Clinical trial NCT02978716
Conditions: Triple-Negative Breast Neoplasms Breast Neoplasm Breast Cancer Triple-Negative Breast Cancer
Keywords: Breast Cancer CDK 4/6 Inhibitor Triple Negative Breast Cancer Metastatic
Sponsor: G1 Therapeutics, Inc.
Start date: 2017-02-02; Completion date: 2020-02-28
Enrollment: 102 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a study to investigate the potential clinical benefit of trilaciclib (G1T28) in preserving the bone marrow and the immune system, and enhancing chemotherapy antitumor efficacy when administered prior to carboplatin and gemcitabine (GC therapy) for participants with metastatic triple negative breast cancer.

The study was an open-label and 102 participants were randomly assigned (1:1:1 fashion) to 1 of the 3 following treatment groups:

* Group 1: GC therapy (Days 1 and 8 of 21-day cycles) only (n=34)
* Group 2: GC therapy (Days 1 and 8) plus trilaciclib (G1T28) on Days 1 and 8 of 21-day cycles (n=33)
* Group 3: GC therapy (Days 2 and 9) plus trilaciclib (G1T28) on Days 1, 2, 8, and 9 of 21-day cycles (n=35)

The study included 3 study phases: Screening Phase, Treatment Phase, and Survival Follow-up Phase. The Treatment Phase begins on the day of first dose with study treatment and completes at the Post-Treatment Visit.

Detailed description:
The posted results represent the final results of Study G1T28-04, a Phase 2 study of the safety, efficacy and pharmacokinetics of trilaciclib (G1T28) in patients with locally recurrent/metastatic triple negative breast cancer receiving gemcitabine and carboplatin chemotherapy.

The final myelopreservation efficacy results are reported from database lock 1 (\[DBL1\], data cut-off \[DCO\] date of 30 July 2018). Final anti-tumor efficacy (ORR, PFS), and final summary exposure and safety data are reported from database lock 2 (\[DBL2\], DCO 28 June 2019) which occurred to support filing of the trilaciclib New Drug Application (NDA). Final overall survival (OS) data are reported from the final database lock which occurred on 17 July 2020 (with a last patient last visit date of 28 February 2020).

Arms: arm 1: Participants received Intravenous (IV) infusion of standard GC chemotherapy (gemcitabine 1000 milligrams per meter square \[mg/m\^2\] and carboplatin area under the curve \[AUC\] 2) on Days 1 and 8 of 21-day cycle. The carboplatin dose was calculated using the Calvert formula, with a target AUC 2 (maximum 300 mg). arm 2: Participants received IV infusion of trilaciclib 240 mg/m\^2 plus GC chemotherapy (gemcitabine 1000 mg/m\^2 and carboplatin AUC 2) IV infusion on Days 1 and 8 of 21-day cycle. Trilaciclib was administered prior to chemotherapy. arm 3: Participants received IV infusion of trilaciclib 240 mg/m\^2 on Days 1, 2, 8, and 9 plus GC chemotherapy (gemcitabine 1000 mg/m\^2 and carboplatin AUC 2) IV infusion on Day 2 and 9 of 21-day Cycle. Trilaciclib was administered prior to chemotherapy.
Interventions: intervention 1: Trilaciclib intervention 2: Gemcitabine intervention 3: Carboplatin
Intervention descriptions: intervention 1: G1T28 intervention 2: Gemcitabine intervention 3: Carboplatin

Protocol documents:
Prot_000.pdf: 
G 1 T hera pe utics C O N FI D E N TI A L  
 
 
 
 
 
P h ase 2 St u d y of t he S afet y, Effic ac y, a n d P h ar m ac o ki netics of G 1 T 2 8 i n P atie nts wit h 
Met ast atic Tri ple Ne g ati ve Bre ast C a ncer Recei vi n g Ge mcit a bi ne a n d C ar b o pl ati n 
C he m ot her a p y  
 
Cli nic al St u d y Pr ot oc ol G 1 T 2 8- 0 4  
E u dr a C T # 2 0 1 6- 0 0 4 4 6 6- 2 6   
 
 
Ori gi nal Pr ot oc ol Iss ue Date: 0 4 Oct o ber 2 0 1 6 
A me n d me nt 1 Iss ue Date: 0 8 Dece m ber  2 0 1 6 
A me n d me nt 2 Iss ue Date:  2 0 Marc h  2 0 1 7 
A me n d me nt 3 Iss ue Date: 3 1 A u g ust 2 0 1 7  
Versi o n: 4. 0 
 
I n vesti gati o nal P hase: 2 
 
S p o ns ore d b y: 
G 1 T hera pe utics 
7 9 T. W. Ale xa n der Dri ve 
4 5 0 1 Researc h C o m m o ns, S uite 1 0 0 
Researc h Tria n gle Par k, N C 2 7 7 0 9 
 
 
 
 
 
T HI S D O C U M E N T C O N T AI N S C O N FI D E N TI A L A N D/ O R T R A D E S E C R E T 
I N F O R M A TI O N T H A T I S DI S C L O S E D O N L Y I N C O N N E C TI O N WI T H T H E 
LI C E N SI N G A N D/ O R R E GI S T R A TI O N O F P R O D U C T S F O R G 1 T H E R A P E U TI C S .  
T HI S D O C U M E N T S H O U L D N O T B E DI S C L O S E D O R U S E D, I N W H O L E O R I N 
P A R T, F O R A N Y O T H E R P U R P O S E WI T H O U T T H E P RI O R W RI T T E N C O N S E N T O F 
G 1 T H E R A P E U TI C S . 
 
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G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-04 
Trilaciclib 
 
Version: 4.0, dated 31 August 2017 
 
Page 3 of 107  
G1 Therapeutics CONFIDENTIAL 
PROTOCOL SIGNATURE PAGE 
Clinical Study Protocol G1T28-04: Phase 2 Study of the Safety, Efficacy, and 
Pharmacokinetics of G1T28 in Patients with Metastatic Triple Negative Breast Cancer 
Receiving Gemcitabine and Carboplatin Chemotherapy 
Original Protocol Issue Date: 04 October 2016 
Version: 4.0, dated 31 August 2017 
By signing below, the investigator agrees to adhere to the protocol as outlined. 
Principal Investigator: 
 
 
Principal Investigator Signature 
Date 
Principal Investigator Name 
Institution 
 


G 1 T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Vers i o n: 4. 0, date d 31 A u g ust  2 0 1 7  
 
Pa ge 4 of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
1.  
T A B L E O F C O N T E N T S  
S P O N S O R SI G N A T U R E P A G E  ........................................................................................................................... 2 
P R O T O C O L SI G N A T U R E P A G E  ........................................................................................................................ 3 
1.  
T A B L E O F C O N T E N T S  ............................................................................................................................... 4 
1. 1.  
List of I n -Te xt Ta bles  ....................................................................................................................... 8 
2.  
LI S T O F A B B R E VI A TI O N S ........................................................................................................................ 9 
3.  
S Y N O P SI S  .................................................................................................................................................. 1 2  
4.  
I N T R O D U C TI O N ....................................................................................................................................... 2 3  
4. 1.  
Bac k gr o u n d  ..................................................................................................................................... 2 3  
4. 2.  
S u m mar y  of Cli nical Data  ............................................................................................................... 2 4  
4. 3. 1.  
P har mac ol o g y St u dies  ................................................................................................... 2 6  
4. 3. 2.  
P har mac o ki netic St u dies  ............................................................................................... 2 7  
4. 3. 3.  
T o xicit y a n d Safet y St u dies  ........................................................................................... 2 8  
4. 3. 4.  
P ote ntial Ris ks  ............................................................................................................... 2 8  
4. 4.  
St u d y a n d D ose Rati o nale  ............................................................................................................... 3 0  
4. 5.  
Ris k/ Be nefit Assess me nt  ................................................................................................................. 3 1  
5.  
S T U D Y O BJ E C TI V E S  ................................................................................................................................ 3 2  
6.  
I N V E S TI G A TI O N A L P L A N ...................................................................................................................... 3 3  
6. 1.  
O verall St u d y Desi g n a n d Pla n  ....................................................................................................... 3 3  
7.  
S T U D Y P O P U L A TI O N  .............................................................................................................................. 3 4  
7. 1.  
Sel ecti o n of Patie nts  ........................................................................................................................ 3 4  
7. 1. 1.  
I ncl usi o n Criteria ........................................................................................................... 3 4  
7. 1. 2.  
E xcl usi o n Criteria  .......................................................................................................... 3 6  
8.  
T R E A T M E N T S ........................................................................................................................................... 3 7  
8. 1.  
Treat me nt s A d mi nistere d ................................................................................................................ 3 7  
8. 2.  
I n vesti gati o nal Pr o d ucts .................................................................................................................. 3 7  
8. 2. 1.  
I de ntit y .......................................................................................................................... 3 7  
8. 2. 1. 1.  
Tri lacicli b ................................................................................................. 3 7  
8. 2. 1. 2.  
Ge mcita bi ne a n d Car b o plati n ................................................................... 3 7  
8. 2. 2.  
Pac ka gi n g a n d La beli n g  ................................................................................................ 3 8  
8. 2. 2. 1.  
Trilacicli b  ................................................................................................. 3 8  
8. 2. 2. 2.  
Ge mcita bi ne a n d Car b o plati n ................................................................... 3 8  
8. 2. 3.  
St ora ge  .......................................................................................................................... 3 8  
8. 2. 3. 1.  
Trilacicli b  ................................................................................................. 3 8  
8. 2. 3. 2.  
Ge mcita bi ne a n d Car b o plati n ................................................................... 3 8  
8. 2. 4.  
Pr oce d ure f or Dis pe nsi n g  .............................................................................................. 3 8  
8. 2. 5.  
I n vesti gati o nal Pr o d uct Acc o u nta bilit y ......................................................................... 3 8  
8. 3.  
Met h o d of Assi g ni n g Patie nts t o Treat me nt Gr o u ps  ....................................................................... 3 9  
8. 4.  
D ose, D osi n g Re gi me n, a n d R o ute  ................................................................................................. 3 9  
8. 4. 1.  
Trilacicli b  ...................................................................................................................... 3 9  
8. 4. 2.  
Ge mcita bi ne a n d Car b o plati n  ........................................................................................ 4 0  
8. 4. 2. 1.  
Car b o plati n  .............................................................................................. 4 0  
8. 4. 2. 2.  
Ge mcita bi ne  ............................................................................................. 4 0  
8. 4. 3.  
T o xicit y Ma na ge me nt G ui deli nes  ................................................................................. 4 0  
8. 4. 3. 1.  
Criteria f or S u bse q ue nt C ycles  ................................................................ 4 1  
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G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-04 
Trilaciclib 
 
Version: 4.0, dated 31 August 2017 
 
Page 5 of 107  
G1 Therapeutics CONFIDENTIAL 
8.4.3.2. 
Dose Modifications for Hematologic Toxicity ........................................ 41 
8.4.3.3. 
Use of Colony Stimulating Factors .......................................................... 46 
8.4.3.4. 
Dose Modifications for Nonhematologic Toxicity .................................. 46 
8.5. 
Randomization and Blinding ........................................................................................................... 52 
8.6. 
Prior and Concomitant Medications and Procedures ...................................................................... 52 
8.7. 
Transfusions .................................................................................................................................... 53 
8.8. 
Treatment Compliance .................................................................................................................... 53 
9. 
STUDY FLOWCHART .............................................................................................................................. 54 
10. SCHEDULE OF STUDY PROCEDURES ................................................................................................. 61 
10.1. 
Screening......................................................................................................................................... 61 
10.2. 
Cycle 1 and Subsequent Cycles ...................................................................................................... 62 
10.3. 
Post-Treatment Visit: Day 22 of last cycle ..................................................................................... 65 
10.4. 
Safety Follow-up Contact: 30 days post last dose ........................................................................... 66 
10.5. 
Post-Treatment Visit: 60 Days Post Last Dose ............................................................................... 66 
10.6. 
Survival Follow-up Phase ............................................................................................................... 66 
10.7. 
Unscheduled Visits ......................................................................................................................... 67 
11. STUDY ASSESSMENTS ........................................................................................................................... 68 
11.1. 
Efficacy Assessments ...................................................................................................................... 68 
11.2. 
Pharmacokinetic Assessments (Optional) ....................................................................................... 68 
11.3. 
Archival Tumor Tissue ................................................................................................................... 70 
11.4. 
Safety Assessments ......................................................................................................................... 71 
11.4.1. 
Adverse Events and Serious Adverse Events ................................................................ 71 
11.4.1.1. 
Definition of Adverse Event .................................................................... 71 
11.4.1.2. 
Definition of Serious Adverse Event ....................................................... 72 
11.4.1.3. 
Assessment of the Severity of Adverse Events ........................................ 73 
11.4.1.4. 
Assessment of the Relationship of Adverse Events to 
Study Drug ............................................................................................... 73 
11.4.1.5. 
Assessment of the Outcome of Adverse Events ....................................... 74 
11.4.1.6. 
Method, Frequency, and Time Period for Detecting 
Adverse Events and Serious Adverse Events ........................................... 75 
11.4.1.7. 
Documentation of Adverse Events and Serious Adverse 
Events ...................................................................................................... 75 
11.4.1.8. 
Adverse Event Coding ............................................................................. 76 
11.4.1.9. 
Reporting of Serious Adverse Events ...................................................... 76 
11.4.1.10. 
Follow-up of Adverse Events .................................................................. 76 
11.4.1.11. 
Regulatory Aspects of Adverse Event Reporting .................................... 77 
11.4.1.12. 
Handling of Overdoses and Toxicity ....................................................... 78 
11.4.1.13. 
Reporting of Pregnancies ......................................................................... 78 
11.4.1.14. 
Infusion-Related Reactions ...................................................................... 78 
11.4.2. 
Clinical Laboratory Assessments .................................................................................. 79 
11.4.3. 
Demographics and Vital Signs ...................................................................................... 80 
11.4.4. 
Physical Examination .................................................................................................... 80 
11.4.5. 
Electrocardiogram Assessments .................................................................................... 80 
11.5. 
Tumor Response ............................................................................................................................. 81 
11.5.1. 
Tumor Assessments ...................................................................................................... 81 
11.5.2. 
Tumor Lesions: Identification and Follow-up ............................................................... 81 
11.5.2.1. 
Measurable Lesions ................................................................................. 81 
11.5.2.2. 
Nonmeasurable Lesions ........................................................................... 82 
11.5.2.3. 
New Lesions ............................................................................................ 82 
11.5.3. 
Definitions of Tumor Response and Disease Progression ............................................. 83 
11.5.3.1. 
Evaluation of Target Lesion Response .................................................... 83 
11.5.3.2. 
Evaluation of Nontarget Lesions .............................................................. 83 
11.5.3.3. 
Evaluation of Overall Response ............................................................... 84 


G 1 T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Vers i o n: 4. 0, date d 31 A u g ust  2 0 1 7  
 
Pa ge 6 of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
1 1. 1 0.  A p pr o priate ness of Meas ure me nts  .................................................................................................. 8 6  
1 2.  S T U D Y T E R MI N A TI O N O R  S T U D Y D R U G DI S C O N TI N U A TI O N  ..................................................... 8 7  
1 2. 1.  
St u d y Ter mi nati o n ........................................................................................................................... 8 7  
1 2. 1. 1.  
Site Ter mi nati o n  ............................................................................................................ 8 7  
1 2. 2.  
Disc o nti n uati o n of St u d y Dr u g  ....................................................................................................... 8 7  
1 2. 3.  
Wit h dra wal of Patie nts fr o m t he St u d y  ........................................................................................... 8 8  
1 3.  S T A TI S TI C S  ............................................................................................................................................... 8 9  
1 3. 1.  
Sa m ple Size a n d P o wer  ................................................................................................................... 8 9  
1 3. 1. 1.  
A nal ysis P o p ulati o ns/ Sets  ............................................................................................. 8 9  
1 3. 1. 2.  
Ti mi n g of A nal yses  ....................................................................................................... 8 9  
1 3. 1. 2. 1.  
Data Safet y M o nit ori n g C o m mittee  ......................................................... 8 9  
1 3. 1. 2. 2.  
Fi nal A nal ysis  .......................................................................................... 9 0  
1 3. 1. 2. 3.  
E n d of St u d y A nal ysis  ............................................................................. 9 0  
1 3. 1. 3.  
Ge neral C o nsi derati o ns f or Data A nal ysis  .................................................................... 9 0  
1 3. 2.  
Baseli ne a n d De m o gra p hic C haracteristics  ..................................................................................... 9 0  
1 3. 3.  
Efficac y A nal ysis  ............................................................................................................................ 9 0  
1 3. 3. 1.  
Efficac y E n d p oi nts  ........................................................................................................ 9 0  
1 3. 3. 2.  
Met h o ds of A nal ysis f or Efficac y E n d p oi nts  ................................................................ 9 2  
1 3. 3. 2. 1.  
A nal ysis of He mat ol o gic Para meter Ki netic E n d p oi nts  ........................... 9 2  
1 3. 3. 2. 2.  
A nal ysis of He mat ol o gic T o xicit y E n d p oi nts  .......................................... 9 4  
1 3. 3. 2. 3.  
A nal ysis of C he m ot hera p y E x p os ure a n d C o m plia nce  ............................ 9 4  
1 3. 3. 2. 4.  
Ot her Efficac y E n d p oi nts  ......................................................................... 9 4  
 
 
1 3. 4.  
Safet y A nal ysis  ............................................................................................................................... 9 5  
1 3. 4. 1.  
Safet y E n d p oi nts  ........................................................................................................... 9 5  
1 3. 4. 2.  
Met h o ds of A nal ysis f or Safet y E n d p oi nts  .................................................................... 9 6  
 
 
1 3. 6.  
P har mac o ki netic A nal ysis  ............................................................................................................... 9 7  
 
 
1 4.  Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E ........................................................................... 9 8  
1 5.  E T HI C S A N D P R O T E C TI O N O F H U M A N P A TI E N T S  .......................................................................... 9 9  
1 5. 1.  
Et hical C o n d uct State me nt  .............................................................................................................. 9 9  
1 5. 2.  
I nstit uti o nal Re vie w B oar d/I n de pe n de nt Et hics C o m mittee  ........................................................... 9 9  
1 5. 3.  
I nf or me d C o nse nt ............................................................................................................................ 9 9  
1 5. 4.  
Patie nt C o nfi de ntialit y  .................................................................................................................... 9 9  
1 5. 5.  
A d here nce t o t he Pr ot o c ol ............................................................................................................. 1 0 0  
1 5. 6.  
Pr ot oc ol A me n d me nts  ................................................................................................................... 1 0 0  
1 5. 7.  
Patie nt C o m plia nce  ....................................................................................................................... 1 0 0  
1 5. 8.  
St u d y Disc o nti n uati o n  ................................................................................................................... 1 0 0  
1 6.  D A T A H A N D LI N G A N D R E C O R D K E E PI N G  ...................................................................................... 1 0 1  
1 6. 1.  
Data C ollecti o n a n d Retrie val  ....................................................................................................... 1 0 1  
1 6. 2.  
Data M o nit ori n g C o m mittee  ......................................................................................................... 1 0 1  
1 6. 3.  
I n vesti gat or Re p orti n g Re q uire me nts............................................................................................ 1 0 1  
1 6. 4.  
Rec or ds Rete nti o n  ......................................................................................................................... 1 0 1  
1 6. 5.  
St u d y M o nit ori n g  .......................................................................................................................... 1 0 2  
1 6. 6.  
A u dits a n d I ns pecti o ns  .................................................................................................................. 1 0 2  
C CI
C CI
C CI
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G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-04 
Trilaciclib 
 
Version: 4.0, dated 31 August 2017 
 
Page 7 of 107  
G1 Therapeutics CONFIDENTIAL 
17. PUBLICATION POLICY ......................................................................................................................... 103 
18. REFERENCES .......................................................................................................................................... 104 
19. APPENDICES ........................................................................................................................................... 107 
 
APPENDIX 1: Common Terminology Criteria for Adverse Events (CTCAE) –Version 4.03 
APPENDIX 2: Package Inserts for Chemotherapy Agents 
 
 
 
 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-04 
Trilaciclib 
 
Version: 4.0, dated 31 August 2017 
 
Page 8 of 107  
G1 Therapeutics CONFIDENTIAL 
1.1. 
List of In-Text Tables 
Table 5-1 
G1T28-04: Study Objectives ......................................................................................... 32 
Table 8-1 
Dose Modification for Hematologic Toxicity (All Groups) .......................................... 43 
Table 8-2 
Patient Risk Factors for Poor Clinical Outcomes Resulting from 
Febrile Neutropenia or Infection ................................................................................... 46 
Table 8-3 
Dose Modifications for Drug-Related Non-Hematologic 
Toxicity at Any Point During the Study (All Groups) .................................................. 47 
Table 9-1 
Schedule of Assessments for Groups 1 and 2 ............................................................... 55 
Table 9-2 
Schedule of Assessments for Group 3 ........................................................................... 58 
Table 11-1 
Cycle 1 Day 1 (Group 1) Blood Sampling Scheme Based on 
Predicted Administration Times of Carboplatin and Gemcitabine ................................ 69 
Table 11-2 
Cycle 1 Day 1 (Group 2)/ Day 2 (Group 3) Blood Sampling 
Scheme Based on Predicted Administration Times of Trilaciclib, 
Carboplatin, and Gemcitabine ....................................................................................... 69 
Table 11-3 
Pharmacokinetic Parameters ......................................................................................... 70 
Table 11-4 
Symptoms Associated with Infusion-Related Reactions ............................................... 79 
Table 11-5 
Evaluation of Overall Response at Each Time Point .................................................... 84 
 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-04 
Trilaciclib 
 
Version: 4.0, dated 31 August 2017 
 
Page 9 of 107  
G1 Therapeutics CONFIDENTIAL 
2. 
LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUCNadir 
area under the concentration-time curve from predose to nadir  
BCRP 
breast cancer resistance protein  
BED 
biologically effective dose 
β-hCG 
beta human chorionic gonadotropin  
bpm 
beats per minute 
BSA 
body surface area 
BSEP 
bile salt export pump   
CBC 
complete blood count 
CD3 
CD8 
cluster of differentiation 3 
cluster of differentiation 8 
CDK2/4/6 
cyclin-dependent kinase 2/4/6 
CFR 
Code of Federal Regulations 
CL 
clearance 
Cmax 
maximum concentration 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
D5W 
dextrose 5% in water 
DDI 
drug-drug interaction 
DLT 
dose limiting toxicity 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic case report form 
EdU 
5 ethynyl-2'-deoxyuridine  


G 1 T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Vers i o n: 4. 0, date d 31 A u g ust  2 0 1 7  
 
Pa ge 1 0  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
A b bre vi ati o n  
Defi niti o n  
E OI 
e n d of i nf usi o n 
E R 
estr o ge n rece pt or  
 
 
 
 
F A S  
f ull a nal ysis set 
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F D G -P E T  
p ositr o n e missi o n t o m o gra p h y wit h 2 -de o x y - 2-[fl u ori ne-1 8]fl u or o - D-gl uc ose  
F O X P 3  
f or k hea d b o x P 3 
G 1 
ga p 1 p hase of t he cell  c ycle 
G 2 
ga p 2 p hase of t he cell c ycle  
G 1 T 2 8  
trilacicli b; f or merl y G 1 T 2 8- 1 
G C  
ge mcita bi ne a n d car b o plati n  
G C t hera p y  
ge mcita bi ne a n d car b o plati n o n Da ys 1 a n d 8 of 2 1 -da y c ycles  
G C P  
G o o d Cli nical Practice  
G- C S F  
gra n ul oc yte c ol o n y -sti m ulati n g fact or 
G F R  
gl o mer ular filtrati o n rate  
G L P 
G o o d La b orat or y Practice  
γ H 2 A X 
p h os p h or ylate d hist o ne H 2 A X  
H E R 2  
h u ma n e pi der mal gr o wt h fact or rece pt or 2  
HI V  
h u ma n i m m u n o deficie nc y vir us  
H S P C  
he mat o p oietic ste m a n d pr o ge nit or cell  
I B 
I n vesti gat or’s Br oc h ure 
I C5 0 
half ma xi mal i n hi bit or y c o nce ntrati o n  
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I E C 
i n de pe n de nt et hics c o m mittee  
I H C 
i m m u n o hist oc he mistr y 
I R B 
i nstit uti o nal re vie w b oar d 
I V 
i ntra ve n o us 
L D 
l o n gest dia meter 
L S 
least s q uare 
M 
mit osis p hase of cell c ycle  
M A T E 1 or 2 - K 
m ulti dr u g a n d t o xi n e xtr usi o n 1 or 2 -K  
M D R 1  
p- gl yc o pr otei n  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M RI  
ma g netic res o na nce i ma gi n g  
M R P 1 or 2  
m ulti dr u g resista nce pr otei n 1 or 2  
N CI  
Nati o nal Ca ncer I nstit ute  
N E  
n ot e val ua ble  
N Y H A  
Ne w Y or k Heart Ass ociati o n  
C CI


G 1 T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Vers i o n: 4. 0, date d 31 A u g ust  2 0 1 7  
 
Pa ge 1 1  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
A b bre vi ati o n  
Defi niti o n  
O A T 1 or 3  
or ga nic a ni o n tra ns p orter 1 or 3  
O A T P 1 B 1 or 1 B 3  
or ga nic a ni o n tra ns p orti n g p ol y pe pti de 1 B 1 or 1 B 3   
O C T 1 or 2  
or ga nic cati o n tra ns p orter 1 or 2  
O S  
o verall s ur vi val  
P D  
pr o gressi ve disease  
P E T 
p ositr o n e missi o n t o m o gra p h y  
P F S  
pr o gressi o n -free s ur vi val 
P K  
p har mac o ki netic(s)  
P P  
per pr ot oc ol  
P R  
partial res p o nse  
 
 
 
 
R b  
reti n o blast o ma pr otei n 
R B  
reti n o blast o ma ge ne 
R B C  
re d bl o o d cell 
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
R H  
relati ve h u mi dit y 
 
 
S 
s y nt hesis p hase of cell c ycle i n w hic h D N A is re plicate d 
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
S C L C  
s mall cell l u n g ca ncer 
S D  
sta ble disease 
S O P  
sta n dar d o perati n g pr oce d ure 
t1/ 2 
ter mi nal half-life 
T ma x  
ti me t o reac h Cma x  
T N B C  
tri ple ne gati ve breast ca ncer 
U L N 
u p per li mit of n or mal  
Vz  
v ol u me of distri b uti o n i n t he ter mi nal eli mi n ati o n p hase  
W B C  
w hite bl o o d cell  
C CI
C CI
C CI


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-04 
Trilaciclib 
 
Version: 4.0, dated 31 August 2017 
 
Page 12 of 107  
G1 Therapeutics CONFIDENTIAL 
3. 
SYNOPSIS 
Title 
Phase 2 Study of the Safety, Efficacy, and Pharmacokinetics of 
G1T28 in Patients with Metastatic Triple Negative Breast Cancer 
Receiving Gemcitabine and Carboplatin Chemotherapy 
Study Rationale 
Chemotherapy-induced myelosuppression continues to represent the 
major dose-limiting toxicity (DLT) of cytotoxic chemotherapy and 
can be manifested as neutropenia, lymphopenia, anemia, and/or 
thrombocytopenia. As such, myelosuppression is the source of many 
important side effects of cancer treatment, such as infection, sepsis, 
bleeding, and fatigue, leading to the need for hospitalizations, growth 
factor support, and transfusions (red blood cells [RBCs] or platelets).  
Moreover, clinical concerns raised by myelosuppression commonly 
lead to chemotherapy dose reductions and limit therapeutic dose 
intensity. In addition to the side effects of chemotherapy, 
chemotherapy-induced immunosuppression may limit antitumor 
efficacy due to an inability of the host immune system to effectively 
mount a response against the cancer. Therefore, preserving the bone 
marrow and immune system from the cytotoxic effects of 
chemotherapy has the potential to maximize the antitumor activity of 
chemotherapy while minimizing myelotoxicity. Trilaciclib (G1T28) is 
a highly potent and selective cyclin-dependent kinase 4/6 (CDK4/6) 
inhibitor that causes a transient and reversible gap 1 (G1) phase cell 
cycle arrest of hematopoietic stem and progenitor cells (HSPCs) 
within the bone marrow, thus protecting their deoxyribonucleic acid 
(DNA) from damage by chemotherapy and preserving long-term 
function. In nonclinical animal models, trilaciclib has been shown to 
induce a transient G1 cell cycle arrest of the HSPCs and 
administration of trilaciclib prior to myelosuppressive chemotherapy 
resulted in improved recovery of complete blood counts (CBCs), 
preservation of the immune system numbers and function, 
maintenance of long-term bone marrow function, the ability to 
tolerate more cumulative chemotherapy, and the enhancement of 
chemotherapy antitumor efficacy.      
The retinoblastoma (RB) tumor suppressor gene is a critical negative 
cell cycle regulator that links growth factor signaling to cell cycle 
progression. When active, the retinoblastoma protein (Rb) blocks cell 
cycle progression by forming repressive complexes with transcription 
factors (notably the E2F family), which are critical for synthesis (S) 
phase entry and progression. CDK4 and CDK6 activate cell cycle 
progression primarily by phosphorylation and the subsequent 
suppression of RB. When RB is lost or inactivated, tumors cells 
become intrinsically resistant to CDK4/6 inhibition. Triple negative 
breast cancer (TNBC) exhibits frequent loss of RB through a variety 
of mechanisms, which leads to reduced Rb protein expression, high 
levels of p16ink4a (natural CDK4/6 inhibitor) expression, and very 
high expression levels of RB/E2F signature genes relative to other 
breast cancer subtypes. Additionally, the relationship between RB and 
development of TNBC is supported by the development of a breast 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-04 
Trilaciclib 
 
Version: 4.0, dated 31 August 2017 
 
Page 13 of 107  
G1 Therapeutics CONFIDENTIAL 
cancer mouse model in which conditional loss of p53 and RB leads to 
the development of breast cancer in the mice that exquisitely 
recapitulates human TNBC.  Finally, gene expression analysis and 
immunohistochemical (IHC) approaches have shown that tumors that 
lack RB have a good response to chemotherapy, as indicated by a 
pathological complete response in neoadjuvant studies or improved 
overall outcome. This finding is counterintuitive because it suggests 
that the most aggressive rapidly growing tumors in fact have the best 
prognosis. The prevailing view of this paradox is that such rapidly 
proliferating tumors lack critical Rb-mediated cell cycle checkpoints 
and are thus very sensitive to chemotherapy. Since a RB-deficient 
phenotype is common in TNBC, it is expected that trilaciclib will 
have no effect on tumor growth or proliferation. Therefore, there is 
little concern that trilaciclib administered in combination with 
traditional chemotherapy (gemcitabine and carboplatin [GC]) will 
antagonize the intended efficacy of the chemotherapy. While 
trilaciclib is not expected to directly impact tumor proliferation, it has 
the potential to improve the current standard of care in TNBC by 
protecting the bone marrow and immune system during 
chemotherapy, thereby allowing faster hematopoietic recovery, 
preservation of long-term stem cell and immune system function, and 
enhancement of chemotherapy antitumor activity. 
The dose of 240 mg/m2 trilaciclib (established in 2 ongoing 
Phase 1b/2a small cell lung cancer [SCLC] studies) will be used for 
each administration of trilaciclib. However, 2 dosing schedules of 
trilaciclib will be tested. All 3 groups in the study will receive 21-day 
cycles of GC as the backbone chemotherapy. Patients in Group 1 will 
receive GC therapy on Days 1 and 8 with no trilaciclib. Patients in 
Group 2 will receive trilaciclib prior to GC therapy on Days 1 and 8. 
Patients in Group 3 will receive trilaciclib on Days 1, 2, 8, and 9, with 
administration prior to GC therapy on Days 2 and 9. The goals of this 
study are to assess the safety and tolerability of combining trilaciclib 
in 2 different schedules with GC therapy, to evaluate the effect of 
trilaciclib on chemotherapy-induced myelosuppression, and to 
evaluate the antitumor activity of trilaciclib + GC therapy (response 
rate, progression-free survival [PFS], and overall survival [OS]). 


G 1 T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Vers i o n: 4. 0, date d 31 A u g ust  2 0 1 7  
 
Pa ge 1 4  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
Cli nical P hase  
2 
I n dicati o n 
Re d ucti o n of c he m ot hera p y -i n d uce d m yel os u p pressi o n 
O bjecti ve s 
Pri m ar y O bjecti ve a 
Assess t he safet y a n d t olera bilit y of trilacicli b a d mi nistere d wit h G C 
t hera p y 
Sec o n d ar y O bjecti ves a 
Assess t u m or res p o nse a n d d urati o n of res p o nse base d o n R E CI S T, 
Versi o n 1. 1  
Assess P F S a n d O S  
Assess d ose i nte nsit y of ge mcita bi ne a n d car b o plati n  
Assess t he P K pr ofile of trilacicli b 
Assess t he P K pr ofile of ge mcita bi ne a n d car b o plati n w he n a d mi nistere d 
wit h  a n d wit h o ut trilacicli b 
Assess t he he mat ol o gic pr ofile ( ki netics a n d i nci de nce/ d urati o n/fre q ue nc y 
of t o xicities) of trilacicli b a d mi nistere d wit h G C t hera p y  
Assess t he i nci de nce of fe brile ne utr o pe nia  
Assess t he i nci de nce of i nfecti o ns  
Assess t he utilizati o n of R B C a n d platelet tra nsf usi o ns  
Assess t he utilizati o n of he mat o p oietic gr o wt h fact ors  
Assess t he utilizati o n of s yste mic a nti bi otics 
Assess t he i nci de nce of c he m ot hera p y d ose re d ucti o ns a n d d ose 
i nterr u pti o ns o verall 
Assess t he i nci de nce of Gra de 2 or greater ne p hr ot o xicit y  
Deter mi ne t he d ose sc he d ule of trilacicli b a d mi nistere d wit h G C t hera p y  
G C t hera p y = ge mcita bi ne + car b o plati n o n Da ys 1 a n d 8 or Da ys 2 a n d 9 of 2 1 -da y 
c y cles; O S = o verall s ur vi val; P F S = pr o gressi o n -free s ur vi val; 
P K  = p har mac o ki netic; 
; R B C = re d bl o o d cell; 
R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors  
a 
T he o bjecti ves will be assesse d f or b ot h sc he d ules of trilacicli b ( Da ys 1 a n d 8 or 
Da ys 1, 2, 8, a n d 9 i n 2 1 -da y c y cles) a d mi nistere d pri or t o  G C t hera p y ( Da ys 1 
a n d 8 or Da ys 2 a n d 9 i n 2 1 -da y c y cles, res pecti vel y)  
C CI
C CI


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-04 
Trilaciclib 
 
Version: 4.0, dated 31 August 2017 
 
Page 15 of 107  
G1 Therapeutics CONFIDENTIAL 
Study Design 
This is a multicenter, randomized, open-label, Phase 2 study of the 
safety, efficacy, and pharmacokinetics (PK) of trilaciclib in 
combination with GC therapy for patients with metastatic TNBC. A 
total of approximately 90 patients will be randomly assigned (1:1:1 
fashion) to 1 of the following 3 groups: 
• Group 1: GC therapy (Days 1 and 8 of 21-day cycles) only 
(n=30) 
• Group 2: GC therapy (Days 1 and 8) plus trilaciclib 
administered intravenous (IV) on Days 1 and 8 of 21-day 
cycles (n=30) 
• Group 3: GC therapy (Days 2 and 9) plus trilaciclib 
administered IV on Days 1, 2, 8, and 9 of 21-day cycles (n=30) 
The study will include 3 study phases: Screening Phase, Treatment 
Phase, and Survival Follow-up Phase. The Treatment Phase begins on 
the day of first dose with study treatment and completes at the 
Post-Treatment Visit.  
Randomization will be stratified as follows: liver involvement (yes or 
no) and the number of prior lines of anticancer therapy in the locally 
recurrent/metastatic setting at the time of randomization (0 or 1-2). 
Criteria for Subsequent Cycles and Study Duration 
In all 3 groups, study drug administration will continue until disease 
progression per Response Evaluation Criteria in Solid Tumors 
(RECIST), Version 1.1, unacceptable toxicity, withdrawal of consent, 
or discontinuation by investigator, whichever occurs first. Treatment 
cycles will occur consecutively without interruption, except when 
necessary to manage toxicities or for administrative reasons as 
described below. There should be no more than 4 weeks between 
doses of chemotherapy. Dosing delays > 4 weeks may be permitted 
on a case-by-case basis with the approval of the investigator and 
medical monitor. 
Patients must meet all of the following criteria to receive the Day 1/2 
dose of each cycle: absolute neutrophil count (ANC) ≥ 1.0 × 109/L, 
platelet count ≥ 100 × 109/L, and nonhematologic toxicities must be 
≤ Grade 2 or have returned to baseline. If the initiation of the next 
cycle is delayed due to toxicity, the patient should have (at least) 
weekly visits to follow the toxicity.  
Patients must meet all of the following criteria to receive the Day 8/9 
dose of each cycle: ANC ≥ 1.0 × 109/L, platelet count ≥ 75 × 109/L, 
and nonhematologic toxicities must be ≤ Grade 2 or have returned to 
baseline. If these criteria are not met, the Day 8/9 GC doses should be 
skipped; no dose reductions or delays are allowed for the Day 8/9 GC 
doses. If the Day 8/9 GC doses are skipped, the next GC doses 
become Day 1/2 of the subsequent cycle. There should be at least 
7 days between a skipped Day 8/9 dose and the start of the next cycle, 
ie, Day 1/2. Note that the criteria for starting Day 1/2 outlined above 
will apply to resumption of dosing. The Survival Follow-up Phase of 
the study will continue until at least 50% of the patients on the study 
have died. The G1T28-04 study will be completed when the Survival 
Follow-up Phase has been completed, or upon sponsor termination of 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-04 
Trilaciclib 
 
Version: 4.0, dated 31 August 2017 
 
Page 16 of 107  
G1 Therapeutics CONFIDENTIAL 
the study. 
Safety Assessments 
Safety assessments will include monitoring of adverse events (AEs) 
and infusion-related reactions, vital signs measurements, physical 
examinations, electrocardiograms (ECGs), and clinical laboratory 
studies. Tumor response criteria are based on RECIST, Version 1.1 
(Eisenhauer et al. 2009), PFS, and OS.  
An independent data monitoring committee (DMC) will perform 
interim reviews of accumulating safety and disposition data 
approximately every 4 months during the Treatment Phase of the 
study, depending upon the enrollment rate. The first DMC meeting 
will occur after approximately the first 20 patients have been enrolled 
and completed at least 1 cycle. Details of the DMC, including 
objectives, composition, scope, and frequency, will be described in a 
DMC charter. 
Tumor Assessment 
Tumor assessments will be based on RECIST v1.1. For tumor 
assessment, all sites of disease should be assessed radiologically by 
computed tomography (CT) or magnetic resonance imaging (MRI) at 
screening and every 9 weeks ± 7 days (Week 9, Week 18, and Week 
27) and then every 12 weeks ± 7 days thereafter until the occurrence 
of disease progression, withdrawal of consent, the initiation of 
subsequent anticancer therapy, or study completion. Tumor 
assessments should include CT with contrast or MRI with contrast (if 
clinically possible) of the chest and abdomen.  
Radionuclide bone scans shall be performed at screening. Skeletal 
lesions identified on the bone scan at baseline, which are not visible 
on the CT or MRI scan, should be imaged at baseline and followed at 
scheduled visits using localized CT, MRI, or x-ray. Bone scans need 
not be repeated after baseline unless clinically indicated.    
Brain scans with contrast (by CT or MRI) shall be performed at 
screening for all patients. If brain metastases are present at screening, 
brain scans shall be done with each protocol-specified tumor 
assessment. If no metastases are present at screening, imaging does 
not need to be performed during the study unless clinically indicated 
or if the subject is neurologically symptomatic. 
Any CT, MRI, bone, or brain scan obtained as standard of care prior 
to screening will not need to be repeated if performed within the 
screening period. 
Additional scans may be obtained at the discretion of the investigator, 
if clinically indicated. If a patient shows a radiological response 
(complete response [CR] or partial response [PR]), a confirmatory 
radiological assessment will be performed at least 4 weeks after the 
response was first noted. For those patients who have not progressed 
at the time of study drug discontinuation, radiological tumor 
assessments will be performed utilizing the same imaging modality as 
used at screening, every 12 weeks ± 7 days from the Post-Treatment 
Visit until progression, withdrawal of consent, initiation of 
subsequent anticancer therapy, or study completion. 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-04 
Trilaciclib 
 
Version: 4.0, dated 31 August 2017 
 
Page 17 of 107  
G1 Therapeutics CONFIDENTIAL 
Treatment Duration  
Study drug administration will continue for each patient until disease 
progression per RECIST, Version 1.1, unacceptable toxicity, 
withdrawal of consent, or discontinuation by investigator, whichever 
occurs first. 
Study Duration 
The total study duration is at least 19 months, assuming 12 months of 
accrual, 4 weeks of screening, 4.5 months of treatment (assuming 
6 cycles), and 2 months of safety follow-up. 
The Survival Follow-up Phase will continue until at least 50% of the 
patients have died. 
Approximate Number of 
Patients 
Overall, approximately 90 patients will be enrolled in the study. The 
90 patients will be randomly assigned (1:1:1) to 1 of 3 groups.  
Number of Study Centers 
Approximately 50 centers in North America and Europe 
Diagnosis and Main Criteria 
for Inclusion 
For a patient to be eligible for participation in this study, all of the 
following criteria must apply. 
1. Female or male patients with evaluable locally recurrent or 
Stage IV metastatic TNBC 
2. Age ≥ 18 years  
3. Histologically or cytologically confirmed hormone (estrogen 
and progesterone) receptor negative tumor on local pathology 
IHC assessment (defined as < 10% nuclei staining) and human 
epidermal growth factor receptor 2 (HER2)-negative, 
nonoverexpressing (by local assessment of IHC [0 or 1+] OR  
fluorescent in situ hybridization [ratio < 2.0] OR average HER2 
gene copy number of < 4 signals/nucleus) 
4. Patients must have tumor tissue available from their TNBC 
diagnostic sample (archived tissue allowed) for retrospective 
analysis of potential biomarkers  
5. Hemoglobin ≥ 9.0 g/dL in absence of RBC transfusion within 
14 days prior to first dose of trilaciclib 
6. ANC ≥ 1.5 × 109/L 
7. Platelet count ≥ 100 × 109/L 
8. Serum creatinine ≤ 1.5 mg/dL or creatinine clearance 
≥ 60 mL/minute   
9. Total bilirubin ≤ 1.5 × upper limit of normal (ULN); 
< 3 × ULN if the patient has documented Gilbert’s disease 
10. Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤ 2.5 × ULN; ≤ 5 × ULN in the presence of liver 
metastases  
11. Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 to 1 
12. Resolution of nonhematologic toxicities from prior therapy or 
surgical procedures to ≤ Grade 1 (except alopecia)  
13. Predicted life expectancy of ≥ 3 months 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-04 
Trilaciclib 
 
Version: 4.0, dated 31 August 2017 
 
Page 18 of 107  
G1 Therapeutics CONFIDENTIAL 
14. Contraception: 
a. 
For females: All females of childbearing potential must 
have a negative serum beta human chorionic 
gonadotropin (β-hCG) test result at screening and a 
negative serum or urine pregnancy test result at baseline 
(within 24 hours of the first dose). Females must be 
either postmenopausal, surgically sterile, or agree to use 
2 forms of highly effective contraception during the 
study and for 6 months following discontinuation of 
study treatment  
i. Postmenopausal is defined as at least 60 years of age, 
medically confirmed ovarian failure, younger than 60 
years of age and have had cessation of regular menses 
for at least 12 consecutive months with no alternative 
pathological or physiological cause, and/or serum levels 
of estradiol and follicle stimulating hormone within the 
laboratory’s reference range for postmenopausal females 
ii. Acceptable surgical sterilization techniques are 
complete or partial hysterectomy or bilateral tubal 
ligation with surgery at least 6 months prior to dosing, 
and bilateral oophorectomy with surgery at least 
2 months prior to dosing  
iii. Highly effective methods of contraception are those that 
result in a low failure rate (ie, less than 1% per year) 
when used consistently and correctly. These include the 
following: 
1. Established use of oral, injected or implanted 
hormonal methods of contraception (stable dose 
at least 3 months prior to dosing)  
2. Placement of an intrauterine device or intrauterine 
system  
3. Barrier methods of contraception: condom or 
occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal 
foam/gel/film/cream/suppository. Barrier 
methods alone (without spermicide) are not 
acceptable methods. Likewise, spermicide alone is 
not an acceptable method 
4. Male sterilization (with the appropriate 
post-vasectomy documentation of the absence of 
sperm in the ejaculate). For female subjects on the 
study, the vasectomized male partner should be 
the sole partner for that subject   
5. True abstinence, when this is in line with the 
preferred and usual lifestyle of the subject. 
Periodic abstinence (eg, calendar, ovulation, 


G1 Therapeutics, Inc. 
Clinical Study Protocol G1T28-04 
Trilaciclib 
 
Version: 4.0, dated 31 August 2017 
 
Page 19 of 107  
G1 Therapeutics CONFIDENTIAL 
symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of 
contraception   
b. For males: Males must be surgically sterile or have a female 
partner who is either postmenopausal, surgically sterile, or 
using 2 forms of highly effective contraception as noted 
above. Acceptable surgical sterilization techniques are 
vasectomy with surgery at least 6 months prior to dosing. 
Males must also refrain from sperm donation during the 
study and for 6 months following discontinuation of 
treatment 
15. Able to understand and sign an informed consent 
Criteria for Exclusion 
A patient will not be eligible for participation in this study if any of 
the following criteria apply. 
1. More than 2 prior chemotherapy regimens for locally recurrent 
or metastatic TNBC (noncytotoxic therapies are not considered 
prior lines of therapy). For a regimen to be a line of therapy, the 
patient must have disease progression after that therapy prior to 
the start date of the next therapy or enrollment in this study. 
Therapy given in the neoadjuvant/adjuvant setting where the 
patient has recurrent disease > 12 months after the last dose of 
therapy will NOT be considered a line of therapy in the locally 
recurrent or metastatic setting. 
2. Malignancies other than TNBC within 3 years prior to 
randomization, with the exception of those with a negligible 
risk of metastasis or death treated with expected curative 
outcome 
3. Presence of CNS metastases/leptomeningeal disease requiring 
immediate treatment with radiation therapy or steroids (ie, 
patient must be off steroids administered for brain metastases 
for at least 14 days prior to the first dose of G1T28).  
4. Uncontrolled ischemic heart disease or uncontrolled 
symptomatic congestive heart failure (Class III or IV as defined 
by the New York Heart Association [NYHA] functional 
classification system) 
5. Known history of stroke or cerebrovascular accident within 
6 months prior to first dose of trilaciclib 
6. Known serious active infection (eg, human immunodeficiency 
virus [HIV], hepatitis B or C, tuberculosis, etc.) 
7. 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 
8. Prior hematopoietic stem cell or bone marrow transplantation 
9. Concurrent radiotherapy to any site or radiotherapy within 
2 weeks prior to the first dose of trilaciclib  




G 1 T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Vers i o n: 4. 0, date d 31 A u g ust  2 0 1 7  
 
Pa ge 2 1  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
Statistical A n al ysis  
Data will be s u m marize d descri pti vel y b y treat me nt gr o u p a n d f or 
c o m bi ne d treat me nt Gr o u ps 2 a n d 3. Treat me nt differe nces bet wee n t he 
G C t hera p y ( Gr o u p 1) a n d eac h of t he ot her treat me nt gr o u ps ( Gr o u ps 2 
a n d 3) will be esti mate d. T he descri pti ve s u m mar y f or t he cate g orical 
varia bles will i ncl u de c o u nts a n d perce nta ges. T he descri pti ve s u m mar y 
f or t he c o nti n u o us varia bles will i ncl u de mea ns, me dia ns, sta n dar d 
de viati o ns, a n d mi ni m u m a n d ma xi m u m val ues. T he descri pti v e 
s u m maries of ti me-t o-e ve nt data will i ncl u de me dia n, t we nt y-fift h a n d 
se ve nt y-fift h perce ntiles, a n d sta n dar d err or. All data will be liste d f or 
all patie nts. 
T his st u d y is descri pti ve i n nat ure, a n d n o f or mal h y p ot hesis testi n g will 
be perf or me d acr oss treat me nt gr o u ps. All c o nfi de nce i nter vals  ( CIs) 
will be 9 5 %, u nless state d ot her wise.  
A D M C will perf or m i nteri m re vie ws of acc u m ulati n g safet y a n d 
dis p ositi o n data d uri n g t he Treat me nt P hase. T he fi nal a nal ysis will be 
perf or me d after all patie nts ha ve c o m plete d t he P ost -Treat me nt Visit. A 
s u p ple me ntal a nal ysis i ncl u di n g t he c u m ulati ve data c ollecte d d uri n g 
t he S ur vi val F oll o w-u p P hase will be c o m plete d at t he e n d of st u d y.  
T he f ull a nal ysis set ( F A S) i ncl u des all patie nts w h o recei ve d at least 
C CI


G 1 T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Vers i o n: 4. 0, date d 31 A u g ust  2 0 1 7  
 
Pa ge 2 2  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
1  d ose of st u d y dr u g a n d will be t he pri mar y p o p ulat i o n f or efficac y a n d 
e x pl orat or y e n d p oi nts. S u m maries of efficac y will be perf or me d usi n g 
t he F A S o n he mat ol o gic ki netics, he mat ol o gic t o xicit y, i nfecti o ns, 
gr o wt h fact or a n d a nti bi otic use, tra nsf usi o ns, c he m ot hera p y e x p os ure, 
a n d 
. Select s u m maries will als o be 
re peate d i n t he per pr ot oc ol ( P P ) a nal ysis set. U nless n ote d ot her wise, 
he mat ol o gic e n d p oi nts will be s u m marize d se paratel y b y eac h 
para meter t y pe (ie, A N C, l y m p h oc ytes, etc.). A nal yses c o m pari n g 
treat me nt gr o u ps will a djust f or pri or c he m ot hera p y re gi me ns a n d ot her 
rele va nt para meters. E ve nt rates will be calc ulate d base d o n c u m ulati ve 
G C e x p os ure t o acc o u nt f or p ote ntial differe nces i n G C e x p os ure acr oss 
treat me nt gr o u ps. 
T he n u m ber a n d perce nta ge of pati e nts e x perie nci n g a n y 
treat me nt-e mer ge nt A E, o verall, a n d b y s yste m or ga n class a n d 
preferre d ter m will be ta b ulate d. T he i nci de nce rates a dj uste d b y 
c u m ulati ve e x p os ure will als o be prese nte d o verall a n d b y c y cle. 
A bs ol ute val ues a n d c ha n ges fr o m scree ni n g i n vital si g ns, E C G 
rea di n gs, a n d he mat ol o g y a n d cli nical c he mistr y para meters will be 
ta b ulate d at eac h visit d uri n g t he Treat me nt P hase. T o xicities f or 
cli nical la bs will be c haracterize d acc or di n g t o t he C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) , Versi o n 4. 0 3. 
S hifts i n t o xicit y gra des fr o m scree ni n g t o eac h visit will be 
s u m marize d. O verall disease res p o nses as deter mi ne d b y R E CI S T, 
Versi o n 1. 1 , will be s u m marize d b y res p o nse le vel at eac h visit a n d best 
o verall res p o nse. P F S  a n d O S will be s u m marize d usi n g Ka pla n -Meier 
met h o ds.  
Plas ma c o nce ntrati o n -ti me data will be ta b ulate d descri pti vel y a n d 
pl otte d f or eac h bl o o d sa m pli n g da y. P K  para meters will be calc ulate d 
usi n g n o nc o m p art me ntal met h o ds ba se d o n t he plas ma 
c o nce ntrati o n -ti me data. P K  para meters will be s u m marize d 
descri pti vel y b y visit a n d a nal yte.  
Rati o nale f or N u m ber of 
Patie nt s 
T he sa m ple size is n ot deter mi ne d fr o m a statistical pers pecti ve. 
A p pr o xi matel y 9 0 patie nts will be e nr olle d i nt o t he st u d y ( 3 0 per 
treat me nt gr o u p). 
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4. 
INTRODUCTION 
4.1. 
Background 
Chemotherapy-induced myelosuppression is a significant issue in cancer treatment, including 
treatment of metastatic triple negative breast cancer (TNBC) (O’Shaughnessy et al. 2014). 
Patients with myelosuppression are more likely to experience infections, sepsis, bleeding, 
and fatigue, often leading to the need for hospitalizations, hematopoietic growth factor 
support, and transfusions (red blood cells [RBCs] and/or platelets). Moreover, 
chemotherapy-induced myelosuppression commonly leads to dose reductions which limit 
therapeutic dose intensity.  
In addition to the side effects of chemotherapy, chemotherapy-induced immunosuppression 
may limit antitumor efficacy due to an inability of the host immune system to effectively 
mount a response against the cancer. Therefore, preserving the bone marrow and immune 
system from the cytotoxic effects of chemotherapy has the potential to maximize antitumor 
activity of the chemotherapy while minimizing myelotoxicity.  
Targeted protection of the bone marrow and immune system through transient gap 1 (G1) 
phase arrest of hematopoietic stem and progenitor cells (HSPCs) offers the potential to 
minimize myelotoxicity, while improving chemotherapy efficacy. This approach, previously 
described as “pharmacological quiescence,” is built on several key principles: a highly potent 
cyclin-dependent kinase (CDK)4/6 inhibitor, highly selective for CDK4/6 versus CDK2 (and 
other kinases); the ability to harness cell cycle control with accuracy (ie, to produce a “clean” 
G1 arrest, without inducing arrest in other phases of the cell cycle); and temporal precision 
(ie, the ability to regulate bone marrow proliferation as desired, producing a “transient, 
reversible” arrest) (Johnson et al. 2010; Roberts et al. 2012).   
Trilaciclib (G1T28) is a highly potent, short-acting, selective, and reversible CDK4/6 
inhibitor that transiently arrests cells in the G1 phase of the cell cycle. Trilaciclib is being 
developed to preserve bone marrow and immune system function (including lymphoid 
progenitors and lymphocytes) from damage by chemotherapy, allowing faster hematopoietic 
recovery, preserving long-term bone marrow function, and enhancing the antitumor activity. 
In addition to preserving bone marrow function, trilaciclib administration prior to 
chemotherapy preserves lymphocyte numbers and function and transiently increases 
proliferation of lymphocytes and other immune cells coinciding with 
chemotherapy-associated neoantigen release. As a result of the effects on immune system 
function, trilaciclib could allow for maximal priming of the immune system to generate a 
more efficacious immune response. 
The principal component of the therapeutic approach in this study is to transiently arrest 
HSPCs in the G1 phase of the cell cycle while chemotherapy is administered. It is imperative 
that this therapeutic approach provides selective bone marrow protection without 
antagonizing the antitumor efficacy of chemotherapy. To ensure this second feature, patients 
are required to have CDK4/6-independent tumors. TNBC is a largely CDK4/6-independent 
tumor (Cancer Genome Atlas Network 2012; Gatza et al. 2014; Finn et al. 2009; Roberts et 
al. 2012; Treré et al. 2009). Therefore, trilaciclib administered prior to chemotherapy 


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(gemcitabine and carboplatin [GC]) in TNBC patients is unlikely to impact the intended 
activity of the chemotherapy agents.  
4.2. 
Summary of Clinical Data 
A brief summary of the clinical data is provided in the following sections. Detailed 
information is presented in the trilaciclib Investigator’s Brochure (IB). 
Study G1T28-1-01 was a Phase 1a, safety, pharmacokinetic (PK), and pharmacodynamic 
study of trilaciclib. Forty-five healthy male and female subjects were enrolled into 7 dose 
cohorts where trilaciclib was administered IV as a 30-minute infusion (randomized, 
double-blind, placebo-controlled ascending doses of 6, 12, 24, 48, 96, or 192 mg/m2, and an 
open-label expanded pharmacodynamic cohort at 192 mg/m2). 
The most frequently (> 10% of subjects) reported adverse events (AEs) were the following: 
headache (17 subjects, 38%), nausea (10 subjects, 22%), pain in extremity (8 subjects, 18%), 
and procedural pain (7 subjects, 16%). The treatment-emergent AEs of headache and nausea 
occurred more frequently in the combined 192 mg/m2 dose group (14 events of headache 
reported by 13 subjects [72%] and 10 events of nausea reported by 9 subjects [50%]) than in 
the lower dose groups. Most treatment-emergent AEs were mild in intensity; 13 subjects 
experienced a total of 19 treatment-emergent AEs of moderate intensity. Four AEs of 
moderate intensity occurred in the 96 mg/m2 dose group (2 events of headache [possibly 
related], 1 event of back pain [unlikely related], and 1 event of nausea [possibly related]). 
Fifteen AEs of moderate intensity occurred in the combined 192 mg/m2 dose group (7 events 
of headache [all possibly related], 6 events of nausea [all possibly related], 1 event of 
procedural anxiety [not related], and 1 event of loss of appetite [possibly related]). No severe 
or life-threatening events were reported. There were no deaths, other serious adverse events 
(SAEs), or treatment-emergent AEs resulting in withdrawal from the study. All 
treatment-emergent AEs were transient and recovered/resolved by the end of the study. No 
significant changes were noted in 12-lead electrocardiograms (ECGs), vital signs, or 
laboratory values (including complete blood counts [CBCs]). 
Following a single 30-minute IV infusion of trilaciclib, the median time to reach the 
maximum concentration (Tmax) ranged between 0.25 and 0.47 hour after the start of infusion. 
The maximum concentration (Cmax) increased in a dose-proportional manner following a 
single 30-minute IV infusion of trilaciclib over the dose range of 6 to 192 mg/m2. Total 
systemic (area under the concentration-time curve [AUC]) exposure increased more than 
dose proportionally over the dose range of 6 to 192 mg/m2 of trilaciclib. The elimination 
kinetics of trilaciclib appeared to follow a 3-compartment model. The geometric mean 
half-life (t1/2) was 12.9 to 14.7 hours for the 48 to 192 mg/m2 dose levels. The interpatient 
variability (%CV) of the PK parameters at the 192 mg/m2 dose level was low (< 15%). The 
PK of trilaciclib suggests that drug accumulation following repeated administration is 
unlikely to occur. Urinary excretion appears to be a minor route of elimination for unchanged 
trilaciclib. 
Trilaciclib showed positive pharmacodynamic effects in 2 assays. Dose-dependent inhibition 
of ex vivo whole blood stimulation occurred following a single IV infusion of trilaciclib at 96 
and 192 mg/m2 (maximum mean inhibition of 37.2% and 60%, respectively, occurred 


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Trilaciclib 
 
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4 hours after the end of infusion). Lymphocyte proliferation started to recover 8 hours after 
the end of infusion, but inhibition of proliferation persisted until the last sampling time point 
of 24 hours. Assessment of bone marrow 24 hours after administration of trilaciclib at the 
biologically effective dose (BED) of 192 mg/m2 revealed a significant decrease in the 
number of HSPCs in the synthesis (S)/gap 2 (G2)/mitosis (M) phases of the cell cycle (ie, an 
increase in the proportion of cells in G1 arrest). This G1 arrest persisted in the different 
progenitor lineages 32 hours after dosing. However, no changes were noted in the peripheral 
blood counts, indicating that the bone marrow arrest is transient and reversible and is 
consistent with the effects seen in animals.  
In 2 ongoing Phase 1b/2a studies (G1T28-02 and G1T28-03) in small cell lung cancer 
(SCLC), which is a CDK4/6-independent tumor, trilaciclib administered prior to every dose 
of etoposide and carboplatin (first line for extensive-stage SCLC) and prior to every dose of 
topotecan (second/third line for SCLC) are being tested. Early results have demonstrated 
minimal clinically significant myelotoxicity at the recommended Phase 2 dose of trilaciclib 
(240 mg/m2) when administered prior to chemotherapy, and antitumor activity has been 
consistent with or better than historical data.  
In G1T28-02, as of the data cutoff date of 20-May-2016, the majority of patients (81.8%; 9 
of 11) reported TEAEs, with the most common (ie, reported by > 30% of patients) being 
fatigue, nausea, anemia, neutropenia, and alopecia. TEAEs considered related to trilaciclib 
per investigator assessment were reported by 4 patients (36.4%). The majority of patients 
(72.7%) reported at least 1 Grade 3, 4, or 5 TEAE; those reported by more than 1 patient 
included neutropenia, anemia, leukopenia, and lymphopenia. Less than one-half of patients 
(36.4%) reported an SAE; all of which were considered unlikely or not related to trilaciclib 
and did not meet dose-limiting toxicity (DLT) criteria. One patient died during participation 
in the study due to an SAE of hypoxia that was considered unrelated to trilaciclib by the 
investigator.   
In G1T28-03, as of the data cutoff date of 20-May-2016, the majority of patients (92.9%; 13 
of 14) reported TEAEs, with the most common (ie, reported by > 50% of patients) being 
thrombocytopenia, neutropenia, anemia, and leukopenia. TEAEs considered related to 
trilaciclib per investigator assessment were reported by 4 patients (28.6%). The majority of 
patients (85.7%) reported at least 1 Grade 3, 4, or 5 TEAE; those reported by more than 1 
patient included thrombocytopenia, leukopenia, neutropenia, anemia, neutrophil count 
decreased, pneumonia, and dyspnea. The majority of the Grade 3, 4, or 5 TEAEs have been 
reported by patients in Cohorts 1 and 2, likely due to the supratherapeutic levels of topotecan 
observed in these patients, which may be responsible for the higher number of hematology-
related TEAEs in Cohorts 1 and 2. Over one-half of patients (64.3%) reported an SAE, all of 
which were considered unlikely or not related to trilaciclib and did not meet DLT criteria. 
One patient died during participation in the study due to an SAE of disease progression that 
was considered unrelated to trilaciclib by the investigator.    
The PK assessments of trilaciclib in the ongoing studies support the findings from the study 
in healthy male and female subjects (GT128-01). Clearance was observed to be high, with 
little or no drug accumulation during 3 or 4 days of dosing, except at the 
trilaciclib 280 mg/m2 dose level tested in Study G1T28-03.    


G 1 T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Vers i o n: 4. 0, date d 31 A u g ust  2 0 1 7  
 
Pa ge 2 6  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
4. 3. 1.  
P h ar m ac ol o g y St u dies 
T hr o u g h a str uct ure- base d desi g n a p pr oac h t o o pti mize p ote nc y, selecti vit y, a n d dr u g 
meta b olis m a n d P K pr o perties, G 1 T hera pe utics , I nc. i de ntifie d trilacicli b as a hi g hl y p ote nt 
i n hi bit or of C D K 4 a n d C D K 6 ( half ma xi mal i n hi bit or y c o nce ntrati o n [I C5 0] val ues of 0. 8 a n d 
6 n M, res pecti vel y) t hat is hi g hl y se lecti ve f or C D K 4 vers us c ycli n- de pe n de nt ki nase 
2 ( C D K 2 ) ( > 2 0 0 0-f ol d selecti vit y). 
T he trilacicli b-i n d uce d G1 arrest of H S P Cs has bee n s h o w n t o be tra nsie nt a n d rea dil y 
re versi ble i n b ot h i n vitr o a n d i n vi v o m o dels. I n vi v o a nal ysis has de m o nstrate d t hat 
trilacicli b i n c o m bi nati o n wit h m yel os u p pressi ve c he m ot hera p y  lea ds t o i m pr o ve d C B C 
rec o ver y of all bl o o d linea ges a n d i ncrease d s ur vi val. I n a d diti o n, a d mi nistrati o n of trilacicli b 
wit h e ver y c ycle of t he hi g hl y m yel os u p pressi ve c he m ot hera p y 5 -fl u or o uracil ( 5-F U) f or a 
t otal of 4 c ycles de m o nstrate d t ha t t he re d ucti o n i n c he m ot hera p y-i n d uce d m yel osu p pressi o n 
persiste d f oll o wi n g C ycle 4. W hile t he e xte nt a n d d urati o n of na dir i n C B Cs w orse ne d after 
eac h c ycl e of 5- F U a d mi nistere d al o ne, trilacicli b i n c o m bi nati o n wit h 5 -F U a meli orat e d t his 
w orse ni n g effect a n d t he a ni mals t hat recei ve d trilacicli b + 5 -F U de m o nstrate d a faster rate  of 
rec o ver y of C B Cs c o m pare d wit h t he 5- F U al o ne gr o u p f oll o wi n g C ycle 4. I n acc or da nce 
wit h t he si n gle -d ose st u d y, trilacicli b a d mi nistrati o n wit h all c yc les of 5-F U mai ntai ne d  t he 
pr otecti ve effect a gai nst 5 -F U -i n d uce d D N A da ma ge i n H S P Cs o ver m ulti ple c ycles, lea di n g 
t o a n effect t hat persiste d a n d was greater f oll owi n g m ulti ple c ycles of trilacicli b + 5-F U 
c o m pare d wit h 5- F U al o ne.   
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G 1 T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Vers i o n: 4. 0, date d 31 A u g ust  2 0 1 7  
 
Pa ge 2 7  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
T he reti n o blast o ma ( R B) t u m or s u p press or ge ne is a critical ne gati ve cell c ycle re g ulat or t hat 
li n ks gr o wt h fact or si g nali n g t o cell c ycle pr o gressi o n. Si g nali n g pat h wa ys t hat sti m ulate 
pr oliferati o n i m pi n ge o n t he cell c ycle mac hi ner y i n se veral wa ys i ncl u di n g t he a u g me nti n g 
pr o d ucti o n of D-t y pe c ycli ns. Acc u m ulati o n of D-t y pe c ycli ns al o n g wit h c o nc o mita nt 
acti vati o n of t heir catal ytic part ners, C D K 4 a n d C D K 6, has bee n s h o w n t o acti vate cell c ycle 
pr o gressi o n pri maril y b y p h os p h or ylati o n a n d t he s u bse q ue nt s u p pressi o n of R B. W he n 
acti ve, t he reti n o blast o ma pr otei n ( R b) l oc ks cell c ycle pr o gressi o n b y f or mi n g re pressi ve 
c o m ple xes wit h tra nscri pti o n fact ors ( n ota bl y t he E 2 F fa mil y), w hic h are critical f or S p hase 
e ntr y a n d pr o gressi o n. U nli ke h u ma n e pi der mal gr o wt h fact or rece pt or 2 ( H E R 2)- p ositi ve or 
estr o ge n rece pt or ( E R )-p ositi ve breast ca ncers t hat ha ve relati vel y li mite d l oss of R B, T N B C 
e x hi bits fre q ue nt l oss of R B t hr o u g h a variet y of mec ha nis ms (Treré et al.  2 0 0 9; 
Hersc h k o witz et al. 2 0 0 8; Stefa nss o n et al. 2 0 1 1 ), w hic h lea ds t o re d uce d R b pr otei n 
e x pressi o n, hi g h le vels of p 1 6i n k 4a o bser ve d i n ma n y T N B C cases (S u b ha w o n g et al. 2 0 0 9 ), 
a n d ver y hi g h e x pressi o n le vels of R B/ E 2 F si g nat ure ge nes relati ve t o ot her t u m or s u bt y pes 
(Hersc h k o witz et al. 2 0 0 8; Ertel et al. 2 0 1 0 ). A d diti o nall y, t he relati o ns hi p bet wee n R B a n d 
de vel o p me nt of T N B C is s u p p orte d b y t he de vel o p me nt of a breast ca ncer m o use m o del i n 
w hic h c o n diti o nal l oss of p 5 3 a n d R B lea ds t o t he de ve l o p me nt of breast ca ncer i n t he mice 
t hat e x q uisitel y reca pit ulates h u ma n T N B C (Mar o ula k o u et al. 1 9 9 4 ). Fi nall y, ge ne 
e x pressi o n a nal ysis a n d i m m u n o hist oc he mical (I H C) a p pr oac hes ha ve s h o w n t hat t u m ors t hat 
lac k R B ha ve a g o o d res p o nse t o c he m ot hera p y, as i n dicate d b y a pat h ol o gical c o m plete 
res p o nse i n ne oa dj u va nt st u dies or i m pr o ve d o verall o utc o me (Hersc h k o witz et al. 2 0 0 8; 
Ertel  et al. 2 0 1 0; Wit kie wicz et al. 2 0 1 2). T his fi n di n g is c o u nteri nt uiti ve beca use it s u g gests 
t hat t he m ost a g gressi ve ra pi dl y gr o wi n g t u m ors i n fact ha ve t he best pr o g n osis. T he 
pre vaili n g vie w of t his para d o x is t hat s uc h ra pi dl y pr olif erati n g t u m ors lac k critical 
R b -me diate d cell c ycle c hec k p oi nts a n d are t h us ver y se nsiti ve t o c he m ot hera p y  
(K n u dse n & Wa n g 2 0 1 0; R o bi ns o n et al. 2 0 1 3 ). Si nce a R B- deficie nt p he n ot y pe is c o m m o n 
i n T N B C, it is e x pecte d t hat trilacicli b will ha ve n o effect o n t u m or gr o wt h or pr oliferati o n. 
T heref ore, t here is little c o ncer n t hat trilaciclib a d mi nistere d i n c o m bi nati o n wit h tra diti o nal 
c he m ot hera p y ( G C ) will a nta g o nize t he i nte n de d efficac y of t he c he m ot hera p y. W hile 
trilacicli b is n ot e x pecte d t o directl y i m pact t u m or pr oliferati o n, it has t he p ote ntial to greatl y 
i m pr o ve t he c urre nt sta n dar d of care i n T N B C b y pr otecti n g t he b o ne marr o w a n d i m m u ne 
s yste m d uri n g c he m ot hera p y, t here b y all o wi n g faster he mat o p oietic rec o ver y, preser vati o n of 
l o n g-ter m ste m cell a n d i m m u ne s yste m f u ncti o n, a n d e n ha nce me nt of c he m ot hera p y 
a ntit u m or acti vit y.  
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G 1 T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Vers i o n: 4. 0, date d 31 A u g ust  2 0 1 7  
 
Pa ge 2 8  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
Ge mcita bi ne has n ot bee n re p orte d t o be a s u bstrate f or M A T E 1 or M A T E 2  
(Blac k hall et al. 2 0 1 0; S he n  et al. 2 0 1 3), a n d is n ot belie ve d t o be a s u bstrate f or O C T 2. As 
s uc h, a cli nicall y si g nifica nt alterati o n of ge mcita bi ne P K d ue t o trilacicli b tra ns p orter 
( O C T 2, M A T E 1, or M A T E 2-K) i n hi biti o n is n ot e x pecte d.  
Ca r b o plati n has n ot bee n re p orte d t o be a s u bstrate f or O C T 2, M A T E 1, or M A T E 2 
(Y o neza wa  2 0 0 6). Base d u p o n t hese data, a cli nicall y si g nifica nt alterati o n of car b o plati n P K 
d ue t o trilacicli b i n hi biti o n of O C T 2, M A T E 1, or M A T E 2 -K is n ot e x pecte d.   
4. 3. 3.  
T o xicit y a n d S afet y St u dies 
T he t o xicit y of I V a n d oral trilacicli b was e val uate d i n s i n gle- a n d re peat- d ose st u dies of u p 
t o 1 4 da ys d urati o n i n rats a n d d o gs a n d i n a batter y of i n vitr o ge n ot o xicit y st u dies. I n 
a d diti o n, t he c o m pati bilit y of trilacicli b cli nical dr u g pr o d uct wit h h u ma n bl o o d was 
e val uate d i n vitr o. 
F or f urt her i nf or mati o n, please refer t o t he trilacicli b I B. 
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G 1 T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Vers i o n: 4. 0, date d 31 A u g ust  2 0 1 7  
 
Pa ge 2 9  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
Alt h o u g h trilacicli b i n d uce d micr o n ucle us f or mati o n i n h u ma n l y m p h oc ytes e x p ose d i n vitr o, 
trilacicli b is n ot c o nsi dere d t o p ose a hazar d t o h u ma n patie nts, as trilacicli b was ne gati ve f or 
m uta ge nic p ote ntial i n a G o o d La b orat or y Practice ( G L P ) (a n d n o n-G L P ) A mes assa y, a n d 
di d n ot i n d uce p h os p h or ylate d hist o ne H 2 A X  (γ H 2 A X) f or mati o n i n pri mar y h u ma n 
fi br o blasts. I n t he prese nt st u d y, trilacicli b will be a d mi nistere d i n c o nj u ncti o n wit h G C , 
w hic h prese nts a ge n ot o xic hazar d t o h u ma n s u bjects. I n t his c o nte xt , a n y sli g ht a d diti o nal 
ge n ot o xic hazar d p ose d b y trilacicli b is ne gli gi ble. 
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Trilaciclib 
 
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4.4. 
Study and Dose Rationale 
Triple negative breast cancer has been characterized by several aggressive clinicopathologic 
features including onset at a younger age, higher mean tumor size, higher grade tumors, and, 
in some cases, a higher rate of node positivity. Population-based studies have demonstrated 
reduced breast cancer-specific survival among patients with TNBC compared with receptor 
positive phenotypes. While targeted-based therapies have greatly impacted other subtypes of 
breast cancer, no targeted-based approaches have been approved for TNBC patients.  
Therefore, this group of patients continues to rely on the use of traditional cytotoxic agents. 
Interestingly, a paradox of higher sensitivity to neoadjuvant anthracycline therapy has been 
observed in patients with TNBC, who as stated above are known to have a poor prognosis 
(Liedtke et al. 2008; Carey et al. 2007; Rouzier et al. 2005). This observation is explained by 
the fact that women with TNBC who achieve a pathological complete response have similar 
outcomes as other breast cancer patients. However, women with the basal-like subtype that 
do not achieve a complete response have a significantly higher rate of recurrence and lower 
rate of survival. This finding highlights the importance of delivering full dose and scheduled 
chemotherapy in the treatment of basal-like breast cancer to ensure maximal response. 
However, chemotherapeutic regimens are often limited by toxic side effects that require 
reductions in chemotherapy dose intensity, through dose reductions, treatment delays, or 
stopping treatment all together. Myelosuppression is the major DLT of cancer chemotherapy, 
resulting in considerable morbidity and mortality along with frequent reductions in 
chemotherapy dose intensity. Reductions in chemotherapy dose intensity have been 
repeatedly shown to compromise disease control and survival of cancer patients including 
patients with TNBC. 
The goals of this study are to assess the safety and tolerability of combining trilaciclib in 
2 different schedules with GC therapy, to evaluate the effect of trilaciclib on 
chemotherapy-induced myelosuppression, and to evaluate the antitumor activity of 
trilaciclib + GC therapy (response rate, duration of response, progression-free survival [PFS], 
and overall survival [OS]). Group 3 of the study will test if there is added benefit in 
achieving maximal arrest of the bone marrow stem and progenitors prior to chemotherapy 
administration.  In naïve bone marrow of humans and other species, the majority of the 
hematopoietic stem cells and multipotent progenitor cells are arrested in the G1 phase of the 
cell cycle. However, proliferation of these cells greatly increases upon exposure to cytotoxic 
chemotherapy, making them more susceptible to chemotherapy exposure on subsequent days. 
In nonclinical animal studies, trilaciclib administration begins to arrest cells in the G1 phase 
of the cell cycle within 2 hours after administration and produces maximal arrest between 8 
to 12 hours. In humans, a single dose of trilaciclib has been shown to maintain G1 arrest for 
at least 32 hours. Previous clinical studies testing trilaciclib in combination with 
chemotherapy have used regimens where the chemotherapy was administered in consecutive 
days (1-3 or 1-5 of 21-day cycles). In these scenarios, it is believed that continued G1 arrest 
throughout the period of chemotherapy administration is required to prevent the 
compensatory proliferative increase of the HSPCs and their subsequent damage while 
chemotherapy is being administered on days 2 and beyond. In this study, the chemotherapy is 
not given on consecutive days, so it is reasonable to test if a predose of trilaciclib 
administered the day before and the day of chemotherapy would add additional benefit by 
producing maximal HSPC G1 arrest at the time of chemotherapy administration. 
Additionally, it is unknown if HSPC proliferation will be increased on Day 8/9 of dosing 


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Trilaciclib 
 
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compared to baseline. If so, a dose of trilaciclib the day before may provide additional 
benefit by reducing HSPC proliferation prior to chemotherapy administration on Day 9.    
4.5. 
Risk/Benefit Assessment 
Trilaciclib (CDK 4/6 inhibitor) is being developed to reduce chemotherapy-induced 
myelosuppression, which is known to cause morbidity and mortality in cancer patients. 
Patients with myelosuppression are more likely to experience infections, sepsis, bleeding, 
and fatigue, often leading to the need for hospitalizations, hematopoietic growth factor 
support, and transfusions (RBCs and/or platelets). Moreover, chemotherapy-induced 
myelosuppression commonly leads to dose reductions which limit therapeutic dose intensity. 
In addition to the side effects of chemotherapy, chemotherapy-induced immunosuppression 
may limit antitumor efficacy due to 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 immune system from the cytotoxic effects of chemotherapy has the 
potential to maximize antitumor activity of the chemotherapy while minimizing 
myelotoxicity. As stated in Section 4.2, the dose of 240 mg/m2 trilaciclib established in 
Phase 1b/2a SCLC studies will be administered in combination with a commonly used 
chemotherapy regimen of GC in order to determine if this will help preserve bone marrow 
and immune system function during chemotherapy. Bone marrow HSPCs require CDK4/6 
for proliferation. Triple negative breast cancer is a largely CDK4/6-independent tumor 
(Cancer Genome Atlas Network 2012; Gatza 2014; Finn 2009; Roberts 2012; Treré 2009). 
Therefore, the risk of producing a G1 cell cycle arrest of the tumor cells, and thereby 
protecting the tumor from chemotherapy, is small.  
In conclusion, there are potential benefits of combining trilaciclib at a dose of 240 mg/m2 
with GC therapy to protect the bone marrow HSPCs. Given that the tumor response should 
not be inhibited by trilaciclib, the potential benefit of combining GC with trilaciclib creates a 
positive benefit-to-risk ratio.   


G 1 T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Vers i o n: 4. 0, date d 31 A u g ust  2 0 1 7  
 
Pa ge 3 2  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
5.  
S T U D Y O B J E C TI V E S  
T he pri mar y, sec o n dar y, a n d 
o bjecti ve s of t his st u d y are prese nte d i n  Ta ble 5- 1 . 
T a ble 5- 1  
G 1 T 2 8- 0 4 : St u d y O bjecti ves 
Pri m ar y O bjecti ve a 
Assess t he safet y a n d t olera bilit y of trilacicli b a d mi nistere d wit h G C t hera p y  
Sec o n d ar y O bjecti ves a 
Assess t u m or res p o nse a n d d urati o n of res p o nse base d o n R E CI S T, Versi o n 1. 1  
Assess P F S a n d O S  
Assess d ose i nte nsit y of g e mcita bi ne a n d car b o plati n 
Assess t he P K pr ofile of trilacicli b 
Assess t he P K pr ofile of ge mcita bi ne a n d car b o plati n w he n a d mi nistere d wit h a n d wit h o ut trilacicli b 
Assess t he he mat ol o gic pr ofile ( ki netics a n d i nci de nce/ d urati o n/fre q ue nc y of t o xicities) of trilacicli b 
a d mi nistere d wit h G C t hera p y  
Assess t he i nci de nce of fe brile ne utr o pe nia  
Assess t he i nci de nce of i nfecti o ns  
Assess t he utilizati o n of R B C a n d platelet tra nsf usi o ns  
Assess t he utilizati o n of he mat o p oietic gr o wt h fact ors  
Assess t he utilizati o n of s yste mic a nti bi otics  
Assess t he i nci de nce of c he m ot hera p y d ose re d ucti o ns a n d d ose i nterr u pti o ns o verall  
Assess t he i nci de nce of Gra de 2 or greater ne p hr ot o xicit y  
Deter mi ne t he d ose sc he d ule of trilacicli b a d mi nistere d wit h G C t hera p y  
G C t hera p y = ge mcita bi ne + car b o plati n o n Da ys 1 a n d 8 or Da ys 2 a n d 9 of 2 1 -da y c y cles; O S = o verall s ur vi val; 
P F S  = pr o gressi o n-free s ur vi val; P K = p har mac o ki netic; 
; R B C = re d bl o o d cell; R E CI S T = Res p o nse 
E val uati o n Criteria i n S oli d T u m ors  
a. 
T he o bjecti ves wi ll be assesse d f or b ot h sc he d ules of trilacicli b ( Da ys 1 a n d 8 or Da ys 1, 2, 8, a n d 9 i n 2 1-da y 
c y cles) a d mi nistere d pri or t o  G C t hera p y  ( Da ys 1 a n d 8 or Da ys 2 a n d 9 i n 2 1-da y c y cles , res pecti vel y)  
C CI
C CI
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Trilaciclib 
 
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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design and Plan 
This is a multicenter, randomized, open-label, Phase 2 study of the safety, efficacy, and PK 
of trilaciclib in combination with GC therapy for patients with metastatic TNBC. A total of 
approximately 90 patients will be randomly assigned (1:1:1 fashion) to 1 of the following 
3 groups: 
• Group 1: GC therapy (Days 1 and 8 of 21-day cycles) only (n=30) 
• Group 2: GC therapy (Days 1 and 8) plus trilaciclib administered IV on Days 1 and 8 of 
21-day cycles (n=30) 
• Group 3: GC therapy (Days 2 and 9) plus trilaciclib administered IV on Days 1, 2, 8, and 
9 of 21-day cycles (n=30)  
Note: The interval between doses of trilaciclib on successive days in Group 3 should not 
be greater than 28 hours. Trilaciclib will be administered 30 minutes prior to GC dosing 
on Days 2 and 9. 
The study will include 3 study phases: Screening Phase, Treatment Phase, and Survival 
Follow-up Phase. The Treatment Phase begins on the day of first dose with study treatment 
and completes at the Post-Treatment Visit.  


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Trilaciclib 
 
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7. 
STUDY POPULATION  
7.1. 
Selection of Patients 
Overall, approximately 90 patients will be enrolled in the study. The 90 patients will be 
randomly assigned (1:1:1) to 1 of 3 groups. 
The study will be conducted at approximately 50 centers in North America and Europe. 
7.1.1. 
Inclusion Criteria 
For a patient to be eligible for participation in this study, all of the following criteria must 
apply. 
1. Female or male patients with evaluable locally recurrent or Stage IV metastatic TNBC 
2. Age ≥ 18 years  
3. Histologically or cytologically confirmed hormone (estrogen and progesterone) receptor 
negative tumor on local pathology IHC assessment (defined as < 10% nuclei staining) 
and HER2-negative, nonoverexpressing (by local assessment of IHC [0 or 1+] OR 
fluorescent in situ hybridization [ratio < 2.0] OR average HER2 gene copy number of <4 
signals/nucleus) 
4. Patients must have tumor tissue available from their TNBC diagnostic sample (archived 
tissue allowed) for retrospective analysis of potential biomarkers 
5. Hemoglobin ≥ 9.0 g/dL in absence of RBC transfusion within 14 days prior to first dose 
of trilaciclib 
6. ANC ≥ 1.5 × 109/L 
7. Platelet count ≥ 100 × 109/L 
8. Serum creatinine of ≤ 1.5 mg/dL or creatinine clearance ≥ 60 mL/minute 
9. Total bilirubin ≤ 1.5 × upper limit of normal (ULN); < 3 × ULN if the patient has 
documented Gilbert’s disease 
10. AST and ALT ≤ 2.5 × ULN; ≤ 5 × ULN in the presence of liver metastases  
11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 
12. Resolution of nonhematologic toxicities from prior therapy or surgical procedures to 
≤ Grade 1 (except alopecia)  
13. Predicted life expectancy of ≥ 3 months 
14. Contraception: 


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Trilaciclib 
 
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a. For females: All females of childbearing potential must have a negative serum beta 
human chorionic gonadotropin (β-hCG) test result at screening and a negative serum 
or urine pregnancy test result at baseline (within 24 hours of the first dose). Females 
must be either postmenopausal, surgically sterile, or agree to use 2 forms of highly 
effective contraception during the study and for 6 months following discontinuation 
of study treatment 
i. 
Postmenopausal is defined as at least 60 years of age, medically confirmed 
ovarian failure, younger than 60 years of age and have had cessation of regular 
menses for at least 12 consecutive months with no alternative pathological or 
physiological cause, and/or serum levels estradiol and of follicle stimulating 
hormone within the laboratory’s reference range for postmenopausal females 
ii. 
Acceptable surgical sterilization techniques are complete or partial hysterectomy 
or bilateral tubal ligation with surgery at least 6 months prior to dosing, and 
bilateral oophorectomy with surgery at least 2 months prior to dosing  
iii. 
Highly effective methods of contraception are those that result in a low failure 
rate (ie, less than 1% per year) when used consistently and correctly. These 
include the following: 
1. Established use of oral, injected or implanted hormonal 
methods of contraception (stable dose at least 3 months 
prior to dosing)  
2. Placement of an intrauterine device or intrauterine system  
3. Barrier methods of contraception: condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository. Barrier methods alone 
(without spermicide) are not acceptable methods. Likewise, 
spermicide alone is not an acceptable method 
4. Male sterilization (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate). 
For female subjects on the study, the vasectomized male 
partner should be the sole partner for that subject 
5. True abstinence, when this is in line with the preferred and 
usual lifestyle of the subject. Periodic abstinence (eg, 
calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of 
contraception  
b. For males: Males must be surgically sterile or have a female partner who is either 
postmenopausal, surgically sterile, or using 2 forms of highly effective contraception 
as noted above. Acceptable surgical sterilization techniques are vasectomy with 
surgery at least 6 months prior to dosing. Males must also refrain from sperm 
donation during the study and for 6 months following discontinuation of treatment 
15. Able to understand and sign an informed consent 


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Trilaciclib 
 
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7.1.2. 
Exclusion Criteria 
A patient will not be eligible for participation in this study if any of the following criteria 
apply. 
1. More than 2 prior chemotherapy regimens for locally recurrent or metastatic TNBC 
(non-cytotoxic therapies are not considered prior lines of therapy). For a regimen to be a 
line of therapy, the patient must have disease progression after that therapy prior to the 
start date of the next therapy or enrollment in this study. Therapy given in the 
neoadjuvant/adjuvant setting where the patient has recurrent disease > 12 months after 
the last dose of therapy will NOT be considered a line of therapy in the locally recurrent 
or metastatic setting. 
2. Malignancies other than TNBC within 3 years prior to randomization, with the exception 
of those with a negligible risk of metastasis or death treated with expected curative 
outcome 
3. Presence of CNS metastases/leptomeningeal disease requiring immediate treatment with 
radiation therapy or steroids (ie, patient must be off steroids administered for brain 
metastases for at least 14 days prior to the first dose of G1T28).  
4. Uncontrolled ischemic heart disease or uncontrolled symptomatic congestive heart failure 
(Class III or IV as defined by the New York Heart Association [NYHA] functional 
classification system) 
5. Known history of stroke or cerebrovascular accident within 6 months prior to first dose of 
trilaciclib 
6. Known serious active infection (eg, human immunodeficiency virus [HIV], hepatitis B or 
C, tuberculosis, etc.) 
7. 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 
8. Prior hematopoietic stem cell or bone marrow transplantation 
9. Concurrent radiotherapy to any site or radiotherapy within 2 weeks prior to the first dose 
of trilaciclib  
10. Receipt of any investigational medication within 30 days prior to the first dose of 
trilaciclib 
11. Receipt of any cytotoxic chemotherapy within 3 weeks prior to the first dose of trilaciclib 
12. Receipt of any low-dose systemic chemotherapeutic agent given for a nononcologic 
purpose within 3 weeks prior to enrollment (eg, low-dose methotrexate for rheumatoid 
arthritis) 
13. Hypersensitivity to cisplatin or other platinum-containing compounds, or mannitol 
14. Pregnant or lactating women 


G 1 T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Vers i o n: 4. 0, date d 31 A u g ust  2 0 1 7  
 
Pa ge 3 7  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
8.  
T R E A T M E N T S  
8. 1.  
Tre at me nts A d mi nistere d  
Patie nts will be ra n d o ml y assi g ne d ( 1: 1: 1 fa s hi o n) t o recei ve 1 of t he f oll o wi n g 3 treat me nts: 
•  Gr o u p 1: G C t hera p y ( Da ys 1 a n d 8 of 2 1- da y c ycles) o nl y  
•  Gr o u p 2: G C t hera p y ( Da ys 1 a n d 8) pl us trilacicli b a d mi nistere d I V o n Da ys 1 a n d 8 of 
2 1- da y c ycles 
•  Gr o u p 3: G C t hera p y ( Da ys 2 a n d 9) pl us trilacicli b a d mi nistere d I V  o n Da ys 1, 2, 8, a n d 
9 of 2 1- da y c ycles  
I n Gr o u ps 1 a n d 2, patie nts will recei ve G C c he m ot hera p y ( ge mcita bi ne 1 0 0 0 m g/ m2 a n d 
car b o plati n A U C = 2 a d mi nistere d I V) o n Da ys 1 a n d 8 i n 2 1- da y c ycles. I n Gr o u p 3, 
patie nts will recei ve G C c he m ot hera p y o n Da ys 2 a n d 9 i n 2 1- da y c ycles. T he car b o plati n 
d ose will be calc ulate d usi n g t he Cal vert  f or m ula wit h a tar get A U C = 2 ( ma xi m u m 3 0 0 m g) 
I V.  
I n Gr o u ps 2 a n d 3, trilacicli b ( 2 4 0 m g/ m2) will be a d mi nistere d as a n I V i nf usi o n o ver 
3 0 ( ± 5) mi n utes pri or t o eac h G C  treat me nt ( o n Da ys 1 a n d 8 f or Gr o u p 2 a n d o n Da ys 2 a n d 
9 f or Gr o u p 3). I n Gr o u p 3, trilacicli b ( 2 4 0 m g/ m2) will als o be a d mi nistere d o n Da ys 1 a n d 
8. T he i nter va l bet wee n d oses of trilacicli b o n s uccessi ve da ys i n Gr o u p 3 s h o ul d n ot be 
greater t ha n 2 8 h o urs.  
St u d y dr u g a d mi nistrati o n will c o nti n ue u ntil disease pr o gressi o n, u nacce pta ble t o xicit y, 
wit h dra wal of c o nse nt, or disc o nti n uati o n b y i n vesti gat or, w hic he ve r occ urs first. Treat me nt 
c ycles will occ ur c o nsec uti vel y wit h o ut i nterr u pti o n, e xce pt w he n necessar y t o ma na ge 
t o xicities (see Secti o n 8. 4. 3 ). 
8. 2.  
I n vesti g ati o n al Pr o d ucts 
8. 2. 1.  
I de ntit y 
8. 2. 1. 1.  
Trilacicli b  
Trilacicli b  is s u p plie d as a si n gle-use, sterile p o w der wit h 3 0 0 m g trilacicli b i n eac h 3 0- m L 
fli nt glass vial. 
, U S P is a d de d as a ca ke f or mi n g a ge nt a n d  
 b uffer is a d de d 
t o mai ntai n t he rec o nstit ute d p H at 4. 0 t o 5. 0. T he pr ocess f or rec o nstit uti o n of st u d y dr u g is 
detaile d i n t he P har mac y Ma n ual.  
8. 2. 1. 2.  
Ge mcita bi ne  a n d Car b o plati n 
Descri pti o ns of t he f or m ulati o ns of c o m merciall y-a va ila ble ge mcita bi ne  a n d car b o plati n ca n 
be f o u n d i n t he res pecti ve c urre nt prescri bi n g i nf or mati o n (see A p pe n di x 2 ).  
C CI
C CI




G 1 T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Vers i o n: 4. 0, date d 31 A u g ust  2 0 1 7  
 
Pa ge 3 9  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
At a mi ni m u m, t he f oll o wi n g data will be trac ke d o n t he dr u g acc o u nta bilit y l o g at t he site 
p har mac y: 
•  Date recei ve d  
•  L ot  n u m ber 
•  Vial n u m ber 
•  Date dis pe nse d  
•  Patie nt n u m ber 
•  I de ntificati o n of t he pers o n dis pe nsi n g t he dr u g 
Rec or ds of st u d y me dicati o n ( use d, l ost, destr o ye d, a n d ret ur ne d c o ntai ners, i n di vi d ual vials) 
s h o ul d be ma de at eac h visit i n t he dr u g acc o u nta bilit y a n d dis pe nsi n g f or ms. Dr u g 
acc o u nta bilit y a n d rec o nciliati o n will be c hec ke d a n d verifie d b y t he p har mac y tea m d uri n g 
t he st u d y a n d b y t he site m o nit or d uri n g a n d at t he c o m pleti o n of t he st u d y. 
O nce t he site m o nit or has verifie d dr u g acc o u nta bilit y at t he site, a n y use d dr u g re mai ni n g at 
t he c o m pleti o n of t he st u d y will be destr o ye d. U n use d a n d u n o pe ne d st u d y me dicati o n will 
be ret ur ne d b y t he site m o nit or t o t he s p o ns or or ma y be destr o ye d o n site acc or di n g t o t he 
i n vesti gati ve site’s S O Ps. 
8. 3.  
Met h o d of Assi g ni n g P atie nts t o Tre at me nt Gr o u ps  
A u ni q ue patie nt i de ntificati o n n u m ber will be assi g ne d t o eac h patie nt w h o si g ns a n 
i nf or me d c o nse nt f or m.  
Pa tie nts meeti n g all i ncl usi o n an d e xcl usi o n criteria will be ra n d o mize d 1: 1: 1  t o recei ve 
st u d y dr u g as descri be d i n Secti o n  8. 1 . Eac h patie nt will be assi g ne d a u ni q ue i de ntificati o n 
n u m ber, w hic h will n ot be re use d.   
8. 4.  
D ose, D osi n g Re gi me n, a n d R o ute 
F or trilacicli b or ge mcita bi ne d osi n g, t he b o d y s urface area ( B S A) calc ulati o n s h o ul d use t he 
act ual b o d y wei g ht, n ot t he i deal b o d y wei g ht. If a patie nt’s wei g ht fl uct uates fr o m visit t o 
visit, t he d ose of trilacicli b  or ge mcita bi ne ca n be a dj uste d at eac h visit O R t he d ose nee d n ot 
be a dj uste d u nless t he c ha n ge i n act ual b o d y wei g ht is ≥ 1 0 %.  
8. 4. 1.  
Tril acicli b  
Trilacicli b  ( 2 4 0 m g/ m2) dil u te d i n 2 5 0 m L of 
 i n 
 
 is t o be a d mi nistere d b y I V i nf usi o n o ver 3 0 ± 5  mi n utes. If t here is 
a n y st u d y dr u g re mai ni n g i n t he i nf usi o n ba g at t he e n d of t he 3 0 ± 5 mi n utes, t he i nf usi o n 
s h o ul d be c o nti n ue d at t he sa me rate u ntil t he e ntire c o nte nts of t he ba g ha ve bee n 
a d mi nistere d t o e ns ure patie nts recei ve t he f ull  d ose . T he i nf usi o n rate ma y be decrease d t o 
ma na ge a n i nf usi o n- relate d A E ; f or e xa m ple, if a patie nt e x perie nces a b ur ni n g se nsati o n 
d uri n g i nf usi o n, t he i nf usi o n ti me ma y be i ncrease d t o 4 5 mi n utes ( or l o n ger if cli nicall y 
i n dicate d) t o alle viate t he s y m pt o ms. T he act ual ti me of i nf usi o n will be d oc u me nte d a n d 
e ntere d i n t he electr o nic c ase re p ort f or m (e C R F). Details re gar di n g t he rec o nstit uti o n a n d 
dil uti o n of trilacicli b vials are detaile d i n t he P har mac y Ma n ual.  
C CI
C CI


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Trilaciclib 
 
Version: 4.0, dated 31 August 2017 
 
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On chemotherapy dosing days, trilaciclib is always administered first. The interval 
between doses of trilaciclib on successive days in Group 3 should not be greater than 
28 hours. If administration of GC therapy is discontinued, trilaciclib will also be 
discontinued. 
8.4.2. 
Gemcitabine and Carboplatin 
Gemcitabine and carboplatin will be administered IV in accordance with the instructions 
below. 
Needles or IV administration sets containing aluminum parts that may come in contact with 
carboplatin should not be used for the preparation or administration of the drug. Aluminum 
can react with carboplatin causing precipitate formation and loss of potency. 
On chemotherapy dosing days, trilaciclib is always administered first, followed by GC.  
GC 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 chemotherapy (gemcitabine or carboplatin) administration should not be 
greater than 4 hours. 
If administration of trilaciclib is discontinued, GC therapy will also be discontinued. 
8.4.2.1. 
Carboplatin 
The carboplatin dose will be calculated using the Calvert formula with a target AUC = 2 on 
Days 1 and 8 (Groups 1 and 2) or Days 2 and 9 (Group 3) of each 21-day cycle and 
administered as an IV infusion according to the local package insert.  
The Calvert formula is as follows: 
Total carboplatin dose (mg) = (target AUC) × (glomerular filtration rate [GFR] + 25)  
Because each patient’s estimated GFR will be based on serum creatinine measurements, the 
dose of carboplatin should be capped at 300 mg to avoid potential toxicity due to 
overdosing. The cap dose of 300 mg for carboplatin is based on a GFR estimate that is 
capped at 125 mL/min for patients with normal renal function (ie, maximum carboplatin 
dose = target AUC of 2 mg•min/mL × 150 = 300 mg). 
8.4.2.2. 
Gemcitabine 
Gemcitabine 1000 mg/m2 will be administered as an IV infusion according to the local 
package insert on Days 1 and 8 (Groups 1 and 2) or Days 2 and 9 (Group 3) of each 21-day 
cycle. 
8.4.3. 
Toxicity Management Guidelines 
The dose of trilaciclib will not be modified and will remain at 240 mg/m2 throughout the 
study. If administration of GC therapy is discontinued, trilaciclib will also be discontinued.   


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Trilaciclib 
 
Version: 4.0, dated 31 August 2017 
 
Page 41 of 107  
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Gemcitabine and carboplatin dose reductions are permitted according to the organ system 
showing the greatest degree of drug-related toxicity. Toxicities will be graded according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE), Version 4.03. 
8.4.3.1. 
Criteria for Subsequent Cycles 
In all 3 groups, study drug administration will continue until disease progression per 
Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, unacceptable toxicity, 
withdrawal of consent, or discontinuation by investigator.  
There should be no more than 4 weeks between doses of chemotherapy in all groups. Dosing 
delays greater than 4 weeks may be permitted on a case by case basis with the approval of the 
investigator and medical monitor. 
Criteria for Day 1/2 of Each Cycle 
Patients must meet all of the following criteria to receive the Day 1/2 dose:  
• ANC ≥ 1.0 × 109/L 
• Platelet count ≥ 100 × 109/L 
• Nonhematologic toxicities (except alopecia) must be ≤ Grade 2 or have returned to 
baseline  
If the initiation of the next cycle is delayed due to toxicity, the patient should have (at least) 
weekly visits to follow the toxicity. Delayed dosing visits will be captured in the eCRF.  
Criteria for Day 8/9 of Each Cycle 
To receive Day 8/9 dose of each cycle, patients must meet all the following criteria: 
• ANC ≥ 1.0 × 109/L 
• Platelet count ≥ 75 × 109/L 
• Nonhematologic toxicities (except alopecia) must be ≤ Grade 2 or have returned to 
baseline  
If these criteria are not met, the Day 8/9 GC doses should be skipped; no dose reductions or 
delays are allowed for the Day 8/9 GC doses. If the Day 8/9 GC doses are skipped, the next 
GC doses become Day 1/2 of the subsequent cycle. There should be at least 7 days between a 
skipped Day 8/9 dose and the start of the next cycle, ie, Day 1/2. Note that the criteria for 
starting Day 1/2 outlined above will now apply to resumption of dosing. 
8.4.3.2. 
Dose Modifications for Hematologic Toxicity 
Section 8.4.3.1 outlines the hematologic criteria each patient must meet to receive study 
drug(s) on Day 1/2 and Day 8/9 of each cycle. Dose reductions for hematologic toxicities are 
based on values obtained within 24 hours of chemotherapy and all dose reductions will only 
be made on Day 1/2 of a cycle (Table 8-1). All dose reductions are permanent and no dose 
increases will occur following a dose reduction. Day 8/9 GC treatment will either be 


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Clinical Study Protocol G1T28-04 
Trilaciclib 
 
Version: 4.0, dated 31 August 2017 
 
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administered at the same dose levels as the Day 1/2 GC doses of that cycle or will be 
skipped. There will be no Day 8/9 GC dose reductions. 








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Trilaciclib 
 
Version: 4.0, dated 31 August 2017 
 
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8.4.3.3. 
Use of Colony Stimulating Factors  
Use of prophylactic colony stimulating factors (eg, granulocyte colony-stimulating factor 
[G-CSF]; granulocyte-macrophage colony-stimulating factor [GM-CSF]) during Cycle 1 (ie, 
prior to the actual Cycle 2 Day 1 dosing visit) is not allowed. In subsequent cycles (Cycle 2 
and beyond), prophylactic colony stimulating factors are allowed as outlined in Tables 8-1, 
which are based on the ASCO guidelines for neutropenia (Smith 2015) and package inserts 
(see Appendix 3). Short-acting G-CSF products (ie, Neupogen or biosimilars) may be 
administered starting 24 to 48 hours after the dose of chemotherapy on Day 1/2 or Day 8/9 
and must be stopped 48 hours prior to trilaciclib administration in Groups 2 and 3 and 24 
hours prior to GC administration in Group 1 (no trilaciclib). Due to its prolonged half-life, 
pegfilgrastim may only be used if the patient received Day 8/9 chemotherapy; it should be 
administered 24 to 48 hours after the dose of Day 8/9 chemotherapy. 
If in any cycle (including Cycle 1), a patient experiences febrile neutropenia and is at high 
risk for infection-associated complications OR has prognostic factors that are predictive of 
poor clinical outcomes (Table 8-2), G-CSF/GM-CSF may be used to treat the febrile 
neutropenia event per the ASCO guidelines and package insert. 
Table 8-2 
Patient Risk Factors for Poor Clinical Outcomes Resulting from Febrile 
Neutropenia or Infection 
Risk Factor 
Sepsis syndrome 
Age > 65 years 
Profound neutropenia (absolute neutrophil count < 0.1 × 109/L) 
Neutropenia expected to last > 10 days 
Pneumonia 
Invasive fungal infection 
Other clinically documented infections 
Hospitalization at time of fever 
Prior episode of febrile neutropenia 
Source: Table recreated from Table 2 of the ASCO guidelines (Smith 2015; Smith 2006) 
 
Erythropoietin stimulating agents (ESAs)  
ESAs may not be used in Cycle 1.  If a patient experiences a hemoglobin level < 9.0 g/dL or 
symptomatic anemia in subsequent cycles, ESAs may be used per the current prescribing 
information (Appendix 4). 
8.4.3.4. 
  Dose Modifications for Nonhematologic Toxicity 
Section 8.4.3.1 outlines the nonhematologic criteria each patient must meet to receive study 
drug(s) on Day 1/2 and Day 8/9 of each cycle. All dose reductions will only be made on Day 
1/2 of a cycle (Table 8-3). All dose reductions are permanent and no dose increases will 
occur following a dose reduction. Day 8/9 GC treatment will either be administered at the 
same dose levels as the Day 1/2 GC doses of that cycle or will be skipped. There will be no 
Day 8/9 GC dose reductions. 












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Trilaciclib 
 
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8.5. 
Randomization and Blinding 
This study is open-label and no blinding will be required. 
Patients meeting all inclusion and exclusion criteria will be randomized 1:1:1 to study 
treatment group by IWRS according to a randomization schedule generated by the 
statistician. Randomization will be stratified as follows: liver involvement (yes or no) and the 
number of prior lines of anticancer therapy in the locally recurrent/metastatic setting at the 
time of randomization (0 or 1-2).  
8.6. 
Prior and Concomitant Medications and Procedures 
All concomitant medications including prescription medications, over-the-counter 
preparations, growth factors, and blood products from informed consent through 30 days 
after the last dose of study treatment (safety follow-up phone call) will be documented, 
where possible. Documentation will include information regarding start and stop date(s), 
dose(s), and reason(s) for the medication use.   
Administration of other concomitant nonprotocol anticancer therapies prior to progression is 
not permitted while on this study. This includes any low-dose systemic chemotherapeutic 
agent given for a nononcologic purpose (eg, low-dose methotrexate for rheumatoid arthritis). 
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 EDC. 
Administration of other concomitant investigational agents for any indication is not permitted 
while on this study. 
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.  
Trilaciclib is a time-dependent inhibitor of CYP3A4 and is a substrate for CYP3A4. 
Trilaciclib exposure may be altered by concomitant use of drugs that are strong CYP3A 
inhibitors or inducers. The exposure of drugs that are CYP3A substrates may be altered by 
concomitant use of trilaciclib (Section 4.3.2).  
• Caution should be exercised with concomitant use of drugs that are strong CYP3A 
inhibitors (eg, aprepitant, clarithromycin, itraconazole, ketoconazole, nefazodone, 
posaconazole, telithromycin, verapamil, and voriconazole).  
• Caution should be exercised with concomitant use of drugs that are strong or 
moderate CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St John’s Wort, 
bosentan, modafinil, and nafcillin).   
• Caution should be exercised with concomitant use of drugs that are extensively 
metabolized by CYP3A. 


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Trilaciclib 
 
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Trilaciclib is a potent inhibitor of MATE1, MATE2-K, and OCT2 membrane transporters 
and therefore caution should be exercised with concomitant use of drugs that are substrates 
for these transporters (Section 4.3.2). 
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.  
Necessary supportive care (eg, antiemetics, antidiarrheals) administered per the standard of 
care at the study center will be permitted. See Section 8.4.3.3 for guidance on the use of 
growth factors (colony stimulating factors and ESAs) during the trial. 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 GC is allowed per the ASCO guidelines (Hesketh et al. 2017). Use of dexamethasone on 
Day 2 and 3 should be limited as much as clinically possible. 
8.7. 
Transfusions 
Platelets should be transfused at a threshold of ≤ 10,000/µL. Platelets should also be 
transfused in any patient who is bleeding with a platelet count < 50,000/µL (100,000/µL for 
central nervous system or ocular bleeding).  
Patients with hemoglobin < 8.0 g/dL or with symptomatic anemia can be treated with RBC 
transfusions at the investigator’s discretion.  
8.8. 
Treatment Compliance 
The investigator or designee will dispense the study medication, via a pharmacist/designee, 
only for use by patients enrolled in the study as described in this protocol. The study drug is 
not to be used for reasons other than those described in this protocol. The investigator or 
other study staff will supervise each dose of the study drug administered in the clinic. The 
clinical study site will maintain records of study drug receipt, preparation, and dispensing, 
including the applicable lot and vial numbers; patient’s height, body weight, and BSA; date 
and time of the start and end of each trilaciclib, gemcitabine, and carboplatin infusion; and 
total drug administered in milligrams.  
 


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Trilaciclib 
 
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9. 
STUDY FLOWCHART 
The procedures and assessments to be performed during the study are outlined in Table 9-1 
(Groups 1 and 2) and Table 9-2 (Group 3).






G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
Pa ge 5 7  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
  
m 1:  Ra di o n ucli de b o ne sca ns  s hall be perf or me d at scree ni n g. S keletal lesi o ns i de ntifie d o n t he b o ne sca n at baseli ne, w hic h are n ot visi ble o n t he C T or M RI sca n s h o ul d be i ma ge d at 
 
baseli ne a n d f oll o we d at sc he d ule d visits usi n g l ocalize d C T, M RI or x -ra y. Bo ne sca ns nee d n ot be re peate d after baseli ne u nless cli nicall y i n dicate d. B o ne sca ns o btai ne d as sta n dar d 
 
of care pri or t o scree ni n g will n ot nee d t o be re peate d if perf or me d wit hi n 2 8 da ys pri or t o t he first d ose of st u d y dr u g(s). 
m 2.  Brai n i ma gi n g wit h c o ntrast ( b y C T or M RI) perf or me d  at Scree ni n g f or all patie nts.  If brai n metastases are prese nt at scree ni n g, brai n i ma gi n g s hall be d o ne wit h eac h  
pr ot oc ol- s pecifie d t u m or assess me nt. If n o metastases are prese nt at scree ni n g, i ma gi n g d oes n ot nee d t o be perf or me d d uri n g t he st u d y u nless cli nicall y i n dicate d or if t he s u bject is 
ne ur ol o gicall y s y m pt o matic . 
  
m 3:  At t he P ost -Treat me nt Visit, o btai n t u m or assess me nt f or patie nts w h o ha ve n ot pr o gresse d at t he ti me of st u d y dr u g disc o nti n uati o n ( ma y be perf or me d wit hi n 4 wee ks).  
  
m 4:  F or t h ose patie nts i n t he S ur vi val F oll o w- u p P hase w h o ha ve n ot pr o gresse d at t he ti me of st u d y dr u g disc o nti n uati o n, ra di ol o gical t u m or assess me nts will be perf or me d  utilizi n g t he 
 
sa me i ma gi n g m o dalit y use d  at scree ni n g, e ver y 1 2 wee ks  ± 7 da ys  fr o m t he P ost-Treat me nt Visit  u ntil t he occ urre nce of pr o gressi ve disease , wit h dra wal of c o nse nt, i nitiati o n of 
 
s u bse q ue nt a ntica ncer t hera p y, or st u d y c o m pleti o n.  
n 
Patie nts w h o  ha ve a gree d t o partici pa te i n t he P K a nal ysis will ha ve bl o o d sa m ples c ollecte d o n Da y 1 of C y cle 1 o nl y at t he ti me p oi nts s pecifie d i n Secti o n 1 1. 2 .  T he e n d of i nf usi o n  ( E OI) 
s a m ple f or tril acicli b s h o ul d be dr a w n 2 t o 5 mi n utes pri or t o t he tril acicli b E OI.  
o 
F or Gr o u p  2:  Trilacicli b  will be a d mi nistere d as a n I V i nf usi o n o ver  3 0 ( ± 5) mi n utes pri or t o G C c he m ot hera p y o n Da ys 1 a n d 8 of e ver y 2 1 -da y c ycle  ( d osi n g i nf or mati o n, see Secti o n  8. 1 ). 
After disc o nti n uati o n of st u d y dr u g, patie nts s h o ul d be str o n gl y e nc o ura ge d t o c o m plete all sc he d ule d assess me nts t hr o u g h t he e n d of t heir c urre nt 2 1 -da y treat me nt c ycle, i ncl u di n g t he P R O 
scales; t he P ost-Treat me nt Visit  ( Da y 2 2); t he safet y f oll o w-u p p h o ne call at 3 0 da ys after t he last d ose of st u d y treat me nt; a n d t he S ur vi val F oll o w -u p P hase of t he st u d y.  
p 
F or Gr o u p 1 : G C t hera p y will be a d mi nistere d as a n I V i nf usi o n o n Da ys 1 a n d 8 of 2 1 -da y c y cles ( d osi n g i nf or mati o n; see Secti o n  8. 1 ). 
 
F or Gr o u p  2: G C t hera p y will be a d mi nistere d as a n I V i nf usi o n after t he trilacicli b i nf usi o n (wit h a n i nter val n ot greater t ha n  4 h o urs) o n Da ys 1 a n d 8 of 2 1 -da y c ycles  ( d osi n g i nf or mati o n; see 
Secti o n  8. 1 ). C he m ot hera p y ca n n ot be a d mi nistere d u ntil after c o m pleti o n of t he trilacicli b i nf usi o n. If trilacicli b i n a n y gi ve n c ycle is n ot a d mi nistere d f or a n y reas o n, d o n ot a d mi nister t he d ose 
of ge mcita bi ne or car b o plati n c he m ot hera p y o n t hat da y.  
s 
S ur vi val f oll o w-u p ma y be a p h o ne c o ntact if s u bject is n ot ret ur ni n g t o t he cli nic f or t u m or assess me nts.  
t 
A Es  will be rec or de d fr o m t he ti me of i nf or me d c o nse nt. All A Es s h o ul d be re p orte d wit hi n 3 0 da ys of t he last d ose of st u d y dr u g,  a n d f oll o we d u ntil t he y are res ol ve d, ha ve ret ur ne d t o baseli ne , 
or it is dee me d t hat f urt her rec o ver y is u nli kel y.   
 
 
C CI
C CI


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
Pa ge 5 8  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
T a ble 9- 2 
Sc he d ule of Assess me nts f or Gr o u p 3  
  
Scree n -
i n g 
C y cle 1 a n d E ver y O d d C y cle a 
( 2 1 d a ys) 
C y cle 2 a n d E ver y E ve n C y cle a   
( 2 1 d a ys) 
P ost - Tre at me nt 
Visit b  
S afet y 
F oll o w -u p 
P h o ne C all c 
S ur vi v al 
F oll o w -u p d  
P ost - Tre at me nt 
Visit + 6 0  d a ys  
C ycle D a y  
-2 8  
1  
2  
8  
9  
1 5  
( ± 1 d a y) 
1  
2  
8  
9  
1 5  
( ± 1 d a y) 
2 2 (l ast c ycle)  
(+ 7 d a ys)  
( + 3 d a ys) 
( ±7 d a ys)  
( ± 7 d a ys)  
I nf or me d C o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical Hist or y
e 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eli gi bilit y E val uati o n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perf or ma nce Stat us  
X  
X  
 
 
 
 
X  
 
 
 
 
X  
 
 
 
P h ysical E xa m  
X  
X  
 
 
 
 
X  
 
 
 
 
X  
 
 
 
Vital Si g ns  
X  
X f 
X f 
X f 
X f 
 
X f 
X f 
X f 
X f 
 
X  
 
 
 
Hei g ht/ Wei g ht  
X g 
X  
 
 
 
 
X g 1 
 
 
 
 
 
 
 
 
Cli nical C he mistr y  
X  
X h 
 
 
 
 
X h 
 
 
 
 
X  
 
 
 
He mat ol o g y i 
X  
X  
 
X  
 
X  
X  
 
X  
 
X  
X  
 
 
X  
Uri nal ysis  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E C G  
X  
 
X j 
 
 
 
 
 
 
 
 
 
 
 
 
Pre g na nc y test k 
X  
X k 
 
 
 
 
 
 
 
 
 
X  
 
 
 
T u m or Assess me nt  
X m, m 1, m 2  
C T/ M RI of c hest/a b d o me n Q 9 wee ks t hr o u g h Wee k 2 7 a n d Q 1 2 wee ks t hereafter.   
Als o i ncl u de b rai n M RI if brai n metastases prese nt at baseli ne.  
S keletal le si o ns i de ntifie d wit h baseli ne b o ne sca n t o be f oll o we d at sc he d ule d visits usi n g l ocalize d 
C T, M RI , or x -ra y m, m 1, m 2, m 3, m 4 
T u m or assess me nt Q 1 2 wee ks t o c o nti n ue i n 
P ost - Treat me nt/ F oll o w-u p o nl y if patie nt disc o nti n ues 
st u d y treat me nt f or reas o n ot her t ha n P D a n d has n ot 
i nitiate d s u bse q ue nt a ntica ncer t hera p ym, m 4  
Arc hi val T u m or Tiss ue  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P K n ( o pti o nal) 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Trilacicli b o  
 
X  
X  
X  
X  
 
X  
X  
X  
X  
 
 
 
 
 
G C t hera p y p  
 
 
X  
 
X  
 
 
X  
 
X  
 
 
 
 
 
S ur vi val c o ntact s 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
A Es t 
X  
 
 
C o n. Me dicati o ns  
X  
 
 
A E = a d verse e ve nt; E C G = 1 2- lea d electr ocar di o gra m;
 
 P K  = p har mac o ki netics, G C t hera p y = Ge mcita bi ne a n d Car b o plati n t hera p y; P D = pr o gressi ve disease  
C CI
C CI
C CI


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
Pa ge 5 9  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
a 
St u d y t hera p y  will c o nti n ue u ntil disease pr o gressi o n, u nacce pta ble t o xicit y, or disc o nti n uati o n b y t he patie nt or i n vesti gat or.  
b 
Patie nts will ret ur n t o t he st u d y ce nter f or a P ost-Treat me nt Visit o n Da y 2 2  (+ 7 da ys ) of t heir last c y cle .  
c 
A safet y f oll o w - u p c o ntact will be ma de t o eac h patie nt at 3 0 da ys after t he last d ose of st u d y treat me nt t o c ollect A Es a n d c o nc o mita nt me dicati o ns.  
d  
F oll o w- u p s h o ul d be atte m pte d a n d d oc u me nte d f or eac h patie nt t hat is i n t he l o n g ter m S ur vi val F oll o w -u p P hase at least o nce e ver y 2 m o nt hs. Patie nts will be f oll o we d f or s ur vi val u ntil at least 
5 0 % of t he patie nts ha ve die d. A n y a ntica ncer t hera pies use d  will be c ollecte d.  
e 
I ncl u di n g me dical, s ur gical, ra diati o n hist or y, s m o ki n g hist or y, pri or s yste mic a nti -ca ncer t hera p y, breast ca ncer hist or y i ncl u di n g B R C A classificati o n, d oc u me ntati o n of t u m or dia g n osis, 
scree ni n g si g ns a n d s y m pt o ms wit hi n 4 wee ks pri or t o ra n d o mizati o n, a n d me dicati o ns. Eli gi bilit y e val uati o n a n d ra n d o mizati o n ma y occ ur u p t o 4 da ys pri or t o Da y 1 C ycle 1 t hera p y. F or all 
treat me nt gr o u ps, st u d y start is o n C y cle 1 Da y 1.    
f 
Vital si g ns ( bl o o d press ure, heart rate, res pirat or y rate a n d b o d y te m perat ure) will be o btai ne d i m me diatel y bef ore a n d after eac h i nf usi o n. Vitals o nl y nee d t o be ta ke n o nce bet wee n eac h 
i nf usi o n.   
g 
Hei g ht will o nl y be meas ure d at t he scree ni n g visit.  B o d y S urface Area ( B S A) will be calc ulate d at Da y 1.  
  
g 1: B S A  ( base d o n act ual b o d y wei g ht) will be re-calc ulate d o n Da y 1  of C y cle 2 a n d s u bse q ue nt c y cles if wei g ht i ncreases or decreases >1 0 % fr o m Da y 1 of t he pre vi o us c ycle. 
h 
Cli nical c he mistr y (see Secti o n 1 1. 4. 2 ) ma y be o btai ne d u p t o 7 2 h o urs pri or  t o Da y 1 of eac h c y cle.  
i  
He mat ol o g y (see Secti o n 1 1. 4. 2 ) ma y be o btai ne d u p t o 2 4 h o urs pri or t o G C d osi n g of o n Da y 2 or Da y 9 of eac h c y cle, Da y 1 5 of eac h c ycle, at t he P ost -Treat me nt Visit, a n d at 6 0 da ys after 
t he P ost-Treat me nt Visit . 
j 
Si n gle 1 2 -lea d E C Gs will be o btai ne d f or all patie nts at scree ni n g . T h ose patie nts w h o a gree t o partici pate i n P K s a m pli n g will ha ve E C Gs c o m plete d  i n tri plicate (at least 1 mi n ute a part) at t he 
f oll o wi n g a d diti o nal ti me p oi nts o n Da y 2 of C y cle 1: pre d ose ( pri or t o trilacicli b) a n d at 0. 5 h o ur (e n d of i nf usi o n [ E OI] of trilacicli b), 2 h o urs ( ± 1 0 mi n utes) after E OI of trilacicli b, a n d 5 h o urs 
( ± 3 0 mi n utes) after E OI of trilacicli b. Patie nts s h o ul d rest f or a p pr o xi matel y 5 mi n utes pri or t o eac h E C G assess me nt. T he E C Gs s h o ul d be o btai ne d j ust pri or t o P K sa m pli n g . 
k  
F e male patie nts of c hil d beari n g p ote ntial : ser u m ß-h C G at scree ni n g a n d ser u m or uri ne ß - h C G o n Da y 1 of C y cle 1, Da y 1 of e ver y o d d c ycle, a n d  at t he P ost-Treat me nt Visit . A pre g na nc y test 
s h o ul d be perf or me d wit hi n 2 4 h o urs of t he C y cle  1 Da y 1 visit  a n d m ust be ne gati ve t o i nitiate treat me nt .  
m 
F or t u m or assess me nt, all sites of disease s h o ul d be assesse d ra di ol o gicall y b y C T or M RI  wit h c o ntrast, w here cli nicall y p ossi ble,  of t he c hest a n d a b d o me n  at scree ni n g  ( u nless o btai ne d wit hi n 
2 8 da ys of d osi n g)  e ver y 9 wee ks ± 7 da ys ( Wee k 9, We ek 1 8, a n d Wee k 2 7) a n d t he n e ver y 1 2 wee ks ± 7 da ys  t hereafter, u ntil t he occ urre nce of disease pr o gressi o n, wit h dra wal of c o nse nt, 
i nitiati o n of s u bse q ue nt a ntica ncer t hera p y, or st u d y c o m pleti o n. If a patie nt s h o ws a ra di ol o gical res p o nse (c o m plete res p o nse [ C R] or partial res p o nse [ P R]), a c o nfir mat or y ra di ol o gical 
assess me nt will be perf or me d at least 4 wee ks after t he res p o nse was first n ote d.  T he sa me met h o d of assess me nt ( C T  or M RI) s h o ul d be use d t o c haracterize t u m ors at scree ni n g a n d at all 
f oll o w-u p assess me nts. If p ositr o n e missi o n t o m o gra p h y is use d, it s h o ul d als o be acc o m pa nie d b y s piral C T or M RI.  
C CI


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
Pa ge 6 0  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
  
m 1:  Ra di o n ucli de b o ne sca ns s hall be perf or me d at scree ni n g. B o ne sca ns o btai ne d as sta n dar d of care pri or t o scree ni n g will n ot nee d t o be re p eate d if perf or me d wit hi n 2 8 da ys pri or t o t he 
 
first d ose of st u d y dr u g(s). S keletal lesi o ns i de ntifie d o n t he b o ne sca n at baseli ne, w hic h are n ot visi ble o n t he C T or M RI sca n s h o ul d be i ma ge d at baseli ne a n d f oll o we d at sc he d ule d 
 
visits usi n g l ocalize d C T, M RI , or x -ra y. Bo ne sca ns nee d n ot be re peate d after baseli ne u nless cli nicall y i n dicate d.  
m 2:  Brai n i ma gi n g wit h c o ntrast ( b y C T or M RI) perf or me d at Scree ni n g f or all patie nts. If brai n metastas es are prese nt at scree ni n g, brai n i ma gi n g s hall be d o ne wit h eac h  
pr ot oc ol- s pecifie d t u m or assess me nt. If n o metastases are prese nt at scree ni n g, i ma gi n g d oes n ot nee d t o be perf or me d d uri n g t he st u d y u nless cli nicall y i n dicate d  or if t he s u bject is 
ne ur ol o gicall y s y m pt o matic.  
  
m 3:  At t he P ost -Treat me nt V isit, o btai n t u m or assess me nt f or patie nts w h o ha ve n ot pr o gresse d at t he ti me of st u d y dr u g disc o nti n uati o n ( ma y be perf or me d wit hi n 4 wee ks).  
  
m 4:  F or t h ose patie nts i n t he S ur vi val F oll o w- u p P hase w h o ha ve n ot pr o gresse d at t he ti me of st u d y dr u g disc o nti n uati o n, ra di ol o gic al t u m or assess me nts will be perf or me d  utilizi n g t he 
 
sa me i ma gi n g m o dalit y as use d at scree ni n g, e ver y 1 2 wee ks  ± 7 da ys fr o m t he P ost-Treat me nt Visit u ntil t he occ urre nce of pr o gressi ve disease , wit h dra wal of c o nse nt,  i nitiati o n of 
 
a ntica ncer t hera p y,  or st u d y c o m pleti o n.  
n 
Patie nts w h o  a gree t o partici pate i n t he  P K a nal ysis will ha ve bl o o d sa m ples c ollecte d o n Da y 2 of  C y cle 1  at t he ti me p oi nts s pecifie d i n Secti o n  1 1. 2 .  T he e n d of i nf usi o n ( E OI) s a m ple f or 
tril acicli b s h o ul d be dr a w n 2 t o 5 mi n utes pri or t o t he tril acicli b E OI.  
o 
F or Gr o u p 3 : trilacicli b will be a d mi nistere d as a n I V i nf usi o n o ver 3 0  ( ± 5) mi n utes o n Da ys 1, 2, 8, a n d 9 of e ver y 2 1 -da y c y cle. Trilacicli b  will be a d mi nistere d pri or t o G C o n Da ys 2 a n d 9 
( d osi n g i nf or mati o n, see Secti o n 8. 1 ). T he i nter val bet wee n d oses of trilacicli b o n s uccessi ve da ys s h o ul d n ot be greater t ha n 2 8 h o urs . After disc o nti n uati o n of st u d y dr u g, patie nts s h o ul d be 
str o n gl y e nc o ura ge d t o c o m plete all sc he d ule d assess me nts t hr o u g h t he e n d of t heir c urre nt 2 1 - da y treat me nt c y cle, i ncl u di n g t he P R O scales; t he P ost -Treat me nt Visit  ( Da y 2 2); t he safet y 
f oll o w-u p p h o ne call at 3 0 da ys after t he last d ose of st u d y treat me nt; a n d t he S ur vi val F oll o w -u p P hase of t he st u d y.  
p 
F or Gr o u p 3:  G C t hera p y will be a d mi nistere d as a n I V i nf usi o n after t he trilacicli b i nf usi o n ( wit h a n i nter val n ot greater t ha n 4 h o urs) o n Da ys 2 a n d 9 of 2 1 -da y c ycles  ( d osi n g i nf or mati o n; see 
Secti o n  8. 1 ). C he m ot hera p y ca n n ot be a d mi nistere d u ntil after c o m pleti o n of t he trilacicli b i nf usi o n. If trilacicli b i n a n y gi ve n c ycle is n ot a d mi nistere d f or a n y reas o n, d o n ot a d mi nister t he d ose 
of ge mcita bi ne or car b o plati n c he m ot hera p y o n t hat da y.  
s 
S ur vi val f oll o w-u p ma y be a p h o ne c o ntact if s u bject is n ot ret ur ni n g t o t he cli nic f or t u m or assess me nts.  
t 
A Es  will be rec or de d fr o m t he ti me of i nf or me d c o nse nt. All A Es s h o ul d be re p orte d wit hi n 3 0 da ys of t he last d ose of st u d y dr u g,  a n d f oll o we d u ntil t he y are res ol ve d, ha ve ret ur ne d t o baseli ne , 
or it is dee me d t hat f urt her rec o ver y is u nli kel y.  
C CI
C CI


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
 
Pa ge 6 1  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
1 0.  
S C H E D U L E O F S T U D Y P R O C E D U R E S  
St u d y pr oce d ures are s u m marize d acr oss all st u d y visits wit hi n t he sc he d ule of assess me nts 
(Ta ble 9- 1  [ Gr o u ps 1 a n d 2] a n d Ta ble 9- 2  [ Gr o u p 3]).  
1 0. 1.  
Scree ni n g  
Patie nts s h o ul d be scree ne d n o m ore t ha n 2 8 da ys bef ore t he first d ose of st u d y treat me nt is 
a d mi nistere d.  Writte n i nf or me d c o nse nt m ust be o btai ne d fr o m eac h patie nt bef ore t he 
i nitiati o n of a n y scree ni n g pr oce d ures. After a patie nt has gi ve n i nf or me d c o nse nt, eli gi bilit y 
will b e deter mi ne d b y a re vie w of t he i ncl usi o n/e xcl usi o n criteria a n d c o m pleti o n of all 
scree ni n g pr oce d ures o utli ne d i n Ta ble 9- 1  ( Gr o u ps 1 a n d 2) or Ta ble 9- 2  ( Gr o u p 3), a n d 
liste d bel o w.  
•  C ollecti o n of de m o gra p hics 
•  C ollecti o n of me dical hist or y  (i ncl u di n g s ur gical, ra diati o n, s m o ki n g, pri or s yste mic 
a ntica ncer t hera pies, breast ca ncer hist or y i ncl u di n g B R C A classificati o n)  
•  E C O G perf or ma nce stat us e val uati o n  
•  P h ysical e xa mi nati o n  
•  Hei g ht a n d wei g ht 
•  V ital si g ns meas ure me nts ( bl o o d press ure, heart rate, res pirat or y rate a n d b o d y 
te m perat ure) 
•  Cli nical c he mistr y, he mat ol o g y, a n d uri nal ysis tests (see Secti o n 1 1. 4. 2 ) (la b orat or y 
assess me nts ma y be re peate d t o deter mi ne eli gi bilit y)  
•  1 2- lea d electr ocar di o gra m  
•  Pre g na nc y test  (ser u m β- h C G)  
•  T u m or assess me nt ( c hest a n d a b d o me n at a mi ni m u m b y c o m p ute d t o m o gra p h y [ C T] or 
ma g netic res o na nce i ma gi n g [ M RI] ; see details i n Secti o n 1 1. 5. 1 ), i ncl u di n g brai n a n d 
b o ne sca n s 
•  C T, M RI, brai n sca ns, a n d b o ne sca ns obtai ne d pri or t o i nf or me d c o nse nt will n ot nee d t o 
be re peate d if perf or me d wit hi n t he scree ni n g wi n d o w.  
•  A vaila ble arc hi ve d t u m or sa m ples m ust be se nt t o a re p osit or y f or f ut ure assess me nt of 
rele va nt 
, s uc h as t h ose i n v ol ve d i n t he C D K 4/ 6 
pat h wa y. F or a d diti o nal g ui da nce re gar di n g t he s hi p me nt of sa m ples, please refer t o t he 
La b orat or y Ma n ual.   
A d verse e ve nts a n d c o nc o mita nt me dicati o ns will be m o nit ore d c o nti n u o usl y fr o m t he ti me 
of i nf or me d c o nse nt t hr o u g h 3 0 da ys after t he last d ose of st u d y treat me nt (safet y f oll o w- u p 
p h o ne call). 
Eli gi bilit y will be deter mi ne d pri or t o ra n d o mizati o n. Ra n d o mizati o n will be perf or me d 
wit hi n 4 da ys of t he first d ose of st u d y treat me nt.  Eli gi ble patie nts will be i nstr ucte d o n all 
pr ot oc ol re q uire me nts, i ncl u di n g a n y restricti o ns o n c o nc o mita nt me dicati o n usa ge. 
C CI


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
 
Pa ge 6 2  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
1 0. 2.  
C ycle 1 a n d S u bse q ue nt C ycles  
A d verse e ve nts a n d c o nc o mita nt me dicati o ns will be m o nit ore d t hr o u g h o ut t he st u d y. Safet y 
s ur veilla nce re p orti n g of A Es c o m me nces at t he ti me i nf or me d c o nse nt is o btai ne d a n d 
c o nti n ues t hr o u g h 3 0 da ys after t he last d ose of st u d y treat me nt (safet y f oll o w- u p p h o ne call).  
 
T he ti mi n g f or critical assess me nts/ pr oce d ures is o utli ne d i n  Ta ble 9- 1  ( Gr o u ps 1 a n d 2) or 
Ta ble 9- 2  ( Gr o u p 3). St u d y treat me nts will be a d mi nistere d as descri be d i n Secti o n  8. 1 .  
 
Cr iteria f or starti n g eac h c ycle as well as t o xicit y ma na ge me nt g ui deli nes are o utli ne d i n 
Secti o n  8. 4. 3 . 
 
All C ycles: D a y s 1 a n d 8   
Pre d ose pr oce d ures will be perf or me d a n d he mat ol o g y res ults re vie we d (at a mi ni m u m) 
bef ore st u d y dr u g a d mi nistrati o n.   
Gr o u p 1 A ssess me nts: 
•  E C O G perf or ma nce stat us e val uati o n ( pre d ose; D a y 1 o nl y ) 
•  P h ysical e xa mi nati o n ( pre d ose; D a y 1 o nl y ) 
•  Wei g ht ( D a y 1 o nl y ) 
•  Cli nical c he mistr y ( u p t o 7 2 h o urs pre d ose; D a y 1 o nl y)  
•  Pre g na nc y test o n Da y 1, C ycle 1 a n d Da y 1, E ver y O d d C ycle.  T he assess me nt 
o n Da y 1, C ycle 1 m ust be wit hi n 2 4 h o urs of t he visit a n d m ust be ne gati ve t o 
i nitiate treat me nt. 
•  Cli nical he mat ol o g y  tests ( u p t o 2 4 h o urs pre d ose) 
•  A d mi ni ster car b o plati n a n d ge mcita bi ne 
•  Vital si g ns meas ure me nts (i m me diatel y bef ore a n d after eac h  i nf usi o n; o nl y 
nee de d o nce bet wee n i nf usi o ns)  
•  P K Assess me nts (se e Secti o n 1 1. 2 ) f or patie nts w h o a gree t o partici pate:   
 
o  Bl o o d sa m pl es will be c ollecte d  at pre d ose a n d 0 . 5 (car b o plati n E OI), 
1 ( ge mcita bi ne E OI), 2, 3. 5, 5, a n d 2 4 h o urs after t he start of t he 
car b o plati n i nf usi o n  o n D a y 1 of C ycle 1 o nl y  f or a mi ni m u m of 6 patie nts  
C CI
C CI


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
 
Pa ge 6 3  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
Refer t o t he la b orat or y ma n ual f or tiss ue re q uire me nts ( pre d ose; C ycle 1 D a y 1 
o nl y) . 
 
Gr o u p 2 A ssess me nts:  
•  E C O G perf or ma nce stat us e val uati o n ( pre d ose; D a y 1 o nl y ) 
•  P h ysical e xa mi nati o n ( pre d ose ; D a y 1 o nl y ) 
•  Wei g ht ( D a y 1 o nl y ) 
•  Cli nical c he mistr y ( u p t o 7 2 h o urs pre d ose; D a y 1 o nl y)  
•  Pre g na nc y test o n Da y 1, C ycle 1 a n d Da y 1, e ver y o d d c ycle. T he assess me nt o n 
Da y 1, C ycle 1 m ust be wit hi n 2 4 h o urs of t he visit a n d m ust be ne gati ve t o 
i nitiate treat me nt. 
•  Cli nical he mat ol o g y tests ( u p t o 2 4 h o urs pre d ose) 
•  A d mi nis ter trilacicli b, car b o plati n, a n d g e mcita bi ne  
•  Vital si g ns meas ure me nts (i m me diatel y bef ore a n d after eac h  i nf usi o n; o nl y 
nee de d o nce bet wee n i nf usi o ns)  
•  P K Assess me nts (se e Secti o n 1 1. 2  a n d Secti o n  1 1. 4. 5 ) f or patie nts w h o a gree t o 
partici pate:  
o  Bl o o d sa m pl es will be c ollecte d at pre d ose a n d 0. 5  (trilacicli b E OI), 
1 (car b o plati n E OI), 1. 5 ( ge mcita bi ne E OI), 2. 5, 4, 5. 5, a n d 2 4 h o urs after 
t he start of t he trilacicli b i nf usi o n o n D a y 1 of C ycle 1 o nl y  f or a 
mi ni m u m of 6  patie nts  
o  Electr ocar di o gra ms will be perf or me d  i n tri plicate (at least 1 mi n ute a part) 
at pre d ose, 0. 5 h o urs ( E OI of trilacicli b), 2 h o urs ( ± 1 0 mi n utes) after E OI 
of trilacicli b, a n d 5 h o urs ( ± 3 0 mi n utes) after E OI of trilacicli b  o nl y if P K 
sa m ples are als o o btai ne d o n D a y 1 of C ycle 1 o nl y. E C Gs s h o ul d be 
o btai ne d j ust pri or t o P K sa m pli n g a n d after a p pr o xi matel y 5 mi n u tes of 
rest.  
 
 
 
Gr o u p 3 A ssess me nts:  
•  E C O G perf or ma nce stat us e val uati o n ( pre d ose; D a y 1 o nl y ) 
C CI
C CI


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
 
Pa ge 6 4  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
•  P h ysical e xa mi nati o n ( pre d ose; D a y 1 o nl y ) 
•  Wei g ht ( D a y 1 o nl y ) 
•  Cli nical c he mistr y ( u p t o 7 2 h o urs pre d ose; D a y 1 o nl y)  
•  Pre g na nc y test o n Da y 1, C ycle 1 a n d Da y 1, e ver y o d d c ycle. T he assess me nt o n 
Da y 1, C ycle 1 m ust be wit hi n 2 4 h o urs of t he visit a n d m ust be ne gati ve t o 
i nitiate treat me nt. 
•  Cli nical he mat ol o g y tests ( u p t o 2 4 h o urs pri or t o G C d osi n g) 
•  A d mi nis ter trilacicli b 
•  Vital si g ns meas ure me nts (i m me diatel y bef ore a n d after trilacicli b i nf usi o n) 
 
All C ycles: D a y s 2 a n d 9   
Gr o u p 3 A ssess me nts:  
•  A d mi nister trilacicli b , car b o plati n, a n d g e mcita bi ne  
•  Vital si g ns meas ure me nts (i m me diatel y bef ore a n d after trilacicli b, car b o plati n, 
a n d ge mcita bi ne i nf usi o ns; o nl y nee de d o nce bet wee n i nf usi o ns)  
•  P K Assess me nts (see Secti o n  1 1. 2  a n d Secti o n  1 1. 4. 5 ) f or patie nts wh o a gree t o 
partici pate:  
o  Bl o o d sa m pl es will be c ollecte d at pre d ose a n d 0. 5  (trilacicli b E OI) , 
1 (car b o plati n E OI), 1. 5 ( ge mcita bi ne E OI), 2. 5, 4, 5. 5, a n d 2 4 h o urs after 
t he start of t he trilacicli b i nf usi o n o n D a y 2 of C ycle 1 o nl y  f or a 
mi ni m u m of 6  patie nts  
o  Electr ocar di o gra ms will be perf or me d i n tri plicate (at least 1 mi n ute a part) 
at pre d ose, 0. 5 h o urs ( E OI of trilacicli b), 2 h o urs ( ± 1 0 mi n utes) after E OI 
of trilacicli b, a n d 5 h o urs ( ± 3 0 mi n utes) after E OI of trilacicli b  o nl y if P K 
sa m ples are als o o btai ne d o n D a y  2 of C ycle 1 o nl y. E C Gs s h o ul d be 
o btai ne d j ust pri or t o P K sa m pli n g a n d after a p pr o xi matel y 5 mi n utes of 
rest.  
 
C CI
C CI


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
 
Pa ge 6 5  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
All C ycles: D a y 1 5 ( ± 1 d a y) ( Gr o u ps 1, 2 a n d 3)  
•  Cli nical he mat ol o g y test  
 
E ver y 9 Wee ks ( Gr o u ps 1, 2, a n d 3)  
•  T u m or assess me nt (e ver y 9 wee ks ± 7 da ys [ Wee k 9, Wee k 1 8, a n d Wee k 2 7]) a n d 
t he n e ver y 1 2 wee ks ± 7 da ys ( be gi n ni n g Wee k 3 9) i ncl u des C T or M RI of c hest a n d 
a b d o me n (at a mi ni m u m) wit h c o ntrast, if cli nicall y p ossi ble; s keletal lesi o ns 
i de ntifie d o n t he b o ne sca n at baseli ne, w hic h are n ot visi ble o n t he C T or M RI sca n, 
s h o ul d be i ma ge d at baseli ne a n d f oll o we d at sc he d ule d visits usi n g l ocalize d C T, 
M RI , or x-ra y. B o ne sca ns nee d n ot be re peate d after baseli ne u nless cli nicall y 
i n dicate d. Brai n i ma gi n g perf or me d o nl y if brai n metastases prese nt at baseli ne or if 
cli nicall y i n dicate d (e g, patie nt is s y m pt o matic).  
T he data m o nit ori n g c o m mittee ( D M C) ma y rec o m me n d decreasi n g t he fre q ue nc y of 
he mat ol o gical e val uati o ns base d o n acc u m ulati n g data. T he i n vesti gat ors a n d i nstit uti o nal 
re vie w b oar ds (I R Bs) or i n de pe n de nt et hics c o m mittees (I E Cs)  will be n otifie d if t he 
fre q ue nc y is re d uce d. 
After disc o nti n uati o n of st u d y dr u g, patie nts s h o ul d be str o n gl y e nc o ura ge d t o c o m plete all 
sc he d ule d assess me nts t hr o u g h t he e n d of t heir c urre nt 2 1- da y treat me nt c ycle, i ncl u di n g t he 
; t he P ost-Treat me nt Visit  ( Da y 2 2); t he safet y 
f oll o w- u p p h o ne call at 3 0 da ys after t he last d ose of st u d y treat me nt; a n d t he S ur vi val 
F oll o w- u p P hase of t he st u d y, w hic h is t o c o nti n ue u ntil at least 5 0 % of patie nts ha ve die d. 
 
1 0. 3.  
P ost -Tre at me nt  Visit : D a y 2 2 of l ast c ycle 
All p atie nts ( Gr o u ps 1, 2, a n d 3) ma y ret ur n t o t he st u d y ce nter f or a P ost -Treat me nt  Visit  o n 
Da y 2 2 ( + 7 da ys) of t heir last c ycle . T he f oll o wi n g pr oce d ures will be perf or me d at t his 
v isit: 
•  E C O G perf or ma nce stat us e val uati o n 
•  P h ysical e xa mi nati o n  
•  V ital si g ns meas ure me nts 
•  Cli nical c he mistr y, he mat ol o g y, a n d pre g na nc y tests  
•  T u m or assess me nt ( c hest a n d a b d o me n (at a mi ni m u m) C T sca n  or M RI  wit h c o ntrast (if 
cli nicall y p ossi ble)  f or patie nts w h o ha ve n ot pr o gresse d at t he ti me of st u d y dr u g 
disc o nti n uati o n [ ma y be perf or me d wit hi n 4 wee ks]); see details i n Secti o n  1 1. 5. 1 ) 
S keletal lesi o ns i de ntifie d o n t he b o ne sca n at baseli ne, w hic h are n ot visi ble o n t he C T or 
M RI sca n s h o ul d be i ma ge d at baseli ne a n d f oll o we d at sc he d ule d visits usi n g l ocalize d 
C T, M RI or  x-ra y. B o ne sca ns nee d n ot be re peate d after baseli ne u nless cli nicall y 
C CI
C CI


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
 
Pa ge 6 6  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
i n dicate d. Brai n i ma gi n g perf or me d o nl y if brai n metastases prese nt at baseli ne or if 
cli nicall y i n dicate d (e g patie nt is s y m pt o matic)  
1 0. 4.  
S afet y F oll o w- u p C o nt act : 3 0 d a ys p ost l ast d ose 
A safet y f oll o w- u p c o ntact will be ma de t o eac h patie nt at 3 0 da ys  ( + 3 da ys) after t he last 
d ose of st u d y treat me nt t o c ollect A Es a n d c o nc o mita nt me dicati o ns. F oll o w- u p ca n be via 
tele p h o ne, e mail, cli nic visits, or b y recei vi n g i nf or mati o n fr o m a fa mil y me m ber or pr o vi der 
w h o is a d mi nisteri n g care. 
1 0. 5.  
P ost - Tre at me nt Visit: 6 0 D a ys P ost L ast D ose 
All patie nts ( Gr o u ps 1, 2, a n d 3) ma y ret ur n t o t he st u d y ce nter f or a P ost- Treat me nt Visit 6 0 
da ys ( ± 7 da ys) after t he last d ose of st u d y treat me nt. T he f oll o wi n g pr oce d ures will be 
perf or me d at t his visit:  
•  He mat ol o g y  
After c o mpl eti n g t he P ost -Treat me nt Visit, patie nts will e nter t he l o n g -ter m S ur vi val 
F oll o w- u p P hase. 
1 0. 6.  
S ur vi v al F oll o w- u p P h ase  
F oll o w- u p s h o ul d be atte m pte d a n d d oc u me nte d f or eac h patie nt t hat is i n t he l o n g- ter m 
S ur vi val F oll o w- u p P hase at least o nce e ver y 2 m o nt hs  ( ±7 da ys). F oll o w - u p ca n be via 
tele p h o ne, e mail, cli nic visits, or b y recei vi n g i nf or mati o n fr o m a fa mil y me m ber or pr o vi der 
w h o is a d mi nisteri n g care.  Patie nts will be f oll o we d f or s ur vi val at a mi ni m u m u ntil at least 
5 0 % of t he patie nts i n t he st ud y ha ve die d.  
T he f oll o wi n g i nf or mati o n will be c ollecte d f or all patie nts:  
•  S ur vi val stat us 
•  Details of a n y a ntica ncer treat me nt  
I n a d diti o n, f or patie nts w h o ha ve n ot ha d disease pr o gressi o n at t he ti me of st u d y dr u g 
disc o nti n uati o n, ra di ol o gical t u m or assess me nts s h o ul d be perf or me d utilizi n g t he sa me 
m o dalit y as use d at scree ni n g e ver y 1 2 wee ks ± 7 da ys fr o m t he P ost- Treat me nt visit u ntil t he 
occ urre nce of pr o gressi v e disease , wit h dra wal of c o nse nt,  i nitiati o n of s u bse q ue nt a ntica ncer 
t hera p y, or st u d y c o m pleti o n.  
Patie nts s h o ul d n ot recei ve ot her a ntica ncer treat me nt, or e nr oll i n a n ot her t hera pe utic 
cli nical trial, u ntil after t he occ urre nce of disease pr o gressi o n, a n d i deall y, after t he 
c o m pleti o n of all st u d y visits (i ncl u di n g P ost- Treat me nt Visit + 6 0 da ys) .  
C CI
C CI


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10.7. 
Unscheduled Visits 
Additional visits can be performed as appropriate and at the discretion of the investigator.  
Assessments completed during unscheduled visits will be captured in the eCRF. 




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Cycle 1 Day 1 (Groups 1 and 2)/ Day 2 (Group 3) 
Blood samples will be collected for a minimum of 6 patients enrolled in each treatment group 
on Cycle 1 Day 1 (Groups 1 and 2) or Cycle 1 Day 2 (Group 3) at the time points described 
in Table 11-1 (for Group 1) and Table 11-2 (for Groups 2 and 3). The actual times in which 
the samples were drawn will be captured in the eCRF. 
Sampling windows per sample number noted in Table 11-1 and Table 11-2: 
Group 1: 
• Samples 1 – 4: ± 5 minutes  
• Samples 5 – 6: ± 10 minutes  
• Sample 7: ± 1 hour  
Group 2 and Group 3: 
• Sample 1: ± 5 minutes  
• Sample 2:  2 to 5 minutes prior to the trilaciclib EOI. Obtaining trilaciclib samples 
any time after the infusion is complete may result in missing the true Cmax. 
• Samples 3 – 5: ± 5 minutes  
• Samples 6 – 7: ± 10 minutes  
• Sample 8: ± 1 hour 
 
Table 11-1 
Cycle 1 Day 1 (Group 1) Blood Sampling Scheme Based on Predicted 
Administration Times of Carboplatin and Gemcitabine 
Sample Number 
1 
2 
3 
4 
5 
6 
7 
Sample  
Time (h) 
0 
(Predosea) 
0.5 
(Carbo 
EOI) 
1.0 
(Gem 
EOI) 
2.0 
 
3.5 
5.0 
24 
Carbo = carboplatin; EOI = end of infusion; Gem = gemcitabine; h = hour 
Times are approximate; all times are calculated from the start of carboplatin infusion. For simplicity, assumptions were 
based on 0.5 hour increments. Actual times will be recorded and may vary from those listed here. 
a 
Predose is defined as prior to the first dose of carboplatin in Group 1. 
 
Table 11-2 
Cycle 1 Day 1 (Group 2)/ Day 2 (Group 3) Blood Sampling Scheme Based 
on Predicted Administration Times of Trilaciclib, Carboplatin, and 
Gemcitabine 
Sample Number 
1 
2 
3 
4 
5 
6 
7 
8 
Sample  
Time (h) 
0 
(Predosea) 
0.5 
(trilaciclib 
EOI) 
1 
(Carbo 
EOI) 
1.5 
(Gem 
EOI) 
2.5 
4.0 
5.5 
24 
Carbo = carboplatin; EOI = end of infusion; Gem = gemcitabine; h = hour 
Times are approximate; all times are calculated from the start of trilaciclib infusion. For simplicity, assumptions were based 
on 0.5 hour increments. Actual times will be recorded and may vary from those listed here. 
a 
Predose is defined as prior to dosing of trilaciclib in Group 2 or Group 3. 
 
 




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11.4. 
Safety Assessments 
Safety evaluations will be conducted as described in Table 9-1 and Table 9-2. Safety 
evaluations will include monitoring of AEs, vital signs measurements, physical 
examinations, ECGs, clinical laboratory studies, infusion-related reactions, tumor response 
and duration of response based on RECIST, Version 1.1 (see Section 11.5), progression-free 
survival (PFS), and overall survival (OS). 
The toxicity of trilaciclib administered IV with or without chemotherapy will be assessed by 
the investigators using the NCI CTCAE, Version 4.03. 
11.4.1. 
Adverse Events and Serious Adverse Events 
11.4.1.1. 
Definition of Adverse Event 
An AE is defined as any untoward medical occurrence in a patient administered a medicinal 
product that does not necessarily have a causal relationship with this treatment. An AE can, 
therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the study (investigational) product. 
Hematologic toxicity includes neutropenia, lymphopenia, anemia, and thrombocytopenia. 
Adverse events include the following: 
• All suspected adverse drug reactions (ADRs) 
• All reactions from medication overdose, abuse, withdrawal, sensitivity, or toxicity 
• Apparently unrelated illnesses, including the worsening of a pre-existing illness (see 
pre-existing conditions below) 
• Injury or accidents (Note that if a medical condition is known to have caused the injury or 
accident [eg, a fall secondary to dizziness], the medical condition [dizziness] and the 
accident [fall] should be reported as 2 separate AEs). The outcome of the accident (eg, 
hip fracture secondary to the fall) should be recorded under comments. 
• Abnormalities in physiological testing or physical examination (findings that require 
clinical intervention or further investigation beyond ordering a repeat [confirmatory] test) 
• Laboratory abnormalities that are clinically significant and require clinical intervention or 
further investigation (beyond ordering a repeat [confirmatory] test) unless they are 
associated with an already reported clinical event. Laboratory abnormalities associated 
with a clinical event (eg, elevated liver enzymes in a patient with jaundice) should be 
described under comments on the report of the clinical event rather than listed as a 
separate AE. 
An AE does not include: 
• Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion); 
the condition that leads to the procedure will be an AE 


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• Pre-existing diseases or conditions present or detected at the start of the study that do not 
worsen 
• Situations where an untoward medical occurrence has not occurred (eg, hospitalization 
for elective surgery, social, and/or convenience admission) 
• Overdose of either study drug or concomitant medication without any signs or symptoms 
• Disease progression 
An unexpected AE is any AE that is not identified in nature, severity, or frequency in the 
current Investigator Brochure or product information. 
• An unexpected adverse drug reaction is an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information (eg, IB for an unapproved 
investigational medicinal product). All noxious and unintended responses to a medicinal 
product related to any dose should be considered ADRs. The phrase “responses to a 
medicinal product” means that a causal relationship between a medicinal product and an 
AE is at least a reasonable possibility, ie, the relationship cannot be ruled out. All serious 
and unexpected ADRs will have expedited reporting to the regulatory agencies following 
the International Conference on Harmonisation (ICH) requirements 
It is the responsibility of the investigator to document all AEs that occur during the study and 
every effort should be made to remain alert to possible AEs. Patients should be encouraged to 
report AEs spontaneously or in response to general, nondirected questioning. Adverse events 
should be reported on the appropriate page of the eCRF. 
In the event of an AE, the primary concern is the safety of the patient. If necessary, 
appropriate medical intervention should be provided, and the investigational drug 
discontinued. 
11.4.1.2. 
Definition of Serious Adverse Event 
The ICH topic E2A on Clinical Safety Data Management, Definitions and Standards for 
Expedited Reporting defines an SAE as any untoward medical occurrence that at any dose:  
• Results in death 
• Is life threatening 
NOTE: The term "life threatening" in the definition of "serious" refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe.  
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
(see Section 11.4.1.9) is appropriate in other situations, such as important medical events that 
may not be immediately life threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes listed 
in the definition above. These should also usually be considered serious. Examples of such 


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events are intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
To ensure there is no confusion or misunderstanding of the difference between the terms 
“serious” and “severe”, the following note of clarification is provided: 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
“serious,” which is based on patient/event outcome or action criteria usually associated with 
events that pose a threat to a patient’s life or functioning. Seriousness (not severity) serves as 
a guide for defining regulatory reporting obligations. 
11.4.1.3. 
Assessment of the Severity of Adverse Events 
The severity (toxicity grade) of AEs will be graded according to the NCI CTCAE, 
Version 4.03 (see Appendix 1). 
11.4.1.4. 
Assessment of the Relationship of Adverse Events to Study Drug 
The investigator will determine the assessment of the causal relationship of the AE to the 
study drugs (trilaciclib, carboplatin, and gemcitabine). Investigators should use their 
knowledge of the patient, the circumstances surrounding the event, and an evaluation of any 
potential alternative causes to determine whether or not an AE is considered to be related to 
the study drugs. The following guidance should be taken into consideration when 
determining causality: 
• Temporal relationship of event onset to the initiation of study drugs 
• Course of the event, considering especially the effects of dose reduction, discontinuation 
of study drugs, or reintroduction of study drugs (as applicable) 
• Known association of the event with the study drugs or with similar treatments 
• Known association of the event with the disease under study 
• Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event 
The following terms for assessment of the causality to study drugs or study procedures are to 
be used: 
• Unrelated: There is not a temporal relationship to study drug administration (eg, too 
early, too late, or study drug not taken), or there is a reasonable causal relationship 
between another drug, concurrent disease, or circumstance and the AE. 
• Unlikely Related: There is a temporal relationship to study drug administration, but there 
is not a reasonable causal relationship between the study drug and the AE (ie, the AE is 
doubtfully related to study drug). 


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• Possibly Related: There is a reasonable causal relationship between the study drug and 
the AE. Information related to withdrawal of study drug is lacking or unclear. 
• Probably Related: There is a reasonable causal relationship between the study drug and 
the AE. The event responds to withdrawal of study drug. Re-challenge is not required. 
• Definitely Related: There is a reasonable causal relationship between the study drug and 
the AE. The event responds to withdrawal of study drug, and recurs with re-challenge, 
when clinically feasible. 
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy. 
11.4.1.5. 
Assessment of the Outcome of Adverse Events 
The action taken for study drugs (eg, dose not changed, dose reduced, dose interrupted, drug 
permanently discontinued, dose skipped, dose delayed, not applicable, unknown) will be 
recorded on the eCRF.  
Other actions (eg, none, concomitant medication given, new or prolonged hospitalization, 
procedural surgery) will also be recorded on the eCRF. 
The outcome will be assessed according to the following: 
• Fatal 
• Not recovered/not resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Recovered/resolved 
• Unknown 


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11.4.1.6. 
Method, Frequency, and Time Period for Detecting Adverse Events and 
Serious Adverse Events 
Safety surveillance reporting of AEs commences at the time of informed consent and 
continues through 30 days after the last dose of study treatment (safety follow-up phone call). 
For screen failures, only SAEs related to study procedures need be collected and only 
through the date of screen failure. 
11.4.1.7. 
Documentation of Adverse Events and Serious Adverse Events 
All AEs will be documented in the appropriate section of the eCRF. The CTCAE, Version 
4.03 grading scale referenced in Appendix 1 is provided to assist in categorizing and grading 
AEs. All SAEs (see Section 11.4.1.2) will be additionally documented on the SAE report 
form. For AEs occurring while the patient is in the clinic setting, ie, before, during, or after 
study drug administration, the start time and stop time of the AE should be recorded in the 
source document. 
The following will be recorded for each AE in the eCRF: 
• A description of the AE in medical terms, not as reported by the patient. Whenever 
possible, a diagnosis should be given when signs and symptoms are due to common 
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be 
reported as “upper respiratory infection”). 
• Date of onset (start date) 
• Date of recovery (stop date) 
• Grade as assessed by the investigator according to the definitions in the AE Grading 
Scale. If the AE is not specifically listed in Appendix 1, use the following grades: 
Grade 1 
mild 
Grade 2  
moderate 
Grade 3 
severe 
Grade 4 
life-threatening or disabling 
Grade 5 
death 


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
 
Pa ge 7 6  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
1 1. 4. 1. 8.  
A d verse E ve nt C o di n g 
A d verse e ve nt ver bati m ter ms pr o vi de d b y t he i n vesti gat or will be c o de d b y G 1 T hera pe utics 
or its desi g nee  usi n g t he latest versi o n of t he Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A) as s pecifie d i n t he statistical a nal ysis pla n ( S A P). 
1 1. 4. 1. 9.  
Re p orti n g of Seri o us A d verse E ve nts 
All S A Es m ust be e ntere d i nt o t he S A E f or m a n d se nt t o t he me dical  m o nit or / dr u g safet y 
tea m wit hi n 2 4 h o urs of first k n o wle d ge of t he e ve nt b y t he st u d y pers o n nel. 
T he re p orti n g peri o d f or S A Es be gi ns fr o m t he ti me of i nf or me d c o nse nt t hr o u g h 3 0 da ys 
after t he last d ose of st u d y treat me nt (safet y f oll o w - u p p h o ne call). A n y S A E t hat is t h o u g ht 
t o be relate d t o t he st u d y dr u g a n d t hat occ urs after t he re p orti n g peri o d m ust be re p orte d 
wit hi n 2 4 h o urs  of disc o ver y of t he S A E. 
S A E i nf or mati o n will be c ollecte d o n t he e C R Fs, t heref ore it is i m perati ve t hat a n y S A E be 
e ntere d o nt o t he electr o nic S A E F or m wit hi n 2 4 h o urs of lear ni n g of t he e ve nt. If t he E D C 
s yste m is n ot o perati o nal, t he pa per S A E F or m m ust be c o m plete d wit hi n 2 4 h o urs a n d fa xe d 
t o t he n u m ber bel o w; if a n S A E is fa xe d, t he e ve nt m ust als o be e ntere d i n E D C o nce t he 
s yste m is a vaila ble. 
P P D P h ar m ac o vi gil a nce:  
U S Sites 2 4  H o ur S afet y H otli ne F a x: 
 
N o n -U S Sites 2 4 H o ur S afet y H otli ne F a x: 
 
I n t he e ve nt of f a x f ail ure or ot her re p orti n g q uesti o ns: 
U S Sites 2 4 H o ur S afet y H otli ne: 
 
N o n -U S Sites  2 4 H o ur S afet y H otli ne: 
 
I n a d diti o n, a n y k n o w n u nt o war d e ve nt t hat occ urs s u bse q ue nt t o t he A E-re p orti n g peri o d 
t hat t he in vesti gat or assesses as relate d t o t he i n vesti gati o nal me dicati o n s h o ul d als o be 
re p orte d as a n A E. 
1 1. 4. 1. 1 0.  
F oll o w- u p of A d verse E ve nts 
All A Es ( b ot h seri o us a n d n o nseri o us) will be f oll o we d u p i n acc or da nce wit h g o o d me dical 
practice u ntil res ol uti o n, ret ur n t o scree ni n g, or it is dee me d t hat f urt her rec o ver y is u nli kel y. 
All meas ures re q uire d f or A E ma na ge me nt a n d t he ulti mate o utc o me of t he A E will be 
rec or de d i n t he s o urce d oc u me nt a n d re p orte d t o t he s p o ns or. 
P P D
P P D
P P D
P P D


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All unresolved AEs should be followed by the investigator until the events are resolved, the 
patient is lost to follow-up, or the AE is otherwise explained, or further recovery is not 
deemed to be feasible. At the last scheduled visit, the investigator should instruct each patient 
to report any subsequent event(s) that the patient, or the patient’s personal physician, believes 
might reasonably be related to participation in this study.  
After study conclusion, the investigator should notify G1 Therapeutics of any death or SAE 
they are aware of occurring at any time after a patient has discontinued or terminated study 
participation that may reasonably be related to the study drug. G1 Therapeutics should also 
be notified if the investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a patient that has participated in 
this study. 
11.4.1.11. 
Regulatory Aspects of Adverse Event Reporting 
Unexpected serious adverse reactions are subject to expedited reporting to the Food and Drug 
Administration (FDA) and European National Competent Authorities, the Medicine 
Evaluation Board, and the Competent Authorities in other Member States, if applicable, in an 
expedited time frame in compliance with current legislation. The sponsor or its representative 
will report all unexpected SAEs to the Competent Authority, the Medicine Evaluation Board, 
and the Competent Authorities in other Member States, as applicable in an expedited time 
frame. 
The investigator is encouraged to discuss with the medical monitor any adverse experiences 
for which the issue of reportability is unclear or questioned. 
It is important that the investigator provide his/her assessment of relationship to study drug at 
the time of the initial report. The following information must be reported on the SAE report 
form: 
• Protocol number 
• Site and/or investigator number 
• Patient number 
• Demographic data 
• Brief description of the event 
• Onset date and time 
• Resolution date and time, if the event has resolved 
• Current status, if event has not yet resolved 
• Any concomitant treatment and medication 
• Investigator’s assessment of whether the SAE was related to investigative product or not 
• Outcome of the event if available 
The medical monitor or member of the safety team will contact the site for clarification of 
data entered in the eCRF and or SAE form, or to obtain missing information. In the event of 
questions regarding SAE reporting, the site may contact the medical monitor or a member of 
the safety team. 


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G1 Therapeutics, or their designee, is responsible for submitting reports of AEs associated 
with the use of the study drug that are both serious and unexpected to the FDA and European 
National Competent Authorities, the Medicine Evaluation Board, and the Competent 
Authorities in other Member States, if applicable, in an expedited time frame in compliance 
with current legislation. Unexpected SAEs that are already reported to the European 
Medicines Agency Eudravigilance database do not have to be reported again to the relevant 
authorities. All investigators participating in ongoing clinical studies with the study 
medication will receive copies of these reports for prompt submission to their IRB or IEC. 
The expedited reporting will occur no later than 15 calendar days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life-threatening cases, the term will be a 
maximum of 7 calendar days for a preliminary report with another 8 days for completion of 
the final report.  
11.4.1.12. 
Handling of Overdoses and Toxicity 
No information on treatment of overdose of trilaciclib is currently available. General 
supportive measures should be used as appropriate. 
11.4.1.13. 
Reporting of Pregnancies  
Pregnancy per se is not considered an AE unless there is cause to believe that the 
investigational drug may have interfered with the effectiveness of a contraceptive 
medication. Hospitalization for normal delivery of a healthy newborn should not be 
considered a SAE. 
Each pregnancy in a study patient or partner of a study patient must be reported to the 
sponsor within 24 hours of learning of its occurrence on the Pregnancy Report Form. If a 
patient becomes pregnant, study drug administration must be discontinued immediately. The 
pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
The avoidance of pregnancy or fathering a child (including sperm donation) is suggested for 
6 months following the discontinuation of study drug. No information is currently available 
regarding the effects of trilaciclib on fertility, gestation, or subsequent child development. 
11.4.1.14. 
Infusion-Related Reactions  
An infusion related reaction is defined as “an adverse reaction to the infusion of 
pharmacological or biological substances” (CTCAE v4.03) and can be divided into two 
categories: local effects and systemic effects. Those AEs that are infusion related should be 
recorded in the eCRF as “infusion-related reactions”. Any associated symptoms as outlined 
in Table 11-4 below should also be recorded as AEs. The associated symptoms and details 
(ie, local versus systemic) will also be captured in the EDC. 


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Table 11-4 
Symptoms Associated with Infusion-Related Reactions 
Redness 
Pyrexia 
Hoarseness 
Edema 
Angioedema 
Hypoxia 
Ulceration 
Flushing 
Mouth Tingling 
Pain 
Rigors/Chills 
Diaphoresis 
Phlebitis 
Bronchospasm/Wheezing 
Rash (non-specific) 
Warmth 
Chest Pain 
Syncope 
Pruritis 
Back Pain 
Tachycardia 
Hypotension 
Difficulty Swallowing 
Throat Tightness 
Shortness of 
Breath/Dyspnea 
Facial Swelling 
 
 
11.4.2. 
Clinical Laboratory Assessments 
Blood samples will be collected for clinical laboratory assessments as outlined in Table 9-1 
and Table 9-2. The following clinical laboratory tests will be performed: 
• Hematology (hemoglobin, white blood cells [WBCs] with differential and platelet 
counts) 
• Chemistry (albumin, alkaline phosphatase, total bilirubin, calcium, chloride, creatinine, 
glucose, inorganic phosphorus or phosphate, potassium, total protein, ALT, AST, LDH, 
sodium, and blood urea nitrogen) 
• Urinalysis (semiquantitative dipstick: specific gravity, pH, evaluation of glucose, protein, 
bilirubin, ketones, leukocytes, and hemoglobin; and a microscopic examination, 
including RBC, WBC, and casts will be performed, if necessary) 
Laboratory parameters will be analyzed by a local certified laboratory and laboratory 
credentials and reference ranges will be sent to the sponsor or designee. The investigator will 
review all laboratory reports and indicate the clinical significance of all abnormal values, and 
subsequently sign and file the laboratory report with the patient’s source records/charts. 
Laboratory parameters for which clinically significant values are noted will be re-measured 
or the appropriate clinical follow-up arranged by the investigator. Values will be documented 
in the source until stabilized, or the laboratory value returns to a clinically acceptable range 
(regardless of relationship to study medication). Any laboratory value that remains abnormal 
at the end of the study and that is considered clinically significant will be followed according 
to accepted medical standards for up to 30 days or until resolution of the abnormality, or it is 
deemed that recovery is not feasible. 
Laboratory toxicities will be assessed by the investigator using the NCI CTCAE, 
Version 4.03 (see Appendix 1). 
The DMC may recommend decreasing the frequency of hematological evaluations based on 
accumulating data. The investigators and IRBs or IECs will be notified if the frequency is 
reduced. 


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11.4.3. 
Demographics and Vital Signs 
Vital signs should be collected before and after infusion of each study drug; vitals need to be 
taken only once between infusions. The following will be collected: 
• Date of birth 
• Age 
• Sex 
• Ethnicity 
• Race 
• Height  
• Body weight  
• Body temperature  
• Systolic and diastolic blood pressure, pulse rate, and respiration rate will be measured. 
Blood pressure should be assessed after 5 minutes of rest, when possible. 
11.4.4. 
Physical Examination 
Full physical examination evaluations at screening should include general appearance, skin, 
breast, neck, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, 
and neurological examinations. Subsequent physical exams should include body systems as 
appropriate. 
Information about the physical examination must be present in the source documentation at 
the study site. The result of the physical examination prior to the start of study drug must be 
included in the relevant eCRF. Clinically relevant findings made after the start of study drug, 
which meet the definition of an AE, must be recorded on the AE eCRF. 
11.4.5. 
Electrocardiogram Assessments 
Standard 12-lead ECGs will be performed and assessed locally as outlined in Table 9-1 and 
Table 9-2. All patients will have single ECGs obtained at Screening.   
Additional ECGs will be obtained in triplicate (at least 1 minute apart) for patients in any 
group who agreed to PK sampling ONLY if PK samples are also obtained. Obtain ECGs on 
Day 1 (Group 2) and Day 2 (Group 3) for Cycle 1 at the following time points: predose (prior 
to trilaciclib), 0.5 hour (EOI of trilaciclib), 2 hours (± 10 minutes) after EOI for trilaciclib, 
and 5 hours (± 30 minutes) after EOI of trilaciclib. Patients should rest for approximately 
5 minutes prior to each ECG assessment. The ECGs should be obtained just prior to PK 
sampling.  
The investigator or designee should review the ECGs for any abnormalities as compared with 
predose ECGs.  


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11.5. 
Tumor Response 
11.5.1. 
Tumor Assessments 
For tumor assessment, all sites of disease should be assessed radiologically by CT or MRI at 
screening, every 9 weeks ± 7 days (Week 9, Week 18 and Week 27) and then every 12 weeks 
± 7 days (beginning Week 39) thereafter, until the occurrence of disease progression, 
withdrawal of consent, the initiation of subsequent anticancer therapy, or study completion 
(see Table 9-1 and Table 9-2). Tumor assessments should include CT or MRI with contrast 
(if clinically possible) of the chest and abdomen. 
Radionuclide bone scans shall be performed at screening. Skeletal lesions identified on the 
bone scan at baseline, which are not visible on the CT or MRI scan should be imaged at 
baseline and followed at scheduled visits using localized CT, MRI or x-ray. Bone scans need 
not be repeated after baseline unless clinically indicated. 
Brain scans with contrast (by CT or MRI) shall be performed at screening for all patients. If 
brain metastases are present at screening, brain scans shall be done with each tumor 
assessment. If no metastases are present at Screening, imaging does not need to be performed 
during the study unless clinically indicated or if the subject is neurologically symptomatic. 
Any CT, MRI, bone or brain scans obtained as standard of care prior to screening will not 
need to be repeated at screening if performed within the screening window. 
Assessments should be performed within 7 days of starting the subsequent cycle. Additional 
scans may be obtained at the discretion of the investigator, if clinically indicated. If a patient 
shows a radiological response (CR or PR), a confirmatory radiological assessment will be 
performed at least 4 weeks after the response was first noted. For those patients who have not 
progressed at the time of study drug discontinuation, radiological tumor assessments will be 
performed utilizing the same imaging modality as used at screening every 12 weeks ± 7 days 
from the Post-Treatment Visit until disease progression, withdrawal of consent, initiation of 
subsequent anticancer therapy, or study completion. 
The same method of assessment (CT or MRI) should be used to characterize tumors at 
screening and at all follow-up assessments. If positron emission tomography (PET) is used, it 
should also be accompanied by spiral CT or MRI. 
Investigators should follow the RECIST, Version 1.1 guidelines (Eisenhauer et al. 2009) for 
tumor assessments.  
11.5.2. 
Tumor Lesions: Identification and Follow-up 
11.5.2.1. 
Measurable Lesions 
Measurable tumor lesions are defined as tumor lesions with a longest diameter (measured in 
at least 1 dimension) with a minimum size as follows (Eisenhauer et al. 2009):  
• 10 mm by CT or MRI (with a scan slice thickness of no greater than 5 mm) 


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Measurable lymph nodes must be ≥ 15 mm on the short axis by CT or MRI (with a scan slice 
thickness of no greater than 5 mm); only the short axis is to be measured at screening 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 screening, up to 5 measurable tumor lesions/lymph nodes (with a 
maximum of 2 lesions per organ) should be identified as target lesions that will be followed 
to quantitate the status of disease during the study. Lesions with the longest diameter, that are 
representative of all involved organs, and for which reproducible repeated measurements can 
be obtained should be selected as the target lesions. NOTE: malignant lymph node is 
considered an organ in this study, therefore only 2 malignant lymph nodes may be selected as 
target lesions and all others should be entered as nontarget lesions. 
At screening and each follow-up time point (see Table 9-1 and Table 9-2), each target lesion 
should be measured and the overall tumor burden will be calculated as the sum of the 
diameters of the target lesions (longest diameter [LD] for tumor lesions and short axis for 
lymph nodes) and documented in the eCRF. If a target lesion fragments into multiple smaller 
lesions, the LDs of all fragmented portions are added to the sum of the diameters. If multiple 
lesions coalesce, the LD of the coalesced lesion will be included in the sum of the diameters. 
11.5.2.2. 
Nonmeasurable Lesions 
Nonmeasurable lesions include tumor lesions with a longest diameter < 10 mm, lymph nodes 
with ≥ 10 to < 15 mm short axis, or nonmeasurable lesions such as leptomeningeal disease, 
ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, or abdominal masses/abdominal organomegaly identified by 
physical exam that is not measurable by CT scan or MRI (Eisenhauer et al. 2009).  
Nontarget lesions: All other lesions (or sites of disease) identified at screening should be 
identified as nontarget lesions and recorded in the eCRF. Measurements of these lesions are 
not required, but the presence, absence, or unequivocal progression of each nontarget lesion 
should be recorded in the eCRF at each follow-up time point. Multiple nontarget lesions in 
the same organ may be noted as a single item on the eCRF.  
11.5.2.3. 
New Lesions 
Any new lesions should be identified and recorded at each follow-up assessment, as these are 
markers of disease progression. As defined in the RECIST, Version 1.1 guidelines 
(Eisenhauer et al. 2009), new lesions include the following: 


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• A lesion in an anatomical location that was not scanned at screening 
• Equivocal new lesion of small size that with continued therapy and follow-up is found to 
progress and represent new disease (progression should be considered as of the date of 
the initial scan) 
• Negative positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose 
(FDG-PET) at screening, but has a positive FDG-PET at follow-up 
• No FDG-PET at screening and a positive FDG-PET at follow-up that corresponds to a 
new site of disease as confirmed by CT (date of disease progression should be the date of 
the initial abnormal FDG-PET scan) 
Note: Findings attributable to differences in scanning technique or a change in type of 
imaging (CT versus MRI) and findings representing something other than tumor (eg, healing 
or flare of exiting bone lesions, necrosis of a liver lesion) should not be considered new 
lesions. 
11.5.3. 
Definitions of Tumor Response and Disease Progression 
The determination of TNBC tumor response and progression will be based on the 
RECIST, Version 1.1 criteria (Eisenhauer et al. 2009). The definitions for tumor response per 
the RECIST, Version 1.1 criteria are as follows: 
11.5.3.1. 
Evaluation of Target Lesion Response 
• Complete response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or nontarget) must have reduction in short axis to < 10 mm. 
• Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the screening sum of diameters.  
• Progressive disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the screening sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new 
lesions is also considered progression. 
• Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum of diameters while on study. 
A response category of not evaluable (NE) is to be used when there is inadequate information 
to otherwise categorize the response status. 
11.5.3.2. 
 Evaluation of Nontarget Lesions 
• Complete response (CR): Disappearance of all nontarget lesions and normalization of 
tumor marker level. All lymph nodes must be < 10 mm short axis. 
• Non-CR/Non-PD: Persistence of 1 or more nontarget lesions and/or maintenance of 
tumor marker level above the normal limits. 
• Progressive Disease (PD): Unequivocal progression of existing nontarget lesions or the 
appearance of at least 1 new lesion.  


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
 
Pa ge 8 4  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
1 1. 5. 3. 3.  
E val uati o n of O v erall Res p o nse 
Patie nts w h o ha ve at least 1 p ost d ose t u m or assess me nt ( C T sca n or M RI) will be c o nsi dere d 
e val ua ble f or t u m or res p o nse.  
Ta ble 1 1- 5  des cri bes t he e val uati o n of o verall res p o nse at eac h  ti me p oi nt base d o n tar get a n d 
n o n tar get lesi o n res p o nses at eac h ti me p oi nt, as well as t he a p peara nce of ne w lesi o ns. T he 
best o verall res p o nse is t he best res p o nse rec or de d fr o m t he start of t he treat me n t u ntil 
disease pr o gressi o n . C o nfir mati o n of C R a n d P R is re q uire d as descri be d i n Secti o ns  1 1. 5. 3. 1  
a n d 1 1. 5. 3. 2 .  
T a ble 1 1- 5 
E v al u ati o n of O ver all Res p o nse at E ac h Ti me P oi nt  
T ar get Lesi o ns  
N o nt ar get Lesi o ns  
Ne w Lesi o ns  
O ver all Res p o nse  
C R  
C R  
N o  
C R  
C R  
N o n -C R/ N o n -P D  
N o  
P R  
C R  
N ot e val uate d  
N o  
P R  
P R  
N o n -P D/ n ot e val uate d  
N o  
P R  
S D  
N o n -P D/ n ot e val uate d  
N o  
S D  
N E  
N o n -P D  
N o  
N E  
P D  
A n y  
Yes or N o  
P D  
A n y  
P D  
Yes or N o  
P D  
A n y  
A n y  
Yes  
P D  
C R = c o m plete res p o nse, P R = partial res p o nse, S D = sta ble disease,  P D = pr o gressi ve disease, N E = n ot e val ua ble  
S o urce: (Eise n ha uer  et al. 2 0 0 9) 
C CI


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
 
Pa ge 8 5  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
C CI


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
 
Pa ge 8 6  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
1 1. 1 0.  
A p pr o pri ate ness of Me as ure me nts  
T he meas ures of efficac y, P K, a n d safet y e val uate d i n t his st u d y are ba se d o n t he mec ha nis m 
a n d acti vit y of trilacicli b, sta n dar d t y pes of assess me nts t y picall y perf or me d i n patie nts wit h 
m T N B C , a n d pri or cli nical o bser vati o ns deri ve d fr o m patie nts recei vi n g G C t hera p y f or 
m T N B C . T he meas ureme nt  of t u m or res p o nse base d o n t he R E CI S T, V ersi o n 1. 1 
(Eise n ha uer  et al. 2 0 0 9) is sta n dar d. T he P K a n d safet y meas ures i ncl u de d i n t his st u d y are 
als o sta n dar d.  
C CI


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
 
Pa ge 8 7  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
1 2.  
S T U D Y T E R MI N A TI O N O R S T U D Y D R U G 
DI S C O N TI N U A TI O N  
1 2. 1.  
St u d y Ter mi n ati o n  
T he e ntire st u d y ma y be ter mi nate d i n t he e ve nt of a n y of t he f oll o wi n g: 
•  Occ u rre nce of A Es u n k n o w n t o date wit h res pect of t heir nat ure, se verit y, a n d d urati o n, 
or t he u ne x pecte d i nci de nce of k n o w n A Es 
•  Me dical or et hical reas o ns affecti n g t he c o nti n ue d perf or ma nce of t he st u d y  
•  Diffic ulties i n t he recr uit me nt of patie nts  
•  Ca ncellati o n of t he dr u g de vel o p me nt pr o gra m 
•  S p o ns or decisi o n f or ot her reas o ns  
 
Patie nts will be f oll o we d f or s ur vi val at a mi ni m u m u ntil at least 5 0 % of t he patie nts i n t he 
st u d y ha ve die d.  
1 2. 1. 1.  
Site Ter mi n ati o n  
A st u d y site will be cl ose d if t here is e vi de nce of fra u d, ot her u net hical c o n d uct, or 
si g nifica nt re g ulat or y n o nc o m plia nc e t o t he pr ot oc ol or t o G o o d Cli nical Practice ( G C P ), or 
if i ns ufficie nt patie nts ha ve bee n e nr olle d t o meet t he site o bjecti ves. 
1 2. 2.  
Disc o nti n u ati o n of St u d y Dr u g  
St u d y dr u g will be disc o nti n ue d if a n y of t he f oll o wi n g e ve nts occ ur d uri n g t he st u d y: 
•  A patie nt s uffers a n A E  t hat, i n t he j u d g me nt of t he i n vesti gat or, s p o ns or, or me dical 
m o nit or, prese nts a n u nacce pta ble ris k t o t he patie nt 
•  Ge n eral or s pecific c ha n ges i n t he patie nt’s c o n diti o n (e g, a si g nifica nt i nterc urre nt ill ness 
or c o m plicati o n) t hat, i n t he j u d g me nt of t he i n vesti gat or, are u nacce pta ble f or f urt her 
a d mi nistrati o n of st u d y dr u g 
•  Occ urre nce of pre g na nc y  
•  Si g nifica nt n o nc o m plia nce wit h pr ot oc ol re q uire me nts 
•  T he s p o ns or or le gal re prese ntati ve of t he s p o ns or re q uests t he patie nt t o wit h dra w 
•  Patie nt has ra di ol o gicall y d oc u me nte d disease  pr o gressi o n 
•  If t otal ti me bet wee n c he m ot hera p y e xcee ds a t otal of > 4 wee ks, u nless a gree d t o b y t he 
treati n g i n vesti gat or a n d me dical m o nit or.  
•  W here per ma ne nt disc o nti n uati o n of st u d y dr u g is i n dicate d i n t he t o xicit y ma na ge me nt 
rec o m me n dati o ns (Ta ble 8- 1 , Ta ble 8- 3 ). 
I n t he e ve nt of st u d y dr u g disc o nti n uati o n, patie nts s h o ul d be str o n gl y e nc o ura ge d t o 
c o m plete all sc he d ule d assess me nts t hr o u g h t he e n d of t heir c urre nt 2 1- da y treat me nt c ycle, 
i ncl u di n g t he  
; t he P ost-Treat me nt Visit  ( Da y 2 2 of last c ycle ); t he safet y 
f oll o w- u p c o ntact at 3 0 da ys after t he last d ose of st u d y treat me nt; a n d t he S ur vi val F oll o w-
u p P hase of t he st u d y. A patie nt w h o disc o nti n ues st u d y treat me nt f or reas o ns ot her t ha n P D 
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will have a CT or MRI scan at the Post-Treatment Visit, if they have not had a scan within 
the prior 4 weeks.  
The investigator will document the reason for study drug discontinuation on the applicable 
eCRF page.   
When discontinuation is due to an AE, the investigator should follow the AE until the events 
are resolved, the patient is lost to follow-up, the AE is otherwise explained, or further 
recovery is not deemed to be feasible. Data on these events should be collected on the AE 
eCRF. 
In the event a patient discontinues due to an AE, toxicity, or pregnancy, the investigator 
should notify the medical monitor by telephone within 48 hours of study drug 
discontinuation. 
A patient can withdraw consent from further treatment/procedures but agree to continue to be 
followed for survival.   
12.3. 
Withdrawal of Patients from the Study 
Patients may withdraw from the study at their own discretion (or at the discretion of the 
investigator) for any reason at any time. The following list of reasons for withdrawing 
patients from the study may include but are not limited to: 
• Withdrawal of informed consent 
• Lost to follow-up (must have at least 2 documented attempts to contact the patient; 
1 attempt must be written to the patient and sent via certified letter) 
All data and stored laboratory samples collected prior to the date of withdrawal of consent 
will remain in the clinical database and stored at the laboratory vendor.  
 


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13. 
STATISTICS 
Full details on the statistical analyses to be performed will be provided in a separate 
statistical analysis plan (SAP). 
13.1. 
Sample Size and Power 
The sample size is not determined from a statistical perspective. Approximately 90 patients 
will be enrolled into the study (30 per treatment group). With 30 patients, the precision for 
point estimates in each arm is as follows: the 95% confidence interval (CI) width for binary 
endpoints based on Wilson score intervals are at most the observed proportion +/- 0.167. The 
95% CI width for continuous endpoints using the t-distribution are the observed mean 
+/- 0.373*standard deviation of the endpoint.  
13.1.1. 
Analysis Populations/Sets 
The full analysis set (FAS) includes all patients who received at least 1 dose of study drug. 
Analyses using the FAS will be conducted on the basis of the assigned treatment. All efficacy 
analyses will be assessed using the FAS and the FAS is the primary population for analysis. 
The safety population includes all enrolled patients who received at least 1 dose of study 
drug. The safety population will be conducted on the basis of the actual treatment received. 
All safety analyses will be assessed using the safety population. 
A per-protocol (PP) subset may also be used to analyze select endpoints and will be based on 
study drug exposure (compliance and/or time on study drug) and major protocol deviations. 
The PK set will include all dosed patients with evaluable PK data. 
13.1.2. 
Timing of Analyses 
13.1.2.1. 
Data Safety Monitoring Committee 
A Data Safety Monitoring Committee (DMC) will monitor accumulating safety data 
according to a charter that defines its roles and responsibilities. The first DMC meeting will 
occur after approximately the first 20 patients have been enrolled and completed at least 
1 cycle. The DMC will perform interim reviews approximately every 4 months during the 
Treatment Phase, depending upon the enrollment rate. Additional reviews may occur based 
on DMC requests. The committee will consist of individuals with extensive multicenter 
clinical study experience drawn from the fields of clinical oncology (specifically, TNBC) and 
biostatistics. These individuals will be entirely independent of the conduct of the study. 
Additional details regarding the committee procedures and policies, including table displays 
and strategy for maintaining study blind, are described in the DMC charter. 
No interim analyses of efficacy are planned. 


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
 
Pa ge 9 0  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
1 3. 1. 2. 2.  
Fi nal A nal ysis  
T he fi nal a nal ysis will occ ur w he n t he la st patie nt c o m pletes t he P ost-Treat me nt Visit. All 
st u d y data c ollecte d u p t hr o u g h t he ti me of t he fi nal a nal ysis data c ut, i ncl u di n g t he S ur vi val 
F oll o w- u p P hase res ults, will be i ncl u de d i n t he fi nal a nal ysis.  
1 3. 1. 2. 3.  
E n d of St u d y A nal ysis 
If t he S ur vi val F oll o w- u p  P hase of t he st u d y c o nti n ues after t he fi nal a nal ysis, a 
s u p ple me ntar y a nal ysis will be d o ne at t he ti me of st u d y c o m pleti o n. Re p orte d res ults will be 
c u m ulati ve i n nat ure, i ncl u di n g all data c ollecte d d uri n g t he e ntire st u d y. 
1 3. 1. 3.  
Ge ner al C o nsi der ati o ns f or D at a A n al ysis  
All statistical a nal yses will be perf or me d usi n g S A S ®  versi o n 9 or hi g her.  
Data will be s u m marize d descri pti vel y b y treat me nt gr o u p a n d f or c o m bi ne d treat me nt 
Gr o u ps 2 a n d 3. Treat me nt differe nces bet wee n t he G C t hera p y ( Gr o u p 1) a n d eac h of t he 
ot her treat me nt gr o u ps ( Gr o u ps 2 a n d 3) will  be esti mate d.  T he descri pti ve s u m mar y f or t he 
cate g orical varia bles will i ncl u de c o u nts a n d perce nta ges. T he descri pti ve s u m mar y f or t he 
c o nti n u o us varia bles will i ncl u de mea ns, me dia ns, sta n dar d de viati o ns, a n d mi ni m u m a n d 
ma xi m u m val ues. T he descri pti ve s u m maries of ti me -t o-e ve nt data will i ncl u de me dia n, 
t we nt y-fift h a n d se ve nt y-fift h perce ntiles, a n d sta n dar d err or. All data will be liste d f or all 
patie nts.  U nless s pecifie d ot her wise, safet y s u m maries will i ncl u de all c ollecte d data, a n d 
s u m maries of efficac y will i ncl u de data c ollecte d t hr o u g h t he Treat me nt P hase. 
T his st u d y is descri pti ve i n nat ure, a n d n o f or mal h y p ot hesis testi n g will be per f or me d acr oss 
treat me nt gr o u ps. All CIs  will be 9 5 %, u nless state d ot her wise.  
T he effects of c o variates a n d wit h dra wal fr o m st u d y t reat me nt d ue t o reas o ns ot her t ha n 
deat h, disease pr o gressi o n , a n d t o xicit y will be assesse d t o deter mi ne t he i m pact o n t he 
ge neral a p plica bilit y of res ults fr o m t his st u d y. F urt her details of t he a nal ysis, i ncl u di n g t he 
ha n dli n g of missi n g data, i m pact of varia ble c he m ot hera p y d ose e x p os ure i ncl u di n g d ose 
re d ucti o ns, tra nsf or mati o ns a n d ot her data ha n dli n g pr oce d ures will be pr o vi de d i n t he S A P . 
  
1 3. 2.  
B aseli ne a n d De m o gr a p hic C h ar acteristics  
De m o gra p hics a n d baseli ne ( scree ni n g) c haracteristics will be s u m marize d descri pti vel y .  
1 3. 3.  
Effic ac y A n al ysis  
1 3. 3. 1.  
Effic ac y E n d p oi nts  
U nless ot her wise state d, t he ter mi n ol o g y ‘ he mat ol o gic para meters’ refers t o A N C , 
l y m p h oc yte, he m o gl o bi n, a n d platelet c o u nts; t he ter mi n ol o g y ‘ he mat ol o gic t o xicities’ refers 
t o ne utr o pe nia, l y m p h o pe nia, a ne mia, a n d t hr o m b oc yt o pe nia. Eac h para meter a n d t o xicit y 
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will be evaluated individually, but are described as such to avoid repetition. Hematologic 
toxicities are assigned based on CTCAE, Version 4.03.  
• Hematologic kinetic endpoints: 
• Change and percent change in hematologic parameter values from screening to the 
Post-Treatment Visit 
• Change and percent change in hematologic parameter values from predose for a 
particular cycle to the end of that cycle 
• Change and percent change in hematologic parameter values from predose for a 
particular cycle to nadir for that cycle 
• Rate of change in hematologic parameter values from predose for a particular cycle to 
nadir for that cycle 
• Change and percent change in hematologic parameter values from nadir for a 
particular cycle to the end of that cycle 
• Rate of change in hematologic parameter values from nadir for a particular cycle to 
the end of that cycle 
• Area under the curve in hematologic parameter values from predose for a particular 
cycle to the end of that cycle 
• Area under the curve in hematologic parameters from predose for a particular cycle to 
nadir for that cycle 
• Area under the curve in hematologic parameter values from nadir for a particular 
cycle to the end of that cycle 
• By cycle and overall study hematologic parameter nadir values 
• Time to hematologic parameter value nadir by cycle 
• Time to return to predose hematologic parameter values by cycle 
• Proportion of patients with a return to predose hematologic parameter values by cycle 
 
• Hematologic toxicity endpoints: 
• Incidence of Grade 3 and 4 hematologic toxicities 
• Total number of Grade 3 and 4 hematologic toxicities 
• Proportion of patients with a hematologic toxicity recovery by cycle 
• Time to hematologic toxicity recovery by cycle 
 
• Chemotherapy exposure and compliance endpoints: 
• Duration on treatment 
• Number of cycles received 
• Dose intensity and cumulative dose 
• Incidence of dose interruptions, delays, and reductions  
• Incidence of dose delays due to hematologic toxicity 
• Incidence of study treatment termination due to hematologic toxicity 
 
• Other efficacy endpoints: 


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
 
Pa ge 9 2  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
•  I nci de nce of i nfecti o ns o verall a n d b y se verit y 
•  I nci de nce of R B C a n d platelet tra nsf usi o ns  
•  I nci de nce of he mat o p oietic gr o wt h fact ors use  
•  I nci de nce a n d d urati o n of s yste mic a nti bi otic use  
 
1 3. 3. 2.  
Met h o d s of A n al ysis f or Effic ac y E n d p oi nts 
S u m maries  of efficac y will be perf or me d usi n g t he F A S. Select s u m maries will als o be 
re peate d i n t he P P a nal ysis set. Stratificati o n fact ors will be i ncl u de d as c o variates, u nless 
ot her wise s pecifie d, i n t he a p plica ble statistical m o deli n g a nal yses.  U nless n ote d ot her wise, 
he mat ol o gic e n d p oi nts will be s u m marize d se paratel y b y eac h para meter t y pe (ie, A N C , 
l y m p h oc ytes, etc.). T he S A P will descri be i n detail t he mi ni m u m sa m pli n g a n d d osi n g 
re q uire me nts f or i ncl usi o n i n t he a nal ysis of eac h e n d p oi nt f or a gi ve n c ycle or o verall, 
partic ularl y f or t h ose t hat i n v ol ve A U C, na dir, a n d e n d of c ycle res ults. Se nsiti vit y a nal yses 
ma y be perf or me d t o assess t he i m pact of i nc o m plete d osi n g wit hi n a c ycle or missi n g 
sa m pli n g ti mes.  
1 3. 3. 2. 1.  
A nal ysis of He mat ol o gic Para meter Ki netic E n d p o i nts 
He mat ol o gic para meter val ues will be ta b ulate d wit h descri pti ve statistics usi n g a bs ol ute 
c o u nts, c ha n ge, a n d perce nt c ha n ge val ues. B y- visit ta b ulati o ns will i ncl u de val ues at st u d y 
scree ni n g (ie, pri or t o first d ose of st u d y treat me nt) a n d eac h p ostscree ni n g visit t hr o u g h all 
c ycles a n d 2 2 ( + 7 da ys) da ys after t he last d ose of st u d y treat me nt . C ha n ges a n d perce nt 
c ha n ges will be calc ulate d at eac h p ostscree ni n g  val ue. A d diti o nal ta b ulati o ns f or eac h c ycle 
of treat me nt will i ncl u de pre d ose, na dir, ma xi m u m p ost na dir, a n d e n d of c ycle val ues. T he 
c ha n ge a n d perce nt c ha n ges fr o m pre d ose t o na dir, pre d ose t o e n d of c ycle, na dir t o 
ma xi m u m p ost na dir, a n d na dir t o e n d of c ycle val ues will als o be ta b ulate d  f or eac h c ycle of 
treat me nt. A nal ysis of c o varia nce  ( A N C O V A) m o dels will be perf or me d se paratel y at eac h 
visit a n d f or eac h of t he f oll o wi n g para meters as de pe n de nt varia bles: c ha n ge fr o m scree ni n g  
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and percent change from screening. Analysis of covariance models will be performed 
separately at each cycle and for each of the following parameters as dependent variables: 
predose (for cycles 2 and onward), nadir, the Post-Treatment Visit counts, change from 
predose to nadir, predose to end of cycle, nadir to maximum postnadir, and nadir to end of 
cycle; and percent change from predose to nadir, predose to end of cycle, nadir to maximum 
postnadir, and nadir to end of cycle. The models will include terms for treatment, the 
stratification factors, and screening hematologic parameter value. The least square (LS) mean 
for each treatment group and LS mean difference between treatment groups will be reported. 
Two-sided 95% CIs will be constructed around the LS mean differences in treatment groups. 
The most extreme Treatment Phase nadir value and the cycle at which the most extreme 
nadir occurred will be summarized descriptively. Time to nadir will be summarized 
descriptively for each cycle and is calculated for each cycle and defined as date of nadir 
minus predose date + 1. 
The AUC in hematologic parameters will be tabulated for each cycle, separately for the 
following windows within a cycle: predose to end of cycle (AUCEOC), predose to nadir 
(AUCNadir), and nadir to end of cycle (AUCNEOC). Analysis of covariance models similar to 
those described above will be performed separately at each cycle using each of the AUC 
parameters as dependent variables. Additionally, a repeated-measures model of AUC 
parameters over all cycles will be performed for each AUC measure separately, with fixed 
effects for treatment, treatment cycle, treatment by cycle interaction, screening hematologic 
value, and the stratification factors. The unstructured covariance model will be used to 
tabulate the LS means for each treatment group and the LS mean difference between 
treatment groups at each cycle. Two-sided 95% CIs will be constructed around the LS mean 
differences in AUC between treatment groups. An analysis accounting for cumulative dose 
exposure at each cycle will be performed to support the evaluation of AUC over cycles. 
The proportion of patients that return to predose values will be summarized by cycle for each 
hematologic parameter. Percentages for by-cycle summaries will be based on the number of 
patients treated in the cycle. For tabulations performed based on data collected, the difference 
in rates between treatment groups will be calculated. Two-sided 95% CIs will be constructed 
around the difference in treatment groups. If there are substantial dose reductions, an 
incidence rate, adjusting for cumulative exposure, may be reported to account for differing 
amount of exposure by cycle. 
Time to return to predose levels will be estimated for each cycle using the Kaplan-Meier 
method. Time to return to predose levels is defined for all patients as the number of days 
from nadir to the first postnadir date of levels greater or equal to predose levels prior to end 
of cycle. A clinically meaningful +/- predose level window will be defined for each 
hematologic parameter and specified in the SAP. Time to return to postnadir predose levels is 
also calculated from the start of the cycle (first dose in the cycle). Patients who do not return 
to predose levels within the window will be censored at the last date with nonmissing results. 
The same analysis will be repeated on the subset of patients that had a Grade 3 or higher 
toxicity.  


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13.3.2.2. 
Analysis of Hematologic Toxicity Endpoints 
The number and percentage of patients with Grade 3 and 4 hematologic toxicities at each 
cycle and overall during the Treatment Phase will be tabulated for each type of hematologic 
toxicity and across all type of hematologic toxicities. Percentages for by-cycle summaries 
will be based on the number of patients treated in the cycle. For tabulations performed based 
on data collected, the difference in rates between treatment groups will be calculated. 
Two-sided 95% CIs will be constructed around the difference in treatment groups. If there 
are substantial dose reductions, an incidence rate, adjusting for cumulative exposure, may be 
reported to account for differing amount of exposure by cycle. 
The total number of Grade 3 and 4 hematologic toxicities will be summed over the entire 
Treatment Phase per patient, separately for each type of hematologic toxicity and across all 
types of hematologic toxicities. To account for differing amount of exposure, a toxicity rate 
will be calculated for each patient, and defined relative to cumulative exposure (total number 
of toxicities divided by cumulative exposure). A recurrent events model may be performed to 
estimate the incidence of Grade 3 or higher hematologic toxicities and test for the difference 
between treatment groups.  
For each hematologic parameter and cycle, the following shift summaries will be performed: 
from predose toxicity to maximum on treatment toxicity; from predose toxicity to end of 
cycle toxicity; from maximum postdose toxicity to end of cycle toxicity.  
Hematologic recovery will be defined in the SAP. The number and percentage of patients 
with hematologic recovery will be calculated at each cycle. Time to postdose recovery within 
a cycle will be estimated using the Kaplan-Meier method. A Cox proportional hazard model 
adjusted for screening hematologic toxicity and the stratification factors will also be 
performed. 
13.3.2.3. 
Analysis of Chemotherapy Exposure and Compliance 
The following parameters will be summarized by treatment group and overall: total duration 
of treatment, total number of cycles received, cumulative dose of GC therapy received, and 
number and percentage patients experiencing one or more doses delayed, skipped, 
interrupted, and reduced. Additionally, the number and percentage of doses delayed, skipped, 
interrupted and reduced will be summarized. The following parameters will be summarized 
for each cycle by treatment group and overall: number and percentage of patients receiving 
dose at the cycle, experiencing one or more dose delay, interruption, and reduction, and 
cumulative dose of GC therapy received. The number and percentage of patients 
experiencing a treatment cycle delay due to a hematologic toxicity will be summarized by 
cycle and overall. The number and percentage of patients discontinuing study treatment due 
to a hematologic toxicity and cycle of discontinuation will also be summarized. 
13.3.2.4. 
Other Efficacy Endpoints 
Infections, RBC and platelet transfusions, systemic antibiotic use, and hematopoietic growth 
factor use will be summarized with the number and percentage of patients experiencing the 
event any time during the Treatment Phase of the study. For tabulations performed based on 


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
 
Pa ge 9 5  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
data c ollecte d, t he differe nce bet wee n treat me nt gr o u ps will be calc ulate d a n d re p orte d as 
descri be d f or t he i nci de nce of he mat ol o gic e n d p oi nts. 
T he n u m ber a n d per ce nt of i nfecti o ns will als o be s u m marize d b y ma xi m u m se verit y. T he 
i nfecti o n rate will be calc ulate d as t he n u m ber of i nfecti o ns occ urri n g d uri n g t he Treat me nt 
P hase di vi de d b y c u m ulati ve e x p os ure.  
 
 
1 3. 4.  
S afet y A n al ysis 
1 3. 4. 1.  
S afet y E n d p oi nts  
•  I nci de nce of treat me nt -e mer ge nt A Es, S A Es, relate d A Es, relate d S A Es, a n d A Es lea di n g 
t o st u d y dr u g disc o nti n uati o n 
•  I nf usi o n-relate d reacti o ns 
•  Vital si g ns  
•  P h ysical e xa mi nati o n  
•  E C G rea di n gs 
•  Cli nical he mat ol o g y, c he mistr y , a n d uri nal ysis res ults  
•  C o nc o mita nt me dicati o ns  
•  T u m or res p o nse, d urati o n of res p o nse, a n d best o verall res p o nse base d o n R E CI S T , 
Versi o n 1. 1 
•  Pr o gressi o n- free s ur vi val 
C CI


G 1 T hera pe utics  
Cli nical St u d y Pr ot oc ol G 1 T 2 8 -0 4  
Trilacicli b  
 
 
Versi o n: 4. 0, date d 3 1 A u g ust  2 0 1 7  
 
Pa ge 9 6  of 1 0 7   
G 1 T hera pe utics C O N FI D E N TI A L  
•  O verall s ur vi val  
1 3. 4. 2.  
Met h o ds of A n al ysis f or S afet y E n d p oi nts  
T he safet y a nal ysis will be perf or me d i n all patie nts w h o ha ve recei ve d at least 1 d ose of 
st u d y dr u g. A d verse e ve nt data will be c o de d t o s yste m or ga n class a n d preferre d ter m usi n g 
Me d D R A ( Versi o n  1 7. 1, or later). Treat me nt e mer ge nce is defi ne d as a n y A E occ urri n g o n 
or after t he da y o f first d ose t hr o u g h 3 0 da ys after t he last d ose of st u d y treat me nt. T he 
n u m ber a n d perce nta ge of patie nts e x perie nci n g a n y treat me nt -e mer ge nt A E  o verall a n d b y 
s yste m or ga n class a n d preferre d ter m will be ta b ulate d. T he i nci de nce rates b y c ycle a n d 
a dj uste d b y e x p os u re ti me will als o be prese nte d. Eac h A E will be c o u nte d o nl y o nce f or a 
gi ve n patie nt at eac h le vel of s u m marizati o n. I n a nal yses of gra de a n d ca usalit y, if t he sa me 
A E occ urs o n m ulti ple occasi o ns, t he hi g hest gra de a n d str o n gest relati o ns hi p t o st u d y dr u g 
will be ass u me d. I nf usi o n-relate d reacti o ns will be ta b ulate d se paratel y fr o m t he A Es. 
A bs ol ute val ues a n d c ha n ges fr o m scree ni n g i n vital si g ns, E C G rea di n gs, a n d he mat ol o g y 
a n d cli nical c he mistr y para meters will be ta b ulate d at eac h visit  d uri n g t he Treat me nt P hase. 
T o xicities f or cli nical la bs will be c haracterize d acc or di n g t o t he C T C A E, Versi o n 4. 0 3. 
S hifts i n t o xicit y gra des fr o m scree ni n g t o eac h visit will be s u m marize d.  
O verall disease res p o nses as deter mi ne d b y R E CI S T , Versi o n 1. 1 will be s u m marize d b y 
res p o nse le vel at eac h visit a n d best o verall res p o nse. T he n u m ber of patie nts wit h a 
c o nfir me d o bjecti ve disease res p o nse, defi ne d as patie nts wit h a best o verall res p o nse of 
c o nfir me d C R or P R o btai ne d d uri n g t he Treat me nt P hase, will be s u m marize d.   
Pr o gressi o n- free s ur vi val is meas ure d fr o m date of first d ose date u ntil date of d oc u me nte d 
disease pr o gressi o n or deat h a n d will be esti mate d  usi n g t he Ka pla n-Meier met h o d.  Patie nts 
w h o ha ve n ot die d or ha d d oc u me nte d disease pr o gressi o n at t he ti me of a nal ysis will b e 
ce ns ore d o n t he last o n-st u d y date wit h n o n missi n g t u m or res p o nse data.  
O verall s ur vi val is meas ure d fr o m first d ose of trilacicli b u ntil deat h a n d will be esti mate d 
usi n g t he Ka pla n- Meier met h o d . Patie nts  ali ve at t he ti me of a nal ysis will b e ce ns ore d o n t he 
last date t he patie nt was k n o w n t o be ali ve.  
Ce ns ori n g tec h ni q ues t hat acc o u nt f or missi n g t u m or assess me nts a n d p ote ntial differe nces i n 
t he d urati o n of ti me patie nt has o n st u d y t u m or assess me nts ma y be a p plie d f or P F S data. 
T he met h o ds will be descri be d i n t he S A P. 
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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
An eCRF must be completed for each patient enrolled. Each completed eCRF, as well as 
records for those patients who discontinue the study, will require a signature by the principal 
investigator at the study site. If a patient withdraws from the study, the reason must be noted 
on the eCRF, and if a patient is withdrawn from the study because of a treatment-limiting 
AE, thorough efforts should be made to clearly document the outcome. The investigator 
should ensure the accuracy, completeness, legibility, and timeliness of the data reported to 
the sponsor in the eCRFs and in all required reports. 
Accurate and reliable data collection will be assured by verification and cross-check of the 
eCRFs against the investigator’s records by the study monitor (source document 
verification), and the maintenance of a drug-dispensing log by the investigator.  
A comprehensive validation check program will verify the data and discrepancy reports will 
be generated accordingly for resolution by the investigator. As patients complete the study 
(or withdraw) and their signed eCRFs become available for review, a comparison check will 
be run to identify and resolve any discrepancies in the data base.  


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15. 
ETHICS AND PROTECTION OF HUMAN PATIENTS 
15.1. 
Ethical Conduct Statement 
The investigator will ensure that this study is conducted in full conformance with the 
principles of the Declaration of Helsinki (as amended in Tokyo, Venice, Hong Kong, and 
South Africa) or with the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the individual. The investigator will 
ensure adherence to the basic principles of GCP as outlined in the current version of 21 CFR, 
subchapter D, Part 312, Responsibilities of Sponsors and Investigators, part 50, Protection of 
Human Subjects, and Part 56, Institutional Review Boards, and ICH E6 GCP. The 
investigator will follow all national, state, and local laws of the pertinent regulatory 
authorities. 
15.2. 
Institutional Review Board/Independent Ethics Committee 
The protocol and all associated amendments and consent/assent materials will be reviewed 
and approved by the investigative site’s local or a central IRB or IEC. It is the investigator’s 
responsibility to obtain approval of the study protocol and informed consent, and any other 
study related materials such as advertising or information leaflets, from their IRB/IEC prior 
to initiating the study. Approval must be obtained in writing via a letter identifying the 
protocol, the date of the IRB/IEC meeting, and the date of approval. Any modifications made 
to the protocol after receipt of the IRB/IEC approval must also be submitted by the 
investigator to the IRB/IEC in accordance with local procedures and regulatory requirements. 
Any updates to the protocol should receive IRB/IEC approval or favorable opinion, which 
should be documented in a letter to the investigator, prior to implementation. 
15.3. 
Informed Consent 
It is the responsibility of the investigator to obtain written informed consent from each 
patient participating in this study, after adequate explanation of the goals, methods, potential 
benefits, and hazards of the study. The investigator or designee must also explain that the 
patients are allowed to withdraw from the study at any time and for any reason. All patients 
should be given a copy of the informed consent and any updates. Original signed consent 
forms will be maintained at the site and be made available for inspection, as appropriate. 
15.4. 
Patient Confidentiality 
The investigator must assure that patients’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. Patient names will not be supplied to the 
sponsor and only the patient number will be recorded in the eCRF and study findings stored 
on a computer will be stored in accordance with local data protection laws. The patients will 
be informed that representatives of the sponsor, IRB/IEC, or regulatory authorities may 
inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 


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15.5. 
Adherence to the Protocol 
The study shall be conducted as described in this protocol, except for an emergency situation 
in which proper care of the patient requires immediate alternative intervention. The sponsor 
will provide this protocol to the IRB/IEC and appropriate local regulatory authorities for 
approval. Any protocol amendments will be done in accordance with the provisions agreed 
upon in Section 15.6. Any deviation from the design of the study as set forth in this 
document will be recorded as a protocol deviation and will be explained in detail as it occurs 
and/or is detected. 
15.6. 
Protocol Amendments 
Protocol modifications must be prepared by a representative of the sponsor and initially 
reviewed and approved by the sponsor. 
All protocol modifications (both nonsubstantial and substantial amendments) must be 
submitted to the appropriate IRB/IEC for information in accordance with local requirements. 
Approval must be received before changes can be implemented (ie, if the risk benefit ratio is 
affected and/or the modification represents a change in basic trial definitions such as 
objectives, design, sample size, and outcome measures, etc.), except for those changes which 
would decrease risk to the patient. All substantial protocol amendments must have approval 
from the relevant competent regulatory authority before changes can be implemented. 
15.7. 
Patient Compliance 
Patients must be available for all scheduled study visits. Any reason for patient 
noncompliance will be documented. 
15.8. 
Study Discontinuation 
Both the sponsor and the investigator reserve the right to terminate the study at any time, 
according to the terms specified in the study contract. The investigator should notify the 
IRB/IEC in writing of the study’s completion or early termination. In terminating the study, 
the sponsor and the investigator will assure that adequate consideration is given to the 
protection of the patient’s interests. 


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16. 
DATA HANDLING AND RECORD KEEPING 
16.1. 
Data Collection and Retrieval 
This study will use a 21 CFR Part 11 compliant electronic data capture system. An eCRF will 
be used for data recording. All data requested on the eCRF must be entered and all missing 
data must be accounted for. 
Accurate and reliable data collection will be assured by verification and cross-check of the 
eCRF against the investigator’s records by the study monitor (source document verification), 
and the maintenance of a study drug-dispensing log by the investigator. 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a sponsor 
representative will review the protocol and eCRFs with the investigators and their staff. 
During the study, a monitor will visit the site regularly to check the completeness of patient 
records, the accuracy of entries on the eCRFs, the adherence to the protocol and to GCP, and 
the progress of screening and randomization. The monitor will ensure during on-site visits 
that study medication is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the monitors during these 
visits. 
The investigator must give the monitor access to relevant hospital or clinical records to 
confirm their consistency with the eCRF entries. No information in these records about the 
identity of the patients will leave the study center. Monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion 
criteria, documentation of SAEs, and the recording of primary efficacy and safety variables. 
Additional checks of the consistency of the source data with the eCRFs are to be performed 
according to the study-specific monitoring plan. 
16.2. 
Data Monitoring Committee 
An external DMC will be used to evaluate safety of the study in an ongoing manner (see 
Section 13.1.2.1 for further details). 
16.3. 
Investigator Reporting Requirements 
Local regulations may require the investigator to provide periodic safety updates on the 
conduct of the study and to notify the IRB/IEC of study closure. Such updates and 
notifications are the responsibility of the investigator. 
16.4. 
Records Retention 
After closure of the study, the investigator will maintain copies of all study records (ie, 
investigator files and patient files) in a secure location. The investigator’s study file will 
contain the protocol, protocol amendments, eCRF and query forms, IRB/IEC, and 
governmental approval with correspondence, informed consent, drug records, staff 


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curriculum vitae and authorization forms, and other appropriate documents and 
correspondence.  
Patient clinical source documents may include (but not limited to) patient hospital records, 
physician's and nurse's notes, original laboratory reports, ECG, X-ray, signed informed 
consent forms, consultant letters, and patient screening and randomization logs.  
These documents must be kept on file by the investigator for a period of 2 years following 
the date the marketing application is approved for the drug indication for which it is being 
investigated. If no application is to be filed or if the application is not approved for such 
indication, all records pertaining to the conduct of the clinical study must be adequately 
maintained until 2 years after the investigation is discontinued and the regulatory authorities 
are notified. After that period of time, the documents may be destroyed, subject to local 
regulations. 
The investigator must not destroy any records associated with the study without receiving 
approval from the sponsor. The investigator must notify the sponsor in the event of 
accidental loss or destruction of any study records and should notify the sponsor of any 
reassignment of study records to another party or move to another location.  
16.5. 
Study Monitoring 
Qualified representatives of the sponsor or sponsor designees (study monitors) will monitor 
the study according to a predetermined monitoring plan. The investigator must permit the 
study monitors to periodically review all eCRFs and source documents supporting the 
participation of each patient in the study. The eCRFs and other documentation supporting the 
study must be kept up to date by the investigator and the staff at the study site. These study 
materials must be available for review by the study monitor, and/or other qualified 
representatives of the sponsor, at each monitoring visit and must be provided in a way such 
that the patient’s confidentiality is maintained in accordance with local institution, state, 
country, and federal requirements.  
16.6. 
Audits and Inspections 
At some point during the study or after the study, appropriately qualified personnel from the 
sponsor’s Quality Assurance group, or their authorized representative, or a representative 
from a regulatory authority may visit the investigator to conduct an inspection of the study 
and the site. During this audit, the investigator agrees to give the auditor direct access to all 
relevant documents supporting the eCRFs and other study-related documents and to discuss 
any findings with the auditor. In the event of an inspection by a regulatory agency, the 
investigator agrees to give the inspector direct access to all relevant documents and to discuss 
any findings with the inspector. 


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17. 
PUBLICATION POLICY 
By signing the study protocol, the investigator and his or her institution agree that the results 
of the study may be used by G1 Therapeutics for the purposes of national and international 
registration, publication, and information for medical and pharmaceutical professionals. If 
necessary, the authorities will be notified of the investigator’s name, address, qualifications, 
and extent of involvement. 
Initial publication of the results of this study will be of a cooperative nature that may include 
authors representing the sponsor, investigator(s), and collaborating scientists. Independent 
publications by involved individuals may follow. Investigators and their institutions agree not 
to publish or publicly present any interim results of studies without the prior written consent 
of G1 Therapeutics. 
At least 60 days prior to expected submission to the intended publisher or meeting 
committee, the investigator will submit a copy of the desired presentation (oral or written) or 
publication manuscript to the sponsor. This review period may be shortened upon mutual 
consent where circumstances require expeditious review. The sponsor reserves the right to 
request modification of any publication, presentation or use by the investigator if such 
activity may jeopardize a patent application, an existing patent, or other proprietary rights. 
The sponsor shall determine order of authorship of any publication combining all clinical 
results of this trial. 


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18. 
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identifies drivers of proliferation in luminal-subtype human breast cancer. Nat Genet. 2014 
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Herschkowitz JI, He X, Fan C, Perou CM. The functional loss of the retinoblastoma tumour 
suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer 
Res. 2008; 10(5):R75. 


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Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology 
Practice Guideline Update. J Clin Oncol. 2017;35: doi:10.1200/JCO.2017.74.4789. 
Johnson SM, Torrice CD, Bell JF, et al. Mitigation of hematologic radiation toxicity in mice 
through pharmacological quiescence induced by CDK4/6 inhibition. J Clin Invest. 2010; 
120(7):2528-2536. 
Knudsen ES, Wang JY. Targeting the RB-pathway in cancer therapy. Clin Cancer Res. 
2010;16(4):1094-1099. 
Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term 
survival in patients with triple-negative breast cancer. J Clin Oncol. 2008; 26(8):1275-1281. 
Maroulakou IG, Anver M, Garrett L, Green JE. Prostate and mammary adenocarcinoma in 
transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene. Proc 
Natl Acad Sci USA 1994;91:11236-11240. 
McDonnell AM, Nowak AK, Lake RA. Contribution of the immune system to the 
chemotherapeutic response. Semin Immunopathol. 2011 Jul;33(4):353-367. 
O'Shaughnessy J, Schwartzberg L, Danso MA, et al. Phase III study of iniparib plus 
gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic 
triple-negative breast cancer. J Clin Oncol. 2014 Dec;32(34):3840-3847. 
Ray-Coquard I, Cropet C, Van Glabbeke M, et al. Lymphopenia as a prognostic factor for 
overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res. 2009 
Jul 1;69(13):5383-5391. 
Roberts PJ, Bisi JE, Strum JC, et al. Multiple roles of cyclin-dependent kinase 4/6 inhibitors 
in cancer therapy. J Natl Cancer Inst. 2012 Mar;104(6):476-487. 
Robinson TJ, Liu JC, Vizeacoumar F, et al. RB1 status in triple negative breast cancer cells 
dictates response to radiation treatment and selective therapeutic drugs. PLoS One. 
2013;8(11):e78641. 
Rouzier R, Perou CM, Symmans WF, et al. Breast cancer molecular subtypes respond 
differently to preoperative chemotherapy. Clin Cancer Res. 2005;11(16):5678-5685. 
Shen H, Yang Z, Zhao W, Zhang Y, Rodrigues AD. Assessment of vandetanib as an inhibitor 
of various human renal transporters: inhibition of multidrug and toxin extrusion as a possible 
mechanism leading to decreased cisplatin and creatinine clearance. Drug Metab Dispos. 
2013 Dec;41(12):2095-2103. 
Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth 
factors: American Society of Clinical Oncology clinical practice guideline update. J Clin 
Oncol. 2015 Oct 1;33(28):3199-3212. 


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Stefansson OA, Jonasson JG, Olafsdottir K, et al. CpG island hypermethylation of BRCA1 
and loss of pRb as co-occurring events in basal/triple-negative breast cancer. Epigenetics 
2011; 6(5):638-49. 
Subhawong AP, Subhawong T, Nassar H, et al. Most basal-like breast carcinomas 
demonstrate the same Rb-/p16+ immunophenotype as the HPV-related poorly differentiated 
squamous cell carcinomas which they resemble morphologically. Am J Surg Pathol. 2009; 
33(2):163-175. 
Treré D, Brighenti E, Donati G, et al. High prevalence of retinoblastoma protein loss in 
triple-negative breast cancers and its association with a good prognosis in patients treated 
with adjuvant chemotherapy. Ann Oncol. 2009 Nov;20(11):1818-23. 
Witkiewicz AK, Ertel A, McFalls J, Valsecchi ME, Schwartz G, Knudsen ES. RB-pathway 
disruption is associated with improved response to neoadjuvant chemotherapy in breast 
cancer. Clin Cancer Res. 2012; 18(18):5110-22. 
Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other 
anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) 
measurement system. J Pain Symptom Manage. 1997 Feb;13(2):63-74. 
Yonezawa A, Masuda S, Yokoo S, Katsura T, Inui K. 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):879-886. 
Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer 
chemotherapy. Nat Rev Immunol. 2008 Jan;8(1):59-73. 


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19. 
APPENDICES 
APPENDIX 1: Common Terminology Criteria for Adverse Events (CTCAE) –Version 4.03 
The NCI CTCAE Version 4.03 (CTCAE 4.03 14 June 2010) can be accessed from the 
following National Cancer Institute (NCI) website: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
APPENDIX 2: Package Inserts for Chemotherapy Agents 
Gemzar® (gemcitabine) package insert link:  
https://pi.lilly.com/us/gemzar.pdf   
Gemcitabine 100 mg/ml Concentrate for Solution for Infusion. Summary of Product 
Characteristics. August 2012. Accessed at: 
https://www.medicines.org.uk/emc/medicine/27136 
Paraplatin® (carboplatin) package insert link: 
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-
4180b_03_05_Carboplatin%20label%201-9-04%20FDA.pdf 
Carboplatin 10 mg/mL concentrate for infusion. Summary of Product Characteristics. 
April 2016. Accessed at: http://www.medicines.org.uk/emcmobile/medicine/25716 
APPENDIX 3: Package Inserts for Colony Stimulating Factors 
Neupogen® (filgrastim) package insert link: 
http://pi.amgen.com/united_states/neupogen/neupogen_pi_hcp_english.pdf 
Neulasta® (pegfilgrastim) package insert link: 
http://pi.amgen.com/united_states/neulasta/neulasta_pi_hcp_english.pdf 
APPENDIX 4: Package Inserts for Erythropoiesis Stimulating Agents 
Aranesp® (darbepoetin alfa) package insert link: 
http://pi.amgen.com/united_states/aranesp/ckd/aranesp_pi_hcp_english.pdf 
Epogen® (epoetin alfa) package insert link: 
http://pi.amgen.com/united_states/epogen/epogen_pi_hcp_english.pdf 
 

SAP_001.pdf: 
  
 
 
 
 
STATISTICAL ANALYSIS PLAN  
– Region 1– 
 
Study Title: 
Phase 2 Study of the Safety, Efficacy, and Pharmacokinetics of 
G1T28 in Patients with Metastatic Triple Negative Breast Cancer 
Receiving Gemcitabine and Carboplatin Chemotherapy   
 
 
 
Sponsor 
G1 Therapeutics 
 
79 T.W. Alexander Drive 
 
4501 Research Commons, Suite 100 
 
Research Triangle Park, NC 27709 
 
 
Name of Test Drug: 
G1T28 
 
 
Protocol Number: 
G1T28-04 
 
 
Phase: 
Phase 2   
 
 
Analysis Plan Version 
Version 1.0 
 
 
Version Date 
28 September 2018 




 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY DETAILS .......................................................................................................9 
2.1. 
Study Objectives ...........................................................................................................9 
2.2. 
Study Design .................................................................................................................9 
2.3. 
Number of Patients .....................................................................................................18 
3. 
ANALYSIS SETS ......................................................................................................19 
3.1. 
Definition of Analysis Sets .........................................................................................19 
3.1.1. 
Intent-to-Treat Analysis Set ........................................................................................19 
3.1.2. 
Modified ITT Analysis Set .........................................................................................19 
3.1.3. 
Safety Analysis Set .....................................................................................................19 
3.1.4. 
Per Protocol (PP) Analysis Set ...................................................................................19 
3.1.5. 
Response Evaluable Analysis Set ...............................................................................19 
3.2. 
Protocol Deviations ....................................................................................................19 
4. 
PROSPECTIVELY DEFINED ANALYSES.............................................................21 
5. 
PRIMARY AND SECONDARY ENDPOINTS ........................................................22 
5.1. 
Efficacy Endpoints ......................................................................................................22 
5.1.1. 
Primary Endpoints ......................................................................................................22 
5.1.1.1. 
Occurrence of Severe (Grade 4) Neutropenia ............................................................22 
5.1.1.2. 
Duration of Severe (Grade 4) Neutropenia (DSN) .....................................................23 
5.1.2. 
Key Secondary Endpoints ...........................................................................................24 
5.1.2.1. 
Occurrence of RBC Transfusions ...............................................................................24 
5.1.2.2. 
Occurrence of GCSF Administrations ........................................................................24 
5.1.2.3. 
Occurrence of Platelet Transfusions ...........................................................................24 
5.1.2.4. 
Total Number of Major Adverse Hematologic Events (MAHE) ...............................24 
5.1.3. 
Supportive Secondary Endpoints ................................................................................26 
5.1.3.1. 
Best Overall Response, Duration of Response, Progression-Free Survival, 
and Overall Survival ...................................................................................................26 
5.1.3.2. 
Occurrence of Grade 3 and 4 Hematologic Toxicities ...............................................32 
5.1.3.3. 
ANC Nadir by Cycle ..................................................................................................33 


 
 
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5.1.3.4. 
ANC, Platelet Count, Absolute Lymphocyte Counts (ALC), and 
Hemoglobin Change over Time ..................................................................................33 
5.1.3.5. 
Occurrence of Erythropoiesis Stimulating Agent (ESA) Administrations .................33 
5.1.3.6. 
Occurrence of IV Antibiotic Uses ..............................................................................33 
5.1.3.7. 
Occurrence of Infection Serious Adverse Events (SAEs) ..........................................34 
5.1.3.8. 
Occurrence Febrile Neutropenia .................................................................................34 
5.1.3.9. 
Occurrence of Grade 4 and Grade 3 or 4 Thrombocytopenia ....................................34 
5.2. 
Safety Endpoints .........................................................................................................35 
5.2.1. 
Chemotherapy Exposure Endpoints ...........................................................................35 
5.2.1.1. 
Duration of Exposure ..................................................................................................35 
5.2.1.2. 
Number of Cycles Received .......................................................................................36 
5.2.1.3. 
Dose Intensity and Cumulative Dose .........................................................................36 
5.2.1.4. 
Modifications of Study Therapy, Including Cycle (Dose) Delay, Skipped 
Doses, Dose Interruptions, and Dose Reductions. ......................................................37 
5.2.2. 
Adverse Events (AEs) .................................................................................................38 
5.2.3. 
Vital Signs ..................................................................................................................39 
5.2.4. 
Laboratory ...................................................................................................................40 
5.2.5. 
Electrocardiograms .....................................................................................................40 
5.2.6. 
Physical Examination .................................................................................................41 
6. 
ANALYSIS METHODS ............................................................................................42 
6.1. 
General Principles of Analysis ...................................................................................42 
6.1.1. 
General Methodology .................................................................................................42 
6.1.2. 
Handling of Missing Data ...........................................................................................43 
6.1.3. 
Visit Windowing .........................................................................................................43 
6.1.4. 
Adjustment for Covariates ..........................................................................................45 
6.2. 
Analysis Methods .......................................................................................................45 
6.2.1. 
Patient Disposition ......................................................................................................45 
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6.2.2. 
Demographic and Other Baseline Characteristics ......................................................45 
6.2.3. 
Disease Characteristics ...............................................................................................46 
6.2.4. 
Medical/Surgical History ............................................................................................46 
6.2.5. 
Concomitant Medications ...........................................................................................46 
6.2.6. 
Prior and Subsequent Anti-Cancer Therapy ...............................................................47 
6.2.7. 
Efficacy Analyses .......................................................................................................47 
6.2.7.1 
Primary and Key Secondary Efficacy Analyses .........................................................48 
6.2.7.2 
Supportive Secondary Efficacy Analyses ...................................................................55 
6.2.8. 
Safety Analyses ..........................................................................................................57 
6.2.8.1. 
Chemotherapy Exposure and Compliance Analyses ..................................................57 
6.2.8.2. 
Adverse Events ...........................................................................................................57 
6.2.8.3. 
Laboratory Evaluations ...............................................................................................58 
6.2.8.4. 
Vital Signs ..................................................................................................................58 
6.2.8.5. 
Performance Status .....................................................................................................58 
6.2.8.6. 
Physical Examination .................................................................................................58 
6.2.8.7. 
ECG ............................................................................................................................58 
6.2.9. 
Subgroup Analyses .....................................................................................................59 
6.2.10. 
Pharmacokinetic Analysis ..........................................................................................59 
6.2.12. 
Planned Analysis ........................................................................................................59 
7. 
CHANGE FROM THE PROTOCOL ........................................................................61 
8. 
REFERENCES ...........................................................................................................63 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event 
ALC 
Absolute Lymphocyte Count 
ALP 
Alkaline Phosphatase 
ALC 
Absolute Lymphocyte Count 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
aRR 
Adjusted Rate Ratio 
AST 
Aspartate Aminotransferase  
 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under Curve 
β-HCG 
Beta Human Chorionic Gonadotropin  
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BPM 
Beats Per Minute 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CBR 
Clinical Benefit Rate 
CDK 
Cyclin Dependent Kinase 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CSR  
Clinical Study Report 
CT 
Computed Tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
DMC 
Data Monitoring Committee 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic Case Report Form 
EOI 
End of Infusion 
ESA 
Erythropoietin Stimulating Agent 
 
 
 
  
 
  
G1T28 
Trilaciclib 
GC 
Gemcitabine and Carboplatin 
GCSF 
Granulocyte Colony-Stimulating Factor 
HR 
Hazard Ratio 
ICH 
International Conference on Harmonization 
ITT 
Intent-to-treat 
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Abbreviation 
Term 
IV 
Intravenous 
LD 
Longest Diameter 
LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal Range 
MAHE 
Major Adverse Hematologic Event 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MRI 
Magnetic Resonance Imaging 
Nadir 
The Lowest Point 
NE 
Not Evaluable 
 
 
NTL 
Non-Target Lesion 
OC 
Observed Case 
ORR 
Objective Response Rate 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic  
 
 
PP 
Per Protocol 
PR 
Partial Response 
 
 
PT 
Preferred Term 
 
 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumors  
 
 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Stable Disease 
SOC 
System Organ Class 
SVN 
TEAE 
Severe Neutropenia 
Treatment Emergent AE 
TL 
Target Lesion 
TLFs 
Tables, Listings, and Figures 
TNBC 
Triple Negative Breast Cancer 
TPR 
Time Point Response 
ULN 
Upper Limit of Normal Range 
WBC 
White Blood Cell 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the analyses to be performed 
following the completion of Study G1T28-04, Phase 2 Study of the Safety, Efficacy, and 
Pharmacokinetics of G1T28 in Patients with Metastatic Triple Negative Breast Cancer Receiving 
Gemcitabine and Carboplatin Chemotherapy.  The SAP is based on the G1T28-04 Protocol 
Version 4, dated 31 August 2017.   
Study measurements and assessments, planned statistical methods, and derived variables are 
summarized in this plan.  Planned tables, figures, and listings are specified.  All decisions 
regarding final analyses, as defined in this SAP document, have been made prior to locking the 
database. Any deviations from these guidelines will be documented in the clinical study report 
(CSR).  
The myelosuppression efficacy endpoints and statistical analysis methods described in this SAP 
are reflective of scientific advice obtained in both the US and EU for evaluation of trilaciclib for 
the reduction of chemotherapy-induced myelosuppression. While the primary objective of 
G1T28-04 does not explicitly state that the trial has been designed to evaluate the effects of 
trilaciclib on chemotherapy-induced myelosuppression, the endpoints of AEs and laboratory 
values used to evaluate safety and tolerability are the same endpoints used to evaluate effects on 
chemotherapy-induced myelosuppression. The data collection for this trial was appropriate for 
the analysis of these myelosuppression endpoints, and the defined endpoints in this SAP are 
consistent with the overall strategy/rationale for Study G1T28-04. 


 
 
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2. 
STUDY DETAILS 
2.1. 
Study Objectives 
The primary, secondary, and exploratory objectives of this study as defined in the study protocol 
are presented in Table 1. 
Table 1  
G1T28-04: Study Objectives 
Primary Objectivea 
Assess the safety and tolerability of trilaciclib administered with GC therapy 
Secondary Objectivesa 
Assess tumor response and duration of response based on RECIST, Version 1.1 
Assess PFS and OS 
Assess dose intensity of gemcitabine and carboplatin 
Assess the PK profile of trilaciclib 
Assess the PK profile of gemcitabine and carboplatin when administered with and without trilaciclib 
Assess the hematologic profile (kinetics and incidence/duration/frequency of toxicities) of trilaciclib 
administered with GC therapy 
Assess the incidence of febrile neutropenia 
Assess the incidence of infections 
Assess the utilization of RBC and platelet transfusions 
Assess the utilization of hematopoietic growth factors  
Assess the utilization of systemic antibiotics 
Assess the incidence of chemotherapy dose reductions and dose interruptions overall 
Assess the incidence of Grade 2 or greater nephrotoxicity  
Determine the dose schedule of trilaciclib administered with GC therapy 
GC therapy = gemcitabine + carboplatin on Days 1 and 8 or Days 2 and 9 of 21-day cycles; OS = overall survival; PFS = 
progression-free survival; PK = pharmacokinetic; 
; RBC = red blood cell; 
; 
RECIST = Response Evaluation Criteria in Solid Tumors 
2.2. 
Study Design 
This is a multicenter, randomized, open-label, Phase 2 study of the safety, efficacy, and 
pharmacokinetics (PK) of trilaciclib in combination with gemcitabine and carboplatin (GC) 
therapy for patients with metastatic triple negative breast cancer (TNBC). A total of 
approximately 90 patients will be randomly assigned (1:1:1 fashion) to 1 of the following 3 
groups: 
• Group 1: GC therapy (Days 1 and 8 of 21-day cycles) only (n=30) 
• Group 2: GC therapy (Days 1 and 8) plus trilaciclib administered intravenous (IV) on 
Days 1 and 8 of 21-day cycles (n=30) 
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• Group 3: GC therapy (Days 2 and 9) plus trilaciclib administered IV on Days 1, 2, 8, and 
9 of 21-day cycles (n=30) 
The study will include 3 study phases: Screening Phase, Treatment Phase, and Survival Follow-
up Phase. The Treatment Phase begins on the day of first dose with study treatment and 
completes at the Post-Treatment Visit. 
An independent data monitoring committee (DMC) will perform interim reviews of 
accumulating safety and disposition data approximately every 4 months during the Treatment 
Phase of the study, depending upon the enrollment rate. The first DMC meeting 
will occur after approximately the first 20 patients have been enrolled and completed at least 1 
cycle. Details of the DMC, including objectives, composition, scope, and frequency, will be 
described in a DMC charter.  
 
Criteria for Subsequent Cycles and Study Duration 
In all 3 groups, study drug administration will continue until disease progression per Response 
Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, unacceptable toxicity, withdrawal 
of consent, or discontinuation by investigator. 
Criteria for Day 1/2 of Each Cycle 
Patients must meet all of the following criteria to receive the Day 1/2 dose: 
• Absolute Neutrophil Count (ANC) ≥ 1.0 × 109/L 
• Platelet count ≥ 100 × 109/L 
• Nonhematologic toxicities (except alopecia) must be ≤ Grade 2 or have returned to 
baseline 
If the initiation of the next cycle is delayed due to toxicity, the patient should have (at least) 
weekly visits to follow the toxicity. 
Criteria for Day 8/9 of Each Cycle 
To receive Day 8/9 dose of each cycle, patients must meet all the following criteria: 
• ANC ≥ 1.0 × 109/L 
• Platelet count ≥ 75 × 109/L 
• Nonhematologic toxicities (except alopecia) must be ≤ Grade 2 or have returned to 
baseline 
If these criteria are not met, the Day 8/9 GC doses should be skipped; no dose reductions or 
delays are allowed for the Day 8/9 GC doses. If the Day 8/9 GC doses are skipped, the next GC 
doses become Day 1/2 of the subsequent cycle. There should be at least 7 days between a 
skipped Day 8/9 dose and the start of the next cycle, i.e., Day 1/2. Note that the criteria for 
starting Day 1/2 outlined above will now apply to resumption of dosing. 
After discontinuation of study drug, patients should be strongly encouraged to complete all 
scheduled assessments through the end of their current 21-day treatment cycle, including the 
; the Post-Treatment Visit (Day 22); the safety follow-up 
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phone call at 30 days after the last dose of study treatment; and the Survival Follow-up Phase of 
the study, which is to continue until at least 50% of patients have died.  
The G1T28-04 study will be completed when the Survival Follow-up Phase has been completed, 
or upon sponsor termination of the study. The total study duration is at least 19 months, 
assuming 12 months of accrual, 4 weeks of screening, 4.5 months of treatment (assuming 6 
cycles), and 2 months of safety follow-up. 
The study scheduled assessments are presented in Table 2 and Table 3 below: 
 


 
 
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Table 2  
Schedule of Assessments for Groups 1 and 2 
  
Screening 
Cycle 1 and Every  
Odd Cyclea (21 days) 
Cycle 2 and Every  
Even Cyclea (21 days) 
Post-Treatment 
Visitb 
Safety Follow-
up Phone Callc 
Survival  
Follow-upd 
Post-Treatment Visit 
+ 60 days 
Cycle Day  
-28 
1 
8 
15 
(±1 day) 
1 
8 
15 
(±1 day) 
22 (last cycle) 
(+7 days) 
(+3 days) 
(±7 days) 
(±7 days) 
Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical Historye 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility Evaluation 
X 
 
 
 
 
 
 
Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
 
Physical Exam 
X 
X 
 
 
X 
 
 
X 
 
 
 
Vital Signs 
X 
Xf 
Xf 
 
Xf 
Xf 
 
X 
 
 
 
Height/Weight 
Xg 
X 
 
 
Xg1 
 
 
 
 
 
 
Clinical Chemistry 
X 
Xh 
 
 
Xh 
 
 
X 
 
 
 
Hematologyi 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
ECG 
X 
Xj 
 
 
 
 
 
 
 
 
 
Pregnancy testk 
X 
Xk 
 
 
 
 
 
X 
 
 
 
Tumor Assessment 
Xm, m1,m2 
CT/MRI of chest/abdomen Q9 weeks through Week 27 and Q12 weeks thereafter.   
Also include brain MRI if brain metastases present at baseline.  
Skeletal lesions identified with baseline bone scan to be followed at scheduled visits using 
localized CT, MRI, or x-ray m, m1, m2, m3,m4 
Tumor assessment Q12 weeks to continue in 
Post-Treatment/Follow-up only if patient discontinues study 
treatment for reason other than PD and has not initiated 
subsequent anticancer therapym,m4 
Archival Tumor Tissue 
X 
 
 
 
 
 
 
 
 
 
 
PKn (optional) 
Xn 
 
 
 
 
 
 
 
 
 
Trilaciclibo 
X 
X 
 
X 
X 
 
 
 
 
 
GC therapyp 
 
X 
X 
 
X 
X 
 
 
 
 
 
Survival Contacts 
 
 
 
 
 
 
 
 
 
X 
 
AEst 
X 
 
 
Con. Medications 
X 
 
 
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AE = adverse event; ECG = 12-lead electrocardiogram; CT = Computed Tomography;
 
; MRI = Magnetic Resonance Imaging; 
; 
PK = pharmacokinetics, GC therapy= Gemcitabine and Carboplatin therapy; PD = progressive disease 
a 
Study therapy will continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.  
b 
Patients will return to the study center for a Post-Treatment Visit on Day 22 (+ 7 days) of their last cycle.  
c 
A safety follow-up contact will be made to each patient at 30 days after the last dose of study treatment to collect AEs and concomitant medications. 
d 
Follow-up should be attempted and documented for each patient that is in the long term Survival Follow-up Phase at least once every 2 months. Patients will be followed for 
survival until at least 50% of the patients have died. Any anticancer therapies used will be collected.  
e 
Including medical, surgical, radiation history, smoking history, prior systemic anti-cancer therapy, breast cancer history including BRCA classification, screening signs and 
symptoms within 4 weeks prior to randomization, and medications. Eligibility evaluation and randomization may occur up to 4 days prior to Day 1 Cycle 1 therapy. For all 
treatment groups, study start is on Cycle 1 Day 1.    
f 
Vital signs (blood pressure, heart rate, respiratory rate and body temperature) will be obtained immediately before and after each infusion. Vitals only need to be taken once 
between each infusion.   
g 
Height will only be measured at the screening visit. Body Surface Area (BSA) will be calculated at Day 1. 
 
g1: BSA (based on actual body weight) will be re-calculated on Day 1 of Cycle 2 and subsequent cycles if weight increases or decreases > 10% from Day 1 of the previous 
cycle. 
h 
Clinical chemistry (see Protocol Section 11.4.2) may be obtained up to 72 hours prior to Day 1 of each cycle.  
i 
Hematology (see Protocol Section 11.4.2) may be obtained up to 24 hours prior to dosing on Days 1 and 8 of each cycle, Day 15 of each cycle, at the Post-Treatment Visit, 
and at 60 days after the Post-Treatment Visit. 
j 
Single 12-lead ECGs will be obtained for all patients at screening. For those patients (Groups 1 and 2) who agree to participate in PK sampling will have ECGs completed in 
triplicate (at least 1 minute apart) at the following additional time points on Day 1 of Cycle 1: predose (prior to trilaciclib) and at 0.5 hour (end of infusion [EOI] of 
trilaciclib), 2 hours (± 10 minutes) after EOI of trilaciclib, and 5 hours (± 30 minutes) after EOI of trilaciclib. Patients should rest for approximately 5 minutes prior to each 
ECG assessment. The ECGs should be obtained just prior to PK sampling.  
k 
Female patients of childbearing potential: serum ß-hCG at screening and serum or urine ß-hCG on Day 1 of Cycle 1, Day 1 of every odd cycle, and at the Post-Treatment 
Visit. A pregnancy test should be obtained within 24 hours of the Cycle 1 Day 1 visit and must be negative to initiate treatment. 
m 
For tumor assessment, all sites of disease should be assessed radiologically by CT or MRI with contrast, where clinically possible, of the chest and abdomen at screening 
(unless obtained within 28 days of dosing), every 9 weeks ± 7 days (Week 9, Week 18 and Week 27) and then every 12 weeks ± 7 days thereafter, until the occurrence of 
disease progression, withdrawal of consent, initiation of subsequent anticancer therapy, or study completion. If a patient shows a radiological response (complete response 
[CR] or partial response [PR]), a confirmatory radiological assessment will be performed at least 4 weeks after the response was first noted. The same method of assessment 
(CT or MRI) should be used to characterize tumors at screening and at all follow-up assessments. If positron emission tomography is used, it should also be accompanied by 
spiral CT or MRI.  
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m1:  Radionuclide bone scans shall be performed at screening. Skeletal lesions identified on the bone scan at baseline, which are not visible on the CT or MRI scan 
should be imaged at  
baseline and followed at scheduled visits using localized CT, MRI or x-ray. Bone scans need not be repeated after baseline unless clinically 
indicated. Bone scans obtained as standard  of care prior to screening will not need to be repeated if performed within 28 days prior to the first dose of study drug(s). 
m2.  Brain imaging with contrast (by CT or MRI) performed at Screening for all patients. If brain metastases are present at screening, brain imaging shall be done with 
each protocol-specified tumor assessment. If no metastases are present at screening, imaging does not need to be performed during the study unless clinically 
indicated or if the subject is neurologically symptomatic. 
 
m3:  At the Post-Treatment Visit, obtain tumor assessment for patients who have not progressed at the time of study drug discontinuation (may be performed within 4 
weeks).  
 
m4:  For those patients in the Survival Follow-up Phase who have not progressed at the time of study drug discontinuation, radiological tumor assessments will be 
performed utilizing the  same imaging modality used at screening, every 12 weeks ± 7 days from the Post-Treatment Visit until the occurrence of progressive disease, 
withdrawal of consent, initiation of  
subsequent anticancer therapy, or study completion. 
n 
Patients who have agreed to participate in the PK analysis will have blood samples collected on Day 1 of Cycle 1 only at the time points specified in Section Error! 
Reference source not found..  The end of infusion (EOI) sample for trilaciclib should be drawn 2 to 5 minutes prior to the trilaciclib EOI. 
o 
For Group 2:  Trilaciclib will be administered as an IV infusion over 30 (±5) minutes prior to GC chemotherapy on Days 1 and 8 of every 21-day cycle (dosing information, 
see Protocol Section 8.1). After discontinuation of study drug, patients should be strongly encouraged to complete all scheduled assessments through the end of their current 
21-day treatment cycle, including the PRO scales; the Post-Treatment Visit (Day 22); the safety follow-up phone call at 30 days after the last dose of study treatment; and the 
Survival Follow-up Phase of the study. 
p 
For Group 1: GC therapy will be administered as an IV infusion on Days 1 and 8 of 21-day cycles (dosing information; see Protocol Section 8.1). 
 
For Group 2: GC therapy will be administered as an IV infusion after the trilaciclib infusion (with an interval not greater than 4 hours) on Days 1 and 8 of 21-day cycles 
(dosing information; see Protocol Section 8.1). Chemotherapy cannot be administered until after completion of the trilaciclib infusion. If trilaciclib in any given cycle is not 
administered for any reason, do not administer the dose of gemcitabine or carboplatin chemotherapy on that day.  
s 
Survival follow-up may be a phone contact if subject is not returning to the clinic for tumor assessments.  
t 
AEs will be recorded from the time of informed consent. All AEs should be reported within 30 days of the last dose of study drug, and followed until they are resolved, have 
returned to baseline, or it is deemed that further recovery is unlikely. 
  
 
 
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Table 3  
Schedule of Assessments for Group 3 
  
Screen-
ing 
Cycle 1 and Every Odd Cyclea 
(21 days) 
Cycle 2 and Every Even Cyclea   
(21 days) 
Post-Treatment 
Visitb 
Safety 
Follow-up 
Phone Callc 
Survival 
Follow-upd 
Post-Treatment 
Visit + 60 days 
Cycle Day  
-28 
1 
2 
8 
9 
15 
(±1 day) 
1 
2 
8 
9 
15 
(±1 day) 
22 (last cycle) 
(+7 days) 
(+3 days) 
(±7 days) 
(±7 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical Historye 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility Evaluation 
X 
 
 
 
 
 
 
 
 
 
 
Performance Status 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Physical Exam 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Vital Signs 
X 
Xf 
Xf 
Xf 
Xf 
 
Xf 
Xf 
Xf 
Xf 
 
X 
 
 
 
Height/Weight 
Xg 
X 
 
 
 
 
Xg1 
 
 
 
 
 
 
 
 
Clinical Chemistry 
X 
Xh 
 
 
 
 
Xh 
 
 
 
 
X 
 
 
 
Hematologyi 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testk 
X 
Xk 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Tumor Assessment  
Xm,m1,m2 
CT/MRI of chest/abdomen Q9 weeks through Week 27 and Q12 weeks thereafter.   
Also include brain MRI if brain metastases present at baseline.  
Skeletal lesions identified with baseline bone scan to be followed at scheduled visits using localized 
CT, MRI, or x-ray m, m1, m2, m3, m4 
Tumor assessment Q12 weeks to continue in 
Post-Treatment/Follow-up only if patient discontinues 
study treatment for reason other than PD and has not 
initiated subsequent anticancer therapym,m4 
Archival Tumor Tissue 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PKn (optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Trilaciclibo 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
GC therapyp 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
Survival contacts 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
AEst 
X 
 
 
Con. Medications 
X 
 
 
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AE = adverse event; ECG = 12-lead electrocardiogram; CT = Computed Tomography;
 
t; MRI = Magnetic Resonance Imaging; 
; 
PK = pharmacokinetics, GC therapy= Gemcitabine and Carboplatin therapy; PD = progressive disease 
a 
Study therapy will continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.  
b 
Patients will return to the study center for a Post-Treatment Visit on Day 22 (+ 7 days) of their last cycle.  
c 
A safety follow-up contact will be made to each patient at 30 days after the last dose of study treatment to collect AEs and concomitant medications. 
d 
Follow-up should be attempted and documented for each patient that is in the long term Survival Follow-up Phase at least once every 2 months. Patients will be followed for 
survival until at least 50% of the patients have died. Any anticancer therapies used will be collected.  
e 
Including medical, surgical, radiation history, smoking history, prior systemic anti-cancer therapy, breast cancer history including BRCA classification, documentation of 
tumor diagnosis, screening signs and symptoms within 4 weeks prior to randomization, and medications. Eligibility evaluation and randomization may occur up to 4 days 
prior to Day 1 Cycle 1 therapy. For all treatment groups, study start is on Cycle 1 Day 1.    
f 
Vital signs (blood pressure, heart rate, respiratory rate and body temperature) will be obtained immediately before and after each infusion. Vitals only need to be taken once 
between each infusion.   
g 
Height will only be measured at the screening visit. Body Surface Area (BSA) will be calculated at Day 1. 
 
g1: BSA (based on actual body weight) will be re-calculated on Day 1 of Cycle 2 and subsequent cycles if weight increases or decreases >10% from Day 1 of the previous 
cycle. 
h 
Clinical chemistry (see Protocol Section 11.4.2) may be obtained up to 72 hours prior to Day 1 of each cycle.  
i 
Hematology (see Protocol Section 11.4.2) may be obtained up to 24 hours prior to GC dosing of on Day 2 or Day 9 of each cycle, Day 15 of each cycle, at the Post-Treatment 
Visit, and at 60 days after the Post-Treatment Visit. 
j 
Single 12-lead ECGs will be obtained for all patients at screening. Those patients who agree to participate in PK sampling will have ECGs completed in triplicate (at least 1 
minute apart) at the following additional time points on Day 2 of Cycle 1: predose (prior to trilaciclib) and at 0.5 hour (end of infusion [EOI] of trilaciclib), 2 hours 
(± 10 minutes) after EOI of trilaciclib, and 5 hours (± 30 minutes) after EOI of trilaciclib. Patients should rest for approximately 5 minutes prior to each ECG assessment. The 
ECGs should be obtained just prior to PK sampling. 
k 
Female patients of childbearing potential: serum ß-hCG at screening and serum or urine ß-hCG on Day 1 of Cycle 1, Day 1 of every odd cycle, and at the Post-Treatment 
Visit. A pregnancy test should be performed within 24 hours of the Cycle 1 Day 1 visit and must be negative to initiate treatment.  
m 
For tumor assessment, all sites of disease should be assessed radiologically by CT or MRI with contrast, where clinically possible, of the chest and abdomen at screening 
(unless obtained within 28 days of dosing) every 9 weeks ± 7 days (Week 9, Week 18, and Week 27) and then every 12 weeks ± 7 days thereafter, until the occurrence of 
disease progression, withdrawal of consent, initiation of subsequent anticancer therapy, or study completion. If a patient shows a radiological response (complete response 
[CR] or partial response [PR]), a confirmatory radiological assessment will be performed at least 4 weeks after the response was first noted. The same method of assessment 
(CT or MRI) should be used to characterize tumors at screening and at all follow-up assessments. If positron emission tomography is used, it should also be accompanied by 
spiral CT or MRI.  
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Clinical Study Protocol G1T28-04            
Statistical Analysis Plan for Region 1 
Version date: 28Sep2018 
 
CONFIDENTIAL 
      Page 17 of 65 
 
                                                 
 
 
m1:  Radionuclide bone scans shall be performed at screening. Bone scans obtained as standard of care prior to screening will not need to be repeated if performed within 
28 days prior to the  
first dose of study drug(s). Skeletal lesions identified on the bone scan at baseline, which are not visible on the CT or MRI scan should be 
imaged at baseline and followed at scheduled  
visits using localized CT, MRI, or x-ray. Bone scans need not be repeated after baseline unless clinically indicated. 
m2:  Brain imaging with contrast (by CT or MRI) performed at Screening for all patients. If brain metastases are present at screening, brain imaging shall be done with 
each protocol-specified tumor assessment. If no metastases are present at screening, imaging does not need to be performed during the study unless clinically 
indicated or if the subject is neurologically symptomatic. 
 
m3:  At the Post-Treatment Visit, obtain tumor assessment for patients who have not progressed at the time of study drug discontinuation (may be performed within 4 
weeks).  
 
m4:  For those patients in the Survival Follow-up Phase who have not progressed at the time of study drug discontinuation, radiological tumor assessments will be 
performed utilizing the  same imaging modality as used at screening, every 12 weeks ± 7 days from the Post-Treatment Visit until the occurrence of progressive disease, 
withdrawal of consent, initiation of  
anticancer therapy, or study completion. 
n 
Patients who agree to participate in the PK analysis will have blood samples collected on Day 2 of Cycle 1 at the time points specified in Protocol Section 11.4.2. The end of 
infusion (EOI) sample for trilaciclib should be drawn 2 to 5 minutes prior to the trilaciclib EOI. 
o 
For Group 3: trilaciclib will be administered as an IV infusion over 30 (±5) minutes on Days 1, 2, 8, and 9 of every 21-day cycle. Trilaciclib will be administered prior to GC 
on Days 2 and 9 (dosing information, see Protocol Section 8.1). The interval between doses of trilaciclib on successive days should not be greater than 28 hours. After 
discontinuation of study drug, patients should be strongly encouraged to complete all scheduled assessments through the end of their current 21-day treatment cycle, including 
the PRO scales; the Post-Treatment Visit (Day 22); the safety follow-up phone call at 30 days after the last dose of study treatment; and the Survival Follow-up Phase of the 
study. 
p 
For Group 3: GC therapy will be administered as an IV infusion after the trilaciclib infusion (with an interval not greater than 4 hours) on Days 2 and 9 of 21-day cycles 
(dosing information; see Protocol Section 8.1). Chemotherapy cannot be administered until after completion of the trilaciclib infusion. If trilaciclib in any given cycle is not 
administered for any reason, do not administer the dose of gemcitabine or carboplatin chemotherapy on that day.  
s 
Survival follow-up may be a phone contact if subject is not returning to the clinic for tumor assessments. 
t 
AEs will be recorded from the time of informed consent. All AEs should be reported within 30 days of the last dose of study drug, and followed until they are resolved, have 
returned to baseline, or it is deemed that further recovery is unlikely.
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2.3. 
Number of Patients 
Overall, approximately 90 patients will be enrolled in the study. The 90 patients will be 
randomly assigned (1:1:1) to 1 of 3 groups. 
The sample size is not determined from a statistical perspective, but rather is based on clinical 
feasibility. Approximately 90 patients will be enrolled into the study (30 per treatment group). 
With 30 patients, the precision for point estimates in each arm is as follows: the maximum 95% 
confidence interval (CI) width for binary endpoints based on Wilson score intervals is the 
observed proportion +/- 0.167. The 95% CI width for continuous endpoints using the t-
distribution are the observed mean +/- 0.373*standard deviation of the endpoint. 
With the changes to the protocol detailed in this SAP, the sample size calculation is now based 
on demonstrating the superiority of Group 3 (GC + Trilaciclib Day 1/2 and 8/9) and Group 1 
(GC therapy alone) with respect to at least one of the primary endpoints. 
With the changes, the overall type I error rate is now 0.025 (1-sided) and the type II error rate 
used to compute sample size is 0.10 (corresponding to 90% power).  
To maintain the overall type I error rate, by using the most conservative Bonferroni procedure 
for the 2 primary endpoints, a 1-sided individualized type I error rate 0.025/2 = 0.0125 is 
assigned to each outcome variable in the sample size calculation. Assuming a common standard 
deviation of 2.5, a true difference in the duration of severe (Grade 4) neutropenia in Cycle 1 of at 
least 3 days between the Group 3 and Group 1 requires, 38 evaluable patients (19 per treatment 
arm in Groups 1 and 3). This implies that 60 patients need to be randomized for all 3 groups 
assuming a 95% evaluability rate. For occurrence endpoints (occurrence of severe (Grade 4) 
neutropenia, assuming its proportion of 45% for Group 1, testing for an absolute reduction of 
41% to 4% with Group 3 would require a sample size of at least 96 patients (32 per treatment 
arm in Groups 1 and 3). Assuming a 95% evaluability rate, at least 102 patients need to be 
randomized for all 3 groups to complete the study. Therefore, the final adjusted sample size is 
102 to account for the evaluation of 2 primary endpoints. All calculations were carried out using 
the POWER procedure in SAS® version 9.4. 
The study will be conducted at up to 50 centers in North America and Europe. 


 
 
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3. 
ANALYSIS SETS 
3.1. 
Definition of Analysis Sets  
Data analyses will be based on the four analysis sets defined below. Analysis sets, including 
exclusions based on key deviations, will be reviewed and approved by G1 Therapeutics prior to 
the study unblinding. See Section 7 for the changes from the protocol defined analysis sets. 
3.1.1. 
Intent-to-Treat Analysis Set 
The Intent-to-Treat (ITT) analysis set includes all randomized patients. Analyses using the ITT 
will be conducted on the basis of the assigned treatment. All myelopreservation efficacy analyses 
will be assessed using the ITT. The ITT will also be used for analyses of progression-free 
survival (PFS) and overall survival (OS). 
3.1.2. 
Modified ITT Analysis Set 
A modified ITT (mITT) analysis set is a subset of the ITT analysis set and will only include the 
ITT patients who received at least 1 dose of study drug (gemcitabine, carboplatin, or trilaciclib). 
Supportive sensitivity analyses will be conducted based on the mITT analysis set for primary and 
key secondary efficacy endpoints to evaluate the robustness of the results.  Analyses using the 
mITT will be conducted on the basis of the assigned treatment. mITT will be used for sensitivity 
of select efficacy analyses.   
3.1.3. 
Safety Analysis Set 
The safety analysis set includes all enrolled patients who received at least 1 dose of study drug 
(gemcitabine, carboplatin, or trilaciclib). Analyses using the safety analysis set will be conducted 
on the basis of the actual treatment received. All safety analyses will be assessed using the safety 
population.  
3.1.4. 
Per Protocol (PP) Analysis Set 
The per-protocol (PP) analysis set is a subset of mITT analysis set and will include only those 
patients who have no key protocol deviations (as described in Section 3.2) and who received the 
treatment to which they were randomized. For any patients who received the wrong treatment 
during any part of the study, their data will be excluded from the PP analysis set. PP analysis set 
may be used to analyze selected endpoints to test the robustness of results. 
3.1.5. 
Response Evaluable Analysis Set 
The Response Evaluable Analysis Set will include all patients who are in the mITT, have 
measurable disease (target lesions) at the baseline tumor assessment, and either (i) have at least 1 
post-baseline tumor assessment, (ii) have clinical progression as noted by the investigator before 
their first post-baseline tumor scan, or (iii) have died due to disease progression before their first 
post-baseline tumor scan. The response evaluable analysis set will be used for sensitivity 
analyses of tumor response. 
3.2. 
Protocol Deviations  
Certain protocol deviations are key in that they may affect the ability to assess the safety and 
efficacy of study drug. Patients with key deviations will be excluded from the PP analysis set. 


 
 
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All patients who meet the definition of the ITT/mITT analysis sets will be included in the 
ITT/mITT analysis set regardless of these deviations. 
The criteria for inclusion in the PP set will be finalized and documented prior to locking data for 
the study. 
If a patient is randomized, but fails to receive treatment, the reason for not receiving treatment 
will be noted in the CSR. Any such patients who are not treated will be excluded from the mITT, 
safety, response evaluable, and PP analysis sets but will be included in the ITT and in the patient 
listings for the CSR.   
If the wrong treatment is administered to a patient, and the reason for the incorrect treatment is 
documented, this will be noted in the CSR and the patient’s data included in the Safety Analysis 
Set based on the actual treatment received. Additional protocol deviations will be reviewed in a 
data review meeting to classify protocol deviations as non-key or key, and to discuss the 
potential impact on statistical analysis.  
    






 
 
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5.1.1.2. 
Duration of Severe (Grade 4) Neutropenia (DSN)  
There will be two different strategies for assessing DSN in each cycle. Both strategies will be 
applied to derive the DSN, with strategy 1 considered as the primary, and strategy 2 being 
supportive sensitivity analyses. The DSN in Cycle 1 is considered for this primary endpoint.  
5.1.1.2.1 Strategy 1: Without Imputation of Missing ANC Values 
Within each cycle, the DSN (days) is defined as the number of days from the date of first ANC 
value of <0.5×109/L observed between start of cycle and end of cycle, to the date of first ANC 
value ≥ 0.5×109/L that meets the following criteria: (1) occurs after the ANC value of 
<0.5×109/L and (2) no other ANC values <0.5×109/L occur between this day and end of cycle. 
DSN is set to 0 in patients who did not experience SVN in a cycle. Any unscheduled data and the 
actual assessment date (rather than visit date) will be included in the derivation. The following 
rules will be applied in the calculation:    
(i) For a cycle where the SVN event does not resolve by end of the cycle, DSN will be assigned 
as above except the end date will be the end of cycle.   
(ii) For a cycle where the patient dies, during the SVN event, DSN will be assigned as above 
except the end date will be the date of death. 
(iii) For a cycle where the patient withdraws consent or is lost to follow-up during the SVN 
event, DSN will be assigned as above except the end date will be the date of the last ANC 
assessment prior to the end of study. 
5.1.1.2.2 Strategy 2: Without Imputation, Censoring Unresolved SVN 
Within each cycle, DSN (days) is defined as the number of days from the date of first ANC value 
of <0.5 x 109/L observed between start of cycle and end of cycle, to the date of first ANC value ≥ 
0.5 x 109/L that meets the following criteria: (1) occurs after the ANC value of <0.5 x 109/L and 
(2) no other ANC values <0.5 x 109/L occur between this day and end of cycle. The following 
censoring rules will be applied in the calculation:   
(iv) For a cycle where the SVN event does not resolve by end of the cycle, DSN will be assigned 
as above except the end date will be the earlier of end of cycle or date of last contact.   
(v) For a cycle where the patient dies, withdraws consent, or is lost to follow-up during the 
SVN event, DSN will be assigned as above except the end date will be the date of the last 
ANC assessment prior to the end of study.    
For the treatment period, the overall DSN (days) is the median value among the DSN (days) from 
all cycles. The following data handling conventions will apply: 
• 
For those patients where all event duration values are derived from cycles with censored 
data, the median value for that patient will be the median censored value. It will be a 
considered a censored value; 
• 
For those patients where a subset of event duration values are derived from cycles with 
censored data, the median value for that patient will be estimated using the Kaplan-Meier 
method. It will be considered as an observed value (i.e. no censored value); 


 
 
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• 
For those patients where the median event duration cannot be derived (e.g. ≤ 2 values), the 
longest event duration amongst all the cycles will be used regardless of censoring, but the 
corresponding censoring flag will be carried over for analysis.  
5.1.2. 
Key Secondary Endpoints 
5.1.2.1. 
Occurrence of RBC Transfusions 
Each RBC transfusion with a unique start date on/after 5 weeks on study during the treatment 
period will be defined as a separate event, and an additional set of all events occurring during the 
treatment period will be examined for sensitivity. 
Occurrence of a RBC transfusion during the treatment period is defined as a binary variable (Yes 
or No); Yes if total number of RBC transfusion ≥ 1 is observed, No for other scenarios.   
5.1.2.2. 
Occurrence of GCSF Administrations 
Administration of GCSF is collected throughout the treatment period. Those cycles where GCSF 
is administered concurrently will be identified by comparing the start and stop dates of each 
administration of GCSF to the start of cycle and end of cycle.  If any of the dates of 
administration of GCSF overlap with any dates between the start of cycle and end of cycle, that 
cycle will be considered as having GCSF administered. Data handling conventions for missing 
start and stop dates are described in Section 6.2.5. 
For the treatment period, the total number GCSF administrations is the number of cycles in 
which there is at least one GCSF dose administered. If a patient did not have any GCSF use, the 
value of 0 will be assigned to that patient. The number of cycles where GCSF was NOT given is 
calculated as total number of treatment cycles received – total number of cycles where GCSF 
was administered. 
Therefore, any occurrence of a GCSF administration during a cycle or the treatment period is 
defined as a binary variable (Yes or No); Yes if total number of cycles with GCSF administration 
≥ 1 is observed, No for other scenarios.    
5.1.2.3. 
Occurrence of Platelet Transfusions 
Each platelet transfusion with a unique start date during the treatment period will be defined as 
separate event. 
Occurrence of a platelet transfusion during the treatment period is defined as a binary variable 
(Yes or No); Yes if total number of platelet transfusion ≥ 1 is observed, No for other scenarios.   
5.1.2.4. 
Total Number of Major Adverse Hematologic Events (MAHE) 
As a composite measure of trilaciclib effect, MAHE is based on a combination of individual 
components specified in Table 5, which also include details about the derivation or data source 
for each component. For each component of composite MAHE, its number of events is derived 
as the number of episodes with a unique start date during the treatment period between the date 
of randomization and the end of the last cycle (i.e. last cycle of GC only or trilaciclib plus GC). 
A patient with absence of an episode will be assigned a value of 0 to the number of events for 
this component. Then, the total number of MAHE during the treatment period is obtained as the 
summation over all components of composite MAHE during the treatment period.   










 
 
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For patients who progress and subsequently have a response, the best overall response is only 
derived from assessments up to and including the time of the progression (i.e., it will not include 
the response after the patient has progressed). 
There are two ways of assigning BOR for a patient when the minimum interval for confirmation 
of CR and PR is not satisfied or if there are no confirmatory scans for CR and PR: 
• Adding two more response categories as: unconfirmed CR, unconfirmed PR; 
• Assigning BOR as SD, that is, both the unconfirmed CR and unconfirmed PR will be SD. 
Both ways of assigning BOR will be implemented.  
The number and percentage of patients in each category of derived BOR (Confirmed CR, 
Confirmed PR, SD, PD, or NE) will be summarized.  
 
 




 
 
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intervening NE or SD (e.g., PR NE PR or PR SD PR). However, only one (1) intervening NE or SD will be allowed between PRs 
for confirmation. Note: in the following scenario, PR SD NE PR, the second PR is not a confirmation of the first PR. 
 
Objective response rate (ORR) will be calculated using two methods: 
Method #1: ORR will be calculated using a strict interpretation of RECIST Version 1.1. 
Objective response will be derived as no/yes (0/1) variable. Patients with a BOR of confirmed 
CR or PR will be assigned ‘Yes’. Patients not having a BOR of confirmed CR or PR will be 
assigned ‘No’. Hence, ORR is defined as the proportion of patients with objective response being 
“Yes”.  
Method #2: ORRUNCONFIRMED will be calculated using all responses regardless of confirmation.  
Objective response will be derived as no/yes (0/1) variable.  Patients with a BOR of confirmed 
CR, confirmed PR, unconfirmed CR or unconfirmed PR will be assigned “Yes”.  All patients 
with other BOR values will be assigned “No”.  Hence, ORRUNCONFIRMED is defined as the 
proportion of patients with objective response being “Yes”.  
Duration of Response (DOR) is the time between first response by RECIST Version 1.1 of CR or 
PR and the first date that progressive disease is documented by RECIST Version 1.1, or death. 
Patients who do not experience PD or death will be censored at the last tumor assessment date.  
Only those patients with confirmed responses will be included in this analysis. Censoring will 
follow the rules outlined below for PFS in Section 5.1.3.1.5.  
Clinical benefit rate (CBR) is defined as the proportion of patients with a BOR of confirmed CR, 
confirmed PR, or SD.  
ORR, ORRUNCONFIRMED, DOR and CBR will be calculated using the derived responses and 
investigator responses. 
5.1.3.1.5 Progression-free Survival  
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. 
Hence, progression-free survival (PFS) is defined as the time (months) from date of 
randomization until date of documented disease progression or death due to any cause, 
whichever comes first. More specifically, PFS will be determined using all the assessment data 
up until the last evaluable visit prior to or on the date of (i) disease progression as defined by 
RECIST Version 1.1 (Eisenhauer et al, 2009); or (ii) withdrawal of consent; or (iii) receiving 
subsequent anti-cancer therapy, whichever is earlier. 
PFS will be calculated using derived responses and progression by RECIST Version 1.1 
(whichever comes first) will be considered. 
Death, regardless of cause, is always considered as a PD event. The detailed censoring rules for 
the analysis are summarized in Table 11. 




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


 
 
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Occurrence of an IV antibiotics administration during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of IV antibiotics administration ≥ 1 is observed, No for 
other scenarios.     
5.1.3.7. 
Occurrence of Infection Serious Adverse Events (SAEs) 
Each infection SAE is captured in the electronic database. The event terms are coded using the 
MedDRA Version 20.1. The criterion for identifying the proper infection SAE records is as 
follows: if the system organ class (SOC) from MedDRA takes value “INFECTIONS AND 
INFESTATIONS”, and the AE is a serious event.    
Each infection SAE with a unique start date during the treatment period will be defined as 
separate event. Data handling conventions for missing start and stop dates for AEs are described 
in Section 5.2.2.    
Any occurrence of an infection SAE during the treatment period is defined as a binary variable 
(Yes or No); Yes if total number of infection SAE events ≥ 1 is observed, No for other scenarios.  
5.1.3.8. 
Occurrence Febrile Neutropenia 
Each febrile neutropenia event is captured in AE data of electronic database, and “FEBRILE 
NEUTROPENIA” is a preferred term which can be used to identify the proper AE records. The 
event terms are coded using the MedDRA Version 20.1.     
Each febrile neutropenia event with a unique start date during the treatment period will be 
defined as a separate event. Data handling conventions for missing start and stop dates for AEs are 
described in Section 5.2.2.    
Any occurrence of a febrile neutropenia event during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of febrile neutropenia events ≥ 1 is observed, No for 
other scenarios.  
5.1.3.9. 
Occurrence of Grade 4 and Grade 3 or 4 Thrombocytopenia 
Hematologic toxicities events are defined as any cycle where any hematologic lab value occurs 
that meets the CTCAE toxicity grade criteria for ≥ Grade 3 and the value is treatment emergent. 
For details on which parameters are included and the definition of treatment emergent see 
Section 5.2.4. 
For the treatment period, the total number of hematologic toxicity events is the number of cycles 
in which there is at least one hematologic toxicity event. If a patient did not have any 
hematologic toxicity events, the value of 0 will be assigned to that patient. The number of cycles 
without hematologic toxicity events is calculated as total number of treatment cycles received – 
total number of cycles with a hematologic toxicity event. 
Therefore, any occurrence of a hematologic toxicity event during a cycle or the treatment period 
is defined as a binary variable (Yes or No); Yes if total number of cycles with a hematologic 
toxicity event ≥ 1 is observed, No for other scenarios. 
CCI


 
 
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5.2. 
Safety Endpoints  
5.2.1. 
Chemotherapy Exposure Endpoints 
5.2.1.1. 
Duration of Exposure 
Duration of exposure (days) = First dose date of study drug from the last cycle – first dose date 
of study drug + 21.  
CCI






 
 
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After the 3rd dose reduction, no further reductions are allowed, and patient will be 
discontinued. Dose reduction will happen only once per cycle and patients who have the dose 
reductions in a cycle will have the reduced dose administered for the rest of the cycle. 
• Dose interruptions for all drugs are also captured on the dosing page and will be summarized 
for each study drug. 
5.2.2. 
Adverse Events (AEs) 
All AEs will be coded from verbatim text to PTs and grouped by SOC using the MedDRA 
Version 20.1. AEs will be collected from the time of signature of informed consent throughout 
the treatment period and up to 30 days after the last dose of study treatment. AEs are graded by 
investigator according to CTCAE, Version 4.03.  
Any AE that started on or after the first dose of study drugs and up to the last dose + 30 days will 
be included as a treatment emergent AE (TEAE). AEs with an unknown/not reported onset date 
will also be included.  
Other AE variables include drug-related AEs, AEs leading to study drug discontinuation or study 
withdrawal, AEs leading to death, and SAEs.  
AEs with onset/end dates that are partially/completely missing will be imputed as follows: 
(i) For onset date: 
− If only the day part of the AE onset date is missing and occurs in the same month and year as 
the first dose date of study drug, the date of first dose of study drug will be used as the onset 
date of the AE. Otherwise, the first day of the month will be used to complete the onset date 
of the AE; 
− If the day and month parts of the AE onset date are missing and occur in the same year as the 
first dose of study drug, the date of the first dose of study drug will be used as the onset date 
of the AE. Otherwise, January 1st will be used to complete the onset date of the AE; 
− If the AE onset date is completely missing, the date of the first dose of study drug will be 
used as the onset date of the AE. 
(ii) For end date: 
− If only the day part of the AE end date is missing, the last day of the month will be used to 
complete the end date of the AE;  
− If the day and month parts of the AE end date are missing, December 31st will be used to 
complete the end date of the AE; 
− If the AE end date is completely missing and the onset date of the AE occurs after the date of 
the first dose of study drug, the last date during the treatment period +30 days will be used as 
the AE end date. If the AE end date is completely missing and the onset date of the AE 
occurs prior to the date of the first dose of study drug the date of the first dose of study drug 
will be used as the AE end date. 
AEs related to hematologic toxicity will be pooled based on the preferred MedDRA Version 
20.1. Table 13 outlines those terms that will be consolidated.  










 
 
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point; if the count is 0, no percentage will be presented. Value of percentage less than 1% will be 
presented as “<1%.” Value of percentage less than 100% but ≥ 99.5% will be presented as 
“>99%.” 
6.1.2. 
Handling of Missing Data 
In general, the observed case (OC) data for a visit will consist of the actual observations recorded 
for the visit. If missing, the OC data will remain missing — no missing imputation will be 
performed. Safety analyses will be conducted on the OC data only. However, imputation of 
missing AE and concomitant medication onset and stop dates will be used to determine the status 
of each AE and the prior/concomitant status of each medication. Please refer to Section 5.2.2 for 
the method of imputation of missing AE onset and stop date and Section 6.2.5 for the method of 
imputation of missing concomitant onset and stop dates.  
For demographic and baseline characteristics, each variable will be analyzed and/or summarized 
using the available data. Patients with missing data will be excluded only from analyses for 
which data are not available. 
6.1.3. 
Visit Windowing 
It is expected that there will be a variation between patients in the actual number of study days 
from the start of administration of study drug within each cycle − defined as Day 1 − to the dates 
that the scheduled visits occur. To handle this, for tables and figures where data are grouped by 
visit, assessments will be categorized using visit windows based on study days (relative to the 
Day 1 of each cycle). The visit-window mapping is described in Table 18. Visit-based 
summaries will be based on the windowed visits. All data, whether or not within the visit 
windows, will be presented in patient listings.  
For windowed visits during the treatment cycles, if more than 1 visit occurs during a visit 
window, the visit closest to the scheduled day will be assigned to the windowed visit. If two 
visits are equidistant from the scheduled day, the later visit will be assigned to the windowed 
visit. If there are multiple assessments on the same day, the worst case will be used.  For the 
assigned follow-up visit, the last assessment in the window will be included in the summary. 
 
 
 
 
 
 
 
 
 
 
 




 
 
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6.1.4. 
Adjustment for Covariates 
Prior to Protocol Amendment 3 Version 4.0, patient randomization was stratified by liver 
involvement (yes or no) and Eastern Cooperative Oncology Group (ECOG) status (0 or 1). With 
implementation of Amendment 3, the stratification factors were changed to number of prior lines 
of systemic therapy (0 vs. 1 or 2) and liver involvement. The number of prior lines of systemic 
therapy was retrospectively collected for those patients randomized prior to the Amendment 3. 
The efficacy analyses will use liver involvement and number of prior lines of therapy as 
covariates in statistical models. Where necessary, additional sensitivity analyses will be 
performed with liver involvement and ECOG status as covariates instead. Where not collected on 
the randomization page, values will be derived from other eCRF pages. 
6.2. 
Analysis Methods  
6.2.1. 
Patient Disposition 
A summary table will be generated to provide the following by study part, as appropriate: 
• 
Number of patients screened 
• 
Number and percentage of screening failures 
• 
Reason for screening failure 
• 
Number of patients dosed 
• 
Number of patients randomized 
• 
Number of patients randomized and not dosed 
A separate table will be presented to show the patients included in each analysis set and reason 
for exclusion from an analysis set. 
Patient status at treatment and study completion will be listed and summarized.  The listing will 
include whether patients discontinued from the treatment and the reasons for the discontinuation, 
along with the date of first and last dose and the date of completion or discontinuation from the 
treatment.  The same information will be provided for patients who discontinued from the study.  
The following summaries will be added to the disposition table: 
• 
End of treatment status (discontinued/ongoing for each study drug)   
• 
Reason for study drug discontinuation (for each study drug) 
• 
Number of patients going into Survival follow-up  
• 
Number and percentage of patients who discontinued the study 
• 
Reason for study discontinuation 
• 
Death and reason for death 
6.2.2. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics, such as age at informed consent date, age groups 
(18-65, >65-75, >75), gender, race, ethnicity, country, screening vital signs (body weight, height, 
BMI, BSA), ECOG status, prior lines of therapy, liver involvement, and smoking history (never 
smoker, former smoker and current smoker), will be summarized and listed.   


 
 
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6.2.3. 
Disease Characteristics 
Disease characteristics including breast cancer gene (BRCA) classification, histological 
classification of initial breast cancer diagnosis, stage of initial breast cancer diagnosis, stage of 
TNBC diagnosis, stage at time of enrollment, and brain scan results will be summarized and 
listed. Date of initial breast cancer diagnosis, and date of TNBC diagnosis will be listed only. 
6.2.4. 
Medical/Surgical History  
Medical history will be coded to SOC and PT using MedDRA Version 20.1. 
The number and percentage of randomized patients with any past medical/surgical history within 
each SOC and PT will be provided. A patient will only be counted once within a particular SOC 
(PT) even if he/she has multiple conditions/diseases in the same SOC (PT). The 
conditions/diseases from medical history are those conditions/diseases that stopped prior to the 
study entry. Additionally, breast cancer surgeries will be summarized separately. 
6.2.5. 
Concomitant Medications 
All medication verbatim terms collected will be coded to Anatomical Therapeutic Classification 
(ATC) and PT using the WHO-DD Version Sep2017.  
Prior medications are defined as those taken by the patient prior to the administration of study 
drug. Concomitant medications are defined as those taken by the patient at any time between the 
date of study drug administration and study completion/discontinuation. Medication with start 
date/time being partially or completely missing will be assumed to be concomitant if it cannot be 
definitely shown that the medication did not occur during the treatment period.   
Medications with onset/end dates that are partially/completely missing will be imputed as 
follows: 
(i) For onset date: 
− If only the day part of the medication onset date is missing and occurs in the same month and 
year as the first dose date of study drug, the date of first dose of study drug will be used as 
the onset date of the medication. Otherwise, the first day of the month will be used to 
complete the onset date of the medication;  
− If the day and month parts of medication onset date are missing and occur in the same year as 
the first dose of study drug, the date of the first dose of study drug will be used as the onset 
date of the medication. Otherwise, January 1st will be used to complete the onset date of the 
medication; 
− If the medication onset date is completely missing, the date of the first dose of study drug 
will be used as the onset date of the medication. 
(ii) For end date: 
− If only the day part of the medication end date is missing, the last day of the month will be 
used to complete the end date of the medication;  
− If the day and month parts of the medication end date are missing, December 31st will be 
used to complete the onset date of the medication; 
− If the medication end date is completely missing and the onset date of the medication occurs 
after the date of the first dose of study drug, the last date during the treatment period will be 


 
 
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used as the medication end date. Otherwise, the date of the first dose of study drug will be 
used as the medication end date.    
Concomitant medications will be summarized by presenting the number and percentage of 
patients by PT and ATC. Patients taking the same medication multiple times will only be 
counted once for that PT or ATC. Each summary will be ordered by descending order of 
incidence of ATC class and PT within each ATC class.  
All prior and concomitant medications will be presented in a patient listing. 
6.2.6. 
Prior and Subsequent Anti-Cancer Therapy 
The prior anti-cancer therapies, such as prior systemic anti-cancer therapy (Yes or No), prior 
breast cancer surgery (Yes or No), and prior radiotherapy (Yes or No), will be summarized and 
listed. All verbatim terms collected of prior and subsequent anti-cancer therapy will be coded to 
Anatomical Therapeutic Classification (ATC) and PT using the WHO-DD Version Sep2017.  
The prior and subsequent anti-cancer therapy will be summarized separately by presenting the 
number and percentage of patients by PT and ATC. Patients taking the same medication multiple 
times will only be counted once for that PT or ATC. Each summary will be ordered by 
descending order of incidence of ATC class and PT within each ATC class.  The data will be 
presented in a patient listing. 
For subsequent anti-cancer therapy, if the term contains the word “RADIATION” or 
‘RADIOTHERAPY’, the therapy will be classified to radiotherapy; it is classified as systemic 
anti-cancer therapy unless the therapy can be grouped to surgery.   The number and percentage 
of randomized patients receiving subsequent anti-cancer therapy will be provided by systemic 
anti-cancer therapy (by drug name and by line), radiotherapy, and surgery. All subsequent anti-
cancer therapies will be presented in a patient listing. 
6.2.7. 
Efficacy Analyses 
All the efficacy variables will be summarized using descriptive statistics by cycle or visit, with 
the supportive data provided in patient listings.  Data will be summarized using descriptive 
statistics and the between treatment comparison (trilaciclib days 1/2/8/9, trilaciclib days 1/8, and 
combined trilaciclib vs GC only), will be performed only for the primary and secondary endpoints 
outlined in Sections 5.1.1 – 5.1.3. The primary comparisons will be between trilaciclib days 
1/2/8/9 vs. GC only and will be built into the multiplicity adjustment described in Section 
6.2.7.1.3. Though relevant statistical tests will be conducted for other treatment comparisons, the 
information to be presented will be considered to be supportive. For these comparisons, all 
statistical tests will be conducted at a two-sided significance level of 5% unless otherwise 
specified. Where appropriate, model-based point estimates, together with their two-sided 95% 
CIs will be presented along with the two-sided p-value for the test unless otherwise specified.  
Graphical presentation of efficacy results will be performed as needed. 
Unless otherwise specified, all analyses for the efficacy endpoints will be conducted for the 
treatment period which is defined to be between the date of randomization and the end of the last 
cycle.  


 
 
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6.2.7.1 Primary and Key Secondary Efficacy Analyses 
6.2.7.1.1 Primary Efficacy Analyses 
The primary efficacy endpoint, occurrence of SVN, is a binary response variable (Yes, No). It 
will be summarized using descriptive statistics by treatment group and will be analyzed to 
compare trilaciclib and GC only using modified Poisson regression (Zou, 2004) to account for 
the variable duration of the treatment period for each patient. The model will include baseline 
ANC as a covariate, the stratification factors of prior lines of systemic therapy (0 vs. 1 or 2) and 
liver involvement (Yes vs No), and treatment as a fixed effect. The logarithm transformation of 
number of cycles will be included as an offset variable in the modeling. The two-sided p-value, 
adjusted rate ratio (aRR) (trilaciclib vs GC only) and its 95% CIs will be presented. 
For the other primary efficacy endpoint, DSN in Cycle 1 based on Strategy 1 in Section 
5.1.1.2.1, a two-sided p-value will be calculated for the nonparametric analysis of covariance 
(ANCOVA) (Stokes 2012). The nonparametric ANCOVA will include study baseline ANC 
value as covariate, stratification factors of lines of systemic therapy (0 vs. 1 or 2) and liver 
involvement (Yes vs No), and treatment as a fixed effect. Along with the descriptive statistics, 
the mean difference and Hodges-Lehmann estimate of median difference between the two 
treatment groups, together with its 95% CIs will be provided. Additionally, DSN for each cycle 
will be presented using descriptive statistics. 
6.2.7.1.2 Key Secondary Efficacy Analyses 
Occurrence of RBC transfusions on/after 5 weeks on study is a binary variable and will be 
summarized using the same method for occurrence of SVN described in Section 6.2.7.1.1 except 
baseline HGB will be used as a covariate instead of baseline ANC in the modified Poisson 
model. Also, the offset will be the logarithm transformation of duration of treatment period 
divided by 7 (i.e. week) instead of number of cycles, and. An additional sensitivity analysis will 
look all transfusions during the treatment period, and all transfusions with a subset of subjects 
completing at least 1 cycle. 
Occurrence of GCSF administration is a binary variable and will be summarized using the same 
method for occurrence of SVN described in Section 6.2.7.1.1.  
Occurrence of platelet transfusion is a binary variable and will be summarized using the same 
method for occurrence of SVN described in Section 6.2.7.1.1 except baseline platelet count will 
be used as a covariate instead of baseline ANC in the modified Poisson model. Also, the offset 
will be the logarithm transformation of duration of treatment period divided by 7 (i.e. week) 
instead of number of cycles. 
The total number of MAHE in Section 5.1.2.15.1.2.4 will be analyzed to compare trilaciclib and 
GC only using a negative binomial regression model to account for the potential over-dispersion. 
The model includes the stratification factors of prior lines of systemic therapy (0 vs. 1 or 2) and 
liver involvement (Yes vs No), and treatment as a fixed effect. The logarithm transformation of 
duration of treatment period divided by 7 (i.e. week) will be included as an offset variable in the 
modeling. The two -sided p-value, aRR (trilaciclib vs GC only) and its 95% CIs will be 
presented. 
The total number of MAHE will be summarized descriptively, along with the weeks of duration, 
and the event rate per week (calculated as the total number of events/durations of treatment 


 
 
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period divided by 7 [i.e. week]). The cumulative incidence of events during the treatment period 
will be summarized and presented graphically in three-week intervals. 
The total number of individual MAHE components (specified in Table 5) will be summarized 
similarly.  
6.2.7.1.3 Multiplicity Adjustments 
The clinical trial evaluates the objectives defined in terms of the comparison of Group 3 (GC + 
Trilaciclib Day 1/2 and 8/9) to Group 1 (GC therapy alone) on the primary and key secondary 
myelosuppression efficacy endpoints in Sections 5.1.1 and 5.1.2. The resulting multiplicity 
problem include the following 12 hypotheses of no effect: 
• Hypothesis 𝐻1. Comparison of Group 3 versus Group 1 for duration of severe (Grade 
4) neutropenia in Cycle 1. 
• Hypothesis 𝐻2. Comparison of Group 3 versus Group 1 for occurrence of severe 
(Grade 4) neutropenia. 
• Hypothesis 𝐻3. Comparison of Group 3 versus Group 1 for occurrence of RBC 
transfusions on/after Week 5 on study. 
• Hypothesis 𝐻4. Comparison of Group 3 versus Group 1 for occurrence of G-CSF 
administration. 
• Hypothesis 𝐻5. Comparison of Group 3 versus Group 1 for occurrence of platelet 
transfusions. 
• Hypothesis 𝐻6. Comparison of Group 3 versus Group 1 for the MAHE composite. 
• Hypothesis 𝐻7. Comparison of Group 3 versus Group 1 for all-cause hospitalizations 
in the MAHE composite. 
• Hypothesis 𝐻8. Comparison of Group 3 versus Group 1 for all-cause dose reductions 
in the MAHE composite. 
• Hypothesis 𝐻9. Comparison of Group 3 versus Group 1 for febrile neutropenia in the 
MAHE composite. 
• Hypothesis 𝐻10. Comparison of Group 3 versus Group 1 for RBC transfusions 
on/after Week 5 in the MAHE composite.  
• Hypothesis 𝐻11. Comparison of Group 3 versus Group 1 for platelet transfusions in 
the MAHE composite.  
• Hypothesis 𝐻12. Comparison of Group 3 versus Group 1 for prolonged severe (Grade 
4) neutropenia (> 5 days) in the MAHE composite. 
A Hochberg-based gatekeeping procedure will be utilized to control the global familywise error 
rate across the multiple null hypotheses in the strong sense at a 1-sided α=0.025 level. The one-
sided 𝑝-values for these comparisons will be used for the multiple test procedure, and the raw 
and adjusted 1-sided 𝑝-values will be provided in the summary.  
Gatekeeping procedure with logical restrictions 


 
 
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A Hochberg-based gatekeeping procedure satisfies the positive dependence condition given the 
1-sided setting. The procedure is built using the mixture methodology developed in Dmitrienko 
and Tamhane (2011) and accounts for the logical restrictions among the 12 hypotheses displayed 
in  
Figure 1 by performing multiplicity adjustments in three steps. The logical restrictions can be 
achieved by defining the parallel set and serial set for each individual hypothesis based the tree-
structured procedure introduced by Dmitrienko et al (2007).  
• Step 1. The Group 3 versus Group 1 comparisons for Family 1 (hypotheses 𝐻1 and 𝐻2) are 
performed using a truncated version of the Hochberg procedure. The truncation parameter γ 
is set to 0.5.  
• Step 2. The Group 3 versus Group 1 comparisons for Family 2 (hypotheses 𝐻3, 𝐻4, 𝐻5, and 
𝐻6) are performed using a truncated version of the Hochberg procedure if there is at least one 
significance in Step 1. Specifically, the hypotheses 𝐻3, 𝐻4, 𝐻5, and 𝐻6 depend on the 
hypotheses 𝐻1 and 𝐻2, ie, 𝐻3, 𝐻4, 𝐻5, and 𝐻6 are tested only if at least one of the hypotheses 
𝐻1 and 𝐻2 is rejected. The truncation parameter γ is set to 0.5.   
• Step 3. The Group 3 versus Group 1 comparisons for Family 3 (hypotheses 𝐻7, 𝐻8, 𝐻9, 
𝐻10, 𝐻11, and 𝐻12) are performed using the regular Hochberg test if 𝐻6 is significant in Step 
2. 
Figure 1 Graphical Display of the Hochberg-based Gatekeeping Procedure 
 
The regular Hochberg test is defined in Dmitrienko et al. (2009) and the truncated Hochberg test 
is defined in Dmitrienko, Tamhane and Wiens (2008). The decision rules used in the regular and 
truncated Hochberg tests will be detailed in the following. In general terms, the truncated version 
of the Hochberg test is defined as a convex combination of the regular Hochberg and Bonferroni 
tests. An important parameter of the truncated Hochberg test is the truncation parameter γ which 


 
 
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ranges between 0 and 1. If the truncation parameter γ is set to 0, the truncated Hochberg test 
simplifies to the Bonferroni test. On the other hand, if the truncation parameter γ is set to 1, the 
truncated Hochberg test is identical to the regular Hochberg test. The truncated Hochberg test 
satisfies the separability condition (Dmitrienko, Tamhane and Wiens, 2008) if the truncation 
parameter γ is strictly less than 1. This condition ensures that in each step of the testing algorithm 
the error rate can be transferred to the next step provided at least one Group 3 versus Group 1 
comparison is significant in the current step without inflating the overall type I error rate (Huque, 
2016; FDA, 2017). 
Testing algorithm 
This section describes the implementation of the Hochberg-based gatekeeping procedure. The 
testing algorithm relies on the general approach to defining multistage gatekeeping procedures 
based on mixtures of multiple tests proposed in Dmitrienko and Tamhane (2011). 
Decision rules 
The aforementioned 12 hypotheses are grouped into 3 families: 
• Family 1 (𝐹1) includes the hypotheses 𝐻1 and 𝐻2. 
• Family 2 (𝐹2) includes the hypothesis 𝐻3, 𝐻4, 𝐻5, and 𝐻6. 
• Family 3 (𝐹3) includes the hypotheses 𝐻7, 𝐻8, 𝐻9, 𝐻10, 𝐻11, and 𝐻12. 
Using more compact notation, the families are defined as follows: 
𝐹1 = {𝐻𝑖, 𝑖∈𝑁1},  𝐹2 = {𝐻𝑖, 𝑖∈𝑁2},  𝐹3 = {𝐻𝑖, 𝑖∈𝑁3}. 
where the index sets are defined as 𝑁1 = {1, 2}, 𝑁2 = {3, 4, 5, 6}, 𝑁3 = {7, 8, 9, 10, 11 12}. Let 
𝑡𝑖 and 𝑝𝑖 denote the test statistic and 1-sided p-values associated with the hypotheses, 
respectively. Let 𝛼 denote the global familywise error rate, i.e., one-sided 𝛼= 0.025. 
Consider the closed family associated with Families 1, 2 and 3, i.e., a family of all non-empty 
intersections of the twelve hypotheses. Each intersection will be identified by an index set 
𝐼⊆𝑁 = {1, . . . ,12} 
(note that the empty set is excluded). For example, the index vector 𝐼= {1, 2, 5, 8} corresponds 
to the intersection of the hypotheses 𝐻1, 𝐻2, 𝐻5, and 𝐻8. 
To construct the Hochberg-based gatekeeping procedure that controls the global familywise error 
rate in the strong sense at an 𝛼 level, an 𝛼-level test needs to be defined for each intersection in 
the closed family. The multiple test and associated 𝑝-value for an intersection are computed in 
two steps. 
Step 1: Define 𝒑-values for subset intersections 
Consider an intersection corresponding to the index set 𝐼⊆𝑁 and define the index sets 𝐼𝑘= 𝐼∩
𝑁𝑘, 𝑘= 1, 2, 3. The 𝑝-values for the index sets 𝐼1, 𝐼2, and 𝐼3 are computed as follows: 
Let 𝑛1 denote the number of hypotheses included in 𝐼1 and let 𝑚1 = 𝑛1. If 𝑛1 > 0, the truncated 
Hochbergp-value is defined using the ordered 𝑝-values associated with the hypotheses included 
in the index set 𝐼1, denoted by  


 
 
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𝑝1(1) ≤⋯≤𝑝1(𝑚1) 
The truncated Hochberg 𝑝-value for the index set 𝐼1 is given by 
𝑝(𝐼1) =
min
𝑖=1,⋯,𝑚1
𝑝1(𝑖)
𝛾1
𝑚1 −𝑖+ 1 + 1 −𝛾1
2
 
Here 𝛾1 is the pre-specified truncation parameter in Family 1. Choosing a larger value of 𝛾1 
improves the power of comparisons in Family 1, and 𝛾1 is set to 0.5. 
Further, let 𝑛2 denote the number of hypotheses included in the index set 𝐼2. If 𝑛2 > 0, consider 
the hypotheses in the index set 𝐼2 and remove the hypotheses that are not consistent with the 
logical restrictions defined in  
Figure 1. Let 𝑚2 denote the number of hypotheses remaining in the index set 𝐼2 after this logical 
restriction operation. If 𝑚2 > 0, let  
𝑝2(1) ≤⋯≤𝑝2(𝑚2) 
denote the ordered 𝑝-values for the hypotheses remaining in the index set 𝐼2. The truncated 
Hochberg 𝑝-value for 𝐼2 is given by 
𝑝(𝐼2) =
min
𝑖=1,⋯,𝑚2
𝑝2(𝑖)
𝛾2
𝑚2 −𝑖+ 1 + 1 −𝛾2
4
 
where 𝛾2 is the pre-specified truncation parameter in Family 2, which plays the same role as 𝛾1 
in Family 1, and 𝛾2 is set to 0.5. 
Finally, let 𝑛3 denote the number of hypotheses included in 𝐼3. If 𝑛3 > 0, remove the hypotheses 
that are not consistent with the logical restrictions defined in  
Figure 1. Let 𝑚3 denote the number of hypotheses remaining in the index set 𝐼3 after this logical 
restriction operation. If 𝑚3 > 0, let  
𝑝3(1) ≤⋯≤𝑝3(𝑚3) 
denote the ordered 𝑝-values for the hypotheses remaining in the index set 𝐼3. The Hochberg 𝑝-
value for 𝐼3 is given by 
𝑝(𝐼3) =
min
𝑖=1,⋯,𝑚3
𝑝3(𝑖)
1
𝑚3 −𝑖+ 1
 
Step 2: Define overall 𝒑-value 
The overall 𝑝-value for the intersection corresponding to the index set 𝐼 is computed by 
combining the 𝑝-values associated with the index sets 𝐼1, 𝐼2, and 𝐼3. Consider the following three 
scenarios: 
• If 𝑛1 > 0, the overall 𝑝-value is found using the following mixing function: 
𝑝(𝐼) = min (𝑝(𝐼1)
𝑏1
, 𝑝(𝐼2)
𝑏2
, 𝑝(𝐼3)
𝑏3
)  


 
 
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where 𝑏1 = 1,  𝑏2 = 𝑏1(1 −𝑓1 ), 𝑏3 = 𝑏2(1 −𝑓2 ) and 𝑓1 and 𝑓2 are computed based on the 
error rate functions of the truncated Hochberg tests used in Families 1 and 2. These quantities are 
defined below. 
• If 𝑛1 = 0 and 𝑛2 > 0, the overall 𝑝-value is given by 
𝑝(𝐼) = min (𝑝(𝐼2)
𝑏2
, 𝑝(𝐼3)
𝑏3
)  
where  𝑏2 = 1, 𝑏3 = 𝑏2(1 −𝑓2 ). 
• If 𝑛1 = 0, 𝑛2 = 0 and 𝑛3 > 0, the overall 𝑝-value is given by 
𝑝(𝐼) = 𝑝(𝐼3)
𝑏3
 
where 𝑏3 = 1. 
The error rate function of the truncated Hochberg test with the truncation parameter 𝛾𝑘 for 
testing an intersection corresponding to the index set 𝐼𝑘, 𝑘= 1, 2, is defined as 
𝑒𝑘(𝐼𝑘) = 𝑃[𝑝(𝐼𝑘) ≤𝛼] 
and 𝑓𝑘= 𝑒𝑘(𝐼𝑘)/𝛼, 𝑘= 1, 2. It is shown in Brechenmacher et al. (2011) that 
𝑒𝑘(𝐼𝑘) = [𝛾𝑘+ (1 −𝛾𝑘)|𝐼𝑘|/𝑛𝑘]𝛼 
if the index set 𝐼𝑘 is non-empty and 𝑒𝑘(𝐼𝑘) = 0 the index set 𝐼𝑘 is empty. Here |𝐼𝑘| denotes the 
number of hypotheses included in the index set 𝐼𝑘.  
As shown in Dmitrienko and Tamhane (2011), the resulting test for the intersection 
corresponding to the index set 𝐼 is an 𝛼-level test. This implies that the Hochberg-based 
gatekeeping procedure controls the global familywise error rate in the strong sense at a one-sided 
𝛼= 0.025. 
Multiplicity-adjusted p-values 
Multiplicity-adjusted 𝑝-values for the Hochberg-based gatekeeping procedure are computed 
using the closure principle. For each hypothesis, the adjusted 𝑝-value is defined as the maximum 
over the 𝑝-values associated with the intersections in the closed family that include the 
hypothesis of interest. For example, the adjusted 𝑝-value for 𝐻2 is the maximum over the 𝑝-
values for intersections containing 𝐻2. The calculations are performed using the decision matrix 
algorithm, see Dmitrienko and Tamhane (2011).  
Regular and truncated Hochberg tests 
Consider a general problem of testing m null hypotheses denoted by 𝐻1, . . . , 𝐻𝑚. Let 𝑝1, . . . , 𝑝𝑚 
denote the associated raw p-values. Further, let 𝑝(1) < ⋯< 𝑝(𝑚) denote the ordered p-values and 
𝐻(1) < ⋯< 𝐻(𝑚) denote the hypotheses corresponding to the ordered p-values. 
The regular Hochberg test is based on the following testing algorithm: 
• Step 1: If 𝑝(𝑚) > 𝛼, accept 𝐻(𝑚) and go to Step 2, otherwise reject all null hypotheses 
and stop. 


 
 
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• Step 𝑖= 2, . . . , 𝑚−1: If 𝑝(𝑚−𝑖+1) > 𝛼/𝑖, accept 𝐻(𝑚−𝑖+1) and go to Step 𝑖+ 1, 
otherwise reject all remaining null hypotheses and stop. 
• Step 𝑚: If 𝑝(1) > 𝛼/𝑚, accept 𝐻(1), otherwise reject 𝐻(1)· 
The truncated Hochberg test with the truncation parameter 𝛾 is based on the following testing 
algorithm: 
• Step 1: If 𝑝(𝑚) > [𝛾+ (1 −𝛾)/𝑚]𝛼, accept 𝐻(𝑚) and go to Step 2, otherwise reject all 
null hypotheses and stop. 
• Step 𝑖= 2, . . . , 𝑚−1: If 𝑝(𝑚−𝑖+1) > [𝛾/𝑖+ (1 −𝛾)/𝑚]𝛼, accept 𝐻(𝑚−𝑖+1) and go to 
Step 𝑖+ 1, otherwise reject all remaining null hypotheses and stop. 
• Step 𝑚: If 𝑝(1) > 𝛼/𝑚, accept 𝐻(1), otherwise reject 𝐻(1) 
6.2.7.1.4 Robustness of Primary and Key Secondary Efficacy Analyses 
A binary response variable (Yes, No) will be analyzed to compare trilaciclib and GC only using 
stratum-adjusted method to account for the liver involvement (Yes or No) and number of prior 
lines of therapy (0, 1-2) as the stratification factor. The adjusted proportion difference (trilaciclib 
vs GC only) and its 95% CIs will be calculated using Cochran-Mantel-Haenszel (CMH) weight 
outlined in Kim et al. 2013. The two-sided p-value will be calculated using stratified exact CMH 
method. Additionally, three sets of sensitivity analysis will be conducted to evaluate the 
robustness of the results from primary or key secondary analyses for a binary response variable 
(Yes, No). 
(i) 
For patients who die during the treatment period without experiencing an event, Yes will 
be assigned to the variable.  
(ii) After the imputation from (i), a worst-comparison analysis will be done to establish a 
stringent boundary of the treatment effect. Patients who die during the treatment period will 
still be set to Yes, and patients who discontinue the study prior to the July 30, 2018 data 
cutoff date without experiencing an event will then be imputed. If the patient is from the 
GC only group, No will be assigned to the variables, Yes will be assigned to the trilaciclib 
groups.  
(iii) After the imputation from (i), a tipping-point analysis (Yan et al,. 2009) will be performed 
by assigning the response to the variable for patients who discontinue the study early 
during the treatment period without experiencing an event. 
The tipping-point analysis assumes all possible combinations of numbers of Yes and No for 
the missing responses (defined as patients without an event who have discontinued the 
study prior to the July 30, 2018 data cutoff date) in the trilaciclib and GC only groups. For 
example, let nt be the number of randomized trilaciclib patients with missing response and 
nc be the number of randomized GC only patients with missing responses. For the 
trilaciclib patients with missing values, there are nt + 1 possible assumptions for number of 
No (i.e. 0, 1, 2, …, to nt); for the GC only patients with missing values, there are nc + 1 
possible assumptions for number of No.  Therefore, there are total of (nt + 1) × (nc + 1) 
possible combination of assumptions for number of No and Yes for the trilaciclib and GC 
only patients with missing responses. The un-stratified exact CMH method will be 


 
 
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performed on the available responses with each of these (nt + 1) × (nc + 1) assumptions and 
will be summarized. A figure will be presented with points representing each possible 
combination where the significant p-value ‘tips’ to greater than a one-sided 0.025, which 
would represent a change in the study conclusions. Clinical justification will be provided to 
evaluate whether the assumption is plausible.   
 
Each of the analyses will be repeated using two additional distinct data sets to evaluate the 
confounding effect of GCSF administration: inclusion of only those patients or cycles who had 
concurrent GCSF administration; and inclusion of only those patients or cycles who did NOT 
have concurrent GCSF administration.  The “with” and “without” GCSF analyses are subsets of 
the total number of patients or cycles. 
Each of the analyses will be similarly repeated for subsets of cycles with and without skipped 
doses. 
Time-to-event endpoints will be summarized using Kaplan-Meier method, and the descriptive 
statistics of median, 25% and 75% percentiles along with their 95% CIs will be calculated for 
• DSN, Strategy 2 (refer to Section 5.1.1.2.2). Additionally, DSN for each cycle will be 
presented using descriptive statistics. 
• Time-to-first MAHE endpoints (overall and individually) in Section 5.1.2.4. 
In addition to the summary from Kaplan-Meier method, the two-sided p-value will be obtained 
from the stratified Kaplan-Meier method to account for the stratification factors. The hazard ratio 
(HR) between the two treatments (trilaciclib vs GC only), together with its 95% CIs will be 
calculated from a Cox proportional hazard model in which treatment and the stratification factors 
will be included as fixed effects. 
For the time (days) to first occurrence of a MAHE event, a graphical display of cumulative 
incidence will be presented. 
The primary and key secondary efficacy endpoints are based on the ITT analysis set, and the 
analysis will be repeated for the mITT analysis set and PP analysis set. 
6.2.7.2 Supportive Secondary Efficacy Analyses 
6.2.7.2.1 Analyses of Objective Response 
The patients in each category of TPR according to the investigator tumor assessment (CR, PR, 
SD, PD, or NE) will be presented in a data listing. The number and percentage of patients in each 
category of BOR (Confirmed CR, Confirmed PR, SD, PD, or NE), ORR, ORRUNCONFIRMED and 
CBR according to the investigator tumor assessment (Confirmed CR, Confirmed PR, SD, PD, or 
NE) will be summarized. Detailed information of deriving tumor relevant responses is provided 
in Section 5.1.3.1.4.    
Similar analyses will be repeated based on the derived responses according to the RECIST 
Version 1.1.  
Estimates of response rate, along with its associated exact 95% two-sided CIs using Clopper-
Pearson method will be computed for ORR and CBR within each treatment group.  


 
 
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The binary endpoint (Yes, No) of ORR for the two treatments (trilaciclib and GC only) will be 
analyzed to compare trilaciclib and GC only using stratum-adjusted method to account for the 
stratification factors. The adjusted proportion difference (trilaciclib vs GC only) and its 95% CIs 
will be calculated using CMH weight outlined in Kim et al. 2013. The two-sided p-value will be 
calculated using stratified exact CMH method.   
The analyses are based on the response evaluable analysis set. The supportive data listings will 
also be provided.  
6.2.7.2.2 Analyses of DOR, PFS, and OS 
DOR (investigator and derived) will be summarized using Kaplan-Meier method, and the 
descriptive statistics of median, 25% and 75% percentiles along with their 95% CIs will be 
calculated. It will be based on the response evaluable analysis set. The supportive data listings 
will also be provided. 
PFS (derived, and derived with clinical progression) and OS will be similarly summarized, and 
in addition to the quartile summary from Kaplan-Meier method, Kaplan-Meier estimates will be 
provided for the survival rates at 3, 6, 9, and 12 months along with their 95% CIs. Comparison 
will also be conducted between trilaciclib and GC only. The two-sided p-value from a Cox 
proportional hazard model will be presented, the model includes treatment and stratification 
factors as fixed effects. The HR between the two treatment groups, together with its 95% CIs 
will be presented. 
Both PFS and OS will be based on the ITT analysis set. For the PFS, the derived endpoint based 
on only radiologic progression will be considered as the primary, and the derived endpoint based 
on both radiologic and clinical progression will be considered as supportive.  
6.2.7.2.3 Analyses of Hematology Lab Values 
For the endpoints specified in Section 5.1.3.3 and 5.1.3.4, in addition to descriptive statistics 
summary, graphical displays will be provided to facilitate evaluation of trends in the change in a 
given variable over time. Moreover, each of the ANC change over time analysis (i.e. observed 
value at windowed visit and cycle nadir) specified above will be done using three distinct data 
sets to evaluate the confounding effect of GCSF administration: all patients or cycles regardless 
of GCSF administration; inclusion of only those patients or cycles who had concurrent GCSF 
administration; and inclusion of only those patients or cycles who did NOT have concurrent 
GCSF administration.  The “with” and “without” GCSF analyses are subsets of the total number 
of patients or cycles.  
6.2.7.2.4 Analyses of Other Binary Efficacy Endpoints 
The following binary response variables (Yes, No) will be analyzed using the same method for 
occurrence of SVN except baseline ANC will not be a covariate in the modified Poisson model. 
See Section 6.2.7.1.1: 
• Occurrence of a Grade 3 or 4 hematologic toxicity during the treatment period (refer to 
Section 5.1.3.2); 
• Occurrence of an ESA administration during the treatment period (refer to Section 5.1.3.5); 


 
 
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• Occurrence of an IV antibiotic administration during the treatment period (refer to Section 
5.1.3.6); The offset in the modified Poisson model will be the logarithm transformation of 
duration of treatment period divided by 7 (i.e. week) instead of number of cycles. Additionally, total 
number of IV antibiotic administrations will be summarized descriptively. 
• Occurrence of an infection SAE during the treatment period (refer to Section 5.1.3.7); The 
offset in the modified Poisson model will be the logarithm transformation of duration of 
treatment period divided by 7 (i.e. week) instead of number of cycles. Additionally total number of 
infection SAEs will be summarized descriptively. 
• Occurrence of all-cause dose reductions during the treatment period (refer to Section 
5.1.2.4.2); 
• Occurrence of a Grade 4 and Grade 3 or 4 thrombocytopenia during the treatment period 
(refer to Section 5.1.3.9); 
6.2.8. 
Safety Analyses 
All safety analyses will be based on the safety analysis set, as defined in Section 3.1.3.  
Descriptive statistics will be used to summarize the safety outcomes. The continuous safety 
variables will be summarized at each visit including end of each cycle (the last non-missing 
assessment during the cycle), end of treatment (the last non-missing assessment during the 
treatment period), and end of study (the last non-missing assessment during the whole study), if 
applicable. No inferential analyses of safety data are planned unless otherwise specified. 
6.2.8.1. 
Chemotherapy Exposure and Compliance Analyses 
Duration on treatment and number of cycles will be summarized by treatment. For each study 
drug, the dosing endpoints described in Section 5.2.1 will be summarized by treatment.   
Dose modifications will be summarized for each study drug (gemcitabine, carboplatin or 
trilaciclib) including the following: 
• Number of cycles received; 
• Number of skipped doses; 
• Number of dose reductions; 
• Number of dose interruptions;  
• Number of patients with skipped doses;  
• Number of patients with dose reductions; 
• Number of patients with dose interruptions. 
The number of cycles delayed, the number and percentage of patients experiencing a treatment 
cycle delay, and reason for cycle delay will be summarized by treatment. The study dosing 
records and the derived dosing endpoints will be listed. 
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6.2.8.2. 
Adverse Events 
Number and incidence rates of AEs will be summarized by SOC and/or PT for the following 
categories of TEAEs: all AEs, SAEs, AEs leading to death, and AEs leading to study drug 
discontinuation or study withdrawal. Patients with more than one occurrence of the same SOC 
(PT) will be counted only once within the SOC (PT) categorization.   
AEs will also be summarized similarly by CTCAE grade and relationship to any study drug 
(gemcitabine, carboplatin or trilaciclib), and by relationship to each drug. Should a patient 
experience more than one occurrence of the same SOC (PT), the patient’s worst occurrence 
(worst grade/most related causality) will be retained in the tabulation.    
All AEs, including AEs that started prior to the study medication, will be presented in patient 
listings. In addition, separate listings of all SAEs, AEs leading to death, drug-related AEs, and 
AEs leading to study drug discontinuation or study withdrawal will be provided. 
The criteria for identifying infusion related reaction AEs or hematologic toxicity AEs are 
described in Section 5.2.2. A summary table showing the incidence of each category of AEs 
related to infusion and related to hematologic toxicity will be presented along with its supportive 
data listing.     
6.2.8.3. 
Laboratory Evaluations 
For hematology and clinical chemistry labs, the observed values and change from baseline will 
be summarized separately for cycles with and without a skipped dose for each visit during the 
treatment period using descriptive statistics.   
Toxicities for clinical labs will be characterized according to CTCAE, Version 4.03 (Table A-1 
of Appendix when possible), and the frequency and percentage of patients with each CTCAE 
grade for each visit (separately by cycles with and without a skipped dose) during the treatment 
period will be described. Moreover, any occurrence of grade 3 or grade 4 during the treatment 
period will be summarized, and shift in grade from baseline to the worst post-baseline value will 
be summarized. Both the scheduled and unscheduled assessments will be used to identify the 
worst post-baseline values. 
Listings of all laboratory data with a flag for cycles with a skipped dose, normal reference 
ranges, and CTCAE grades (when possible) will be provided.    
6.2.8.4. 
Vital Signs 
For vital sign parameters (Systolic Blood Pressure, Diastolic Blood Pressure, Pulse Rate, 
Temperature, and Weight) the observed values and change from baseline will be summarized 
using descriptive statistics at each visit during the treatment period.  
Additionally, the frequency and percentage of patients with any potentially clinically significant 
findings (defined in Table 14) during the treatment period will be presented. A listing of all vital 
sign data will be provided.  
6.2.8.5. 
Performance Status  
Descriptive statistics will be presented for ECOG score for the observed values and change from 
baseline. A listing of ECOG score for all patients will be provided.   


 
 
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6.2.8.6. 
Physical Examination 
A listing of screening physical examination findings for all patients will be provided (where 
available). 
6.2.8.7. 
ECG 
Descriptive statistics will be presented for each ECG parameter for the observed values and 
change from baseline to post baseline. A listing of all ECG data will be provided.  
The criteria for potentially clinically significant findings are defined in Table 16. The frequency 
and percentage of patients with any potentially clinically significant findings during the 
treatment period will be presented. The supportive data will be provided in patient data listings.  
6.2.9. 
Subgroup Analyses 
The PFS, OS, and MAHE will be examined in the following subgroups: 
− Age group (ages <65; >65). 
− Liver involvement (Yes; No). 
− ECOG performance status (0; 1). 
− Prior lines of therapy (0; 1-2). 
− Race (Caucasian; non-Caucasian). 
− Region (US; Ex-US). 
− BRCA classification (Positive; Unknown)  
− Histological classification (TNBC; Acquired TNBC)  
 Descriptive statistics by treatment group will be presented for each subgroup of patients.  
Additional subgroups or endpoints may be identified and explored.  
6.2.10. 
Pharmacokinetic Analysis 
The PK analysis for a subset of patients will be documented separately and is not covered in this 
SAP. 
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6.2.12. 
Planned Analysis  
The final myelosuppression analysis will be conducted after all patients have had the opportunity 
to receive at least 12 weeks of treatment. All study data collected through the time of the final 
myelosuppression analysis data cut will be included. This includes, but is not limited to the final 
myelosuppression analysis, interim ORR analysis based on investigator assessment, and interim 
PFS/OS analysis. 
The time of analysis with at least 80% of patients having experienced a progression will be 
considered to be final PFS analysis. Patients will be followed for survival until at least 70% of 
the patients have died, and a final OS analysis will be done then. 
 
. Reported 
results, with the exception of the myelosuppression analyses, will be cumulative in nature, 
including all data collected during the entire study; the myelosuppression analyses will be 
complete at the final analysis and no additional data will be expected. 
 
CCI


 
 
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7. 
CHANGE FROM THE PROTOCOL 
The timing of the final analysis, analysis sets, and endpoints were updated based on scientific 
advice, regulatory guidance, and feedback on other trilaciclib studies. The endpoints and 
analyses listed below are based on the Statistics Section in the Protocol Amendment 3, dated 31 
August 2017. The list displays the endpoints and analyses which are removed from the initial 
analysis and are therefore not described in the SAP.  
Protocol Section 13.3.1 (Efficacy Endpoints): 
• Hematologic kinetic endpoints: 
o Change and percent change in hematologic parameter values from predose for a 
particular cycle to the end of that cycle 
o Change and percent change in hematologic parameter values from predose for a 
particular cycle to nadir for that cycle 
o Rate of change in hematologic parameter values from predose for a particular cycle to 
nadir for that cycle 
o Change and percent change in hematologic parameter values from nadir for a 
particular cycle to the end of that cycle 
o Rate of change in hematologic parameter values from nadir for a particular cycle to 
the end of that cycle 
o Area under the curve in hematologic parameter values from predose for a particular 
cycle to the end of that cycle 
o Area under the curve in hematologic parameters from predose for a particular cycle to 
nadir for that cycle 
o Area under the curve in hematologic parameter values from nadir for a particular 
cycle to the end of that cycle 
o Time to hematologic parameter value nadir by cycle 
o Time to return to predose hematologic parameter values by cycle 
o Proportion of patients with a return to predose hematologic parameter values by cycle 
• Hematologic toxicity endpoints: 
o Proportion of patients with a hematologic toxicity recovery by cycle. 
o Time to hematologic toxicity recovery by cycle 
Protocol Section 13.3.2.1 (Analysis of Hematologic Parameter Kinetic Endpoints) 
• Additional tabulations for each cycle of treatment in maximum postnadir values. 
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• The tabulation of the changes and percent changes from predose to nadir, predose to end of 
cycle, nadir to maximum postnadir, and nadir to end of cycle values for each cycle of 
treatment. 
• Analysis of covariance (ANOVA) models on hematologic parameter kinetic endpoints 
• Summarization of time to nadir. 
• Descriptive statistics and ANOVA of AUC in hematologic parameters 
• Repeated-measures model of AUC 
• Summary of proportion of patients return to predose value for each cycle, calculation on 
incidence rate, adjusting for cumulative exposure 
• Analysis of time to return to predose level for each cycle using Kaplan-Meier method. 
• Analysis of Time to return to postnadir predose levels 
Protocol Section 13.3.2.2 (Analysis of Hematologic Toxicity Endpoints)  
• Calculation and analysis of incidence rate of hematologic toxicity, adjusting for cumulative 
exposure 
• Calculation and analysis of toxicity rate relative to cumulative exposure (total number of 
toxicities divided by cumulative exposure).  
• Recurrent events model estimating the incidence of Grade 3 or higher hematologic toxicities 
and testing for the difference between treatment groups. 
• For each hematologic parameter and cycle, the shift summaries of the following: 
o From predose toxicity to maximum on treatment toxicity;  
o from predose toxicity to end of cycle toxicity; 
o from maximum postdose toxicity to end of cycle toxicity. 
Protocol Section 13.3.2.4 (Other Efficacy Endpoints) 
• The number and percent of infections summarized by maximum severity 
• The infection rate: The number of infections occurring during the Treatment divided by 
cumulative exposure. 
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8. 
REFERENCES 
Brechenmacher T, Xu J, Dmitrienko A, Tamhane AC. A mixture gatekeeping procedure based 
on the Hommel test for clinical trial applications. Journal of biopharmaceutical statistics. 2011; 
21: 748-767. 
Dmitrienko A, Wiens BL, Tamhane AC, Wang X. Tree-structured gatekeeping tests in clinical 
trials with hierarchically ordered multiple objectives. Statistics in medicine. 2007; 26: 2465-
2478. 
Dmitrienko A, Tamhane, AC, Wiens B. General multistage gatekeeping procedures. Biometrical 
Journal. 2008; 50, 667-677. 
Dmitrienko A, Tamhane, AC, Bretz F. Multiple testing problems in pharmaceutical statistics. 
2009. Chapman and Hall/CRC. 
Dmitrienko A, Tamhane  AC. Mixtures of multiple testing procedures for gatekeeping 
applications in clinical trials. Statistics in Medicine. 2011; 30, 1473-1488. 
Eisenhauer, E., Therasse, P., Bogaerts, J., Schwartz, L.H., Sargent, D., Ford, R., Dancey, J., 
Arbuck, S., Gwyther, S., Mooney, M. and Rubinstein, L., 2009. New response evaluation criteria 
in solid tumours: revised RECIST guideline (version 1.1). European journal of cancer, 45(2), 
228-247.  
FDA Center for Biologics Evaluation and Research (CBER). Multiple Endpoints in Clinical 
Trials Guidance for Industry. https://www.fda.gov/downloads/drugs/guidancecompliance 
regulatoryinformation/guidances/ucm536750.pdf. Published January 2017. Accessed 
13 September 2018. 
Huque MF. Validity of the Hochberg procedure revisited for clinical trial applications. Statistics 
in medicine. 2016; 35:5-20. 
Kim Y, Won S. (2013) Adjusted proportion difference and confidence interval in stratified 
randomized trials. PharmaSUG; Paper SP-04  
Yan X, Lee, S and Li N. Missing data handling methods in medical device clinical trials, Journal of 
Biopharmaceutical Statistics, 2009, 19 (6): 1085 — 1098 
Zou G. A modified Poisson regression approach to prospective studies with binary data. 
American journal of epidemiology. 2004;159(7):702-6. 






  
 
 
 
 
STATISTICAL ANALYSIS PLAN  
– Region 2 – 
 
Study Title: 
Phase 2 Study of the Safety, Efficacy, and Pharmacokinetics of 
G1T28 in Patients with Metastatic Triple Negative Breast Cancer 
Receiving Gemcitabine and Carboplatin Chemotherapy   
 
 
 
Sponsor 
G1 Therapeutics 
 
79 T.W. Alexander Drive 
 
4501 Research Commons, Suite 100 
 
Research Triangle Park, NC 27709 
 
 
Name of Test Drug: 
G1T28 
 
 
Protocol Number: 
G1T28-04 
 
 
Phase: 
Phase 2   
 
 
Analysis Plan Version 
Version 1.0 
 
 
Version Date 
28 September 2018 




 
 
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Statistical Analysis Plan for Region 2  
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY DETAILS .......................................................................................................9 
2.1. 
Study Objectives ...........................................................................................................9 
2.2. 
Study Design .................................................................................................................9 
2.3. 
Number of Patients .....................................................................................................18 
3. 
ANALYSIS SETS ......................................................................................................19 
3.1. 
Definition of Analysis Sets .........................................................................................19 
3.1.1. 
Intent-to-Treat Analysis Set ........................................................................................19 
3.1.2. 
Modified ITT Analysis Set .........................................................................................19 
3.1.3. 
Safety Analysis Set .....................................................................................................19 
3.1.4. 
Per Protocol (PP) Analysis Set ...................................................................................19 
3.1.5. 
Response Evaluable Analysis Set ...............................................................................19 
3.2. 
Protocol Deviations ....................................................................................................19 
4. 
PROSPECTIVELY DEFINED ANALYSES.............................................................21 
5. 
PRIMARY AND SECONDARY ENDPOINTS ........................................................22 
5.1. 
Efficacy Endpoints ......................................................................................................22 
5.1.1. 
Primary Endpoints ......................................................................................................22 
5.1.1.1. 
Occurrence of Severe (Grade 4) Neutropenia ............................................................22 
5.1.1.2. 
Duration of Severe (Grade 4) Neutropenia (DSN) .....................................................23 
5.1.2. 
Key Secondary Endpoints ...........................................................................................24 
5.1.2.1. 
Occurrence of RBC Transfusions ...............................................................................24 
5.1.2.2. 
Occurrence of GCSF Administrations ........................................................................24 
5.1.2.3. 
Occurrence of Platelet Transfusions ...........................................................................24 
5.1.2.4. 
Occurrence of All-Cause Dose Reductions ................................................................24 
5.1.2.5. 
Overall Survival ..........................................................................................................25 
5.1.3. 
Supportive Secondary Endpoints ................................................................................25 
5.1.3.1. 
Total Number of Major Adverse Hematologic Events (MAHE) ...............................25 
5.1.3.2. 
Best Overall Response, Duration of Response, and Progression-Free 
Survival .......................................................................................................................26 
5.1.3.3. 
Occurrence of Grade 3 and 4 Hematologic Toxicities ...............................................32 




 
 
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6.2.1. 
Patient Disposition ......................................................................................................46 
6.2.2. 
Demographic and Other Baseline Characteristics ......................................................46 
6.2.3. 
Disease Characteristics ...............................................................................................47 
6.2.4. 
Medical/Surgical History ............................................................................................47 
6.2.5. 
Concomitant Medications ...........................................................................................47 
6.2.6. 
Prior and Subsequent Anti-Cancer Therapy ...............................................................48 
6.2.7. 
Efficacy Analyses .......................................................................................................48 
6.2.7.1 
Primary and Key Secondary Efficacy Analyses .........................................................49 
6.2.7.2 
Supportive Secondary Efficacy Analyses ...................................................................56 
6.2.8. 
Safety Analyses ..........................................................................................................58 
6.2.8.1. 
Chemotherapy Exposure and Compliance Analyses ..................................................58 
6.2.8.2. 
Adverse Events ...........................................................................................................58 
6.2.8.3. 
Laboratory Evaluations ...............................................................................................59 
6.2.8.4. 
Vital Signs ..................................................................................................................59 
6.2.8.5. 
Performance Status .....................................................................................................59 
6.2.8.6. 
Physical Examination .................................................................................................59 
6.2.8.7. 
ECG ............................................................................................................................59 
6.2.9. 
Subgroup Analyses .....................................................................................................59 
6.2.10. 
Pharmacokinetic Analysis ..........................................................................................60 
6.2.12. 
Planned Analysis ........................................................................................................60 
7. 
CHANGE FROM THE PROTOCOL ........................................................................61 
8. 
REFERENCES ...........................................................................................................63 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event 
ALC 
Absolute Lymphocyte Count 
ALP 
Alkaline Phosphatase 
ALC 
Absolute Lymphocyte Count 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
aRR 
Adjusted Rate Ratio 
AST 
Aspartate Aminotransferase  
 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under Curve 
β-HCG 
Beta Human Chorionic Gonadotropin  
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BPM 
Beats Per Minute 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CBR 
Clinical Benefit Rate 
CDK 
Cyclin Dependent Kinase 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CSR  
Clinical Study Report 
CT 
Computed Tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
DMC 
Data Monitoring Committee 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic Case Report Form 
EOI 
End of Infusion 
ESA 
Erythropoietin Stimulating Agent 
 
 
 
  
 
  
G1T28 
Trilaciclib 
GC 
Gemcitabine and Carboplatin 
GCSF 
Granulocyte Colony-Stimulating Factor 
HR 
Hazard Ratio 
ICH 
International Conference on Harmonization 
ITT 
Intent-to-treat 
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Abbreviation 
Term 
IV 
Intravenous 
LD 
Longest Diameter 
LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal Range 
MAHE 
Major Adverse Hematologic Event 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MRI 
Magnetic Resonance Imaging 
Nadir 
The Lowest Point 
NE 
Not Evaluable 
 
 
NTL 
Non-Target Lesion 
OC 
Observed Case 
ORR 
Objective Response Rate 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic  
 
 
PP 
Per Protocol 
PR 
Partial Response 
 
 
PT 
Preferred Term 
 
 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumors  
 
 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Stable Disease 
SOC 
System Organ Class 
SVN 
TEAE 
Severe Neutropenia 
Treatment Emergent AE 
TL 
Target Lesion 
TLFs 
Tables, Listings, and Figures 
TNBC 
Triple Negative Breast Cancer 
TPR 
Time Point Response 
ULN 
Upper Limit of Normal Range 
WBC 
White Blood Cell 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the analyses to be performed 
following the completion of Study G1T28-04, Phase 2 Study of the Safety, Efficacy, and 
Pharmacokinetics of G1T28 in Patients with Metastatic Triple Negative Breast Cancer Receiving 
Gemcitabine and Carboplatin Chemotherapy.  The SAP is based on the G1T28-04 Protocol 
Version 4, dated 31 August 2017.   
Study measurements and assessments, planned statistical methods, and derived variables are 
summarized in this plan.  Planned tables, figures, and listings are specified.  All decisions 
regarding final analyses, as defined in this SAP document, have been made prior to locking the 
database. Any deviations from these guidelines will be documented in the clinical study report 
(CSR).  
The myelosuppression efficacy endpoints and statistical analysis methods described in this SAP 
are reflective of scientific advice obtained in both the US and EU for evaluation of trilaciclib for 
the reduction of chemotherapy-induced myelosuppression. While the primary objective of 
G1T28-04 does not explicitly state that the trial has been designed to evaluate the effects of 
trilaciclib on chemotherapy-induced myelosuppression, the endpoints of AEs and laboratory 
values used to evaluate safety and tolerability are the same endpoints used to evaluate effects on 
chemotherapy-induced myelosuppression. The data collection for this trial was appropriate for 
the analysis of these myelosuppression endpoints, and the defined endpoints in this SAP are 
consistent with the overall strategy/rationale for Study G1T28-04. 


 
 
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2. 
STUDY DETAILS 
2.1. 
Study Objectives 
The primary, secondary, and 
 objectives of this study as defined in the study protocol 
are presented in Table 1. 
Table 1  
G1T28-04: Study Objectives 
Primary Objectivea 
Assess the safety and tolerability of trilaciclib administered with GC therapy 
Secondary Objectivesa 
Assess tumor response and duration of response based on RECIST, Version 1.1 
Assess PFS and OS 
Assess dose intensity of gemcitabine and carboplatin 
Assess the PK profile of trilaciclib 
Assess the PK profile of gemcitabine and carboplatin when administered with and without trilaciclib 
Assess the hematologic profile (kinetics and incidence/duration/frequency of toxicities) of trilaciclib 
administered with GC therapy 
Assess the incidence of febrile neutropenia 
Assess the incidence of infections 
Assess the utilization of RBC and platelet transfusions 
Assess the utilization of hematopoietic growth factors  
Assess the utilization of systemic antibiotics 
Assess the incidence of chemotherapy dose reductions and dose interruptions overall 
Assess the incidence of Grade 2 or greater nephrotoxicity  
Determine the dose schedule of trilaciclib administered with GC therapy 
GC therapy = gemcitabine + carboplatin on Days 1 and 8 or Days 2 and 9 of 21-day cycles; OS = overall survival; PFS = 
progression-free survival; PK = pharmacokinetic; 
; RBC = red blood cell; 
; 
RECIST = Response Evaluation Criteria in Solid Tumors 
a. The objectives will be assessed for both schedules of trilaciclib (Days 1 and 8 or Days 1, 2, 8, and 9 in 21-day cycles) 
administered prior to GC therapy (Days 1 and 8 or Days 2 and 9 in 21-day cycles, respectively)  
2.2. 
Study Design 
This is a multicenter, randomized, open-label, Phase 2 study of the safety, efficacy, and 
pharmacokinetics (PK) of trilaciclib in combination with gemcitabine and carboplatin (GC) 
therapy for patients with metastatic triple negative breast cancer (TNBC). A total of 
approximately 90 patients will be randomly assigned (1:1:1 fashion) to 1 of the following 3 
groups: 
• Group 1: GC therapy (Days 1 and 8 of 21-day cycles) only (n=30) 
• Group 2: GC therapy (Days 1 and 8) plus trilaciclib administered intravenous (IV) on 
Days 1 and 8 of 21-day cycles (n=30) 
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• Group 3: GC therapy (Days 2 and 9) plus trilaciclib administered IV on Days 1, 2, 8, and 
9 of 21-day cycles (n=30) 
The study will include 3 study phases: Screening Phase, Treatment Phase, and Survival Follow-
up Phase. The Treatment Phase begins on the day of first dose with study treatment and 
completes at the Post-Treatment Visit. 
An independent data monitoring committee (DMC) will perform interim reviews of 
accumulating safety and disposition data approximately every 4 months during the Treatment 
Phase of the study, depending upon the enrollment rate. The first DMC meeting 
will occur after approximately the first 20 patients have been enrolled and completed at least 1 
cycle. Details of the DMC, including objectives, composition, scope, and frequency, will be 
described in a DMC charter.  
 
Criteria for Subsequent Cycles and Study Duration 
In all 3 groups, study drug administration will continue until disease progression per Response 
Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, unacceptable toxicity, withdrawal 
of consent, or discontinuation by investigator. 
Criteria for Day 1/2 of Each Cycle 
Patients must meet all of the following criteria to receive the Day 1/2 dose: 
• Absolute Neutrophil Count (ANC) ≥ 1.0 × 109/L 
• Platelet count ≥ 100 × 109/L 
• Nonhematologic toxicities (except alopecia) must be ≤ Grade 2 or have returned to 
baseline 
If the initiation of the next cycle is delayed due to toxicity, the patient should have (at least) 
weekly visits to follow the toxicity. 
Criteria for Day 8/9 of Each Cycle 
To receive Day 8/9 dose of each cycle, patients must meet all the following criteria: 
• ANC ≥ 1.0 × 109/L 
• Platelet count ≥ 75 × 109/L 
• Nonhematologic toxicities (except alopecia) must be ≤ Grade 2 or have returned to 
baseline 
If these criteria are not met, the Day 8/9 GC doses should be skipped; no dose reductions or 
delays are allowed for the Day 8/9 GC doses. If the Day 8/9 GC doses are skipped, the next GC 
doses become Day 1/2 of the subsequent cycle. There should be at least 7 days between a 
skipped Day 8/9 dose and the start of the next cycle, i.e., Day 1/2. Note that the criteria for 
starting Day 1/2 outlined above will now apply to resumption of dosing. 
After discontinuation of study drug, patients should be strongly encouraged to complete all 
scheduled assessments through the end of their current 21-day treatment cycle, including the 
; the Post-Treatment Visit (Day 22); the safety follow-up 
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phone call at 30 days after the last dose of study treatment; and the Survival Follow-up Phase of 
the study, which is to continue until at least 50% of patients have died.  
The G1T28-04 study will be completed when the Survival Follow-up Phase has been completed, 
or upon sponsor termination of the study. The total study duration is at least 19 months, 
assuming 12 months of accrual, 4 weeks of screening, 4.5 months of treatment (assuming 6 
cycles), and 2 months of safety follow-up. 
The study scheduled assessments are presented in Table 2 and Table 3 below: 
 


 
 
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Table 2  
Schedule of Assessments for Groups 1 and 2 
  
Screening 
Cycle 1 and Every  
Odd Cyclea (21 days) 
Cycle 2 and Every  
Even Cyclea (21 days) 
Post-Treatment 
Visitb 
Safety Follow-
up Phone Callc 
Survival  
Follow-upd 
Post-Treatment Visit 
+ 60 days 
Cycle Day  
-28 
1 
8 
15 
(±1 day) 
1 
8 
15 
(±1 day) 
22 (last cycle) 
(+7 days) 
(+3 days) 
(±7 days) 
(±7 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical Historye 
X 
 
 
 
 
 
 
Eligibility Evaluation 
X 
 
 
 
 
 
 
 
 
 
Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
 
Physical Exam 
X 
X 
 
 
X 
 
 
X 
 
 
 
Vital Signs 
X 
Xf 
Xf 
 
Xf 
Xf 
 
X 
 
 
 
Height/Weight 
Xg 
X 
 
 
Xg1 
 
 
 
 
 
 
Clinical Chemistry 
X 
Xh 
 
 
Xh 
 
 
X 
 
 
 
Hematologyi 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
Xj 
 
 
 
 
 
 
 
 
 
Pregnancy testk 
X 
Xk 
 
 
 
 
 
X 
 
 
 
Tumor Assessment 
Xm, m1,m2 
CT/MRI of chest/abdomen Q9 weeks through Week 27 and Q12 weeks thereafter.   
Also include brain MRI if brain metastases present at baseline.  
Skeletal lesions identified with baseline bone scan to be followed at scheduled visits using 
localized CT, MRI, or x-ray m, m1, m2, m3,m4 
Tumor assessment Q12 weeks to continue in 
Post-Treatment/Follow-up only if patient discontinues study 
treatment for reason other than PD and has not initiated 
subsequent anticancer therapym,m4 
Archival Tumor Tissue 
X 
 
 
 
 
 
 
 
 
 
 
PKn (optional) 
Xn 
 
 
 
 
 
 
 
 
 
Trilaciclibo 
X 
X 
 
X 
X 
 
 
 
 
 
GC therapyp 
 
X 
X 
 
X 
X 
 
 
 
 
 
Survival Contacts 
 
 
 
 
 
 
 
 
 
X 
 
AEst 
X 
 
 
Con. Medications 
X 
 
 
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AE = adverse event; ECG = 12-lead electrocardiogram; CT = Computed Tomography; FACT-An = Functional Assessment of Cancer Therapy – Anemia quality of life instrument; 
FACT-B = Functional Assessment of Cancer Therapy –Breast quality of life instrument; MRI = Magnetic Resonance Imaging; PRO = patient reported outcome; 
PK = pharmacokinetics, GC therapy= Gemcitabine and Carboplatin therapy; PD = progressive disease 
a 
Study therapy will continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.  
b 
Patients will return to the study center for a Post-Treatment Visit on Day 22 (+ 7 days) of their last cycle.  
c 
A safety follow-up contact will be made to each patient at 30 days after the last dose of study treatment to collect AEs and concomitant medications. 
d 
Follow-up should be attempted and documented for each patient that is in the long term Survival Follow-up Phase at least once every 2 months. Patients will be followed for 
survival until at least 50% of the patients have died. Any anticancer therapies used will be collected.  
e 
Including medical, surgical, radiation history, smoking history, prior systemic anti-cancer therapy, breast cancer history including BRCA classification, screening signs and 
symptoms within 4 weeks prior to randomization, and medications. Eligibility evaluation and randomization may occur up to 4 days prior to Day 1 Cycle 1 therapy. For all 
treatment groups, study start is on Cycle 1 Day 1.    
f 
Vital signs (blood pressure, heart rate, respiratory rate and body temperature) will be obtained immediately before and after each infusion. Vitals only need to be taken once 
between each infusion.   
g 
Height will only be measured at the screening visit. Body Surface Area (BSA) will be calculated at Day 1. 
 
g1: BSA (based on actual body weight) will be re-calculated on Day 1 of Cycle 2 and subsequent cycles if weight increases or decreases > 10% from Day 1 of the previous 
cycle. 
h 
Clinical chemistry (see Protocol Section 11.4.2) may be obtained up to 72 hours prior to Day 1 of each cycle.  
i 
Hematology (see Protocol Section 11.4.2) may be obtained up to 24 hours prior to dosing on Days 1 and 8 of each cycle, Day 15 of each cycle, at the Post-Treatment Visit, 
and at 60 days after the Post-Treatment Visit. 
j 
Single 12-lead ECGs will be obtained for all patients at screening. For those patients (Groups 1 and 2) who agree to participate in PK sampling will have ECGs completed in 
triplicate (at least 1 minute apart) at the following additional time points on Day 1 of Cycle 1: predose (prior to trilaciclib) and at 0.5 hour (end of infusion [EOI] of 
trilaciclib), 2 hours (± 10 minutes) after EOI of trilaciclib, and 5 hours (± 30 minutes) after EOI of trilaciclib. Patients should rest for approximately 5 minutes prior to each 
ECG assessment. The ECGs should be obtained just prior to PK sampling.  
k 
Female patients of childbearing potential: serum ß-hCG at screening and serum or urine ß-hCG on Day 1 of Cycle 1, Day 1 of every odd cycle, and at the Post-Treatment 
Visit. A pregnancy test should be obtained within 24 hours of the Cycle 1 Day 1 visit and must be negative to initiate treatment. 
m 
For tumor assessment, all sites of disease should be assessed radiologically by CT or MRI with contrast, where clinically possible, of the chest and abdomen at screening 
(unless obtained within 28 days of dosing), every 9 weeks ± 7 days (Week 9, Week 18 and Week 27) and then every 12 weeks ± 7 days thereafter, until the occurrence of 
disease progression, withdrawal of consent, initiation of subsequent anticancer therapy, or study completion. If a patient shows a radiological response (complete response 
[CR] or partial response [PR]), a confirmatory radiological assessment will be performed at least 4 weeks after the response was first noted. The same method of assessment 
(CT or MRI) should be used to characterize tumors at screening and at all follow-up assessments. If positron emission tomography is used, it should also be accompanied by 
spiral CT or MRI.  
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m1:  Radionuclide bone scans shall be performed at screening. Skeletal lesions identified on the bone scan at baseline, which are not visible on the CT or MRI scan 
should be imaged at  
baseline and followed at scheduled visits using localized CT, MRI or x-ray. Bone scans need not be repeated after baseline unless clinically 
indicated. Bone scans obtained as standard  of care prior to screening will not need to be repeated if performed within 28 days prior to the first dose of study drug(s). 
m2.  Brain imaging with contrast (by CT or MRI) performed at Screening for all patients. If brain metastases are present at screening, brain imaging shall be done with 
each protocol-specified tumor assessment. If no metastases are present at screening, imaging does not need to be performed during the study unless clinically 
indicated or if the subject is neurologically symptomatic. 
 
m3:  At the Post-Treatment Visit, obtain tumor assessment for patients who have not progressed at the time of study drug discontinuation (may be performed within 4 
weeks).  
 
m4:  For those patients in the Survival Follow-up Phase who have not progressed at the time of study drug discontinuation, radiological tumor assessments will be 
performed utilizing the  same imaging modality used at screening, every 12 weeks ± 7 days from the Post-Treatment Visit until the occurrence of progressive disease, 
withdrawal of consent, initiation of  
subsequent anticancer therapy, or study completion. 
n 
Patients who have agreed to participate in the PK analysis will have blood samples collected on Day 1 of Cycle 1 only at the time points specified in Section Error! 
Reference source not found..  The end of infusion (EOI) sample for trilaciclib should be drawn 2 to 5 minutes prior to the trilaciclib EOI. 
o 
For Group 2:  Trilaciclib will be administered as an IV infusion over 30 (±5) minutes prior to GC chemotherapy on Days 1 and 8 of every 21-day cycle (dosing information, 
see Protocol Section 8.1). After discontinuation of study drug, patients should be strongly encouraged to complete all scheduled assessments through the end of their current 
21-day treatment cycle, including the PRO scales; the Post-Treatment Visit (Day 22); the safety follow-up phone call at 30 days after the last dose of study treatment; and the 
Survival Follow-up Phase of the study. 
p 
For Group 1: GC therapy will be administered as an IV infusion on Days 1 and 8 of 21-day cycles (dosing information; see Protocol Section 8.1). 
 
For Group 2: GC therapy will be administered as an IV infusion after the trilaciclib infusion (with an interval not greater than 4 hours) on Days 1 and 8 of 21-day cycles 
(dosing information; see Protocol Section 8.1). Chemotherapy cannot be administered until after completion of the trilaciclib infusion. If trilaciclib in any given cycle is not 
administered for any reason, do not administer the dose of gemcitabine or carboplatin chemotherapy on that day.  
s 
Survival follow-up may be a phone contact if subject is not returning to the clinic for tumor assessments.  
t 
AEs will be recorded from the time of informed consent. All AEs should be reported within 30 days of the last dose of study drug, and followed until they are resolved, have 
returned to baseline, or it is deemed that further recovery is unlikely. 
  
 
 
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Table 3  
Schedule of Assessments for Group 3 
  
Screen-
ing 
Cycle 1 and Every Odd Cyclea 
(21 days) 
Cycle 2 and Every Even Cyclea   
(21 days) 
Post-Treatment 
Visitb 
Safety 
Follow-up 
Phone Callc 
Survival 
Follow-upd 
Post-Treatment 
Visit + 60 days 
Cycle Day  
-28 
1 
2 
8 
9 
15 
(±1 day) 
1 
2 
8 
9 
15 
(±1 day) 
22 (last cycle) 
(+7 days) 
(+3 days) 
(±7 days) 
(±7 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical Historye 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility Evaluation 
X 
 
 
 
 
 
 
 
 
 
 
Performance Status 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Physical Exam 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Vital Signs 
X 
Xf 
Xf 
Xf 
Xf 
 
Xf 
Xf 
Xf 
Xf 
 
X 
 
 
 
Height/Weight 
Xg 
X 
 
 
 
 
Xg1 
 
 
 
 
 
 
 
 
Clinical Chemistry 
X 
Xh 
 
 
 
 
Xh 
 
 
 
 
X 
 
 
 
Hematologyi 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
Xj 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testk 
X 
Xk 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Tumor Assessment  
Xm,m1,m2 
CT/MRI of chest/abdomen Q9 weeks through Week 27 and Q12 weeks thereafter.   
Also include brain MRI if brain metastases present at baseline.  
Skeletal lesions identified with baseline bone scan to be followed at scheduled visits using localized 
CT, MRI, or x-ray m, m1, m2, m3, m4 
Tumor assessment Q12 weeks to continue in 
Post-Treatment/Follow-up only if patient discontinues 
study treatment for reason other than PD and has not 
initiated subsequent anticancer therapym,m4 
Archival Tumor Tissue 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PKn (optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Trilaciclibo 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
GC therapyp 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
Survival contacts 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
AEst 
X 
 
 
Con. Medications 
X 
 
 
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AE = adverse event; ECG = 12-lead electrocardiogram; CT = Computed Tomography; FACT-An = Functional Assessment of Cancer Therapy – Anemia quality of life instrument; 
FACT-B = Functional Assessment of Cancer Therapy –Breast quality of life instrument; MRI = Magnetic Resonance Imaging; PRO = patient reported outcome; 
PK = pharmacokinetics, GC therapy= Gemcitabine and Carboplatin therapy; PD = progressive disease 
a 
Study therapy will continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator.  
b 
Patients will return to the study center for a Post-Treatment Visit on Day 22 (+ 7 days) of their last cycle.  
c 
A safety follow-up contact will be made to each patient at 30 days after the last dose of study treatment to collect AEs and concomitant medications. 
d 
Follow-up should be attempted and documented for each patient that is in the long term Survival Follow-up Phase at least once every 2 months. Patients will be followed for 
survival until at least 50% of the patients have died. Any anticancer therapies used will be collected.  
e 
Including medical, surgical, radiation history, smoking history, prior systemic anti-cancer therapy, breast cancer history including BRCA classification, documentation of 
tumor diagnosis, screening signs and symptoms within 4 weeks prior to randomization, and medications. Eligibility evaluation and randomization may occur up to 4 days 
prior to Day 1 Cycle 1 therapy. For all treatment groups, study start is on Cycle 1 Day 1.    
f 
Vital signs (blood pressure, heart rate, respiratory rate and body temperature) will be obtained immediately before and after each infusion. Vitals only need to be taken once 
between each infusion.   
g 
Height will only be measured at the screening visit. Body Surface Area (BSA) will be calculated at Day 1. 
 
g1: BSA (based on actual body weight) will be re-calculated on Day 1 of Cycle 2 and subsequent cycles if weight increases or decreases >10% from Day 1 of the previous 
cycle. 
h 
Clinical chemistry (see Protocol Section 11.4.2) may be obtained up to 72 hours prior to Day 1 of each cycle.  
i 
Hematology (see Protocol Section 11.4.2) may be obtained up to 24 hours prior to GC dosing of on Day 2 or Day 9 of each cycle, Day 15 of each cycle, at the Post-Treatment 
Visit, and at 60 days after the Post-Treatment Visit. 
j 
Single 12-lead ECGs will be obtained for all patients at screening. Those patients who agree to participate in PK sampling will have ECGs completed in triplicate (at least 1 
minute apart) at the following additional time points on Day 2 of Cycle 1: predose (prior to trilaciclib) and at 0.5 hour (end of infusion [EOI] of trilaciclib), 2 hours 
(± 10 minutes) after EOI of trilaciclib, and 5 hours (± 30 minutes) after EOI of trilaciclib. Patients should rest for approximately 5 minutes prior to each ECG assessment. The 
ECGs should be obtained just prior to PK sampling. 
k 
Female patients of childbearing potential: serum ß-hCG at screening and serum or urine ß-hCG on Day 1 of Cycle 1, Day 1 of every odd cycle, and at the Post-Treatment 
Visit. A pregnancy test should be performed within 24 hours of the Cycle 1 Day 1 visit and must be negative to initiate treatment.  
m 
For tumor assessment, all sites of disease should be assessed radiologically by CT or MRI with contrast, where clinically possible, of the chest and abdomen at screening 
(unless obtained within 28 days of dosing) every 9 weeks ± 7 days (Week 9, Week 18, and Week 27) and then every 12 weeks ± 7 days thereafter, until the occurrence of 
disease progression, withdrawal of consent, initiation of subsequent anticancer therapy, or study completion. If a patient shows a radiological response (complete response 
[CR] or partial response [PR]), a confirmatory radiological assessment will be performed at least 4 weeks after the response was first noted. The same method of assessment 
(CT or MRI) should be used to characterize tumors at screening and at all follow-up assessments. If positron emission tomography is used, it should also be accompanied by 
spiral CT or MRI.  
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m1:  Radionuclide bone scans shall be performed at screening. Bone scans obtained as standard of care prior to screening will not need to be repeated if performed within 
28 days prior to the  
first dose of study drug(s). Skeletal lesions identified on the bone scan at baseline, which are not visible on the CT or MRI scan should be 
imaged at baseline and followed at scheduled  
visits using localized CT, MRI, or x-ray. Bone scans need not be repeated after baseline unless clinically indicated. 
m2:  Brain imaging with contrast (by CT or MRI) performed at Screening for all patients. If brain metastases are present at screening, brain imaging shall be done with 
each protocol-specified tumor assessment. If no metastases are present at screening, imaging does not need to be performed during the study unless clinically 
indicated or if the subject is neurologically symptomatic. 
 
m3:  At the Post-Treatment Visit, obtain tumor assessment for patients who have not progressed at the time of study drug discontinuation (may be performed within 4 
weeks).  
 
m4:  For those patients in the Survival Follow-up Phase who have not progressed at the time of study drug discontinuation, radiological tumor assessments will be 
performed utilizing the  same imaging modality as used at screening, every 12 weeks ± 7 days from the Post-Treatment Visit until the occurrence of progressive disease, 
withdrawal of consent, initiation of  
anticancer therapy, or study completion. 
n 
Patients who agree to participate in the PK analysis will have blood samples collected on Day 2 of Cycle 1 at the time points specified in Protocol Section 11.4.2. The end of 
infusion (EOI) sample for trilaciclib should be drawn 2 to 5 minutes prior to the trilaciclib EOI. 
o 
For Group 3: trilaciclib will be administered as an IV infusion over 30 (±5) minutes on Days 1, 2, 8, and 9 of every 21-day cycle. Trilaciclib will be administered prior to GC 
on Days 2 and 9 (dosing information, see Protocol Section 8.1). The interval between doses of trilaciclib on successive days should not be greater than 28 hours. After 
discontinuation of study drug, patients should be strongly encouraged to complete all scheduled assessments through the end of their current 21-day treatment cycle, including 
the PRO scales; the Post-Treatment Visit (Day 22); the safety follow-up phone call at 30 days after the last dose of study treatment; and the Survival Follow-up Phase of the 
study. 
p 
For Group 3: GC therapy will be administered as an IV infusion after the trilaciclib infusion (with an interval not greater than 4 hours) on Days 2 and 9 of 21-day cycles 
(dosing information; see Protocol Section 8.1). Chemotherapy cannot be administered until after completion of the trilaciclib infusion. If trilaciclib in any given cycle is not 
administered for any reason, do not administer the dose of gemcitabine or carboplatin chemotherapy on that day.  
s 
Survival follow-up may be a phone contact if subject is not returning to the clinic for tumor assessments. 
t 
AEs will be recorded from the time of informed consent. All AEs should be reported within 30 days of the last dose of study drug, and followed until they are resolved, have 
returned to baseline, or it is deemed that further recovery is unlikely.
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2.3. 
Number of Patients 
Overall, approximately 90 patients will be enrolled in the study. The 90 patients will be 
randomly assigned (1:1:1) to 1 of 3 groups. 
The sample size is not determined from a statistical perspective, but rather is based on clinical 
feasibility. Approximately 90 patients will be enrolled into the study (30 per treatment group). 
With 30 patients, the precision for point estimates in each arm is as follows: the maximum 95% 
confidence interval (CI) width for binary endpoints based on Wilson score intervals is the 
observed proportion +/- 0.167. The 95% CI width for continuous endpoints using the t-
distribution are the observed mean +/- 0.373*standard deviation of the endpoint. 
With the changes to the protocol detailed in this SAP, the sample size calculation is now based 
on demonstrating the superiority of Group 3 (GC + Trilaciclib Day 1/2 and 8/9) and Group 1 
(GC therapy alone) with respect to at least one of the primary endpoints. 
With the changes, the overall type I error rate is now 0.025 (1-sided) and the type II error rate 
used to compute sample size is 0.10 (corresponding to 90% power).  
To maintain the overall type I error rate, by using the most conservative Bonferroni procedure 
for the 2 primary endpoints, a 1-sided individualized type I error rate 0.025/2 = 0.0125 is 
assigned to each outcome variable in the sample size calculation. Assuming a common standard 
deviation of 2.5, a true difference in the duration of severe (Grade 4) neutropenia in Cycle 1 of at 
least 3 days between the Group 3 and Group 1 requires, 38 evaluable patients (19 per treatment 
arm in Groups 1 and 3). This implies that 60 patients need to be randomized for all 3 groups 
assuming a 95% evaluability rate. For occurrence endpoints (occurrence of severe (Grade 4) 
neutropenia, assuming its proportion of 45% for Group 1, testing for an absolute reduction of 
41% to 4% with Group 3 would require a sample size of at least 96 patients (32 per treatment 
arm in Groups 1 and 3). Assuming a 95% evaluability rate, at least 102 patients need to be 
randomized for all 3 groups to complete the study. Therefore, the final adjusted sample size is 
102 to account for the evaluation of 2 primary endpoints. All calculations were carried out using 
the POWER procedure in SAS® version 9.4. 
The study will be conducted at up to 50 centers in North America and Europe. 


 
 
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3. 
ANALYSIS SETS 
3.1. 
Definition of Analysis Sets  
Data analyses will be based on the four analysis sets defined below. Analysis sets, including 
exclusions based on key deviations, will be reviewed and approved by G1 Therapeutics prior to 
the study unblinding. See Section 7 for the changes from the protocol defined analysis sets. 
3.1.1. 
Intent-to-Treat Analysis Set 
The Intent-to-Treat (ITT) analysis set includes all randomized patients. Analyses using the ITT 
will be conducted on the basis of the assigned treatment. All myelopreservation efficacy analyses 
will be assessed using the ITT. The ITT will also be used for analyses of progression-free 
survival (PFS) and overall survival (OS). 
3.1.2. 
Modified ITT Analysis Set 
A modified ITT (mITT) analysis set is a subset of the ITT analysis set and will only include the 
ITT patients who received at least 1 dose of study drug (gemcitabine, carboplatin, or trilaciclib). 
Supportive sensitivity analyses will be conducted based on the mITT analysis set for primary and 
key secondary efficacy endpoints to evaluate the robustness of the results.  Analyses using the 
mITT will be conducted on the basis of the assigned treatment. mITT will be used for sensitivity 
of select efficacy analyses.   
3.1.3. 
Safety Analysis Set 
The safety analysis set includes all enrolled patients who received at least 1 dose of study drug 
(gemcitabine, carboplatin, or trilaciclib). Analyses using the safety analysis set will be conducted 
on the basis of the actual treatment received. All safety analyses will be assessed using the safety 
population.  
3.1.4. 
Per Protocol (PP) Analysis Set 
The per-protocol (PP) analysis set is a subset of mITT analysis set and will include only those 
patients who have no key protocol deviations (as described in Section 3.2) and who received the 
treatment to which they were randomized. For any patients who received the wrong treatment 
during any part of the study, their data will be excluded from the PP analysis set. PP analysis set 
may be used to analyze selected endpoints to test the robustness of results. 
3.1.5. 
Response Evaluable Analysis Set 
The Response Evaluable Analysis Set will include all patients who are in the mITT, have 
measurable disease (target lesions) at the baseline tumor assessment, and either (i) have at least 1 
post-baseline tumor assessment, (ii) have clinical progression as noted by the investigator before 
their first post-baseline tumor scan, or (iii) have died due to disease progression before their first 
post-baseline tumor scan. The response evaluable analysis set will be used for sensitivity 
analyses of tumor response. 
3.2. 
Protocol Deviations  
Certain protocol deviations are key in that they may affect the ability to assess the safety and 
efficacy of study drug. Patients with key deviations will be excluded from the PP analysis set. 


 
 
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All patients who meet the definition of the ITT/mITT analysis sets will be included in the 
ITT/mITT analysis set regardless of these deviations. 
The criteria for inclusion in the PP set will be finalized and documented prior to locking data for 
the study. 
If a patient is randomized, but fails to receive treatment, the reason for not receiving treatment 
will be noted in the CSR. Any such patients who are not treated will be excluded from the mITT, 
safety, response evaluable, and PP analysis sets but will be included in the ITT and in the patient 
listings for the CSR.   
If the wrong treatment is administered to a patient, and the reason for the incorrect treatment is 
documented, this will be noted in the CSR and the patient’s data included in the Safety Analysis 
Set based on the actual treatment received. Additional protocol deviations will be reviewed in a 
data review meeting to classify protocol deviations as non-key or key, and to discuss the 
potential impact on statistical analysis.  
    






 
 
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5.1.1.2. 
Duration of Severe (Grade 4) Neutropenia (DSN)  
There will be two different strategies for assessing DSN in each cycle. Both strategies will be 
applied to derive the DSN, with strategy 1 considered as the primary, and strategy 2 being 
supportive sensitivity analyses. The DSN in Cycle 1 is considered for this primary endpoint.  
5.1.1.2.1 Strategy 1: Without Imputation of Missing ANC Values 
Within each cycle, the DSN (days) is defined as the number of days from the date of first ANC 
value of <0.5×109/L observed between start of cycle and end of cycle, to the date of first ANC 
value ≥ 0.5×109/L that meets the following criteria: (1) occurs after the ANC value of 
<0.5×109/L and (2) no other ANC values <0.5×109/L occur between this day and end of cycle. 
DSN is set to 0 in patients who did not experience SVN in a cycle. Any unscheduled data and the 
actual assessment date (rather than visit date) will be included in the derivation. The following 
rules will be applied in the calculation:    
(i) For a cycle where the SVN event does not resolve by end of the cycle, DSN will be assigned 
as above except the end date will be the end of cycle.   
(ii) For a cycle where the patient dies, during the SVN event, DSN will be assigned as above 
except the end date will be the date of death. 
(iii) For a cycle where the patient withdraws consent or is lost to follow-up during the SVN 
event, DSN will be assigned as above except the end date will be the date of the last ANC 
assessment prior to the end of study. 
5.1.1.2.2 Strategy 2: Without Imputation, Censoring Unresolved SVN 
Within each cycle, DSN (days) is defined as the number of days from the date of first ANC value 
of <0.5 x 109/L observed between start of cycle and end of cycle, to the date of first ANC value ≥ 
0.5 x 109/L that meets the following criteria: (1) occurs after the ANC value of <0.5 x 109/L and 
(2) no other ANC values <0.5 x 109/L occur between this day and end of cycle. The following 
censoring rules will be applied in the calculation:   
(iv) For a cycle where the SVN event does not resolve by end of the cycle, DSN will be assigned 
as above except the end date will be the earlier of end of cycle or date of last contact.   
(v) For a cycle where the patient dies, withdraws consent, or is lost to follow-up during the 
SVN event, DSN will be assigned as above except the end date will be the date of the last 
ANC assessment prior to the end of study.    
For the treatment period, the overall DSN (days) is the median value among the DSN (days) from 
all cycles. The following data handling conventions will apply: 
• 
For those patients where all event duration values are derived from cycles with censored 
data, the median value for that patient will be the median censored value. It will be a 
considered a censored value; 
• 
For those patients where a subset of event duration values are derived from cycles with 
censored data, the median value for that patient will be estimated using the Kaplan-Meier 
method. It will be considered as an observed value (i.e. no censored value); 


 
 
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• 
For those patients where the median event duration cannot be derived (e.g. ≤ 2 values), the 
longest event duration amongst all the cycles will be used regardless of censoring, but the 
corresponding censoring flag will be carried over for analysis.  
5.1.2. 
Key Secondary Endpoints 
5.1.2.1. 
Occurrence of RBC Transfusions 
Each RBC transfusion with a unique start date on/after 5 weeks on study during the treatment 
period will be defined as a separate event, and an additional set of all events occurring during the 
treatment period will be examined for sensitivity. 
Occurrence of a RBC transfusion during the treatment period is defined as a binary variable (Yes 
or No); Yes if total number of RBC transfusion ≥ 1 is observed, No for other scenarios.   
5.1.2.2. 
Occurrence of GCSF Administrations 
Administration of GCSF is collected throughout the treatment period. Those cycles where GCSF 
is administered concurrently will be identified by comparing the start and stop dates of each 
administration of GCSF to the start of cycle and end of cycle.  If any of the dates of 
administration of GCSF overlap with any dates between the start of cycle and end of cycle, that 
cycle will be considered as having GCSF administered. Data handling conventions for missing 
start and stop dates are described in Section 6.2.5. 
For the treatment period, the total number GCSF administrations is the number of cycles in 
which there is at least one GCSF dose administered. If a patient did not have any GCSF use, the 
value of 0 will be assigned to that patient. The number of cycles where GCSF was NOT given is 
calculated as total number of treatment cycles received – total number of cycles where GCSF 
was administered. 
Therefore, any occurrence of a GCSF administration during a cycle or the treatment period is 
defined as a binary variable (Yes or No); Yes if total number of cycles with GCSF administration 
≥ 1 is observed, No for other scenarios.    
5.1.2.3. 
Occurrence of Platelet Transfusions 
Each platelet transfusion with a unique start date during the treatment period will be defined as 
separate event. 
Occurrence of a platelet transfusion during the treatment period is defined as a binary variable 
(Yes or No); Yes if total number of platelet transfusion ≥ 1 is observed, No for other scenarios. 
5.1.2.4. 
All-Cause Dose Reductions (number of events) 
Dose (mg/m2) reductions are not permitted for trilaciclib. Dose reductions for carboplatin and 
gemcitabine are derived from changes in the planned dose on the dosing page.  
Up to 3 total dose reductions are allowed for carboplatin and gemcitabine, each will be counted 
as a unique event. For more details see Section 5.2.1.4 




 
 
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Time to first occurrence of a MAHE will be used as a sensitivity analysis in support of the total 
number of MAHE. It is defined as the first time to observe an event among all the components, 
starting from the date of randomization. Therefore, for a patient with presence of MAHE, time 
(months) to first occurrence of a MAHE will be the minimum among the 6 potentially derived 
duration (i.e. calculated as (date of first occurrence of a MAHE component event – date of 
randomization + 1)/30).  A patient without any MAHE will be censored at the end of the last 
cycle (i.e. last cycle of GC only or trilaciclib plus GC), death, end of study, or date of last 
contact, whichever is earlier. 
5.1.3.1.1 All-Cause Hospitalizations 
See Section 5.1.3.1. 
5.1.3.1.2 Prolonged severe (Grade 4) neutropenia (duration > 5 days) 
See Section 5.1.3.1. 
5.1.3.2. 
Best Overall Response, Duration of Response, and Progression-Free Survival  
For tumor assessment, all sites of disease will be assessed radiologically by CT or MRI at 
screening, every 6-12 weeks thereafter as determined by the protocol, until the date of (i) disease 
progression as defined by RECIST Version 1.1 (Eisenhauer et al, 2009); or (ii) withdrawal of 
consent; or (iii) receiving subsequent anti-cancer therapy, whichever is earlier. At each tumor 
assessment visit, the overall visit response by RECIST will be determined two ways: (1) derived 
programmatically using the information from target lesions (TL), non-target lesions (NTLs) and 
new lesions as entered into the eCRF, and (2) by the investigator and collected in the eCRF.  
For all patients, the RECIST tumor response data will be used to determine each patient’s visit 
response according to RECIST Version 1.1 and the best overall response (BOR).  
5.1.3.2.1 Target Lesions (TLs) 
Measurable disease is defined as having at least one measurable lesion which is  
• ≥10 mm in the longest diameter (LD) (except lymph nodes which must have short axis ≥15 
mm) with computed tomography (CT) or magnetic resonance imaging (MRI); or  
• ≥10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable); or 
• ≥ 20 mm by chest X-ray. 
Previously irradiated lesions (or lesions treated with loco-regional therapies) may be considered 
measurable if unequivocal growth of the lesion has been demonstrated. A patient can have a 
maximum of 5 measurable lesions representative of all involved organs (maximum of 2 lesions 
per organ, both the lymph node and skin will be considered as a single organ) recorded at 
baseline and these are referred to as target lesions. If more than one baseline scan is recorded 
then measurements from the one that is closest to start of treatment will be used to define the 
baseline sum of TLs. Table 6 gives definition of TL visit responses. 










 
 
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Objective response rate (ORR) will be calculated using two methods: 
Method #1: ORR will be calculated using a strict interpretation of RECIST Version 1.1. 
Objective response will be derived as no/yes (0/1) variable. Patients with a BOR of confirmed 
CR or PR will be assigned ‘Yes’. Patients not having a BOR of confirmed CR or PR will be 
assigned ‘No’. Hence, ORR is defined as the proportion of patients with objective response being 
“Yes”.  
Method #2: ORRUNCONFIRMED will be calculated using all responses regardless of confirmation.  
Objective response will be derived as no/yes (0/1) variable.  Patients with a BOR of confirmed 
CR, confirmed PR, unconfirmed CR or unconfirmed PR will be assigned “Yes”.  All patients 
with other BOR values will be assigned “No”.  Hence, ORRUNCONFIRMED is defined as the 
proportion of patients with objective response being “Yes”.  
Duration of Response (DOR) is the time between first response by RECIST Version 1.1 of CR or 
PR and the first date that progressive disease is documented by RECIST Version 1.1, or death. 
Patients who do not experience PD or death will be censored at the last tumor assessment date.  
Only those patients with confirmed responses will be included in this analysis. Censoring will 
follow the rules outlined below for PFS in Section 5.1.3.2.5.  
Clinical benefit rate (CBR) is defined as the proportion of patients with a BOR of confirmed CR, 
confirmed PR, or SD.  
ORR, ORRUNCONFIRMED, DOR and CBR will be calculated using the derived responses and 
investigator responses. 
5.1.3.2.5 Progression-free Survival  
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. 
Hence, progression-free survival (PFS) is defined as the time (months) from date of 
randomization until date of documented disease progression or death due to any cause, 
whichever comes first. More specifically, PFS will be determined using all the assessment data 
up until the last evaluable visit prior to or on the date of (i) disease progression as defined by 
RECIST Version 1.1 (Eisenhauer et al, 2009); or (ii) withdrawal of consent; or (iii) receiving 
subsequent anti-cancer therapy, whichever is earlier. 
PFS will be calculated using derived responses and progression by RECIST Version 1.1 
(whichever comes first) will be considered. 
Death, regardless of cause, is always considered as a PD event. The detailed censoring rules for 
the analysis are summarized in Table 11. 
 
 




 
 
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5.1.3.4. 
ANC Nadir by Cycle 
See table in Section 5 for the definition of cycle nadir. 
5.1.3.5. 
ANC, Platelet Count, Absolute Lymphocyte Counts (ALC), and Hemoglobin 
Change over Time  
For the hematologic parameters consisting of ANC, hemoglobin, platelet count, and ALC, the 
observed lab values in each windowed visit as detailed in Section 6.1.3 will be appropriately 
identified for further analysis. 
5.1.3.6. 
Occurrence of Erythropoiesis Stimulating Agent (ESA) Administrations 
Administration of ESAs is collected throughout the treatment period. Those cycles where ESAs 
are administered concurrently will be identified by comparing the start and stop dates of each 
ESA to the start of cycle and end of cycle.  If any of the dates of administration of an ESA 
overlap with any dates between the start of cycle and end of cycle, that cycle will be considered 
as having an ESA administered. Data handling conventions for missing start and stop dates are 
described in Section 6.2.5.   
For the treatment period, the total number of ESA administrations is the total number of cycles in 
which there is at least one ESA dose administered;. If a patient did not receive an ESA, the value 
of 0 will be assigned to that patient. The number of cycles where ESAs were NOT given is 
calculated as total number of treatment cycles received – total number of cycles where ESAs 
were administered. 
Therefore, any occurrence of an ESA administration during the treatment period is defined as a 
binary variable (Yes or No); Yes if total number of cycles with ESA administration ≥ 1 is 
observed, No for other scenarios.   
5.1.3.7. 
Occurrence of IV Antibiotic Uses 
IV antibiotic administration is collected with concomitant medications which are coded using 
World Health Organization Drug Dictionary (WHO-DD) Version Sep2017.  The criteria for 
identifying an IV antibiotic administration event is 
− If the Therapeutic subgroup from WHO-DD Version Sep2017 (i.e. TEXT2 for CODE2) 
takes value “ANTIBACTERIALS FOR SYSTEMIC USE”, and  
− The route of medication is “intravenous” or the route is “other” with the detailed 
specification as “IVPB”.  
Each IV antibiotic with a unique start date during the treatment period will be defined as a 
separate event. Data handling conventions for missing start and stop dates are described in 
Section 6.2.5. 
Occurrence of an IV antibiotics administration during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of IV antibiotics administration ≥ 1 is observed, No for 
other scenarios.     
5.1.3.8. 
Occurrence of Infection Serious Adverse Events (SAEs) 
Each infection SAE is captured in the electronic database. The event terms are coded using the 
MedDRA Version 20.1. The criterion for identifying the proper infection SAE records is as 


 
 
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follows: if the system organ class (SOC) from MedDRA takes value “INFECTIONS AND 
INFESTATIONS”, and the AE is a serious event.    
Each infection SAE with a unique start date during the treatment period will be defined as 
separate event. Data handling conventions for missing start and stop dates for AEs are described 
in Section 5.2.2.    
Any occurrence of an infection SAE during the treatment period is defined as a binary variable 
(Yes or No); Yes if total number of infection SAE events ≥ 1 is observed, No for other scenarios.  
5.1.3.9. 
Occurrence Febrile Neutropenia 
Each febrile neutropenia event is captured in AE data of electronic database, and “FEBRILE 
NEUTROPENIA” is a preferred term which can be used to identify the proper AE records. The 
event terms are coded using the MedDRA Version 20.1.     
Each febrile neutropenia event with a unique start date during the treatment period will be 
defined as a separate event. Data handling conventions for missing start and stop dates for AEs are 
described in Section 5.2.2.    
Any occurrence of a febrile neutropenia event during the treatment period is defined as a binary 
variable (Yes or No); Yes if total number of febrile neutropenia events ≥ 1 is observed, No for 
other scenarios.  
5.1.3.10. Occurrence of Grade 4 and Grade 3 or 4 Thrombocytopenia 
Hematologic toxicities events are defined as any cycle where any hematologic lab value occurs 
that meets the CTCAE toxicity grade criteria for ≥ Grade 3 and the value is treatment emergent. 
For details on which parameters are included and the definition of treatment emergent see 
Section 5.2.4. 
For the treatment period, the total number of hematologic toxicity events is the number of cycles 
in which there is at least one hematologic toxicity event. If a patient did not have any 
hematologic toxicity events, the value of 0 will be assigned to that patient. The number of cycles 
without hematologic toxicity events is calculated as total number of treatment cycles received – 
total number of cycles with a hematologic toxicity event. 
Therefore, any occurrence of a hematologic toxicity event during a cycle or the treatment period 
is defined as a binary variable (Yes or No); Yes if total number of cycles with a hematologic 
toxicity event ≥ 1 is observed, No for other scenarios. 
CCI
CCI


 
 
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5.2. 
Safety Endpoints  
5.2.1. 
Chemotherapy Exposure Endpoints 
5.2.1.1. 
Duration of Exposure 
Duration of exposure (days) = First dose date of study drug from the last cycle – first dose date 
of study drug + 21.  
5.2.1.2. 
Number of Cycles Received 
Patients are considered to have started a cycle if they have received at least one dose of any study 
drug (carboplatin, gemcitabine, or trilaciclib).  In addition to the numeric summary for the 
number of cycles, the number of cycles will be categorized as 1, 2, 3 or 4, 5 or 6, and > 6.  
CCI


















 
 
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point; if the count is 0, no percentage will be presented. Value of percentage less than 1% will be 
presented as “<1%.” Value of percentage less than 100% but ≥ 99.5% will be presented as 
“>99%.” 
6.1.2. 
Handling of Missing Data 
In general, the observed case (OC) data for a visit will consist of the actual observations recorded 
for the visit. If missing, the OC data will remain missing — no missing imputation will be 
performed. Safety analyses will be conducted on the OC data only. However, imputation of 
missing AE and concomitant medication onset and stop dates will be used to determine the status 
of each AE and the prior/concomitant status of each medication. Please refer to Section 5.2.2 for 
the method of imputation of missing AE onset and stop date and Section 6.2.5 for the method of 
imputation of missing concomitant onset and stop dates.  
For demographic and baseline characteristics, each variable will be analyzed and/or summarized 
using the available data. Patients with missing data will be excluded only from analyses for 
which data are not available. 
6.1.3. 
Visit Windowing 
It is expected that there will be a variation between patients in the actual number of study days 
from the start of administration of study drug within each cycle − defined as Day 1 − to the dates 
that the scheduled visits occur. To handle this, for tables and figures where data are grouped by 
visit, assessments will be categorized using visit windows based on study days (relative to the 
Day 1 of each cycle). The visit-window mapping is described in Table 18. Visit-based 
summaries will be based on the windowed visits. All data, whether or not within the visit 
windows, will be presented in patients listings.  
For windowed visits during the treatment cycles, if more than 1 visit occurs during a visit 
window, the visit closest to the scheduled day will be assigned to the windowed visit. If two 
visits are equidistant from the scheduled day, the later visit will be assigned to the windowed 
visit. If there are multiple assessments on the same day, the worst case will be used.  For the 
assigned follow-up visit, the last assessment in the window will be included in the summary. 
 
 
 
 
 
 
 
 
 
 
 




 
 
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Clinical Study Protocol G1T28-04                                     
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6.1.4. 
Adjustment for Covariates 
Prior to Protocol Amendment 3 Version 4.0, patient randomization was stratified by liver 
involvement (yes or no) and Eastern Cooperative Oncology Group (ECOG) status (0 or 1). With 
implementation of Amendment 3, the stratification factors were changed to number of prior lines 
of systemic therapy (0 vs. 1 or 2) and liver involvement. The number of prior lines of systemic 
therapy was retrospectively collected for those patients randomized prior to the Amendment 3. 
The efficacy analyses will use liver involvement and number of prior lines of therapy as 
covariates in statistical models. Where necessary, additional sensitivity analyses will be 
performed with liver involvement and ECOG status as covariates instead. Where not collected on 
the randomization page, values will be derived from other eCRF pages. 
6.2. 
Analysis Methods  
6.2.1. 
Patient Disposition 
A summary table will be generated to provide the following by study part, as appropriate: 
• 
Number of patients screened 
• 
Number and percentage of screening failures 
• 
Reason for screening failure 
• 
Number of patients dosed 
• 
Number of patients randomized 
• 
Number of patients randomized and not dosed 
A separate table will be presented to show the patients included in each analysis set and reason 
for exclusion from an analysis set. 
Patient status at treatment and study completion will be listed and summarized.  The listing will 
include whether patients discontinued from the treatment and the reasons for the discontinuation, 
along with the date of first and last dose and the date of completion or discontinuation from the 
treatment.  The same information will be provided for patients who discontinued from the study.  
The following summaries will be added to the disposition table: 
• 
End of treatment status (discontinued/ongoing for each study drug)   
• 
Reason for study drug discontinuation (for each study drug) 
• 
Number of patients going into Survival follow-up  
• 
Number and percentage of patients who discontinued the study 
• 
Reason for study discontinuation 
• 
Death and reason for death 
6.2.2. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics, such as age at informed consent date, age groups 
(18-65, >65-75, >75), gender, race, ethnicity, country, screening vital signs (body weight, height, 
BMI, BSA), ECOG status, prior lines of therapy, liver involvement, and smoking history (never 
smoker, former smoker and current smoker), will be summarized and listed.   


 
 
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6.2.3. 
Disease Characteristics 
Disease characteristics including breast cancer gene (BRCA) classification, histological 
classification of initial breast cancer diagnosis, stage of initial breast cancer diagnosis, stage of 
TNBC diagnosis, stage at time of enrollment, and brain scan results will be summarized and 
listed. Date of initial breast cancer diagnosis, and date of TNBC diagnosis will be listed only. 
6.2.4. 
Medical/Surgical History  
Medical history will be coded to SOC and PT using MedDRA Version 20.1. 
The number and percentage of randomized patients with any past medical/surgical history within 
each SOC and PT will be provided. A patient will only be counted once within a particular SOC 
(PT) even if he/she has multiple conditions/diseases in the same SOC (PT). The 
conditions/diseases from medical history are those conditions/diseases that stopped prior to the 
study entry. Additionally, breast cancer surgeries will be summarized separately. 
6.2.5. 
Concomitant Medications 
All medication verbatim terms collected will be coded to Anatomical Therapeutic Classification 
(ATC) and PT using the WHO-DD Version Sep2017.  
Prior medications are defined as those taken by the patient prior to the administration of study 
drug. Concomitant medications are defined as those taken by the patient at any time between the 
date of study drug administration and study completion/discontinuation. Medication with start 
date/time being partially or completely missing will be assumed to be concomitant if it cannot be 
definitely shown that the medication did not occur during the treatment period.   
Medications with onset/end dates that are partially/completely missing will be imputed as 
follows: 
(i) For onset date: 
− If only the day part of the medication onset date is missing and occurs in the same month and 
year as the first dose date of study drug, the date of first dose of study drug will be used as 
the onset date of the medication. Otherwise, the first day of the month will be used to 
complete the onset date of the medication;  
− If the day and month parts of medication onset date are missing and occur in the same year as 
the first dose of study drug, the date of the first dose of study drug will be used as the onset 
date of the medication. Otherwise, January 1st will be used to complete the onset date of the 
medication; 
− If the medication onset date is completely missing, the date of the first dose of study drug 
will be used as the onset date of the medication. 
(ii) For end date: 
− If only the day part of the medication end date is missing, the last day of the month will be 
used to complete the end date of the medication;  
− If the day and month parts of the medication end date are missing, December 31st will be 
used to complete the onset date of the medication; 
− If the medication end date is completely missing and the onset date of the medication occurs 
after the date of the first dose of study drug, the last date during the treatment period will be 


 
 
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used as the medication end date. Otherwise, the date of the first dose of study drug will be 
used as the medication end date.    
Concomitant medications will be summarized by presenting the number and percentage of 
patients by PT and ATC. Patients taking the same medication multiple times will only be 
counted once for that PT or ATC. Each summary will be ordered by descending order of 
incidence of ATC class and PT within each ATC class.  
All prior and concomitant medications will be presented in a patient listing. 
6.2.6. 
Prior and Subsequent Anti-Cancer Therapy 
The prior anti-cancer therapies, such as prior systemic anti-cancer therapy (Yes or No), prior 
breast cancer surgery (Yes or No), and prior radiotherapy (Yes or No), will be summarized and 
listed. All verbatim terms collected of prior and subsequent anti-cancer therapy will be coded to 
Anatomical Therapeutic Classification (ATC) and PT using the WHO-DD Version Sep2017.  
The prior and subsequent anti-cancer therapy will be summarized separately by presenting the 
number and percentage of patients by PT and ATC. Patients taking the same medication multiple 
times will only be counted once for that PT or ATC. Each summary will be ordered by 
descending order of incidence of ATC class and PT within each ATC class.  The data will be 
presented in a patient listing. 
For subsequent anti-cancer therapy, if the term contains the word “RADIATION” or 
‘RADIOTHERAPY’, the therapy will be classified to radiotherapy; it is classified as systemic 
anti-cancer therapy unless the therapy can be grouped to surgery.   The number and percentage 
of randomized patients receiving subsequent anti-cancer therapy will be provided by systemic 
anti-cancer therapy (by drug name and by line), radiotherapy, and surgery. All subsequent anti-
cancer therapies will be presented in a patient listing. 
6.2.7. 
Efficacy Analyses 
All the efficacy variables will be summarized using descriptive statistics by cycle or visit, with 
the supportive data provided in patient listings.  Data will be summarized using descriptive 
statistics and the between treatment comparison (trilaciclib days 1/2/8/9, trilaciclib days 1/8, and 
combined trilaciclib vs GC only), will be performed only for the primary and secondary endpoints 
outlined in Sections 5.1.1 – 5.1.3. The primary comparisons will be between trilaciclib days 
1/2/8/9 vs. GC only and will be built into the multiplicity adjustment described in Section 
6.2.7.1.4. Though relevant statistical tests will be conducted for other treatment comparisons, the 
information to be presented will be considered to be supportive. For these comparisons, all 
statistical tests will be conducted at a two-sided significance level of 5% unless otherwise 
specified. Where appropriate, model-based point estimates, together with their two-sided 95% 
CIs will be presented along with the two-sided p-value for the test unless otherwise specified.  
Graphical presentation of efficacy results will be performed as needed. 
Unless otherwise specified, all analyses for the efficacy endpoints will be conducted for the 
treatment period which is defined to be between the date of randomization and the end of the last 
cycle.  


 
 
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6.2.7.1 Primary and Key Secondary Efficacy Analyses 
6.2.7.1.1 Primary Efficacy Analyses 
The primary efficacy endpoint, occurrence of SVN, is a binary response variable (Yes, No). It 
will be summarized using descriptive statistics by treatment group and will be analyzed to 
compare trilaciclib and GC only using modified Poisson regression (Zou, 2004) to account for 
the variable duration of the treatment period for each patient. The model will include baseline 
ANC as a covariate, the stratification factors of prior lines of systemic therapy (0 vs. 1 or 2) and 
liver involvement (Yes vs No), and treatment as a fixed effect. The logarithm transformation of 
number of cycles will be included as an offset variable in the modeling. The two-sided p-value, 
adjusted rate ratio (aRR) (trilaciclib vs GC only) and its 95% CIs will be presented. 
For the other primary efficacy endpoint, DSN in Cycle 1 based on Strategy 1 in Section 
5.1.1.2.1, a two-sided p-value will be calculated for the nonparametric analysis of covariance 
(ANCOVA) (Stokes 2012). The nonparametric ANCOVA will include study baseline ANC 
value as covariate, stratification factors of lines of systemic therapy (0 vs. 1 or 2) and liver 
involvement (Yes vs No), and treatment as a fixed effect. Along with the descriptive statistics, 
the mean difference and Hodges-Lehmann estimate of median difference between the two 
treatment groups, together with its 95% CIs will be provided. Additionally, DSN for each cycle 
will be presented using descriptive statistics. 
6.2.7.1.2 Key Secondary Efficacy Analyses 
Occurrence of RBC transfusions on/after 5 weeks on study is a binary variable and will be 
summarized using the same method for occurrence of SVN described in Section 6.2.7.1.1 except 
baseline HGB will be used as a covariate instead of baseline ANC in the modified Poisson 
model. Also, the offset will be the logarithm transformation of duration of treatment period 
divided by 7 (i.e. week) instead of number of cycles, and. An additional sensitivity analysis will 
look all transfusions during the treatment period, and all transfusions with a subset of subjects 
completing at least 1 cycle. 
Occurrence of GCSF administration is a binary variable and will be summarized using the same 
method for occurrence of SVN described in Section 6.2.7.1.1.  
Occurrence of all-cause dose reductions is a binary variable and will be summarized using the 
same method for occurrence of SVN described in Section 6.2.7.1.1.  
Occurrence of platelet transfusion is a binary variable and will be summarized using the same 
method for occurrence of SVN described in Section 6.2.7.1.1 except baseline platelet count will 
be used as a covariate instead of baseline ANC in the modified Poisson model. Also, the offset 
will be the logarithm transformation of duration of treatment period divided by 7 (i.e. week) 
instead of number of cycles. 
6.2.7.1.3 Key Secondary OS Analyses 
OS will be summarized using Kaplan-Meier method, and the descriptive statistics of median, 
25% and 75% percentiles along with their 95% CIs will be calculated. It will be based on the ITT 
analysis set. The supportive data listings will also be provided. 
In addition to the quartile summary from Kaplan-Meier method, Kaplan-Meier estimates will be 
provided for the survival rates at 3, 6, 9, and 12 months along with their 95% CIs. 


 
 
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Additionally, a comparison will be conducted between trilaciclib and GC only. The two-sided p-
value from a Cox proportional hazard model will be presented, the model includes treatment and 
stratification factors as fixed effects. The HR between the two treatment groups, together with its 
95% CIs will be presented. 
6.2.7.1.4 Multiplicity Adjustments 
The clinical trial evaluates the objectives defined in terms of the comparison of Group 3 (GC + 
Trilaciclib Day 1/2 and 8/9) to Group 1 (GC therapy alone) on the primary and key secondary 
myelosuppression efficacy endpoints in Sections 5.1.1 and 5.1.2. The resulting multiplicity 
problem include the following six hypotheses of no effect: 
• Hypothesis 𝐻1. Comparison of Group 3 versus Group 1 for duration of severe (Grade 
4) neutropenia in Cycle 1. 
• Hypothesis 𝐻2. Comparison of Group 3 versus Group 1 for occurrence of severe 
(Grade 4) neutropenia. 
• Hypothesis 𝐻3. Comparison of Group 3 versus Group 1 for all-cause dose reductions 
in the MAHE composite. 
• Hypothesis 𝐻4. Comparison of Group 3 versus Group 1 for occurrence of RBC 
transfusions on/after Week 5 on study. 
• Hypothesis 𝐻5. Comparison of Group 3 versus Group 1 for occurrence of G-CSF 
administration. 
• Hypothesis 𝐻6. Comparison of Group 3 versus Group 1 for occurrence of platelet 
transfusions. 
A Hochberg-based gatekeeping procedure will be utilized to control the global familywise error 
rate across the multiple null hypotheses in the strong sense at a 1-sided α=0.025 level. The one-
sided 𝑝-values for these comparisons will be used for the multiple test procedure, and the raw 
and adjusted 1-sided 𝑝-values will be provided in the summary.  
Gatekeeping procedure with logical restrictions 
A Hochberg-based gatekeeping procedure satisfies the positive dependence condition given the 
1-sided setting. The procedure is built using the mixture methodology developed in Dmitrienko 
and Tamhane (2011) and accounts for the logical restrictions among the six hypotheses displayed 
in Figure 1 by performing multiplicity adjustments in three steps. The logical restrictions can be 
achieved by defining the parallel set and serial set for each individual hypothesis based the tree-
structured procedure introduced by Dmitrienko et al (2007).  
• Step 1. The Group 3 versus Group 1 comparisons for Family 1 (hypothesis 𝐻1) is performed 
using a truncated version of the Hochberg procedure. The truncation parameter γ is set to 0.  
• Step 2. The Group 3 versus Group 1 comparisons for Family 2 (hypothesis 𝐻2) is performed 
using a truncated version of the Hochberg procedure if 𝐻1 is significant in Step 1. The 
truncation parameter γ is set to 0.   
• Step 3. The Group 3 versus Group 1 comparisons for Family 3 (hypotheses 𝐻3, 𝐻4, 𝐻5, and 
𝐻6) are performed using the regular Hochberg test if 𝐻2 is significant in Step 2. 


 
 
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Clinical Study Protocol G1T28-04                                     
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Figure 1 Graphical Display of the Hochberg-based Gatekeeping Procedure 
 
The logical restrictions in the Step 1 and Step 2 contain only one single hypothesis, and the Step 
3 has three hypotheses 𝐻3, 𝐻4, 𝐻5, though the testing procedure can be broadly considered as a 
fixed sequence procedure, its implementation can be performed through the framework of 
Hochberg-based gatekeeping procedure as described in detail below. 
The regular Hochberg test is defined in Dmitrienko et al. (2009) and the truncated Hochberg test 
is defined in Dmitrienko, Tamhane and Wiens (2008). The decision rules used in the regular and 
truncated Hochberg tests will be detailed in the following. In general terms, the truncated version 
of the Hochberg test is defined as a convex combination of the regular Hochberg and Bonferroni 
tests. An important parameter of the truncated Hochberg test is the truncation parameter γ which 
ranges between 0 and 1. If the truncation parameter γ is set to 0, the truncated Hochberg test 
simplifies to the Bonferroni test. On the other hand, if the truncation parameter γ is set to 1, the 
truncated Hochberg test is identical to the regular Hochberg test. The truncated Hochberg test 
satisfies the separability condition (Dmitrienko, Tamhane and Wiens, 2008) if the truncation 
parameter γ is strictly less than 1. This condition ensures that in each step of the testing algorithm 
the error rate can be transferred to the next step provided at least one Group 3 versus Group 1 
comparison is significant in the current step without inflating the overall type I error rate (Huque, 
2016; FDA, 2017). 
Testing algorithm 
This section describes the implementation of the Hochberg-based gatekeeping procedure. The 
testing algorithm relies on the general approach to defining multistage gatekeeping procedures 
based on mixtures of multiple tests proposed in Dmitrienko and Tamhane (2011). 
Decision rules 
The aforementioned 6 hypotheses are grouped into 3 families: 


 
 
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• Family 1 (𝐹1) includes the hypotheses 𝐻1. 
• Family 2 (𝐹2) includes the hypothesis 𝐻2. 
• Family 3 (𝐹3) includes the hypotheses 𝐻3, 𝐻4, 𝐻5, and 𝐻6. 
Using more compact notation, the families are defined as follows: 
𝐹1 = {𝐻𝑖, 𝑖∈𝑁1},  𝐹2 = {𝐻𝑖, 𝑖∈𝑁2},  𝐹3 = {𝐻𝑖, 𝑖∈𝑁3}. 
where the index sets are defined as 𝑁1 = {1}, 𝑁2 = {2}, 𝑁3 = {3, 4, 5, 6}. Let 𝑡𝑖 and 𝑝𝑖 denote 
the test statistic and 1-sided p-values associated with the hypotheses, respectively. Let 𝛼 denote 
the global familywise error rate, i.e., one-sided 𝛼= 0.025. 
Consider the closed family associated with Families 1, 2 and 3, i.e., a family of all non-empty 
intersections of the twelve hypotheses. Each intersection will be identified by an index set 
𝐼⊆𝑁 = {1, . . . ,6} 
(note that the empty set is excluded). For example, the index vector 𝐼= {1, 2, 5} corresponds to 
the intersection of the hypotheses 𝐻1, 𝐻2, and 𝐻5. 
To construct the Hochberg-based gatekeeping procedure that controls the global familywise error 
rate in the strong sense at an 𝛼 level, an 𝛼-level test needs to be defined for each intersection in 
the closed family. The multiple test and associated 𝑝-value for an intersection are computed in 
two steps. 
Step 1: Define 𝒑-values for subset intersections 
Consider an intersection corresponding to the index set 𝐼⊆𝑁 and define the index sets 𝐼𝑘= 𝐼∩
𝑁𝑘, 𝑘= 1, 2, 3. The 𝑝-values for the index sets 𝐼1, 𝐼2, and 𝐼3 are computed as follows: 
Let 𝑛1 denote the number of hypotheses included in 𝐼1 and let 𝑚1 = 𝑛1. If 𝑛1 > 0, the truncated 
Hochbergp-value is defined using the ordered 𝑝-values associated with the hypotheses included 
in the index set 𝐼1, denoted by  
𝑝1(1) ≤⋯≤𝑝1(𝑚1) 
The truncated Hochberg 𝑝-value for the index set 𝐼1 is given by 
𝑝(𝐼1) =
min
𝑖=1,⋯,𝑚1
𝑝1(𝑖)
𝛾1
𝑚1 −𝑖+ 1 + (1 −𝛾1)
 
Here 𝛾1 is the pre-specified truncation parameter in Family 1. Choosing a larger value of 𝛾1 
improves the power of comparisons in Family 1, and 𝛾1 is set to 0. 
Further, let 𝑛2 denote the number of hypotheses included in the index set 𝐼2. If 𝑛2 > 0, consider 
the hypotheses in the index set 𝐼2 and remove the hypotheses that are not consistent with the 
logical restrictions defined in Figure 1. Let 𝑚2 denote the number of hypotheses remaining in the 
index set 𝐼2 after this logical restriction operation. If 𝑚2 > 0, let  
𝑝2(1) ≤⋯≤𝑝2(𝑚2) 
denote the ordered 𝑝-values for the hypotheses remaining in the index set 𝐼2. The truncated 
Hochberg 𝑝-value for 𝐼2 is given by 


 
 
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𝑝(𝐼2) =
min
𝑖=1,⋯,𝑚2
𝑝2(𝑖)
𝛾2
𝑚2 −𝑖+ 1 + (1 −𝛾1)
 
where 𝛾2 is the pre-specified truncation parameter in Family 2, which plays the same role as 𝛾1 
in Family 1, and 𝛾2 is set to 0. 
Finally, let 𝑛3 denote the number of hypotheses included in 𝐼3. If 𝑛3 > 0, remove the hypotheses 
that are not consistent with the logical restrictions defined in Figure 1. Let 𝑚3 denote the number 
of hypotheses remaining in the index set 𝐼3 after this logical restriction operation. If 𝑚3 > 0, let  
𝑝3(1) ≤⋯≤𝑝3(𝑚3) 
denote the ordered 𝑝-values for the hypotheses remaining in the index set 𝐼3. The Hochberg 𝑝-
value for 𝐼3 is given by 
𝑝(𝐼3) =
min
𝑖=1,⋯,𝑚3
𝑝3(𝑖)
1
𝑚3 −𝑖+ 1
 
Step 2: Define overall 𝒑-value 
The overall 𝑝-value for the intersection corresponding to the index set 𝐼 is computed by 
combining the 𝑝-values associated with the index sets 𝐼1, 𝐼2, and 𝐼3. Consider the following three 
scenarios: 
• If 𝑛1 > 0, the overall 𝑝-value is found using the following mixing function: 
𝑝(𝐼) = min (𝑝(𝐼1)
𝑏1
, 𝑝(𝐼2)
𝑏2
, 𝑝(𝐼3)
𝑏3
)  
where 𝑏1 = 1,  𝑏2 = 𝑏1(1 −𝑓1 ), 𝑏3 = 𝑏2(1 −𝑓2 ) and 𝑓1 and 𝑓2 are computed based on the 
error rate functions of the truncated Hochberg tests used in Families 1 and 2. These quantities are 
defined below. 
• If 𝑛1 = 0 and 𝑛2 > 0, the overall 𝑝-value is given by 
𝑝(𝐼) = min (𝑝(𝐼2)
𝑏2
, 𝑝(𝐼3)
𝑏3
)  
where  𝑏2 = 1, 𝑏3 = 𝑏2(1 −𝑓2 ). 
• If 𝑛1 = 0, 𝑛2 = 0 and 𝑛3 > 0, the overall 𝑝-value is given by 
𝑝(𝐼) = 𝑝(𝐼3)
𝑏3
 
where 𝑏3 = 1. 
The error rate function of the truncated Hochberg test with the truncation parameter 𝛾𝑘 for 
testing an intersection corresponding to the index set 𝐼𝑘, 𝑘= 1, 2, is defined as 
𝑒𝑘(𝐼𝑘) = 𝑃[𝑝(𝐼𝑘) ≤𝛼] 
and 𝑓𝑘= 𝑒𝑘(𝐼𝑘)/𝛼, 𝑘= 1, 2. It is shown in Brechenmacher et al. (2011) that 


 
 
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𝑒𝑘(𝐼𝑘) = [𝛾𝑘+ (1 −𝛾𝑘)|𝐼𝑘|/𝑛𝑘]𝛼 
if the index set 𝐼𝑘 is non-empty and 𝑒𝑘(𝐼𝑘) = 0 the index set 𝐼𝑘 is empty. Here |𝐼𝑘| denotes the 
number of hypotheses included in the index set 𝐼𝑘.  
As shown in Dmitrienko and Tamhane (2011), the resulting test for the intersection 
corresponding to the index set 𝐼 is an 𝛼-level test. This implies that the Hochberg-based 
gatekeeping procedure controls the global familywise error rate in the strong sense at a one-sided 
𝛼= 0.025. 
Multiplicity-adjusted p-values 
Multiplicity-adjusted 𝑝-values for the Hochberg-based gatekeeping procedure are computed 
using the closure principle. For each hypothesis, the adjusted 𝑝-value is defined as the maximum 
over the 𝑝-values associated with the intersections in the closed family that include the 
hypothesis of interest. For example, the adjusted 𝑝-value for 𝐻2 is the maximum over the 𝑝-
values for intersections containing 𝐻2. The calculations are performed using the decision matrix 
algorithm, see Dmitrienko and Tamhane (2011).  
Regular and truncated Hochberg tests 
Consider a general problem of testing m null hypotheses denoted by 𝐻1, . . . , 𝐻𝑚. Let 𝑝1, . . . , 𝑝𝑚 
denote the associated raw p-values. Further, let 𝑝(1) < ⋯< 𝑝(𝑚) denote the ordered p-values and 
𝐻(1) < ⋯< 𝐻(𝑚) denote the hypotheses corresponding to the ordered p-values. 
The regular Hochberg test is based on the following testing algorithm: 
• Step 1: If 𝑝(𝑚) > 𝛼, accept 𝐻(𝑚) and go to Step 2, otherwise reject all null hypotheses 
and stop. 
• Step 𝑖= 2, . . . , 𝑚−1: If 𝑝(𝑚−𝑖+1) > 𝛼/𝑖, accept 𝐻(𝑚−𝑖+1) and go to Step 𝑖+ 1, 
otherwise reject all remaining null hypotheses and stop. 
• Step 𝑚: If 𝑝(1) > 𝛼/𝑚, accept 𝐻(1), otherwise reject 𝐻(1)· 
The truncated Hochberg test with the truncation parameter 𝛾 is based on the following testing 
algorithm: 
• Step 1: If 𝑝(𝑚) > [𝛾+ (1 −𝛾)/𝑚]𝛼, accept 𝐻(𝑚) and go to Step 2, otherwise reject all 
null hypotheses and stop. 
• Step 𝑖= 2, . . . , 𝑚−1: If 𝑝(𝑚−𝑖+1) > [𝛾/𝑖+ (1 −𝛾)/𝑚]𝛼, accept 𝐻(𝑚−𝑖+1) and go to 
Step 𝑖+ 1, otherwise reject all remaining null hypotheses and stop. 
• Step 𝑚: If 𝑝(1) > 𝛼/𝑚, accept 𝐻(1), otherwise reject 𝐻(1) 
6.2.7.1.5 Robustness of Primary and Key Secondary Efficacy Analyses 
A binary response variable (Yes, No) will be analyzed to compare trilaciclib and GC only using 
stratum-adjusted method to account for the liver involvement (Yes or No) and number of prior 
lines of therapy (0, 1-2) as the stratification factor. The adjusted proportion difference (trilaciclib 
vs GC only) and its 95% CIs will be calculated using Cochran-Mantel-Haenszel (CMH) weight 
outlined in Kim et al. 2013. The two-sided p-value will be calculated using stratified exact CMH 


 
 
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method. Additionally, three sets of sensitivity analysis will be conducted to evaluate the 
robustness of the results from primary or key secondary analyses for a binary response variable 
(Yes, No). 
(i) 
For patients who die during the treatment period without experiencing an event, Yes will 
be assigned to the variable.  
(ii) After the imputation from (i), a worst-comparison analysis will be done to establish a 
stringent boundary of the treatment effect. Patients who die during the treatment period will 
still be set to Yes, and patients who discontinue the study prior to the July 30, 2018 data 
cutoff date without experiencing an event will then be imputed. If the patient is from the 
GC only group, No will be assigned to the variables, Yes will be assigned to the trilaciclib 
groups.  
(iii) After the imputation from (i), a tipping-point analysis (Yan et al,. 2009) will be performed 
by assigning the response to the variable for patients who discontinue the study early 
during the treatment period without experiencing an event. 
The tipping-point analysis assumes all possible combinations of numbers of Yes and No for 
the missing responses (defined as patients without an event who have discontinued the 
study prior to the July 30, 2018 data cutoff date) in the trilaciclib and GC only groups. For 
example, let nt be the number of randomized trilaciclib patients with missing response and 
nc be the number of randomized GC only patients with missing responses. For the 
trilaciclib patients with missing values, there are nt + 1 possible assumptions for number of 
No (i.e. 0, 1, 2, …, to nt); for the GC only patients with missing values, there are nc + 1 
possible assumptions for number of No.  Therefore, there are total of (nt + 1) × (nc + 1) 
possible combination of assumptions for number of No and Yes for the trilaciclib and GC 
only patients with missing responses. The un-stratified exact CMH method will be 
performed on the available responses with each of these (nt + 1) × (nc + 1) assumptions and 
will be summarized. A figure will be presented with points representing each possible 
combination where the significant p-value ‘tips’ to greater than a one-sided 0.025, which 
would represent a change in the study conclusions. Clinical justification will be provided to 
evaluate whether the assumption is plausible.   
Each of the analyses will be repeated using two additional distinct data sets to evaluate the 
confounding effect of GCSF administration: inclusion of only those patients or cycles who had 
concurrent GCSF administration; and inclusion of only those patients or cycles who did NOT 
have concurrent GCSF administration.  The “with” and “without” GCSF analyses are subsets of 
the total number of patients or cycles. 
Each of the analyses will be similarly repeated for subsets of cycles with and without skipped 
doses. 
DSN, Strategy 2 (refer to Section 5.1.1.2.2) endpoint will be summarized using Kaplan-Meier 
method, and the descriptive statistics of median, 25% and 75% percentiles along with their 95% 
CIs will be calculated for. Additionally, DSN for each cycle will be presented using descriptive 
statistics. 
In addition to the summary from Kaplan-Meier method, the two-sided p-value will be obtained 
from the stratified Kaplan-Meier method to account for the stratification factors. The hazard ratio 
(HR) between the two treatments (trilaciclib vs GC only), together with its 95% CIs will be 


 
 
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calculated from a Cox proportional hazard model in which treatment and the stratification factors 
will be included as fixed effects. 
The primary and key secondary efficacy endpoints are based on the ITT analysis set, and the 
analysis will be repeated for the mITT analysis set and PP analysis set. 
6.2.7.2 Supportive Secondary Efficacy Analyses 
6.2.7.2.1 Analysis of Total Number of MAHE 
The total number of MAHE in Section 5.1.2.15.1.3.1 will be analyzed to compare trilaciclib and 
GC only using a negative binomial regression model to account for the potential over-dispersion. 
The model includes the stratification factors of prior lines of systemic therapy (0 vs. 1 or 2) and 
liver involvement (Yes vs No), and treatment as a fixed effect. The logarithm transformation of 
duration of treatment period divided by 7 (i.e. week) will be included as an offset variable in the 
modeling. The two -sided p-value, aRR (trilaciclib vs GC only) and its 95% CIs will be 
presented. 
The total number of MAHE will be summarized descriptively, along with the weeks of duration, 
and the event rate per week (calculated as the total number of events/ duration of treatment 
period divided by 7 [i.e. week]). The cumulative incidence of events during the treatment period 
will be summarized and presented graphically in three-week intervals. 
The total number of individual MAHE components (specified in Table 5) will be summarized 
similarly. 
Time-to-first MAHE endpoints (overall and individually) in Section 5.1.3.1 will be summarized 
similar to DSN, Strategy 2 as described in Section 6.2.7.1.5. A graphical display of cumulative 
incidence will also be presented. 
The MAHE endpoints are based on the ITT analysis set, and the analysis will be repeated for the 
mITT analysis set and PP analysis set. 
6.2.7.2.2 Analyses of Objective Response 
The patients in each category of TPR according to the investigator tumor assessment (CR, PR, 
SD, PD, or NE) will be presented in a data listing. The number and percentage of patients in each 
category of BOR (Confirmed CR, Confirmed PR, SD, PD, or NE), ORR, ORRUNCONFIRMED and 
CBR according to the investigator tumor assessment (Confirmed CR, Confirmed PR, SD, PD, or 
NE) will be summarized. Detailed information of deriving tumor relevant responses is provided 
in Section 5.1.3.2.4.    
Similar analyses will be repeated based on the derived responses according to the RECIST 
Version 1.1.  
Estimates of response rate, along with its associated exact 95% two-sided CIs using Clopper-
Pearson method will be computed for ORR and CBR within each treatment group.  
The binary endpoint (Yes, No) of ORR for the two treatments (trilaciclib and GC only) will be 
analyzed to compare trilaciclib and GC only using stratum-adjusted method to account for the 
stratification factors. The adjusted proportion difference (trilaciclib vs GC only) and its 95% CIs 
will be calculated using CMH weight outlined in Kim et al. 2013. The two-sided p-value will be 
calculated using stratified exact CMH method.   


 
 
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The analyses are based on the response evaluable analysis set. The supportive data listings will 
also be provided.  
6.2.7.2.3 Analyses of DOR and PFS 
The analysis method as described in Section 6.2.7.1.36.2.7.1.5 for OS will be applied to PFS 
(derived, and derived with clinical progression) and DOR (investigator and derived), except 
DOR will exclude the Kaplan-Meier estimates for the survival rates at 3, 6, 9, and 12 months as 
well as the Cox proportional hazard model. 
For DOR, the analysis is based on the response evaluable analysis set; for PFS the analysis will 
be based on the ITT. The supportive data listings will also be provided. For the PFS, the derived 
endpoint based on only radiologic progression will be considered as the primary, and the derived 
endpoint based on both radiologic and clinical progression will be considered as supportive.  
6.2.7.2.4 Analyses of Hematology Lab Values 
For the endpoints specified in Section 5.1.3.4 and 5.1.3.5, in addition to descriptive statistics 
summary, graphical displays will be provided to facilitate evaluation of trends in the change in a 
given variable over time. Moreover, each of the ANC change over time analysis (i.e. observed 
value at windowed visit and cycle nadir) specified above will be done using three distinct data 
sets to evaluate the confounding effect of GCSF administration: all patients or cycles regardless 
of GCSF administration; inclusion of only those patients or cycles who had concurrent GCSF 
administration; and inclusion of only those patients or cycles who did NOT have concurrent 
GCSF administration.  The “with” and “without” GCSF analyses are subsets of the total number 
of patients or cycles.  
6.2.7.2.5 Analyses of Other Binary Efficacy Endpoints 
The following binary response variables (Yes, No) will be analyzed using the same method for 
occurrence of SVN except baseline ANC will not be a covariate in the modified Poisson model. 
See Section 6.2.7.1.1: 
• Occurrence of a Grade 3 or 4 hematologic toxicity during the treatment period (refer to 
Section 5.1.3.3); 
• Occurrence of an ESA administration during the treatment period (refer to Section 5.1.3.6); 
• Occurrence of an IV antibiotic administration during the treatment period (refer to Section 
5.1.3.7); The offset in the modified Poisson model will be the logarithm transformation of 
duration of treatment period divided by 7 (i.e. week) instead of number of cycles. 
Additionally, total number of IV antibiotic administrations will be summarized descriptively. 
• Occurrence of an infection SAE during the treatment period (refer to Section 5.1.3.8); The 
offset in the modified Poisson model will be the logarithm transformation of duration of 
treatment period divided by 7 (i.e. week) instead of number of cycles. Additionally total 
number of infection SAEs will be summarized descriptively. 
• Occurrence of a Grade 4 and Grade 3 or 4 thrombocytopenia during the treatment period 
(refer to Section 5.1.3.10); 


 
 
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6.2.8. 
Safety Analyses 
All safety analyses will be based on the safety analysis set, as defined in Section 3.1.3.  
Descriptive statistics will be used to summarize the safety outcomes. The continuous safety 
variables will be summarized at each visit including end of each cycle (the last non-missing 
assessment during the cycle), end of treatment (the last non-missing assessment during the 
treatment period), and end of study (the last non-missing assessment during the whole study), if 
applicable. No inferential analyses of safety data are planned unless otherwise specified. 
6.2.8.1. 
Chemotherapy Exposure and Compliance Analyses 
Duration on treatment and number of cycles will be summarized by treatment. For each study 
drug, the dosing endpoints described in Section 5.2.1 will be summarized by treatment.   
Dose modifications will be summarized for each study drug (gemcitabine, carboplatin or 
trilaciclib) including the following: 
• Number of cycles received; 
• Number of skipped doses; 
• Number of dose reductions; 
• Number of dose interruptions;  
• Number of patients with skipped doses;  
• Number of patients with dose reductions; 
• Number of patients with dose interruptions. 
The number of cycles delayed, the number and percentage of patients experiencing a treatment 
cycle delay, and reason for cycle delay will be summarized by treatment. The study dosing 
records and the derived dosing endpoints will be listed. 
6.2.8.2. 
Adverse Events 
Number and incidence rates of AEs will be summarized by SOC and/or PT for the following 
categories of TEAEs: all AEs, SAEs, AEs leading to death, and AEs leading to study drug 
discontinuation or study withdrawal. Patients with more than one occurrence of the same SOC 
(PT) will be counted only once within the SOC (PT) categorization.   
AEs will also be summarized similarly by CTCAE grade and relationship to any study drug 
(gemcitabine, carboplatin or trilaciclib), and by relationship to each drug. Should a patient 
experience more than one occurrence of the same SOC (PT), the patient’s worst occurrence 
(worst grade/most related causality) will be retained in the tabulation.    
All AEs, including AEs that started prior to the study medication, will be presented in patient 
listings. In addition, separate listings of all SAEs, AEs leading to death, drug-related AEs, and 
AEs leading to study drug discontinuation or study withdrawal will be provided. 
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The criteria for identifying infusion related reaction AEs or hematologic toxicity AEs are 
described in Section 5.2.2. A summary table showing the incidence of each category of AEs 
related to infusion and related to hematologic toxicity will be presented along with its supportive 
data listing.     
6.2.8.3. 
Laboratory Evaluations 
For hematology and clinical chemistry labs, the observed values and change from baseline will 
be summarized separately for cycles with and without a skipped dose for each visit during the 
treatment period using descriptive statistics.   
Toxicities for clinical labs will be characterized according to CTCAE, Version 4.03 (Table A-1 
of Appendix when possible), and the frequency and percentage of patients with each CTCAE 
grade for each visit (separately by cycles with and without a skipped dose) during the treatment 
period will be described. Moreover, any occurrence of grade 3 or grade 4 during the treatment 
period will be summarized, and shift in grade from baseline to the worst post-baseline value will 
be summarized. Both the scheduled and unscheduled assessments will be used to identify the 
worst post-baseline values. 
Listings of all laboratory data with a flag for cycles with a skipped dose, normal reference 
ranges, and CTCAE grades (when possible) will be provided.    
6.2.8.4. 
Vital Signs 
For vital sign parameters (Systolic Blood Pressure, Diastolic Blood Pressure, Pulse Rate, 
Temperature, and Weight) the observed values and change from baseline will be summarized 
using descriptive statistics at each visit during the treatment period.  
Additionally, the frequency and percentage of patients with any potentially clinically significant 
findings (defined in Table 14) during the treatment period will be presented. A listing of all vital 
sign data will be provided.  
6.2.8.5. 
Performance Status  
Descriptive statistics will be presented for ECOG score for the observed values and change from 
baseline. A listing of ECOG score for all patients will be provided.   
6.2.8.6. 
Physical Examination 
A listing of screening physical examination findings for all patients will be provided (where 
available). 
6.2.8.7. 
ECG 
Descriptive statistics will be presented for each ECG parameter for the observed values and 
change from baseline to post baseline. A listing of all ECG data will be provided.  
The criteria for potentially clinically significant findings are defined in Table 16. The frequency 
and percentage of patients with any potentially clinically significant findings during the 
treatment period will be presented. The supportive data will be provided in patient data listings.  
6.2.9. 
Subgroup Analyses 
The PFS, OS, and MAHE will be examined in the following subgroups: 


 
 
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− Age group (ages <65; >65). 
− Liver involvement (Yes; No). 
− ECOG performance status (0; 1). 
− Prior lines of therapy (0; 1-2). 
− Race (Caucasian; non-Caucasian). 
− Region (US; Ex-US). 
− BRCA classification (Positive; Unknown)  
− Histological classification (TNBC; Acquired TNBC)  
 Descriptive statistics by treatment group will be presented for each subgroup of patients.  
Additional subgroups or endpoints may be identified and explored.  
6.2.10. 
Pharmacokinetic Analysis 
The PK analysis for a subset of patients will be documented separately and is not covered in this 
SAP. 
6.2.12. 
Planned Analysis  
The final myelosuppression analysis will be conducted after all patients have had the opportunity 
to receive at least 12 weeks of treatment. All study data collected through the time of the final 
myelosuppression analysis data cut will be included. This includes, but is not limited to the final 
myelosuppression analysis, interim ORR analysis based on investigator assessment, and interim 
PFS/OS analysis. 
The time of analysis with at least 80% of patients having experienced a progression will be 
considered to be final PFS analysis. Patients will be followed for survival until at least 70% of 
the patients have died, and a final OS analysis will be done then. Additional exploratory analyses 
of OS/PFS may between the final myelosuppression analysis and study completion. Reported 
results, with the exception of the myelosuppression analyses, will be cumulative in nature, 
including all data collected during the entire study; the myelosuppression analyses will be 
complete at the final analysis and no additional data will be expected. 
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7. 
CHANGE FROM THE PROTOCOL 
The timing of the final analysis, analysis sets, and endpoints were updated based on scientific 
advice, regulatory guidance, and feedback on other trilaciclib studies. The endpoints and 
analyses listed below are based on the Statistics Section in the Protocol Amendment 3, dated 31 
August 2017. The list displays the endpoints and analyses which are removed from the initial 
analysis and are therefore not described in the SAP.  
Protocol Section 13.3.1 (Efficacy Endpoints): 
• Hematologic kinetic endpoints: 
o Change and percent change in hematologic parameter values from predose for a 
particular cycle to the end of that cycle 
o Change and percent change in hematologic parameter values from predose for a 
particular cycle to nadir for that cycle 
o Rate of change in hematologic parameter values from predose for a particular cycle to 
nadir for that cycle 
o Change and percent change in hematologic parameter values from nadir for a 
particular cycle to the end of that cycle 
o Rate of change in hematologic parameter values from nadir for a particular cycle to 
the end of that cycle 
o Area under the curve in hematologic parameter values from predose for a particular 
cycle to the end of that cycle 
o Area under the curve in hematologic parameters from predose for a particular cycle to 
nadir for that cycle 
o Area under the curve in hematologic parameter values from nadir for a particular 
cycle to the end of that cycle 
o Time to hematologic parameter value nadir by cycle 
o Time to return to predose hematologic parameter values by cycle 
o Proportion of patients with a return to predose hematologic parameter values by cycle 
• Hematologic toxicity endpoints: 
o Proportion of patients with a hematologic toxicity recovery by cycle. 
o Time to hematologic toxicity recovery by cycle 
Protocol Section 13.3.2.1 (Analysis of Hematologic Parameter Kinetic Endpoints) 
• Additional tabulations for each cycle of treatment in maximum postnadir values. 
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• The tabulation of the changes and percent changes from predose to nadir, predose to end of 
cycle, nadir to maximum postnadir, and nadir to end of cycle values for each cycle of 
treatment. 
• Analysis of covariance (ANOVA) models on hematologic parameter kinetic endpoints 
• Summarization of time to nadir. 
• Descriptive statistics and ANOVA of AUC in hematologic parameters 
• Repeated-measures model of AUC 
• Summary of proportion of patients return to predose value for each cycle, calculation on 
incidence rate, adjusting for cumulative exposure 
• Analysis of time to return to predose level for each cycle using Kaplan-Meier method. 
• Analysis of Time to return to postnadir predose levels 
Protocol Section 13.3.2.2 (Analysis of Hematologic Toxicity Endpoints)  
• Calculation and analysis of incidence rate of hematologic toxicity, adjusting for cumulative 
exposure 
• Calculation and analysis of toxicity rate relative to cumulative exposure (total number of 
toxicities divided by cumulative exposure).  
• Recurrent events model estimating the incidence of Grade 3 or higher hematologic toxicities 
and testing for the difference between treatment groups. 
• For each hematologic parameter and cycle, the shift summaries of the following: 
o From predose toxicity to maximum on treatment toxicity;  
o from predose toxicity to end of cycle toxicity; 
o from maximum postdose toxicity to end of cycle toxicity. 
Protocol Section 13.3.2.4 (Other Efficacy Endpoints) 
• The number and percent of infections summarized by maximum severity 
• The infection rate: The number of infections occurring during the Treatment divided by 
cumulative exposure. 
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8. 
REFERENCES 
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Dmitrienko A, Tamhane, AC, Wiens B. General multistage gatekeeping procedures. Biometrical 
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Dmitrienko A, Tamhane, AC, Bretz F. Multiple testing problems in pharmaceutical statistics. 
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Dmitrienko A, Tamhane  AC. Mixtures of multiple testing procedures for gatekeeping 
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Arbuck, S., Gwyther, S., Mooney, M. and Rubinstein, L., 2009. New response evaluation criteria 
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FDA Center for Biologics Evaluation and Research (CBER). Multiple Endpoints in Clinical 
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regulatoryinformation/guidances/ucm536750.pdf. Published January 2017. Accessed 
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Huque MF. Validity of the Hochberg procedure revisited for clinical trial applications. Statistics 
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Kim Y, Won S. (2013) Adjusted proportion difference and confidence interval in stratified 
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Yan X, Lee, S and Li N. Missing data handling methods in medical device clinical trials, Journal of 
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Zou G. A modified Poisson regression approach to prospective studies with binary data. 
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