will be collected at the time points indicated in the 
Schedule of Assessments (Table 6) from all patients.  
Chemotherapeutic agents may elicit part of their anti-tumor efficacy by modulating the immune 
system to enhance antigen presentation, uptake, and processing; prime the immune response 
through immunodepletion; inhibit regulatory cells; and stimulate immune effector cells 
(Zitvogel, 2008; McDonnell, 2011; Bracci, 2014). Conversely, immunosuppression from direct 
cytotoxicity to the bone marrow and immune system over repeated cycles of chemotherapy may 
counterbalance the positive immunostimulatory effects of chemotherapy. Therefore, therapeutic 
approaches to maintain bone marrow health and immune system function should enhance the 
immune-mediated anti-tumor activity.  
Trilaciclib and other CDK4/6 inhibitors have been shown to augment anti-tumor responses in 
preclinical settings (Klein, 2018) by enhancing T-cell activation through modulation of nuclear 
factor of activated T-cell activity (Deng, 2018), as well as increasing antigen presentation 
through upregulation of MHC class I and II in CDK4/6-sensitive tumors and myeloid cells 
(Goel, 2017; Schaer, 2018). Additionally, CDK4/6 inhibition can upregulate and stabilize the 
protein expression of PD-L1 on tumor cells (Zhang, 2018). 
To evaluate the impact of trilaciclib administration on chemotherapy-induced changes of the 
immune and hematopoietic system, immunophenotypic and hematologic changes will be 
compared (as data warrant) between trilaciclib and placebo on patients receiving docetaxel 
therapy. To assess these changes, peripheral blood will be collected per the timepoints in the 
Schedule of Assessments (Table 6). At each time point (Cycle 1 Day 1, Cycle 1 Day 9, Cycle 2 
Day 1, Cycle 3 Day 1, and Cycle 5 Day 1), collection should occur prior to trilaciclib dosing. 
These blood samples will be banked and may be analyzed for relevant DNA, RNA, or protein 
biomarkers and their role in cancer. Samples may be stored for up to 10 years if patients sign the 
consent form and allow their samples to be stored for any future research. Note: No blood will be 
archived for study centers in China. 
11.8. 
Data Monitoring Committee 
An unblinded, independent Data Monitoring Committee will monitor accumulating safety and 
disposition data with the first meeting planned for when approximately 20 patients have enrolled 
and completed at least 2 cycles of study treatment. The meetings will continue approximately 
every 4 months while patients are on study treatment depending upon the enrollment rate. 
Additional reviews may occur based on DMC requests.  
79


A DMC charter will define the roles and responsibilities of the DMC and its members. 
Additional details regarding the committee’s composition, scope, objectives, procedures and 
policies, including detailed data analysis plan and strategy for maintaining study blind for the 
Sponsor, Investigators and patients, are described in the DMC charter. The DMC will monitor 
accumulating safety and disposition data entirely independent of the conduct of the study. 
11.9. 
Post-Treatment Visit 
When a patient permanently discontinues study treatment, the patient should complete a 
Post-Treatment Visit 30 days (± 7 days) from last dose of study drug as outlined in Table 6.  
11.10. 
Survival Follow-up Phase 
Starting from the last dose of study drug, the patient will be followed approximately every 
2 months for survival. Survival Follow-up Visits can be via telephone, email, or clinic visits.  
For those patients who have not progressed clinically or radiologically at the time of study drug 
discontinuation, every effort should be made to continue radiological tumor assessments every 
12 weeks (±7 days) during survival follow-up, utilizing the same imaging modality as used at 
Screening, as outlined in the Schedule of Assessments (Table 6), until progressive disease, 
initiation of subsequent anti-cancer therapy, withdrawal of consent, or study completion, 
whichever occurs first. 
Information will be collected until the end of the study (or death) to record their status (alive or 
dead). In addition, details of any subsequent systemic anti-cancer therapy initiated, including 
name(s) of agent(s), dates (start/stop) administered, best response to the treatment, and date of 
progression should also be reported to the best of their ability.  
If a patient withdraws consent for further study procedures, the site should clarify if the patient 
(or legally authorized representative where allowed by local regulation) remains open to survival 
contact and associated data collection. Provided that the patient has not withdrawn consent for 
follow up contact, information from medical records may be substituted for phone or other 
contact, provided that records are available as source documentation. Public records may be used 
to verify survival status if permitted by institutional or country guidance.  
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12. 
STATISTICAL CONSIDERATIONS 
Full details on the statistical analyses to be performed will be provided in a separate statistical 
analysis plan (SAP).  
12.1. 
Sample Size Determination 
The sample size is determined to support the primary objective of the study. That is, to evaluate 
the effect of trilaciclib compared to placebo on the overall survival of patients with metastatic 
NSCLC receiving docetaxel in the 2nd/3rd line setting. A total of 104 deaths will be required to 
achieve 85% power to detect a hazard ratio (HR) of 0.55 in OS at a 2-sided significance level of 
0.05. A HR of 0.55 corresponds to a median OS of 16.5 months for the trilaciclib group 
assuming a median OS of 9.1 months for the placebo group (Garon, 2014). With a 12-month 
enrollment period and a 30-month study duration (after the first patient is randomized), a total of 
146 patients are required for randomization at a 1:1 ratio to trilaciclib or placebo. This sample 
size has taken into consideration an interim analysis for OS at the information fraction of 0.70 
using the O'Brien-Fleming method for α-spending to ensure strong control of Type I error rate at 
1-sided 0.025 between the interim and the final analysis for OS. In the sample size calculation, it 
is also assumed that about 5% of patients are lost-to-follow-up during the 30-month study 
duration. EAST® v6.5 is used for the power and sample size calculations. 
12.2. 
Analysis Population 
The intent-to-treat (ITT) population includes all randomized patients. Analyses for the ITT 
population will be conducted according to the randomly assigned treatment regardless of whether 
the patient received study treatment or was compliant with the protocol. Unless otherwise 
specified, the ITT population is the primary analysis population for all efficacy analyses.  
The Response Evaluable (RE) population includes all patients who are in the ITT population and 
who have measurable (target) tumor lesion(s) at the baseline tumor assessment and either (i) 
have at least 1 post-baseline tumor assessment, or (ii) do not have post-dose tumor assessment 
but have clinical progression as noted by the Investigator, or (iii) died due to disease progression 
prior to their first post-baseline tumor scan. Analyses using this analysis population will be 
conducted according to the randomly assigned treatment. The RE population will be the primary 
analysis set for tumor response analyses.  
The safety population includes all randomized patients who received at least 1 dose of study 
drug. Analyses using the safety population will be conducted according to the actual treatment 
received. All safety analyses will be evaluated using the safety population.  
The pharmacokinetic (PK) population will include all patients who received at least one dose of 
study drug and had evaluable PK data. 
12.3. 
Timing of Planned Analysis  
12.3.1. 
First Planned Analysis – Interim Analysis for Overall Survival and Analyses for 
Progression Free Survival, Tumor Responses and Myelosuppression Endpoints 
The first planned analysis will take place primarily to perform the interim analysis for OS. The 
timing of this analysis will be based on the timing when 73 deaths are observed. Following the 
81


assumptions that are used in the sample size calculation (Section 12.1), this analysis might be 
conducted approximately 19 months after the first patient is randomized.  
Per literature, the expected median PFS for patients receiving docetaxel is 3 months 
(Garon, 2014). Assuming trilaciclib can achieve a treatment effect of HR of 0.60, it is estimated 
that at the time of performing the OS interim analysis, 86% of patients would have had 
radiographic-determined disease progression or died. Therefore, the analysis for PFS will be 
conducted at the time when the OS interim analysis is conducted since the PFS events are 
considered mature. It is also anticipated that the treatment effect on tumor response will be 
mature at this time, thus, ORR and DOR will also be analyzed at this time. In addition, analyses 
for myelosuppression and PRO endpoints will be performed at this time.   
The study database will be locked to perform these planned analyses.  
If the interim OS analysis result is positive as determined by the pre-specified statistical 
criterion, the study will be stopped for success and the OS analysis results are considered final. If 
the interim OS analysis result does not meet the criterion of success, the study will continue until 
a total of 104 deaths are observed. 
12.3.2. 
Second Planed Analysis – Final Analysis for Overall Survival and Safety Data 
Analyses 
At the time when 104 deaths are observed, the study database will be locked to perform the final 
analysis for OS. This will be the closure of the study. Safety data and anti-tumor efficacy 
evaluation by CDK 4/6 status and 
 analyses will be performed at this time. 
Under the assumptions used in sample size calculation (Section 12.1), this analysis could be 
performed approximately 30 months after the first patient is randomized.  
It is expected that PFS data are mature at the time of performing the OS interim analysis (i.e., the 
first planned analysis). However, if the percentage of patients with a radiographic determined 
disease progression or death at the time of the first planned analysis is less than 80%, PFS will be 
analyzed again at this time and the results from this analysis will be considered as primary to 
interpret trilaciclib’s effect on PFS in this study.  
At this time, other SAP specified analyses that are not mentioned in Section 12.3.1 will all be 
conducted.  
12.4. 
Statistical Analysis Methods 
A SAP will be developed and finalized prior to the first database lock of the study and will 
include more details related to the statistical analysis of data collected in this study. This section 
is a summary of the key aspects of the planned statistical analyses. 
12.4.1. 
General Considerations 
Data will be summarized by treatment group. The descriptive summary for the categorical 
variables will include counts and percentages. The descriptive summary for the continuous 
variables will include means, medians, standard deviations, 25% and 75% percentiles, and 
minimum and maximum values.  
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There are two stratification factors for randomization: country and ECOG performance status (0-
1 versus 2). A randomization schema will be in place to ensure the best possible balance of 
treatment assignment within each stratum produced by these stratification factors. Countries will 
be grouped into the factor of “region” with 3 components: US, Europe, and Asia. The factor 
“region” will be used instead of “country” in the statistical analysis models to account for 
regional differences in clinical practice. Unless otherwise specified, ECOG status as entered in 
IWRS at the time of randomization will be used as the factor for all stratified analyses. 
12.4.2. 
Patient Disposition 
Patient disposition will be summarized for all patients by treatment group and overall. The 
summary will include number of all screened patients, and number and percentage of patients 
who were randomized, received study drug, discontinued from the study drug with the reasons, 
and discontinued from study with the reasons.  
12.4.3. 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the ITT population by 
treatment group and overall. The demographics to be summarized include age, age group (<65 
versus ≥65 years old), gender, race, ethnicity, and region. The baseline characteristics to be 
summarized include ECOG status, NSCLC history (date of diagnosis, histologic type, and prior 
therapies by line (eg, surgery, radiation, systemic chemotherapy, or immunotherapy). In addition, 
the recorded PD-L1 status at the screening visit will also be summarized along with vital signs at 
the screening visit (body weight, body mass index [BMI], BSA). 
12.4.4. 
Prior and Subsequent Anticancer Therapies 
Prior and subsequent anticancer therapy verbatim terms will be coded to Anatomical Therapeutic 
Classification (ATC) and preferred term (PT) using the latest version of World Health 
Organization-Drug Dictionary (WHO-DD) for the ITT population. Summary statistics will be 
provided for prior systemic anti-cancer therapies given in different setting (1st line or 2nd line) by 
treatment group and overall. For the subsequent systemic anti-cancer therapies, the lines of 
therapy, response to each treatment regimen, and disease progression status will also be 
summarized by treatment group and overall.  
12.4.5. 
Study Drug Exposure, Modification and Dose Intensity  
The summary described below will be based on the safety population. 
Duration of study drug exposure will be calculated for docetaxel and for trilaciclib/placebo by 
treatment group.  
For each treatment group, the number of cycles that patients have received will be summarized 
by descriptive statistics as a continuous variable, while the number of cycles that are completed 
will be summarized as a categorical variable.  
Study drug modifications will be summarized by treatment group in three categories: 
chemotherapy dose reductions, chemotherapy cycle delay, and infusion interruption. The number 
and percentage of patients who have at least one dose reduction for docetaxel will be 
summarized along with a summary of the number of dose reductions that have occurred; the 
number and percentage of patients who have at least one cycle delay will be summarized along 
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with a summary of the number of cycles that have been delayed; the number and percentage of 
patients who have at least one infusion interruption for trilaciclib/placebo or docetaxel will be 
summarized along with a summary of the number of interruptions. Lastly, the primary reason for 
each form of study drug modification (docetaxel dose reduction, cycle delay, and infusion 
interruption) will also be summarized by treatment group. 
For trilaciclib/placebo and docetaxel, respectively, cumulative dose, dose intensity, relative dose, 
and relative dose intensity will be derived and summarized by treatment group. 
12.4.6. 
Efficacy Analyses  
Unless otherwise specified, all efficacy analyses will be performed on the ITT population.  
12.4.6.1. Analyses of Primary Efficacy Endpoint – Overall Survival 
The primary endpoint OS is defined as the time (months) from the date of randomization to the 
date of death for patients who died in the study due to any cause, and the time to the last contact 
date known to be alive for those who survived as of the data cutoff date for the interim OS 
analysis or as of the date when the study database is locked for the final analysis (censored 
cases). Patients lacking data beyond the date of randomization will have their survival time 
censored at the date of randomization.  
The targeted number of deaths for the final analysis in 104 and the final analysis for OS is event-
driven. The number and percentage of patients who died or censored will be summarized by 
treatment group along with the reason for death.  
Treatment effect on OS will be primarily evaluated using a stratified log-rank test controlling for 
the stratification factors of region (US, Europe, or Asia) and ECOG performance status (0-1 
versus 2). The magnitude of the treatment effect, HR (trilaciclib versus placebo), will be 
estimated using a Cox proportional hazard model with the same factors as included in the 
stratified log-rank test. At the final analysis, the (1-α)*100% confidence interval (CI) will be 
generated for the HR, where the α is a 2-sided statistically significant level to be used for the 
final OS analysis determined by actual information fraction used at the interim and the O’Brian-
Fleming α-spending function.  
For each treatment group, the Kaplan-Meier plot will be generated, and the median, 25% and 
75% percentile of OS will be estimated using the Kaplan-Meier method with their corresponding 
95% confidence interval calculated using the method by Brookmeyer and Crowley (1982). 
Additionally, Kaplan-Meier estimates will be provided for the survival probability along with 
their two-sided 95% CIs (Kalbfleisch, 1980) at selected landmarks of 6, 12, 18, and 24 months.  
12.4.6.1.1. Interim Analysis for Overall Survival 
An interim analysis of OS will be conducted at the 70% information fraction, that is, when 
73 deaths are observed. The timing of the interim analysis is estimated to be approximately 19 
months after the first patient is randomized in the study. O'Brien-Fleming method for α-spending 
is applied to ensure strong control family-wise Type I error rate of 1-sided of 0.025 between the 
interim and the final analysis for OS. At the interim analysis, the significant treatment effect of 
trilaciclib compared with placebo for OS is established if the 1-sided p-value from the stratified 
log-rank test is less than or equal to 0.0075 (Table 13). If the final analysis is performed at 104 
84


cumulative deaths as planned, a 1-sided significance level of 0.0227 will be used to evaluate 
treatment effect for OS at the final analysis. The actual significance level at the final analysis for 
OS will be re-calculated if the actual information fraction for the interim OS analysis is different 
than the planned 0.70 using the O'Brien-Fleming α-spending function.  
There will be no final OS analysis if the superiority of trilaciclib over placebo for OS is 
established at the interim analysis. 
Table 13: 
Thresholds for Claiming Statistical Superiority (Trilaciclib versus Placebo) 
at Interim or Final Analysis for Overall Survival 
Analysis 
# of Deaths 
Analysis Timing 
from FPI (month)a 
Z-scale 
HR-scale 
P-value 
Scale  
(1-Sided) 
Interim 
Analysis 
73 
19 
2.434 
0.562 
0.0075 
Final Analysisb 
104 
30 
2.000 
0.673 
0.0227 
FPI=first patient randomized; HR=hazard ratio. 
a Estimated based on the assumptions of accrual period and duration of follow up as used in the sample size 
calculation. 
bStatistical criteria judging the significance at the final analysis could be re-calculated if the interim analysis 
information fraction is different than 0.70. 
The aforementioned analyses will be conducted on the ITT population. 
12.4.6.2. Analysis for Secondary Anti-tumor Efficacy Endpoints 
Secondary anti-tumor endpoints include the following:  
• Progression free survival (PFS) 
• Objective response rate (ORR)  
• Duration of objective response (DOR) 
Progressive disease (PD) and tumor response status are derived per RECIST v1.1 based on tumor 
assessment data entered into the EDC by Investigators.  
12.4.6.2.1. Analysis for Progression Free Survival 
Progression free survival is defined as the time (months) from date of randomization to the date 
of documented radiologic PD per RECIST v1.1 or date of death regardless the cause, whichever 
comes first. PFS will be determined using all available data up to the date of (i) radiographic 
disease progression per RECIST v1.1; (ii) withdrawal of consent to obtain additional scans on 
study; or (iii) initiation of subsequent anticancer therapy, whichever is earliest. Censoring rules 
for patients who do not experience PD or death at the data cutoff date or at the date for final 
database lock will be detailed in the study SAP.  
The treatment effect on PFS will be evaluated by using a stratified log-rank test controlling for 
the two stratification factors. A Cox proportional hazard model with the same terms as in the 
stratified log-rank test will be used to estimate the HR (trilaciclib versus placebo) for PFS along 
with its 95% confidence interval. In addition, Kaplan-Meier plots will be generated and the 
85


median, 25% and 75% percentile of PFS will be estimated using the Kaplan-Meier method by 
treatment group with their corresponding 95% confidence interval calculated using the method 
by Brookmeyer and Crowley (1982).  
Per literature, the expected median PFS for patients receiving docetaxel is 3 months 
(Garon, 2014). Assuming trilaciclib can achieve a treatment effect of HR of 0.60, it is estimated 
that 86% of patients would have a radiographic disease progression or died at the time when OS 
interim analysis is performed. Therefore, the analysis for PFS will be conducted at the time of 
performing interim OS analysis. However, if the observed PD or deaths at the date of data cutoff 
for the OS interim analysis is less than 80%, the final PFS will be performed using the final 
database if the study is not stopped for success after the interim OS analysis. In that event, the 
treatment effect for PFS as observed at the final analysis will be considered to be primary. 
PFS will be analyzed on the ITT population.  
12.4.6.2.2. Analysis for Tumor Response Status and Duration of Objective Response 
At each tumor assessment visit, an overall time point response per RECIST v1.1 will be 
determined programmatically using the measurements of target lesions, non-target lesions, and 
new lesions entered to the eCRF by the Investigators. Best overall response (BOR) will be 
determined per RECIST v1.1 using all timepoint responses prior to or on the date of (i) 
radiographic disease progression; (ii) withdrawal of consent to obtain tumor scans; (iii) death; 
(iv) lost to follow-up; or (v) initiation of subsequent anticancer therapy, whichever is earliest. 
The BOR status for patients will be summarized by the number and percentage of patients in 
each of the following categories: complete response (CR) (confirmed), partial response (PR) 
(confirmed), stable disease (SD) and Not Evaluable (NE).  
ORR is defined as the proportion of patients with confirmed CR or confirmed PR as the BOR 
status. ORR along with its exact 95% two-sided confidence interval using the Clopper-Pearson 
method will be computed for each treatment group. The treatment group difference for ORR will 
be evaluated using a stratified Cochran–Mantel–Haenszel (CMH) test accounting for the two 
stratification factors. The adjusted proportion difference (trilaciclib minus placebo) and its 95% 
CI will be calculated using CMH weight (Kim, 2013).  
DOR is the time (months) from the first date when CR or PR was achieved and confirmed in the 
next tumor scan to the date when the patient experienced disease progression or died in the 
absence of PD. For those who achieved objective response status and did not have disease 
progression or death at the time of data analysis, the earliest date of the following, if it exists, 
will be used to calculate censored time: (i) withdrew consent to obtain scans; (ii) last contact; 
(iii) initiated subsequent anticancer therapy; otherwise, the censored DOR will be calculated 
using the last date known with retained response status as of the data cutoff date for the analysis. 
DOR will be analyzed for the patients who have achieved objective response. The Kaplan-Meier 
method will be used to estimate the median, 25% and 75% percentile of DOR by treatment 
group, along with the 95% CI calculated using the method by Brookmeyer and Crowley (1982).  
Analyses for ORR and DOR will be based on the Response Evaluable patient population. 
86


12.4.6.3. Analysis for Myelosuppression Endpoints 
Myelosuppression endpoints are grouped by lineage and consequence of CIM as follows.  
• Neutrophils related (including DSN in Cycle 1, occurrence of SN, occurrence of FN, and 
occurrence of G-CSF administration) 
• RBC related (including occurrence of Grade 3/4 decrease of hemoglobin, occurrence and 
number of RBC transfusions on/after Week 5, and occurrence of ESA administration) 
• Platelet related (including occurrence of Grade 3 /4 decrease of platelets, occurrence and 
number of platelet transfusions) 
• Endpoints related to trilaciclib’s effect on chemotherapy dosing and hospitalization due 
to CIM (including occurrence and number of dose reductions or dose delay, and 
occurrence and number of hospitalization due to CIM)  
12.4.6.3.1. Analysis for DSN in Cycle 1 
For patients with at least one SN event (ANC value <0.5 × 109/L) in Cycle 1, DSN (days) in 
Cycle 1 is defined as the number of days from the date of the first ANC value of <0.5 × 109/L 
observed at Cycle 1 to the date of the first ANC value ≥0.5 × 109/L and no other ANC 
values <0.5 × 109/L occurred between this day and end of Cycle 1. DSN will be set to 0 for 
patients who do not experience SN in Cycle 1. Data from both scheduled and unscheduled 
assessments will be included in the calculation, and the actual assessment date will be used in the 
derivation of DSN in Cycle 1.  
Treatment effect on DSN in Cycle 1 will be evaluated using a nonparametric analysis of 
covariance (ANCOVA) (Quade, 1967). In this analysis, the rank-transformed (within each 
stratum) DSN values are analyzed by an ANCOVA model with the terms of treatment, and the 
two stratification factors as fixed effects and the rank-transformed baseline ANC as a covariate. 
In addition, the mean difference (trilaciclib – placebo), the standard error and the 95% 
confidence interval for the difference generated from a Satterthwaite t-test will be presented.  
12.4.6.3.2. Analysis for Binary Myelosuppression Endpoints 
For the binary myelosuppression endpoints (e.g., the occurrence of SN and the occurrence of 
RBC transfusions on/after Week 5), the number and percentage of patients with at least one 
occurrence during the treatment period will be summarized by treatment group. The treatment 
effect will be evaluated using a Poisson regression model (Zou, 2004). The model will include 
the two stratification factors as the fixed effect with corresponding baseline value as a covariate 
when applicable (e.g., baseline ANC for occurrence of SN, and baseline hemoglobin for RBC 
transfusions on/after Week 5). The log transformed- duration of exposure either in week or in 
cycle will be used as the offset in the model to account for the variable duration for each patient 
(e.g., the number of cycles for occurrence of SN, and the number of weeks for RBC transfusions 
on/after Week 5). A 2-sided p-value, adjusted relative risk (aRR) (trilaciclib versus placebo) and 
its 95% CI will be generated from the statistical model as applied.  
87


12.4.6.3.3. Analysis for Counting Myelosuppression Endpoints 
For the counting myelosuppression endpoints (e.g., the number of RBC transfusions on/after 
Week 5, and the number of dose reductions during the treatment period), the total number of the 
event, the total number of exposure (either in the unit of week or cycle determined by the 
medical meaning), and event rate per 100 weeks or cycles will be summarized by treatment 
group. For example, the event rate for RBC transfusions on/after Week 5 will be reported by 100 
weeks and that for dose reduction will be reported by 100 cycles. For a given event, patients 
without any of the event during the treatment period will be assigned a value 0 to be included in 
the analysis. The treatment group difference in the event rate will be assessed by a negative 
binomial model. The model will include the two stratification factors as the fixed effect with 
corresponding baseline value as a covariate when applicable (e.g., baseline hemoglobin for the 
analysis of number of RBC transfusions on/after Week 5). The log-transformed duration of 
exposure in week or in cycle will be used as the offset in the model to account for the variable 
duration for each patient (e.g., number of weeks for RBC transfusions on/after Week 5, and 
number of cycles for dose reduction). A 2-sided p-value, aRR (trilaciclib versus placebo) and its 
95% CI will be generated from the statistical model as applied.  
12.4.6.4. Subgroup Analysis for Primary Efficacy Endpoint 
Treatment effect for the primary endpoint OS will be evaluated for each of the stratification 
factors: Region (US, Europe, or Asia) and ECOG status (0-1 versus 2). The treatment effects in 
each category of a factor will be evaluated by using a stratified log-rank test controlling for the 
other stratification factor. A Cox proportional hazard model with the same terms as used in the 
stratified log-rank test will be employed to estimate the HR and its 95% CIs within each category 
of the factor. A forest plot for the HR of OS and its 95% CI will be produced.  
Subgroup analysis will be conducted for some baseline characteristics that might have impact on 
the treatment effect for OS and the details will be specified in the study SAP. 
12.4.7. 
PRO Analyses 
The EORTC QLQ-C30, EORTC QLQ-LC13 with supplemental weight loss item (EORTC 
IL118), FACIT-Fatigue, EQ-5D-5L, PGIC, and PGIS instruments will be used to collect the 
quality-of-life data to assess the impact of trilaciclib on various quality of life measures 
compared with placebo. Analysis for the variables derived from these questionaries will be based 
on the ITT population and detailed in the study SAP.  
12.4.8. 
Safety Analyses  
Safety and tolerability will be assessed by AEs, laboratory tests, vital signs and ECGs. All safety 
data will be summarized using descriptive statistics by treatment group on the safety population. 
Data collected through scheduled or non-scheduled visits will all be included in the safety 
analyses.  
12.4.8.1. Adverse Events  
AEs are defined as those events occurring or worsening after treatment has begun on this study. Adverse 
event data will be coded to system organ class (SOC) and PT using the latest version of 
MedDRA. The severity (toxicity grades 1-5) of AEs will be graded according to the 
88






13. 
ETHICS 
13.1. 
Ethics Review 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., advertisements) 
must be submitted to an IRB/IEC by the Investigator and reviewed and approved by the IRB/IEC 
before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), International Council for 
Harmonisation (ICH) guidelines, the IRB/IEC, European regulation 536/2014 for 
clinical studies (if applicable), and all other applicable local regulations 
13.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
• Applicable ICH GCP Guidelines 
• Applicable laws and regulations 
13.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the patient is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study. 
Patients must also be notified that they are free to discontinue from the study at any time. The 
patient should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The patient’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF 
must be given to the patient or the patient’s legally authorized representative where allowed by 
local regulation. 
91


14. 
DATA HANDLING AND RECORDKEEPING 
14.1. 
Data Protection 
Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets that 
are transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred.  
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient who will be required to give consent for their data to be used as described in the 
informed consent.  
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
14.2. 
Data Quality Assurance 
• All patient data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or Designee electronically. The Investigator is responsible for verifying 
that data entries are accurate and correct by physically or electronically signing the 
eCRF.  
• The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF.  
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk 
Based Monitoring), methods, responsibilities, and requirements, including handling 
of noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• The Sponsor or Designee is responsible for the data management of this study 
including quality checking of the data.  
• Study Monitors will perform ongoing source data verification (SDV) at the 
frequencies and SDV extent as outlined in the Monitoring Plan to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of patients are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
• The Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved 2 years 
following the discontinuance of the investigation of trilaciclib. If it becomes 
necessary for the Sponsor or the Regulatory Authority to review any documentation 
92


relating to the study, the Investigator must permit access to such records. No records 
may be destroyed during the retention period without the written approval of the 
Sponsor. No records maybe transferred to another location or party without written 
notification to the Sponsor. The Investigator must ensure that the records continue to 
be stored securely for as long as they are maintained. It is the responsibility of the 
Sponsor to inform the investigator when these documents no longer need to be 
retained. However, if required by local regulation that these documents should be 
retained for a longer period, then Retention of Documentation will abide by local 
regulation.  
A study-specific COVID-19 Assessment Plan will be utilized for any necessary modifications 
and/or mitigation to the data collection, monitoring or other associated activities during this 
study due to the COVID-19 pandemic. 
14.3. 
Dissemination of Clinical Study Data 
The Sponsor fulfills its commitment to publicly disclose clinical study results through posting 
the results of studies on www.clinicaltrials.gov, the EudraCT, and other public registries in 
accordance with appliable local laws/regulations.  
Data results are posted in an objective, accurate, balanced, and complete manner. Results are 
posted regardless of outcome of the study. 
14.4. 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site. All data reported in 
the eCRF should be supported by source documents; direct entry of data into the eCRF is not 
permitted in this study. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
14.5. 
Audits and Inspections 
Authorized representatives of G1 Therapeutics, Inc., a regulatory authority, an IEC, or IRB may 
visit the site to perform audits or inspections, including source data verification. The purpose of 
an audit or inspection is to systematically and independently examine all study-related activities 
and documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, GCP guidelines of the ICH, and any 
applicable regulatory requirements. The Investigator should contact G1 Therapeutics, Inc. 
immediately if contacted by a regulatory agency about an inspection. 
93


15. 
PUBLICATION POLICY 
By signing the study protocol, the Investigator and his or her institution agree that the results of 
the study may be used by G1 Therapeutics, Inc. for the purposes of national and international 
registration, publication, and information for medical and pharmaceutical professionals. If 
necessary, the authorities will be notified of the Investigator’s name, address, qualifications, and 
extent of involvement. 
Initial publication of the results of this study will be of a cooperative nature that may include 
authors representing the Sponsor, Investigator(s), and collaborating scientists. Independent 
publications by involved individuals may follow. Investigators and their institutions agree not to 
publish or publicly present any interim results of studies without the prior written consent of 
G1 Therapeutics, Inc. G1 Therapeutics Inc. reserves the right to request modification of any 
publication, presentation or use by the Investigator if such activity may jeopardize a patent 
application, an existing patent, or other proprietary rights. G1 Therapeutics, Inc. shall determine 
order of authorship of any publication combining all clinical results of this study. 
94


16. 
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17. 
APPENDICES 
17.1. 
Clinical Laboratory Tests 
• The timing and laboratory tests detailed in Schedule of Assessments (Table 6) will be 
performed by a local laboratory.  
• Protocol-specific requirements for inclusion or exclusion of patients are detailed in 
Section 7 of the protocol. 
• Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
Table 14: 
Protocol-Specified Safety Laboratory Assessments 
Laboratory Assessment 
Parameters 
Hematology 
WBC 
Hemoglobin 
Absolute neutrophil 
count 
Platelets 
Lymphocytes 
Hematocrit 
Serum Chemistry 
Blood Urea Nitrogen 
(BUN) or Urea 
Serum Creatinine 
Bicarbonate 
Aspartate 
Aminotransferase 
(AST) 
Alanine 
Aminotransferase 
(ALT) 
Calcium 
Potassium 
Sodium 
Chloride 
Glucose 
Total Protein 
Albumin 
Alkaline phosphatase 
Total Bilirubin 
 
Other Tests 
Serum or urine human chorionic gonadotropin (hCG) pregnancy test 
(for WOCBP only) 
hCG=human chorionic gonadotropin; RBC=red blood cell; WBC=white blood cell; WOCBP=woman of 
childbearing potential 
105


17.2. 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
17.2.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study patient, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of study intervention. 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, serum chemistry) or other safety assessments 
(e.g., ECG, radiological scans, vital signs measurements), including those that worsen from 
baseline, considered clinically significant and require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) in the medical and scientific judgment of the 
Investigator (i.e., not related to progression of underlying disease) unless they are associated with 
an already reported clinical event, e.g. elevated liver enzymes in a patient with jaundice. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even though it may 
have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which 
are associated with the underlying disease, unless judged by the Investigator to be more severe than 
expected for the patient’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen. 
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17.2.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient was at risk 
of death at the time of the event. It does not refer to an event, which hypothetically might have caused 
death, if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE. 
4. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 
 
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17.2.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the eCRF. 
• 
It is not acceptable for the Investigator to send photocopies of the patient’s medical records to G1 
Therapeutics, Inc. (or designee) in lieu of completion of the AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
G1 Therapeutics, Inc. (or designee). In this case, all patient identifiers, with the exception of the 
patient number, will be redacted on the copies of the medical records before submission to G1 
Therapeutics, Inc. (or designee). 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) 
will be documented as the AE/SAE. 
• 
All SAEs should be reported to G1 Therapeutics, Inc. PVG (or designee) within 24 hours of 
notification on an SAE Form in the eCRF. Any relevant source data related to the SAE that cannot 
be entered in the EDC should be emailed or faxed to G1 Therapeutics, Inc. PVG (or designee): 
G1 Therapeutics, Inc. Pharmacovigilance 
Email: safetyreporting@g1therapeutics.com 
Fax: +1-984-285-7131 
Assessment of Intensity 
Intensity will be assessed using NCI-CTCAE v5.0 criteria, as follows: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living. 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living. 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5: Death related to AE. 
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AE and SAE Recording 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE (Related or Not Related); i.e., is there a “reasonable possibility” the 
study intervention caused the event (yes/no). 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 
• 
The Investigator will also consult the IB and/or Product Information, for marketed products, in 
his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to G1 Therapeutics, Inc. PVG (or designee). However, 
it is very important that the Investigator always make an assessment of causality (Not Related or 
Related) for every event before the initial transmission of the SAE data to G1 Therapeutics, Inc. 
PVG (or designee). 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by G1 Therapeutics, 
Inc. PVG (or designee) to elucidate the nature and/or causality of the SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any new or updated SAE data to G1 Therapeutics, Inc. PVG (or 
designee) within 24 hours of receipt of the information: 
G1 Therapeutics, Inc. Pharmacovigilance 
Email: safetyreporting@g1therapeutics.com 
Fax: +1-984-285-7131 
 
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17.2.4. 
Reporting of SAEs 
SAE Reporting to G1 Therapeutics, Inc. (or designee) via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to G1 Therapeutics, Inc. (or designee) will be the 
EDC. 
• 
If the electronic system is unavailable, then the site will use the paper SAE Report Form in order 
to report the event within 24 hours via email or fax (see below for SAE reporting contact 
information). 
• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
After the study is completed at a given site, the electronic data collection tool will be taken off-
line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study patient or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, then the 
site should report this information on a paper SAE Report form or notify the Medical Monitor by 
telephone. 
• 
Contact for SAE reporting: 
G1 Therapeutics, Inc. Pharmacovigilance 
Email: safetyreporting@g1therapeutics.com 
Fax: +1-984-285-7131  
110


17.3. 
Contraceptive Guidance and Collection of Pregnancy Information 
WOCBP Definition 
Woman of Childbearing Potential  
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes), additional evaluation should be 
considered. 
Women in the following categories are not considered Woman of Childbearing Potential 
1. Premenarchal 
Note: Documentation can come from the site personnel’s review of the patient’s medical 
records, medical examination, or medical history interview. 
2. Premenopausal female with 1 of the following acceptable surgical sterilization 
techniques: complete or partial hysterectomy, bilateral tubal ligation, or occlusion with 
surgery at least 6 months prior to dosing, or bilateral oophorectomy with surgery at least 
2 months prior to dosing. 
3. Postmenopausal female: defined as spontaneous amenorrhea for >12 months prior to 
Screening without alternative cause (e.g., implantable contraceptive, side effect of 
medication, etc.) and a serum follicle stimulating hormone (FSH) within the laboratory’s 
reference range for postmenopausal females. 
• Women taking hormone replacement therapy (HRT) must discontinue HRT at least 
2-4 weeks prior to Screening for accurate assessment of FSH (though exact interval 
will depend on the type and dosage of HRT and should be determined by the 
principal Investigator). 
Contraception Guidance 
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
• Male patients: Males must be surgically sterile prior to Screening with appropriate 
documentation (absence of sperm in ejaculate 6 months after procedure) or have a 
female partner(s) who is either postmenopausal, surgically sterile, or using 2 forms of 
concurrent contraception as defined below. In addition, males must also refrain from 
sperm donation during the study and utilize a barrier method with intercourse during 
and for 6 months following discontinuation of treatment. 
• Female patients: All females of childbearing potential must have a negative serum β-
hCG test result at Screening, and negative serum or urine pregnancy test at each cycle 
during treatment and at the Post Treatment Visit (see Section 11.3.5 and Table 6).  
• Females must be either postmenopausal, surgically sterile, or agree to use 
2 concurrent forms of contraception during the study and for 6 months following last 
dose of study drug. Acceptable forms of contraception include: 
111


− Established use of oral, injected or implanted hormonal methods of contraception 
(stable dose at least 3 months prior to dosing) 
− Intrauterine device or intrauterine system 
− Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. Barrier 
methods alone (without spermicide) are not acceptable methods. Likewise, 
spermicide alone is not an acceptable method 
− Male sterilization prior to Screening with the appropriate post-vasectomy 
documentation (absence of sperm in the ejaculate 6 months after procedure). For 
female patients on the study, the vasectomized male partner should be the sole 
partner for that patient 
− True abstinence when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception 
• For patients who are exclusively in same-sex relationships, contraceptive 
requirements do not apply. If a patient who is in a same-sex relationship at the time of 
signing the ICF becomes engaged in a heterosexual relationship, they must agree to 
use contraception as described previously. If a patient who is abstinent at the time of 
signing the ICF becomes sexually active, they must agree to use contraception as 
described above. 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
• The Investigator or designee will attempt to collect pregnancy information on any 
male patient’s female partner who becomes pregnant while the male patient is in this 
study. This applies only to males who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator or designee will record pregnancy information on the 
Pregnancy – Initial Report Form and submitted to G1 Therapeutics, Inc. PVG or 
designee within 24 hours of learning of the partner’s pregnancy. The female partner 
will also be followed to determine the outcome of the pregnancy. The Pregnancy – 
Follow-up Report Form should be used to report information on the status of the 
mother and child and will be forwarded to G1 Therapeutics, Inc. PVG or designee. 
Generally, the follow-up will be no longer than 12 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for the procedure.  
• Contact for Pregnancy reporting: 
G1 Therapeutics Pharmacovigilance 
Email: safetyreporting@g1therapeutics.com 
Fax: +1-984-285-7131 
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Female Patients who become pregnant 
• The Investigator or designee will collect pregnancy information on any female patient 
who becomes pregnant while participating in this study. The initial Information will 
be recorded on the Pregnancy Reporting and Outcome Form (Pregnancy – Initial 
Report Form) and submitted to G1 PVG or designee within 24 hours of learning of a 
patient’s pregnancy within 24 hours of learning of a patient’s pregnancy.  
• The patient will be followed to determine the outcome of the pregnancy. The 
Investigator or designee will collect follow-up information on the patient and the 
neonate and the information will be collected on the Pregnancy – Follow-up Report 
Form and forwarded to G1 Therapeutics, Inc. PVG or designee. Generally, follow-up 
will not be required for longer than 12 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. A spontaneous abortion (occurring at <22 weeks 
gestational age) or still birth (occurring at >22 weeks gestational age) is always 
considered to be an SAE and will be reported as such. Any post-study pregnancy 
related SAE considered reasonably related to the study intervention by the 
Investigator will be reported to G1 Therapeutics, Inc. PVG or designee. While the 
Investigator is not obligated to actively seek this information in former study patients, 
he or she may learn of an SAE through spontaneous reporting. 
• Any female patient who becomes pregnant while participating in the study will 
discontinue study intervention. 
• Contact for Pregnancy reporting: 
G1 Therapeutics Pharmacovigilance 
Email: safetyreporting@g1therapeutics.com 
Fax: +1-984-285-7131 
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17.4. 
Definitions of Tumor Response and Disease Progression (per 
RECIST v1.1) 
The determination of tumor response and progression will be based on the RECIST v1.1 
(Eisenhauer, 2009). Disease progression may also be determined clinically by the Investigator. 
Tumor lesions will be categorized as follows: 
Measurable lesions: tumor lesions with a longest diameter (measured in at least 1 dimension) 
with a minimum size as follows:  
• 10 mm by CT or MRI (with a scan slice thickness of no greater than 5 mm) 
• Measurable lymph nodes must be ≥15 mm on the short axis by CT or MRI (with a 
scan slice thickness of no greater than 5 mm); only the short axis is to be measured at 
baseline and follow-up.  
• Lytic bone lesions or mixed lytic-blastic lesions with a soft tissue component meeting 
the definition of measurability above can be considered measurable lesions.  
• Cystic lesions representing cystic metastases that meet the definition of measurability 
described above can be considered measurable lesions. If present, noncystic lesions 
should be selected as target lesions for this study. 
• A tumor lesion that has been previously irradiated may be considered measurable if 
unequivocal growth of the lesion has been demonstrated.  
Target lesions: At baseline, up to 5 measurable tumor lesions/lymph nodes (with a maximum of 
2 lesions per organ) should be identified as target lesions. Lesions with the longest diameter, that 
are representative of all involved organs, and for which reproducible repeated measurements can 
be obtained should be selected as the target lesions. Malignant lymph node is considered an 
organ in this study, therefore only 2 malignant lymph nodes (regardless of location) may be 
selected as target lesions and all others should be entered as nontarget lesions. 
Non-measurable Lesions: tumor lesions with a longest diameter <10 mm, lymph nodes with 
≥10 to <15 mm short axis, or non-measurable lesions such as leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, or abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by CT scan or MRI.  
Nontarget lesions: All other lesions (or sites of disease) identified at baseline should be 
identified as nontarget lesions and recorded in the eCRF. Measurements of these lesions are not 
required, but the presence, absence, or unequivocal progression of each nontarget lesion should 
be recorded in the eCRF at each follow up time point. Multiple nontarget lesions in the same 
organ may be noted as a single item on the eCRF. 
Evaluation of Target Lesions 
The definitions for tumor response for the target lesion per RECIST v1.1 are as follows: 
Complete Response: Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm (<1 cm). 
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Partial Response: At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters. 
Progressive Disease: At least a 20% increase in the sum of the diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm (0.5 cm). (Note: the appearance of one or more new lesions is also 
considered progression). 
Stable Disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
Evaluation of Non-Target Lesions 
Complete Response: Disappearance of all non-target lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease: Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. ‘Unequivocal progression’ represents a substantial increase in overall 
tumor burden such that treatment should be discontinued even in the setting of SD or PR in the 
target disease. Although a clear progression of “non-target” lesions only is rare, the opinion of 
the treating physician should prevail in such circumstances. 
Appearance of New Lesions 
The appearance of new lesion(s) is considered PD according to RECIST v1.1.  
Timepoint Response 
Patients with Measurable Disease (i.e., Target ± Non-Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-CR/Non-PD/NE 
No 
PR 
SD 
Non-CR/Non-PD/NE 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PDa 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response; NE=not evaluable; PD: progressive disease; PR=partial response; SD=stable disease. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort should 
be made to document the objective progression even after discontinuation of treatment. 
a Unequivocal progression in non-target lesions may be accepted as disease progression. 
115


Patients with Evaluable or Non-Measurable Disease Only (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR=complete response; NE=not evaluable; PD: progressive disease; SD=stable disease. 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an 
endpoint for assessment of efficacy in some studies so to assign this category when no lesions can be measured is 
not advised. 
116