Clinical trial NCT04887831
Conditions: Urothelial Carcinoma Bladder Cancer Myelosuppression Adult Chemotherapy-induced Neutropenia Metastatic Bladder Cancer
Keywords: Trilaciclib dihydrochloride/Cosela Metastatic Urothelial Carcinoma Cyclin-dependent kinase 4/6 inhibitor Immuno-oncology Solid tumor Chemotherapy-induced myelosuppression Myeloprotective
Sponsor: G1 Therapeutics, Inc.
Start date: 2021-06-04; Completion date: 2024-03-01
Enrollment: 92 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, multicenter, randomized, open-label study evaluating the safety and efficacy of trilaciclib administered with platinum-based chemotherapy followed by trilaciclib administered with avelumab maintenance therapy compared with platinum-based chemotherapy followed by avelumab maintenance therapy in participants receiving first-line treatment for advanced/metastatic urothelial carcinoma.

Detailed description:
Participants will be randomly assigned (1:1) to receive standard of care platinum-based chemotherapy (with or without the addition of trilaciclib) administered intravenously (IV) in 21-day cycles followed by standard of care avelumab maintenance therapy (with or without the addition of trilaciclib) administered IV in 14-day cycles.

Participants enrolled in the study will be eligible to receive 4-6 cycles of platinum-based chemotherapy, and participants without progressive disease (PD) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines (i.e., with an ongoing complete response \[CR\], partial response \[PR\], or stable disease \[SD\]) after platinum-based chemotherapy will be eligible to receive avelumab maintenance therapy until disease progression, unacceptable toxicity, withdrawal of consent, Investigator decision, or the end of the trial, whichever comes first.

Participants will be followed for survival approximately every 3 months after receiving the last dose of study medication.

Arms: arm 1: Gemcitabine 1000 milligram per square meter (mg/m\^2) + Cisplatin (70 mg/m\^2) or Carboplatin (Area under the concentration-time curve \[AUC\] 4.5) followed by Avelumab (800 mg) arm 2: Trilaciclib (240 mg/m\^2) + Gemcitabine (1000 mg/m\^2) + Cisplatin (70 mg/m\^2) or Carboplatin (AUC 4.5) followed by Trilaciclib (240 mg/m\^2) + Avelumab (800 mg)
Interventions: intervention 1: Trilaciclib intervention 2: Gemcitabine intervention 3: Cisplatin intervention 4: Carboplatin intervention 5: Avelumab
Intervention descriptions: intervention 1: Trilaciclib administered IV prior to chemotherapy and avelumab maintenance therapy on each day chemotherapy and avelumab maintenance therapy is administered. intervention 2: Gemcitabine administered IV on Day 1 and Day 8 of each 21-day cycle intervention 3: Cisplatin administered IV on Day 1 of each 21-day cycle intervention 4: Carboplatin administered IV on Day 1 of each 21-day cycle intervention 5: Avelumab administered IV on Day 1 of each 14-day maintenance cycle

Protocol documents:
Prot_000.pdf: 
Protocol Amendment 2 
G1T28-209: PRESERVE 3 
Version 3.0 dated 03 February 2022 
1 
Protocol Title: A Phase 2, Randomized, Open-Label Study of Trilaciclib Administered with 
First-Line Platinum-Based Chemotherapy and Avelumab Maintenance Therapy 
in Patients with Untreated, Locally Advanced or Metastatic Urothelial 
Carcinoma (PRESERVE 3) 
Protocol Number: G1T28-209 
Compound: Trilaciclib for Injection, 300 mg/vial 
Study Phase: 2 
Study Name: PRESERVE 3 
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: 156967 
EudraCT: 2021-000205-24 
Approval Date: 03 February 2022 (Version 3.0) 
Previous Version (Amendment 1): 13 April 2021 (Version 2.0) 
Original protocol: 22 February 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. 


PPD
PPD


Protocol Amendment 2 
 
G1T28-209: PRESERVE 3 
Version 3.0 dated 03 February 2022 
 
3 
 
 
 
INVESTIGATOR’S AGREEMENT 
 
Clinical Study Protocol G1T28-209: A Phase 2, Randomized, Open-Label Study of Trilaciclib 
Administered with First-Line Platinum-Based Chemotherapy and Avelumab Maintenance 
Therapy in Patients with Untreated, Locally Advanced or Metastatic Urothelial Carcinoma 
(PRESERVE 3) 
 
Version 3.0 (Amendment 2) Issue Date: 03 February 2022 
Replaces Version 2.0 (Amendment 1) Issue Date: 13 April 2021 
Original Protocol (Version 1.0) Issue Date: 22 February 2021 
 
I have read the G1T28-209 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 
 
 


Protocol Amendment 2 
 
G1T28-209: PRESERVE 3 
Version 3.0 dated 03 February 2022 
 
4 
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: G1T28-209 
Phase: 2 
Regions: North America, Europe 
Title of Study:  
A Phase 2, Randomized, Open-Label Study of Trilaciclib Administered with First-Line 
Platinum-Based Chemotherapy and Avelumab Maintenance Therapy in Patients with Untreated, 
Locally Advanced or Metastatic Urothelial Carcinoma (PRESERVE 3) 
Study centers: Approximately 45 centers 
Studied period (years): Approximately 34 months 
Estimated date first patient randomized: Q2 2021 
Estimated date last patient completed: Q1 2024 
Objectives:  
Primary: 
To evaluate the anti-tumor efficacy of trilaciclib when combined with platinum-based chemotherapy 
followed by trilaciclib administered with avelumab maintenance therapy as measured by progression-
free survival (PFS) during the overall study. 
Secondary: 
To evaluate the anti-tumor efficacy of trilaciclib as measured by the objective response rate (ORR), 
disease control rate (DCR), duration of objective response (DOR), PFS in the maintenance period, 
overall survival (OS), and probability of survival at Month 16; evaluate the myeloprotective effects of 
trilaciclib on chemotherapy-induced myelosuppression; and assess the safety and tolerability of 
trilaciclib in patients receiving platinum-based chemotherapy followed by avelumab maintenance 
therapy. 
Study Design: 
This is a Phase 2, multicenter, randomized, open-label study evaluating the safety and efficacy of 
trilaciclib administered with platinum-based chemotherapy followed by trilaciclib administered with 
avelumab maintenance therapy compared with platinum-based chemotherapy followed by avelumab 
maintenance therapy in patients receiving first-line treatment for advanced/metastatic urothelial 
carcinoma.  
Approximately 90 patients will be randomly assigned (1:1) to one of two treatment arms:  
• 
Arm A – platinum-based chemotherapy followed by avelumab maintenance therapy 
• 
Arm B – trilaciclib plus platinum-based chemotherapy followed by trilaciclib plus 
avelumab maintenance therapy 
A Data Monitoring Committee (DMC) will monitor accumulating safety and anti-tumor response data 
with the first meeting planned when approximately 10 patients treated with trilaciclib + cisplatin or 10 
patients treated with trilaciclib + carboplatin have completed at least 2 cycles of study treatment, 
whichever occurs first. The meetings will continue approximately every 6 months or as defined in the 
DMC charter while patients are on study treatment depending upon the enrollment rate. Additional 


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Version 3.0 dated 03 February 2022 
 
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reviews may occur. 
Standard of care platinum-based chemotherapy (with or without the addition of trilaciclib) will be 
administered intravenously (IV) in 21-day cycles and standard of care avelumab maintenance therapy 
(with or without the addition of trilaciclib) will be administered IV in 14-day cycles.  
There will be two stratification factors for randomization: presence of visceral metastasis (yes or no) 
at randomization, and initial platinum-based chemotherapy to be administered (cisplatin or 
carboplatin). 
Study drugs will be administered as indicated in the respective dosage and administration sections of 
the synopsis.  
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 and completes at the End of 
Treatment Visit. Survival Follow-up assessments should occur every 3 months after the End of 
Treatment Visit (including assessments at Month 17 Day 1).  
Patients enrolled in the study will be eligible to receive 4-6 cycles of platinum-based chemotherapy, 
and patients without progressive disease (PD) as per Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 guidelines (i.e., with an ongoing complete response [CR], partial response [PR], or 
stable disease) after platinum-based chemotherapy will be eligible to receive avelumab maintenance 
therapy until disease progression, unacceptable toxicity, withdrawal of consent, Investigator decision, 
or the end of the trial, whichever comes first. Treatment visits will occur consecutively as planned, 
without interruption, except when necessary to manage toxicities or for administrative reasons (long 
weekends, holidays, weather conditions, etc.). There should be no more than 42 days between the 
start of each platinum-based chemotherapy cycle (with or without trilaciclib). Dosing delays >42 days 
between the start of each platinum-based chemotherapy cycle may be permitted on a case-by-case 
basis with the approval of the Investigator and Medical Monitor. There should be no more than 56 
days between doses of avelumab maintenance therapy (with or without trilaciclib). Dosing delays >56 
days between doses of avelumab may be permitted on a case-by-case basis with the approval of the 
Investigator and Medical Monitor. Avelumab maintenance therapy (with or without trilaciclib) should 
begin at a minimum of 4 and not more than 10 weeks after the last dose of platinum-based 
chemotherapy (with or without trilaciclib). Criteria which patients must meet in order to receive study 
drug on Day 1 and on Day 8 of each chemotherapy cycle are provided in the full protocol. 
An End of Treatment Visit will occur approximately 14 days following a patient’s last dose of study 
drug. Safety Follow-up Visits (which may be a phone call) will occur 30 days after the last dose of 
study drug and 90 days after the last dose of avelumab. Patients will be followed for survival 
approximately every 3 months (including an assessment at Month 17 Day 1) after the End of 
Treatment Visit. Survival Follow-up Visits may be done via telephone, email, or clinic visit. Unless 
otherwise decided by the Sponsor, the study will continue until at least 60% of patients enrolled in the 
study have died.  
Methodology:  
Sample Size Justification: 
The sample size is calculated to support the primary objective of the study, that is, to evaluate 
trilaciclib’s effect on PFS in patients who receive platinum-based chemotherapy followed by 
avelumab maintenance therapy as first-line treatment. From the literature, patients with urothelial 
carcinoma receiving avelumab maintenance therapy after platinum-based chemotherapy had a median 
PFS duration of 3.7 months (Powles, 2020). Considering 4 months of chemotherapy prior to 
maintenance therapy in this study, the median PFS duration for the control group (Arm A: platinum-
based chemotherapy followed by avelumab maintenance therapy) in this study is assumed to be 7 
months. 
A total of 63 PFS events will be required to achieve 77% power to detect a hazard ratio (HR) of 0.6 in 


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PFS at a 2-sided significance of 0.2. An HR of 0.6 corresponds to a median PFS duration of 11.7 
months for trilaciclib arm. Assuming 10 months of enrollment and final PFS analysis taking place at 
approximately 22 months after the first patient is randomized, a total of 90 patients are required to be 
randomized at a 1:1 ratio to the control group (Arm A) or trilaciclib group (Arm B). In the sample 
size calculation, it is also assumed that about 5% of patients are lost-to-follow-up during the 22 
months (equivalent to a monthly lost to-follow-up rate of 0.0023315 assuming an exponential 
distribution). EAST® v6.5 is used for the power and sample size calculations. 
Number of patients (planned):  
Approximately 90 patients 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 locally advanced or 
metastatic urothelial carcinoma receiving first line treatment and with an Eastern Cooperative 
Oncology Group (ECOG) performance status of 0-2. Patients must have documented, locally 
advanced (T4b, any N; or any T, N 2-3) or metastatic urothelial carcinoma (M1, Stage IV) (also 
termed transitional cell carcinoma [TCC] or urothelial cell carcinoma [UCC] of the urinary tract; 
including renal pelvis, ureters, urinary bladder, and urethra). Patients must have measurable disease as 
defined by RECIST v1.1, considered eligible to receive platinum-based chemotherapy and avelumab 
maintenance therapy, and no prior systemic therapy in the inoperable, locally advanced, or metastatic 
setting. A treatment-free interval > 12 months between the last perioperative/adjuvant treatment 
administration and the date of recurrence is required in order to be considered treatment-naïve in the 
metastatic setting. Patients must have tumor tissue available from a metastatic or locally recurrent 
urothelial carcinoma lesion (archival or fresh biopsy). Patients must also have adequate organ 
function as demonstrated by the laboratory values. 
Investigational product, dosage, and mode of administration:  
Trilaciclib 
In each chemotherapy cycle at Day 1 and Day 8, a dose of trilaciclib 240 mg/m2 reconstituted and 
diluted in 250 mL of dextrose 5% in water (D5W) or normal saline (sodium chloride solution 0.9%) 
will be administered as a 30-minute IV infusion completed within 4 hours prior to the start of 
chemotherapy on each day chemotherapy is administered. If administration of platinum-based 
chemotherapy is skipped or discontinued, trilaciclib will also be skipped or discontinued. 
In each avelumab maintenance cycle at Day 1, a dose of trilaciclib 240 mg/m2 reconstituted as 
described above will be administered as a 30-minute IV infusion completed within 4 hours prior to 
the start of avelumab on each day avelumab is administered. If administration of avelumab 
maintenance therapy is delayed or skipped, then trilaciclib should be administered as scheduled. If 
administration of avelumab maintenance therapy is permanently discontinued, trilaciclib will also be 
permanently discontinued. 
Duration of treatment:  
Patients enrolled in the study will be eligible to receive 4-6 cycles of platinum-based chemotherapy 
followed by avelumab maintenance therapy (with or without trilaciclib) until disease progression, 
unacceptable toxicity, withdrawal of consent, Investigator decision, or the end of the trial, whichever 
comes first. In specific circumstances, study treatment may continue beyond disease progression with 
approval from the Medical Monitor. 
Reference therapy, dosage, and mode of administration:  
Platinum-based chemotherapy 
Gemcitabine 1000 mg/m2 by IV infusion on Day 1 and Day 8 of each 21-day chemotherapy cycle.  
Cisplatin eligible: cisplatin 70 mg/m2 administered IV on Day 1 of each 21-day chemotherapy cycle. 


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Gemcitabine should be administered before cisplatin. 
Cisplatin ineligible: carboplatin using Calvert formula with a target area under the curve (AUC) = 4.5 
administered IV on Day 1 of each 21-day chemotherapy cycle. Gemcitabine should be administered 
before carboplatin. 
Other platinum-based chemotherapies, such as methotrexate/carboplatin/vinblastine for example, are 
not permitted in this study. 
Avelumab Maintenance Therapy 
Avelumab 800 mg administered IV on Day 1 of each 14-day maintenance cycle as a 60-minute 
infusion. Premedication with an antihistamine and with paracetamol (acetaminophen) approximately 
30 to 60 minutes prior to each dose of avelumab is mandatory for the first 4 infusions. Premedication 
should be administered for subsequent avelumab doses based upon clinical judgment and 
presence/severity or prior infusion reactions. 
Criteria for evaluation:  
Efficacy: 
Anti-tumor efficacy assessments include PFS, ORR (unconfirmed and confirmed), DCR, DOR, OS, 
and the probability of survival at Month 16. Tumor response criteria will be based on RECIST v1.1. 
Myelosuppression endpoints 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 oral body temperature), 12-lead 
safety electrocardiogram (ECG) results, dose modifications, and physical examination findings.  
Pharmacokinetics: 
The pharmacokinetics (PK) of trilaciclib and metabolites, cisplatin and avelumab will be determined 
using a non-linear mixed effects modeling approach. 
Pharmacodynamics: 
Pharmacodynamics may be assessed using peripheral blood and tumor biopsies to evaluate potential 
markers of response and resistance, including immune markers. 
Statistical methods:  
Unless otherwise specified, all analyses for the efficacy and safety endpoints will be conducted on 
data collected from both the chemotherapy period and the maintenance period in all patients 
irrespective of which platinum-based treatment (cisplatin and/or carboplatin) was administered as of 
the data cutoff date determined for a specific analysis. 
Summary statistics will be provided by treatment group for all endpoints, when appropriate. 
Categorical variables will be summarized by counts and percentages, while continuous variables will 
be summarized by mean, standard deviations, median, 25% and 75% percentiles, and minimum and 
maximum values.  
Patients will be randomized according to the stratification factors of presence of visceral metastasis 
(yes or no) and initial platinum-based chemotherapy to be administered (cisplatin or carboplatin). 
When appropriate, presence of visceral metastasis (yes or no) at randomization and initial platinum-
based chemotherapy to be administered (cisplatin or carboplatin) will be included in statistical models 
for efficacy analyses with the strata information as entered in the Interactive Web Response System at 
the time of randomization. 
 


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Version 3.0 dated 03 February 2022 
 
8 
Analysis population 
The following analysis populations are defined for the study.  
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 set 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 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 any study drug. 
Analyses using the safety population will be conducted according to the actual treatment received. All 
safety analyses will be conducted using the safety population. 
The PK population will include all patients who received at least one dose of trilaciclib or cisplatin or 
avelumab and have evaluable PK data. 
Statistical analysis methods for primary and secondary endpoints 
Analysis for primary efficacy endpoint 
The primary efficacy endpoint, PFS (months) during the overall study, is defined as the time from the 
date of randomization to the date of documented radiologic disease progression per RECIST v1.1 or 
death due to any cause, whichever comes first regardless of in which treatment period the event 
occurs. For patients who do not experience PD or are alive at time of performing the PFS analysis, 
PFS will be calculated per censoring rules detailed in the statistical analysis plan (SAP). The primary 
analysis for PFS will be conducted at the time when 63 patients have radiographic-determined disease 
progression or died. The treatment effect on PFS will be primarily evaluated using a stratified log-
rank test accounting for the two stratification factors. The magnitude of the treatment effect will be 
estimated by an HR (Arm B versus Arm A) using a stratified Cox proportional hazards model 
controlling for the two stratification factors. The 80% confidence interval (CI) will be generated for 
the HR. The Kaplan-Meier plots will be produced for PFS, respectively. Analysis of PFS will be 
based on the ITT population. 
Analysis for secondary anti-tumor efficacy endpoints 
ORR will be evaluated at the time when all randomized patients have finished chemotherapy and at 
the end of the treatment phase. ORR in the chemotherapy period is defined as the proportion of 
patients with best overall response (BOR) of confirmed or unconfirmed CR or PR. Unconfirmed CR 
or PR will be only allowed if there is lack of time to perform confirmed tumor scan in the 
chemotherapy period before the patient enters the maintenance period. ORR in the maintenance 
period is defined as the proportion of patients with BOR of confirmed CR or PR as determined using 
all tumor scan data from the maintenance period. ORR during the overall study is defined as the 
proportion of patients with BOR of confirmed CR or PR as determined using all tumor scan data from 
both chemotherapy and maintenance periods. ORR along with its exact 95% two-sided CI 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 (Arm B – Arm A) and its 95% CI will be 
calculated using CMH weight (as described in Kim, 2013). ORR will be analyzed based on the RE 
population. Other tumor response related endpoints will be defined similarly for different study 
periods.  


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In addition to PFS during the overall study, PFS in the maintenance period will be analyzed using 
similar statistical approaches. PFS in the maintenance period is defined as the time from the date of 
entering the maintenance period to the date of documented radiologic disease progression per 
RECIST v1.1 or death due to any cause in that period, whichever comes first. PFS in maintenance 
period will be analyzed based on the ITT population with at least a visit in the maintenance period.  
OS (months) during the overall study is defined as the time from the date of randomization to the date 
of death for patients who died in the study due to any cause or the time to the last contact date known 
to be alive for those who survived as of the data cutoff date for the planned OS analysis (censored 
cases). In addition, OS in the maintenance period will also be analyzed. For OS in maintenance 
period, the date of entering the maintenance period will be used as the start time in the OS calculation. 
OS in maintenance phase will be analyzed based on the ITT population with at least one visit in the 
maintenance period. The treatment effect on OS will be evaluated by applying the same statistical 
models used for PFS analysis. Survival probability at Month 16 will be estimated using Kaplan-Meier 
method along with its two-sided 95% confidence interval (CI) (Kalbfleisch, 1980) for each treatment 
group, based on the ITT population.  
 
Analysis for safety endpoints 
Safety and tolerability will be assessed by AEs, dose modifications, laboratory tests, and vital signs. 
All safety data will be summarized using descriptive statistics by treatment group using the safety 
population. Adverse events 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 and preferred term using 
the latest version of Medical Dictionary for Regulatory Activities (MedDRA). The severity (toxicity 
grades 1-5) of AEs will be graded by Investigators according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Any AE, AEs related to 
each component of study treatment, AEs leading to study drug discontinuation, dose reductions, cycle 
delays, trilaciclib adverse events of special interest (AESIs), and avelumab AESIs will be summarized 
by system organ class, preferred term, and CTCAE grade, as appropriate. For laboratory assessments 
and vital signs, 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, Version 5.0 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. Both scheduled and unscheduled data will be included in the safety 
evaluation. 


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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 ...............10 
3. 
LIST OF ABBREVIATIONS .....................................................................................16 
4. 
INTRODUCTION ......................................................................................................20 
4.1. 
Urothelial Carcinoma ..................................................................................................20 
4.2. 
Treatment of Metastatic Urothelial Carcinoma ..........................................................21 
4.2.1. 
Platinum-Based Chemotherapy ..................................................................................21 
4.2.2. 
Immune Checkpoint Inhibitors ...................................................................................21 
4.3. 
Urothelial Carcinoma and Trilaciclib .........................................................................23 
4.4. 
Study Rationale ...........................................................................................................26 
4.5. 
Background .................................................................................................................27 
4.5.1. 
Summary of Nonclinical Data ....................................................................................27 
4.5.1.1. 
Pharmacology Studies ................................................................................................27 
4.5.1.2. 
Pharmacokinetic Studies .............................................................................................29 
4.5.2. 
Summary of Clinical Data ..........................................................................................30 
4.5.2.1. 
Efficacy .......................................................................................................................30 
4.5.2.2. 
Pharmacokinetics ........................................................................................................34 
4.5.3. 
Risks ...........................................................................................................................35 
4.5.3.1. 
Trilaciclib ....................................................................................................................35 
4.5.3.2. 
Gemcitabine/Carboplatin/Cisplatin ............................................................................37 
4.6. 
Benefit/Risk Assessment ............................................................................................38 
5. 
OBJECTIVES AND ENDPOINTS ............................................................................40 
6. 
INVESTIGATIONAL PLAN .....................................................................................43 
6.1. 
Overall Study Design ..................................................................................................43 
6.2. 
Rationale for Primary and Secondary Endpoints ........................................................45 
6.2.1. 
Anti-tumor Efficacy ....................................................................................................45 


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6.2.2. 
Myeloprotection Efficacy ...........................................................................................45 
6.2.3. 
Safety ..........................................................................................................................46 
6.3. 
Rationale for Dose and Schedule of Study Treatment ................................................46 
6.4. 
Rationale for Patient Population .................................................................................46 
6.5. 
Rationale for Platinum-Based Chemotherapy and Avelumab Therapy .....................46 
6.6. 
Rationale for Supportive Care Interventions (Growth Factors and 
Transfusions) ..............................................................................................................48 
6.7. 
Rationale for Stratification Factors .............................................................................48 
7. 
STUDY POPULATION .............................................................................................49 
7.1. 
Inclusion Criteria ........................................................................................................49 
7.2. 
Exclusion Criteria .......................................................................................................51 
8. 
SCHEDULE OF ASSESSMENTS .............................................................................53 
9. 
STUDY TREATMENT ..............................................................................................58 
9.1. 
Study Drugs Administered .........................................................................................58 
9.1.1. 
Dose, Dosing Regimen, and Route .............................................................................60 
9.1.1.1. 
Trilaciclib ....................................................................................................................60 
9.1.1.2. 
Gemcitabine and Cisplatin or Carboplatin .................................................................61 
9.1.1.3. 
Avelumab ....................................................................................................................62 
9.1.2. 
Preparation, Handling, Storage, and Accountability ..................................................63 
9.1.3. 
Treatment Compliance ................................................................................................64 
9.2. 
Criteria for Starting Cycle 1 and Each Subsequent Chemotherapy Cycle .................64 
9.3. 
Toxicity Management and Dose Modifications .........................................................64 
9.3.1. 
Dose Modifications for Hematologic and Non-Hematologic Toxicity during 
Chemotherapy Period .................................................................................................65 
9.3.1.1. 
Recommended Dose Reductions of Gemcitabine and Cisplatin or 
Carboplatin for Hematologic and Non-Hematologic Toxicity ...................................67 
9.3.2. 
Recommended Actions with Trilaciclib for Adverse Events of Special 
Interest ........................................................................................................................68 
9.3.3. 
Recommended Actions with Avelumab for AESIs ....................................................69 
9.3.4. 
Hy’s Law Management ...............................................................................................79 
9.3.5. 
Management of Nausea and Vomiting .......................................................................80 
9.4. 
Supportive Care Interventions ....................................................................................80 
9.4.1. 
Colony Stimulating Factor Usage ...............................................................................80 
9.4.2. 
Erythropoiesis-Stimulating Agent Usage ...................................................................81 


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9.4.3. 
Transfusions ................................................................................................................81 
9.5. 
Prior/Concomitant Medications and Procedures ........................................................81 
9.5.1. 
Concomitant Surgery ..................................................................................................82 
9.5.2. 
Concomitant Radiotherapy .........................................................................................82 
9.6. 
Prohibited Therapy .....................................................................................................82 
9.6.1. 
Trilaciclib ....................................................................................................................82 
9.6.2. 
Gemcitabine ................................................................................................................82 
9.6.3. 
Carboplatin .................................................................................................................83 
9.6.4. 
Cisplatin ......................................................................................................................83 
9.6.5. 
Avelumab ....................................................................................................................83 
9.7. 
Measures to Minimize Bias: Randomization and Blinding ........................................84 
9.8. 
Intervention after End of Study Treatment .................................................................84 
10. 
DISCONTINUATION OF STUDY INTERVENTION AND PATIENT 
DISCONTINUATION/WITHDRAWAL ..................................................................85 
10.1. 
Discontinuation of Study Treatment ...........................................................................85 
10.2. 
Discontinuation/Withdrawal from the Study ..............................................................85 
10.3. 
Lost to Follow-Up .......................................................................................................86 
10.4. 
Study and Site Start and Closure ................................................................................86 
11. 
STUDY ASSESSMENTS ..........................................................................................88 
11.1. 
Screening Assessments ...............................................................................................88 
11.1.1. 
Documentation of Locally Advanced or Metastatic Urothelial Carcinoma ...............88 
11.1.2. 
Randomization ............................................................................................................88 
11.1.3. 
Demographics .............................................................................................................88 
11.1.4. 
Medical History and Urothelial Carcinoma Disease History .....................................89 
11.2. 
Efficacy Assessments .................................................................................................89 
11.2.1. 
Anti-tumor Efficacy Assessment ................................................................................89 
11.2.1.1. 
Treatment Beyond Disease Progression during Avelumab Maintenance per 
RECIST Version 1.1 ...................................................................................................90 
11.2.2. 
Hematologic Assessments ..........................................................................................91 
11.3. 
Safety Assessments .....................................................................................................91 
11.3.1. 
Vital Signs ..................................................................................................................91 
11.3.2. 
Physical Examination .................................................................................................92 
11.3.3. 
ECOG Performance Status .........................................................................................92 


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11.3.4. 
Electrocardiogram .......................................................................................................92 
11.3.5. 
Clinical Safety Laboratory Assessments ....................................................................93 
11.3.6. 
Adverse and Serious Adverse Events .........................................................................93 
11.3.6.1. 
Time Period and Frequency for Collecting Adverse and Serious Adverse 
Event Information .......................................................................................................94 
11.3.6.2. 
Method of Detecting Adverse and Serious Adverse Events .......................................94 
11.3.6.3. 
Follow-up of Adverse and Serious Adverse Events ...................................................94 
11.3.6.4. 
Regulatory Reporting Requirements for Serious Adverse Events .............................95 
11.3.6.5. 
Pregnancy ...................................................................................................................95 
11.4. 
Pharmacokinetics ........................................................................................................95 
11.5. 
Biomarkers ..................................................................................................................96 
11.5.1. 
Rationale for Archival or Fresh Tumor Collection at Screening ................................96 
11.5.2. 
Rationale for Peripheral Blood Collection .................................................................96 
11.6. 
Anti-Avelumab Antibody and Neutralizing Antibody Testing ..................................97 
11.7. 
Data Monitoring Committee .......................................................................................97 
11.8. 
End of Treatment Visit ...............................................................................................97 
11.9. 
Safety Follow-up Visit ................................................................................................98 
11.10. 
Survival Follow-up .....................................................................................................98 
12. 
STATISTICAL CONSIDERATIONS .......................................................................99 
12.1. 
Sample Size Determination ........................................................................................99 
12.2. 
Analysis Population ....................................................................................................99 
12.3. 
Time of Planned Analysis .........................................................................................100 
12.3.1. 
First Planned Analysis – Analyses for Objective Response Rate in the 
Chemotherapy Period, and Myelosuppression Endpoints ........................................100 
12.3.2. 
Intermediate Planned Analyses – Analyses for Progression Free Survival and 
Probability of Survival at Month 16 .........................................................................100 
12.3.3. 
Final Planned Analysis – Analyses for Overall Survival .........................................100 
12.4. 
Statistical Analysis Methods .....................................................................................100 
12.4.1. 
General Considerations .............................................................................................101 
12.4.2. 
Patient Disposition ....................................................................................................101 
12.4.3. 
Demographic and Baseline Characteristics ..............................................................101 
12.4.4. 
Prior and Subsequent Anticancer Therapies .............................................................101 
12.4.5. 
Study Drug Exposure, Modification, and Dose Intensity .........................................101 


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12.4.6. 
Efficacy Analyses .....................................................................................................102 
12.4.6.1. 
Analyses of Primary Efficacy Endpoint –Progression Free Survival during 
the Study ...................................................................................................................102 
12.4.6.2. 
Analysis for Secondary Anti-tumor Efficacy Endpoints ..........................................102 
12.4.6.3. 
Analysis of Myelosuppression Endpoints ................................................................104 
12.4.7. 
Safety Analyses ........................................................................................................106 
12.4.7.1. 
Adverse Events .........................................................................................................106 
12.4.7.2. 
Other Safety Endpoints .............................................................................................106 
12.4.8. 
Exploratory Analyses ................................................................................................106 
12.4.9. 
Pharmacokinetic Analyses ........................................................................................107 
12.4.10. 
Pharmacokinetic/Pharmacodynamic Analyses .........................................................107 
13. 
ETHICS ....................................................................................................................108 
13.1. 
Ethics Review ...........................................................................................................108 
13.2. 
Ethical Conduct of the Study ....................................................................................108 
13.3. 
Written Informed Consent ........................................................................................108 
14. 
DATA HANDLING AND RECORDKEEPING .....................................................110 
14.1. 
Data Protection .........................................................................................................110 
14.2. 
Data Quality Assurance ............................................................................................110 
14.3. 
Dissemination of Clinical Study Data ......................................................................111 
14.4. 
Source Documents ....................................................................................................111 
14.5. 
Audits and Inspections ..............................................................................................111 
15. 
PUBLICATION POLICY ........................................................................................112 
16. 
REFERENCES .........................................................................................................113 
17. 
APPENDICES ..........................................................................................................121 
17.1. 
Clinical Laboratory Tests .........................................................................................121 
17.2. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .........................................................................................122 
17.2.1. 
Definition of AE .......................................................................................................122 
17.2.2. 
Definition of SAE .....................................................................................................123 
17.2.3. 
Recording and Follow-Up of AE and/or SAE ..........................................................124 
17.2.4. 
Reporting of SAEs ....................................................................................................126 
17.3. 
Contraceptive Guidance and Collection of Pregnancy Information .........................127 
17.4. 
Definitions of Tumor Response and Disease Progression (per RECIST v1.1) ........130 


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17.5. 
Preexisting Autoimmune Diseases ...........................................................................133 
 
LIST OF TABLES 
Table 1: 
Abbreviations ..............................................................................................................16 
Table 2: 
G1T28-04: Summary of Overall Survival and Progression-Free Survival 
(ITT Analysis Set) ......................................................................................................31 
Table 3: 
G1T28-04: Tumor Response According to PD-L1 Status ..........................................33 
Table 4: 
Objectives and Endpoints ...........................................................................................40 
Table 5: 
Schedule of Assessments ............................................................................................54 
Table 6: 
Study Drugs ................................................................................................................59 
Table 7: 
Recommended Dose Modification for Hematologic Toxicity during 
Chemotherapy Period .................................................................................................66 
Table 8: 
Recommended Dose Modifications for Non-Hematologic Toxicity during 
Chemotherapy Period .................................................................................................67 
Table 9: 
Recommended Actions with Trilaciclib Following Adverse Events of 
Special Interest ............................................................................................................68 
Table 10: Treatment Modification for Symptoms of Avelumab Infusion-Related 
Reactions .....................................................................................................................70 
Table 11: Management of Avelumab Immune-mediated Adverse Reactions ............................71 
Table 12: Recommended Treatment Modification for Other Avelumab Product-
Related Toxicity ..........................................................................................................79 
Table 13: Patient Risk Factors for Poor Clinical Outcomes Resulting from Febrile 
Neutropenia or Infection .............................................................................................81 
Table 14: ECOG Performance Status .........................................................................................92 
Table 15: Protocol-Specified Safety Laboratory Assessments .................................................121 
 
LIST OF FIGURES 
Figure 1: 
Trilaciclib Transiently Arrests Normal Cells to Prevent 
Chemotherapy-Induced Myelosuppression and Improve Anti-Tumor 
Efficacy .......................................................................................................................23 
Figure 2: 
The Addition of Trilaciclib to Chemotherapy/Checkpoint Inhibitor 
Treatment Enhances Efficacy Through T Cell Activation .........................................28 
Figure 3: 
Trilaciclib Augments Anti-PD-1 Antibody-Induced Antitumor Activity ..................29 
Figure 4: 
G1T28-04: Overall Survival – Kaplan-Meier Curve (ITT Analysis Set) ...................32 
Figure 5: 
Study Schema .............................................................................................................44 


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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 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
aRR 
adjusted relative risk 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BCG 
bacille Calmette-Guérin 
β-hCG 
beta human chorionic gonadotropin  
BMI 
body mass index 
BOR 
best overall response 
BSA 
body surface area 
CBC 
complete blood count 
CDK 
cyclin-dependent kinase  
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIM 
chemotherapy-induced myelosuppression 
CMH 
Cochran–Mantel–Haenszel 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography  
CTLA-4 
cytotoxic T-lymphocyte associated protein 4 
CYP 
cytochrome P450 
D5W 
dextrose 5% in water 


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Abbreviation 
Definition 
DCR 
disease control rate 
DDI 
drug-drug interaction 
DMC 
Data Monitoring Committee 
DOR 
duration of response 
DSN 
duration of sever neutropenia 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic case report form 
EDC 
electronic data capture 
E/P/A 
etoposide/carboplatin/atezolizumab 
ESA 
erythropoiesis stimulating agent 
FACT-An 
Functional Assessment of Cancer Therapy – Anemia 
FDA 
Food and Drug Administration 
FDG 
[18F]-fluorodeoxyglucose 
FFPE 
formalin-fixed paraffin-embedded 
FN 
febrile neutropenia 
FSH 
follicle stimulating hormone 
G1 
gap 1 phase of the cell cycle 
G1T28 
trilaciclib; formerly G1T28-1 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GFR 
glomerular filtration rate 
GINA 
Global Initiative for Asthma 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HR 
hazard ratio 
HRT 
hormone replacement therapy 
HSPC 
hematopoietic stem and progenitor cell 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICI 
immune checkpoint inhibitors 


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Abbreviation 
Definition 
ICR 
independent central review 
IEC 
independent ethics committee  
IFN 
interferon 
IHC 
immunohistochemistry 
IL 
interleukin 
INR 
International Normalized Ratio 
irAE 
immune-related AE 
IRB 
institutional review board 
irPD 
immune-related disease progression 
ITT 
Intent-to-treat 
IV 
intravenous 
IWRS 
Interactive Web Response System 
LFT 
liver function test 
MATE1 or 2-K 
multidrug and toxin extrusion 1 or 2-K  
M-CAVI 
methotrexate/carboplatin/vinblastine 
MDSC 
myeloid-derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOA 
mechanism of action 
MRI 
magnetic resonance imaging 
MRP1 or 2 
multidrug resistance protein 1 or 2 
NaF 
sodium fluoride 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
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 
PAM50 
Prosigna Breast Cancer Prognostic Gene Signature Assay 
PET 
Positron Emission Tomography 
PCS 
potentially clinically significant 


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Abbreviation 
Definition 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PTFE 
polytetrafluorethylene 
PVG 
Pharmacovigilance 
RB 
retinoblastoma gene 
RBC 
red blood cell 
RE 
Response Evaluable 
RECIST 
Response Evaluation Criteria in Solid Tumors  
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCLC 
small cell lung cancer 
SD 
stable disease 
SN 
severe neutropenia 
SUSAR 
suspected unexpected serious adverse reactions 
TCC 
transitional cell carcinoma 
TCR 
T cell receptor 
TNBC 
triple-negative breast cancer 
TURBT 
transurethral resection of bladder tumor 
UCC 
urothelial cell carcinoma 
ULN 
upper limit of normal 
US 
United States 
 


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4. 
INTRODUCTION 
4.1. 
Urothelial Carcinoma 
Bladder cancer is the most common malignancy involving the urinary system and is the sixth 
most common cancer in the United States (US) (NCCN, 2020). Approximately 2.4% of the US 
population will be diagnosed with bladder cancer at some point during their lifetime; the median 
age at diagnosis is 73 years and it is rarely diagnosed in people less than 40 years of age 
(NCCN, 2020; SEER, 2020). The rates of new cases and deaths were 20.0 and 4.3 per 100,000 
men and women per year, respectively (using age-adjusted rates and based on 2013-2017 cases 
and 2014–2018 deaths) (SEER, 2020; NCCN, 2020).  
Urothelial carcinoma, also known as transitional cell carcinoma (TCC), urothelial bladder 
cancer, or urothelial cell carcinoma (UCC) of the urinary tract, is the predominant histologic type 
in the US and Europe, where it accounts for 90% of all bladder cancers (NCCN, 2020). The 
overall 5-year survival rate for metastatic urothelial carcinoma is approximately 5.5%, which has 
remained unchanged over the past 25 years (SEER, 2020). Poor prognostic factors for survival in 
patients with metastatic urothelial carcinoma include advanced stage of disease at the time of 
initial diagnosis, Karnofsky Performance Status <80%, and visceral metastasis (i.e., lung, liver, 
or bone; Bajorin, 1999). The presence of these unfavorable features was associated with a 
median survival of 4 months compared with 18 months in patients without these features 
(Loehrer, 1992). In addition, a Phase 3 study in second-line urothelial carcinoma comparing 
vinflunine with best supportive care identified presence of visceral involvement (i.e., liver or 
lung metastasis) one of the strongest prognostic factors associated with overall survival (OS) 
(Bellmunt, 2009). 
In addition to the predictors of poor outcomes described above, chemotherapy-induced 
immunosuppression, a known side effect of platinum-based chemotherapy regimens, may also 
affect anti-tumor efficacy due to an inability of the host immune system to effectively mount a 
response against the cancer. Therefore, preserving the bone marrow from the cytotoxic effects of 
chemotherapy and potentially enhancing the immune system has the potential to maximize the 
anti-tumor activity of the chemotherapy while minimizing myelotoxicity.  
While urothelial cancer has one of the highest mutation burdens among all types of cancer which 
is a known predictor of treatment response to immune checkpoint inhibitors (Crispen, 2020; 
Cancer Genome Atlas Network, 2014), the clinical efficacy of cancer immunotherapy is limited 
due to tumor-induced immune suppression and immune tolerance in urothelial carcinoma which 
is characterized by high levels of myeloid-derived suppressor cells (MDSCs), up-regulation of 
programmed death-ligand 1 (PD-L1) expression and tumor infiltration of immunosuppressive 
cells including regulatory T cells (Crispen, 2020). Therefore, coadministration of trilaciclib to 
re-activate the immune system and an immune checkpoint inhibitor (ICI) has the potential to 
further enhance the anti-tumor immune response and generate a greater anti-neoplastic effect 
than immunotherapy alone.  
While the combination of ICIs with chemotherapy have indicated a meaningful step forward for 
the treatment of patients with PD-L1 positive advanced/metastatic urothelial carcinoma, it should 
be noted that due to the potential treatment toxicities associated with ICIs, not all patients with 


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PD-L1 positive urothelial carcinoma are appropriate candidates for ICI treatment and, as would 
be expected, the patient population with PD-L1 negative urothelial carcinoma derived only 
limited benefit. Overall, the urothelial carcinoma patient population continues to represent an 
area of high unmet medical need. Novel therapeutic options that can offer similar or better 
anti-tumor efficacy without the associated high-grade toxicities are clearly needed. 
4.2. 
Treatment of Metastatic Urothelial Carcinoma 
4.2.1. 
Platinum-Based Chemotherapy 
Cisplatin-based chemotherapy became the standard first-line treatment for metastatic urothelial 
carcinoma in the 1980s, with long-term remissions observed in ~10% of patients (Galsky, 2020). 
While patients administered platinum-based chemotherapy have experienced clinical benefit 
(objective response in 40 to 50% of patients; disease control in 75 to 80%), most have disease 
progression within approximately 9 months, with the median OS 14 to 15 months for cisplatin-
based-regimens and 9 to 10 months with carboplatin-based regimens (von der Maase, 2005; 
Galsky, 2012; Gartrell, 2017; Balar, 2017; Bamias, 2018). However, about 50% of patients with 
metastatic urothelial carcinoma are not eligible to receive cisplatin because of renal dysfunction 
or Eastern Cooperative Group (ECOG) performance status of 2, or both. Furthermore, hearing 
loss, Grade 2 neuropathy, heart failure, and age-associated diminished renal function may also 
confer cisplatin ineligibility (Dash, 2006; Galsky, 2011; Galsky, 2011). Carboplatin is often 
substituted for cisplatin in such patients, but it is associated with inferior outcomes 
(Galsky, 2011; Galsky, 2012). In addition, platinum-based chemotherapy regimens are 
associated with chemotherapy-induced myelosuppression. In the Phase 3 IMvigor130 study, 37% 
of patients in the gemcitabine/carboplatin arm experienced Grade 3 or 4 neutropenia, 21% 
experienced Grade 3 or 4 thrombocytopenia, and 40% experienced Grade 3 or 4 anemia. 
(Galsky, 2020). Thus, there remains a significant unmet medical need for well-tolerated therapies 
with improved anti-tumor and survival outcomes. 
4.2.2. 
Immune Checkpoint Inhibitors 
The first use of immunotherapy in patients with advanced urothelial carcinoma began in 1976 
with the tuberculosis vaccine bacille Calmette-Guérin (BCG) and is used as locoregional therapy 
after surgical resection of non-muscle-invasive disease (Morales, 1976; Shelley, 2001). Multiple 
immunotherapies including interferon (IFN)-α, interleukin (IL)-2, IL-12, and IL-10 have been 
investigated, either as adjuncts with BCG or as a solo replacement therapy (Kamat, 2001; 
Askeland, 2012). Years later, Wang and colleagues analyzed the gene expression patterns of 
32 different cancer types from The Cancer Genome Atlas and created a tumor immunogenicity 
score for each cancer type. Tumor immunogenicity determined by two factors (the antigenicity 
of tumor cells and the processing and presentation of tumor antigens) revealed that urothelial 
carcinoma had one of the higher tumor immunogenicity scores (Wang, 2019), indicating that it is 
a prime candidate for ICI treatment.  
Expression of PD-L1 has been associated with poor prognosis in urothelial carcinoma, with 
Nakanishi and colleagues being one of the first groups to observe an association between 
expression of PD-L1 and outcomes in urothelial carcinoma. In their study, PD-L1 expression 
was significantly associated with a high frequency of disease recurrence and poor survival rate 
(Nakanishi, 2007). Subsequently, the programmed cell death protein 1 (PD-1)/PD-L1 pathway 


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has emerged as an important biological pathway in urothelial carcinoma. The PD-1/PD-L1 
interaction inhibits T-lymphocyte activation, proliferation, survival, and effector functions during 
anti-cancer immune response. Several tumors, including urothelial carcinoma, present with high 
rates of somatic mutations (Kandoth, 2013; Lawrence, 2013; 
Cancer Genome Atlas Network, 2014), possibly enhancing the host immune system’s ability to 
recognize tumor cells as foreign and stimulate a T cell response (Chen, 2013). However, tumors 
may elude the immune response through the expression of PD-L1 in the tumor 
microenvironment (Dong, 2002), making them potential targets of ICI therapies.  
PD-1/PD-L1inhibitors are the most recent systemic therapies developed for metastatic urothelial 
carcinoma, both for first-line treatment of cisplatin-ineligible patients and for patients with 
disease progression despite platinum-based chemotherapy, as well as a maintenance treatment 
for patients who have not progressed on platinum-based chemotherapy (Massard, 2016; 
Rosenberg, 2016; Apolo, 2017; Balar, 2017; Balar, 2017; Sharma, 2017; Powles, 2018; 
Galsky, 2020; Powles, 2020). Indeed, ICIs have demonstrated significant and durable response in 
patients with advanced urothelial carcinoma. The US Food and Drug Administration (FDA) has 
approved the PD-L1 inhibitors avelumab, atezolizumab and durvalumab as well as the PD-1 
inhibitors nivolumab and pembrolizumab for patients with urothelial carcinoma (NCCN, 2020). 
Avelumab, pembrolizumab, nivolumab, and durvalumab are approved for the treatment of 
locally advanced or metastatic urothelial carcinoma that has progressed during or after platinum-
based chemotherapy or that has progressed within 12 months of neoadjuvant or adjuvant 
platinum-containing chemotherapy, regardless of PD-L1 expression levels (Imfinzi®, 2017; 
Opdivo®, 2018; Bavencio®, 2020, Keytruda®, 2020). In March 2021, as part of an industry-wide 
assessment of indications based on accelerated approval, Roche in consultation with the FDA 
withdrew the indication for atezolizumab in patients with urothelial carcinoma following 
platinum-based chemotherapy. Additionally, atezolizumab and pembrolizumab are approved as a 
first-line treatment option for patients with locally advanced or metastatic urothelial carcinoma 
who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 or 
in patients who are not eligible for any platinum-based chemotherapy regardless of PD-L1 
expression (Keytruda, 2020; Tecentriq, 2020). Finally, avelumab is approved for maintenance 
treatment of patients with locally advanced or metastatic urothelial carcinoma that has not 
progressed with first-line platinum-containing chemotherapy (Bavencio, 2020 [US]; 
Bavencio, 2020 [EU]). 
While the combination of ICIs with chemotherapy have indicated a meaningful step forward for 
the treatment of patients with PD-L1 positive advanced/metastatic urothelial carcinoma, it should 
be noted that due to the potential treatment toxicities associated with ICIs, not all patients with 
PD-L1 positive urothelial carcinoma are appropriate candidates for ICI treatment and, as would 
be expected, the patient population with PD-L1 negative urothelial carcinoma derived only 
limited benefit. In addition to the limitations described above, chemotherapy-induced 
immunosuppression, a known side effect of platinum-based chemotherapy regimens, may also 
affect anti-tumor efficacy due to an inability of the host immune system to effectively mount a 
response against the cancer. Therefore, preserving the bone marrow from the cytotoxic effects of 
chemotherapy, in addition to preserving and enhancing the immune system potentially through 
T cell receptor (TCR) modulation, has the potential to maximize the anti-tumor activity of the 
chemotherapy while minimizing myelotoxicity.  


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Novel therapeutic options that can offer similar or better anti-tumor efficacy without the 
associated high-grade toxicities are needed.  
4.3. 
Urothelial Carcinoma and Trilaciclib 
Trilaciclib is a highly potent and selective, reversible, cyclin-dependent kinase (CDK) 4/6 
inhibitor that preserves hematopoietic stem and progenitor cells (HSPCs) as well as immune 
system function during chemotherapy (myeloprotection) in addition to directly enhancing 
anti-tumor immunity (anti-cancer efficacy) (Figure 1). Both HSPCs 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 when combined with chemotherapy 
(He, 2017; Bisi, 2016; Lai, 2020). In February 2021, the United States Food and Drug 
Administration (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 
 


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As stated previously, patients treated with platinum-based chemotherapy experience 
chemotherapy-induced myelosuppression. Whereas current treatments for chemotherapy-induced 
myelosuppression are lineage specific, used after the damage to HSPCs has occurred, and place 
patients at risk for additional toxicities, trilaciclib improves the overall chemotherapy experience 
for patients by the prevention of damage to HSPCs and therefore chemotherapy-induced 
myelosuppression, thus resulting in an overall improved safety profile and reduced utilization of 
available standard of care treatments. 
Three randomized, double-blind, Phase 2 clinical trials evaluating trilaciclib/placebo 
administered prior to chemotherapy in patients with small cell lung cancer (SCLC) have 
demonstrated in a variety of clinical settings (patients receiving first-, second-, or third-line 
SCLC treatments with several different classes of chemotherapy) that trilaciclib can prevent 
chemotherapy-induced myelosuppression as measured by multiple endpoints (Weiss, 2019; 
Hart, 2019; Daniel, 2019). In an analysis of integrated data from all three studies, the delivery of 
trilaciclib prior to chemotherapy results in a 4-day reduction in the duration of severe 
neutropenia (DSN) in Cycle 1 and an approximately 76% reduction (52.9% placebo to 11.4% 
trilaciclib) in the occurrence of severe neutropenia (SN) during chemotherapy treatment. The 
occurrence of red blood cell (RBC) transfusions on or after 5 weeks on study was reduced by 
almost half from 26.1% in those treated with placebo to 14.6% in those receiving trilaciclib with 
an associated 31.9% to 20.3% reduction in the rates of Grade 3 or 4 anemia. Grade 3 or 4 
thrombocytopenia was decreased from 36.1% to 19.5% with the addition of trilaciclib, and 
diarrhea was decreased from 17.8% to 13.1%. 
The exploratory patient-reported outcome endpoints in these patients suggested that trilaciclib 
administered prior to chemotherapy may offer potential benefit in multiple aspects of health-
related quality of life with a greater magnitude of effect observed for fatigue and anemia 
symptoms and functional limitations (Weiss, 2019). An analysis of integrated fatigue subscale 
data from Functional Assessment of Cancer Therapy – Anemia (FACT-An) in the three studies 
showed that trilaciclib delayed the median time to deterioration by approximately 5 months for 
fatigue (7.03 months in the trilaciclib group vs. 2.33 months in the placebo group, hazard ratio 
[HR]: 0.56 [0.37, 0.85]). In addition, these myeloprotection benefits were observed in the setting 
of minor improvements in progression-free survival (PFS) and OS as evidenced by hazard ratios 
(HRs) <1.0 in almost all clinical settings for trilaciclib compared to placebo. For more detailed 
information, refer to the trilaciclib Investigator’s Brochure (IB). 
In a randomized Phase 2 study (G1T28-04) in patients with triple-negative breast cancer 
(TNBC), the addition of trilaciclib to chemotherapy had a substantial impact on anti-tumor 
efficacy as measured by OS (as discussed below) but did not result in the striking statistically 
significant effects on chemotherapy-induced myelosuppression observed in the SCLC trials 
described previously. The differences between the observed results in the SCLC trials and those 
in the TNBC trial are hypothesized to result from differences in the key variables between the 
two clinical situations.  
Unlike chemotherapy-induced myelosuppression, the effects of trilaciclib on anti-tumor efficacy 
are predicted to be primarily driven by the tumor type, chemotherapy type, and host, i.e., (1) the 
tumor type must be sufficiently responsive to chemotherapy such that maintenance of 
chemotherapy dose intensity is beneficial, (2) the tumor must be sufficiently immunogenic and 


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sensitive to the host cytolytic efforts as to see improvement in anti-tumor endpoints like OS, (3) 
the chemotherapy should promote immune activation, (4) the host must be able to tolerate the 
standard of care chemotherapy dose intensity, and (5) 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, relapses quickly after 
completion of chemotherapy, has been shown to be relatively insensitive to multiple attempts to 
intensify the chemotherapy regimen beyond the current standard of care, and is not particularly 
immunogenic or sensitive to immune modulation. In contrast, TNBC has been shown to be 
immunogenic and more sensitive to immune modulation compared to SCLC (Semenova, 2015; 
He, 2017, Carvajal-Hausdorf, 2019; Liu, 2018). The observation that trilaciclib, when added to 
standard of care therapy in TNBC patients, improved anti-tumor efficacy outcomes provides 
support for the hypothesis that given urothelial carcinoma has been shown to be immunogenic 
(Wang, 2019) and responds to ICIs (Galsky, 2020; Powles, 2020), trilaciclib may enhance anti-
tumor outcomes when added to platinum-based chemotherapy and avelumab maintenance 
therapy. 
As discussed above, based on trilaciclib’s 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. Therefore, trilaciclib 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 chemotherapy for patients with locally recurrent/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 + gemcitabine/carboplatin treatment 
regimens or gemcitabine/carboplatin alone.  
In the Phase 2 G1T28-04 TNBC study, the addition of trilaciclib to chemotherapy resulted in 
improvements in anti-tumor efficacy as measured by OS (median OS duration in the control 
group was 12.6 months vs. 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) and by PFS (median PFS in the control group 
was 5.7 months vs. 9.4 months or 7.3 months in the two trilaciclib groups HR: 0.62 and 0.63, 
respectively; not statistically significant), and ORR (29.2% in the control group vs. 50.0% and 
38.7% in the two trilaciclib groups, respectively; not statistically significant) (Tan, 2019; 
O’Shaughnessy, 2020). 
The clinically meaningful anti-tumor efficacy results observed in Study G1T28-04 (a secondary 
endpoint) were noted across both of the trilaciclib treatment groups and in patients with both 
PD-L1 positive and negative tumors, and these benefits were observed for multiple anti-tumor 
efficacy endpoints, with ORR, PFS, and OS endpoints all showing numerical improvement with 
the addition of trilaciclib to chemotherapy compared with chemotherapy alone.  
In addition, while the sample size in Study G1T28-04 was small, the results were generally 
consistent across patient subgroups, including CDK4/6 status. Patient tumors were characterized 
as CDK4/6 independent, dependent, or indeterminate using two established signatures (Prosigna 
Breast Cancer Prognostic Gene Signature Assay [PAM50] and Lehmann triple-negative breast 


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cancer type) (Prat, 2014; Lehmann, 2016; Asghar, 2017). As expected, these data suggest 
trilaciclib does not antagonize chemotherapy efficacy regardless of CDK4/6 status, including 
tumors that are CDK4/6 indeterminate or dependent (Tan, 2019; O’Shaughnessy, 2020). While 
some tumors have been shown to be predominantly CDK4/6 dependent, CDK2NA is lost in 
20-30% of bladder cancers (Cancer Genome Atlas Network, 2014; Robertson, 2017), and 
preclinical studies have demonstrated some efficacy of CDK4/6 inhibition in bladder cancer 
(Choi, 2014; Damrauer, 2014). In addition, a Phase 2 trial evaluating palbociclib monotherapy in 
patients with metastatic urothelial carcinoma after failure of first-line platinum-based 
chemotherapy showed that palbociclib did not demonstrate meaningful activity as measured by 
PFS at 4 months, with RB status not correlating with response (Rose, 2018), suggesting bladder 
cancer is not as CDK4/6 dependent as expected. This information, along with the clinical data in 
TNBC, suggest trilaciclib will not antagonize the anti-tumor effects of chemotherapy in bladder 
cancer. 
Lastly, to evaluate the effect of trilaciclib on T cell activation, peripheral blood was collected and 
the TCR was evaluated. Simpson clonality decreased over time in patients that received 
trilaciclib in addition to gemcitabine/carboplatin when compared to gemcitabine/carboplatin 
alone. Furthermore, after stratification above or below median Simpson clonality at baseline, an 
exploratory analysis showed patients above the median demonstrated a greater OS benefit with 
the addition of trilaciclib. In addition to a decrease in Simpson clonality, responders receiving 
trilaciclib prior to gemcitabine/carboplatin had more newly detected expanded clones compared 
with responders receiving gemcitabine/carboplatin alone. These data suggest trilaciclib enhances 
anti-tumor immunity through T cell activation leading to an anti-tumor response in TNBC 
(O’Shaughnessy, 2020).  
4.4. 
Study Rationale 
Trilaciclib is an intravenous (IV), short-acting, selective, and reversible CDK4/6 inhibitor that 
transiently arrests cells in the G1 phase of the cell cycle. Trilaciclib was originally developed to 
preserve bone marrow function from chemotherapy (myeloprotection). An integrated analysis 
across three SCLC studies demonstrated this myeloprotection activity by reducing the rate and 
duration of severe neutropenia, reducing the rate of thrombocytopenia and anemia, and reducing 
the rate of RBC transfusions. Study G1T28-04, a Phase 2 study in metastatic TNBC patients 
showed a clinically meaningful OS benefit (a secondary endpoint) in patients receiving trilaciclib 
prior to chemotherapy versus chemotherapy alone; this benefit was observed across both 
trilaciclib treatment arms. Subgroup analyses demonstrated both PD-L1 positive and negative 
patients benefitted from the addition of trilaciclib. In addition to the improved OS results, 
Study G1T28-04 indicated an improvement in patient-reported outcomes as measured by the 
FACT scales, and a manageable safety profile.  
Given the encouraging results of improved anti-tumor efficacy, myeloprotection, and patient 
outcomes observed in trilaciclib studies to date (Section 4.5.2), this exploratory Phase 2 clinical 
trial in patients with urothelial carcinoma receiving first-line treatment for advanced/metastatic 
disease is designed to assess whether or not trilaciclib can improve anti-tumor efficacy when 
administered prior to platinum-based chemotherapy followed by avelumab maintenance therapy 
and reduce the chemotherapy-induced myelosuppression observed with platinum-based 
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4.5. 
Background 
In February 2021, the United States Food and Drug Administration (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). 
4.5.1. 
Summary of Nonclinical Data 
A brief summary of the trilaciclib nonclinical data is provided in the following sections. Detailed 
information is presented in the trilaciclib IB. 
Nonclinical data related to avelumab and gemcitabine/carboplatin/cisplatin are provided in the 
local prescribing information. 
4.5.1.1. 
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 values of 1 nM and 4 nM, 
respectively) that is highly selective for CDK4/Cyclin D1 versus CDK2/Cyclin E (>2500-fold 
selectivity). Trilaciclib also demonstrated reversible inhibition of CDK4/Cyclin D1, with an 
inhibition constant 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 highly 
myelosuppressive chemotherapy 5-fluorouracil (5-FU), while 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 have shown trilaciclib enhances immune activation and promotes anti-tumor 
immunity by differentially arresting cytotoxic and regulatory T cell subsets followed by a faster 
recovery of cytotoxic T lymphocytes than 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 2; 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 
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.  


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Figure 2: 
The Addition of Trilaciclib to Chemotherapy/Checkpoint Inhibitor 
Treatment Enhances Efficacy Through T Cell Activation 
 
 
CD=cluster of differentiation; PD-1=programmed cell death protein 1; PD-L1=programmed death-ligand 1; 
Treg=regulatory T cell. 
Ex vivo and in vivo studies revealed that the inhibition of CDK4/6 by trilaciclib resulted in 
increased antitumor activity, particularly in conjunction with PD-1 blockade, and this effect was 
largely dependent on T cells (Deng, 2018). In vivo PD-1 blockade induced partial tumor growth 
inhibition in the murine colon carcinoma MC38 model and the addition of intermittent exposure 
to trilaciclib nearly eliminated tumor growth (Figure 3, LEFT). Profiling of tumor infiltrating 
lympocytes from MC38 tumors revealed that anti-PD-1 alone increased CD8+ IFNγ production 
but not CD4+ IL2 production (Figure 3, RIGHT and MIDDLE). Thus, in this model, PD-1 
blockade increased the cytotoxicity of CD8+ T cells but did not increase T-cell proliferation 
through IL2. Addition of trilaciclib to PD-1 blockade resulted in an approximately 10-fold 
increase in the levels of IFNγ in CD8+ TILs and approximately 2-fold increase in CD4+ IL2 
production. These data demonstrate that trilaciclib augmented anti-tumor immunity, which 
translated to an improved antitumor response that was largely dependent on the activity of T 
cells, thereby sensitizing tumors to immune checkpoint blockade. 
 


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Figure 3: 
Trilaciclib Augments Anti-PD-1 Antibody-Induced Antitumor Activity 
 
Combination treatment of trilaciclib synergize anti–PD-1 antibody–induced antitumor immunity through T cells. 
(LEFT) Tumor growth curves of MC38 cells treated with trilaciclib or PD-1 antibody alone or in combination. 
MC38 murine cancer cells were injected subcutaneously into C57BL/6 mice. The mice were treated with trilaciclib 
100 mg/kg intermittently (3 days on, 4 days off) with or without PD-1 antibody (200 μg/mouse, 3 times a week) as 
indicated starting from day 3 (MC38). Tumor volumes were monitored every 2–3 days. The graph shows 
representative results from two independent experiments (n = 8; *, P < 0.05; **, P < 0.01; ***, P < 0.001). 
(MIDDLE and RIGHT) Quantification of cytokine production produced by MC38 tumor-infiltrating T lymphocytes. 
At the end of the treatment (day 17), mice were sacrificed and tumor infiltrating lymphocytes were isolated from the 
tumor for cytokine analysis for IL2 from CD4+ T cells (MIDDLE) and IFNγ from CD8+ T cells (RIGHT) (*, P < 
0.05; **, P < 0.01; ***, P < 0.001). 
Preclinical data have shown that in a highly CDK4/6 dependent estrogen receptor positive breast 
cancer model, intermittent trilaciclib dosing during the time of chemotherapy treatment did not 
negatively affect chemotherapy treatment. The lack of antagonism when trilaciclib was added to 
chemotherapy treatment was observed in multiple CDK4/6 dependent models (Sorrentino, 2018). 
While trilaciclib is not expected to directly impact tumor proliferation, it has the potential to 
greatly improve the current standard of care in urothelial carcinoma by protecting the bone 
marrow and immune system function during chemotherapy in addition to activating T cell 
mediated immunity and potentially enhancing anti-tumor activity. 
4.5.1.2. 
Pharmacokinetic Studies 
Pharmacokinetic studies in rats and dogs showed that the relationship between dose level and 
plasma exposure to trilaciclib was generally similar between males and females and did not 
change with repeated daily dosing. Exposure to trilaciclib increased with dose level, but not 
always proportionally.  
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, but clinical studies have confirmed no clinically significant drug-drug interaction 
(DDI) based on CYP3A (see Section 4.5.2.2 for additional details). 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 DDI based on inhibition of breast cancer resistance protein-, bile salt export 
pump-, organic anion transporter 1 (OAT1)-, organic anion transporter 3 (OAT3)-, organic anion 
transporting polypeptide 1B1 (OATP1B1)-, p-glycoprotein-, multidrug resistance protein 1 


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(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 4.5.2.2 for additional details).  
4.5.2. 
Summary of Clinical Data 
A brief summary of the trilaciclib clinical data is provided in the following sections. Detailed 
information is presented in the trilaciclib IB. 
4.5.2.1. 
Efficacy 
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 etoposide plus carboplatin (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) gemcitabine/carboplatin therapy only on Days 1 and 8 of a 21-day cycle, 2) 
trilaciclib and gemcitabine/carboplatin once daily on Days 1 and 8 of each 21-day 
cycle, OR 3) trilaciclib on Days 1, 2, 8 and 9 with gemcitabine/carboplatin 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 DSN in 
Cycle 1 and occurrence of 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 myeloprotection 
benefits come with an overall improved safety profile compared with available therapy, as 


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evidenced by reduced high grade treatment-emergent adverse events (AEs) across all SCLC 
studies, and no detriment to anti-tumor efficacy results. For a more detailed description of the 
results, refer to the trilaciclib IB. 
Results from the TNBC Study G1T28-04 demonstrated that although the addition of trilaciclib at 
the RP2D to gemcitabine/carboplatin 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, anti-tumor efficacy results demonstrated a clinically 
meaningful improvement in PFS and OS (Figure 4; Table 2). This meaningful anti-tumor 
efficacy was observed across multiple subgroups, including both PD-L1 positive and negative 
tumor types (Table 3), and in both trilaciclib groups compared with the control group. 
Table 2: 
G1T28-04: Summary of Overall Survival and Progression-Free Survival 
(ITT Analysis Set) 
Category 
Group 1 
Gem/Carbo 
(Day 1+8) 
(N=34) 
Group 2  
Gem/Carbo + 
Trilaciclib 
(Day 1+8) 
(N=33) 
Group 3  
Gem/Carbo + 
Trilaciclib 
(Day 1/2+8/9) 
(N=35) 
Groups 2+3 
(N=68) 
Overall survival (months) (95% CI)a, b 
 
 
 
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) 
NR (32.7, NR) 
Comparison (treatment group versus Group 1) 
 
 
 
Adjusted HR (SE)c 
NA 
0.31 (0.111) 
0.40 (0.125) 
0.37 (0.101) 
95% CIc 
NA 
0.15, 0.63 
0.22, 0.74 
0.21, 0.63 
2-sided p-valued 
NA 
0.0016 
0.0004 
<0.0001 
Progression-free survival (months) (95% CI)a, b 
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)c 
NA 
0.62 (0.209) 
0.63 (0.212) 
0.62 (0.180) 
95% CIc 
NA 
0.32, 1.20 
0.32, 1.22 
0.36, 1.10 
2-sided p-valued 
NA 
0.2099 
0.1816 
0.1291 
CI=confidence interval; Gem/Carbo=gemcitabine/carboplatin; HR=hazard ratio; ITT=intent-to-treat; N=total 
number of patients in each treatment group; NA=not applicable; NR=not reached; OS=overall survival; 
SE=standard error. 
a Calculated using the Kaplan-Meier method 
b OS reported from final database; PFS reported from earlier data cutoff on 15 May 2020. 
c The HR and its 95% CI were calculated using the Cox regression model controlling for the stratification factors, 
namely, number of prior lines of therapy (0 versus 1 or 2) and liver involvement. 
d P-value was calculated using the stratified log-rank test controlling for the two stratification factors. 


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Figure 4: 
G1T28-04: Overall Survival – Kaplan-Meier Curve (ITT Analysis Set) 
 
CI=confidence interval; GC=gemcitabine and carboplatin; HR=hazard ratio; ITT=intent-to-treat; NR=not reached; OS=overall survival. 
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 1 and 8 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. 


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Table 3: 
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) 
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) 
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) 
CI=confidence interval; 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 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. 


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As mentioned in Section 4.5.1.1, there is a hypothetical risk that administration of trilaciclib 
prior to chemotherapy could decrease chemotherapy efficacy. 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 gemcitabine/carboplatin 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 
gemcitabine/carboplatin. Specifically, PFS and OS did not decrease when trilaciclib was added 
to gemcitabine/carboplatin in the most CDK4/6-dependent population (see trilaciclib IB). 
4.5.2.2. 
Pharmacokinetics 
Trilaciclib has a terminal half-life of approximately 14 hours and undergoes extensive 
metabolism. Mild hepatic impairment and mild and moderate renal impairment had no effect on 
trilaciclib exposure. Population PK analysis indicated that age, gender, weight and race had no 
clinically relevant effect on the systemic exposure of trilaciclib. For more information about PK 
profile of trilaciclib, please refer to the trilaciclib IB. 
A clinical DDI study in healthy subjects using the index CYP3A substrate midazolam indicated 
that trilaciclib had no impact on CYP3A activity and that the strong CYP3A inducer rifampin 
had no clinically meaningful effect on trilaciclib PK. 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. 
Gemcitabine has not been reported to be a substrate for MATE1 or MATE2 (Blackhall, 2010; 
Shen, 2013), and is not believed to be a substrate for OCT2. Carboplatin has not been reported to 
be a substrate for OCT2, MATE1, or MATE2 (Yonezawa, 2006). As such, based on a previous 
clinical trial with gemcitabine/carboplatin and trilaciclib (Study G1T28-04), 
gemcitabine/carboplatin administration following trilaciclib administration had no effect on 
trilaciclib PK and trilaciclib administered prior to chemotherapy had little to no effect on the PK 
of carboplatin or gemcitabine (for more detailed information, please refer to the trilaciclib IB). 
Cisplatin has been reported to be a substrate of OCT2, MATE1 and MATE2-K (Wagner, 2016) 
and as such has the potential for DDI with trilaciclib, the net effect of which is difficult to predict 
due to the multiple drug transporters involved. Therefore, blood samples for the assessment of 
cisplatin PK will be collected in this study and signs of nephrotoxicity will be closely monitored. 
In an additional clinical DDI assessment in healthy subjects, trilaciclib increased metformin 
(MATE1, MATE2-K and OCT2 substrate) exposure by 65% compared with administration of 
metformin alone. Avoid concomitant use of trilaciclib with certain OCT2, MATE1, and 
MATE2-K 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. 


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4.5.3. 
Risks 
4.5.3.1. 
Trilaciclib 
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 and avelumab maintenance 
therapy (which carries their own risk of reproductive/embryo-fetal toxicity), the risks specific to 
trilaciclib are consistent with those experienced with chemotherapy and avelumab. 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. 
At the clinical dose of 240 mg/m2 being used in this study, trilaciclib did not have a clinically 
relevant effect on QTc (i.e., >10 msec).  
In an integrated safety analysis from the four Phase 2 oncology studies conducted with trilaciclib 
to date (G1T28-02 [complete], G1T28-03 [data cutoff: 31 May 2019], G1T28-05 [data cutoff: 
28 Jun 2019], and G1T28-04 [complete]), the most common TEAEs (≥10%) that occurred more 
frequently in patients receiving trilaciclib compared to placebo were nausea, fatigue, headache, 
dyspnea, cough, hypokalemia, and infusion related reaction. Trilaciclib-related TEAEs occurring 
in ≥5% of patients with at least a ≥2% higher incidence in trilaciclib compared to placebo were 
nausea, fatigue, anemia, headache, infusion related reaction, neutrophil count decreased, 
decreased appetite, vomiting, and constipation. 
Adverse events of special interest (AESIs) identified for trilaciclib in the integrated safety 
summary are described below. 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 9.3. 
Trilaciclib AESIs: 
1. Injection Site Reaction/Phlebitis/Thrombophlebitis: Infusion of trilaciclib can cause 
injection-site reactions including phlebitis and thrombophlebitis. Injection-site reactions 
including phlebitis and thrombophlebitis occurred in 56 (21%) of 272 patients receiving 
trilaciclib in clinical trials, including Grade 2 (10%) and Grade 3 (0.4%) AEs. The 
median time to onset from start of trilaciclib was 15 days (range 1 to 542) and from the 
preceding dose of trilaciclib was 1 day (1 to 15).The median duration was 1 day (range 1 
to 151 for the resolved cases). Injection-site reactions including phlebitis and 
thrombophlebitis resolved in 49 (88%) of the 56 patients and led to discontinuation of 
treatment in 3 (1%) of the 272 patients. 
Monitor patients for signs and symptoms of injection-site reactions, phlebitis, and 
thrombophlebitis, including infusion-site pain and erythema during infusion. For mild 


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(Grade 1) to moderate (Grade 2) injection-site reactions, flush line/cannula with at least 
20 mL of sterile 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP 
after end of infusion. For severe (Grade 3) or life-threatening (Grade 4) injection-site 
reactions, stop infusion and permanently discontinue trilaciclib. 
2. Acute Drug Hypersensitivity Reaction: Trilaciclib can cause acute drug 
hypersensitivity reactions, including facial edema and urticaria. Acute drug 
hypersensitivity reactions occurred in 16 (6%) of 272 patients receiving trilaciclib in 
clinical trials, including Grade 2 reactions (2%). One patient experienced a Grade 2 
anaphylactic reaction 4 days after receiving trilaciclib, which resolved with epinephrine, 
and treatment with trilaciclib was continued. The median time to onset from start of 
trilaciclib was 77 days (range 2 to 256) and from the preceding dose of trilaciclib was 
1 day (range 1 to 28). The median duration was 6 days (range 1 to 69 for the resolved 
cases). Acute drug hypersensitivity reactions resolved in 12 (75%) of the 16 patients. 
Monitor patients for signs and symptoms of acute drug hypersensitivity reactions 
including facial, eye, and tongue edema, urticaria, pruritus, and anaphylactic reactions. 
For moderate (Grade 2) acute drug hypersensitivity reactions, stop infusion and hold 
trilaciclib until the adverse reaction recovers to Grade ≤1. For severe (Grade 3) or 
life-threatening (Grade 4) acute drug hypersensitivity reactions, stop infusion and 
permanently discontinue trilaciclib. 
3. Pneumonitis/Interstitial Lung Disease: Severe, life-threatening, or fatal interstitial lung 
disease and/or pneumonitis can occur in patients treated with CDK4/6 inhibitors, the 
same drug class as trilaciclib. Interstitial lung disease /pneumonitis occurred in 1 (0.4%) 
of 272 patients receiving trilaciclib in clinical trials. The event was Grade 3 and reported 
2 months after discontinuing trilaciclib, in a patient receiving a confounding medication. 
The event did not resolve. 
Monitor patients for pulmonary symptoms indicative of interstitial lung 
disease/pneumonitis such as cough, dyspnea, and hypoxia. For recurrent moderate 
(Grade 2) interstitial lung disease/pneumonitis, permanently discontinue trilaciclib. For 
severe (Grade 3) or life-threatening (Grade 4) interstitial lung disease/pneumonitis, 
permanently discontinue trilaciclib.  
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.  
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 


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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.  
4.5.3.2. 
Gemcitabine/Carboplatin/Cisplatin 
4.5.3.2.1. Gemcitabine 
Per Warnings and Precautions in the prescribing information/summary of product characteristics 
for gemcitabine (Gemzar®, 2019 [US]; Gemzar, 2019 [EU]), the following are important risks 
related to gemcitabine use: 
• Bone marrow suppression: neutropenia, thrombocytopenia, and anemia, including 
Grade 3 or 4 hematologic toxicity  
• Capillary leak syndrome 
• Hemolytic uremic syndrome: may lead to renal failure and dialysis (including 
fatalities).  
• Hepatotoxicity 
• Hypersensitivity: Anaphylaxis and allergic reactions (including bronchospasm and 
anaphylactoid reactions) have been observed 
• Posterior reversible encephalopathy syndrome: may manifest with blindness, 
confusion, headache, hypertension, lethargy, seizure, and other visual and neurologic 
disturbances  
• Pulmonary toxicity: including adult respiratory distress syndrome, interstitial 
pneumonitis, pulmonary edema, and pulmonary fibrosis 
4.5.3.2.2. Carboplatin 
Per Warnings and Precautions in the prescribing information/summary of product characteristics 
for carboplatin (Carboplatin, 2020 [EU]; Carboplatin, 2018 [US]), the following are important 
risks related to carboplatin use: 
• Bone marrow suppression: leukopenia, neutropenia, and thrombocytopenia  
• Nephrotoxic potential: concomitant treatment with aminoglycosides has resulted in 
increased renal and/or audiologic toxicity  
• Emesis 
• Peripheral neurotoxicity: observed infrequently, but its incidence is increased in 
patients older than 65 years and in patients previously treated with cisplatin  
• Loss of vision 
• Allergic reactions, including anaphylaxis  


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• Abnormal liver function tests  
• Fetal harm 
4.5.3.2.3. Cisplatin 
Per Warnings and Precautions in the prescribing information/summary of product characteristics 
for cisplatin (Cisplatin, 2020 [EU]; Cisplatin, 2019 [US]), the following are important risks 
related to cisplatin use: 
• Hypersensitivity reactions: anaphylaxis and death may occur 
• Ototoxicity: cumulative toxicity may be severe 
• Ocular toxicity: optic neuritis, papilledema, and cortical blindness may occur 
• Nephrotoxicity 
• Secondary acute leukemia 
• Fetal harm 
Trilaciclib may increase cisplatin exposure in some patients. 
4.5.3.2.4. Avelumab 
Per Warnings and Precautions in the prescribing information/summary of product characteristics 
for avelumab (Bavencio, 2020 [US]; Bavencio, 2020 [EU]), the following are important risks 
related to avelumab use: 
• Immune-mediated adverse reactions: may be severe or fatal, can occur in any organ 
system or tissue, including immune-mediated pneumonitis, colitis, hepatitis, 
endocrinopathies (type I diabetes mellitus which can present with diabetic 
ketoacidosis, thyroiditis, hypothyroidism, hyperthyroidism, adrenal insufficiency, 
hypophysitis), dermatologic adverse reactions, nephritis and renal dysfunction, and 
solid organ transplant rejection. 
• Infusion-related reactions 
• Complications with allogeneic hematopoietic stem cell transplant: fatal and other 
serious complications can occur in patients who receive hematopoietic stem cell 
transplant before or after being treated with a PD-1/PD-L1-blocking antibody 
• Fetal harm 
Any AE that is suspected to be a potential immune-related AE is considered an avelumab AESI. 
Refer to the avelumab prescribing information/summary of product characteristics for a detailed 
description of anticipated safety risks for avelumab and their management (Bavencio, 2020 [US]; 
Bavencio, 2020 [EU]). 
4.6. 
Benefit/Risk Assessment 
Trilaciclib (a CDK4/6 inhibitor) is being evaluated for anti-tumor efficacy as well as its ability to 
improve the patient experience while receiving chemotherapy. In addition to the side effects of 
chemotherapy, chemotherapy-induced immunosuppression may limit anti-tumor efficacy due to 


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an inability of the host immune system to effectively mount a response against the cancer. 
Therefore, administration of trilaciclib to preserve the bone marrow and the immune system from 
the cytotoxic effects of chemotherapy has the potential to maximize anti-tumor activity of the 
chemotherapy. As stated in Section 4.5.2, the dose of 240 mg/m2 trilaciclib established in Phase 
1b/2a SCLC studies and in the Phase 2 TNBC study, will be used in this study and administered 
prior to a commonly used platinum-based chemotherapy regimen and maintenance regimen; a 
dose that has shown efficacy in myeloprotection (in SCLC studies) as well as in survival 
outcomes (TNBC).  
Studies to date with trilaciclib have demonstrated a manageable safety profile (see 
Section 4.5.3.1). In Study G1T28-04, the rates of overall toxicity were comparable in TNBC 
patients who received trilaciclib with gemcitabine/carboplatin versus gemcitabine/carboplatin 
alone despite the 2-fold increase in the median number of cycles and 50% increase in the 
cumulative dose of both gemcitabine and carboplatin in patients who received trilaciclib. Rates 
of discontinuation due to an AE were not different between the trilaciclib groups and the 
gemcitabine/carboplatin alone group. Similarly, in patients with SCLC administered trilaciclib 
with etoposide/carboplatin/atezolizumab (E/P/A) in Study G1T28-05, the rates of overall toxicity 
profile were comparable in patients who received trilaciclib plus E/P/A versus placebo plus 
E/P/A despite the lower relative dose intensity of E/P/A being lower in patients in the placebo 
group compared with the trilaciclib group, with the trilaciclib group having fewer having a lower 
number of dose delays/reduction. In addition, patients receiving trilaciclib had lower rates of 
discontinuation due to an AE and atezolizumab AEs of special interest as compared with patients 
receiving placebo. In conclusion, combination treatment with trilaciclib and platinum-based 
chemotherapy and ICI maintenance therapy offers the potential for clinical benefit with a 
favorable safety profile. 
A COVID-19 risk assessment has been performed, documented, and will be provided as a 
separate document. 


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5. 
OBJECTIVES AND ENDPOINTS 
The primary, secondary, and exploratory objectives of this study in patients treated with 
platinum-based chemotherapy and avelumab maintenance therapy for untreated locally advanced 
or metastatic urothelial carcinoma, and their associated endpoints, are presented in Table 4. 
Table 4: 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary Objective 
• 
To evaluate the anti-tumor efficacy of 
trilaciclib compared to a control 
group  
• 
PFS during the overall study  
Secondary Objectives: Efficacy 
• 
To evaluate the anti-tumor efficacy of 
trilaciclib compared to a control 
group  
• 
ORR defined as the proportion of patients 
who had an objective response (unconfirmed 
or confirmed) per RECIST v1.1 
(chemotherapy period, maintenance period, 
during the overall study) 
• 
DCR defined as the proportion of patients 
with best overall response of confirmed CR or 
PR, or SD per RECIST v1.1 (maintenance 
period, during the overall study) 
• 
DOR per RECIST v1.1 (during the overall 
study) 
• 
PFS (maintenance period) 
• 
Probability of survival at Month 16  
• 
OS (maintenance period, during the overall 
study) 
To evaluate the myeloprotective effects of trilaciclib when combined with platinum-based 
chemotherapy compared with chemotherapy alone 
• 
To assess the effects of trilaciclib on 
the neutrophil lineage compared to a 
control group 
• 
Duration of severe (Grade 4) neutropenia in 
Cycle 1 
• 
Occurrence of severe (Grade 4) neutropenia 
• 
Occurrence of febrile neutropenia AEs 
• 
Occurrence of G-CSF administration 
• 
To assess the effects of trilaciclib on 
the RBC lineage compared to a 
control group 
• 
Occurrence of Grade 3 or 4 decreased 
hemoglobin laboratory values  
• 
RBC transfusions on or after Week 5 
(occurrence and number of transfusions) 
• 
Occurrence of ESA administration 


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Objectives 
Endpoints 
• 
To assess the effects of trilaciclib on 
the platelet lineage compared to a 
control group 
• 
Occurrence of Grade 3 or 4 decreased platelet 
count laboratory values  
• 
Platelet transfusions (occurrence and number 
of transfusions) 
• 
To assess the effects of trilaciclib on 
hospitalizations due to chemotherapy-
induced myelosuppression compared 
to a control group 
• 
Occurrence and number of hospitalizations 
due to chemotherapy-induced 
myelosuppression 
• 
To assess the effects of trilaciclib on 
chemotherapy dosing compared to a 
control group 
• 
All-cause dose reductions (occurrence and 
number of reductions) 
• 
All-cause cycle delays (occurrence and 
number of delays) 
Secondary Objectives: Safety 
• 
To assess the safety and tolerability of 
trilaciclib compared to a control 
group  
• 
Occurrence and severity of AEs by 
NCI-CTCAE v5.0  
• 
Trilaciclib AESIs 
• 
Avelumab AESIs 
• 
Changes in laboratory parameters 
(hematology and serum chemistry), vital signs 
and ECG parameters 
• 
Grade 3 or 4 abnormalities in serum 
chemistry laboratory parameters  
• 
Occurrence of trilaciclib dose delays and 
infusion interruptions  
• 
Occurrence of chemotherapy dose reductions 
• 
Occurrence of chemotherapy dose delays and 
infusion interruptions 
• 
Occurrence of avelumab dose delays and 
infusion interruptions 
Exploratory Objectives 
• 
To assess the pharmacodynamic 
effects, including immune-based 
mechanism, of trilaciclib when added 
to platinum-based chemotherapy and 
avelumab therapy in tumor biopsies 
and peripheral blood  
• 
Differences in pharmacodynamic parameters, 
including those relating to immune-based 
mechanisms, in tumor and peripheral blood 


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Objectives 
Endpoints 
• 
To understand the effect of trilaciclib 
in CDK4/6-dependent tumors when 
added to platinum-based 
chemotherapy and avelumab 
maintenance therapy 
• 
PFS, OS, and ORR (per RECIST v1.1) during 
the study in patients with each of the 
following CDK4/6 dependence signatures: 
− 
CDK4/6 dependent 
− 
CDK4/6 independent 
− 
CDK4/6 indeterminant 
• 
To assess the effects of trilaciclib on 
PFS, OS, ORR, DOR, and DCR in 
the PD-L1 subgroups 
• 
PFS, OS, ORR, DOR and DCR during the 
study in PD-L1 subgroups (as measured by 
retrospective analysis) 
• 
To assess the PK of trilaciclib and 
metabolites, cisplatin, and avelumab 
when trilaciclib is administered with 
either cisplatin or avelumab 
• 
PK parameters as data permit 
• 
To assess the immunogenicity of 
avelumab when administered with 
trilaciclib 
• 
Anti-avelumab antibodies 
• 
Neutralizing antibodies 
AE=adverse event; AESI=adverse event of special interest; CDK=cyclin-dependent kinase; CR=complete response; 
CTCAE=Common Terminology Criteria for Adverse Events; DCR=disease control rate; DOR=duration of 
response; ECG=electrocardiogram; ESA=erythropoiesis stimulating agent; G-CSF=granulocyte colony-
stimulating factor; NCI=National Cancer Institute; ORR=objective response rate; OS=overall survival; PD-
L1=programmed death-ligand 1; PFS=progression free survival; PK=pharmacokinetic; PR=partial response; 
RBC=red blood cell; RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease. 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is an exploratory Phase 2, multicenter, randomized, open-label study evaluating the safety 
and efficacy of trilaciclib administered with platinum-based chemotherapy followed by trilaciclib 
administered with avelumab maintenance therapy compared with platinum-based chemotherapy 
followed by avelumab maintenance therapy in patients receiving first-line treatment for 
advanced/metastatic urothelial carcinoma. Inclusion/exclusion criteria are outlined in Section 7.1 
and Section 7.2, respectively. 
Approximately 90 patients will be randomly assigned (1:1) to one of two treatment arms:  
• Arm A – platinum-based chemotherapy followed by avelumab maintenance therapy 
• Arm B – trilaciclib plus platinum-based chemotherapy followed by trilaciclib plus 
avelumab maintenance therapy 
Platinum-based chemotherapy (with or without trilaciclib) will be administered IV in 21-day 
cycles, and avelumab maintenance therapy (with or without trilaciclib) will be administered IV 
in 14-day cycles. There will be two stratification factors for randomization: presence of visceral 
metastasis (yes or no) at randomization and initial platinum-based chemotherapy to be 
administered (cisplatin or carboplatin). 
Common Design Features for All Treatment Arms 
Study drugs will be administered as follows: 
• Gemcitabine 1000 mg/m2 administered IV on Day 1 and Day 8 of each 21-day 
chemotherapy cycle.  
• Cisplatin eligible: cisplatin 70 mg/m2 administered IV on Day 1 of each 21-day 
chemotherapy cycle. Split dosing on Day 1 and Day 8 is permitted for toxicity 
management as described in Section 9.3.1.1. Gemcitabine should be administered 
prior to cisplatin. 
• Cisplatin ineligible: carboplatin using Calvert formula with a target area under the 
curve (AUC) = 4.5 administered IV on Day 1 of each 21-day chemotherapy cycle. 
Gemcitabine should be administered prior to carboplatin. 
• Other platinum-based chemotherapies, such as methotrexate/carboplatin/vinblastine 
(M-CAVI) for example, are not permitted in this study. 
• Avelumab 800 mg administered IV on Day 1 of each 14-day maintenance cycle as a 
60-minute infusion. In order to mitigate infusion-related reactions, premedication 
with an antihistamine and with paracetamol (acetaminophen) approximately 30 to 
60 minutes prior to each dose of avelumab is mandatory for the first 4 infusions (for 
example, 25-50 mg diphenhydramine and 500-650 mg paracetamol [acetaminophen] 
IV or oral equivalent). This may be modified based on local treatment standards and 
guidelines, as appropriate. Premedication should be administered for subsequent 


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avelumab doses based upon clinical judgment and presence/severity or prior infusion 
reactions. 
• Trilaciclib 240 mg/m2 administered as a 30-minute IV infusion completed within 
4 hours prior to the start of platinum-based chemotherapy (Day 1 and Day 8) or 
avelumab maintenance therapy (Day 1) 
The study will include 3 study phases: Screening Phase, Treatment Phase, and Survival 
Follow-up Phase (Figure 5). The Treatment Phase begins on the day of randomization and 
completes at the End of Treatment Visit. Survival Follow-up assessments should occur every 
3 months after the End of Treatment Visit (including assessments at Month 17 Day 1. 
Figure 5: 
Study Schema 
 
Patients enrolled in the study will be eligible to receive 4-6 cycles of platinum-based 
chemotherapy, per Investigator’s discretion. Patients without progressive disease (PD) per 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (i.e., with an ongoing complete 
response [CR], partial response [PR], or stable disease [SD]) after platinum-based chemotherapy 
will be eligible to receive avelumab maintenance therapy until disease progression, unacceptable 
toxicity, withdrawal of consent, Investigator decision, or the end of the trial, whichever comes 
first. Treatment visits will occur consecutively as planned without interruption, except when 
necessary to manage toxicities or for administrative reasons (long weekends, holidays, weather 
conditions, etc.). There should be no more than 42 days between the start of each platinum-based 
chemotherapy cycle (with or without trilaciclib). Dosing delays >42 days between the start of 
each platinum-based chemotherapy cycle may be permitted on a case-by-case basis with the 
approval of the Investigator and Medical Monitor. There should be no more than 56 days 
between doses of avelumab maintenance therapy (with or without trilaciclib). Dosing delays 
>56 days between doses of avelumab maintenance therapy may be permitted on a case-by-case 
basis with the approval of the Investigator and Medical Monitor. Avelumab maintenance therapy 
(with or without trilaciclib) should begin at a minimum of 4 and not more than 10 weeks after the 
last dose of platinum-based chemotherapy (with or without trilaciclib). 
Criteria which patients must meet in order to receive study drug on Day 1 and on Day 8 during 
chemotherapy treatment are provided in Section 9.2. 


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An End of Treatment Visit will occur approximately 14 days following a patient’s last dose of 
study drug. Safety Follow-up visits (which may be a phone call) will occur 30 days after their 
last dose of study drug and 90 days after the last dose of avelumab. Patients will be followed for 
survival approximately every 3 months (including and assessment at Month 17 Day 1) after the 
End of Treatment Visit. Survival Follow-up Visits may be done via telephone, email, or clinic 
visit. Patients will be followed for survival, at a minimum, until at least 60% of patients in the 
study have died, or the end of study, whichever occurs first. 
A Data Monitoring Committee (DMC) will monitor accumulating safety and anti-tumor response 
data with the first meeting planned when approximately10 patients treated with trilaciclib + 
cisplatin or 10 patients treated with trilaciclib + carboplatin have completed at least 2 cycles, 
whichever occurs first. The meetings will continue approximately every 6 months or as defined 
in the DMC charter while patients are on study treatment depending upon the enrollment rate. 
Additional reviews may occur. For more information, refer to Section 11.7.  
The study will be completed when the criteria outlined in Section 10.4 have been met or upon 
sponsor termination of the study. 
6.2. 
Rationale for Primary and Secondary Endpoints 
6.2.1. 
Anti-tumor Efficacy 
Measurements of anti-tumor efficacy as measured by probability of survival, OS and PFS, as 
well as anti-tumor response rates by RECIST v1.1, ORR, disease control rate (DCR), and 
duration of response (DOR), are standard assessments used in oncology solid tumor studies to 
measure the effects of study treatment on the underlying malignant disease. Additionally, clinical 
benefit in oncology should be based on direct evidence, such as improvement in duration of OS, 
improvement in a patient’s quality of life, improved physical functioning, or improved tumor 
related- symptoms, which may not be adequately measured by response rates alone. Therefore, 
improvement in survival is considered one of the most reliable measures in providing direct 
evidence of clinical benefit to patients and is a preferred clinical endpoint. Survival is considered 
easy to measure via documentation of the date of death and is not prone to bias (FDA, 2008). 
6.2.2. 
Myeloprotection Efficacy 
Patients experiencing chemotherapy-induced myelosuppression often face severe clinical 
consequences (e.g., febrile neutropenia [FN] predisposes patients to serious infections and even 
death). For those patients with neutropenia requiring hospitalization, the estimated inpatient 
mortality rates ranged from 3.4% to 10.5% depending on tumor type in 1 study, with an overall 
mortality rate of 6.8% (Caggiano, 2005). In another analysis, the overall rate of death was 9.5%, 
with rates for solid tumor cancer patients ranging from 3.6% for breast cancer patients to 13.4% 
for lung cancer patients (Kuderer, 2006). Because both the severity and duration of neutropenia 
correlate with the risk of FN and infections (Bodey, 1966; Gustinetti, 2016; Li, 2016), a 
reduction in its occurrence and duration will decrease the risk of these events and provide an 
improved patient experience while receiving chemotherapy (Padilla, 2005). The measurement of 
DSN is limited to Cycle 1 because the risk of FN is highest in Cycle 1 (Culakova, 2014) and 
because the data collected in Cycle 1 in this study will not be subject to bias due to granulocyte 


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colony-stimulating factor (G-CSF) administration since primary prophylactic G-CSF will be 
prohibited in Cycle 1. 
6.2.3. 
Safety 
Assessment of AEs, changes in laboratory parameters, vital signs, and ECOG performance status 
are all standard assessments used in oncology trials to measure patient safety. 
6.3. 
Rationale for Dose and Schedule of Study Treatment 
Previous studies demonstrated the RP2D of trilaciclib was 240 mg/m2. When trilaciclib was 
administered prior to chemotherapy to cancer patients, doses of 200 (rounded up from 192), 240, 
and 280 mg/m2 were evaluated. Trilaciclib exposures in cancer patients were slightly lower 
compared with healthy subjects, such that the dose of 240 mg/m2 (rather than 200 mg/m2) more 
closely matched the biologically effective dose of 192 mg/m2. In addition, the dose of 240 mg/m2 
demonstrated maximal myeloprotection efficacy benefits (compared with 200 and 280 mg/m2) as 
measured by a variety of myelosuppression endpoints. The myeloprotective effect at 240 mg/m2 
was further evaluated and confirmed in three randomized controlled Phase 2 studies in SCLC 
patients. In addition, both the planned schedule and the planned doses of trilaciclib, gemcitabine, 
and carboplatin were used in the previous TNBC study (G1T28-04) and demonstrated clinically 
meaningful benefits in OS duration. See the trilaciclib IB for details. The dose and schedule for 
avelumab maintenance therapy follows the instructions located in the local prescribing 
information/summary of product characteristics. 
6.4. 
Rationale for Patient Population 
Inoperable locally-advanced/metastatic urothelial carcinoma is a uniformly lethal disease with 
high unmet medical need. Platinum-based chemotherapy is the current standard of care for 
patients with previously untreated metastatic urothelial carcinoma. Systemic chemotherapy in 
metastatic urothelial carcinoma is, however, characterized by significant toxicity with poor OS 
and low response rates and limited durability in a frail population of advancing age and multiple 
co-morbidities. 
Many first-line patients are medically unfit or ineligible to receive treatment with cisplatin-based 
chemotherapy (cis-ineligible) and need more effective therapeutic options. For patients who are 
deemed ineligible to receive cisplatin, treatment options include carboplatin-based or non-
platinum-based combinations and best supportive care. For patients who do not receive 
chemotherapy, the outcomes remain extremely poor. The addition of trilaciclib to platinum-
based chemotherapy and avelumab maintenance therapy could provide a meaningful treatment 
option for patients receiving first-line treatment. 
6.5. 
Rationale for Platinum-Based Chemotherapy and Avelumab 
Therapy 
In accordance with treatment guidelines, patients with previously untreated urothelial carcinoma 
typically receive platinum-based chemotherapy such as gemcitabine and cisplatin or gemcitabine 
and carboplatin. Participation in clinical studies of new or more-tolerable therapy is also 
recommended (NCCN, 2020).  


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The efficacy of platinum-based chemotherapy in treating urothelial carcinoma may be due to the 
capacity to stimulate an immune response (Zitvogel, 2008). Gemcitabine chemotherapy has been 
shown to reduce MDSCs in murine mouse models and lead to more effective anti-cancer 
immunity (Suzuki, 2005; Ko, 2007; Le, 2009; Sawant, 2013). While MDSCs have been 
described in both the blood and tumors of patients with urothelial carcinoma, the role they play 
remains unclear (Eruslanov, 2012). Gemcitabine may also have beneficial immune effects 
mediated through depletion of regulatory T cells in selected animal models (Shevchenko, 2013). 
In a nonclinical study, cisplatin enhanced tumor cell susceptibility to cytotoxic T cell-mediated 
killing (Ramakrishnan, 2010). 
The benefit of carboplatin-based therapy in cisplatin-ineligible patients was demonstrated in the 
EORTC Trial 30986. In this study, 238 patients with previously untreated advanced urothelial 
carcinoma and either a poor performance status and/or impaired renal function (glomerular 
filtration rate [GFR] <60 but >30 mL/min) were enrolled to receive gemcitabine/carboplatin or 
M-CAVI (De Santis, 2012). The confirmed ORR of gemcitabine/carboplatin was 36.1% versus 
21.0% for the M-CAVI arm. However, there was no evidence of a difference in OS (HR=0.94; 
95% CI: 0.72, 1.22; p=0.64); median OS was 9.3 and 8.1 months, respectively. 
Immunotherapy in urothelial carcinoma has shown significant promise (Galsky, 2020; 
Powles, 2020). Tumor-cell killing by cytotoxic chemotherapy alone can be expected to expose 
the immune system to high levels of tumor antigens; invigorating tumor-specific T cell immunity 
in this setting by inhibiting PD-L1/PD-1 signaling and by using the combination of avelumab 
and chemotherapy may result in deeper and more durable responses compared with standard 
chemotherapy alone. 
Treatment with avelumab in treatment-resistant urothelial carcinoma has shown responses in 
patients with platinum-refractory cancer and has received approval from the US FDA for the 
treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease 
progression during or following platinum-containing chemotherapy or have disease progression 
within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy 
(Bavencio, 2020). Patients enrolled in the Phase 1b JAVELIN Solid Tumor study with 
previously treated advanced/metastatic urothelial carcinoma received avelumab 10 mg/kg every 
2 weeks until disease progression. The ORR in all patients was 16.5% (CR in 4.1% and PR in 
12.5%), with a median DOR of 20.5 months. Median PFS was 1.6 months with a 12-month PFS 
rate of 16.8%, and median OS was 7.0 months with a 24-month OS rate of 20.1%. Avelumab 
also showed antitumor activity in high-risk subgroups, including elderly patients and those with 
renal insufficiency or upper tract disease (Apolo, 2020). 
Treatment with avelumab has also shown responses as a maintenance treatment in patients with 
locally advanced or metastatic urothelial carcinoma that has not progressed with first-line 
platinum-containing chemotherapy and has received approval from the US FDA 
(Bavencio, 2020) and a positive opinion from the European Committee for Medicinal Products 
for Human Use (European Medicines Agency, 2020) and approval by the European Commission. 
In the pivotal Phase 3 JAVELIN Bladder 100 study, patients with unresectable locally advanced 
or metastatic urothelial carcinoma who did not have disease progression after 4-6 cycles of 
platinum-based chemotherapy were randomly assigned to receive best supportive care (control) 
or best supportive care with avelumab 10 mg/kg administered every 2 weeks until disease 
progression. Median OS in the avelumab group versus the control group was 21.4 months versus 


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14.3 months (HR=0.69, p=0.001), with OS at 1 year of 71.3% in the avelumab group and 58.4% 
in the control group. Median PFS in the avelumab group versus control group was 3.7 months 
versus 2.0 months (HR=0.62). Disease control rates (defined as a best overall response of CR, 
PR, SD, or non–CR or non–progressive disease) was 41.1% in the avelumab group and 27.4% in 
the control group (Powles, 2020). Based on local prescribing guidelines, this study will use the 
flat dose of 800 mg. 
The addition of trilaciclib to platinum-based chemotherapy and avelumab maintenance therapy 
may offer the potential for clinical benefit and a manageable tolerability profile in patients with 
metastatic urothelial carcinoma receiving first-line treatment. 
6.6. 
Rationale for Supportive Care Interventions (Growth Factors and 
Transfusions) 
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 9.4.1 and Investigator discretion (Aapro, 2011; 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.  
6.7. 
Rationale for Stratification Factors 
As outlined in Section 6.1, randomization of patients will be stratified by two stratification 
factors: presence of visceral metastasis (yes or no) at randomization and initial platinum-based 
chemotherapy to be administered (cisplatin or carboplatin). These stratification factors were 
chosen because they are predicted to have an impact on study endpoints such that if there is an 
imbalance in this factor, interpretation of the results of the study could be compromised. In a 
Phase 3 study in second-line urothelial carcinoma comparing vinflunine with best supportive 
care and which examined 16 potential prognostic factors for their association with survival, 
patients with visceral involvement had the worst OS outcome (Bellmunt, 2009). In a separate 
study, liver metastasis was a disease factor included in a model that showed prognostic 
performance for survival across three PD-L1 inhibitors to treat metastatic urothelial carcinoma 
after platinum-based chemotherapy (Sonpavde, 2020). Finally, multiple studies have shown 
differences in survival outcomes in patients with urothelial carcinoma administered cisplatin 
versus carboplatin treatment (Powles, 2020; Galsky, 2020; Galsky, 2012). 


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7. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, 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  
2. Histologically documented, locally advanced (T4b, any N; or any T, N 2-3) or metastatic 
urothelial carcinoma (M1, Stage IV) (also termed TCC or UCC of the urinary tract; 
including renal pelvis, ureters, urinary bladder, and urethra) 
a. Patients with mixed histologies are required to have a dominant transitional cell 
pattern (small cell carcinoma of any proportion is not allowed) 
b. Locally advanced bladder cancer must be inoperable on the basis of involvement of 
pelvic sidewall or adjacent viscera (clinical Stage T4b) or bulky nodal metastasis 
(N2-N3) 
3. Measurable disease as defined by RECIST v1.1 
a. Previously irradiated lesions should not be counted as target lesions unless there has 
been demonstrated progression in the lesion since radiotherapy and no other lesions 
are available for selection as target lesions. 
4. Considered to be eligible to receive platinum-based chemotherapy and avelumab 
maintenance therapy, in the Investigator’s judgment 
5. No prior systemic therapy in the inoperable, locally advanced, or metastatic setting 
including chemotherapy, immune checkpoint inhibitor therapy, targeted therapy, or 
investigational agents  
a. For patients who received prior adjuvant/neoadjuvant chemotherapy for urothelial 
carcinoma, a treatment-free interval > 12 months between the last treatment 
administration and the date of recurrence is required in order to be considered 
treatment-naïve in the metastatic setting. If a patient received adjuvant/neoadjuvant 
chemoradiation for urothelial carcinoma, a treatment-free interval >12 months 
between last platinum dose and the date of recurrence is required.  
b. For patients who received prior ICI therapy in the adjuvant/neoadjuvant setting, a 
treatment-free interval > 3 months between the last dose of ICI and date of recurrence 
is required. 
c. Prior local intravesical chemotherapy or immunotherapy is allowed if completed 
≥4 weeks prior to the initiation of study treatment 
6. A formalin-fixed paraffin-embedded (FFPE) tumor tissue block (75-micron) or at least 15 
(5-micron) unstained slides from archival or fresh tumor biopsy or resection; the most 
recent biopsy tissue preferred. Patients who have fewer than 15 unstained slides available 


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at baseline (but no fewer than 10) may be eligible following discussion with the Medical 
Monitor. 
a. Tumor tissue should be of good quality based on total and viable tumor content. For 
core-needle biopsy specimens, at least three cores should be submitted for evaluation. 
b. Transurethral resection of bladder tumor (TURBT) specimens must contain a 
muscle -invasive component (i.e., T2 or greater) of the bladder tumor as verified by 
local pathology review. If the TURBT specimens do not contain a muscle-invasive 
component, then specimens obtained at the time of cystectomy/nephroureterectomy 
(i.e., pT2 or greater) or metastatic spread (i.e., a sample from a metastatic lesion) will 
be required prior to randomization. An archival specimen, if available, should also be 
submitted. 
c. Patients who do not have tissue specimens that meet eligibility requirements may 
undergo a biopsy during the screening period. Acceptable samples include core 
needle biopsies for deep tumor tissue (minimum three cores) or excisional, incisional, 
punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. 
d. Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is 
therefore not acceptable. 
7. ECOG performance status of 0-2 
8. Adequate organ function as demonstrated 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 study drug 
b. Absolute neutrophil count (ANC) ≥1.5 × 109/L  
c. Platelet count ≥100 × 109/L  
d. Estimated glomerular filtration rate ≥ 30 mL/minute/1.73 m2  
e. Total bilirubin ≤1.5 × upper limit of normal (ULN) (<3 ULN if Gilbert’s disease) 
f. ALT and AST ≤2.5 × ULN in the absence of liver metastasis or <5 × ULN in the 
presence of liver metastasis 
9. Resolution of nonhematologic toxicities from prior systemic therapy, radiation therapy, 
or surgical procedures to ≤ Grade 1  
a. Alopecia and sensory neuropathy ≤ Grade 2, as well as any electrolyte laboratory 
abnormalities not constituting a safety risk based on investigator’s judgment are 
acceptable  
10. Predicted life expectancy of ≥3 months 
11. 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.  
12. 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  


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7.2. 
Exclusion Criteria 
A patient will not be eligible for participation in this study if any of the following criteria apply: 
1. Prior treatment with IL-2, IFN-α, anti-PD-L2, anti-CD137 or CD137 agonists, or 
cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibody (including ipilimumab), 
or any other therapeutic antibody or drug specifically targeting T cell co-stimulation or 
immune checkpoint pathways in any setting within 12 months prior to randomization 
2. Malignancies other than urothelial carcinoma within 2 years prior to randomization, 
except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in 
situ, or low-grade (Gleason ≤6) prostate cancer on surveillance without any plans for 
treatment intervention (e.g., surgery, radiation, or castration), or other non-clinically 
significant cancers, which may be considered after discussion with the medical monitor  
3. Presence of central nervous system (CNS) metastases/leptomeningeal disease requiring 
immediate treatment with radiation therapy or steroids. Patient must be off steroids 
administered for brain metastases for at least 2 weeks prior to the first dose of study 
drugs. No stereotactic radiation within 1 week or whole-brain radiation within 14 days 
prior to first dose of study drugs 
4. Uncontrolled ischemic heart disease or uncontrolled symptomatic congestive heart failure 
(≥ Class II New York Heart Association functional classification system), myocardial 
infarction within 6 months prior to first dose of study drugs, unstable angina, or serious 
cardiac arrhythmia requiring medication 
5. QTcF interval > 480 msec. For patients with ventricular pacemakers, QTcF > 500 msec 
6. Known history of stroke or cerebrovascular accident within 6 months prior to first dose of 
study drugs 
7. Known history of serious, chronic active infection (e.g., human immunodeficiency virus, 
hepatitis B or C, tuberculosis, etc.) 
a. Viral load indicative of HIV, HIV 1/2 antibodies, positive hepatitis B virus surface 
antigen or hepatitis C virus ribonucleic acid (RNA) if anti-hepatitis C virus antibody 
screening test positive 
8. Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia  
a. Therapeutic oral or IV antibiotic use within 2 weeks prior to randomization 
b. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or chronic obstructive pulmonary disease or for dental extraction) are 
eligible 
9. 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 
10. Receipt of any investigational medication within 4 weeks, or at least 5 half-lives, 
whichever is greater, prior to the first dose of study drugs 
11. Known hypersensitivity or allergy to study drugs or any component in their formulations 


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12. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3), any 
history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more features of asthma 
symptom control per Global Initiative for Asthma [GINA] 2020) (GINA, 2020) 
13. Prior hematopoietic stem cell or bone marrow transplantation, or solid organ 
transplantation 
14. Radiotherapy to any non-CNS site within 1 week prior to the first dose of study drugs, or 
within 2 weeks to any CNS sites  
15. Pregnant or lactating women 
a. Women of childbearing potential must have negative serum pregnancy test result 
within 7 days prior to initiating study treatment 
16. Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks 
prior to study treatment start, or anticipation of the need for major surgical procedure 
during the course of the study 
17. Received a live, attenuated vaccine within 4 weeks prior to the first dose of study drugs 
a. Inactive vaccines, including but not limited to influenza vaccine, pneumococcal 
vaccine, shingles vaccine, and regionally approved Covid-19 vaccines are allowed  
b. Patients must agree not to receive a live, attenuated influenza vaccine during study 
treatment  
18. History of immune colitis, inflammatory bowel disease, idiopathic pulmonary fibrosis 
(including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., 
bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan 
a. History of radiation pneumonitis in the radiation field (fibrosis) is permitted 
19. Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease 
not requiring immunosuppressive treatment are eligible  
20. Current use of immunosuppressive medication, EXCEPT for the following: 
a. Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection)  
b. Systemic corticosteroids at physiological doses ≤10 mg/day of prednisone or 
equivalent 
c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) 
21. Patients who are investigational site staff members directly involved in the conduct of the 
study and their family members, site staff members otherwise supervised by the 
Investigator, or patients who are employees of G1 Therapeutics, Inc. directly involved in 
the conduct of the study. 


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8. 
SCHEDULE OF ASSESSMENTS 
The procedures and assessments to be performed during the study are outlined in Table 5. 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.  
Unless otherwise specified, assessments are to be completed within ±1 day of the scheduled visit 
date. 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). 


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Table 5: 
Schedule of Assessments 
 
Study Treatment 
Follow-Up 
See Protocol 
Section 
 
Screening 
Chemotherapy Period 
(4-6 cycles; 1 cycle=21d) 
Maintenance 
Period 
(1 cycle=14d) 
End of 
Treatment 
Visit 
(ETV) 
Safety Follow-up Visit 
Survival  
Follow-Up 
 
Assessment 
30 days 
prior to 
C1D1 
Day 1 
(±1d) 
Day 2 
Day 8 
(±1d) 
Day 
13 and 
Day 
17 
(±1d) 
Day 1 
(±1d) 
Day 2 
14 days 
after last 
dose of 
study drug 
(±3d) 
30 days 
after last 
dose of 
study drug 
(+7d)  
90 days 
after last 
dose of 
avelumab 
(±7d) 
Every 
3 months 
after ETV 
(±7d) a 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Section 13.3  
Randomization 
 
X 
[C1 
only (-
7d)] 
 
 
 
 
 
 
 
 
 
Section 11.1.2 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Section 7  
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Section 11.1.3  
Medical History and 
Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
Section 11.1.4  
Archival and/or fresh 
FFPE tumor specimen 
or 15 unstained slides 
X 
 
 
 
 
 
 
 
 
 
 
Section 11.5.1  
Concomitant 
Medications  
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
Section 11.1.4  
Complete Physical 
Examination  
X 
 
 
 
 
 
 
 
 
 
 
Section 11.3.2  
Physical Examination 
when symptoms 
warrant per 
Investigator discretion 
 
X 
 
 
 
X 
 
X 
 
 
 
Section 11.3.2  
Vital Signs 
X 
X 
 
X 
 
X 
 
X 
 
 
 
Section 11.3.1  


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Study Treatment 
Follow-Up 
See Protocol 
Section 
 
Screening 
Chemotherapy Period 
(4-6 cycles; 1 cycle=21d) 
Maintenance 
Period 
(1 cycle=14d) 
End of 
Treatment 
Visit 
(ETV) 
Safety Follow-up Visit 
Survival  
Follow-Up 
 
Assessment 
30 days 
prior to 
C1D1 
Day 1 
(±1d) 
Day 2 
Day 8 
(±1d) 
Day 
13 and 
Day 
17 
(±1d) 
Day 1 
(±1d) 
Day 2 
14 days 
after last 
dose of 
study drug 
(±3d) 
30 days 
after last 
dose of 
study drug 
(+7d)  
90 days 
after last 
dose of 
avelumab 
(±7d) 
Every 
3 months 
after ETV 
(±7d) a 
ECOG Performance 
Status 
X 
X 
 
 
 
X 
[every
-other 
cycle] 
 
X 
 
 
 
Section 11.3.3  
AE Reporting 
 
X 
 
Section 11.3.6  
Laboratory Assessments and Procedures 
Hematology 
X 
X 
X 
[C1 
only] 
X 
X 
[C1 
only] 
X 
 
X 
X 
 
 
Section 11.3.5 
Chemistry 
X 
X 
 
 
 
X 
 
X 
X 
 
 
Section 11.3.5 
Free T4 and TSH 
X 
 
 
 
 
X 
[Q8 
wk] 
 
X 
 
 
 
Section 11.3.5 
Urinalysis (dipstick) 
X 
 
 
 
 
 
 
X 
 
 
 
Section 11.3.5  
Pregnancy Test 
(WOCBP only) 
X 
X 
 
 
 
X 
[every
-other 
cycle; 
C1 
start] 
 
X 
 
 
 
Section 11.3.5  
Anti-avelumab 
antibody and 
neutralizing antibody 
testing 
 
 
 
 
 
X 
[C1, 
C3, C6 
only] 
 
X 
 
 
 
Section 11.6  
12-lead ECG  
X 
 
 
 
 
 
 
 
 
 
 
Section 11.3.4 


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Study Treatment 
Follow-Up 
See Protocol 
Section 
 
Screening 
Chemotherapy Period 
(4-6 cycles; 1 cycle=21d) 
Maintenance 
Period 
(1 cycle=14d) 
End of 
Treatment 
Visit 
(ETV) 
Safety Follow-up Visit 
Survival  
Follow-Up 
 
Assessment 
30 days 
prior to 
C1D1 
Day 1 
(±1d) 
Day 2 
Day 8 
(±1d) 
Day 
13 and 
Day 
17 
(±1d) 
Day 1 
(±1d) 
Day 2 
14 days 
after last 
dose of 
study drug 
(±3d) 
30 days 
after last 
dose of 
study drug 
(+7d)  
90 days 
after last 
dose of 
avelumab 
(±7d) 
Every 
3 months 
after ETV 
(±7d) a 
Blood samples for 
biomarkers 
 
X 
[C1, 
C2, C3 
only] 
 
X 
[C1 
only] 
 
X 
[C1, 
C3 
only] 
 
 
 
 
 
Section 11.5.2 
Blood samples for 
trilaciclib and 
metabolites PK  
(Arm B only) 
 
X 
[C1 
only] 
X 
[C1 
only] 
 
 
X 
[C1, 
C3, 
only] 
X 
[C1, 
C3, 
only] 
 
 
 
 
Section 11.4 
Blood samples for 
cisplatin PK  
(only patients treated 
with cisplatin) 
 
X 
[C1 
only] 
 
X 
[C1 
only] 
 
 
 
 
 
 
 
Section 11.4 
Blood samples for 
avelumab PK  
(Arm B only) 
 
 
 
 
 
X 
[C1, 
C3, C6 
only] 
 
 
 
 
 
Section 11.4 
Study Treatment 
Trilaciclib (Arm B 
only) 
 
X 
 
X 
 
X 
 
 
 
 
 
Section 9.1 
gemcitabine 
 
X 
 
X 
 
 
 
 
 
 
 
Section 9.1  
cisplatin b or 
carboplatin 
 
X 
 
X b 
 
 
 
 
 
 
 
Section 9.1 
avelumab 
 
 
 
 
 
X 
 
 
 
 
 
Section 9.1  


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Study Treatment 
Follow-Up 
See Protocol 
Section 
 
Screening 
Chemotherapy Period 
(4-6 cycles; 1 cycle=21d) 
Maintenance 
Period 
(1 cycle=14d) 
End of 
Treatment 
Visit 
(ETV) 
Safety Follow-up Visit 
Survival  
Follow-Up 
 
Assessment 
30 days 
prior to 
C1D1 
Day 1 
(±1d) 
Day 2 
Day 8 
(±1d) 
Day 
13 and 
Day 
17 
(±1d) 
Day 1 
(±1d) 
Day 2 
14 days 
after last 
dose of 
study drug 
(±3d) 
30 days 
after last 
dose of 
study drug 
(+7d)  
90 days 
after last 
dose of 
avelumab 
(±7d) 
Every 
3 months 
after ETV 
(±7d) a 
Disease Assessment 
Tumor Assessments 
(CT/MRI) 
X 
CT/MRI of chest/abdomen/pelvis Q6 weeks (±7d) during the chemotherapy period and Q8 weeks (±7d) during the 
avelumab maintenance period for up to 1 year relative to Cycle 1 Day 1 and Q12 weeks (±7d) thereafter relative to 
Cycle 1 Day 1 until documented disease progression or subsequent anticancer therapy. Brain scan (MRI preferred) 
during screening is not required and should be performed per investigator discretion based on clinical signs and 
symptoms. Additional brain MRI should be conducted if there are brain metastases present at baseline or new clinical 
signs and symptoms suggestive of brain metastases. Bone metastases identified at baseline via a bone scan or PET 
(such as FDG-PET, NaF-PET, or other locally available PET options) to be followed at scheduled visits using 
localized CT or MRI as clinically indicated. If bone metastases cannot be seen on CT or MRI scans, bone scans, or 
PET should be repeated, using the same diagnostic procedure bone metastases were at baseline, when CR is identified 
in target disease or when progression in bone is suspected. 
Section 11.2.1  
Survival Follow-Up 
and Subsequent Anti-
Cancer Treatments a 
 
 
 
 
 
 
 
 
 
 
X 
Section 11.10 
AE=adverse event; C=cycle(s); CR=complete response; CT=computed tomography; d=day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology 
Group; ETV=End of Treatment Visit; FDG=[18F]-fluorodeoxyglucose; FFPE=formalin-fixed paraffin-embedded; MRI=magnetic resonance imaging; 
NaF=sodium fluoride; PET=positron emission tomography; PK=pharmacokinetic; Q6=every six; Q8=every 8; Q12=every 12; rand.=randomization; 
T4=thyroxine; TSH=thyroid stimulating hormone; wk=weeks; WOCBP=women of childbearing potential. 
a Survival follow-up assessments should occur every 3 months after the End of Treatment Visit (including assessments at Month 17 Day 1 [±7d].  
b Splitting the dose of cisplatin to Day 1 and Day 8 dosing is an allowed alternative for toxicity management (refer to Section 9.3.1.1). 


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9. 
STUDY TREATMENT 
9.1. 
Study Drugs Administered 
Study drugs are defined as any investigational product, chemotherapy, or other therapy 
intended to be administered to a study patient according to the study protocol. Study drugs 
used in this protocol are described in Table 6. 


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Table 6: 
Study Drugs 
Name 
Trilaciclib  
Gemcitabine 
Cisplatin or Carboplatin 
Avelumab 
Type  
Investigational Product 
Chemotherapy 
Chemotherapy 
PD-L1 inhibitor 
Dose 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 
See local prescribing 
information 
See local prescribing 
information 
See local prescribing 
information 
Unit Dose Strength(s) 
300 mg/20 mL  
See local prescribing 
information 
See local prescribing 
information 
See local prescribing 
information 
Dosage Level(s) 
240 mg/m2 administered on 
Days 1 and 8 of each 21-day 
chemotherapy cycle and on 
Day 1 of each 14-day 
maintenance cycle 
1000 mg/m2 administered on 
Days 1 and 8 of each 21-day 
chemotherapy cycle 
Cisplatin eligible: cisplatin 
70 mg/m2 administered on 
Day 1 of each 21-day 
chemotherapy cycle (split 
dosing allowed as presented 
in Section 9.3.1.1)  
Cisplatin ineligible: The dose 
of carboplatin will be 
calculated using the Calvert 
formula with a target AUC = 
4.5. on Day 1 of each 21-day 
chemotherapy cycle 
800 mg administered on Day 
1 of each 14-day maintenance 
cycle 
Route of Administration 
IV 
IV 
IV 
IV 
Infusion Time 
30 minutes 
Per Institution standards 
Per Institution standards 
60 minutes  
AUC=area under the concentration-time curve; IV=intravenous; PD-L1=programmed death-ligand 1. 
Other platinum-based chemotherapies, such as methotrexate/carboplatin/vinblastine (M-CAVI) for example, are not permitted in this study.


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9.1.1. 
Dose, Dosing Regimen, and Route 
Trilaciclib must be administered before gemcitabine, cisplatin/carboplatin and avelumab. 
Gemcitabine should be administered before cisplatin/carboplatin.  
9.1.1.1. 
Trilaciclib 
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. Upon 
reconstitution, the solution must then be diluted to the calculated dose based on the body surface 
area (BSA) of the patient. Actual 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 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. No trilaciclib dose reductions for 
toxicity management will be allowed during the study. 
9.1.1.1.1. Administration of Trilaciclib (For Arm B patients only) 
• Administer diluted trilaciclib solution as a 30-minute IV infusion completed within 
4 hours prior to the start of chemotherapy on each day chemotherapy is administered 
or within 4 hours prior to the start of avelumab on each day avelumab is administered. 
Do not administer trilaciclib as a bolus. 
• Trilaciclib is always administered first. Results from hematology labs should be 
reviewed prior to administration of trilaciclib. If administration of platinum-based 
chemotherapy is skipped or discontinued, trilaciclib will also be skipped or 
discontinued. 
• If administration of avelumab maintenance therapy is delayed or skipped, then 
trilaciclib should be administered as scheduled. If administration of avelumab 
maintenance therapy is permanently discontinued, trilaciclib will also be permanently 
discontinued. 
• Diluted trilaciclib solution must be administered with an infusion set, including an 
in-line filter (0.2 or 0.22 micron). Compatible in-line filters include polyether sulfone, 
polyvinylidene fluoride, and cellulose acetate.  
• Do not administer diluted trilaciclib solution with a polytetrafluorethylene (PTFE) 
in-line filter. PTFE in-line filters are not compatible with diluted trilaciclib 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.  


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If there is any study drug remaining in the infusion bag at the end of the 30 minutes, the infusion 
should be continued at the same rate until the entire contents of the bag have been administered 
to ensure patients receive the full dose. Upon completion of infusion of diluted trilaciclib 
solution, the infusion line/cannula must be flushed with at least 20 mL sterile dextrose 5% in 
water (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. 
Gemcitabine and Cisplatin or Carboplatin 
Descriptions of the formulations of commercially-available gemcitabine and cisplatin or 
carboplatin can be found in the respective current prescribing information/summary of product 
characteristics. Protocol-specified doses of gemcitabine and cisplatin or carboplatin 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. 
Patients will be eligible to receive 4-6 cycles of gemcitabine + carboplatin/cisplatin treatment, 
per Investigator’s discretion. Other platinum-based chemotherapies, such as M-CAVI for 
example, are not permitted in this study. 
Anti-emetic prophylaxis may be administered at the Investigator’s discretion per institutional 
guidelines. To reduce effects on the immune system, the use of dexamethasone as an antiemetic 
should be minimized where possible; however, since this is a moderately emetogenic regimen, 
dexamethasone on the day of platinum-based chemotherapy is allowed per the American Society 
of Clinical Oncology (ASCO) guidelines (Hesketh, 2017).  
Patients treated with cisplatin should receive pre-treatment hydration per institutional guidelines. 
Maintain adequate hydration and urinary output for 24 hours after cisplatin administration.  
Patients will be allowed to switch from cisplatin to carboplatin chemotherapy if they become 
ineligible for cisplatin due to toxicity, or from carboplatin to cisplatin chemotherapy in the event 
that patient becomes eligible to receive cisplatin. Changes in protocol chemotherapy will not be 
allowed for the reason of suspected or confirmed disease progression by RECIST v1.1. 
Ineligibility to receive cisplatin-based chemotherapy should be based upon the criteria published 
by Galsky et al. (Galsky, 2011) and will be documented in the eCRF. Patients who meet at least 
one of the following criteria should be considered for treatment with carboplatin plus 
gemcitabine; however, the final decision will be made by the Investigator: 
• Impaired renal function (GFR >30 but <60 mL/min) 
• NCI-CTCAE v5.0 Grade ≥2 audiometric hearing loss of 25 decibels at two contiguous 
frequencies 
• NCI-CTCAE v5.0 Grade ≥2 peripheral neuropathy (i.e., sensory alteration or paresthesia, 
including tingling) 
Needles or IV administration sets containing aluminum parts that may come in contact with 
cisplatin or carboplatin should not be used for the preparation or administration of the drug. 


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Aluminum can react with cisplatin or carboplatin causing precipitate formation and loss of 
potency. 
Trilaciclib is always administered first, followed by gemcitabine + carboplatin/cisplatin which 
may be administered immediately following trilaciclib, but not until the completion of the 
trilaciclib infusion. The interval between trilaciclib administration and the first dose of 
gemcitabine + carboplatin/cisplatin administration should not be greater than 4 hours. If 
gemcitabine + carboplatin/cisplatin therapy is discontinued or skipped, trilaciclib will also be 
discontinued or skipped. 
9.1.1.2.1. Dose Calculation Recommendations 
Patients who have a ≥10% weight change relative to the weight at the time of the last dose 
calculation, or as per institutional standards, will require recalculation of the dose for subsequent 
cycles. Dose 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. 
For patients who are cisplatin ineligible, the carboplatin dose should be calculated using Calvert 
formula with a target AUC = 4.5 administered IV on Day 1 of each 21-day cycle. 
In patients who require carboplatin dose modification, if creatinine at the time of the dose 
modification is lower than the baseline creatinine that was used, the prior (higher) creatinine 
value should be used. This is to ensure that patients receive the intended dose reduction. In 
patients with abnormally low serum creatinine, a minimum of 0.7 mg/dL should be used for the 
calculation of dose. The maximum carboplatin dose based on target AUC will be capped at 
675 mg. 
9.1.1.3. 
Avelumab 
A description of the formulation of commercially-available avelumab can be found in the local 
prescribing information/summary of product characteristics. Avelumab 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. 
Avelumab 800 mg will be administered IV on Day 1 of each 14-day maintenance cycle as a 60-
minute infusion. In order to mitigate infusion-related reactions, premedication with an 
antihistamine and with paracetamol (acetaminophen) approximately 30 to 60 minutes prior to 
each dose of avelumab is mandatory for the first 4 infusions (for example, 25-50 mg 
diphenhydramine and 500-650 mg paracetamol [acetaminophen] IV or oral equivalent). This 
may be modified based on local treatment standards and guidelines, as appropriate, provided it 
does not include systemic corticosteroids. Premedication should be administered for subsequent 
avelumab doses based upon clinical judgment and presence/severity or prior infusion reactions. 
Sites should make every effort to target infusion timing to be as close to 60 minutes as possible. 
However, given the variability of infusion pumps from site to site, time windows of -10 minutes 
and +20 minutes is permitted (i.e., infusion time is 60 minutes -10 min/+20 min). Possible 
modifications of the infusion rate for the management of infusion-related reactions are described 
in Section 9.3.3. 
No dose reductions for toxicity management will be allowed during the study. 


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Trilaciclib is always administered first, followed by avelumab which may be administered 
immediately following trilaciclib, but not until the completion of the trilaciclib infusion. The 
interval between the completion of trilaciclib administration and avelumab administration should 
not be greater than 4 hours. If avelumab therapy is delayed or skipped, trilaciclib should be 
administered as scheduled. If avelumab therapy is permanently discontinued, trilaciclib should 
also be permanently discontinued. 
As with all monoclonal antibody therapies, there is a risk of allergic reactions including 
anaphylactic shock. Avelumab should be administered in a setting that allows for immediate 
access to an intensive care unit or equivalent environment and administration of therapy for 
anaphylaxis, such as the ability to implement immediate resuscitation measures. Steroids 
(dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy medications (IV antihistamines), 
bronchodilators, or equivalents, and oxygen should be available for immediate access.  
Patients without progressive disease as per RECIST v1.1 guidelines (i.e., with an ongoing CR, 
PR, or SD) following completion of 4-6 cycles of platinum-based chemotherapy may receive 
avelumab in maintenance until disease progression, unacceptable toxicity, withdrawal of 
consent, Investigator decision, or the end of the trial, whichever comes first. 
Systemic immune activation is a rare condition characterized by an excessive immune response. 
Given the mechanism of action of avelumab, systemic immune activation is considered a 
potential risk when given in combination with other immunomodulating agents. Systemic 
immune activation should be included in the differential diagnosis for patients who, in the 
absence of an alternative etiology, develop a sepsis-like syndrome after administration of 
avelumab, and the initial evaluation should include the following: 
• CBC with peripheral smear 
• Prothrombin time, partial thromboplastin time, fibrinogen, and D-dimer 
• Ferritin 
• Triglycerides 
• AST, ALT, and total bilirubin 
• Lactate dehydrogenase 
• Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
Other immune-related AEs attributed to avelumab not listed above should be assessed by the 
Investigator and discussed with the medical monitor to determine if avelumab should be held or 
discontinued. 
If corticosteroids have been initiated as part of the immune-related AE management, avelumab 
can be resumed with complete or partial resolution (Grade 0 or 1) of the AE after corticosteroid 
taper – refer to the local prescribing information/summary of product characteristics 
(Bavencio, 2020 [US]; Bavencio, 2020 [EU]). 
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 


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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 drug, via a Pharmacist/Designee, only for 
use by patients enrolled in the study as described in this protocol (Section 9.7). The study drug is 
not to be used for reasons other than those described in this protocol. The clinical study site will 
maintain records of study drug receipt, preparation, and dispensing, including the applicable lot 
and vial numbers; patient’s height, body weight, and BSA; date and time of the start and end of 
each trilaciclib, avelumab, gemcitabine, and cisplatin or carboplatin infusion; and total drug 
administered in milligrams. 
9.2. 
Criteria for Starting Cycle 1 and Each Subsequent Chemotherapy 
Cycle 
Patients must meet specific hematologic criteria for each platinum-based chemotherapy dosing 
day and any non-hematologic toxicities (except alopecia) must be ≤Grade 2 or have returned to 
baseline. Please note the ANC for Cycle 1 Day 1 is required to be ≥1.5 x 109/L (Table 7).  
For dose delays due to toxicity, the patient should be followed (at least) weekly to monitor the 
toxicity until treatment criteria are met or until they discontinue treatment. If the Day 1 or Day 8 
doses are delayed, any assessments completed as part of the planned Day 1 visit will be captured 
in the eCRF as unscheduled visits.  
Patients enrolled in the study will be eligible to receive 4-6 cycles of platinum-based 
chemotherapy, per Investigator’s discretion.  
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. 
Trilaciclib is always administered first. If administration of gemcitabine + carboplatin/cisplatin 
chemotherapy is discontinued, trilaciclib will also be discontinued. If administration of avelumab 
maintenance therapy is discontinued, trilaciclib will also be discontinued. If administration of 
chemotherapy is delayed or skipped, trilaciclib will also be delayed or skipped. If administration 
of avelumab is delayed or skipped, then trilaciclib should be administered as scheduled. 
Gemcitabine and carboplatin/cisplatin dose reductions are permitted according to the organ 
system showing the greatest degree of drug-related toxicity per Investigator discretion and 
institutional guidelines; recommendations are provided in Table 7, Table 8, and Section 9.3.1.1. 
Toxicities will be graded according to the NCI-CTCAE, Version 5.0. 
No dose reductions will be allowed for avelumab during the study. 
Management of AEs may include decreasing the infusion rate (that is, extending the infusion 
time) for avelumab, administration of corticosteroids, delay of a scheduled dose, or 
discontinuation of therapy. The total infusion time for avelumab should not exceed 120 minutes. 
Refer to the current avelumab prescribing information/summary of product characteristics for 


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guidance on the management of avelumab-related AEs (Bavencio, 2020 [US]; 
Bavencio, 2020 [EU]). 
9.3.1. 
Dose Modifications for Hematologic and Non-Hematologic Toxicity during 
Chemotherapy Period 
Gemcitabine + carboplatin/cisplatin dose reductions for hematologic toxicities are based on 
values obtained within 24 hours of chemotherapy on Day 1 or Day 8 of a cycle per Investigator 
discretion and institutional guidelines; recommendations are provided in Table 7, Table 8, and 
Section 9.3.1.1). Gemcitabine + carboplatin/cisplatin dose modifications for non-hematologic 
toxicities may occur at any time during chemotherapy treatment per Investigator discretion and 
institutional guidelines; recommendations are provided in Table 7, Table 8, and Section 9.3.1.1. 
Secondary prophylactic G-CSF is strongly recommended to avoid the need for dose reductions 
for neutropenia; however, primary prophylactic G-CSF use during Cycle 1 (i.e., prior to the 
actual Cycle 2 Day 1 dosing visit) is not allowed. 


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Table 7: 
Recommended Dose Modification for Hematologic Toxicity during Chemotherapy Period 
Lab Value 
Time point 
Gemcitabine + Carboplatin or Cisplatin and G-CSF b Recommendations 
Trilaciclib  
ANC ≥1.0 x 109/La AND 
platelets ≥100 x 109/L 
Day 1 or 8 of 
any cycle 
No dose reduction 
Trilaciclib is given 
only on days that 
chemotherapy is 
given. 
 
If both chemotherapy 
drugs are held, 
trilaciclib is held. 
 
No dose reductions 
are permitted for 
trilaciclib. 
ANC <1.0 x 109/L OR 
platelets <100 x 109/L 
Day 1 of any 
cycle 
Hold chemotherapy. Recheck CBC weekly.  
Once ANC ≥1.0 x 109/L AND platelets ≥100 x 109/L, restart drugs depending on toxicity: 
If chemotherapy was held for ANC <1.0 x 109/L, restart drugs at the same dose and add 
G-CSF b with each subsequent cycle. If Day 1 is held for neutropenia in the setting of G-
CSF b use, then administer drugs at next lower dose (see Section 9.3.1.1) and continue G-
CSF b with each subsequent cycle. 
If chemotherapy was held for platelets <100 X 109/L, administer drugs at next lower dose 
(see Section 9.3.1.1).  
ANC ≥0.75 x 109/L but  
<1.0 x 109/L 
OR  
platelets ≥75 x 109/L but  
<100 x 109/L 
Day 8 of any 
cycle 
If ANC <1.0 x 109/L and no prior use of G-CSF b, then administer both drugs at the same 
dose and add G-CSF with this cycle and subsequent cycles.  
If ANC <1.0 x 109/L in the setting of G-CSF b use, then administer drugs at next lower 
dose and continue G-CSF b in this cycle and subsequent cycles.  
If platelets <100 x 109/L, then administer drugs at next lower dose. 
ANC <0.75 x 109/L OR 
platelets <75 x 109/L 
Day 8 of any 
cycle 
Hold chemotherapy. Recheck CBC weekly. Once ANC ≥1.0 x 109/L AND platelets 
≥100 x 109/L (Day 1 criteria are met), restart drugs at next lower dose (see 
Section 9.3.1.1), which will be considered Day 1 of the next cycle and Day 8 will not be 
made up. If chemotherapy was held for ANC <0.75 x 109/L, administer G-CSF b with 
each subsequent cycle. 
Febrile neutropenia OR 
platelet <50 x 109/L with 
bleeding 
At any time 
Hold chemotherapy. Recheck CBC weekly. Once ANC ≥1.0 x 109/L AND platelets 
≥100 x 109/L, restart drugs at next lower dose (see Section 9.3.1.1), which will be 
considered Day 1 of the next cycle and Day 8 will not be made up if it had not yet 
occurred. For febrile neutropenia, administer G-CSF b with subsequent cycles. 
ANC=absolute neutrophil count; CBC=complete blood count; G-CSF=granulocyte colony-stimulating factor; RBC=red blood cell 
a Except for Cycle 1 Day 1 where ANC is required to be ≥1.5 x 109/L.  
b Use of prophylactic colony stimulating factors (e.g., G-CSF; granulocyte-macrophage colony-stimulating factor) during Cycle 1 (i.e., prior to the actual Cycle 2 
Day 1 dosing visit) is not allowed. 


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Table 8: 
Recommended Dose Modifications for Non-Hematologic Toxicity during 
Chemotherapy Period 
NCI-CTCAE Grade 
Action Taken 
Gemcitabine + Carboplatin or 
Cisplatin 
Trilaciclib a  
Grade 1-2 
No change in dose 
Trilaciclib is given only on days that 
chemotherapy is given. 
 
If both chemotherapy drugs are held, 
trilaciclib is held. 
 
No dose reductions are permitted for 
trilaciclib. 
≥Grade 3 
Hold both drugs. Once toxicity 
resolves to ≤Grade 2 or baseline, 
restart gemcitabine at the next lower 
dose and carboplatin or cisplatin at 
the same dose (or at next lower dose 
per discretion of Investigator) 
(Section 9.3.1.1). 
NCI-CTCAE=National Cancer Institute–Common Terminology Criteria for Adverse Events v5.0 
a Arm B only. 
9.3.1.1. 
Recommended Dose Reductions of Gemcitabine and Cisplatin or Carboplatin 
for Hematologic and Non-Hematologic Toxicity 
For hematologic toxicity requiring a dose reduction, chemotherapy drug doses will be reduced 
based on institutional guidelines. If a patient experiences any toxicity requiring a third dose 
reduction, either gemcitabine or carboplatin/cisplatin will be discontinued (at discretion of the 
Investigator) and the other chemotherapy drug (with or without trilaciclib) may be continued. If a 
patient experiences additional toxicity requiring further dose reductions, all study drugs will be 
permanently discontinued. 
All dose reductions are permanent and no dose increases will occur following a dose reduction. 
The recommended dose reductions for gemcitabine following a hematologic or non-hematologic 
toxicity are as follows:  
• Starting dose: 1000 mg/m2 
• First dose reduction: 800 mg/m2 
• Second dose reduction: 600 mg/m2 
• Third dose reduction: continue only one chemotherapy 
• Fourth dose reduction: discontinue all study drugs 
The recommended dose reductions for carboplatin following a hematologic or non-hematologic 
toxicity are as follows:  
• Starting dose: AUC=4.5 
• First dose reduction: 20% from original dose  
• Second dose reduction: 40% from original dose 
• Third dose reduction: continue only one chemotherapy 
• Fourth dose reduction: discontinue all study drugs 


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The recommended dose reductions for cisplatin following a hematologic or non-hematologic 
toxicity are as follows:  
• Starting dose: 70 mg/m2 
• First dose reduction: 60 mg/m2 (splitting the dose of cisplatin to Day 1 and Day 8 
dosing is an allowed alternative) 
• Second dose reduction: 50 mg/m2 (splitting the dose of cisplatin to Day 1 and Day 8 
dosing is an allowed alternative) 
• Third dose reduction: continue only one chemotherapy 
• Fourth dose reduction: discontinue all study drugs 
9.3.2. 
Recommended Actions with Trilaciclib for Adverse Events of Special Interest 
Recommended actions to be taken with trilaciclib following an AESI are provided in Table 9. 
Table 9: 
Recommended Actions with Trilaciclib Following Adverse Events of Special 
Interest 
AESI 
Severity (NCI-CTCAE) 
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% Sodium Chloride Injection, USP, is 
being used as a diluent/flush, consider 
changing to 5% Dextrose Injection, USP 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% Sodium Chloride 
Injection, USP is being used as a 
diluent/flush, consider changing to 5% 
Dextrose Injection, USP 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. 


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AESI 
Severity (NCI-CTCAE) 
Recommended Action 
Acute drug 
hypersensitivity 
reactions  
Grade 2: Moderate; minimal, local 
or noninvasive intervention 
indicated; limiting age-appropriate 
instrumental Activities of Daily 
Living (ADL) 
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. 
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. 
Grade 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 trilaciclib 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; NCI-CTCAE=National Cancer Institute–
Common Terminology Criteria for Adverse Events; USP=United States Pharmacopeia. 
9.3.3. 
Recommended Actions with Avelumab for AESIs  
Any AE that is suspected to be a potential immune-related AE (irAE) is considered an avelumab 
AESI. 
See Section 9.1.1.3 for further details on associated risks of treatment with avelumab. 


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The recommended actions for the management of irAEs are provided in Table 10 and Table 11 
below. Refer to the current avelumab prescribing information/summary of product characteristics 
for additional guidance on the management of avelumab AESIs (Bavencio, 2020 [US]; 
Bavencio, 2020 [EU]).  
As with all monoclonal antibody therapies, avelumab can induce flu-like symptoms. For 
prophylaxis of flu-like symptoms, 25 mg indomethacin or comparable nonsteroidal 
anti-inflammatory drug dose (e.g., ibuprofen 600 mg, naproxen sodium 500 mg) may be 
administered at Investigator discretion 2 hours before and 8 hours after the start of each dose of 
avelumab IV infusion. Alternative treatments for fever (e.g., paracetamol or ibuprofen) and 
rigors (e.g., meperidine) may be given to patients at the discretion of the Investigator. 
Table 10: 
Treatment Modification for Symptoms of Avelumab Infusion-Related 
Reactions 
NCI-CTCAE Grade 
Treatment Modification for Avelumab 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease avelumab infusion rate by 50% and 
monitor closely for any worsening. 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (for 
example, antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for ≤24 
hours.  
Temporarily decrease avelumab infusion. 
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or decreased 
to at least Grade 1 in severity and monitor closely 
for any worsening. 
Grade 3 or Grade 4 – severe or life-threatening 
Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms 
following initial improvement; hospitalization 
indicated for clinical sequelae. 
Grade 4: Life-threatening consequences; urgent 
intervention indicated. 
Stop avelumab infusion immediately and 
disconnect infusion tubing from the patient. 
Patients have to be withdrawn immediately from 
study drug treatment and must not receive any 
further study drug treatment. 
- 
If avelumab infusion rate has been decreased by 50% or interrupted due to an infusion reaction, it 
must remain decreased for the next scheduled infusion. If no infusion reaction is observed in the next 
scheduled infusion, the infusion rate may be returned to baseline at the subsequent infusions based on 
Investigator’s medical judgment. The total infusion time for avelumab should not exceed 120 
minutes. 
- 
If hypersensitivity reaction occurs, the patient must be treated according to the best available medical 
practice. 
IV=intravenous, NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Events, 
NSAID=nonsteroidal anti-inflammatory drug. 
Additional Modifications for Patients with Grade 2 Infusion-Related Reactions: In the event 
of a Grade 2 infusion-related reaction that does not improve or worsens after implementation of 
the modifications indicated in Table 10 (including reducing the infusion rate by 50%), the 
Investigator may consider treatment with corticosteroids, and the infusion should not be resumed 
for that cycle. At the next cycle, the Investigator may consider the addition of H2-blocker 


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antihistamines (e.g., famotidine or ranitidine), meperidine, or ibuprofen to the mandatory 
premedication. Prophylactic steroids are NOT permitted. 
Table 11: 
Management of Avelumab Immune-mediated Adverse Reactions 
Gastrointestinal irAEs 
Severity of Diarrhea/Colitis 
(NCI-CTCAE) 
Initial Management 
Follow-up Management 
Grade 1 
Diarrhea: <4 stools/day over 
Baseline 
Colitis: asymptomatic 
Continue avelumab therapy 
Symptomatic treatment (e.g., 
loperamide) 
Close monitoring for worsening 
symptoms 
Educate patient to report 
worsening immediately 
If worsens: treat as Grade 2, 3 or 
4 
Grade 2  
Diarrhea: 4 to 6 stools per day 
over Baseline; IV fluids indicated 
<24 hours; not interfering with 
ADL 
Colitis: abdominal pain; blood in 
stool 
Withhold avelumab therapy 
Symptomatic treatment 
If improves to Grade ≤1: resume 
avelumab therapy 
If persists >5-7 days or recurs: 
treat as Grade 3 or 4 
Grade 3 to 4 
Diarrhea (Grade 3): ≥7 stools per 
day over Baseline; incontinence; 
IV fluids ≥24 hours; interfering 
with ADL 
Colitis (Grade 3): severe 
abdominal pain, medical 
intervention indicated, peritoneal 
signs 
Grade 4: life-threatening, 
perforation 
Withhold avelumab for Grade 3. 
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3 
1.0 to 2.0 mg/kg/day prednisone 
IV or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Consider lower endoscopy 
If improves: continue steroids 
until Grade ≤1, then taper over at 
least 1 month; resume avelumab 
therapy following steroids taper 
(for initial Grade 3) 
If worsens, persists >3 to 5 days, 
or recurs after improvement: add 
infliximab 5 mg/kg (if no 
contraindication). Note: 
infliximab should not be used in 
cases of perforation or sepsis 


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Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE) 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering ≤30% body surface 
area 
Continue avelumab therapy 
Symptomatic therapy (for 
example, antihistamines, topical 
steroids) 
If Grade 2 persists >1 to 2 weeks 
or recurs: withhold avelumab 
therapy; consider skin biopsy  
Consider 0.5-1.0 mg/kg/day 
prednisone or equivalent. Once 
improving, taper steroids over at 
least 1 month, consider 
prophylactic antibiotics for 
opportunistic infections, and 
resume avelumab therapy 
following steroids taper 
If worsens: treat as Grade 3 to 4. 
Grade 3 to 4 
Grade 3: Covering >30% body 
surface area  
Grade 4: Life threatening 
consequences 
Withhold avelumab for Grade 3 
Permanently discontinue for 
Grade 4 or recurrent Grade 3  
Consider skin biopsy  
Dermatology consult  
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
If improves to Grade ≤1: taper 
steroids over at least 1 month; 
resume avelumab therapy 
following steroids taper (for 
initial Grade 3) 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE) 
Initial Management 
Follow-up Management 
Grade 1 
Radiographic changes only 
Consider withholding avelumab 
therapy  
Monitor for symptoms every 2 to 
3 days  
Consider Pulmonary and 
Infectious Disease consults 
Re-assess at least every 3 weeks 
If worsens: treat as Grade 2 or 
Grade 3 to 4 


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Grade 2 
Mild to moderate new symptoms 
Withhold avelumab therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily; 
consider hospitalization  
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Consider bronchoscopy, lung 
biopsy 
Re-assess every 1 to 3 days  
If improves: when symptoms 
return to Grade ≤1, taper steroids 
over at least 1 month, and then 
resume avelumab therapy 
following steroids taper  
If not improving after 2 weeks or 
worsening or for recurring Grade 
2: treat as Grade 3 to 4 
Grade 3 to 4 
Grade 3: Severe new symptoms; 
New/worsening hypoxia 
Grade 4: Life-threatening 
Permanently discontinue 
avelumab therapy 
Hospitalize 
Pulmonary and Infectious 
Disease consults. 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent  
Add prophylactic antibiotics for 
opportunistic infections  
Consider bronchoscopy, lung 
biopsy 
If improves to Grade ≤1: taper 
steroids over at least 1 month  
If not improving after 48 hours or 
worsening: add additional 
immunosuppression (for 
example, infliximab, 
cyclophosphamide, IV 
immunoglobulin, or 
mycophenolate mofetil) 
Hepatic irAEs 
Grade of Liver Test Elevation 
(NCI-CTCAE) 
Initial Management 
Follow-up Management 
Grade 1 
Grade 1 AST or ALT >ULN to 
3.0 × ULN and/or Total bilirubin 
>ULN to 1.5 × ULN 
Continue avelumab therapy 
Continue liver function 
monitoring  
If worsens: treat as Grade 2 or 3 
to 4 
Grade 2 
AST or ALT > 3.0 to ≤5 x ULN 
and/or total bilirubin > 1.5 to 
≤3 × ULN 
Withhold avelumab therapy 
Increase frequency of monitoring 
to every 3 days 
If returns to Grade ≤1: resume 
routine monitoring; resume 
avelumab therapy 
If elevation persists >5 to 7 days 
or worsens: treat as Grade 3 to 4 


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Grade 3 to 4 
AST or ALT >5 × ULN and/or 
total bilirubin >3 × ULN 
Permanently discontinue 
avelumab therapy  
Increase frequency of monitoring 
to every 1 to 2 days  
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Consult gastroenterologist/ 
hepatologist 
Consider obtaining MRI/CT scan 
of liver and liver biopsy if 
clinically warranted 
If returns to Grade ≤1: taper 
steroids over at least 1 month  
If does not improve in >3 to 5 
days, worsens or rebounds: add 
mycophenolate mofetil 1 g twice 
daily  
If no response within an 
additional 3 to 5 days, consider 
other immunosuppressants per 
local guidelines 
Renal irAEs 
Grade of Creatinine Increased 
(NCI-CTCAE) 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased >ULN to 
1.5 × ULN 
Continue avelumab therapy 
Continue renal function 
monitoring 
If worsens: treat as Grade 2 to 3 
or 4 
Grade 2 to 3 
Creatinine increased >1.5 and ≤6 
× ULN 
Withhold avelumab therapy 
Increase frequency of monitoring 
to every 3 days 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
If returns to Grade ≤1: taper 
steroids over at least 1 month, 
and resume avelumab therapy 
following steroids taper 
If worsens: treat as Grade 4 
Grade 4 
Creatinine increased >6 × ULN 
Permanently discontinue 
avelumab therapy 
Monitor creatinine daily 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
Nephrology consult 
If returns to Grade ≤1: taper 
steroids over at least 1 month 


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Cardiac irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
New onset of cardiac signs or 
symptoms and / or new 
laboratory cardiac biomarker 
elevations (e.g., troponin, 
CK-MB, BNP) or cardiac 
imaging abnormalities suggestive 
of myocarditis 
Withhold avelumab therapy 
Hospitalize 
In the presence of 
life-threatening cardiac 
decompensation, consider 
transfer to a facility experienced 
in advanced heart failure and 
arrhythmia management 
Cardiology consult to establish 
etiology and rule-out immune-
mediated myocarditis  
Guideline-based supportive 
treatment as per cardiology 
consult* 
Consider myocardial biopsy if 
recommended per cardiology 
consult 
If symptoms improve and 
immune mediated etiology is 
ruled out, re-start avelumab 
therapy 
If symptoms do not 
improve/worsen, viral 
myocarditis is excluded, and 
immune-mediated etiology is 
suspected or confirmed following 
cardiology consult, manage as 
immune-mediated myocarditis 
Immune-mediated myocarditis 
Permanently discontinue 
avelumab 
Guideline-based supportive 
treatment as appropriate as per 
cardiology consult* 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
Once improving, taper steroids 
over at least 1 month 
If no improvement or worsening, 
consider additional 
immunosuppressants (e.g., 
azathioprine, cyclosporine A) 
*Local guidelines, or e.g., ESC or AHA guidelines  
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 


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Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Continue avelumab therapy 
Endocrinology consult if needed 
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate  
Rule-out secondary 
endocrinopathies (i.e., 
hypopituitarism/hypophysitis) 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Withhold avelumab therapy 
Consider hospitalization 
Endocrinology consult 
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for type 
I diabetes mellitus) as 
appropriate  
Rule-out secondary 
endocrinopathies (i.e., 
hypopituitarism/hypophysitis) 
Resume avelumab once 
symptoms and/or laboratory tests 
improve to Grade ≤1 (with or 
without hormone 
replacement/suppression) 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate 


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Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid and/or 
adrenal insufficiency is 
confirmed (i.e., subnormal serum 
free T4 with inappropriately low 
TSH and/or low serum cortisol 
with inappropriately low ACTH): 
• 
Refer to endocrinologist for 
dynamic testing as indicated 
and measurement of other 
hormones (FSH, LH, 
GH/IGF-1, PRL, testosterone 
in men, estrogens in women)  
• 
Hormone 
replacement/suppressive 
therapy as appropriate  
• 
Perform pituitary MRI and 
visual field examination as 
indicated 
If hypophysitis confirmed: 
• 
Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month 
• 
Withhold avelumab if 
moderate, severe or 
life-threatening symptoms of 
hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 
2 mg/kg/day prednisone or 
equivalent) followed by 
corticosteroids taper during 
at least 1 month. 
• 
Add prophylactic antibiotics 
for opportunistic infections 
Resume avelumab once 
symptoms and hormone tests 
improve to Grade ≤1 (with or 
without hormone replacement) 
In addition, for hypophysitis with 
abnormal MRI, resume avelumab 
only once shrinkage of the 
pituitary gland on MRI/CT scan 
is documented  
Continue hormone 
replacement/suppression therapy 
as appropriate 
Other irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE) 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical 
signs or symptoms suggestive 
of a potential irAE 
Withhold avelumab therapy 
pending clinical investigation 
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider re-starting 
avelumab therapy 
If irAE is confirmed, treat as 
Grade 2 or 3 irAE 


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Grade 2 irAE or first 
occurrence of Grade 3 irAE 
Withhold avelumab therapy 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent  
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤1: taper 
steroids over at least 1 month and 
resume avelumab therapy 
following steroids taper 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue 
avelumab therapy 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤1: taper 
steroids over at least 1 month 
Grade 4  
 
Permanently discontinue 
avelumab therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent and/or 
other immunosuppressant as 
needed 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult 
If improves to Grade ≤1:  
Taper steroids over at least 1 
month 
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency 
 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
Permanently discontinue 
avelumab therapy 
Specialty consult 
 
ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine aminotransferase; 
AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine kinase MB; CT=computed 
tomography; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; 
irAE=immune-related adverse event; IV=intravenous; LH=luteinizing hormone; MRI=magnetic resonance 
imaging; NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Events; 
PRL=prolactin; T4=thyroxine; TSH=thyroid stimulating hormone; ULN=upper limit of normal. 


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Table 12: 
Recommended Treatment Modification for Other Avelumab Product-
Related Toxicity 
Toxicity 
NCI CTCAE 
Severity Grade 
Avelumab 
Treatment Modification 
 
Drug-related adverse 
reactions 
(excluding infusion-
related reaction / 
hypersensitivity and 
immune-related AE) 
Grade 1 
Continue avelumab therapy 
Grade 2 
Continue avelumab therapy 
Grade 3 
Withold avelumab until recovery to Grade ≤1 or baseline 
If toxicities do not resolve to Grade ≤1 or baseline within 12 weeks 
of last administration or if the same Grade 3 toxicity recurs, 
permanently discontinue avelumab 
Exceptions are: 
Laboratory values out of normal range that do not have any clinical 
correlate 
Grade 4 
Permanently discontinue avelumab 
Exceptions are: 
Laboratory values out of normal range that do not have any clinical 
correlate 
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. 
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.  
• Pre-existing baseline ALT, AST, OR total bilirubin values are above the ULN, and 
the patient subsequently presents with: 
− AST or ALT ≥2 × baseline value AND ≥3 × ULN, or ≥8 × ULN (whichever is 
smaller)  
− concurrent with total bilirubin ≥2 × baseline value OR ≥3 × ULN (whichever is 
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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/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 reported as serious adverse events (SAEs). 
9.3.5. 
Management of Nausea and Vomiting 
Necessary supportive care (e.g., antiemetics, antidiarrheals) administered 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. To reduce effects on the immune 
system, the use of dexamethasone as an antiemetic should be minimized where possible; 
however, since this is a moderately emetogenic regimen, dexamethasone on the day of 
gemcitabine + carboplatin/cisplatin is allowed per the ASCO guidelines (Hesketh, 2017).  
9.4. 
Supportive Care Interventions 
9.4.1. 
Colony Stimulating Factor Usage 
Use of primary 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 Table 7, which are based on the ASCO guidelines 
for neutropenia (Smith, 2015) and package inserts/summary of product characteristics. If in any 
cycle (including Cycle 1), a patient experiences febrile neutropenia and is at high risk for 
infection-associated complications, G-CSF/GM-CSF may be used to treat the febrile neutropenia 
event per ASCO guidelines and package inserts/summary of product characteristics. If a patient 
has risk factors that are predictive of poor clinical outcomes (Table 12), G-CSF/GM-CSF may 
also be used as prophylaxis, except during Cycle 1. 
Short acting G-CSF products (i.e., Neupogen or biosimilars) may be administered starting 24 to 
48 hours after the dose of chemotherapy on Day 1 or Day 8 and must be stopped 48 hours prior 
to the next chemotherapy administration. Due to its prolonged half-life, pegfilgrastim may only 
be used if the patient received Day 8 chemotherapy; it should be administered 24 to 48 hours 
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Table 13: 
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 after receiving 
the first dose of 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, 2017); 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 x 109/L. Platelets should also be 
transfused in any patient who is bleeding with a platelet count <50 x 109/L (100 x 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 90 days after the last dose of 
study treatment (90-day Safety Follow-up Visit) will be documented, where possible. 


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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. 
9.5.1. 
Concomitant Surgery 
In the case that a surgical procedure is required for palliative care, all attempts should be made to 
rule out disease progression beforehand. 
In the case of a surgical procedure, study treatment should be withheld. Postoperatively, the 
decision to reinitiate study treatment should be discussed with the Medical Monitor. 
9.5.2. 
Concomitant Radiotherapy  
Local radiotherapy of isolated lesions with palliative intent is acceptable (e.g., bleeding, pain, 
compression), however all attempts should be made to rule out disease progression. 
Palliative radiotherapy is permitted if considered medically necessary by the treating physician. 
If palliative radiotherapy is needed to control pain, the site(s) of disease-causing pain should also 
be present at baseline; otherwise, painful lesion(s) requiring radiotherapy will be considered a 
sign of disease progression.  
9.6. 
Prohibited Therapy  
Administration of other concomitant non-protocol anticancer or herbal therapies prior to disease 
progression is not permitted while on this study. This includes any low-dose systemic 
chemotherapeutic agent given for a non-oncologic purpose (e.g., low-dose methotrexate for 
rheumatoid arthritis). Palliative radiotherapy/surgery is allowed to control disease symptoms, but 
not to aid in the response of the tumor. If palliative radiotherapy/surgery includes a lesion being 
followed by RECIST in this study, that lesion must be identified accordingly in the eCRF. 
Administration of other concomitant investigational agents for any indication is not permitted 
while on this study. 
Patients who have achieved a PR or CR of target lesions and who develop new lesions 
(≤3 lesions) that are amenable to surgery or ablative techniques (e.g., radiotherapy, 
radiofrequency ablation) may continue to receive study treatment if they demonstrate no further 
progression of disease at the next imaging assessment and continue to demonstrate clinical 
benefit per the Investigator. 
9.6.1. 
Trilaciclib 
Avoid concomitant use of trilaciclib with certain OCT2, MATE1, and MATE2-K 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 4.5.2.2). 
9.6.2. 
Gemcitabine 
Gemcitabine is not indicated for use in combination with radiation therapy. Patients should not 
receive gemcitabine within 7 days before or after radiation therapy. Concurrent therapy (given 
together or ≤7 days apart) with gemcitabine and thoracic radiation has led to life-threatening 


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mucositis, especially esophagitis and pneumonitis. Excessive toxicity has not been observed 
when gemcitabine is administered more than 7 days before or after radiation. Radiation recall has 
been reported in patients who receive gemcitabine after prior radiation. 
9.6.3. 
Carboplatin 
Although carboplatin has limited nephrotoxic potential, caution should be exercised when 
administering carboplatin with aminoglycosides, which has resulted in increased renal and/or 
audiologic toxicity. Any medication that is contraindicated when using gemcitabine or 
carboplatin is not permitted, and special warnings and precautions for use of gemcitabine or 
carboplatin should be observed.  
Caution should be exercised with concomitant use of drugs that are substrates for OCT2 with 
narrow therapeutic index (Section 4.5.1.2). 
9.6.4. 
Cisplatin 
Simultaneous use of myelosuppressive agents or radiation will boost the effects of cisplatin's 
myelosuppressive activity. The occurrence of nephrotoxicity caused by cisplatin may be 
intensified by concomitant treatment with antihypertensive agents containing furosemide, 
hydralazine, diazoxide, and propranolol. 
Concomitant administration of ototoxic (e.g., aminoglycosides, loop diuretics) medicinal 
products will potentiate the toxic effect of cisplatin on auditory function. 
Simultaneous use of antihistamines, buclizine, cyclizine, loxapine, meclozine, phenothiazines, 
thioxanthenes, or trimethobenzamides may mask ototoxic symptoms (such as dizziness and 
tinnitus). 
In the event of the simultaneous use of oral anticoagulants, it is advisable to more frequently 
check the INR. 
9.6.5. 
Avelumab 
Patients are not allowed to receive immunostimulatory agents, including but not limited to 
IFN-α, IFN-γ, or IL-2, during the avelumab maintenance period. These agents, in combination 
with avelumab, could potentially increase the risk for autoimmune conditions. Patients are also 
not allowed to receive live attenuated vaccines during the avelumab maintenance period. 
Patients should not receive bisphosphonate or denosumab treatment unless it has been initiated 
more than 14 days prior to receiving the first dose of avelumab. 
Avelumab should not be given to patients with a condition requiring systemic treatment with 
either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive 
medications (including but not limited to cyclophosphamide, sirolimus, tacrolimus, azathioprine, 
methotrexate, thalidomide, and anti- tumor necrosis factor agents) within 14 days of avelumab 
administration. Inhaled or topical steroids and adrenal replacement doses >10 mg daily 
prednisone equivalents are permitted in the absence of active autoimmune disease. 
Clarifications About Steroid Use: Data indicate that corticosteroids have an adverse effect on 
T cell function and that they inhibit and damage lymphocytes (Khan, 2008; Schleimer, 1984). 
Furthermore, as with all immunotherapies intended to augment T cell-mediated immunity, there 


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is a risk that concomitant immunosuppressives such as steroids will counteract the intended 
benefit of the proposed study treatment. However, studies with anti-CTLA-4 agents indicate that 
short-term use of steroids may be employed without compromising clinical outcomes 
(Weber, 2010). Therefore, the use of steroids during avelumab maintenance is restricted as 
follows: 
• Therapeutic use: for the treatment of infusion-related reactions and short-term treatment 
of immune-related AEs, steroids are permitted according to institutional guidelines. 
• Physiologic use: steroid replacement for adrenal insufficiency at doses equivalent to ≤10 
mg prednisone daily is acceptable. 
• Prophylactic use, e.g., for the prevention of acute infusion-related reactions, is prohibited, 
except prophylactic use prior to CT or MRI. 
The above lists of medications are not necessarily comprehensive. The Investigator should 
contact the Medical Monitor if questions arise regarding medications not listed above. 
9.7. 
Measures to Minimize Bias: Randomization and Blinding 
The study will be randomized and open-label.  
Patients meeting all inclusion and exclusion criteria will be stratified according to the 
stratification factors of presence of visceral metastasis (yes or no) at randomization and initial 
platinum-based chemotherapy to be administered (cisplatin or carboplatin). Patients will be 
randomly assigned in a 1:1 ratio to platinum-based chemotherapy followed by avelumab 
maintenance therapy (Arm A) or trilaciclib + platinum-based chemotherapy followed by 
trilaciclib + avelumab maintenance therapy (Arm B) by an interactive web response system 
(IWRS) according to a randomization schedule generated by an external statistician. A patient 
who is randomized and discontinues from the study, even if no study drug was administered, will 
not be replaced. 
If a patient does not receive the correct study treatment for their allocated treatment arm, the 
reason must be clearly documented in 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 Schedule of Assessments table (Table 5). 
Details regarding the preparation and administration of trilaciclib, platinum-based chemotherapy, 
and avelumab will be included in the Pharmacy Manual. 
9.8. 
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 11.8). 


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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 in a female patient 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). 
Local treatment of isolated lesion(s) with palliative radiation therapy or surgery is 
permitted to control disease symptoms but not to aid in the response of the tumor (see 
Section 9.5). Patients requiring palliative radiation 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 11.2.1.1.  
• If total time between chemotherapy exceeds a total of >42 days, unless agreed to by 
the treating Investigator and Medical Monitor. 
• If total time between avelumab maintenance therapy exceeds a total >56 days, unless 
agreed to by the treating Investigator and Medical Monitor. 
• Where permanent discontinuation of all study drugs is indicated in the toxicity 
management recommendations (Section 9.3).  
At the time of study drug discontinuation, an End of Treatment Visit should be completed with 
assessments performed as shown in the Schedule of Assessments (Table 5). The Investigator or 
Designee will document the reason for study drug discontinuation on the applicable eCRF. When 
discontinuation is due to an SAE or a Grade 3 or 4 toxicity considered to be related to study 
drug, 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). 
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 the patient has not already 


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discontinued study intervention, an End of Treatment Visit should be completed with 
assessments performed as shown in the Schedule of Assessments (Table 5).  
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. 
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, 
utilizing the same imaging modality as used at Screening as outlined in the Schedule of 
Assessments (Table 5), 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 1.1 and data entered in electronic data capture (EDC) in the 
corresponding tumor assessment forms.  
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 ICF. 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 patient 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 study ends when 60% of the randomized patients have died, 
which is estimated to be approximately 34 months after first patient is randomized.  
The Sponsor reserves the right to close a study site(s) or terminate the study at any time for any 
reason. 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 
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. 


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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. 


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11. 
STUDY ASSESSMENTS 
Study procedures and their timing are summarized in the Schedule of Assessments (Table 5). 
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, 
serum 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 the permitted 30-day Screening period.  
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; only the qualifying result should be entered in the 
eCRF.  
11.1.1. 
Documentation of Locally Advanced or Metastatic Urothelial Carcinoma 
Eligibility will be based on locally advanced or metastatic urothelial carcinoma status from the 
most recent tumor biopsy report obtained prior to Screening.  
Locally advanced or metastatic urothelial carcinoma status should be histologically confirmed by 
local pathology immunohistochemistry (IHC) assessment (see Inclusion Criterion 2). 
11.1.2. 
Randomization 
Eligibility will 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 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 following confirmation that the patient is eligible 
for the study. 
11.1.3. 
Demographics 
Age, gender, race (when reporting is allowed per local regulations), and ethnicity will be 
collected during the Screening Period. 


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11.1.4. 
Medical History and Urothelial Carcinoma Disease History 
Medical and surgical history, including past and current conditions, will be collected. 
Concomitant medications taken within 30 days prior to the first dose of study drug through the 
End of Treatment Visit will be recorded.  
Documentation of urothelial carcinoma history, including date of diagnosis, will be collected.  
Prior radiation, surgery, and systemic chemotherapy for urothelial carcinoma will also be 
recorded.  
11.2. 
Efficacy Assessments 
11.2.1. 
Anti-tumor Efficacy Assessment 
All sites of measurable and non-measurable disease must be documented at screening and 
re-assessed at each subsequent tumor evaluation. Tumor assessment will be performed at the 
timepoints relative to Cycle 1 Day 1, as specified in the Schedule of Assessments (Table 5), 
regardless of drug (cycle) delays, skips, or interruptions. Tumor assessments will continue until 
disease progression, withdrawal of consent, initiation of subsequent anti-cancer therapy, or study 
completion, whichever occurs first.  
Baseline imaging should include CT (preferred) or magnetic resonance imaging (MRI) of the 
chest, abdomen, and pelvis. Brain scan (MRI preferred) during screening is not required and 
should be performed per investigator discretion based on clinical signs and symptoms. Bone scan 
or Positron Emission Tomography (PET) (such as [18F]-fluorodeoxyglucose [FDG]-PET, sodium 
fluoride [NaF]-PET, or other locally available PET options) should also be performed in all 
patients to evaluate for bone metastases at baseline. Bone lesion(s) identified at baseline by bone 
scan will be further assessed by CT or MRI as per local practice (where bone scans are not used 
as a routine restaging tool) and subsequently re-assessed by CT or MRI as per the tumor 
assessment schedule as an alternative to bone scans. If bone metastases cannot be seen on CT or 
MRI scans, bone scans, or PET should be repeated, using the same diagnostic procedure bone 
metastases were at baseline, when CR is identified in target disease or when progression in bone 
is suspected. Any CT, MRI, bone scan, or PET obtained as standard of care prior to screening 
visit will not need to be repeated as long as those imaging tests were obtained within 30 days 
prior to the date of randomization.  
After baseline tumor assessments, evaluation of tumor response per RECIST v1.1 will be 
performed every 6 weeks (±7 days) during the chemotherapy period and every 8 weeks (±7 days) 
during the avelumab maintenance period for up to 1 year relative to Cycle 1 Day 1 and every 
12 weeks (±7 days) thereafter relative to Cycle 1 Day 1, until documented disease progression or 
subsequent anticancer therapy; additional scans may be performed as clinically indicated. Bone 
scans will only be repeated during the study as clinically indicated or considered local standard 
of care (e.g., patient describes new or worsening bone pain, or has increasing alkaline 
phosphatase level, or other signs and symptoms of new/progressing bone metastases) and at the 
time of CR confirmation. Brain must be included in subsequent tumor assessments if a patient 
has brain metastases at baseline; otherwise, brain will only be evaluated when clinically 
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CT and MRI are the primary imaging modalities. IV contrast should be used unless 
contraindicated. Oral contrast can be used at the Investigator’s discretion. Post-baseline tumor 
assessments should use the same imaging modality as at baseline. 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, utilizing the same imaging modality 
as used at screening as outlined in the Schedule of Assessments. Patients with bone metastases 
identified on the baseline bone scan should be followed at scheduled visits using localized CT, 
MRI, or PET. Patients with known brain metastases should also be followed at scheduled visits 
using CT or MRI brain, with additional scans performed as clinically indicated (Table 5). 
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 (including a 
bone lesion assessment) not less than 4 weeks from the date the response was first documented 
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 independent central review 
(ICR) of disease assessments. At the discretion of the Sponsor, ICR of all scans by RECIST v1.1 
may be conducted retrospectively. 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. 
11.2.1.1. Treatment Beyond Disease Progression during Avelumab Maintenance per 
RECIST Version 1.1 
Evidence indicates some patients treated with immunotherapy may derive clinical benefit after 
initial evidence of apparent disease progression (Nishino, 2013). Therefore, with approval from 
the Medical Monitor, avelumab maintenance treatment (with or without trilaciclib) may be 
continued until loss of clinical benefit, provided the patient appears to be deriving clinical 
benefit, the Investigator believes it is in the best interest of the patient to continue and the patient 
has provided re-consent. Treatment past disease progression per RECIST v1.1 should only be 
considered if a patient is clinically stable and has the following: 
• Evidence of clinical benefit as assessed by the Investigator 
• Absence of symptoms and signs (including worsening of laboratory values; e.g., new or 
worsening hypercalcemia) indicating unequivocal progression of disease 
• No decline in ECOG performance status that can be attributed to disease progression 
• Absence of tumor growth at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions 
The assessment of clinical benefit should take into account whether the patient is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. Decisions to 
continue treatment beyond initial progression per RECIST v1.1 may be discussed with the 
Medical Monitor and should be documented in the study records. 


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Patients with radiographic disease progression confirmed at a subsequent tumor assessment may 
be considered for continued study treatment at the discretion of the Investigator if they continue 
to meet the criteria above and have evidence of clinical benefit. 
Immune-related disease progression (irPD) must be confirmed with worsening of disease bulk on 
the next tumor assessment, performed at a minimum of 4 weeks after the disease progression by 
RECIST v1.1 was first noted. If the criteria of worsening disease bulk are met on 2 consecutive 
scans, the patient is determined to have confirmed irPD. If following an initial progression, the 
patient has a subsequent immune-related response (immune-related CR, PR, or SD; determined 
from baseline), then the original progression is not confirmed and the patient may continue to 
receive study treatment and any subsequent progression must be confirmed on the next 
consecutive tumor assessment. 
Confirmation of progression due to worsening disease bulk is defined as an additional 20% or 
greater increase in tumor burden volume from the time of initial RECIST v1.1 defined 
progression (including all target lesions and new measurable lesions) or an unequivocal further 
increase in nontarget lesions. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. New lesions are considered measurable at the 
time of initial progression if the longest diameter is at least 10 mm (except for pathological 
lymph nodes, which must have a short axis of at least 15 mm). Any new lesion considered non-
measurable at the time of initial progression may become measurable and therefore included in 
the tumor burden measurement if the longest diameter increases to at least 10 mm (except for 
pathological lymph nodes, which must have an increase in short axis to at least 15 mm). 
11.2.2. 
Hematologic Assessments 
The myeloprotective effects of trilaciclib administered in patients receiving platinum-based 
chemotherapy and avelumab maintenance therapy will be evaluated based on the following: 
kinetics of changes in CBCs (including DSN in chemotherapy Cycle 1 and rate of SN); 
hematologic toxicities, including febrile neutropenia; 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 5): 
• Body temperature, pulse rate, blood pressure (diastolic and systolic) 
• Height in centimeters (Screening visit only) and body weight in kilograms  
Assessments may be performed by a physician, registered nurse, or other qualified health care 
provider.  


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11.3.2. 
Physical Examination 
Full physical examination evaluations at Screening should include all major body systems, 
including general appearance, skin, neck, eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, and neurological examinations. Subsequent physical exams should be 
performed as symptoms warrant per Investigator discretion and should include the appropriate 
body systems (e.g., limited physician exam based on symptoms).  
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 13). ECOG performance status will also be assessed per the Schedule of Assessments 
(Table 5).  
Table 14: 
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 house work, 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  
Oken, 1982. 
11.3.4. 
Electrocardiogram 
A single, standard12-lead electrocardiogram (ECG) will be performed in all patients at Screening 
(Table 5). 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 10 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.  
The Investigator or qualified designee shall review the ECGs for any abnormalities. 


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11.3.5. 
Clinical Safety Laboratory Assessments 
Hematology, serum chemistry, and urinalysis will be performed at the site’s local certified 
laboratory per the schedule outlined in the Schedule of Assessments (Table 5). Any 
consideration for laboratory assessments to be performed at an alternate laboratory outside of the 
facilities identified for the conduct of the study may impact the integrity of the study data. As 
such, any such testing should be discussed with the study Medical Monitor and considered as a 
means to continue appropriate testing for the safety of the patient during COVID-19 restrictions. 
Clinical laboratory samples may be collected from patients at a different location than 
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 and urinalysis may be 
obtained up to 72 hours prior to each time point on Schedule of Assessments. For women of 
childbearing potential, pregnancy tests will be performed as follows: serum beta human 
chorionic gonadotropin (ß-hCG) at Screening and serum or urine ß-hCG on Day 1 of each 
chemotherapy cycle, Day 1 of every-other avelumab maintenance cycle beginning with the first 
cycle of avelumab maintenance therapy, and at the End of Treatment Visit. A pregnancy test 
should be performed within 7 days prior to initiating treatment and must be negative.  
Serum chemistry and hematology results shall be reviewed before dosing. Laboratory toxicities 
will be assessed using the NCI-CTCAE v5.0. 
An abnormal laboratory value is not an AE unless it is considered to be clinically significant 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/skipped for toxicity, the patient should still complete the clinical 
laboratory assessments on the scheduled Day 1 (entered as an Unscheduled assessment in the 
eCRF) 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 9.2; Table 7). 
11.3.6. 
Adverse and Serious Adverse Events 
Study-procedure related SAEs will be collected after the ICF is signed; all AEs will be collected 
starting from the first dose of study drug through the Safety Follow-up Visit. Toxicity will be 
assessed by Investigators using NCI-CTCAE v5.0. 
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. 


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Adverse events (serious and non-serious) should be reported on the appropriate page of the eCRF 
from the first dose of study treatment through last patient visit. 
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 Safety Follow-up 
Visits at 30 and 90 days. After initiation of study drug, all SAEs and AESIs for avelumab will be 
reported until 90 days after the last dose of avelumab or initiation of another anti-cancer therapy, 
whichever occurs first. All other AEs will be reported until 30 days after the last dose of study 
drug or until the initiation of another anti-cancer therapy, whichever occurs first. 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 recorded as an SAE. 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 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 90 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 PVG or designee. 
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 PVG or designee. 
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. 


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11.3.6.4. Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification of G1 Therapeutics PVG or designee by the Investigator (or designee) of an 
SAE, as described in Section 17.2.4, 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 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 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 policy and forwarded to Investigators, as necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from G1 Therapeutics 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 will be collected after the start of study intervention 
and until 5 months after the last dose of avelumab or 6 months after the last dose of gemcitabine, 
carboplatin, or cisplatin, whichever is longer. Female partners of male patients will be instructed 
through the Informed Consent Form to immediately inform the Investigator if their partner 
becomes pregnant during the study or within 6 months of the last dose of gemcitabine, 
carboplatin, or cisplatin, or 4 months after the last dose of trilaciclib, whichever is longer. 
If a pregnancy is reported, the Investigator or designee should inform G1 Therapeutics 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. 
11.4. 
Pharmacokinetics 
Four blood samples for PK analysis of cisplatin will be collected from each patient treated with 
cisplatin on chemotherapy Cycle 1 Day 1 and one blood sample on chemotherapy Cycle 1 Day 8 
(Table 5) as follows: 20-30 minutes after the start of cisplatin infusion, 5-10 minutes prior to end 
of cisplatin infusion, 1 hour after the end of cisplatin infusion (±15 minutes), 3.5 hours 
(±30 minutes) after the end of cisplatin infusion, and a single sample on Day 8 prior to dosing of 
any study drugs. Sites that do not have access to a refrigerated centrifuge should follow the 
sample processing steps provided in the Study Laboratory Manual. 
For those patients randomized to receive trilaciclib, the following blood samples will be 
collected. 
• Five blood samples for PK analysis of trilaciclib and metabolites will be collected from 
each patient on chemotherapy Cycle 1 Days 1 and 2 (Table 5) as follows: 5-20 minutes 


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after the start of trilaciclib infusion, within 5 minutes prior to end of trilaciclib infusion, 
and 25-45 minutes, 4-6 hours, and 18-24 hours after the end of trilaciclib infusion.  
• Five blood samples for PK analysis of trilaciclib and metabolites will be collected from 
each patient on maintenance Cycle 1 Days 1 and 2 and maintenance Cycle 3 Days 1 and 
2 (Table 5) as follows: 5-20 minutes after the start of trilaciclib infusion, within 5 minutes 
prior to end of trilaciclib infusion, and 25-45 minutes, 4-6 hours, and 18-24 hours after 
the end of trilaciclib infusion.  
• One blood sample for PK analysis of avelumab will be collected from each patient on 
Day 1 of maintenance Cycles 1, 3 and 6 (Table 5) prior to the start of avelumab infusion 
but after the end of trilaciclib 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 PK 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 Study Laboratory Manual. Do not collect blood for PK 
samples from the same arm being infused. 
11.5. 
Biomarkers 
11.5.1. 
Rationale for Archival or Fresh Tumor Collection at Screening 
In addition to the inclusion criteria requirements, the archival tissue will be used to evaluate in a 
retrospective fashion the relationship between CDK4/6 status and measures of anti-tumor 
efficacy as there is a hypothetical risk that trilaciclib could antagonize the intended anti-tumor 
efficacy of chemotherapy (see Section 4.3). All patients with archival tissue available from their 
urothelial carcinoma diagnostic sample or fresh biopsy obtained during Screening shall have it 
sent to a central storage facility for further biomarker evaluation. Tumor tissue must consist of a 
minimum of 15 slides (preferably 20) or a fixed paraffin block with a depth of at least 
75 microns, which includes the tissue needed for PD-L1 evaluations. If archival tissue is not 
available, a fresh biopsy must be obtained, unless otherwise approved by the Sponsor. 
The stored tumor tissue may be used to test for exploratory markers of trilaciclib sensitivity such 
as genomic profiles, mRNA expression, CDK4/6 dependency, and IHC staining including 
PD-L1. Additional details regarding tumor tissue collection, processing, handling, and shipping 
may be found in the laboratory manual. 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. 
11.5.2. 
Rationale for Peripheral Blood Collection 
For all patients on study, blood samples for biomarkers will be drawn pre-dose on Cycle 1 Day 
1, Cycle 1 Day 8, Cycle 2 Day 1, and Cycle 3 Day 1, maintenance Cycle 1 Day 1 and 
maintenance Cycle 3 Day 1 (Table 5). 
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 


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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 major histocompatibility complex 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 system, immunophenotypic changes will be compared from serial peripheral blood 
samples between patients receiving either trilaciclib or avelumab.  
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. 
11.6. 
Anti-Avelumab Antibody and Neutralizing Antibody Testing 
Avelumab may elicit an immune response. Patients with signs of any potential immune response 
to avelumab will be closely monitored.  
For patients randomized to receive trilaciclib, one blood sample for the evaluation of avelumab 
immunogenicity will be collected from each patient on Day 1 of maintenance Cycles 1, 3 and 6 
and at the End of Treatment Visit (Table 5). All samples should be drawn within 2 hours before 
the start of avelumab infusion. All of the samples that are positive for anti-avelumab antibodies 
may also undergo characterization for neutralizing antibodies. 
11.7. 
Data Monitoring Committee 
A DMC will monitor accumulating safety and anti-tumor response data with the first meeting 
planned for when approximately 10 patients treated with trilaciclib + cisplatin or 10 patients 
treated with trilaciclib + carboplatin have completed at least 2 cycles of study treatment, 
whichever occurs first. The meetings will continue approximately every 6 months or as defined 
in the DMC charter while patients are on study treatment depending upon the enrollment rate. 
Additional reviews may occur. 
A single 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 the associated analysis plan and data to be reviewed 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. 
11.8. 
End of Treatment Visit 
When a patient permanently discontinues study treatment, the patient should complete an End of 
Treatment Visit from last dose of study drug as outlined in Table 5.  


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11.9. 
Safety Follow-up Visit 
The patient should complete a Safety Follow-up Visit 30 days (+7 days) from the last dose of 
study drug and 90 days (±7 days) from last dose of avelumab as outlined in Table 5. The safety 
follow-up visit 90 days (±7 days) from last dose of avelumab may occur at the study site or can 
be via a telephone call with subsequent site visit requested in case any concerns noted during the 
telephone call.  
11.10. 
Survival Follow-up 
After completion of the End of Treatment Visit, the patient will be followed for survival 
approximately every 3 months (±7 days) (including an assessment at Month 17 Day 1 [±7days]). 
Survival Follow-up Visits may be done via telephone, email, or clinic visits.  
Information will be collected until the end of the study (or death) to record the patient’s 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 in EDC to the best of their ability. 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 guidances.  


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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 calculated to support the primary objective of the study, that is, to evaluate 
trilaciclib’s effect on PFS in patients who receive platinum-based chemotherapy followed by 
avelumab therapy as first-line treatment. From the literature, patients with urothelial carcinoma 
receiving avelumab maintenance therapy after platinum-based chemotherapy had a median PFS 
duration of 3.7 months (Powles, 2020). Considering 4 months chemotherapy prior to 
maintenance therapy in this study, the median PFS duration for the control group (Arm A: 
platinum-based chemotherapy followed by avelumab maintenance therapy) in this study is 
assumed to be 7 months.  
A total of 63 PFS events will be required to achieve 77% power to detect an HR of 0.6 in PFS at 
a 2-sided significance of 0.2. An HR of 0.6 corresponds to a median PFS duration of 11.7 
months for trilaciclib arm. Assuming 10 months of enrollment period and final PFS analysis 
taking place at approximately 22 months after the first patient is randomized, a total of 90 
patients are required to be randomized at a 1:1 ratio to the control group (Arm A) or trilaciclib 
group (Arm B). In the sample size calculation, it is also assumed that about 5% of patients are 
lost-to-follow-up during the 22 months (equivalent to a monthly lost to-follow-up rate of 
0.0023315 assuming an exponential distribution). EAST® v6.5 is used for the power and sample 
size calculations. 
12.2. 
Analysis Population 
The following analysis populations are defined for the study.  
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 set 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 PK population will include all patients who received at least one dose of trilaciclib or 
cisplatin or avelumab and have evaluable PK data. 


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12.3. 
Time of Planned Analysis 
12.3.1. 
First Planned Analysis – Analyses for Objective Response Rate in the 
Chemotherapy Period, and Myelosuppression Endpoints 
The first planned analysis will be conducted when all randomized patients have either completed 
chemotherapy or discontinued during the chemotherapy period. Trilaciclib’s effect on ORR 
during the chemotherapy period will be evaluated in this analysis.  
In addition, myelosuppression endpoints and safety data collected during the chemotherapy 
period will be performed at this time.  
12.3.2. 
Intermediate Planned Analyses – Analyses for Progression Free Survival and 
Probability of Survival at Month 16  
The intermediate planned analyses will evaluate the effect of trilaciclib on PFS (the primary 
endpoint) and the survival probability at Month 16. The timing to perform each analysis is 
conditional on the respective events. When the pre-specified condition for a given endpoint is 
met, the analysis for that endpoint will be performed. Therefore, these analyses could happen 
concurrently or separately.  
 
• PFS. The analysis for PFS will be conducted at the time when 63 patients have 
radiographic determined disease progression or died.  
• Probability of survival at Month 16. This analysis will be performed when all randomized 
patients have either completed the survival assessment at Day 1 of Month 17 or 
discontinued prior to the that visit.  
12.3.3. 
Final Planned Analysis – Analyses for Overall Survival 
Analysis for OS will be conducted when approximately 60% randomized patients have died (i.e., 
54 deaths). Study database will be locked to perform the final OS analysis and other SAP 
specified analyses, including the following analyses:  
• Analysis of tumor response endpoints (ORR, DCR, and DOR) in the overall study on the 
pooled data from both the chemotherapy and maintenance periods. 
• Analysis of tumor response endpoints (ORR and DCR) during the maintenance period. 
• Analysis of safety data from the maintenance period. 
• Analysis of anti-tumor endpoints during the overall study by CDK4/6 biomarker 
signature status and by PD-L1 subgroup as described in Section 12.4.8 . 
12.4. 
Statistical Analysis Methods 
An SAP will be developed and finalized prior to the first planned analysis and will include more 
details related to the statistical analysis of this study’s data. This section is a summary of the key 
aspects of the planned statistical analyses. 


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12.4.1. 
General Considerations 
All statistical analyses will be performed using SAS® v9.4 or higher. Categorical variables will 
be summarized by counts and percentages, while continuous variables will be summarized by 
mean, standard deviations, median, 25% and 75% percentiles, and minimum and maximum 
values by treatment group.  
Patients will be randomized according to the two stratification factors: presence of visceral 
metastasis (yes or no), and choice of initial platinum-based chemotherapy (cisplatin or 
carboplatin). When appropriate, these two stratification factors will be included in statistical 
models for efficacy analyses with the strata information as entered in IWRS at the time of 
randomization. 
12.4.2. 
Patient Disposition 
Patient disposition will be summarized separately for all patients by treatment group and overall. 
The summary will include the following: number of all screened patients; number and 
percentage of patients that were randomized, received study drug, and discontinued from each 
study drug, as well as the reasons for study drug discontinuation; and reasons for study 
discontinuation. 
12.4.3. 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized separately for the ITT population 
by treatment group and overall. The summary will include age, age groups, gender, race, 
ethnicity, screening vital signs (body weight, height, BMI, BSA), ECOG status (0-2), PD-L1 
status (positive or negative), visceral metastasis (yes or no) at, and initial platinum-based 
chemotherapy administered (cisplatin or carboplatin).  
12.4.4. 
Prior and Subsequent Anticancer Therapies 
Prior and subsequent anticancer therapy verbatim terms will be coded to Anatomical Therapeutic 
Classification and preferred term using the latest version of World Health Organization-Drug 
Dictionary. For the ITT population, summary statistics will be provided for prior and subsequent 
systemic anti-cancer therapies by treatment group and overall. For the subsequent systemic anti-
cancer therapies, the lines of therapy, best 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 defined for each chemotherapy drug (gemcitabine, 
cisplatin or carboplatin) and for trilaciclib or avelumab and summarized 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 any chemotherapy dose reductions and have at least one 


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dose reduction for a particular chemotherapy will be summarized along with a summary of the 
number of dose reductions for each chemotherapy; the number and percentage of patients who 
have at least one cycle delay will be summarized along 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, avelumab, or any chemotherapy will be summarized along with a 
summary of the number of interruptions. Lastly, the primary reason for each form of study drug 
modification (chemotherapy dose reductions, cycle delay, and infusion interruption) will also be 
summarized by treatment group. 
For trilaciclib, avelumab, gemcitabine, cisplatin or carboplatin, cumulative dose, dose intensity, 
relative dose, and relative dose intensity will be derived and summarized by treatment group, 
respectively, 
12.4.6. 
Efficacy Analyses 
12.4.6.1. Analyses of Primary Efficacy Endpoint –Progression Free Survival during the 
Study  
The primary efficacy endpoint PFS (months) during the overall study is defined as the time from 
the date of randomization to the date of documented radiologic disease progression per RECIST 
v1.1 or death due to any cause, whichever comes first regardless of in which treatment period of 
the event occurs. Progression-free survival will be determined using all data until the last 
evaluable visit prior to or on 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 earlier. Death (in absence of PD) is always categorized as an 
event in the PFS analysis. Censoring rules for patients who do not experience PD or death at the 
data cutoff date will be described in the study SAP. 
The primary analysis for PFS will be conducted at the time when 63 patients have radiographic 
determined disease progression or died. The treatment effect on PFS will be primarily evaluated 
using a stratified log-rank test accounting for the two stratification factors. The magnitude of the 
treatment effect will be estimated by hazard ratio (HR) (Arm B versus Arm A) using a stratified 
Cox proportional hazards model controlling for the two stratification factors. The 80% 
confidence interval (CI) will be generated for the HR. The Kaplan-Meier plots will be produced 
for each treatment group. The within-group median, 25%, and 75% percentile of PFS will be 
estimated using the Kaplan-Meier method with their corresponding 95% CI calculated using the 
method by Brookmeyer and Crowley (1982). The number and percentage of patients who do not 
have progressive disease ≥1 year after randomization will be summarized by treatment group.  
Analysis of PFS during the study will be based on the ITT population. 
12.4.6.2. Analysis for Secondary Anti-tumor Efficacy Endpoints  
Secondary anti-tumor endpoints include the following: 
• Tumor response related endpoints for chemotherapy period maintenance period and 
during the overall study 
- Objective response rate (ORR) in the chemotherapy and maintenance periods, and 
during the overall study  


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- Disease control rate (DCR) in the maintenance period and during the overall study 
- Duration of objective response (DOR) during the overall study 
• Progression free survival (PFS) in the maintenance period 
• Probability of survival at Month 16 and Overall Survival (OS) in the maintenance period 
and during the overall study 
Analysis for Tumor Responses 
At each tumor assessment visit, an overall time point response by RECIST v1.1 will be derived 
programmatically using the measurements provided by the Investigator for target lesions, 
non-target lesions, and new lesions collected in the eCRF. Best overall response (BOR) will be 
determined using all visit 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 earlier.  
The number and percentage of patients in each category of derived BOR (confirmed or 
unconfirmed CR, confirmed or unconfirmed PR, SD, PD, or Not Evaluable) will be summarized. 
For all tumor response endpoint analyses, unconfirmed CR or PR will be only allowed if there is 
lack of time to perform confirmed tumor scan in the period of chemotherapy before the patient 
entering the maintenance period. 
ORR will be evaluated at the time when all randomized patients have finished chemotherapy and 
at the end of the treatment period. ORR in the chemotherapy period is defined as the proportion 
of patients with BOR of confirmed or unconfirmed CR or PR. ORR in the maintenance period is 
defined as the proportion of patients with BOR of confirmed CR or PR during maintenance 
period. ORR in the overall study is defined as the proportion of patients with BOR of confirmed 
CR or PR as determined using all tumor scan data from both chemotherapy and maintenance 
periods. ORR along with its exact 95% two-sided CI 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 (Arm B – Arm A) and its 95% CI will be calculated using 
CMH weight (as described in Kim, 2013). ORR will be analyzed based on the RE population. 
DCR is defined as the proportion of patients with BOR of CR, or PR (confirmed), or SD lasting 
at least 24 weeks, as appropriate to each study period as described for ORR. The analysis of 
DCR will be performed using the methods similarly to ORR.  
Duration of objective response is the time between first objective response of CR or PR 
(confirmed), as appropriate to each treatment period as described for ORR, and the first date that 
progressive disease is documented or death, whichever comes first. DOR will only be analyzed 
for the patients who have achieved objective response. For patients with objective response but 
did not reach radiographically determined PD or died, the last adequate tumor assessment date 
prior to the earliest time of the following will be used to calculate censored time: (i) withdrew 
consent to obtain scans; (ii) lost to follow-up; (iii) initiated subsequent anticancer therapy. The 
Kaplan-Meier method will be used to estimate the median, 25%, and 75% percentile of DOR for 
each treatment group, along with the 95% CI, which is calculated using the method by 
Brookmeyer and Crowley (1982). 


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Analysis for PFS in the maintenance period 
In addition, PFS in the maintenance period is defined as the time from the date of entering the 
maintenance period to the date of documented radiologic disease progression per RECIST v1.1 
or death due to any cause, whichever comes first in that period. The PFS in maintenance period 
will be analyzed using the statistical methods as used for the analysis for PFS during the study.  
Analysis for OS 
Overall survival during the overall study 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 or the time 
to the last contact date known to be alive for those who survived as of the data cutoff date for the 
planned OS analysis (censored cases). For patients who drop out of the study right after 
randomization, their survival time is censored at the date of randomization. In addition, OS in the 
maintenance period will also be analyzed. For OS in the maintenance period, the date of entering 
the maintenance period is used as the start time in the OS calculation. The treatment effect on OS 
will be evaluated by applying the same statistical model used for the PFS analysis. The number 
and percentage of patients who survive ≥ 1 year after randomization will be summarized by 
treatment group. Survival distribution of OS will be based on Kaplan-Meier method used for the 
analysis for PFS. The survival probability at Month 16 will be estimated using Kaplan-Meier 
method along with its two-sided 95% CI (Kalbfleisch, 1980) for each treatment group. In 
addition, the number and percentage of patients who died or censored will be summarized along 
with the eCRF collected reasons for death by treatment group. The total duration of follow-up 
will also be summarized by treatment group.  
The analysis for OS during the study will be based on the ITT population while the analysis for 
PFS and OS in the maintenance period will be based on the ITT population with at least a visit in 
the maintenance period.  
The analysis for ORR, DCR and DOR during the study and ORR in the chemotherapy will be 
based on the RE population while the analysis for ORR and DCR in the maintenance period will 
be based on the RE population with at least a visit in the maintenance period.  
12.4.6.3.  Analysis of Myelosuppression Endpoints 
Myelosuppression endpoints are grouped by lineage and consequence of chemotherapy-induced 
myelosuppression (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 or hospitalizations due to 
chemotherapy-induced myelosuppression (including occurrence and number of dose 
reductions, or dose delay, and occurrence and number of hospitalizations due to CIM) 
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Continuous Myelosuppression Endpoint: 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. The actual assessment date, rather than visit date, will be used in 
the derivation of DSN in Cycle 1.  
The treatment effect on DSN in Cycle 1 will be evaluated using 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 (within each 
stratum) as a covariate. In addition, the mean difference (Arm B – Arm A), the standard error 
and the 95% CI for the difference generated from a Satterthwaite t-test will be presented.  
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 the modified Poisson regression model (Zou, 2004). The model 
will include the treatment and the two stratification factors as the fixed effect and corresponding 
baseline 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) 
(Arm B versus Arm A) and their 95% CIs will be calculated.  
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), 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 
treatment and 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 (Arm B versus Arm A) and its 95% CI will be generated 
from the statistical model as applied. 


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12.4.7. 
Safety Analyses 
Safety and tolerability will be assessed by AEs, laboratory tests, and vital signs. All safety data 
will be summarized using descriptive statistics by treatment group using the safety population. 
Data collected through scheduled or non-scheduled visits will all be included in the safety 
analyses.  
Safety data collected from the chemotherapy period and from the chemotherapy maintenance 
period will be summarized separately.  
12.4.7.1. 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 and preferred term using the latest 
version of MedDRA. The severity (toxicity grades 1-5) of AEs will be graded by Investigators 
according to the NCI-CTCAE Version 5.0. The number and percentage of patients experiencing 
any AE overall, will be tabulated for each treatment group, and broken down as well by system 
organ class, preferred term, and CTCAE grade. Adverse events considered by the Investigator to 
be related to treatment will also be summarized by the treatment to which it is attributed 
(e.g., trilaciclib/avelumab, chemotherapy) for each treatment group. Severity of AEs will be 
tabulated based on the greatest severity observed for each patient. In the tabulation of grade and 
causality, if the same AE occurs on multiple occasions, the highest grade and strongest 
relationship to study drug will be used in a summary. AESIs for trilaciclib, AESIs for avelumab, 
AEs leading to study drug discontinuation, dose reductions, cycle delays, and use of concomitant 
medications to treat AEs will be tabulated separately.  
12.4.7.2. Other Safety Endpoints 
Observed values and changes from baseline in vital signs and laboratory assessments of 
hematology, serum chemistry, and liver function parameters will be summarized by treatment 
group for each scheduled visit, maximum and minimum post-baseline by cycle, overall 
maximum and minimum post-baseline during treatment period, and last on-treatment assessment.  
Serum chemistry and hematology laboratory parameters will be characterized according to 
CTCAE toxicity grade from 1 to 5, Version 5.0, when possible. The number and percentage of 
patients within each CTCAE grade will be summarized for the overall treatment period as well 
as for each cycle. If a patient has multiple laboratory assessments in an interval of interest, the 
maximum grade will be reported.  
For vital signs potentially clinically significant (PCS) findings will be summarized by treatment 
group. The potentially clinically significant vital signs are defined either by post-baseline 
assessment or by the change from baseline with respect to the pre-specified thresholds. The 
criteria defining PCS for vital signs will be detailed in the study SAP. 
12.4.8. 
Exploratory Analyses 
Differences in pharmacodynamic parameters in tumor and peripheral blood including those 
relating to immune-based mechanisms will be summarized.  
The number and percentage of patients in different CDK4/6 signature status (i.e., CDK4/6 
independent, CDK4/6 dependent, and CDK4/6 indeterminate) will be summarized by treatment 


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group. Selected anti-tumor endpoints (PFS, ORR, and OS during the overall study) will be 
evaluated by subgroup of patients with different CDK4/6 signature status. Within each type of 
signature, the analysis methods for PFS, ORR, and OS during the overall study will follow the 
approaches outlined in Section 12.4.6.2.  
Anti-tumor endpoints of PFS, OS, ORR, DOR and DCR during the study will be evaluated by 
subgroup of patients with different PD-L1 status. Within each subgroup, the analysis methods for 
these anti-tumor endpoints will follow the approaches as outlined in Section 12.4.6.2.  
12.4.9. 
Pharmacokinetic Analyses 
The PK of trilaciclib and metabolites, cisplatin, and avelumab will be determined using a non-
linear mixed effects modeling approach. Relevant population pharmacokinetic parameters will 
be estimated and reported. Details of population pharmacokinetic analyses will be described in 
the population pharmacokinetic/pharmacodynamic analysis plan. 
12.4.10. 
Pharmacokinetic/Pharmacodynamic Analyses 
If data warrant, exploratory analyses may be performed to examine the relationship(s) between 
exposure to trilaciclib and pharmacodynamic endpoints or other efficacy and safety endpoints. 
Details of population PK/pharmacodynamic analyses will be described in a separate population 
PK/pharmacodynamic analysis plan. 


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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. 


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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. 


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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 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 


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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. 
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, 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 
immediately if contacted by a regulatory agency about an inspection. 


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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. 


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16. 
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Tan AR, Wright GS, Thummala AR, et al. Trilaciclib plus chemotherapy versus chemotherapy 
alone in patients with metastatic triple-negative breast cancer: a multicentre, randomized, open-
label, Phase 2 trial. Lancet Oncol. 2019;20:1587-601. 
Tecentriq® (atezolizumab) Prescribing Information. Genentech, Inc. 2020. 
Tecentriq® (atezolizumab) Summary of Product Characteristics. Roche Products Limited. 2020. 
von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial 
comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin 
in patients with bladder cancer. J Clin Oncol. 2005;23(21):4602-8. 
Wagner DJ, Hu T, Wang J. Polyspecific organic cation transporters and their impact on drug 
intracellular levels and pharmacodynamics. Pharmacol Res. 2016;111:237-46. 
Wang S, He Z, Wang X, Li H, Liu XS. Antigen presentation and tumor immunogenicity in 
cancer immunotherapy response prediction. Elife. 2019;8:e49020. 
Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics 
of response with ipilimumab. J Clin Oncol 2012;30 (21):2691-7. 
Weiss JM, Csoszi T, Maglakelidze M, et al. Myelopreservation with the CDK4/6 inhibitor 
trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase 
Ib/randomized phase II trial. Ann Oncol. 2019;30:1613-21. 
Yonezawa A, Masuda S, Yokoo S, et al. Cisplatin and oxaliplatin, but not carboplatin and 
nedaplatin, are substrates for human organic cation transporters (SLC22A1-3 and multidrug and 
toxin extrusion family). J Pharmacol Exp Ther. 2006 Nov;319(2):879-86. 
Zhang J, Bu X, Wang H, et al. Cyclin DCDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to 
control cancer immune surveillance. Nature. 2018;553:91-5. 
Zitvogel L, Apetoh L, Ghiringhelli F, et al. Immunological aspects of cancer chemotherapy. Nat 
Rev Immunol. 2008;8:59-73. 
Zou G. A modified poisson regression approach to prospective studies with binary data. Am J 
Epidemiol. 2004;159(7):702-6. 


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17. 
APPENDICES 
17.1. 
Clinical Laboratory Tests 
• The timing and laboratory tests detailed in Schedule of Assessments (Table 5) 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 15: 
Protocol-Specified Safety Laboratory Assessments 
Laboratory Assessment 
Parameters 
Hematology 
Absolute neutrophil 
count  
Hemoglobin 
Platelets 
Hematocrit 
Lymphocytes 
WBC 
Serum Chemistry 
Alanine 
Aminotransferase 
(ALT) 
Calcium 
Serum Creatinine 
Albumin 
Chloride 
Sodium 
Alkaline phosphatase 
Glucose 
Thyroid Stimulating 
Hormone (TSH) 
Aspartate 
Aminotransferase 
(AST) 
Magnesium 
Thyroxine (T4, free) 
Bicarbonate 
Phosphate 
(inorganic) 
Total Bilirubin 
Blood Urea Nitrogen 
(BUN) or Urea 
Potassium 
Total Protein 
Urinalysis 
Semiquantitative dipstick: specific gravity, pH, evaluation of glucose, 
protein, bilirubin, ketones, leukocytes, and hemoglobin 
Microscopic examination (including RBC, WBC, and casts) will be 
performed, if clinically warranted 
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 
 
 


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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 urinalysis) 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 (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 (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 
(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 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 PVG (or designee): 
G1 Therapeutics 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 PVG (or designee). However, it is very important 
that the Investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to G1 Therapeutics 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 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 PVG (or designee) 
within 24 hours of receipt of the information: 
G1 Therapeutics 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 (or designee) via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to G1 Therapeutics (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 Pharmacovigilance 
Email: safetyreporting@g1therapeutics.com 
Fax: +1-984-285-7131  
 
 
 


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17.3. 
Contraceptive Guidance and Collection of Pregnancy Information 
Woman of Childbearing Potential 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 pregnancy test within 7 days of 
starting study treatment and at the End of Treatment Visit.  
• 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: 


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− 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. 
In addition, patients are to comply with the following guidelines: 
• For women: Contraceptive use is required during the Treatment Phase and for at least 
6 months after the last dose of carboplatin, cisplatin, or gemcitabine or for 1 month 
after the last dose of avelumab or trilaciclib. 
• For men: Contraceptive use is required during the Treatment Phase and for at least 
6 months after the last dose of carboplatin, cisplatin, or gemcitabine. 
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 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 PVG or designee. Generally, the 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. 


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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 
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 PVG or designee. Generally, follow-up will 
not be required for longer than 6 to 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 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 
PD
a 
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. 
 


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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-PD
a 
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. 
 


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17.5. 
Preexisting Autoimmune Diseases 
Patients should be carefully questioned regarding their history of acquired or congenital immune 
deficiencies or autoimmune disease. Patients with any history of immune deficiencies or 
autoimmune disease listed in the table below are excluded from participating in the study (see 
Section 7.2 for specific exceptions). Possible exceptions to this exclusion could be patients with 
a medical history of such entities as atopic disease or childhood arthralgias where the clinical 
suspicion of autoimmune disease is low. Patients with a history of autoimmune-related 
hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study. 
In addition, transient autoimmune manifestations of an acute infectious disease that resolved 
upon treatment of the infectious agent are not excluded (e.g., acute Lyme arthritis). Contact the 
Medical Monitor regarding any uncertainty over autoimmune exclusions. 
Autoimmune Diseases and Immune Deficiencies 
Acute disseminated 
Encephalomyelitis 
Addison’s disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet’s disease 
Bullous pemphigold 
Chronic fatigue syndrome 
Chronic inflammatory demyelinating 
Polyneuropathy 
Chung-Strauss syndrome 
Crohn’s disease 
Dermatomyositis 
Interstitial cystitis 
Kawasaki’s disease 
Lambert-Eaton myasthenia syndrome 
Lupus erythematosus 
Lyme disease - chronic 
Meniere’s syndrome 
Mooren’s ulcer 
Morphea 
Multiple sclerosis 
Myasthenia gravis Neuromyotonia 
Opsoclonus myoclonus syndrome 
Optic neuritis 
Ord’s thyroiditis 
Pem phigus 
Pernicious anemia 
Polyarteritis nodusa 
Polyarthritis 
Polyglandular autoimmune syndrome 
Primary biliary cirrhosis 
Psoriasis 
Reiter’s syndrome 
Rheumatoid arthritis 


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Diabetes mellitus type 1 
Dysautonomia 
Epidermolysis bullosa acquista 
Gestational pemphigoid 
Giant cell arteritis 
Goodpasture’s syndrome 
Graves’ disease 
Guillain-Barré syndrome 
Hashimoto’s disease 
IgA nephropathy 
Inflammatory bowel disease  
Sarcoidosis 
Scleroderma 
Sjögren’s syndrome 
Stiff-Person syndrome 
Takayasu’s arteritis 
Ulcerative colitis 
Vitiligo 
Vogt-Kovanagi-Harada disease 
Wegener’s granulomatosis 
 

SAP_001.pdf: 
 
1 
                            
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
PRESERVE 3: A Phase 2, Randomized, Open-Label 
Study of Trilaciclib Administered with First-Line 
Platinum-Based Chemotherapy and Avelumab 
Maintenance Therapy in Patients with Untreated, 
Locally Advanced or Metastatic Urothelial 
Carcinoma 
Protocol Version 
3.0 
Protocol Number: 
G1T28-209 
Compound: 
Trilaciclib for Injection, 300 mg/vial 
Study Phase: 
Phase 2 
Study Name: 
PRESERVE 3 
Sponsor: 
G1 Therapeutics, Inc. 
Legal Registered Address: 
700 Park Offices Dr. Suite 200 
PO Box 110341  
Research Triangle Park, NC 27709 
Regulatory Agency Identifier 
Numbers: 
IND: 156967 
EudraCT: 2021-000205-24 
Statistical Analysis Plan 
Version: 
2.0 
Approval Date: 
06 MAR 2024 
 
 
 
 
 


Statistical Analysis Plan for Protocol G1T28-209 
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SAP SIGNATURE PAGE 
I have read and understand the contents of this Statistical Analysis Plan, Version 2.0 for 
Study G1T28-209 dated 06 March 2024 and I agree with all the statistical approaches, variable 
derivations and data presentation detailed as described in this document. 
 
 
 
Date 
 
Date 
 
Date 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................1 
LIST OF ABBREVIATIONS ..........................................................................................................7 
1. 
INTRODUCTION ........................................................................................................9 
1.1. 
Study Design .................................................................................................................9 
1.2. 
Study Objectives .........................................................................................................11 
1.3. 
Sample Size Consideration .........................................................................................13 
2. 
THE NUMBER OF PLANNED ANALYSES ...........................................................14 
2.1. 
First Planned Analysis – Analyses for Objective Response Rate in the 
Chemotherapy Period, and Myelosuppression Endpoints ..........................................14 
2.2. 
Intermediate Planned Analysis for Progression-Free Survival ...................................14 
2.3. 
Final Analysis – Analysis for Overall Survival ..........................................................14 
2.4. 
Change of Scope for Intermediate Planned and Final Analyses .................................15 
3. 
ANALYSIS POPULATIONS ....................................................................................16 
3.1. 
The Intent-to-treat Population .....................................................................................16 
3.2. 
The Response Evaluable Population ..........................................................................16 
3.3. 
The Safety Population .................................................................................................16 
3.4. 
The Maintenance Population ......................................................................................16 
4. 
GENERAL CONSIDERATIONS FOR DATA SUMMARY AND 
DISPLAY ...................................................................................................................17 
4.1. 
Treatment Group Descriptions and Display in Table, Listings and Figures ..............17 
4.2. 
Data Summary and Precision......................................................................................19 
4.3. 
Definitions for Analysis Related Timepoint and Time Interval .................................20 
4.4. 
Study Day ...................................................................................................................21 
4.5. 
General Principles of Missing Data Handling ............................................................21 
5. 
DISPOSITION AND BASELINE CHARACTERISTICS ........................................22 
5.1. 
Patient Disposition ......................................................................................................22 
5.2. 
Demographics and Baseline Disease Characteristics .................................................24 
5.3. 
Medical History and Ongoing Conditions ..................................................................24 
5.4. 
Prior and Concomitant Medications ...........................................................................24 
5.5. 
Summary of Protocol Deviations................................................................................26 
5.5.1. 
Definitions and Process for Identifying Protocol Deviations .....................................26 


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5.5.2. 
Summary of Protocol Deviations................................................................................26 
6. 
CLASSIFICATION OF PRIOR, CONCOMITANT, AND SUBSEQUENT 
ANTICANCER THERAPIES ....................................................................................27 
6.1. 
Prior Anticancer Therapies .........................................................................................27 
6.2. 
Concomitant Anticancer Therapies ............................................................................27 
6.3. 
Subsequent Anticancer Treatments ............................................................................28 
7. 
STUDY DRUG EXPOSURE, DOSE INTENSITY AND MODIFICATION ...........29 
7.1. 
Duration of Study Drug Exposure ..............................................................................29 
7.1.1. 
Duration of Study Drug Exposure in Chemotherapy period ......................................29 
7.1.2. 
Duration of Study Drug Exposure in Maintenance period and during the 
Study ...........................................................................................................................29 
7.2. 
Study Drug Modifications ..........................................................................................30 
7.2.1. 
Chemotherapy Period .................................................................................................30 
7.2.2. 
Maintenance Period ....................................................................................................31 
7.3. 
Duration of Total Follow-up .......................................................................................31 
8. 
EFFICACY ANALYSIS ............................................................................................32 
8.1. 
Definitions of Efficacy Endpoints ..............................................................................32 
8.1.1. 
Primary Efficacy Endpoint – Progression-Free Survival during the Study ................32 
8.1.2. 
Secondary Efficacy Endpoints ....................................................................................33 
8.1.2.1. 
Anti-tumor Efficacy Endpoints...................................................................................33 
8.1.2.2. 
Myelosuppression Efficacy Endpoints .......................................................................39 
8.2. 
Statistical Analysis Methods.......................................................................................43 
8.2.1. 
General Considerations for Efficacy Analysis ...........................................................43 
8.2.2. 
Analysis for Primary Efficacy Endpoint – Progression-Free Survival during 
the Study .....................................................................................................................44 
8.2.2.1. 
Primary Analysis ........................................................................................................44 
8.2.3. 
Analysis for Secondary Endpoint - Overall Survival during the Study......................44 
8.2.4. 
Analysis for Secondary Endpoints - Other Anti-tumor Efficacy Endpoints ..............45 
8.2.5. 
Analysis for Secondary Endpoints – Progression-free Survival and Overall 
Survival in the Maintenance and Survival Follow-up Periods ...................................46 
8.2.6. 
Analysis for Secondary Endpoints - Myelosuppression Endpoints ............................46 
8.2.6.1. 
Analysis for Duration of Severe Neutropenia ............................................................46 
8.2.6.2. 
Analysis for Binary Myelosuppression Endpoints .....................................................46 


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8.2.6.3. 
Analysis for Counting Myelosuppression Endpoints .................................................47 
8.3. 
Handling of Missing Data ...........................................................................................47 
8.4. 
Subgroup Analysis ......................................................................................................47 
8.4.1. 
Subgroup Analysis for PFS ........................................................................................48 
9. 
SAFETY ANALYSIS ................................................................................................49 
9.1. 
General Consideration of Safety Analysis ..................................................................49 
9.2. 
Adverse Events ...........................................................................................................49 
9.2.1. 
Definition and Classification of Adverse Events ........................................................49 
9.2.2. 
Imputation Rules for Missing Start or Stop Date for Adverse Events .......................50 
9.2.3. 
Analysis for Adverse Events ......................................................................................51 
9.3. 
Clinical Laboratory Data ............................................................................................52 
9.3.1. 
Laboratory Parameters ................................................................................................52 
9.3.2. 
Analysis for Laboratory Parameters ...........................................................................53 
9.4. 
Vital Signs ..................................................................................................................54 
9.4.1. 
Vital Sign Parameters .................................................................................................54 
9.4.2. 
Analysis for Vital Signs ..............................................................................................55 
9.5. 
ECOG Performance Status .........................................................................................55 
9.6. 
12-lead Electrocardiograms ........................................................................................56 
10. 
CHANGES FROM THE PROTOCOL ......................................................................57 
11. 
REFERENCES ...........................................................................................................58 
12. 
APPENDICES ............................................................................................................59 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................60 
APPENDIX 2. CUSTOMIZED MEDDRA QUERIES FOR TRILACICLIB AESIS ...............64 
 


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LIST OF TABLES 
Table 1: 
Primary and Secondary Objectives and Endpoints .....................................................12 
Table 2: 
Descriptions of Treatment Groups in Protocol, SAP, and Their Orders of 
Appearance in Table/Listing/Figures .........................................................................18 
Table 3: 
Definitions for Timepoints, Timepoint Related Assessments and Time 
Intervals ......................................................................................................................21 
Table 4: 
Protocol Permitted Dose Reduction by Study Drug ...................................................31 
Table 5: 
Calculation of PFS during the Study and Censoring Rules ........................................33 
Table 6: 
Time Point Response for Maintenance and Survival Follow-up Periods: 
Patients with Target Lesion(s) at Maintenance Baseline ............................................37 
Table 7: 
Time Point Response for Maintenance and Survival Follow-up Periods: 
Patients with Non-target Lesion(s) Only at Maintenance Baseline ............................37 
Table 8: 
Calculation of PFS in the Maintenance and Survival Follow-up Periods and 
Censoring Rules ..........................................................................................................39 
Table 9: 
Myelosuppression Endpoints ......................................................................................40 
Table 10: Laboratory Categories and Parameters .......................................................................53 
Table 11: Criteria for Potentially Clinically Significant Vital Signs ..........................................56 
 
 
LIST OF FIGURES 
Figure 1: 
G1T28-209 Study Design Diagram ............................................................................12 
 
 
 


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LIST OF ABBREVIATIONS  
Abbreviation  
 Term 
aCSR 
Abbreviated CSR 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ALC 
Absolute lymphocyte count 
ANC 
Absolute neutrophil count 
ANCOVA 
Analysis of covariance 
aRR 
Adjusted relative risk 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
BOR 
Best overall response 
BPM 
Beats per minute 
BUN 
Blood urea nitrogen 
CDK 
Cyclin dependent kinase 
CI 
Confidence interval 
CIM 
Chemotherapy-induced myelosuppression 
CMH 
Cochran–Mantel–Haenszel 
CR 
Complete response 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic blood pressure 
DCO 
Data cutoff 
DCR 
Disease control rate 
DMC 
Data Monitoring Committee 
DOR 
Duration of response 
DSN 
Duration of severe neutropenia 
ECG 
Electrocardiogram 


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Abbreviation  
 Term 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ESA 
Erythropoiesis-stimulating agent 
ETV 
End of Treatment Visit 
FN 
Febrile neutropenia 
G-CSF 
Granulocyte colony stimulating factor 
Hgb 
Hemoglobin 
HR 
Hazard ratio 
ITT 
Intent-to-treat 
IV 
Intravenous 
IWRS 
Interactive Wed Response System 
LDH 
Lactate dehydrogenase 
mCRC 
Metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NE 
Not evaluable 
ORR 
Objective response rate 
OS 
Overall survival 
PCS 
Potentially clinically significant 
PD 
Progressive disease 
PD-L1 
Programmed death-ligand 1 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
pMMR/MSS 
Proficient mismatch repair/microsatellite stable 
PR 
Partial response 
PT 
Preferred term 
RBC 
Red blood cell 
RE 
Response evaluable 
RECIST 
Response Evaluable Criteria in Solid Tumors 
SACT 
Subsequent anticancer treatment 


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Abbreviation  
 Term 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
SE 
Standard error 
SI 
Standard international 
SN 
Severe neutropenia 
SOC 
System organ class 
SPSD 
Statistical Programming Supportive Documents 
TLF 
Tables, listings, and figures 
TOC 
Table of contents 
WBC 
White blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
 
 


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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides the detailed statistical methods, variable definitions 
and derivations, and data handling that will be applied to analyze clinical trial data (except 
pharmacokinetics [PK] data) collected from Study G1T28-209,  “PRESERVE 3: A Phase 2, 
Randomized, Open-Label Study of Trilaciclib Administered with First-Line Platinum-Based 
Chemotherapy and Avelumab Maintenance Therapy in Patients with Untreated, Locally 
Advanced or Metastatic Urothelial Carcinoma” protocol version 3.0. 
If there are differences between the statistical analysis approaches described in the SAP and 
those in the protocol, the methods and approaches in the SAP will supersede those in the 
protocol.  
Statistical Programming Supportive Documents (SPSD) will be developed based on the SAP to 
serve as companion documents of the SAP to guide programming realization of the SAP. SPSD 
contain three separate documents: the table of contents (TOC) for planned analyses (in Excel 
Spreadsheet), reporting conventions (in Word), and shells or specificities for tables, listings, and 
figures (TLFs) generation (in Word). 
Statistical software SAS® (SAS Institute Inc., Cary, NC) Version 9.4 or later will be used to 
perform data analyses following the plan as laid out in this SAP.  
Changes and additions to the last signed off version of the SAP will be documented with 
corresponding rationale in the clinical study report (CSR).  
The SAP for PK and PK/Pharmacodynamics analyses for Study G1T28-209 will be written as a 
separate document.  
1.1. 
Study Design 
This is an exploratory Phase 2, multicenter, randomized, open-label study evaluating the safety 
and efficacy of trilaciclib administered with platinum-based chemotherapy followed by trilaciclib 
administered with avelumab maintenance therapy compared with platinum-based chemotherapy 
followed by avelumab maintenance therapy in patients receiving first-line treatment for 
advanced/metastatic urothelial carcinoma.  
Patients will be randomly assigned (1:1) to receive one of the following two treatment arms: 
x Arm A – platinum-based chemotherapy followed by avelumab maintenance therapy 
(hereafter abbreviated as platinum/avelumab) 
x Arm B – trilaciclib plus platinum-based chemotherapy followed by trilaciclib plus 
avelumab maintenance therapy (hereafter abbreviated as trilaciclib + 
platinum/avelumab) 
There will be two stratification factors for randomization: presence of visceral metastasis (yes or 
no) at randomization and initial platinum-based chemotherapy to be administered (cisplatin or 
carboplatin).  


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Study drugs will be administered as follows: 
x Gemcitabine 1000 mg/m2 administered IV on Day 1 and Day 8 of each 21-day 
chemotherapy cycle.  
x Cisplatin eligible: cisplatin 70 mg/m2 administered IV on Day 1 of each 21-day 
chemotherapy cycle. Split dosing on Day 1 and Day 8 is permitted for toxicity 
management as described in Protocol Section 9.3.1.1. Gemcitabine should be 
administered prior to cisplatin. 
x Cisplatin ineligible: carboplatin using Calvert formula with a target area under the 
curve (AUC) = 4.5 administered IV on Day 1 of each 21-day chemotherapy cycle. 
Gemcitabine should be administered prior to carboplatin. 
x Avelumab 800 mg administered IV on Day 1 of each 14-day maintenance cycle as a 
60-minute infusion. To mitigate infusion-related reactions, premedication with an 
antihistamine and with paracetamol (acetaminophen) approximately 30 to 60 minutes 
prior to each dose of avelumab is mandatory for the first 4 infusions (for example, 25-
50 mg diphenhydramine and 500-650 mg paracetamol [acetaminophen] IV or oral 
equivalent). This may be modified based on local treatment standards and guidelines, 
as appropriate. Premedication should be administered for subsequent avelumab doses 
based upon clinical judgment and presence/severity of prior infusion reactions. 
x Trilaciclib 240 mg/m2 administered as a 30-minute IV infusion completed within 
4 hours prior to the start of platinum-based chemotherapy (Day 1 and Day 8) at each 
cycle in chemotherapy period or avelumab maintenance therapy (Day 1) at each cycle 
in maintenance period. 
The study will include 3 study phases: Screening Phase, Treatment Phase, and Survival 
Follow-up Phase (Figure 1: G1T28-209 Study Design Diagram). Patients enrolled in the study 
will be eligible to receive 4-6 cycles of platinum-based chemotherapy. The choice of either 
Cisplatin or Carboplatin will be determined by the Investigator. Patients will be allowed to 
switch from cisplatin to carboplatin chemotherapy if they become ineligible for cisplatin due to 
toxicity, or from carboplatin to cisplatin chemotherapy if they become eligible to receive 
cisplatin. Changes in protocol chemotherapy will not be allowed for the reason of suspected or 
confirmed disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 
Patients without progressive disease (PD) per RECIST v1.1 after platinum-based chemotherapy 
will be eligible to receive avelumab maintenance therapy until disease progression, unacceptable 
toxicity, withdrawal of consent, Investigator decision, or the end of the trial, whichever comes 
first. 
Upon discontinuation of study treatment, patients will be followed for survival until at least 60% 
of patients in the study have died, or the end of study, whichever occurs first.  
A Data Monitoring Committee (DMC) will monitor accumulating safety and one-time anti-
tumor response data as defined in the DMC charter. 
The general design of the study, including study drugs administration in chemotherapy and 
maintenance periods, is depicted in the design diagram below. 


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Figure 1: 
G1T28-209 Study Design Diagram 
 
1.2. 
Study Objectives  
Primary: 
To evaluate the anti-tumor efficacy of trilaciclib as compared to a control group. 
Specifically, the primary and secondary objectives and their associated endpoints are described 
in Table 1.  
Table 1: 
Primary and Secondary Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objective 
x 
To evaluate the anti-tumor efficacy of 
trilaciclib compared to a control 
group  
x 
Progression-free survival (PFS) during the 
study  
Secondary Objectives: Efficacy 
x 
To evaluate the anti-tumor efficacy of 
trilaciclib compared to a control 
group  
x 
ORR (chemotherapy period, maintenance 
period, during the study) 
x 
DCR (maintenance period, during the study) 
x 
DOR (maintenance period, during the study) 
x 
PFS (maintenance period)  
x 
OS (maintenance period, during the study) 
Secondary Objectives: Myeloprotection  (to evaluate the myeloprotective effects of trilaciclib when 
combined with platinum-based chemotherapy compared with chemotherapy alone)  
x 
To assess the effects of trilaciclib on 
the neutrophil lineage compared to a 
control group during chemotherapy 
period 
x 
Duration of severe (Grade 4) neutropenia in 
Cycle 1 
x 
Occurrence of severe (Grade 4) neutropenia 
x 
Occurrence of febrile neutropenia AEs 
x 
Occurrence of G-CSF administration 


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Objectives 
Endpoints 
x 
To assess the effects of trilaciclib on 
the RBC lineage compared to a 
control group during chemotherapy 
period 
x 
Occurrence of Grade 3 or 4 decreased 
hemoglobin laboratory values  
x 
RBC transfusions on or after Week 5 
(occurrence and number of transfusions) 
x 
Occurrence of ESA administration 
x 
To assess the effects of trilaciclib on 
the platelet lineage compared to a 
control group during chemotherapy 
period 
x 
Occurrence of Grade 3 or 4 decreased platelet 
count laboratory values  
x 
Platelet transfusions (occurrence and number 
of transfusions) 
x 
To assess the effects of trilaciclib on 
chemotherapy administrations 
compared to a control group during 
chemotherapy period 
x 
All-cause dose reductions (occurrence and 
number of reductions) 
x 
All-cause cycle delays (occurrence and 
number of delays) 
Secondary Objectives: Safety 
x 
To assess the safety and tolerability of 
trilaciclib compared to a control 
group  
x 
Occurrence and severity of AEs by 
NCI-CTCAE v5.0 during chemotherapy and 
maintenance period 
x 
Trilaciclib AESIs during chemotherapy and 
maintenance period 
x 
Avelumab AESIs during maintenance period 
x 
Changes in laboratory parameters 
(hematology and serum chemistry), vital signs 
and ECG parameters during chemotherapy 
and maintenance period 
x 
Grade 3 or 4 abnormalities in serum 
chemistry laboratory parameters during 
chemotherapy and maintenance period 
x 
Occurrence of trilaciclib dose delays and 
infusion interruptions during chemotherapy 
and maintenance period 
x 
Occurrence of chemotherapy dose reductions 
during chemotherapy period 
x 
Occurrence of chemotherapy dose delays and 
infusion interruptions during chemotherapy 
period 
x 
Occurrence of avelumab dose delays and 
infusion interruptions during maintenance 
period 
AE=adverse event; AESI=adverse event of special interest; CTCAE=Common Terminology Criteria for Adverse 
Events; DCR=disease control rate; DOR=duration of response; ECG=electrocardiogram; ESA=erythropoiesis 
stimulating agent; G-CSF=granulocyte colony-stimulating factor; NCI=National Cancer Institute; ORR=objective 
response rate; OS=overall survival; PFS=progression-free survival; RBC=red blood cell. 


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Other objectives and endpoints can be found in Section 8 and Section 9 of the protocol. 
1.3. 
Sample Size Consideration  
The sample size is calculated to support the primary objective of the study, that is, to evaluate 
trilaciclib’s effect on PFS in patients who receive platinum-based chemotherapy followed by 
avelumab therapy as first-line treatment. From the literature, patients with urothelial carcinoma 
receiving avelumab maintenance therapy after platinum-based chemotherapy had a median PFS 
duration of 3.7 months (Powles, 2020). Considering 4 months chemotherapy prior to 
maintenance therapy in this study, the median PFS duration for the control group (Arm A): 
platinum-based chemotherapy followed by avelumab maintenance therapy) in this study is 
assumed to be 7 months.  
A total of 63 PFS events will be required to achieve 77% power to detect a hazard ratio (HR) of 
0.6 in PFS at a 2-sided significance of 0.2. An HR of 0.6 corresponds to a median PFS duration 
of 11.7 months for trilaciclib arm. Assuming 10 months of enrollment period and final PFS 
analysis taking place at approximately 22 months after the first patient is randomized, a total of 
90 patients are required to be randomized at a 1:1 ratio to the control group (Arm A) or trilaciclib 
group (Arm B). In the sample size calculation, it is also assumed that about 5% of patients are 
lost-to-follow-up during the 22 months (equivalent to a monthly lost-to-follow-up rate of 
0.0023315 assuming an exponential distribution). EAST® v6.5 is used for the power and sample 
size calculations. 


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2. 
THE NUMBER OF PLANNED ANALYSES 
2.1. 
First Planned Analysis – Analyses for Objective Response Rate in the 
Chemotherapy Period, and Myelosuppression Endpoints  
The first planned analysis will be conducted when all randomized patients have either completed 
at least 4 cycles of chemotherapy or discontinued during the chemotherapy period. The primary 
purpose of conducting the first planned analysis is to evaluate trilaciclib’s effect on 
myelosuppression endpoints. It is believed that 4 cycles of chemotherapy exposure should be 
sufficient to perform the evaluation. Trilaciclib’s effect on ORR will be evaluated in this 
analysis. Tumor assessment collected as of the data cutoff (DCO) date for this analysis will be 
included. As 4 cycles allow post-baseline tumor assessments, patients who achieved complete 
response (CR) or partial response (PR) from the first assessment will have the chance to be 
confirmed on the second assessment.  
In addition, trilaciclib’s safety in this patient population will be evaluated in this analysis.  
There is no plan to lock the database to perform the analysis. Instead, a data snapshot will be 
taken at the time of a pre-specified DCO date following G1’s Standard Operating Procedure for 
data snapshot to support the analyses planned at this time.  
2.2. 
Intermediate Planned Analysis for Progression-Free Survival 
The intermediate planned analysis will evaluate the effect of trilaciclib on PFS (the primary 
endpoint). The analysis for PFS, including subgroup analyses specified in Section 8.4.1, will be 
conducted at the time when 63 patients have radiographic determined disease progression or 
died.  
In addition to the analysis of PFS, the following analyses may be conducted at the time when the 
intermediate planned analysis takes place:  
x Overall Survival. Analysis of overall survival during the study, and selected overall 
survival analyses by subgroup as specified in Section 8.4.1. 
x Myelosuppression Endpoints. Select myelosuppression endpoints specified in Table 9.    
Similar to the first planned analysis, there is no plan to lock the database and a data snapshot will 
be taken to support these analyses. 
Due to study termination prior to reaching the specified condition for conducting probability of 
survival at Month 16, the analysis for probability of survival at Month 16 will not be performed 
(see Section 2.4 and Section 10).    
2.3. 
Final Analysis – Analysis for Overall Survival 
The timing for the final analysis of OS was initially planned when approximately 60% 
randomized patients have died (i.e., 54 deaths). Due to study termination prior to reaching the 
specified number of deaths (see Section 2.4), the timing of final analysis is no longer contingent 
upon the number of deaths and will occur shortly after database lock (DBL). In addition to final 


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analysis of OS, the following analyses will be conducted, which represent a subset of analyses 
initially planned for the final analysis (see Section 2.4 and Section 10) according to the protocol:     
x Analysis of tumor response endpoints (ORR, DCR, and DOR) during the study on the 
pooled data from both the chemotherapy and maintenance periods. 
x Analysis of safety data from the maintenance period. 
2.4. 
Change of Scope for Intermediate Planned and Final Analyses 
The study was terminated early due to the changing landscape of bladder cancer treatment.  
Termination was not related to any safety issue. The last patient was dosed on 30NOV2023. An 
abbreviated CSR (aCSR) will be prepared in place of a full CSR after completion of final 
analysis. As a result, the following planned analyses from the intermediate planned analyses and 
final analysis will not be conducted: 
x Intermediate planned analyses: 
o Probability of survival at Month 16. 
x Final analysis: 
o Analysis of tumor response endpoints (ORR and DCR) during the maintenance 
period.  
o Analysis of anti-tumor endpoints during the overall study by CDK4/6 biomarker 
signature status and by PD-L1 subgroup.  
 
 


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3. 
ANALYSIS POPULATIONS 
3.1. 
The Intent-to-treat 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 any study treatment or was compliant with the protocol. Unless otherwise 
specified, the ITT population is the primary population for all efficacy analyses.  
3.2. 
The Response Evaluable Population 
The Response Evaluable (RE) population includes those patients who are in the ITT population 
and receive at least one dose of any study drug, have measurable (target) tumor lesion(s) at 
baseline tumor assessment, and have at least one of the following: (1) at least 1 post-baseline 
tumor assessment; (2) discontinued treatment because of clinical progression prior to their first 
post-baseline tumor scan; (3) died due to disease progression prior to their first post-baseline 
tumor scan. Analyses using the RE population will be conducted on the basis of the randomly 
assigned treatment. It will be the primary analysis population for efficacy endpoints evaluating 
tumor responses. 
3.3. 
The Safety Population 
The Safety Population includes all randomized patients who received at least one dose of any 
study drug. Analyses using the safety population will be conducted on the basis of the actual 
treatment received at Day 1 of Cycle 1 in chemotherapy period. Unless otherwise specified, all 
safety data analyses for the chemotherapy period and overall treatment period will be performed 
based on this population. 
3.4. 
The Maintenance Population 
The Maintenance Population includes all randomized patients who received at least one dose of 
any study drug during the maintenance period. Unless otherwise specified, all analyses using this 
population will be based on the treatment group as initially assigned at randomization. That is, in 
Arm A (Chemotherapy/Avelumab) or Arm B (Trilaciclib + Chemotherapy/Avelumab).  
 


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4. 
GENERAL CONSIDERATIONS FOR DATA SUMMARY AND 
DISPLAY 
4.1. 
Treatment Group Descriptions and Display in Table, Listings and 
Figures 
As described in Section 1.1, eligible patients will be randomized at a 1:1 ratio to the treatment 
group of Chemotherapy/Avelumab or Trilaciclib + Chemotherapy/Avelumab. Depending on the 
type of platinum chemotherapies, each treatment group is further divided into Cisplatin-based or 
Carboplatin-based. 
Patients enrolled in the study will be eligible to receive 4-6 cycles of platinum-based 
chemotherapy, per Investigator’s discretion. Patients without progressive disease (PD) per 
RECIST v1.1 after platinum-based chemotherapy will be eligible to receive avelumab 
maintenance therapy until disease progression, unacceptable toxicity, withdrawal of consent, 
Investigator decision, or the end of the trial, whichever comes first.  
Avelumab maintenance therapy (with or without trilaciclib) should begin at a minimum of 4 and 
not more than 10 weeks after the last dose of platinum-based chemotherapy (with or without 
trilaciclib). 
An overview of treatment group descriptions by treatment phase that will be used in the SAP and 
TLFs with their corresponding descriptions in the protocol is provided in Table 2: Descriptions 
of Treatment Groups in Protocol, SAP, and Their Orders of Appearance in 
Table/Listing/Figures. In addition, the order by which the treatment groups will be displayed in 
TLFs is also provided in the table.  


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Table 2: 
Descriptions of Treatment Groups in Protocol, SAP, and Their Orders of Appearance in Table/Listing/Figures 
Data included in 
the Analysis 
Description in protocol 
Description in SAP  
Description in TLF 
Order in TLF 
Display  
Safety 
Others 
Chemotherapy Period 
Platinum-based chemotherapy (Gemcitabine/Cisplatin or 
Gemcitabine/Carboplatin) 
Chemo 
Chemo 
5 
1 
Gemcitabine/Cisplatin 
  Gemcitabine/Cisplatin 
   Gem + Cis 
1 
 
Gemcitabine/Carboplatin 
  Gemcitabine/Carboplatin 
   Gem + Carbo 
3 
 
Trilaciclib + Platinum-based chemotherapy 
Trilaciclib + Chemo 
Trila + Chemo 
6 
2 
Trilaciclib + Gemcitabine/Cisplatin 
   Trilaciclib + Gemcitabine/   
                        Cisplatin 
   Trila + Gem + Cis  
2 
 
Trilaciclib + Gemcitabine/Carboplatin 
   Trilaciclib + Gemcitabine/  
                        Carboplatin 
   Trila + Gem + Carbo  
4 
 
Maintenance Period 
Avelumab 
Avelumab 
Avelumab 
1 
Trilaciclib + Avelumab 
Trilaciclib/ Avelumab 
Trilaciclib/ Avelumab 
2 
Overall Treatment 
Period (Chemotherapy 
and Maintenance) OR 
During the study 
Platinum-based chemotherapy followed by avelumab 
maintenance therapy (Arm A) 
Chemo/Avelumab 
Chemo/Avelumab 
1 
Trilaciclib plus platinum-based chemotherapy followed by 
trilaciclib plus avelumab maintenance therapy (Arm B) 
Trilaciclib + Chemo/Avelumab 
Trilaciclib +  
Chemo/Avelumab 
2 
Cisplatin-based chemotherapy = Gemcitabine + cisplatin; Carboplatin-based chemotherapy = Gemcitabine + carboplatin; Platinum-based chemotherapy is either 
cisplatin-based chemotherapy or carboplatin-based chemotherapy. Carbo = carboplatin; Chemo = chemotherapy (Gemcitabine/Cisplatin or 
Gemcitabine/Carboplatin); Cis = cisplatin; Gem = gemcitabine; Trila = trilaciclib 


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4.2. 
Data Summary and Precision 
General Principles of Data Summary 
Data will be summarized by treatment group in table format. Tables summarizing disposition, 
demographics and baseline disease characteristics will include an overall column for patients 
pooled from all treatment groups. In general, continuous variables will be summarized 
descriptively, i.e., the following summary statistics will be presented:  
x Number of patients with non-missing data (indicated by n) 
x Mean and standard deviation 
x Median 
x Q1 (first quartile) and Q3 (third quartile) 
x Minimum and maximum values.  
Categorical variables will be summarized categorically, i.e., number (n) and percentage of 
patients in each category will be presented.  
General Principles of Data Listings 
All collected data and derived variables will be included in patient data listings. An indicator will 
be provided for any imputed data element (e.g., imputed adverse event [AE] start date). Columns 
in listings will be ordered by treatment group, country, study site, patient identification, visit, and 
assessment or event date, if applicable, and then the data elements. The treatment group 
presented in listings will be based on the randomly assigned treatment, unless otherwise noted.  
General Principles of Precision for Summary Statistics and Calculated Statistical 
Quantities 
The precision of summary statistics for continuous variables, including mean, median, Q1, Q3, 
minimum, and maximum, will be consistent with the precision of the variable as collected. 
Calculated quantities of variability (e.g., standard deviation, standard error [SE]) will be 
presented with one more decimal place than the precision of the variable that is collected. The 
boundaries of a confidence interval (CI) will keep the same precision as the point estimate.  
For whole numbers (including counting variables), the mean, median, Q1, and Q3 will be 
presented with one decimal place. 
For percentages, 1 digit will be presented after the decimal point (e.g., 10.1%). A percentage 
value less than 0.1% will be displayed as “<0.1%.” A percentage value that is >99.9% and 
<100% will be displayed as “>99.9%.”  
P-values, in general, will be displayed in 3 decimal places except for when a p-value is <0.001, it 
will be presented as “<0.001”. If a p-value is greater than 0.999, it will be displayed as “>0.999”.  
Rounding will take place after all calculation steps are completed prior to result display. 


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4.3. 
Definitions for Analysis Related Timepoint and Time Interval 
Efficacy and safety data collected from this study will be summarized by chemotherapy period, 
maintenance period, during the overall treatment period (including chemotherapy and 
maintenance periods), or during the study (i.e., regardless of whether the patient was in 
chemotherapy, maintenance or survival follow-up period), depending on the category of the data 
to be summarized. For each specific category of data, the time interval by which the data will be 
analyzed or summarized will be specified in the respective section in which the data analysis 
plan is described.  
The maximum duration for chemotherapy period is 6 cycles, which is equal to 18 weeks (126 
days) under the assumption that there are no cycle delays or treatment interruptions.  
To clarify data inclusion for each time interval of interest and baseline or end values for each 
given time interval, Table 3 presents definitions for timepoints, timepoint related assessments, 
and time intervals involved in statistical data analysis or summary.  
Table 3: 
Definitions for Timepoints, Timepoint Related Assessments and Time 
Intervals 
Term 
Definition 
Start of study (date) 
Date of randomization  
Study baseline 
(assessment) 
The last non-missing value prior to or on the date of the first dose of any 
study drug at the time that is before the time of the first study drug 
administration.  
Day 1 of Cycle X (date) 
The date when the first dose of any study drug for Cycle X is administered. 
End of cycle (date) 
Day 1 of the subsequent cycle if there is a subsequent cycle, allowing 
crossing from chemotherapy period to maintenance period. For two special 
cases, 1) for the last Chemotherapy cycle and the patient did not enter 
maintenance and 2) the last maintenance cycle, the End of cycle is defined 
as the date of the End of Treatment Visit (ETV). If the ETV does not occur 
for a patient, the End of cycle for the patient will be defined as 14 days 
post the last dose of any study drugs in the respective cycle. 
Duration of a cycle 
(days) 
Total number of days from Day 1 of the cycle to End of the cycle, that is, 
End of the cycle – Day 1 of the cycle + 1. 
Duration of study drug 
exposure in 
chemotherapy period 
(weeks)  
Total number of weeks from Day 1 of Cycle 1 in chemotherapy period to 
the End of last chemotherapy cycle. That is, (End of last chemotherapy 
cycle – Day 1 of chemotherapy Cycle 1 + 1)/7. 
Duration of study drug 
exposure in maintenance 
period (weeks) 
Total number of weeks from Day 1 of Cycle 1 in maintenance period to the 
End of last maintenance cycle. That is, (End of last maintenance cycle – 
Day 1 of maintenance cycle 1 + 1)/7. 
Duration of overall study 
drug exposure (weeks)  
The total number of weeks from Day 1 of Cycle 1 in chemotherapy period 
to the End of the last cycle in the study (could be in chemotherapy or 
maintenance period). That is, (End of the last cycle in the study – Day 1 of 
chemotherapy Cycle 1 + 1) / 7.  


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Term 
Definition 
Duration of total  
follow-up (months) 
The total number of months from date of randomization to either the date 
of death or last contact date in the study known alive. That is, duration of 
total follow-up = (date of death or date of last contact date known alive – 
date of randomization + 1) /30.4375. 
4.4. 
Study Day 
Study Day will be calculated for an event date or an assessment date to provide additional 
information for interpretation of the event occurrence. Study Day is calculated as:  
x The start date of the event (visit date, onset date of an event, assessment date etc.) − 
the date of randomization + 1, if the event occurred on or after the reference date. 
Date of randomization will be Study Day 1. 
x The start date of the event (visit date, onset date of an event, assessment date etc.) − 
the date of randomization, if the event occurred prior to the reference date. The day 
before the date of randomization will be Study Day -1. 
4.5. 
General Principles of Missing Data Handling 
For primary and secondary efficacy endpoints, handling of missing data is described in 
Section 8.3.  
For all other data analyses, in general, the observed data are used for analyses or data summary. 
That is, no missing imputation will be performed. However, imputation of missing start or stop 
dates for AE and medications/therapies will be used to determine the status of each AE and the 
prior/concomitant/subsequent status of each non-study treatment medication/treatment. Please 
refer to Section 9.2.2 for the rules of imputation of missing AE start or stop date and Section 5.4 
for the rules of imputation of missing medication start or stop dates. 
For demographic and baseline characteristics, continuous variables will be summarized based on 
non-missing observations with the number of patients with non-missing data indicated. For a 
categorical variable with missing data, a category of “Missing” will be included as a separate 
category for the summary. That is, the number and percentage of patients in each category of the 
variable (including “Missing”) will be summarized and reported with the number of randomized 
patients as the denominator for the percentage calculation.  


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5. 
DISPOSITION AND BASELINE CHARACTERISTICS 
5.1. 
Patient Disposition  
A summary of patient disposition will be generated for each planned analysis using all 
accumulated data as of the data cutoff date for the respective analysis that will be conducted.  
Patient disposition summary will include the following 4 major sections:  
1. Disposition of all screened patients who signed informed consent  
2. Study drug disposition for patients who received at least one dose of any study drug 
3. Study disposition for patients who were randomized 
4. Deaths among patients who were randomized  
For Categories 2 and 3, the contents to be summarized and reported differ slightly among the 
planned analyses. Therefore, details are provided for each planned analysis. Specific details for 
each section are described below.  
1. Disposition of all screened patients  
The total number of screened patients who signed informed consent will be presented as two 
mutually exclusive groups: those who were screen failures and those who were randomized. For 
those who were randomized, patients who received at least one dose of any study drug and those 
who did not receive any dose of any study drug are further presented by treatment group and 
overall. The number of randomized patients will be the denominator for calculating percentages 
in each treatment group and overall.  
2. Study drug disposition 
A summary of study drug disposition will be generated for each planned analysis using all 
accumulated data as of the data cutoff date for the respective analysis that will be conducted. 
For each study drug prescribed in chemotherapy period (trilaciclib, gemcitabine, cisplatin, and 
carboplatin), the number and percentage of patients who discontinued the study drug will be 
summarized by treatment group. Dispositions of cisplatin and carboplatin will be summarized for 
the patients who were treated at chemotherapy Cycle 1 Day 1 by the specific chemotherapy. In 
addition, the number and percentage of patients who have switched from cisplatin to carboplatin 
chemotherapy or from carboplatin to cisplatin chemotherapy will be summarized, with 
percentages calculated based on the number of patients who received the cisplatin and 
carboplatin chemotherapy at the start of chemotherapy, respectively. 
For trilaciclib, the number and percentage of patients who continued with the study drug at 
maintenance Cycle 1 will also be summarized by treatment group. The number of patients who 
took trilaciclib at chemotherapy Cycle 1 will be the denominator for the percentage calculation.  
For trilaciclib and avelumab during maintenance period, the number and percentage of patients 
who discontinued each study drug will be summarized by treatment group. The number of 
patients in the Maintenance population will be the denominator for the percentage calculation in 
each treatment group. Primary reasons for study drug discontinuation during maintenance period 
will be presented with the number and percentage of patients in each reason category, with 


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percentages calculated based on the number of patients who discontinued the study drug during 
maintenance period.   
3. Study disposition  
Disposition of Chemotherapy period 
Out of those who entered chemotherapy period (i.e., who were randomized and had at least one 
dose of any study drug in chemotherapy period, the same as the Safety population), the number 
and percentage of patients in the following mutually exclusive categories will be summarized by 
treatment group and overall:  
x Patients who are ongoing with chemotherapy 
x Patients who have entered maintenance after chemotherapy  
x Patients who have entered Survival follow-up without entering maintenance 
x Patients who have discontinued from the study during chemotherapy period  
The number of patients in the Safety population in each treatment group and overall will be the 
denominator for calculating percentages of patients in each of the categories.  
Disposition of Maintenance period  
Out of those in the maintenance population, the number and percentage of patients in the 
following mutually exclusive categories will be summarized by treatment group and overall: 
x Patients who are ongoing with the treatment in maintenance period 
x Patients who have entered Survival follow-up 
x Patients who have discontinued from the study during maintenance period 
The number of patients in the Maintenance population in each treatment group and overall will 
be the denominator for calculating percentages of patients in each of the categories.  
Reason for Study Discontinuation  
The primary reason for study discontinuation will also be summarized by treatment group and 
overall, and the number of patients who discontinued in the respective treatment group will be 
the denominator for the percentage calculation for each reason of discontinuation. 
4. Death 
The number and percentage of patients who died during the chemotherapy period, during the 
maintenance period, or during the study will be summarized by treatment group and overall for 
all randomized patients along with the primary reason of death (Progressive Disease, Adverse 
Event, Other). For calculating percentages of death, the number of randomized patients will be 
the denominator for during the chemotherapy period and during the study, and the number of 
patients in the maintenance period will be the denominator for during the maintenance period. 
The number of patients who died will be the denominator for calculating the percentage of 
patients within each primary reason for death. 
Study drug and study disposition information will be provided in data listings for all randomized 
patients.  


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5.2. 
Demographics and Baseline Disease Characteristics 
Demographics and baseline disease characteristics will be summarized for the first planned and 
final analyses.  
Demographics will be summarized descriptively by treatment group and overall on the ITT 
population. Demographics include age (at screening), age group (≥18 to <65, or ≥ 65), gender, 
race, ethnicity, and country.  
Baseline disease characteristics will also be summarized descriptively by treatment group and 
overall on the ITT population. Baseline disease characteristics include: 
x Stage at initial diagnosis 
x Stage at screening 
x Site of the primary tumor  
x Disease status 
x Eastern Cooperative Oncology Group (ECOG) status  
x Prior systemic therapy in adjuvant/neo-adjuvant setting 
x Visceral metastasis (yes or no)  
x Initial platinum-based chemotherapy administered (cisplatin or carboplatin) 
All these baseline disease characteristics are categorical.  
Data listings for demographics and baseline disease characteristics for the ITT population will be 
produced, respectively.  
5.3. 
Medical History and Ongoing Conditions 
Medical history and ongoing conditions at the Screening Visit will be summarized for the ITT 
population at the first planned and final analyses.  
Non-cancer medical history and ongoing medical conditions collected at the Screening Visit will 
be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 25.1 or later, 
and then summarized by treatment group and overall for the ITT population. Medical history and 
ongoing conditions will be presented by system organ class (SOC) and preferred term (PT), with 
SOC and PT all sorted in descending frequency based on the overall column. A patient will only 
be counted once within a particular SOC (or PT) even if the patient had multiple 
conditions/diseases in the same SOC (or PT). 
In addition, a data listing for medical history and ongoing medical conditions collected at the 
Screening Visit will be provided. 
5.4. 
Prior and Concomitant Medications  
Summaries of concomitant medications will be generated for the ITT population for the first 
planned and final analyses. Concomitant medications will be summarized for chemotherapy and 
maintenance period, separately. 


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Concomitant medications during chemotherapy period are those medications that were given 
during the time interval from the first dose of any study drug to the end of last chemotherapy 
cycle for patients who entered maintenance period. Concomitant medications during 
chemotherapy period for patients that did not enter the maintenance period are those medications 
that were given during the time interval from the first dose of any study drug to the last dose date 
of any study drug + 30 days. Concomitant medications during maintenance period are those 
medications that were given during the time interval from the first dose of any maintenance 
study drug to the last dose date during maintenance period + 90 days. Medications collected 
through electronic case report forms (eCRFs) will be coded to Anatomical Therapeutic 
Classification (ATC) and PT, where applicable, using the most recent World Health 
Organization Drug Dictionary (WHO-DD) version WHODrug-Global-B3 202309.   
Prior and concomitant medications will be summarized by ATC classifications and PT and 
presented in a descending order of frequency for ATC and PT within an ATC based on the 
overall group. Terms at the lowest available level (Level 5 excluded) will be used for the ATC 
classifications. If a patient took multiple medications within the same ATC, the patient will only 
be counted once for that ATC. Similar logic applies to PT summaries. The number and 
percentage of patients receiving any prior/concomitant medications will be summarized by 
treatment group and overall. 
Handling of Missing Start and/or End Date for Medications Entered into EDC 
Medications with incomplete start and/or end dates will be imputed according to the 
specifications described below. Those with incomplete start and/or end dates will be assumed to 
be concomitant if it cannot be shown that the medication was not taken outside the treatment 
period.  
For completely missing or partially missing start dates: 
x If the start date has month and year but day is missing, the first dose date will be used 
if the month and year is the same as the first dose date, otherwise, the first day of the 
month will be used. 
x If the start date has year, but day and month are missing, then the first dose date will 
be used if the year is the same as the first dose date, otherwise January 1st will be 
used. 
x If the start date is completely missing, then it will be imputed as the first dose date of 
study drug. 
After the imputation, the imputed start date will be compared with corresponding stop date, if 
available. If the imputed start date is later than the stop date, the start date will be imputed with 
the stop date instead. 
For completely missing or partially missing stop dates: 
x If the stop date has month and year but day is missing, the last day of the month will 
be used. 
x If the stop date has year, but day and month are missing, December 31st will be used.  


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x If the stop date is completely missing, the last dose date will be used.  
After the imputation, the imputed stop date will be compared against the death date for patients 
who died. If the date is later than the death date, the date of death will be used to impute the stop 
date instead. 
Prior and concomitant medications will be listed with a flag for prior or concomitant.  
5.5. 
Summary of Protocol Deviations  
5.5.1. 
Definitions and Process for Identifying Protocol Deviations  
A protocol deviation refers to situations where a patient’s eligibility for study entry or a specific 
data collection deviate from the entry criteria or study procedure as specified in the protocol. 
Protocol deviation cases at the patient level with specific data elements of concern need to be 
summarized and reported in the aCSR. Protocol deviations will be categorized as major or minor. 
Major protocol deviations are those that could affect the integrity of the data or adversely affect 
patients’ safety. Criteria that define major or minor protocol deviations will be specified, 
documented, and signed off on prior to study database lock. Specifically, a protocol deviation 
specifications document that describes the criteria defining major and minor protocol deviations, 
the categories of major protocol deviations, and the list of patients who had at least one protocol 
deviation case with the classification of major or minor will be created and signed off prior to 
study database lock to perform the unblinded statistical analysis.  
The deviation of receiving a treatment that was not randomly assigned will be the only exception 
to the process described above. It will only be recognized after database lock. These cases will 
have an impact on the composition of the Safety population and a data listing for these patients 
will be included in the aCSR.  
5.5.2. 
Summary of Protocol Deviations   
A protocol deviation summary will be generated for the final analysis (including all protocol 
deviations occurring during and after chemotherapy period, separately).  
The number and percentage of patients in the ITT population with protocol deviations will be 
tabulated for each of the following categories by treatment group and overall.  
x Patients with at least one protocol deviation (major or minor) 
x Patients with at least one major protocol deviation 
x Patients with at least one protocol deviation in each of the major deviation categories 
Protocol deviations will be listed with details and a flag for major or minor. 


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6. 
CLASSIFICATION OF PRIOR, CONCOMITANT, AND 
SUBSEQUENT ANTICANCER THERAPIES 
Prior therapies refer to those anticancer treatments that patients received prior to first dose of any 
study drug, including medications, surgical procedures, or radiotherapy treatments.  
Concomitant therapies refer to those treatments, other than study drugs, that could be utilized 
concurrently with study drug(s) as specified in the protocol. Equivalently, concomitant therapies 
include all non-study-treatment therapies that have started between the first dose date of any 
study drug and the last dose date of any study drug, inclusively.  
Subsequent therapies refer to anticancer treatments received following investigational study drug 
discontinuation while the patient was still in the study (i.e., in the Survival Follow-up period).  
The rules of imputation of missing start or stop dates for medications described in Section 5.4 
are, in general, applicable for missing start or stop dates imputation for anticancer therapies in 
any format (medications, surgical procedures, or radiotherapy treatments). 
6.1. 
Prior Anticancer Therapies 
Summaries of prior anticancer therapies will be generated for the first planned analysis based on 
the ITT population.  
The number and percentage of patients with any prior systemic anticancer treatments will be 
summarized by treatment group and overall. Prior anticancer medications will be further 
summarized based on ATC and PT and presented in a descending order of frequency for ATC 
and PT withing an ATC based on the overall group.  
The number and percentage of patients with any prior surgical procedures that were related to 
bladder cancer and radiotherapies will be summarized by treatment group and overall, 
respectively. 
6.2. 
Concomitant Anticancer Therapies 
Summaries for concomitant anticancer therapies will be generated at the final analysis for the 
ITT population.  
Concomitant anticancer therapies during chemotherapy period are defined as all anticancer 
therapies that start during the time interval from the first dose of any study drug to the end of last 
chemotherapy cycle for patients who entered maintenance period. Concomitant anticancer 
therapies during chemotherapy period for patients that did not enter the maintenance period are 
those medications that were given during the time interval from the first dose of any study drug 
to the last dose date of any study drug + 30 days. Concomitant anticancer therapies during 
maintenance period are those anticancer therapies that were given during the time interval from 
the first dose of any maintenance study drug to the last dose date during maintenance period + 90 
days. The number and percentage of patients receiving any concomitant surgical procedures or 
radiotherapies will be summarized by treatment group and overall, respectively. 


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6.3. 
Subsequent Anticancer Treatments 
Due to the early termination of the study (aCSR), subsequent anticancer treatments (SACTs) will 
not be summarized (see Section 2.4).  
However, SACTs will be needed for the purpose of censoring in the programmatic derivation of 
parameters related to objective response rate (ORR), duration of objective response (DOR), and 
progression-free survival (PFS) (see Section 8.1.2.1.2).  
Handling of Missing Start Date for SACTs Entered into EDC 
SACTs with completely missing or partially missing start dates will be imputed according to the 
specifications described below.  
x If the start date has month and year but day is missing, the date of discontinuation of 
last study drug will be used if the month and year is the same as the date of 
discontinuation of last study drug, otherwise, the first day of the month will be used. 
x If the start date has year, but day and month are missing, then the date of 
discontinuation of last study drug will be used if the year is the same as the date of 
discontinuation of last study drug, otherwise January 1st will be used. 
x If the start date is completely missing, then it will be imputed as the date of 
discontinuation of last study drug. 


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7. 
STUDY DRUG EXPOSURE AND MODIFICATION  
7.1. 
Duration of Study Drug Exposure  
Analyses described in this section will be based on the Safety population and will be performed 
at the first and final planned analyses unless otherwise specified.  
7.1.1. 
Duration of Study Drug Exposure in Chemotherapy period 
Duration of study drug exposure (weeks) in chemotherapy period is defined as the duration from 
Day 1 of Cycle 1 in chemotherapy period to the End of cycle for the last cycle in chemotherapy 
period. That is, duration of study drug exposure in chemotherapy period (weeks) = (End of cycle 
for the last chemotherapy cycle – Day 1 of chemotherapy Cycle 1 + 1)/7, where the definitions 
for End of cycle and Day 1 of Cycle 1 can be found in Section 4.3. 
The duration of study drug exposure in chemotherapy period will be summarized by treatment 
group and overall. For each treatment group, the total number of cycles that a patient received 
will be summarized both categorically and descriptively.  
Corresponding data listings will be provided.  
7.1.2. 
Duration of Study Drug Exposure in Maintenance period and during the Study 
Two additional variables will be calculated to report study drug exposure: the duration of study 
drug exposure in maintenance period and the duration of total study drug exposure (i.e., 
exposures from chemotherapy period and maintenance period combined). Specifically:   
x Duration of study drug exposure in maintenance period (weeks) is defined as (End of 
cycle for the last maintenance cycle – Day 1 of maintenance Cycle 1 + 1)/7. 
x Duration of total study drug exposure (chemotherapy and maintenance periods 
combined) (weeks) is defined as (End of cycle for the last cycle in the study – Day 1 
of chemotherapy Cycle 1 + 1)/7.  
The definitions for End of cycle and Day 1 of Cycle 1 can be found in Section 4.3. 
Study drug exposure during the maintenance period will be summarized at the first planned, 
intermediate planned, and final analyses. For the patients in the Maintenance population, the 
duration of study drug exposure in maintenance period will be calculated and summarized by 
treatment group and overall. For each treatment group, the total number of maintenance cycles 
that a patient received will be summarized both categorically and descriptively. 
Similarly, based on the Safety population, the duration of total study drug exposure will be 
summarized by treatment group and overall. For each treatment group, the total number of cycles 
that a patient received during the study will be summarized both categorically and descriptively. 
These analyses will only be performed at the final analysis. 
Corresponding data listings will be provided.  


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7.2. 
Study Drug Modifications 
Study drug modifications will be summarized at the first planned and final analyses unless 
otherwise specified.  
There are three types of study drug modification: dose reduction, cycle delay, and infusion 
interruption. Protocol permitted dose reductions for each study drug are summarized in Table 4.  
Table 4: 
Protocol Permitted Dose Reduction by Study Drug 
Study Drug 
Number of Dose Reductions Allowed 
Trilaciclib 
0 
Gemcitabine 
2 
Cisplatin 
2 
Carboplatin 
2 
Avelumab 
0 
7.2.1. 
Chemotherapy Period 
The number and percentage of patients will be summarized by treatment group based on the 
Safety population for each of the following categories:  
1. Any study drug modification 
2. Any dose reduction  
3. Any cycle delay  
4. Any cycle delay due to hematologic toxicity 
5. Any infusion interruption  
The number of any dose reduction and the number of any infusion interruption will be 
summarized descriptively and categorically by treatment group.  
In addition, more detailed summaries outlined below will be provided. 
Dose reduction for each chemotherapy. For each of the chemotherapies that dose can be 
reduced by protocol (in chemotherapy period: gemcitabine, cisplatin, and carboplatin), the 
number of dose reductions will be summarized descriptively and categorically by treatment 
group. The mutually exclusive categories are: Not Applicable (only one cycle), 0, 1, 2, and 3+. 
Reason for dose reduction will be summarized by treatment group. 
Cycle delay. Information regarding whether a cycle was delayed was collected in the eCRF for 
each cycle. The number of cycles that have been delayed will be summarized descriptively and 
categorically by treatment group. The mutually exclusive categories are: Not Applicable (only 
one cycle), 0, 1, 2, and 3+. Reason for cycle delay will be summarized by treatment group. 
Trilaciclib Infusion interruption. The number of trilaciclib infusion interruptions will be 
summarized descriptively and categorically by treatment group.  
     


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7.2.2. 
Maintenance Period 
Study drug modifications during maintenance period will be summarized at the first planned, 
intermediate planned, and final analyses. The number and percentage of patients will be 
summarized by treatment group based on the Maintenance population for cycle delay and any 
infusion interruption.  
The number of cycle delays and the number of any infusion interruption will be summarized 
descriptively and categorically by treatment group. Reason for cycle delays will be summarized 
by treatment group. 
In addition, the number of trilaciclib infusion interruptions will be summarized descriptively and 
categorically by treatment group. 
Corresponding data listings will be provided.  
7.3. 
Duration of Total Follow-up 
Duration of total follow-up will be summarized at the intermediate planned and final analyses.  
Duration of total follow-up (months) refers to the time interval that a patient participated in this 
clinical study starting from the date of randomization. It will be calculated based on the 
definition provided below.     
Duration of total follow-up (months) = (date of death or date of last contact date known as alive 
– date of randomization + 1) /30.4375. 
The descriptive statistics for this variable will be included in the summary table for the OS 
analysis, and the patient level data will be included in the data listing described in Section 45.  


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8. 
EFFICACY ANALYSIS 
Myelosuppression efficacy will be evaluated based on the data collected during chemotherapy 
period. Myelosuppression endpoints will be analyzed at the first planned analysis (see 
Section 2.1). Selected myelosuppression endpoints will be analyzed at intermediate and final 
planned analyses, unless otherwise specified.  
Treatment effects on PFS and OS will be evaluated based on the estimated number of events and 
will not be limited by which study phase that the event was observed (e.g., in chemotherapy 
period, maintenance period, or survival follow-up period). When the number of events as 
specified in Sample Size Consideration (Section 1.3) are observed for PFS, data snapshot will be 
used to support the analyses of PFS and selected OS (see Section 15). Due to study termination 
prior to reaching the specified number of deaths (see Sections 2.3 and 2.4), the timing of final OS 
analysis is no longer contingent upon the number of deaths and will occur shortly after database 
lock (DBL).  
8.1. 
Definitions of Efficacy Endpoints 
8.1.1. 
Primary Efficacy Endpoint – Progression-Free Survival during the Study 
Progressive disease (PD) and tumor response status are programmatically determined according 
to RECIST v1.1 based on the radiographic tumor measurements recorded on the eCRF by the 
Investigator for target lesions, the investigator assessment of non-target lesions, and the status of 
new lesions. For a patient, the status of PD will be determined using all radiographic tumor scan 
data assessed prior to or on the date of the data cutoff to conduct the analysis for PFS. In the 
situation where PD and withdrawal of consent, or PD and initiation of subsequent anticancer 
therapy, occurred on the same day for a patient, the PD status will be assumed for that patient. 
When applying RECIST v1.1, study baseline tumor assessment will be used. 
PD and death due to any cause are referred to as PFS events. The PFS events during the study are 
cumulative and not limited to a specific treatment phase (chemotherapy, maintenance, or survival 
follow-up).  
PFS is defined as the time (months) from date of randomization to the date of the first 
documented disease progression, or death in the absence of PD for those who had a PFS event, 
and the time from randomization to the censoring date for those who did not have a PFS event. 
Specifically, PFS is calculated as (date of PFS event or censoring – date of randomization + 1)/ 
30.4375. 
If a patient undergoes a palliative surgery/radiotherapy or a curative intent surgical procedure 
that impacts RECIST evaluation of one or more target lesions, then the patient will be censored 
on the last adequate radiologic assessment prior to the date of the surgery/radiotherapy.       
Details for PFS calculation and censoring rules can be found in Table 5.  
Table 5: 
Calculation of PFS during the Study and Censoring Rules 
Situation 
Date of Event or Censoring 
Outcome 
Disease progression per 
RECIST v1.1 
Date of the first documented progression 
PFS event 


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Death without a PD 
Date of death 
PFS event 
Incomplete or no baseline 
tumor assessments 
Date of randomization 
Censored 
Lacking information beyond 
randomization 
Date of randomization 
Censored 
No progression 
Date of the last adequate radiological 
tumor assessment with no documented 
disease progression 
Censored 
Subsequent anticancer 
treatment started prior to 
documented disease 
progression 
Date of last adequate radiologic 
assessment prior to the date of initiation 
of subsequent anticancer treatment 
Censored 
Palliative therapy started 
prior to documented disease 
progression 
Date of last adequate radiologic 
assessment prior to the date of initiation 
of palliative therapy 
Censored 
Underwent curative intent 
surgical procedure 
Date of last adequate radiologic 
assessment prior to the date of surgery 
Censored 
8.1.2. 
Secondary Efficacy Endpoints 
8.1.2.1. 
Anti-tumor Efficacy Endpoints 
8.1.2.1.1. Overall Survival during the Study 
OS during the study is defined as the time (months) from the date of randomization to the date of 
death for patients who died in the study regardless of cause, or to the last contact date known to 
be alive for those who survived as of the date of data snapshot for intermediate planned analysis 
or final database lock for final analyses (censored cases). Patients lacking data beyond the date of 
randomization will have their survival time censored at the date of randomization. OS will not be 
censored even if a patient receives subsequent anticancer treatments. 
8.1.2.1.2. Tumor Response and Duration of Objective Response 
The following endpoints will be summarized for the chemotherapy, maintenance and survival 
follow-up periods, and the overall treatment period: 
x Best overall response  
x Objective response rate 
x Duration of objective response (not applicable to chemotherapy period) 
x Disease control rate 
For derivation of these endpoints in the chemotherapy period, tumor scan data collected during 
chemotherapy period will be the basis to classify tumor response status for all patients in the RE 
population. For derivation of these endpoints in the maintenance and survival follow-up period, 
tumor scan data collected during maintenance period and survival follow-up periods will be the 
basis to classify tumor response status for patients in the Maintenance population. For derivation 


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of these endpoints in the overall treatment period, tumor scan data collected during 
chemotherapy, maintenance, and survival follow-up periods will be the basis to classify tumor 
response status for patients in the RE population.  
If a patient has all or some of the following records prior to or on the DCO, the earliest date of 
those will be used to determine the inclusion of tumor scan data for response status derivation: (i) 
radiographic disease progression; (ii) withdrawal of consent to obtain scans; (iii) death; (iv) lost 
to follow-up; (v) initiation of palliative therapy; (vi) initiation of curative intent surgery; or (vii) 
initiation of subsequent anti-cancer therapy.  
8.1.2.1.2.1. Tumor Response Status in Chemotherapy Period and in Overall Treatment 
Period 
At each tumor assessment visit, an overall time point response by Response Evaluation Criteria 
in Solid Tumors (RECIST) v1.1 will be determined programmatically using the measurements 
recorded on the eCRF by the Investigator for target lesions, the Investigator assessment of 
non-target lesions, and records of new lesions. When applying RECIST v1.1, the tumor 
assessment at Screening will be used as the baseline to derive tumor response status in the 
chemotherapy period and overall treatment period.  
Best Overall Response  
BOR categorizes a patient’s tumor response status into one of following mutually exclusive 
categories per RECIST v1.1: Complete Response (CR), Partial Response (PR), Stable Disease 
(SD), Progressive Disease (PD), and Not Evaluable (NE). The minimum duration of stable 
disease must be 5 weeks starting from the date of randomization (the protocol scheduled tumor 
assessments is every 6 weeks ± 1 week in the chemotherapy period, every 8 weeks ± 1 week in 
the maintenance period for up to 1 year from Cycle 1 Day 1, and every 12 weeks ± 1 week 
thereafter). 
Objective Response Rate 
Achieving an objective response for a patient is defined as having a confirmed or unconfirmed 
CR or PR as the BOR. Objective response rate (ORR) is defined as the proportion of the patients 
who achieved objective response.   
Confirmed Objective Response Rate 
Confirmed CR or PR will be derived based on the principles described in RECIST v1.1. In the 
derivation, the minimum interval for confirmation of CR or PR is 4 weeks, and the minimum 
duration of treatment is 5 weeks (the protocol scheduled tumor assessments is every 6 weeks ± 
1 week in the chemotherapy period). Confirmed ORR (confirmed CR or PR) is defined as the 
proportion of the patients who achieved confirmed objective response based on the RE 
population. 
Duration of Objective Response (DOR) 
Duration of Objective Response (DOR) in the overall treatment period is calculated for patients 
who achieved confirmed CR or confirmed PR as the BOR status. It is defined as the time 
(months) from the date when the objective response of CR or PR was first documented to the 
date that radiographic progressive disease is documented, or death, whichever comes first. That 


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is, DOR = (Date of documented disease progression or death – date of first documented 
confirmed CR or PR + 1)/30.4375. Patients who achieved SD, PD, or NE as the BOR status will 
be excluded from this analysis. 
Censored DOR follows the same rules as the censoring rules for PFS (Table 5), except that the 
two scenarios of “Incomplete or no baseline tumor assessments” and “Lacking information 
beyond randomization” do not apply to DOR. 
Disease Control Rate (DCR) 
DCR is defined as the proportion of patients with BOR of confirmed CR, confirmed PR, or SD 
lasting at least 5 weeks. 
8.1.2.1.2.2. Tumor Response Status in Maintenance and Survival Follow-up Periods 
For the derivation of time point responses in the maintenance and survival follow-up periods, the 
last non-missing tumor assessment during chemotherapy period will be used as the baseline to 
derive tumor response status (hereafter referred to as maintenance baseline). 
Patients who entered the maintenance period of the study (also defined as those patients in the 
Maintenance population) will be classified into three mutually exclusive groups based on their 
maintenance baseline tumor assessment status. For Group 1 and Group 2, timepoint tumor 
response status will be derived based on RECIST v1.1 principle with detailed rules as described 
in the following.  
1. For patients with target lesion(s) at maintenance baseline (Group 1), Table 6 will be used 
for assessing time point response. 
2. For patients with non-target lesion(s) only at maintenance baseline (Group 2), Table 7 
will be used for assessing time point response. 
3. For patients with neither target lesions nor non-target lesions (Group 3) at maintenance 
baseline, they will be reported as “No evidence of disease at maintenance baseline” in the 
summary of BOR.  


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Table 6: 
Time Point Response for Maintenance and Survival Follow-up Periods: 
Patients with Target Lesion(s) at Maintenance Baseline 
Target Lesions 
Response 
Non-Target Lesions  
New Lesions 
Overall 
Response 
Change from Maintenance 
baseline to Maintenance post-
baseline 
Response 
CR 
Present Æ Absent* 
CR 
No 
CR 
CR 
Present Æ Present 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
NE 
No 
PR 
PR 
Present Æ Present 
Non-CR/Non-PD/NE 
No 
PR 
SD 
Present Æ Present 
Non-CR/Non-PD/NE 
No 
SD 
NE 
Present Æ Present 
Non-PD 
No 
NE 
PD 
Any 
Any 
Yes or No 
PD 
Any 
Absent Æ Present 
or  Present Æ Unequivocal 
Progression 
PD 
Yes or No 
PD 
Any 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not 
evaluable 
* All non-target lesions need to be absent for a response of CR 
For patients with target lesions and without any non-target lesion at maintenance baseline, if there is neither 
reappearance of any non-target lesion(s) nor any new lesion(s), overall response will be the same as response 
from target lesions. 
 
 
Table 7: 
Time Point Response for Maintenance and Survival Follow-up Periods: 
Patients with Non-target Lesion(s) Only at Maintenance Baseline 
Non-Target Lesions  
New Lesions 
Overall Response 
Change from Maintenance baseline 
to  Maintenance post-baseline 
Response 
Present Æ Absent* 
CR 
No 
CR 
or  Present Æ Present 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Absent Æ Present 
or  Present Æ Unequivocal Progression 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
NE 
NE 
No 
NE 
CR = complete response, PD = progressive disease, and NE = not evaluable 
* All non-target lesions need to be absent for a response of CR 
 
 
 


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Best Overall Response  
The BOR status for patients in Group 1 is CR, PR, SD, PD, or NE. The minimum duration of 
stable disease must be 7 weeks starting from the first dose date of study drug in the maintenance 
period. The reason for using 7 weeks is that the protocol scheduled tumor assessments is every 8 
weeks ± 1 week in the maintenance period for up to 1 year from Cycle 1 Day 1 and every 12 
weeks ± 1 week thereafter. For patients in Group 2 the BOR status is CR, Non-CR/Non-PD, PD, 
or NE. Patients in the same BOR category (CR, PD, or NE) from Group 1 and Group 2 will be 
combined and summarized. 
In summary, BOR in Maintenance and Survival Follow-up periods categorizes all patients who 
entered the Maintenance period into the following mutually exclusive categories: CR, PR, SD, 
Non-CR/Non-PD, PD, No evidence of disease at maintenance baseline, and NE.  
Objective Response Rate 
Achieving an objective response for a patient is defined as having a confirmed or unconfirmed 
CR or PR as the BOR. Objective response rate (ORR) is defined as the proportion of the patients 
who achieved objective response.   
Confirmed Objective Response Rate 
Confirmed CR or PR will be derived based on the principle described in RECIST v1.1. In the 
derivation, the minimum interval for confirmation of CR or PR is 4 weeks, and the minimum 
duration of maintenance treatment is 7 weeks (the protocol scheduled tumor assessments is every 
8 weeks ± 1 week in the maintenance period for up to 1 year from Cycle 1 Day 1, and every 12 
weeks ± 1 week thereafter). Confirmed ORR (confirmed CR or PR) is defined as the proportion 
of the patients who achieved confirmed objective response based on the Maintenance population. 
Duration of Objective Response (DOR) 
Duration of Objective Response (DOR) in the maintenance and survival follow-up periods is 
calculated for patients who achieved confirmed CR or confirmed PR as the BOR status in the 
maintenance and survival follow-up periods. It is defined as the time (months) from the date 
when the objective response of confirmed CR or PR was first documented to the date that 
radiographic progressive disease is documented, or death, whichever comes first. That is, DOR = 
(Date of documented disease progression or death – date of first documented CR or PR + 
1)/30.4375. Only patients who achieved confirmed CR or confirmed PR as their BOR status in 
this reporting period will be included in this analysis. 
Censored DOR follows the same rules as the censoring rules for PFS (Table 5), except that the 
two scenarios of “Incomplete or no baseline tumor assessments” and “Lacking information 
beyond randomization” do not apply to DOR. 
Disease Control Rate (DCR) 
DCR is defined as the proportion of patients with BOR of confirmed CR, confirmed PR, SD, or 
Non-CR/Non-PD. 


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8.1.2.1.3. Progression-free Survival and Overall Survival in the Maintenance and Survival 
Follow-up Periods  
Both PFS and OS in the maintenance and survival follow-up periods are calculated for patients 
in the Maintenance population.  
PD events in Groups 1 and 2 will be determined by rules specified in Table 6 and Table 7 in 
Section 8.1.2.1.2.2, respectively. For patients in Group 3, the appearance of any lesion(s) as 
recorded on either target lesion CRF, non-target lesion CRF, or new lesion CRF from any tumor 
assessments conducted in maintenance or survival follow-up period will be considered as a PD. 
PFS in the maintenance and survival follow-up periods is defined as the time (months) from date 
of first dose of study drug in maintenance period to the date of the first documented disease 
progression or death in the absence of PD for those who had a PFS event during maintenance or 
survival follow-up period. For those who do not have any PFS event, PFS was censored.  
Specifically, PFS in the maintenance and survival follow-up periods is calculated as (date of PFS 
event or censoring – date of first dose of study drug in maintenance period + 1)/ 30.4375. Details 
for PFS calculation and censoring rules can be found in Table 8.  
Table 8: 
Calculation of PFS in the Maintenance and Survival Follow-up Periods and 
Censoring Rules 
Situation 
Date of Event or Censoring 
Outcome 
Disease progression per 
RECIST v 1.1 
Date of the first documented progression 
PFS event 
Death without a PD 
Date of death 
PFS event 
Incomplete or no tumor 
assessments at maintenance 
baseline 
Date of first dose of study drug in 
maintenance period 
Censored 
Lacking information beyond 
start of maintenance period 
Date of first dose of study drug in 
maintenance period 
Censored 
No progression 
Date of the last adequate radiological 
tumor assessment with no documented 
disease progression 
Censored 
Subsequent anticancer 
treatment started prior to 
documented disease 
progression 
Date of last adequate radiologic 
assessment prior to the date of initiation 
of subsequent anticancer treatment 
Censored 
Palliative therapy started 
prior to documented disease 
progression 
Date of last adequate radiologic 
assessment prior to the date of initiation 
of palliative therapy 
Censored 
Underwent curative intent 
surgical procedure 
Date of last adequate radiologic 
assessment prior to the date of surgery 
Censored 
 
OS in the maintenance and survival follow-up periods is defined as the time (months) from the 
date of first dose of study drug in maintenance period to the date of death for patients who died 


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in the Maintenance or Survival Follow up period regardless of cause, or to the last contact date 
known to be alive for those who survived as of the date for final database lock (censored cases).  
8.1.2.2. 
Myelosuppression Efficacy Endpoints 
Myelosuppression endpoints that are defined to assess trilaciclib’s effect on multiple lineage 
protection in chemotherapy period are described in Table 9 by lineage (i.e., neutrophils, red 
blood cells [RBCs] and platelets). Endpoints that evaluate trilaciclib’s impact on administration 
of current standard of care interventions to treat chemotherapy-induced myelosuppression 
(CIM), as well as to evaluate trilaciclib’s impact on chemotherapy delivery in chemotherapy 
period and hospitalizations due to CIM are also described in Table 9.  
All endpoints related to neutrophils, RBC, platelet, and lymphocyte will be derived from 
laboratory parameters. Unless otherwise specified, all endpoints described in Table 9 are derived 
based on data collected through scheduled and unscheduled visits during chemotherapy period. 
Table 9: 
Myelosuppression Endpoints 
Lineage  
Endpoint 
Type of 
Variable 
Conducted  
in first 
planned 
analysis 
Neutrophils 
Duration of Severe Neutropenia in Cycle 1 
Continuous 
Yes 
Occurrence of severe neutropenia 
Binary 
Yes 
Number of cycles with severe neutropenia 
Counting 
Yes 
Occurrence of febrile neutropenia 
Binary 
Yes 
Occurrence of G-CSF administration 
Binary 
Yes 
Number of cycles with G-CSF administrations (event rate per 
100 cycles) 
Counting 
Yes 
Occurrence of Grade 3 or 4 neutropenia 
Binary 
Yes 
RBCs 
Occurrence of Grade 3 or 4 decreased hemoglobin  
Binary 
Yes 
Occurrence of RBC transfusion on/after Week 5 
Binary 
Yes 
Number of RBC transfusions on/after Week 5 (event rate per 
100 weeks) 
Counting 
Yes 
Occurrence of ESA administration 
Binary 
Yes 
Platelets  
Occurrence of Grade 3 or 4 decreased platelet counts 
Binary 
Yes 
Occurrence of platelet transfusion 
Binary 
Yes 
Number of platelet transfusions (event rate per 100 weeks) 
Counting 
Yes 
Chemotherapy 
Modifications 
Occurrence of chemotherapy dose reduction (all causes) 
Binary 
Yes 
Number of chemotherapy dose reductions (event rate per 100 
cycles) 
Counting 
Yes 
Occurrence of cycle delay due to hematologic toxicity  
Binary 
Yes 
Number of cycle delays due to hematologic toxicity (event rate 
per 100 cycles) 
Counting 
Yes 
ESA=erythropoiesis-stimulating agent; G-CSF=granulocyte colony stimulating factor; RBC=red blood cell; CIM= 
chemotherapy-induced myelosuppression 


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8.1.2.2.1.1. Neutrophil-Related Endpoints 
Duration of Severe Neutropenia in Cycle 1  
In Cycle 1, hematology laboratory parameters, including absolute neutrophil count (ANC), will 
be collected at Day 1 (prior to dosing), Days 1, 2,  8, 13, 17, and at the End of Cycle 1 (Day 1 
pre-dose of Cycle 2) (See Table 3 in Section 4.3 for End of cycle definition). These ANC 
assessments along with unscheduled assessments obtained in Cycle 1, if they exist, will be used 
to calculate the DSN.  
Severe neutropenia (SN) is defined as an ANC value < 0.5 × 109/L (Grade 4 neutropenia per 
National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] 
criteria, Version 5.0).  
For patients with at least one SN event in Cycle 1, the following rules will be applied to calculate 
DSN (Days) in Cycle 1. 
x For patients whose SN is resolved within Cycle 1 (defined as an ANC value ≥ 0.5 × 
109/L at a date after the initial SN occurrence, and maintained until the end of 
Cycle 1), DSN in Cycle 1 will be derived as the number of days from the date of the 
first SN occurrence to the date of SN resolution.  
x For patients who withdraw from the study during Cycle 1 with unresolved 
neutropenia, DSN in Cycle 1 will be derived as the total number of days from the date 
of the first SN occurrence to the date of withdrawal or the date of last contact in 
Cycle 1.  
For patients without any SN in Cycle 1 or those who randomized but who did not receive any 
study drug, DSN will be set to 0. Actual ANC assessment dates rather than visit dates are used in 
the calculation of DSN in Cycle 1.  
DSN is a continuous random variable but is not normally distributed given that a proportion of 
the values are set as 0 per definition described above.  
Occurrence of Severe Neutropenia 
Occurrence of SN during chemotherapy period (also referred to as occurrence of SN in the SAP) 
for a patient is defined as having as least one ANC value < 0.5 × 109/L among all ANC 
measurements during chemotherapy period regardless of scheduled or unscheduled visits. 
Occurrence of SN is a binary random variable (Yes or No).  
Number of Cycles with Severe Neutropenia 
The number of cycles with SN in chemotherapy period for a patient is the total number of cycles 
in chemotherapy period where the patient had at least one SN event. For patients who did not 
have any SN event during chemotherapy period and those who were randomized but did not 
receive any study treatment, the value of 0 will be assigned. Number of cycles with SN is a 
counting random variable and the summary statistics for this variable is event rate per 100 
cycles. 
Occurrence of Febrile Neutropenia 


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Febrile neutropenia (FN) is an AE as reported by the Investigator and captured in the eCRF. A 
PT of FEBRILE NEUTROPENIA is used to identify a FN event. The occurrence of FN for a 
patient is defined as having at least one FN event in chemotherapy period and is a binary random 
variable (Yes or No). 
Occurrence and Number of Granulocyte Colony Stimulating Factor (G-CSF) Administrations 
Administration of G-CSF is collected throughout chemotherapy period. Cycles where G-CSF 
was administered will be identified by comparing the start and stop dates of each administration 
of G-CSF to cycle interval. If any of the time intervals in which G-CSF was administered 
overlapped with any dates between the start of a cycle and the end of the cycle, that cycle will be 
considered as having a G-CSF administration. Data handling conventions for missing start and 
stop dates are described in Section 5.4. 
The occurrence of G-CSF administration during chemotherapy period for a patient is defined as 
having at least one cycle in which G-CSF was administrated for the patient during chemotherapy 
period. It is a binary random variable (Yes or No).  
The number of cycles with G-CSF administrations in chemotherapy period for a patient is the 
total number cycles in chemotherapy period where the patient received at least one dose of G-
CSF. If a dose of G-CSF was administrated on Day 1 of Cycle X (> 1), the following counting 
rules will apply:  
x If the stop date was on Cycle X Day 1 and the start date was in the middle of Cycle X-1 
or on Cycle X Day 1, an occurrence will be counted for Cycle X – 1 only. It was assumed 
that the triggering event has occurred in Cycle X-1. 
x If the start date was on Cycle X Day 1 and stop date was in the middle of Cycle X, both 
Cycle X and Cycle X – 1 will be considered as having G-CSF administered. It was 
assumed that the triggering event has occurred in Cycle X-1, therefore, Cycle X-1 would 
be counted as an additional cycle in which G-CSF is administered. 
For patients who did not have any G-CSF use during chemotherapy period and those who were 
randomized but did not receive any study treatment, the value of 0 will be assigned. Number of 
cycles with G-CSF administrations is a counting random variable and the summary statistics for 
this variable is event rate per 100 cycles. 
Occurrence of Grade 3 or 4 Neutropenia 
Occurrence of Grade 3 or 4 neutropenia during chemotherapy period for a patient is defined as 
having as least one ANC value < 1.0 × 109/L among all ANC measurements during 
chemotherapy period regardless of scheduled or unscheduled visits. Occurrence of SN is a binary 
random variable (Yes or No). 
8.1.2.2.1.2. RBC-Related Endpoints 
Occurrence of Grade 3 or 4 Decreased Hemoglobin  
Occurrence of Grade 3 or 4 decreased hemoglobin (Hgb) in chemotherapy period for a patient is 
defined as having at least one Hgb value that was < 8.0 g/dL among all scheduled or unscheduled 
assessments during chemotherapy period. It is a binary random variable (Yes or No).  


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Occurrence and Number of RBC Transfusion on/after Week 5 
These two endpoints will be derived for those patients who had more than 4 weeks of study drug 
exposure during chemotherapy period. 
Occurrence of RBC transfusions on/after Week 5 for a patient is defined as having at least one 
RBC transfusion on or after Week 5 (following Day 1 of Cycle 1) during chemotherapy period. 
Occurrence of RBC transfusions on/after Week 5 is a binary random variable (Yes or No). 
The number of RBC transfusions on/after Week 5 for a patient is defined as the total number of 
RBC transfusions the patient had on/after Week 5 during chemotherapy period. Transfusions 
with a unique start date were counted as different events. For patients who did not have any RBC 
transfusion on/after Week 5 in chemotherapy period and those who were randomized but did not 
receive any study treatment, a value of 0 will be assigned. Number of RBC transfusions on/after 
Week 5 is a counting random variable and the summary statistics for this variable is event rate 
per 100 weeks. 
Occurrence of Erythropoiesis-Stimulating Agent (ESA) Administration 
Administration of ESA is collected throughout chemotherapy period. Cycles where ESA was 
administered will be identified by comparing the start and stop dates of each administration of 
ESA to cycle interval. If any of the time interval in which ESA was administered overlapped 
with any dates between the start of a cycle and the end of the cycle, that cycle will be considered 
as having an ESA administered. Data handling conventions for missing start and stop dates are 
described in Section 5.4. 
The occurrence of ESA administration during chemotherapy period for a patient is defined as 
having at least one cycle in which ESA was administrated for the patient during chemotherapy 
period. It is a binary random variable (Yes or No). 
8.1.2.2.1.3. Platelet-Related Endpoints 
Occurrence of Grade 3 or 4 Decreased Platelet Counts 
Occurrence of Grade 3 or 4 decreased platelet counts for a patient is defined as having at least 
one platelet count value that was < 50.0 x 109/L among all scheduled or unscheduled assessments 
during chemotherapy period. Occurrence of Grade 3 or 4 decreased platelet counts is a binary 
random variable (Yes or No). 
Occurrence and Number of Platelet Transfusions 
Occurrence of platelet transfusion for a patient is defined as having at least one platelet 
transfusion during chemotherapy period. It is a binary random variable (Yes or No). 
The number of platelet transfusions for a patient is defined as the total number of platelet 
transfusions the patient had during chemotherapy period. Transfusions with a unique start date 
during chemotherapy period were counted as different events. For patients who did not have any 
platelet transfusion in chemotherapy period and those who were randomized but did not receive 
any study treatment, the value of 0 will be assigned. Number of platelet transfusions is a 
counting random variable and the summary statistics for this variable is event rate per 100 
weeks. 


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8.1.2.2.1.4. Chemotherapy Modifications 
Occurrence and Number of Chemotherapy Dose Reduction  
The occurrence of a chemotherapy dose reduction for a patient is defined as having at least one 
dose reduction in a cycle during chemotherapy period (regardless of which chemotherapy). 
Chemotherapies that allow dose reduction and the maximum number of reductions in 
chemotherapy period can be found in Section 7.2. Occurrence of chemotherapy dose reduction is 
a binary random variable (Yes or No). 
Number of chemotherapy dose reductions for a patient is defined as the total number of 
chemotherapy dose reductions across 3 chemotherapies (Gemcitabine, Cisplatin, and 
Carboplatin), for which dose reduction was allowed per protocol during chemotherapy period.  
In addition, chemotherapy that was stopped due to toxicity will also be counted as one dose 
reduction event. The value of 0 will be assigned to those patients who did not have any 
chemotherapy dose reductions during chemotherapy period and those who were randomized but 
did not receive any study treatment. Number of chemotherapy dose reductions is a counting 
random variable and the summary statistics for this variable is event rate per 100 cycles. 
Occurrence and Number of Cycle Delays Due to Hematologic Toxicity 
Occurrence of cycle delays and the associated reason is collected in detail in the eCRF with the 
following mutually exclusive categories: low neutrophil count, low platelet count, both low 
neutrophil count and low platelet count, Other hematologic toxicity, Non-hematologic toxicity, 
or Other. A cycle delay is considered due to hematologic toxicity, if the associated reason is “low 
neutrophil count”, “low platelet count”, “both low neutrophil count and low platelet count”, or 
“Other hematologic toxicity”.  
Occurrence of cycle delays due to hematologic toxicity for a patient is defined as having at least 
one cycle delay due to hematologic toxicity during chemotherapy period and is a binary random 
variable (Yes or No). The number of cycle delays due to hematologic toxicity for a patient is 
defined as the total number of cycles that were delayed due to hematologic toxicity for the 
patient during chemotherapy period. For patients who did not have any cycle delays due to 
hematologic toxicity in chemotherapy period and those who were randomized but did not receive 
any study treatment, the value of 0 will be assigned. Number of cycle delays due to hematologic 
toxicity is a counting random variable and the summary statistics for this variable is event rate 
per 100 cycles. 
8.2. 
Statistical Analysis Methods  
8.2.1. 
General Considerations for Efficacy Analysis 
Unless otherwise specified, all efficacy analyses will be performed on the ITT population. 
Unless otherwise specified, the treatment effect on myelosuppression endpoints will be evaluated 
based on the data collected during chemotherapy period. Treatment effect on PFS and OS will be 
evaluated based on the number of events as stated in Section 1.3 and will not be limited to 
treatment phase (e.g., chemotherapy period, maintenance period, or Survival Follow-Up). 
Stratification Factors and Factored to be Included in Statistical Models for Analysis 


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There will be two stratification factors for randomization: presence of visceral metastasis (yes or 
no) at randomization and initial platinum-based chemotherapy to be administered (cisplatin or 
carboplatin). Presence of visceral metastasis will be abbreviated as “Visceral Metastasis” and 
initial platinum-based chemotherapy to be administered will be abbreviated as “Chemo Type” 
hereafter.  
It is anticipated that both stratification factors will have an impact on patients’ anti-tumor 
efficacy outcome, but only Chemo Type will have an impact on myelosuppression efficacy. 
Therefore, Chemo Type will be included as the factors in statistical analysis models evaluating 
trilaciclib’s effect of myeloprotection, while both stratification factors will be included in the 
statistical analysis models to assess trilaciclib’s anti-tumor efficacy. Unless otherwise specified, 
the strata information as entered in IWRS at the time of randomization will be used as the factors 
for all stratified statistical analyses. 
Family-wise Type 1 Error Rate Control and Nominal P-values 
As described in the protocol and further detailed in the sections below, the family-wise Type 1 
error rate of 2-sided 0.2 is only applied for the primary endpoint. For secondary efficacy 
endpoints, nominal p-value and 95% CI will be generated as the reference for judging strength of 
the evidence and the precision of point estimation.  
8.2.2. 
Analysis for Primary Efficacy Endpoint – Progression-Free Survival during the 
Study 
8.2.2.1. 
Primary Analysis  
The analysis for PFS during the study will be performed when 63 PFS events are obtained. It will 
also be conducted at the final analysis of the study.  
For PFS, the number and percentage of patients with a PFS event (radiographic disease 
progression or died due to any cause) or censored will be summarized by treatment group along 
with the reasons for censoring. Furthermore, the number and percentage of patients with disease 
progression or who died due to any cause will be summarized by treatment group with the 
number of PFS events as the denominator for percentage calculation.  
The treatment effect for PFS will be primarily evaluated using a stratified log-rank test 
accounting for the two stratification factors. The magnitude of treatment effect, HR (Arm B vs. 
Arm A) along with its 80% CI will be estimated using a Cox proportional hazard model 
controlling for the same factors as included in the stratified log-rank test.  
For each treatment group, the Kaplan-Meier plots will be generated 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). Additionally, Kaplan-Meier estimates will be provided for the survival 
probability along with their 95% confidence intervals (Kalbfleisch, 1980) at selected landmarks 
of 12, 24, 36, and 48 months. 
8.2.3. 
Analysis for Secondary Endpoint - Overall Survival during the Study 
The analysis for OS during the study will be performed at two timepoints: 


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1. When the intermediate planned PFS analysis is conducted, i.e., when 63 PFS events have 
occurred.  
2. At the final analysis when approximately 60% randomized patients have died (i.e., 54 
deaths), which will trigger the lock of study database to perform all SAP specified 
analyses. 
Due to study termination prior to reaching the specified number of deaths (see Sections 2.3 and 
2.4), the timing of final OS analysis specified in point 2 above is no longer contingent upon the 
number of deaths and will occur shortly after database lock (DBL). 
For OS, the number and percentage of patients who died or are censored will be summarized by 
treatment group. In addition, duration of total follow-up will also be summarized by treatment 
group. 
The treatment effect for OS will be primarily evaluated using a stratified log-rank test accounting 
for the two stratification factors. The magnitude of treatment effect, HR (Arm B vs. Arm A) 
along with its 80% CI will be estimated using a Cox proportional hazard model controlling for 
the same factors as included in the stratified log-rank test.  
For each treatment group, 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). 
Additionally, Kaplan-Meier estimates will be provided for the survival probability along with 
their 95% confidence intervals (Kalbfleisch, 1980) at selected landmarks of 12, 16, 24, 36, and 
48 months. 
8.2.4. 
Analysis for Secondary Endpoints - Other Anti-tumor Efficacy Endpoints 
The analysis for BOR, ORR, DCR, and DOR (see variable definitions in Section 8.1.2.1.2) for 
both chemotherapy period and overall treatment period will be based on the RE population. The 
analysis of these endpoints for maintenance and survival follow-up periods will be based on the 
Maintenance RE population and it will be conducted at following timepoints:  
1. At the first planned analysis  
2. At the time of PFS analysis 
Tumor response status classified by BOR will be tabulated by treatment group with the number 
and percentage of patients in each response category, where the percentages are calculated based 
on the number of patients in the population for the respective period.  
ORR and DCR, along with their exact 95% two-sided CIs using the Clopper-Pearson method 
will be computed for each treatment group. The treatment effect on ORR and DCR will be 
evaluated using a Cochran–Mantel–Haenszel (CMH) test accounting for the stratification factors. 
The adjusted proportion difference (Arm B vs. Arm A) and its 95% CI will be calculated using 
CMH weight (as described in Kim, 2013). 
For patients who achieved confirmed CR or confirmed PR as BOR status, DOR will be analyzed. 
The Kaplan-Meier method will be used to estimate the median, 25% and 75% percentile of DOR 


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for each treatment group, along with its 95% CI calculated using the method by Brookmeyer and 
Crowley (1982).  
8.2.5. 
Analysis for Secondary Endpoints – Progression-free Survival and Overall 
Survival in the Maintenance and Survival Follow-up Periods 
Analysis of PFS in the maintenance and survival Follow-up periods and OS in the Maintenance 
Period will be performed at the final analysis. 
PFS in the maintenance and survival follow-up periods will be analyzed using the same methods 
as used for the primary analysis of PFS during the study.  
OS in the maintenance and survival follow-up periods will be analyzed using the same methods 
as used for the analysis of OS during the study. 
8.2.6. 
Analysis for Secondary Endpoints - Myelosuppression Endpoints 
Statistical analysis methods for myelosuppression endpoints derived based on data collected in 
chemotherapy period (Section Error! Reference source not found.) are described in this 
section. The analysis of myelosuppression endpoints will be based on the ITT population and 
performed for the first planned (see the selected list in Table 9), intermediate planned (selected 
endpoints), and final analyses (selected endpoints). Corresponding data listings will be provided.  
8.2.6.1. 
Analysis for Duration of Severe Neutropenia 
Treatment effect on DSN in Cycle 1 will be evaluated using nonparametric analysis of 
covariance (ANCOVA) (Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for 
Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383(13):1218-30. 
Quade 1967). In this analysis, the rank-transformed (within each stratum) DSN values will be 
analyzed by an ANCOVA model with the terms of treatment and Chemo Type. Rank-
transformed baseline ANC (within each stratum) will be included as a covariate in the model. In 
addition, the group-difference in DSN in Cycle 1 (trilaciclib/SOC – SOC), its standard error and 
95% CI will be generated and reported from a Satterthwaite t-test and presented.  
8.2.6.2. 
Analysis for Binary Myelosuppression Endpoints 
For each binary myelosuppression endpoint as specified in Table 9 in Section 8.1.2.1.2.1, the 
number and percentage of patients with at least one occurrence during chemotherapy period will 
be summarized by treatment group.  
The treatment effect will be evaluated using a modified Poisson regression model (Zou, 2004). 
The model includes the factors of treatment and Chemo Type as the fixed effect and 
corresponding baseline value as a covariate when applicable. The variable duration of 
chemotherapy period among patients will be adjusted by using the log-transformed duration of 
chemotherapy period (in the unit of cycles or weeks) as the offset variable in the model. A 2-
sided p-value, adjusted relative risk (aRR, Arm B vs. Arm A) and its 95% CI will be generated 
from the modified Poisson regression model and reported.  
Baseline value to be used as a covariate in the model is determined by the lineage of the endpoint 
(Table 9 in Section 8.1.2.1.2.1) and they are paired in the following manner: baseline ANC for 


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neutrophil-related endpoints, baseline hemoglobin for RBC-related endpoints, and baseline 
platelet for platelet-related endpoints.  
The duration of chemotherapy period that is used to construct an offset variable in the model is 
the number of cycles in chemotherapy period for all binary endpoints but two: occurrence of 
RBC transfusion on/after Week 5 and occurrence of platelet transfusion. For these two 
endpoints, the total number of weeks in chemotherapy period that is the same as the duration of 
study drug exposure in chemotherapy period (defined in Table 3, Section 4.3) will be used as the 
duration variable.  
8.2.6.3. 
Analysis for Counting Myelosuppression Endpoints 
For the counting myelosuppression endpoints as specified in Table 9 (Section 8.1.2.1.2.1), the 
total number of the events, the duration of chemotherapy period (in the unit of cycles or weeks), 
and raw event rate per 100 units (weeks or cycles) will be summarized by treatment group.   
The treatment group difference in the event rate will be assessed by a negative binomial model. 
The model includes the treatment and Chemo Type as the fixed effect and corresponding 
baseline value as a covariate when applicable. The various duration among patients will be 
adjusted in assessing treatment effect by using the log-transformed duration of chemotherapy 
period as the offset variable in the model. A 2-sided p-value, aRR (Arm B vs. Arm A) and its 
95% CI will be generated from the negative binomial model and reported. 
Baseline value to be used as a covariate in the model is determined by the lineage of the endpoint 
(Table 9 in Section 8.1.2.1.2.1) and they are paired in the following manner: baseline ANC for 
neutrophil-related endpoint, baseline hemoglobin for RBC-related endpoints, and baseline 
platelet for platelet-related endpoints.  
The duration of chemotherapy period (used to calculate the raw event rate and to construct an 
offset variable in the model) is the number of cycles in chemotherapy period for the endpoints of 
number of G-CSF administrations and number of dose reductions, and it is the number of weeks 
in chemotherapy period for the two other counting random variables: number of RBC 
transfusions on/after Week 5 and number of platelet transfusions. The total number of weeks in 
chemotherapy period is the same as the duration of study drug exposure in chemotherapy period, 
which is defined in Table 3 (Section 4.3).  
8.3. 
Handling of Missing Data 
Unless otherwise specified, all efficacy data will be evaluated as reported and no imputation of 
missing values will be done. Impact of missing data on efficacy endpoints are in general 
managed by derivation rules (Section 8.1).  
8.4. 
Subgroup Analysis 
Subgroup analysis for the primary efficacy endpoint PFS will be performed at the intermediate 
planned analysis for PFS.  


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8.4.1. 
Subgroup Analysis for PFS 
The following subgroups have been identified to assess whether treatment effect on PFS is 
consistent for each of the identified subgroups.  
1. Age group (< 65 or ≥ 65) 
2. Gender (male or female) 
3. Baseline ECOG Status (0 or 1) 
4. Region (US, Western Europe, or Eastern Europe) 
5. Visceral metastasis (yes or no) 
6. Chemo Type (cisplatin or carboplatin)  
7. PD-L1 status (positive or negative) 
Within each stratum of Age group, Gender, and ECOG, a Cox proportional hazard model with 
the terms of treatment, Visceral metastasis, and Chemo Type will be used to estimate the HR 
(Arm B vs. Arm A) and its 95% CI for PFS. Treatment-by-subgroup interaction will be tested by 
a different Cox model based on the ITT population with additional terms of the subgroup and the 
treatment-by-subgroup interaction. Statistically significant interaction is judged by an interaction 
p-value that is < 0.25. 
To generate HR and its 95% CI within each stratum for the subgroup that is used as the 
stratification factors, Visceral metastasis or Chemo Type, the same factor will be eliminated 
from the Cox model to estimate the HR and its 95% CI. Treatment-by-subgroup interaction for 
these subgroups will not be tested, since these two were chosen as randomization stratification 
factors because of the anticipated impact on the outcome of PFS. 
 


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9. 
SAFETY ANALYSIS 
9.1. 
General Consideration of Safety Analysis 
Safety data summaries will be based on the Safety Population as defined in Section 3.3 of this 
SAP. The main purpose of safety analysis is to assess the safety and tolerability of trilaciclib in 
patients receiving platinum-based chemotherapy followed by avelumab maintenance therapy. 
This can be broken down to evaluate the safety of trilaciclib when added on to chemotherapy and 
the safety of trilaciclib when added on to maintenance therapy of avelumab. The safety of 
trilaciclib when added on to chemotherapy can be further evaluated by the type of platinum used 
in chemotherapy: safety of trilaciclib when added on to cisplatin-based chemotherapy and safety 
of trilaciclib when added on to carboplatin-based chemotherapy. 
Unless otherwise specified, safety data collected in chemotherapy period and maintenance period 
will be summarized separately. For the chemotherapy period, safety data will be tabulated for the 
comparison of the following treatment groups:  
1. Trilaciclib + Chemo vs Chemo 
2. Trilaciclib + Gemcitabine/Cisplatin vs Gemcitabine/Cisplatin 
3. Trilaciclib + Gemcitabine/Carboplatin vs Gemcitabine/Carboplatin 
For the maintenance period, safety data will be tabulated for the Avelumab and Trilaciclib + 
Avelumab treatment groups. The scheme of table layouts has been defined in Table 2:
 
Descriptions of Treatment Groups in Protocol, SAP, and Their Orders of Appearance in 
Table/Listing/Figures. 
At the time of first planned and final analysis, all safety data collected during the study will be 
summarized. Safety variable definitions and the data analysis plan as described in this section 
will be applied to both analyses unless otherwise specified. As such, the phrase of “during the 
treatment period” refers to the respective analysis period of interest.  
Safety data will be summarized using descriptive statistics by treatment group and for overall 
patients when appropriate. No inferential statistical comparisons for between-group differences 
will be made. All safety data collected through scheduled or non-scheduled visits from Day 1 of 
Cycle 1 to the safety follow-up visit will be included in the safety data analyses. Missing safety 
data will generally not be imputed, unless otherwise specified.  
Baseline assessment is, in general, defined as the last non-missing observation prior to receiving 
the first dose of any study drug.  
9.2. 
Adverse Events  
9.2.1. 
Definition and Classification of Adverse Events 
AEs are defined as those AEs occurring on or worsening in severity after the first dose of any 
study drug (i.e., the conventional treatment-emergent AEs). Only AEs as described above are 
collected in the study database. For patients not in the Maintenance population, all AEs will be 
reported since the first dose of any study drug until 30 days after the last dose of study drug and 


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they will be reported for the chemotherapy period and overall treatment period. For patients in 
the Maintenance population, all AEs will be reported for the overall treatment period since the 
first dose of any study drug until 90 days after the last dose date during maintenance period. All 
AEs that start from the first dose of any study drug to end of last chemotherapy cycle will be 
reported for the chemotherapy period. All AEs that start from the first dose of any maintenance 
study drug to the last dose date during maintenance period will be reported for the maintenance 
period. Serious adverse events (SAEs) thought to be related to a study specific procedure are also 
collected between the time the patient signs the informed consent and the first dose of any study 
drug.  
AEs will be coded from verbatim text to PT and grouped by primary SOC according to 
MedDRA version 25.1 or higher. The severity (toxicity grades 1-5) of AEs will be graded 
according to the NCI CTCAE version 5.0 by the Investigator.  
Trilaciclib Adverse Events of Special Interest 
AEs of special interest (AESI) for trilaciclib have been identified, reflecting either the findings in 
the AEs from the previous studies of trilaciclib or class effects for CDK 4/6 inhibitors. AESI for 
trilaciclib will be identified by searching MedDRA PTs based on the Customized MedDRA 
Queries as detailed in Appendix 2.  
Specifically, trilaciclib AESI include the following 5 categories: 
x Injection site reaction/Phlebitis/Thrombophlebitis 
x Acute drug hypersensitivity reaction 
x Hepatotoxicity 
x Interstitial lung disease/Pneumonitis 
x Embolic and thrombotic events, venous 
9.2.2. 
Imputation Rules for Missing Start or Stop Date for Adverse Events 
AEs with start/stop dates that are partially or completely missing that are not ongoing at the time 
of data cutoff will be imputed according to the specifications below in order to classify AEs. 
For completely missing or partially missing AE start date: 
x If the start date has month and year but day is missing, the first dose date will be used 
if the month and year is the same as the first dose date, otherwise, the first day of the 
month will be used. 
x If the start date has year, but day and month are missing, then the first dose date will 
be used if the year is the same as the first dose date, otherwise January 1st will be 
used. 
x If the start date is completely missing, then it will be imputed as the first dose date of 
study drug. 


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After the imputation, the imputed start date will be compared with AE stop date, if available. If 
the imputed start date is later than the stop date, the start date will be imputed with the stop date 
instead. 
For completely missing or partially missing AE stop dates: 
x If the stop date has month and year but day is missing, the last day of the month will 
be used. 
x If the stop date has year, but day and month are missing, December 31st will be used.  
x If the stop date is completely missing, the date of ETV will be used; if ETV does not 
exist, then the last dose date + 30 days will be used. 
After the imputation, the imputed AE stop date will be compared against the death date for 
patients who died. If the date is later than the death date, the date of death will be used to impute 
the stop date instead. 
Every attempt will be made to obtain complete information for AEs regarding severity 
(i.e., CTCAE Grade) and relationship to drug. However, in the rare case of missing data, the 
following conservative approach will be taken for summary purpose. The non-imputed raw data 
will be presented in AE listings. 
x Missing AE grade will be classified as “Grade 3”  
x Missing AE relationship will be classified as “Related”  
9.2.3. 
Analysis for Adverse Events 
AEs will be summarized by number and percentage of patients having at least one occurrence at 
the PT and SOC level by treatment group and overall. Patients with more than one occurrence of 
the same SOC (PT) will be counted only once within the SOC (PT) categorization. In general, 
the percentage of patients with an event will be calculated using the number of patients in the 
safety population as the denominator either by each treatment group or overall.  
AEs will also be summarized by CTCAE grade and relationship to study drug (to any study 
drugs and to each individual study drug). Should a patient experience more than one occurrence 
of the same SOC (PT), the patient’s worst occurrence (highest grade or highest related causality) 
will be used for the analysis and reporting.  
In AE summaries for chemotherapy period, the SOC and PT within a SOC will be presented in 
descending order based on the incidence from the Trilaciclib + Chemo column. In AE summaries 
for maintenance period, the SOC and PT within a SOC will be presented in descending order 
based on the incidence from the Trilaciclib + Avelumab column. If the incidence for two or more 
PTs is equal, these PTs will be presented in alphabetical order.  
An overall AE summary table will be generated to present general information related to AEs 
including the following categories: number and percentage of patients with any AE, Serious 
AEs, AEs with CTCAE Grade ≥ 3 or 4, AEs leading to discontinuation of any study drug, AEs 
leading to death, AEs related to study drug (to any study drug, to trilaciclib, and to each other 
study drug), and AESI for trilaciclib.  


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At the time of performing final analysis, in addition to generating the overall AE summary table 
for the data collected during the chemotherapy and maintenance period, an overall AE summary 
table will also be generated for the AEs collected during the overall treatment period.  
In addition, the following summary tables will be generated, and they will be, in general, 
presented by SOC and PT unless otherwise specified.   
1. AEs by decreasing frequency of PT 
2. AEs by SOC, PT, and CTCAE Grade 
3. AEs with CTCAE Grade 3 or 4 by PT and CTCAE Grade 
4. AEs leading to discontinuation of any study drug  
5. AEs leading to discontinuation of trilaciclib 
6. AEs leading to death 
7. AEs related to any study drug  
8. AEs related to trilaciclib 
9. Serious AEs 
10. Serious AEs related to any and each study drug  
11. AESI for trilaciclib   
Corresponding AE listings will be provided to clearly indicate, at the patient level, the AE and 
SAE occurrence, start/stop date, relative study days to start or stop, grade and causality for each 
AE. AESI for trilaciclib will also be listed with a similar level of detail.  
9.3. 
Clinical Laboratory Data 
9.3.1. 
Laboratory Parameters 
Blood and urine samples for the determination of clinical chemistry, hematology, and urinalysis 
laboratory variables described in Table 10 will be measured according to Schedule of 
Assessments in Appendix 1. 
Table 10: 
Laboratory Categories and Parameters 
Lab Category 
Lab Parameters 
Chemistry 
albumin, alkaline phosphatase (ALP), total bilirubin, calcium, chloride, creatinine, 
glucose, inorganic phosphorus, potassium, total protein, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), sodium, 
blood urea nitrogen (BUN) 
Hematology 
hemoglobin, white blood cell (WBC), platelet counts, absolute neutrophil count 
(ANC), absolute lymphocyte count (ALC) 
Urinalysis 
semiquantitative dipstick: specific gravity, pH, evaluation of glucose, protein, 
bilirubin, ketones, leukocytes, and hemoglobin microscopic examination, including 


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red blood cell (RBC), white blood cell (WBC), and casts will be performed, if 
necessary 
Lab = laboratory.  
 
Lab data during chemotherapy period are those that were collected during the time interval from 
the first dose of any study drug to the end of last chemotherapy cycle for patients who entered 
maintenance period or last dose date of any study drug + 30 days for patients who did not. Lab 
data during maintenance period are those that were collected during the time interval from the 
first dose of any maintenance study drug to the last dose date during maintenance period + 30 
days.  
For hematology parameters, if absolute counts are not provided, those values will be derived 
from the differential counts by multiplying differential value with leukocyte value from the same 
sample. The normal ranges will be left missing in those cases.  
Clinical chemistry and hematology assessments will be graded according to NCI CTCAE 
criteria, Version 5.0 or later. The determination of CTCAE grade for each measurement will be 
based on the collected laboratory values and will not involve clinical judgement. For laboratory 
parameters that CTCAE toxicity grade are not available, they will not be included in the analyses 
in which toxicity grades are reported. Instead, these parameter results will be classified and 
reported by the low/normal/high based on the laboratory normal reference ranges.  
Abnormal Hepatic Laboratory Values 
Abnormal hepatic laboratory values are defined in the following categories including any 
occurrence among all on-treatment, post-baseline assessments including scheduled and 
unscheduled values.  
x Hy’s Law:  
o Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 
3x the upper limit of normal (ULN), alkaline phosphatase (ALP) < 2xULN, 
and total bilirubin ≥ 2xULN 
o Pre-existing baseline ALT, AST, OR total bilirubin values are above the upper 
limit of normal, and the patient subsequently presents with:  
- 
AST or ALT ≥ 2 times the baseline value and ≥ 3x ULN, or ≥ 8x ULN 
(whichever is smaller) 
- 
Concurrent with total bilirubin ≥ 2 times the baseline value OR ≥ 3x 
ULN (whichever is smaller) 
x AST:  > 3 and ≤ 5x ULN, > 5 and ≤ 8x ULN, > 8 and ≤ 10x ULN, > 10 and ≤ 20x 
ULN, and > 20x ULN; AST > 5x ULN for more than 5 weeks. 
x ALT:  >3 and ≤ 5x ULN, > 5 and ≤ 8x ULN, > 8 and ≤ 10x ULN, > 10 and ≤ 20x 
ULN, and > 20x ULN; ALT > 5x ULN for more than 5 weeks. 
x Total bilirubin > 1.5xULN and < 2xULN, ≥ 2xULN  
 


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9.3.2. 
Analysis for Laboratory Parameters  
Laboratory data from all central and local laboratories will be included in analyses. Different 
laboratories are likely using slightly different normal reference ranges, which should not affect 
the planned analysis since they are all categorical and reported based on CTCAE toxicity grade 
or relationship to the normal ranges. The default convention for reporting of laboratory units will 
be standard international (SI) units. If a lab value is reported using an inequality symbol e.g., less 
than (<) a certain value, or greater than (>) a certain value, the given numeric value will be used 
in the summary. Data will be presented in listings with their inequality symbol.  
For each lab parameter, baseline for the chemotherapy period is defined as the last non-missing 
value prior to, or on the first date of administration of any study drug(s) in the chemotherapy 
period; baseline for maintenance period is defined as the last non-missing value prior to, or on 
the first date of administration of any study drug(s) during maintenance period. In both scenarios, 
baseline assessment must be done prior to the time of study drug administration. 
For each parameter in the clinical chemistry and hematology laboratory groups, CTCAE toxicity 
grading is used to classify patients into a toxicity grade from 1 to 4 for each timepoint 
assessment. The number and percentage of patients with highest grade during the treatment 
period will be summarized for each grade from 1 to 4 and Grade 3-4 by treatment group, along 
with such summary for the value collected at baseline.   
For the laboratory parameters that cannot be classified by CTCAE grade, the number and 
percentage of patients in the categories of treatment-emergent low or treatment-emergent high 
based on the normal reference range associated with the parameter will be summarized by 
treatment group.  
The number and percentage of patients in each category of abnormal hepatic laboratory values 
will be summarized by treatment group. 
Laboratory parameters will be listed by the groups of chemistry, hematology, and urinalysis. In 
the data listing, flags that indicate the corresponding CTCAE grades and the classifications 
relative to the laboratory reference ranges will be included. In addition, a separate listing will be 
prepared for patients who met Hy’s law.  
9.4. 
Vital Signs  
9.4.1. 
Vital Sign Parameters 
Vital signs including heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP), 
weight, height, and body temperature will be measured according to Schedule of Assessments in 
Appendix 1.  
Vital signs during chemotherapy period are those that were collected during the time interval 
from the first dose of any study drug to the end of last chemotherapy cycle. Vital signs during 
maintenance period are those that were collected during the time interval from the first dose of 
any maintenance study drug to end of last maintenance cycle.  
Baseline vital signs for the chemotherapy period is defined as the last non-missing value prior to, 
or on the first date of administration of any study drug(s) in the chemotherapy period; baseline 


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vital signs for maintenance period is defined as the last non-missing value prior to, or on the first 
date of administration of any study drug(s) during maintenance period. In both scenarios, 
baseline assessment must be done prior to the time of study drug administration. 
Post-baseline assessments refer to the measurements taken after the first dose of any study drug 
and during treatment period. Change from baseline to the highest/lowest value across all post-
baseline measurements for each vital sign parameter will be calculated. Patients with a 
non-missing baseline and at least one non-missing measurement post-first dose for a given 
parameter will be included in the calculation.  
Patients are classified with respect to the criteria of potentially clinically significant (PCS) 
findings of vital signs, which are defined by the highest/lowest value among post-baseline 
assessments and/or the change from baseline to the highest/lowest observed value. Details of 
PCS criteria for vital signs can be found in Table 11.  
 
 
Table 11: 
Criteria for Potentially Clinically Significant Vital Signs 
 Parameter   
Direction  
Highest/Lowest Observed 
Value   
Change from Baseline to the 
Highest/Lowest Observed Value 
 SBP   
High 
 
 ≥ 180 mmHg   
 Increase ≥ 40 mmHg   
    
Low 
 
 ≤ 90 mmHg   
 Decrease ≥ 40 mmHg   
 DBP   
High 
 
 ≥ 105 mmHg   
 Increase ≥ 20 mmHg   
    
Low 
 
 ≤ 50 mmHg   
 Decrease ≥ 20 mmHg   
 Heart Rate 
High 
 
 ≥ 120 bpm   
 Increase ≥ 40 bpm   
    
Low 
 
 ≤ 50 bpm   
 Decrease ≥ 40 bpm  
 Weight   
High 
 
--   
 Increase ≥ 10%   
 
Low 
 
 -- 
 Decrease ≥ 10% 
bpm=beats per minute; DBP=diastolic blood pressure; SBP=systolic blood pressure 
9.4.2. 
Analysis for Vital Signs   
Number and percentage of patients who meet any PCS criteria for each vital sign parameter as 
well as for each criterion will be summarized by treatment group.  
All observed vital sign values and PCS flag will be listed. 
9.5. 
ECOG Performance Status  
ECOG performance status was assessed at the Screening Visit and at Day 1 of each treatment 
cycle during the study.  
ECOG status during chemotherapy period are those that were collected during the time interval 
from the first dose of any study drug to the end of last chemotherapy cycle. ECOG status during 


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maintenance period are those that were collected during the time interval from the first dose of 
any maintenance study drug to end of last maintenance cycle.  
Baseline ECOG for the chemotherapy period is defined as the last non-missing value prior to, or 
on the first date of administration of any study drug(s) in the chemotherapy period; baseline 
ECOG for maintenance period is defined as the last non-missing value prior to, or on the first 
date of administration of any study drug(s) during maintenance period. In both scenarios, 
baseline assessment must be done prior to the time of study drug administration. 
9.6. 
12-lead Electrocardiograms 
As ECG is only collected at screening, no analysis will be planned. 
  
 


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10. 
CHANGES FROM THE PROTOCOL 
x The protocol has defined the timing for the first planned analysis as “The first planned 
analysis will be conducted when all randomized patients have either completed 
chemotherapy or discontinued during the chemotherapy period”. This has been changed 
to “The first planned analysis will be conducted when all randomized patients have either 
completed at least 4 cycles of chemotherapy or discontinued during the chemotherapy 
period”. This is because the primary purpose of conducting the first planned analysis was 
to evaluate trilaciclib’s effect on myelosuppression endpoints. It is believed that 4 cycles 
of chemotherapy exposure should be sufficient to perform the evaluation. 
x The protocol listed “occurrence and number of hospitalizations due to chemotherapy-
induced myelosuppression” as an endpoint to assess the effects of trilaciclib on 
hospitalizations due to chemotherapy-induced myelosuppression compared to a control 
group (Protocol Section 5 and Table 4). Due to the early termination of the study (aCSR), 
this endpoint will not be evaluated.  
x The protocol has included the analysis of “Probability of survival at Month 16” as part of 
the intermediate planned analyses (Protocol Section 12.3.2). Due to the early termination 
of the study (aCSR), this analysis will not be conducted (See Section 2.2 and Section 2.4 
for details).  
x The protocol indicated that subsequent anticancer therapies (surgical procedure, 
radiotherapy, and systemic anticancer medication) for the ITT population will be 
summarized by treatment group and overall (Protocol Section 12.4.4). Due to the early 
termination of the study (aCSR), this summary is deemed non-critical and will not be 
provided (See Section 2.4 and Section 6.3). 
x The protocol indicated that for trilaciclib, avelumab, gemcitabine, cisplatin/carboplatin, 
cumulative dose, dose intensity, relative dose, and relative dose intensity will be derived 
and summarized by treatment group (Protocol Section 12.4.5). Due to the early 
termination of the study (aCSR), this summary is deemed non-critical and will not be 
provided (See Section 2.4).    
x To understand the effects of trilaciclib in CDK 4/6-dependent tumors when added to 
platinum-based chemotherapy and avelumab maintenance therapy, the protocol listed a 
summary of number and percentage of patients in different CDK 4/6 biomarker signature 
status (CDK 4/6 independent, CDK 4/6 dependent, and CDK 4/6 indeterminate) and the 
analysis of anti-tumor endpoints (PFS, ORR, and OS) during the overall study by CDK 
4/6 signature status subgroup as an exploratory analysis at the time of final planned 
analysis (Protocol Section 12.4.8). Due to the early termination of the study (aCSR), 
these analyses will not be conducted. 
  
 


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11. 
REFERENCES  
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 
1982;29-41.  
Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. New York: John 
Wiley & Sons. 1980 
Kim Y, Won S. (2013) Adjusted proportion difference and confidence interval in stratified 
randomized trials. PharmaSUG; Paper SP-04. 
Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic 
Urothelial Carcinoma. N Engl J Med. 2020;383(13):1218-30. 
Quade. Rank analysis of covariance. Journal of the American Statistical Association 
1967;62:1187-1200. 
Wiens BL. A fixed sequence Bonferroni procedure for testing multiple endpoints. 
Pharmaceutical Statistics. 2003;2:211-15. 
Zou G. A modified poisson regression approach to prospective studies with binary data. Am J 
Epidemiol. 2004;159(7):702-6. 
 


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12. 
APPENDICES  


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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
 
Study Treatment 
Follow-Up 
 
Screening 
Chemotherapy Period 
(4-6 cycles; 1 cycle=21d) 
Maintenance 
Period 
(1 cycle=14d) 
End of 
Treatment 
Visit (ETV) 
Safety Follow-up Visit 
Survival  
Follow-Up 
Assessment 
30 days 
prior to 
C1D1 
Day 1 
(±1d) 
Day 2 
Day 8 
(±1d) 
Day 13 
and 
Day 17 
(±1d) 
Day 1 
(±1d) 
Day 2 
14 days 
after last 
dose of 
study drug 
(±3d) 
30 days 
after last 
dose of 
study drug 
(+7d)  
90 days 
after last 
dose of 
avelumab 
(±7d) 
Every 
3 months 
after ETV 
(±7d) a 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
[C1 
only (-
7d)] 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History and 
Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
Archival and/or fresh 
FFPE tumor specimen 
or 15 unstained slides 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications  
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
Complete Physical 
Examination  
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
when symptoms warrant 
per Investigator 
discretion 
 
X 
 
 
 
X 
 
X 
 
 
 


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Study Treatment 
Follow-Up 
 
Screening 
Chemotherapy Period 
(4-6 cycles; 1 cycle=21d) 
Maintenance 
Period 
(1 cycle=14d) 
End of 
Treatment 
Visit (ETV) 
Safety Follow-up Visit 
Survival  
Follow-Up 
Assessment 
30 days 
prior to 
C1D1 
Day 1 
(±1d) 
Day 2 
Day 8 
(±1d) 
Day 13 
and 
Day 17 
(±1d) 
Day 1 
(±1d) 
Day 2 
14 days 
after last 
dose of 
study drug 
(±3d) 
30 days 
after last 
dose of 
study drug 
(+7d)  
90 days 
after last 
dose of 
avelumab 
(±7d) 
Every 
3 months 
after ETV 
(±7d) a 
Vital Signs 
X 
X 
 
X 
 
X 
 
X 
 
 
 
ECOG Performance 
Status 
X 
X 
 
 
 
X 
[every-
other 
cycle] 
 
X 
 
 
 
AE Reporting 
 
X 
 
Hematology 
X 
X 
X 
[C1 
only] 
X 
X 
[C1 
only] 
X 
 
X 
X 
 
 
Chemistry 
X 
X 
 
 
 
X 
 
X 
X 
 
 
Free T4 and TSH 
X 
 
 
 
 
X 
[Q8 
wk] 
 
X 
 
 
 
Urinalysis (dipstick) 
X 
 
 
 
 
 
 
X 
 
 
 
Pregnancy Test 
(WOCBP only) 
X 
X 
 
 
 
X 
[every-
other 
cycle; 
C1 
start] 
 
X 
 
 
 
Anti-avelumab antibody 
and neutralizing 
antibody testing 
 
 
 
 
 
X 
[C1, 
C3, C6 
only] 
 
X 
 
 
 


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Study Treatment 
Follow-Up 
 
Screening 
Chemotherapy Period 
(4-6 cycles; 1 cycle=21d) 
Maintenance 
Period 
(1 cycle=14d) 
End of 
Treatment 
Visit (ETV) 
Safety Follow-up Visit 
Survival  
Follow-Up 
Assessment 
30 days 
prior to 
C1D1 
Day 1 
(±1d) 
Day 2 
Day 8 
(±1d) 
Day 13 
and 
Day 17 
(±1d) 
Day 1 
(±1d) 
Day 2 
14 days 
after last 
dose of 
study drug 
(±3d) 
30 days 
after last 
dose of 
study drug 
(+7d)  
90 days 
after last 
dose of 
avelumab 
(±7d) 
Every 
3 months 
after ETV 
(±7d) a 
12-lead ECG  
X 
 
 
 
 
 
 
 
 
 
 
Blood samples for 
biomarkers 
 
X 
[C1, C2, 
C3 
only] 
 
X 
[C1 
only] 
 
X 
[C1, 
C3 
only] 
 
 
 
 
 
Blood samples for 
trilaciclib and 
metabolites PK  
(Arm B only) 
 
X 
[C1 
only] 
X 
[C1 
only] 
 
 
X 
[C1, 
C3, 
only] 
X 
[C1, 
C3, 
only] 
 
 
 
 
Blood samples for 
cisplatin PK  
(only patients treated 
with cisplatin) 
 
X 
[C1 
only] 
 
X 
[C1 
only] 
 
 
 
 
 
 
 
Blood samples for 
avelumab PK  
(Arm B only) 
 
 
 
 
 
X 
[C1, 
C3, C6 
only] 
 
 
 
 
 
Trilaciclib (Arm B only) 
 
X 
 
X 
 
X 
 
 
 
 
 
gemcitabine 
 
X 
 
X 
 
 
 
 
 
 
 
cisplatin b or carboplatin 
 
X 
 
X b 
 
 
 
 
 
 
 
avelumab 
 
 
 
 
 
X 
 
 
 
 
 


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Study Treatment 
Follow-Up 
 
Screening 
Chemotherapy Period 
(4-6 cycles; 1 cycle=21d) 
Maintenance 
Period 
(1 cycle=14d) 
End of 
Treatment 
Visit (ETV) 
Safety Follow-up Visit 
Survival  
Follow-Up 
Assessment 
30 days 
prior to 
C1D1 
Day 1 
(±1d) 
Day 2 
Day 8 
(±1d) 
Day 13 
and 
Day 17 
(±1d) 
Day 1 
(±1d) 
Day 2 
14 days 
after last 
dose of 
study drug 
(±3d) 
30 days 
after last 
dose of 
study drug 
(+7d)  
90 days 
after last 
dose of 
avelumab 
(±7d) 
Every 
3 months 
after ETV 
(±7d) a 
Tumor Assessments 
(CT/MRI) 
X 
CT/MRI of chest/abdomen/pelvis Q6 weeks (±7d) during the chemotherapy period and Q8 weeks (±7d) during the avelumab 
maintenance period for up to 1 year relative to Cycle 1 Day 1 and Q12 weeks (±7d) thereafter relative to Cycle 1 Day 1 until 
documented disease progression or subsequent anticancer therapy. Brain scan (MRI preferred) during screening is not required 
and should be performed per investigator discretion based on clinical signs and symptoms. Additional brain MRI should be 
conducted if there are brain metastases present at baseline or new clinical signs and symptoms suggestive of brain metastases. 
Bone metastases identified at baseline via a bone scan or PET (such as FDG-PET, NaF-PET, or other locally available PET 
options) to be followed at scheduled visits using localized CT or MRI as clinically indicated. If bone metastases cannot be 
seen on CT or MRI scans, bone scans, or PET should be repeated, using the same diagnostic procedure bone metastases were 
at baseline, when CR is identified in target disease or when progression in bone is suspected. 
Survival Follow-Up and 
Subsequent Anti-Cancer 
Treatments a 
 
 
 
 
 
 
 
 
 
 
X 
AE=adverse event; C=cycle(s); CR=complete response; CT=computed tomography; d=day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology 
Group; ETV=End of Treatment Visit; FDG=[18F]-fluorodeoxyglucose; FFPE=formalin-fixed paraffin-embedded; MRI=magnetic resonance imaging; 
NaF=sodium fluoride; PET=positron emission tomography; PK=pharmacokinetic; Q6=every six; Q8=every 8; Q12=every 12; rand.=randomization; 
T4=thyroxine; TSH=thyroid stimulating hormone; wk=weeks; WOCBP=women of childbearing potential. 
a Survival follow-up assessments should occur every 3 months after the End of Treatment Visit (including assessments at Month 17 Day 1 [±7d].  
b Splitting the dose of cisplatin to Day 1 and Day 8 dosing is an allowed alternative for toxicity management (refer to Protocol Section 9.3.1.1). 


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APPENDIX 2. CUSTOMIZED MedDRA QUERIES FOR TRILACICLIB 
AESIs 
AESI Categories 
Preferred Terms 
Injection Site 
Reaction/ 
Phlebitis/ 
Thrombophlebitis 
 
Administration site phlebitis 
Periphlebitis 
Application site phlebitis 
Phlebitis 
Catheter site phlebitis 
Phlebitis deep 
Chemical phlebitis 
Phlebitis infective 
Infusion site phlebitis 
Septic phlebitis 
Infusion site thrombosis 
Thrombophlebitis 
Injection site phlebitis 
Thrombophlebitis septic 
Injection site thrombosis 
Thrombophlebitis superficial 
  
Vascular access site thrombosis 
Administration related reaction 
Infusion site erythema 
Administration site dermatitis 
Infusion site hypersensitivity 
Administration site hypersensitivity 
Infusion site pain 
Administration site pain 
Infusion site rash 
Administration site rash 
Infusion site reaction 
Administration site recall reaction 
Infusion site recall reaction 
Administration site urticaria 
Infusion site urticaria 
Administration site vasculitis 
Infusion site vasculitis 
Application site dermatitis 
Injection related reaction 
Application site hypersensitivity 
Injection site dermatitis 
Application site pain 
Injection site erythema 
Application site rash 
Injection site hypersensitivity 
Application site recall reaction 
Injection site pain 
Application site urticaria 
Injection site rash 
Application site vasculitis 
Injection site reaction 
Catheter site dermatitis 
Injection site recall reaction 
Catheter site hypersensitivity 
Injection site urticaria 
Catheter site pain 
Injection site vasculitis 
Catheter site rash 
Installation site urticaria 
Catheter site urticaria 
instillation site hypersensitivity 
Catheter site vasculitis 
instillation site pain 
Immediate post-injection reaction 
instillation site rash 
Infusion-related reaction 
Skin reaction 
Infusion site dermatitis 
Vessel puncture site rash 
  
Vessel puncture site vesicles 


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AESI Categories 
Preferred Terms 
Acute drug 
hypersensitivity 
reaction  
Allergic bronchitis 
Laryngitis allergic 
Allergic cough 
Laryngospasm 
Allergic eosinophilia 
Laryngotracheal oedema 
Allergic oedema 
Lip edema 
Allergic pharyngitis 
Lip swelling mast cell degranulation 
present 
Allergic reaction to excipient 
Mouth swelling 
Allergic respiratory disease 
Oedema mouth 
Allergic respiratory symptom 
Oropharyngeal oedema 
Anaphylactic reaction 
Oropharyngeal spasm 
Anaphylactic shock 
Oropharyngeal swelling 
Anaphylactic transfusion reaction 
Palatal oedema 
Anaphylactoid reaction 
Palatal swelling 
Anaphylactoid shock 
Periorbital oedema 
Anaphylaxis treatment 
Periorbital swelling 
Angioedema 
Pharyngeal oedema 
Bronchospasm 
Pharyngeal swelling 
Circulatory collapse 
Pruritus allergic 
Circumoral oedema 
Reaction to excipient 
Circumoral swelling 
Shock 
Distributive shock 
Shock symptom 
Documented hypersensitivity to 
administered product 
Swelling face 
Drug hypersensitivity 
Swelling of eyelid 
Drug reaction with eosinophilia and 
systemic symptoms 
Swollen tongue 
Epiglottic oedema 
Therapeutic product cross-reactivity 
Eye oedema 
Tongue oedema 
Eye swelling 
Tracheal oedema 
Eyelid oedema 
Type I hypersensitivity 
Face oedema 
Urticaria 
Hypersensitivity 
Urticaria contact 
Immune-mediated adverse reaction 
Urticaria popular 
Infusion related hypersensitivity 
reaction 
Urticarial dermatitis 
Laryngeal oedema 
Urticarial vasculitis 


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AESI Categories 
Preferred Terms 
Hepatotoxicity  
Acute hepatic failure 
Hepatitis acute 
Acute on chronic liver failure 
Hepatitis cholestatic 
Acute yellow liver atrophy 
Hepatitis chronic active 
Allergic hepatitis 
Hepatitis chronic persistent 
Autoimmune hepatitis 
Hepatitis fulminant 
Cholestatic liver injury 
Hepatitis toxic 
Chronic hepatic failure 
Hepatocellular foamy cell syndrome 
Chronic hepatitis 
Hepatocellular injury 
Coma hepatic 
Hepatotoxicity 
Drug-Induced Liver Injury 
Immune-mediated hepatitis 
Hepatic failure 
Liver disorder 
Hepatic infiltration eosinophilia 
Liver injury 
Hepatic necrosis 
Mixed liver injury 
Hepatic steato-fibrosis 
Non-alcoholic steatohepatitis 
Hepatic steatosis 
Steatohepatitis 
Hepatitis 
Subacute hepatic failure 
Interstitial Lung 
Disease (ILD) 
/Pneumonitis 
Acute interstitial pneumonitis 
Idiopathic interstitial pneumonia 
Acute lung injury 
Idiopathic pneumonia syndrome 
Acute respiratory distress syndrome 
Idiopathic pulmonary fibrosis 
Alveolar lung disease 
Immune-mediated pneumonitis 
Alveolitis 
Interstitial lung disease 
Alveolitis necrotizing 
Necrotizing bronchiolitis 
Autoimmune lung disease 
Obliterative bronchiolitis 
Diffuse alveolar damage 
Pneumonitis 
Eosinophilic pneumonia 
Pneumonitis chemical 
Eosinophilic pneumonia acute 
Progressive massive fibrosis  
Eosinophilic pneumonia chronic 
Pulmonary fibrosis 
Granulomatous pneumonitis 
Hypersensitivity pneumonitis 
Pulmonary toxicity 
  
Restrictive pulmonary disease 


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AESI Categories 
Preferred Terms 
Embolic and 
thrombotic 
events, venous  
Axillary vein thrombosis 
Pulmonary thrombosis 
Brachiocephalic vein occlusion 
Pulmonary vein occlusion 
Brachiocephalic vein thrombosis 
Pulmonary veno-occlusive disease 
Deep vein thrombosis 
Pulmonary venous thrombosis 
Embolism venous 
Subclavian vein occlusion 
Iliac vein occlusion 
Subclavian vein thrombosis 
Obstructive shock 
Superior vena cava occlusion 
Pelvic venous thrombosis 
Thrombosis 
Peripheral vein occlusion 
Vena cava embolism 
Peripheral vein thrombus extension 
Vena cava thrombosis 
Phlebectomy 
Venous occlusion 
Pulmonary embolism 
Venous thrombosis 
Pulmonary microemboli 
Venous thrombosis limb