Conditions: Colorectal Cancer Metastatic Myelosuppression-Adult Chemotherapeutic Toxicity
Keywords: Colorectal Cancer mCRC colon chemotherapy-induced myelosuppression chemotherapy-induced neutropenia chemotherapy-induced anemia CDK 4/6 inhibitor trilaciclib FOLFOXIRI bevacizumab myelosuppression cyclin-dependent kinase 4/6 inhibitor myelopreservation rectum Preserve PRESERVE 1
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 326
Healthy volunteers: no

Brief summary:
This was a randomized, double-blind, placebo-controlled, global, multicenter, Phase 3 trial evaluating the impact of trilaciclib on myelopreservation and anti-tumor efficacy when administered prior to FOLFOXIRI/bevacizumab in patients with pMMR/MSS mCRC who have not received systemic therapy for metastatic disease.

Detailed description:
Patients were randomly assigned (1:1) to receive placebo or trilaciclib on Days 1 and 2 administered intravenously (IV) prior to FOLFOXIRI/bevacizumab in 14-day cycles for up to 12 cycles (Induction).

Following completion of Induction, patients continued in Maintenance, where they received trilaciclib or placebo per randomization allocation at study entry. Trilaciclib/placebo will be administered prior to infusional-5FU/leucovorin/bevacizumab at the same dose and schedule used during Induction. The patient continued to receive treatment on study until disease progression, unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the trial, whichever occurs first. Treatment cycles occurred consecutively without interruption, except when necessary to manage toxicities or for administrative reasons.

Arms:
arm 1: During Induction the following study drugs are administered on Day 1:

Irinotecan - IV, Oxaliplatin - IV, Leucovorin- IV, Fluorouracil - continuous infusion (CI) over 46 to 48 hours beginning on Day 1, Bevacizumab - IV

Following completion of Induction, patients will continue in Maintenance, where they will continue to receive trilaciclib per randomization allocation at study entry. Trilaciclib will be administered prior to infusional- 5FU/leucovorin/bevacizumab at the same dose and schedule used during Induction. arm 2: The subjects in the placebo arm will follow the same schedule as the trilaciclib arm, but will receive placebo instead of trilaciclib.

Interventions: intervention 1: Trilaciclib intervention 2: Placebo
Intervention descriptions: intervention 1: Trilaciclib diluted in dextrose 5% in water or normal saline (sodium chloride solution 0.9%) administered by IV infusion over approximately 30 (±10) minutes no more than 4 hours prior to each Day 1 chemotherapy administration. Second dose of trilaciclib was administered on Day 2. intervention 2: Dextrose 5% in water or normal saline (sodium chloride solution 0.9%) administered by IV infusion over 30 (±10) minutes no more than 4 hours prior to each Day 1 chemotherapy administration. Second dose of placebo was administered on Day 2.

Protocol document:
Prot_000.pdf: 
Oﬃcial Title: 
PRESERVE 1: A Phase 3 Randomized, Double-blind Trial of Trilaciclib versus 
Placebo in PaƟents Receiving FOLFOXIRI/Bevacizumab for MetastaƟc Colorectal 
Cancer 
NCT Number: 
 
NCT04607668 
Document Date: 
15-Dec-2022 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
1 
 
 
Protocol Title: PRESERVE 1: A Phase 3 Randomized, Double-blind Trial of Trilaciclib versus 
Placebo in Patients Receiving FOLFOXIRI/Bevacizumab for Metastatic 
Colorectal Cancer 
Protocol Number: G1T28-207 
Compound: Trilaciclib for Injection, 300 mg/vial 
Study Phase: 3 
Short Title: Trilaciclib versus placebo in patients receiving FOLFOXIRI/bevacizumab for 
metastatic colorectal cancer 
Study Name: PRESERVE 1 
Sponsor Name: G1 Therapeutics, Inc. 
Legal Registered Address:  G1 Therapeutics, Inc. 
700 Park Offices Dr. Suite 200 
Research Triangle Park, NC 27709 
 
Regulatory Agency Identifier Numbers:  IND: 119254 
EudraCT: 2019-003826-25 
Approval Date: 15 December 2022 (Version 6.1) 
Replaces Amendment v5.1 (21 November 2022) _ Released to Italy AIFA 
Original Protocol: 12 June 2020 (Version 1.0) 
 
 
 
This document contains confidential and/or trade secret information that is disclosed only in connection 
with the licensing and/or registration of products for G1 Therapeutics. This document should not be 
disclosed or used, in whole or in part, for any other purpose without the prior written consent of 
G1 Therapeutics. 
 
 


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P R O T O C O L SI G N A T U R E P A G E  
S p o ns or’s A p pr o v al  
I h a ve rea d a n d u n dersta n d t he c o nte nts of t his cli nical pr ot oc ol, Versi o n 6 .1  f or St u d y 
G 1 T 2 8 -2 0 7 date d 1 5 D ece m ber  2 0 2 2  a n d I a gree t o meet all o bli gati o ns of t he S p o ns or as 
detaile d i n all a p plica ble re g ulati o ns a n d g ui deli nes. I n a d diti o n, I will i nf or m t he Pri nci pal 
I n v esti gat or a n d all ot her i n vesti gat ors of all rele va nt i nf or mati o n t hat bec o mes a vaila ble d uri n g 
t he c o n d uct of t he st u d y.  
 
 
 M D 
E xec uti ve Direct or, Cli nical De vel o p me nt  
P h ysicia n S p o ns or Re prese ntati ve  
G 1 T hera pe utics  
 
Date  
 
 
 
 
 
 
 
P P D


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
3 
INVESTIGATOR’S AGREEMENT 
 
Clinical Study Protocol G1T28-207: PRESERVE 1: A Phase 3 Randomized, Double-blind 
Trial of Trilaciclib versus Placebo in Patients Receiving FOLFOXIRI/Bevacizumab for 
Metastatic Colorectal Cancer 
 
Version 6.1 Issue Date: 15 December 2022 
Version 5.1 Issue Date: 21 November 2022 
Version 4.1 Issue Date:  06 September 2022 
Version 3.1 Issue Date: 27 July 2021 
Version 2.1 Issue Date: 20 January 2021 
 
 
Original Protocol (Version 1.0) Issue Date: 12 June 2020 
 
I have read the G1T28-207 protocol and agree to conduct the study as outlined. I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol.  
 
 
 
 
 
 
Principal Investigator Signature 
 
Date 
 
 
 
 
 
 
Principal Investigator Name 
 
Institution 
 
 


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1.  
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:  G 1 T hera pe utics  
N a me of I n vesti g ati o n al Pr o d uct:  trilacicli b f or i njecti o n, 3 0 0 m g/ vial 
N a me of Acti ve I n gre die nt:  trilacicli b h y dr oc hl ori de ( hereafter referre d t o as trilacicli b) ( G 1 T 2 8) 
Pr ot oc ol N u m ber:  
G 1 T 2 8 -2 0 7  
P h ase: 3  
Re gi o ns : U nite d States , Wester n 
E ur o pe, Easter n E ur o pe , C hi na 
Title of St u d y:  
P R E S E R V E 1 : A P hase 3 Ra n d o mize d, D o u ble -bli n d Trial of Trilacicli b vers us Place b o i n Patie nts 
Recei vi n g F O L F O XI RI/ Be vaciz u ma b f or Metastatic C ol orectal Ca ncer  
St u d y ce nter(s):  A p pr o xi matel y 1 2 0  ce nters 
St u die d peri o d ( ye ars):  
Esti mate d date first patie nt ra n d o mize d: Ja n 2 0 2 1  
Esti mate d date last patie nt c o m plete d: Q 2 2 0 2 5  
P h ase of de vel o p me nt: 3  
 
O bjecti ves:  
Pri m ar y:  
T o assess t he effects of trilacicli b o n t he ne utr o p hil li nea ge c o m pare d wit h  place b o i n patie nts 
recei vi n g F O L F O XI RI/ be vaciz u ma b f or pr oficie nt mis matc h re pair/ micr osatellite sta ble 
( p M M R/ M S S) metastatic c ol orectal ca ncer  (m C R C ). 
Ke y Sec o n d ar y:  
T o assess t he effect of trilacicli b o n o verall s ur vi val ( O S ) c o m pare d wit h  place b o i n patie nts recei vi n g 
F O L F O XI RI/ be vaciz u ma b f or p M M R/ M S S m C R C.  
St u d y Desi g n:  
T his is a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, gl o bal, m ultice nter, P hase 3 trial e val uati n g 
t he i m pact of trilacicli b o n m yel o preser vati o n a n d a nti-t u m or efficac y w he n a d mi nistere d pri or t o 
F O L F O XI RI/ be vaciz u ma b i n patie nts wit h p M M R/ M S S m C R C w h o ha ve n ot recei ve d s yste mic 
t hera p y f or metastatic disease. Patie nts will be ra n d o ml y assi g ne d ( 1: 1) t o recei ve place b o or 
trilacicli b o n Da ys 1 a n d 2 a d mi nistere d i ntra ve n o usl y (I V) pri or t o F O L F O XI RI/ be vaciz u ma b i n 
1 4 -da y c ycles f or u p t o 1 2  c ycles (I n d ucti o n). T here will be t hree stratificati o n f act ors f or 
ra n d o mizati o n: c o u ntr y, pri or t hera p y i n a dj u va nt/ ne oa dj u va nt setti n g , a n d prese nce of B R A F V 6 0 0 E 
m utati o n. Wit hi n eac h c o u ntr y,  patie nt  ra n d o mizati o n will be stratifie d b y hist or y of s yste mic 
c yt ot o xic t hera p y i n t he a dj u va nt/ ne oa dj u va nt setti n g ( yes/ n o) a n d B R A F V 6 0 0 E m utati o nal stat us 
( yes/ n o). St u d y dr u gs a d mi nistere d d uri n g I n d ucti o n are as f oll o ws: 
•  
Trilacicli b ( 2 4 0 m g/ m 2) or place b o –  a d mi nistere d as a 3 0 -mi n ute I V i nf usi o n n o m ore 
t ha n 4 h o urs pri or t o c he m ot hera p y o n eac h da y c he m ot hera p y is a d mi nistere d. T he 
sec o n d d ose of trilacicli b/ place b o s h o ul d be a d mi nistere d as a 3 0 -mi n ute i nf usi o n o n 
Da y  2 .  
•  
Iri n oteca n 1 6 5 m g/ m2 – I V, Da y 1  
•  
O xali plati n 8 5 m g/ m 2 –  I V, Da y 1  
•  
Le uc o v ori n 4 0 0  m g/ m 2 –  I V, Da y 1; L E V O Le uc o v ori n 2 0 0 m g/ m 2 is a n acce pta ble 
alter nati ve 
•  
Fl u or o uracil 2 4 0 0 –  3 2 0 0 m g/ m 2 –  c o nti n u o us i nf usi o n ( CI ) o ver 4 6 –  4 8 h o urs be gi n ni n g 
o n Da y 1 ; t his d ose ra n ge is pr o vi de d t o reflect ge o gra p hic variati o ns i n prescri be d 


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fl u or o uracil (5 F U ) d ose; h o we ver, t he sa me d ose s h o ul d be c o nti n ue d t hr o u g h o ut t he 
st u d y f or eac h patie nt, e xce pt w here d ose m o dificati o ns are re q uire d f or t o xicit y 
ma na ge me nt.  
•  
Be vaciz u ma b 5 m g/ k g –  I V, Da y 1  
T h o u g h t here is n o re q uire me nt f or a mi ni m u m n u m ber of c he m ot hera p y c ycles d uri n g I n d ucti o n, 
patie nts s h o ul d c o nti n ue wit h I n d ucti o n t hera p y (i n t he a bse nce of disease pr o gressi o n) as l o n g as it is 
t olerate d. H o we ver, if a patie nt  is u na ble t o c o m plete t he ma xi m u m n u m ber of 1 2 I n d ucti o n c ycles 
beca use of t o xicit y, a n d t he treati n g p h ysicia n feels t he patie nt will recei ve a d diti o nal cli nical be nefit 
b y tra nsiti o ni n g t o Mai nte na nce, t he patie nt will be all o we d t o disc o nti n ue o xali plati n a n d iri n oteca n, 
a n d c o nti n ue o n Mai nte na nce t hera p y as descri be d bel o w.  
F oll o wi n g c o m pleti o n of I n d ucti o n, patie nts will c o nti n ue in Mai nte na nce , w here t he y will recei ve 
trilacicli b or place b o per ra n d o mizati o n all ocati o n at st u d y e ntr y. Trilaci cli b/ place b o  will be  
a d mi nistere d pri or t o i nf usi o nal -5 F U/ le uc o v ori n/be vaciz u ma b at t he sa me d ose a n d sc he d ule use d 
d uri n g I n d ucti o n . T he patie nt ma y c o nti n ue t o recei ve treat me nt o n st u d y u ntil disease pr o gressi o n, 
u nacce pta ble t o xicit y, wit h dra wal of c o n se nt, disc o nti n uati o n b y I n vesti gat or, or t he e n d of t he trial, 
w hic he ver 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 or f or a d mi nistrati ve reas o ns.  
U p o n disc o nti n uati o n of st u d y  treat me nt, patie nts will be f oll o we d f or s ur vi val, ie, patie nts or t heir 
care gi vers will be c o ntacte d a p pr o xi matel y e ver y 2 m o nt hs  u ntil t he e n d of t he trial ( or deat h) t o 
rec or d t heir stat us (ali ve or dea d) as well as details of a n y s u bse q ue nt s yste mic anti -ca ncer t hera p y 
i nitiate d. 
Met h o d ol o g y:  
S a m ple Size J ustific ati o n:  
T he pri mar y a n d ke y sec o n dar y o bjecti ves of t his st u d y are t o e val uate t he m yel o preser vati o n a n d 
a nti-t u m or efficac y of trilacicli b a d mi nistere d pri or t o F O L F O XI RI/ be vaciz u ma b (referre d t o as 
trilacicli b hereafter) c o m pare d wit h place b o a d mi nistere d pri or t o  F O L F O XI RI/ be vaciz u ma b 
(referre d t o as place b o hereafter). T he st u d y has t w o pri mar y m yel os u p pressi o n e n d p oi nts ( d urati o n of 
se vere [ Gra de 4] ne utr o pe nia [ D S N] i n C ycle  1 –  4 a n d occ urre nce of se vere ne utr o pe nia [ S N] d uri n g  
I n d ucti o n a n d o ne  ke y sec o n dar y a nti -t u m or efficac y e n d p oi nt , O S. T o e ns ure str o n g c o ntr ol of 
fa mil y-wise t y pe  I err or rate at t he le vel of 2 -si de d 0. 0 5 w he n perf or mi n g statistical a nal yses , t he 
o verall 2 -side d α of 0. 0 5 will be s plit bet wee n t he a nal yses of t he t w o pri mar y e n d p oi nts ( usi n g 𝛼1 =
0 .0 4 ) a n d a nal yses f or O S ( usi n g 𝛼2 = 0 .0 1 ).  
T he sa m ple size is deter mi ne d t o s u p p ort pri mar y efficac y a nal ysis o n t he t w o pri mar y efficac y 
e n d p oi nts.  O verall, 2 8 2 pat ie nts ( 1 4 1 per gr o u p) are nee de d t o detect t he ass u me d treat me nt effect f or 
eac h of t he t w o c o -pri mar y m yel os u p pressi o n e n d p oi nts wit h 9 0 % p o wer at t he 2 -si de d si g nifica nce 
le vel of 0. 0 4. Ass u mi n g 5 % of ra n d o mize d patie nts will n ot ha ve a n y p ost -baseli ne d ata, a t otal of 
2 9 6 patie nts ( 1 4 8 per gr o u p) will be re q uire d f or t he st u d y.   
Alt h o u g h t he n u m ber of patie nts is deter mi ne d t o e ns ure a de q uate p o wer f or t he e val uati o n of t he 
m yel o preser vati o n efficac y of trilacicli b, statistical c o m paris o ns f or a nti -t u m or efficac y will als o be 
c o n d ucte d a n d t he statistical si g nifica nce is set t o  be  0. 0 1 i nitiall y f or testi n g t he treat me nt effect f or 
O S. A  t otal of 1 5 7 deat hs  are esti mate d t o be o bser ve d d uri n g 5 2-m o nt h of st u d y d urati o n base d o n 
t he f oll o wi n g ass u m pti o ns: 1 8 m o nt hs of  accr ual wit h  3 4 m o nt hs  f oll o w u p after t he last patie nt is 
ra n d o mize d, a m o nt hl y dr o p-o ut rate of 0. 0 0 2 9 (ass u mi n g a n e x p o ne ntial distri b uti o n ), a n d t he 
me dia n O S of 3 1  m o nt hs f or place b o gr o u p ( patie nts recei vi n g F O L F O X I RI/ be vaciz u ma b pl us 
place b o) ( L o u pa kis , 2 0 1 4). It is als o ass u me d t hat t he hazar d rati o (trilacicli b vs. place b o) is 0. 7 5. 
A t otal of 4 4 patie nts fr o m U krai ne were ra n d o mize d t o t he st u d y as of  2 4  Fe br uar y 2 0 2 2. T o miti gate 
t he p ote ntial i m pact of R ussia n-U krai ne war o n data i nte grit y a n d e ns ure t he o bjecti ves of 
P R E S E R V E -1 will n ot be c o m pr o mise d, patie nts w h o were ra n d o mize d fr o m U krai ne pri or t o 0 9 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
6 
September 2021 will be included in efficacy analyses while all randomized patients from Ukraine will 
be included in the safety evaluation. Therefore, a total of 30 randomized patients from Ukraine will be 
excluded from the efficacy evaluation. This will preserve the study power as it was originally 
designed, as patients randomized prior to 09 September 2021 should have completed or had the 
opportunity to complete Induction period per protocol (approximately 24 weeks), prior to the start of 
the war (24 February 2022). 
Number of patients (planned):  
Approximately 326 patients (296 patients in the mITT population) with mCRC are planned in this 
study.  The original study population included 296 patients; 30 additional patients are planned to be 
enrolled to replace patients in Ukraine for the efficacy analyses. 
Diagnosis and main criteria for inclusion:  
Patients ≥18 years of age at the time of signing the informed consent (patients > 70 years of age must 
have a G8 Health State Screening Tool [geriatric screening tool] score > 14) with pMMR/MSS, and 
histologically or cytologically-confirmed adenocarcinoma of the colon or rectum. Patients with any 
BRAF or KRAS mutation status (wild type or mutant) are eligible. If historical pMMR/MSS and/or 
BRAF V600E mutational status are not known, a tumor specimen (archival or fresh biopsy) must be 
sent for testing and results must be available at the time of randomization in interactive web response 
system (IWRS). If testing cannot be completed using a standard clinical assay performed 
institutionally/locally, the tumor specimen may be sent to the Sponsor’s designated central laboratory 
for analysis; only historical KRAS mutational status will be collected (ie, no testing required prior to 
study entry). Patients must have unresectable and evaluable disease per Response Evaluation Criteria 
in Solid Tumors (RECIST) v1.1, and Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 to 1. At the time of providing informed consent, a formalin-fixed paraffin-embedded 
(FFPE) tumor specimen (from archival or fresh biopsy) with an associated pathology report 
documenting pMMR/MSS mCRC for retrospective biomarker analysis must be confirmed to be 
available to send to Sponsor for planned retrospective biomarker analyses.  
Investigational product, dosage, and mode of administration:  
In each 14-day cycle in Induction and Maintenance, a dose of trilaciclib 240 mg/m2 diluted in 250 mL 
of dextrose 5% in water or sodium chloride solution 0.9% will be administered by IV infusion over 
approximately 30 (±10) minutes no more than 4 hours prior to each Day 1 chemotherapy 
administration. The second dose of trilaciclib should be administered on Day 2.  
Duration of treatment:  
Each patient may receive a maximum of 12 cycles of therapy (trilaciclib or placebo plus 
FOLFOXIRI/bevacizumab) during Induction. Following completion of Induction, patients will 
continue on Maintenance therapy. Patients will receive trilaciclib or placebo (per randomization 
allocation at study entry) administered prior to infusional-5FU/leucovorin/bevacizumab at the same 
dose and schedule used during Induction. Treatment in both Induction and Maintenance will continue 
until disease progression, unacceptable toxicity, withdrawal of consent, discontinuation by 
Investigator, or the end of the trial, whichever occurs first. 
Reference therapy, dosage and mode of administration:  
In each 14-day cycle in Induction and Maintenance, a dose of placebo (250 mL of dextrose 5% in 
water or sodium chloride solution 0.9%) will be administered by IV infusion over approximately 
30 (±10) minutes no more than 4 hours prior to each Day 1 chemotherapy administration. The second 
dose of placebo should be administered on Day 2.  
FOLFOXIRI/bevacizumab will be administered IV in accordance with the prescribing information 
and according to the study site’s standard practice. 


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Criteri a f or e v al u ati o n:  
Effic ac y:  
M yel o preser vati o n efficac y will be assesse d base d o n re p orte d he mat ol o g y assess me nts, se vere 
a d verse e ve nt ( A E) details, a n d s u p p orti ve care i nter ve nti o ns (i ncl u di n g tra nsf usi o ns ). Fati g ue will be 
assesse d wit h t he F u ncti o nal Assess me nt of C hr o nic Ill ness T hera p y –  Fati g ue ( F A CI T -F). T u m or 
res p o nse criteria i ncl u di n g P F S, O S, d urati o n of o bjecti ve res p o nse ( D O R) a n d best o verall res p o nse 
( B O R) will be base d o n R E CI S T v 1. 1. 
S afet y:  
Safet y will be e val uate d b y m o nit ori n g A Es, cli nical la b orat or y test res ults ( he mat ol o g y, cli nical 
c he mistr y, c oa g ulati o n [i nter nati o nal n or malize d rati o, acti vate d partial t hr o m b o plasti n ti me], a n d 
uri nal ysis), vital si g n meas ure me nts ( bl o o d press ure, heart rate [ H R], a n d b o d y te m perat ure), 1 2 -lea d 
safet y electr ocar di o gra m  ( E C G) res ults, d ose m o dificati o ns, a n d p h ysical e xa mi nati o n fi n di n gs.  
St atistic al met h o ds:  
Data will be s u m marize d b y treat me nt gr o u p. 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, 2 5 % a n d 7 5 % perce ntiles, a n d mi ni m u m a n d ma xi m u m 
val ues.  
Str atific ati o n f act ors a n d f act ors use d i n st atistic al m o dels:  
T here are t hree stratificati o n fact ors f or ra n d o mizati o n: c o u ntr y, pri or t hera p y i n a dj u va nt/ ne oa dj u va nt 
setti n g, a n d B R A F V 6 0 0 E m utati o nal stat us. A ra nd o mizati o n sc he ma will be i n place t o e ns ure t he 
best p ossi ble bala nce of treat me nt assi g n me nt wit hi n eac h c o u ntr y, a n d bet wee n patie nts wit h hist or y 
of s yste mic c yt ot o xic t hera p y i n t he a dj u va nt/ ne oa dj u va nt setti n g ( yes/ n o) a n d patie nts wit h/ wit h o ut 
B R A F V 6 0 0 E m utati o n. T he c o u ntries will be gr o u pe d i nt o f o ur differe nt re gi o ns as U S, Easter n 
E ur o pe, Wester n E ur o pe, a n d C hi na i n t he statistical m o dels t o acc o u nt f or re gi o nal differe nces i n 
cli nical practice. It is a ntici pate d t hat all t hree fact ors (re gi o n,  pri or t hera p y i n t he 
a dj u va nt/ ne oa dj u va nt setti n g, a n d B R A F stat us) w o ul d ha ve a n i m pact o n patie nt’s a nti -t u m or 
efficac y o utc o me, b ut o nl y re gi o n a n d pri or t hera p y i n a dj u va nt/ ne oa dj u va nt setti n g c o ul d i m pact t he 
m yel os u p pressi o n meas ures. T heref ore, re g i o n a n d pri or t hera p y i n a dj u va nt/ ne oa dj u va nt setti n g will 
be i ncl u de d as t he fact ors i n statistical a nal ysis m o dels e val uati n g trilacicli b’s m yel o preser vati o n 
efficac y, w hile all t hree fact ors are i ncl u de d i n t he statistical a nal ysis m o dels t o assess tril acicli b’s 
a nti-t u m or efficac y. U nless ot her wise s pecifie d, t he strata i nf or mati o n as e ntere d i n I W R S at t he ti me 
of ra n d o mizati o n e xce pt f or “re gi o n” will be use d as t he fact ors f or  all stratifie d statistical a nal yses.  
A n al ysis p o p ul ati o n  
T he i nte nt -t o-treat (I T T) p o p ulati o n i ncl u des all ra n d o mize d patie nts. A nal yses f or t he I T T p o p ulati o n 
will be c o n d ucte d base d o n t he ra n d o ml y assi g ne d treat me nt re gar dless of w het her t he patie nt 
recei ve d st u d y treat me nt or was c o m plia nt  wit h t he pr ot oc ol.  
T o acc o u nt f or t he data i nte grit y iss ues p ote ntiall y res ulti n g fr o m t he war i n U krai ne, a m o difie d 
i nte nt-t o-treat ( mI T T) p o p ulati o n is t he pri mar y p o p ulati o n f or all efficac y e val uati o ns. T he criteria 
f or t he mI T T p o p ulati o n are as f oll o ws:   
•  All patie nts  ra n d o mize d i n c o u ntries ot her t ha n t he U krai ne. 
•  All patie nts i n t he U krai ne w h o were ra n d o mize d pri or t o 0 9  Se pte m ber 2 0 2 1. T his gr o u p 
s h o ul d ha ve c o m plete d, or ha d t he o p p ort u nit y t o c o m plete, I n d ucti o n peri o d  per pr ot oc ol 
(a p pr o xi matel y 2 4 wee ks) pri or t o t he start of t he war ( 2 4 Fe b r uar y 2 0 2 2).  


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As a subset of ITT population, the analyses performed on mITT will be consistent with the ITT 
principle, that is, data will be analyzed based on the randomly assigned treatment regardless of 
whether the patient received study treatment or was compliant with the protocol.   
A per-protocol (PP) population is a subset of the mITT population that includes only those patients 
who have no key protocol deviations (eg, a subset of major protocol deviations that might 
substantially affect the accuracy of the study efficacy data) and who receive at least one dose of the 
randomly assigned treatment. The PP population will be used to analyze selected efficacy endpoints 
to evaluate the robustness of the efficacy findings observed in the mITT population. Analyses on the 
PP population will be based on the randomly assigned treatment.  
The response evaluable (RE) population will include patients in the mITT population who have a 
measurable lesion (target lesions) at the baseline tumor assessment, and either (i) have at least 
1 post-dose tumor assessment, or (ii) do not have post-dose tumor assessment but have clinical 
progression as noted by the Investigator, or (iii) have died due to disease progression before their first 
post-dose tumor scan. RE population will be the primary analysis set to evaluate tumor response and 
the data will be analyzed based on the actual treatment received. 
The safety population includes all enrolled patients who received at least 1 dose of study drug. 
Analyses conducted on the safety population will be based on the actual treatment received. All safety 
analyses will be conducted using the safety population. 
The pharmacokinetic (PK) population will include all dosed patients with evaluable PK data. 
Unless otherwise specified, myelopreservation efficacy and its effect on PRO endpoints will be 
evaluated based on the data that are collected during Induction, which is defined as the time period 
between the date of randomization and the end of the last cycle in Induction (ie, last cycle of placebo 
or trilaciclib plus FOLFOXIRI/bevacizumab). Treatment effect on OS will be evaluated based on the 
estimated number of events and will not be limited to where the patient is in the study (eg, Induction, 
Maintenance or Survival Follow-Up). 
Statistical analysis methods for primary and key secondary endpoints 
General testing strategy 
The treatment effects on the primary myelosuppression endpoints (DSN in Cycle 1 – 4 and 
occurrence of SN during Induction) will be tested as 2-sided α1=0.04 level, while the treatment effect 
on OS will be tested at 2-sided α2=0.01 level. Both DSN in Cycle 1 – 4 and occurrence of SN in 
Induction will be tested at the 2-sided α1=0.04 level simultaneously. If statistical significance is 
established at the 2-sided 0.04 level for the two primary endpoints, the assigned 𝛼1=0.04 will be 
recycled to test treatment effect on OS following a fallback procedure (Wiens, 2003). In that 
occasion, testing OS will be conducted at the level of 2-sided 0.05 (ie, at the level of 𝛼1 + 𝛼2).  
Analysis for primary and key secondary efficacy endpoints 
The primary myelosuppression endpoints are DSN in Cycle 1 – 4 and occurrence of SN during 
Induction. Severe neutropenia (SN) is defined as the absolute neutrophil count (ANC) laboratory 
value that meets the common terminology criteria for adverse events (CTCAE) criteria for ≥ Grade 4 
toxicity (ie, ANC < 0.5 x 109/L in SI Unit). For patients with at least one SN event in Cycle 1 – 4, the 
duration of SN (DSN) is defined as the number of days for the first SN event that occurred in Cycle 1, 
2, 3, or 4 for patients who had at least one SN event in the first 4 cycles of Induction. Specifically, it 
is calculated as the days from the date of the first ANC value of <0.5 × 109/L to the date of the first 
ANC value ≥0.5 × 109/L where no additional ANC values <0.5 × 109/L are observed for the 
remainder of that cycle. All observed data from scheduled or non-scheduled visits within Cycle 1 – 4 
will be included in the derivation. For those patients without any SN in Cycle 1– 4, DSN will be set to 
be 0. The treatment group difference in DSN in Cycle 1 – 4 will be evaluated using a nonparametric 
analysis of covariance (ANCOVA) (Quade, 1967). In this analysis, the rank-transformed (within each 
stratum) DSN values are analyzed by an ANCOVA model with the terms of treatment, region (US, 


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Eastern Europe, Western Europe, and China), and history of systemic cytotoxic therapy in the 
adjuvant/neoadjuvant setting (Yes or No). The rank-transformed baseline ANC (within each stratum) 
will be included as a covariate in the model. In addition, the mean difference (trilaciclib – placebo), 
the standard error and the 96% confidence interval generated from a Satterthwaite t-test will be 
presented. 
The occurrence of SN during Induction is defined as having SN in at least one cycle in Induction and 
is thus a binary variable (yes vs no). This co-primary endpoint will be analyzed using a modified 
Poisson regression model with the same terms as used in the non-parametric ANCOVA model for 
DSN in Cycle 1 – 4 with baseline ANC value as a covariate. The log-transformed number of cycles 
will be used as the offset in the model. The adjusted relative risk (aRR) (trilaciclib vs placebo) and its 
96% confidence interval will be calculated and reported along with the 2-sided p-value.  
Analysis for OS 
At the time when 157 death events are observed or at 52 months after the date of first randomization, 
whichever comes first, the study will be concluded, and the final study database will be locked to 
perform the OS analysis. Treatment effect on OS will be evaluated using the stratified log-rank test 
controlling for three factors of region, history of systemic cytotoxic therapy in the 
adjuvant/neoadjuvant setting, and presence of BRAF V600E mutation (yes, or no). In addition, a Cox 
proportional hazard model with the same terms as in the stratified log-rank test will be used to 
estimate the HR between the 2 treatment groups (trilaciclib vs placebo) for OS along with its (1-α) 
x100% confidence interval. 
Analysis for safety endpoints 
AEs are defined as those events occurring or worsening after treatment has begun on this study. AE 
data will be coded to system organ class and preferred term using the Medical Dictionary for 
Regulatory Activities (MedDRA). The number and percentage of patients experiencing any AE 
overall, and by system organ class and preferred term will be tabulated for each treatment group. 
Adverse events considered by the Investigator to be related to treatment will also be summarized by 
the treatment to which it is attributed (eg, trilaciclib/placebo, fluorouracil, leucovorin, irinotecan, 
oxaliplatin, bevacizumab) for each treatment group. Severity of AEs will be tabulated based on 
greatest severity observed for each patient. In the tabulation of grade and causality, if the same AE 
occurs on multiple occasions, the highest grade and strongest relationship to study drug will be used 
in a summary. Adverse event of special interests (AESI) for trilaciclib, AEs leading to study drug 
discontinuation, and use of concomitant medications to treat AEs will be tabulated separately. 
Concomitant medications, as well as prior and subsequent anti-cancer therapies, will be coded to 
Anatomical Therapeutic Classification (ATC) using the World Health Organization-Drug Dictionary 
(WHO-DD) 
Observed values and change (including maximum and minimum values) from baseline to each visit in 
vital signs, ECG intervals, and laboratory assessments of hematology, clinical chemistry, urinalysis, 
and liver function parameters will be tabulated, as appropriate. Toxicity grades for clinical lab 
parameters (eg, hematology, chemistry) will be characterized according to National Cancer Institute 
(NCI) -CTCAE v5.0, when possible, and the number and percentage of patients within each CTCAE 
grade will be summarized for the overall treatment period as well as for each cycle. Scheduled and 
unscheduled safety data will be included in safety evaluation. 
The pharmacokinetics of trilaciclib and any metabolites will be determined using a non-linear mixed 
effects modeling approach. Population pharmacokinetic parameters including clearance (CL), volume 
of distribution (V), and other parameters will be estimated as data permit. 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............10 
3. 
LIST OF ABBREVIATIONS.....................................................................................16 
4. 
INTRODUCTION ......................................................................................................21 
4.1. 
Study Rationale ...........................................................................................................23 
4.2. 
Background .................................................................................................................27 
4.2.1. 
Summary of Nonclinical Data ....................................................................................27 
4.2.1.1. 
Pharmacology Studies ................................................................................................27 
4.2.1.2. 
Pharmacokinetic Studies .............................................................................................29 
4.2.2. 
Summary of Clinical Data ..........................................................................................31 
4.2.2.1. 
Trilaciclib ....................................................................................................................31 
4.2.2.2. 
FOLFOXIRI/Bevacizumab .........................................................................................33 
4.2.3. 
Risks ...........................................................................................................................33 
4.2.3.1. 
Trilaciclib ....................................................................................................................33 
4.2.3.2. 
FOLFOXIRI/Bevacizumab .........................................................................................35 
4.3. 
Benefit/Risk Assessment ............................................................................................38 
5. 
OBJECTIVES AND ENDPOINTS ............................................................................40 
5.1. 
Rationale for Primary and Key Secondary Endpoints ................................................43 
5.1.1. 
Myelopreservation Efficacy ........................................................................................43 
5.1.2. 
Anti-tumor Efficacy ....................................................................................................43 
5.1.3. 
Safety ..........................................................................................................................43 
6. 
INVESTIGATIONAL PLAN .....................................................................................44 
6.1. 
Overall Study Design ..................................................................................................44 
6.2. 
Rationale for Dose and Schedule of Study Treatment ................................................45 
6.2.1. 
Trilaciclib ....................................................................................................................45 
6.2.2. 
FOLFOXIRI/bevacizumab .........................................................................................46 
6.3. 
Rationale for Supportive Care Interventions (Growth Factors and 
Transfusions) ..............................................................................................................47 


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6.4. 
Rationale for Stratification Factors .............................................................................48 
7. 
STUDY POPULATION .............................................................................................50 
7.1. 
Inclusion Criteria ........................................................................................................50 
7.2. 
Exclusion Criteria .......................................................................................................51 
8. 
SCHEDULE OF ASSESSMENTS.............................................................................53 
9. 
STUDY TREATMENT ..............................................................................................60 
9.1. 
Study Drugs Administered .........................................................................................60 
9.1.1. 
Dose, Dosing Regimen, and Route .............................................................................62 
9.1.1.1. 
Trilaciclib ....................................................................................................................62 
9.1.1.2. 
Placebo ........................................................................................................................62 
9.1.1.3. 
FOLFOXIRI/bevacizumab .........................................................................................62 
9.1.2. 
Preparation, Handling, Storage, and Accountability ..................................................63 
9.1.3. 
Treatment Compliance ................................................................................................63 
9.2. 
Induction .....................................................................................................................63 
9.3. 
Maintenance ................................................................................................................63 
9.4. 
Criteria for Starting Cycle 2 and Each Subsequent Cycle in Induction or 
Maintenance ................................................................................................................64 
9.5. 
Toxicity Management and Dose Modifications .........................................................65 
9.5.1. 
Trilaciclib and FOLFOXIRI .......................................................................................66 
9.5.2. 
Hepatobiliary Toxicity Management ..........................................................................78 
9.5.3. 
Bevacizumab ...............................................................................................................79 
9.6. 
Supportive Care Interventions ....................................................................................80 
9.6.1. 
Colony Stimulating Factor Usage ...............................................................................80 
9.6.2. 
Erythropoiesis-Stimulating Agent Usage ...................................................................81 
9.6.3. 
Transfusions ................................................................................................................81 
9.7. 
Prior/Concomitant Medications ..................................................................................82 
9.8. 
Measures to Minimize Bias: Randomization and Blinding ........................................83 
9.9. 
Intervention after End of Study Treatment .................................................................84 
10. 
DISCONTINUATION OF STUDY INTERVENTION AND PATIENT 
DISCONTINUATION/WITHDRAWAL ..................................................................85 
10.1. 
Discontinuation of Study Treatment ...........................................................................85 
10.2. 
Discontinuation/Withdrawal from the Study ..............................................................85 
10.3. 
Lost to Follow Up .......................................................................................................86 


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10.4. 
Study and Site Start and Closure ................................................................................86 
11. 
STUDY ASSESSMENTS ..........................................................................................88 
11.1. 
Randomization ............................................................................................................88 
11.2. 
Myelopreservation Efficacy Assessments ..................................................................88 
11.2.1. 
Hematology Sampling Schedule .................................................................................88 
11.3. 
Anti-tumor Efficacy Assessment ................................................................................89 
11.4. 
Safety Assessments .....................................................................................................89 
11.4.1. 
Demographics .............................................................................................................89 
11.4.2. 
Medical History and Colorectal Cancer Disease History ...........................................89 
11.4.3. 
Vital Signs ..................................................................................................................90 
11.4.4. 
Physical Examination .................................................................................................91 
11.4.5. 
Electrocardiogram .......................................................................................................91 
11.4.6. 
Clinical Safety Laboratory Assessments ....................................................................91 
11.5. 
Geriatric 8 Health Status Screening Tool ...................................................................92 
11.6. 
Patient Reported Outcomes ........................................................................................92 
11.6.1. 
Functional Assessment of Cancer Scales ...................................................................92 
11.6.2. 
Patient Global Impression of Change and Patient Global Impression of 
Severity .......................................................................................................................93 
11.6.3. 
5-Level EQ-5D ...........................................................................................................93 
11.7. 
Pharmacokinetics ........................................................................................................93 
11.8. 
Biomarkers (CDK4/6 Signature) ................................................................................94 
11.8.1. 
Rationale for Archival Tumor Collection ...................................................................94 
11.8.2. 
Description of CDK4/6 Signature ..............................................................................94 
11.9. 
Immunologic and Hematologic Markers ....................................................................95 
11.10. 
Adverse and Serious Adverse Events .........................................................................96 
11.10.1. 
Time Period and Frequency for Collecting Adverse and Serious Adverse 
Event Information .......................................................................................................96 
11.10.2. 
Method of Detecting Adverse and Serious Adverse Events .......................................96 
11.10.3. 
Follow-up of Adverse and Serious Adverse Events ...................................................97 
11.10.4. 
Regulatory Reporting Requirements for Serious Adverse Events .............................97 
11.10.5. 
Pregnancy ...................................................................................................................97 
11.10.6. 
Adverse Events of Special Interest .............................................................................98 
11.11. 
Data Monitoring Committee .......................................................................................98 


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11.12. 
Survival Follow-up .....................................................................................................98 
12. 
STATISTICAL CONSIDERATIONS .....................................................................100 
12.1. 
Sample Size Determination ......................................................................................100 
12.2. 
Analysis Population ..................................................................................................101 
12.3. 
Timing of Planned Analyses .....................................................................................102 
12.3.1. 
First Planned Analysis – Evaluation of Myelopreservation Efficacy .......................102 
12.3.2. 
Second Planned Analysis - Analysis for Progression Free Survival  .......................102 
12.3.3. 
Third Analysis – Analysis for Overall Survival .......................................................102 
12.4. 
Statistical Analysis Methods.....................................................................................102 
12.4.1. 
General Considerations .............................................................................................103 
12.4.2. 
Demographic and Baseline Characteristics ..............................................................103 
12.4.3. 
Prior and Subsequent Anti-cancer Therapies ...........................................................103 
12.4.4. 
Efficacy Analyses .....................................................................................................104 
12.4.4.1. 
Analyses of Primary Myelosuppression Endpoints: DSN in Cycle 1 – 4 and 
Occurrence of SN during Induction ..........................................................................104 
12.4.4.2. 
Multiplicity Control for the Primary Myelosuppression Endpoints .........................105 
12.4.4.3. 
Analysis of Key Secondary Anti-Tumor Efficacy Endpoint: Overall Survival .......105 
12.4.4.4. 
Analysis for Secondary Myelosuppression Endpoints .............................................106 
12.4.4.5. 
Analysis for Secondary Anti-tumor Efficacy Endpoints ..........................................106 
12.4.4.6. 
Analysis of Secondary Endpoint – Progression Free Survival .................................107 
12.4.4.7. 
Analysis of Secondary Endpoint - Time to Confirmed Deterioration of 
Fatigue ......................................................................................................................107 
12.4.4.8. 
Analysis of Exploratory Endpoints ...........................................................................108 
12.4.5. 
Safety Analyses ........................................................................................................108 
12.4.5.1. 
Analysis of Anti-tumor Endpoints by CDK4/6 Biomarker Signature ......................109 
12.4.6. 
Pharmacokinetic Analyses ........................................................................................109 
12.4.7. 
Pharmacokinetic/Pharmacodynamic Analyses .........................................................109 
13. 
ETHICS ....................................................................................................................110 
13.1. 
Ethics Review ...........................................................................................................110 
13.2. 
Ethical Conduct of the Study ....................................................................................110 
13.3. 
Written Informed Consent ........................................................................................110 
14. 
DATA HANDLING AND RECORDKEEPING .....................................................111 
14.1. 
Data Protection .........................................................................................................111 


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14.2. 
Data Quality Assurance ............................................................................................111 
14.3. 
Source Documents ....................................................................................................112 
14.4. 
Audits and Inspections ..............................................................................................112 
15. 
PUBLICATION POLICY ........................................................................................113 
16. 
REFERENCES .........................................................................................................114 
17. 
APPENDICES ..........................................................................................................123 
17.1. 
Informed Consent Process Recommendations .........................................................123 
17.2. 
Clinical Laboratory Tests .........................................................................................124 
17.3. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .........................................................................................126 
17.3.1. 
Definition of AE .......................................................................................................126 
17.3.2. 
Definition of SAE .....................................................................................................127 
17.3.3. 
Recording and Follow-Up of AE and/or SAE ..........................................................128 
17.3.4. 
Reporting of SAEs ....................................................................................................130 
17.4. 
Contraceptive Guidance and Collection of Pregnancy Information .........................131 
17.5. 
FOLFOXIRI Components Package Inserts ..............................................................134 
17.5.1. 
Fluorouracil ...............................................................................................................134 
17.5.2. 
Leucovorin ................................................................................................................134 
17.5.3. 
Oxaliplatin ................................................................................................................134 
17.5.4. 
Irinotecan ..................................................................................................................134 
17.6. 
Bevacizumab Package Insert ....................................................................................135 
17.7. 
Definitions of Tumor Response and Disease Progression (per RECIST v1.1) ........136 
 


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LIST OF TABLES 
Table 1: 
Abbreviations ..............................................................................................................16 
Table 2: 
Integrated Analysis for Myelopreservation Efficacy in SCLC (Studies 
G1T28-02, G1T28-03, and G1T28-05) ......................................................................32 
Table 3: 
Objectives and Endpoints ...........................................................................................40 
Table 4: 
Schedule of Assessments: Screening and Induction Cycle 1 .....................................54 
Table 5: 
Schedule of Assessments: Induction (Cycle 2-12), Maintenance, and 
Survival Follow-up .....................................................................................................57 
Table 6: 
Study Drugs ................................................................................................................61 
Table 7: 
Recommended Chemotherapy Dose Modifications ...................................................65 
Table 8: 
Dose Modifications for Drug-related Hematologic Toxicity .....................................67 
Table 9: 
Dose Modification for Drug-related Non-hematologic Toxicity ................................70 
Table 10: Dose Modification for Bevacizumab-related Toxicity Management at Any 
Point During the Study ...............................................................................................79 
Table 11: Patient Risk Factors for Poor Clinical Outcomes Resulting from Febrile 
Neutropenia or Infection .............................................................................................81 
Table 12: Protocol-specified Safety Laboratory Assessments ..................................................124 
 
LIST OF FIGURES 
Figure 1: 
Comparison of Trilaciclib and Current Myelosuppression Therapies ........................24 
Figure 2: 
Proliferation Kinetics Are Different Between Bone Marrow and Tumor Cells .........28 
Figure 3:  CDK4/6 Inhibition Does Not Antagonize Anti-Tumor Efficacy of 
Chemotherapy in CDK4/6 Dependent Xenograft Models ..........................................29 
Figure 4: 
Study Schema .............................................................................................................45 
 


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3. 
LIST OF ABBREVIATIONS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations 
Abbreviation 
Definition 
AC 
adriamycin and cyclophosphamide 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
aPTT 
activated partial thromboplastin time 
aRR 
adjusted relative risk 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
BCRP 
breast cancer resistance protein 
BED 
biologically effective dose 
Bev 
bevacizumab 
β-hCG 
beta human chorionic gonadotropin 
BICR 
blinded independent central review 
BSEP 
bile salt export pump 
CBC 
complete blood count 
CD 
cluster of differentiation 
CDK 
cyclin-dependent kinase 
CFR 
Code of Federal Regulations 
CI 
continuous infusion 
CIM 
chemotherapy-induced myelosuppression 
CL 
clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
CMH 
Cochran–Mantel–Haenszel 
CNS 
central nervous system 
CR 
complete response 


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Abbreviation 
Definition 
CRC 
colorectal cancer 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
D5W 
dextrose 5% in water 
DCAF 
d-type cyclin activating features 
DDI 
drug-drug interaction 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DOR 
duration of objective response 
DPD 
dipyrimidine dehydrogenase 
DSN 
duration of severe (Grade 4) neutropenia 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EdU 
5-ethynyl-2´-deoxyuridine 
EGFR 
epidermal growth factor receptor 
E/P 
etoposide plus carboplatin 
ER 
estrogen receptor 
ESA 
erythropoiesis-stimulating agent 
ESMO 
European Society of Medical Oncology 
EQ-5D-5L 
5-level EQ-5D 
EQ-VAS 
EQ visual analogue scale 
FACT-An 
Functional Assessment of Cancer Therapy – Anemia 
FACT-C 
Functional Assessment of Cancer Therapy – Colorectal 
FACT-G 
Functional Assessment of Cancer Therapy – General 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FN 
febrile neutropenia 
FSH 
follicle stimulating hormone 


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Abbreviation 
Definition 
5FU/FU 
fluorouracil 
G1 
gap 1 
G2 
gap 2 
G8 
geriatric 8 
G/C 
gemcitabine plus carboplatin 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
GI 
gastrointestinal 
HFS 
Hand-Foot Syndrome 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRT 
hormone replacement therapy 
HSPCs 
hematopoietic stem and progenitor cells 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ID 
identification 
IEC 
Independent Ethics Committee 
ILD 
interstitial lung disease 
INR 
international normalized ratio 
IP 
intraperitoneal 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
intravenous 
IWRS 
interactive web response system 
Ki 
inhibitory constant 
LCV 
leucovorin 
M 
mitosis 


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Abbreviation 
Definition 
mab 
monoclonal antibody 
MATE 
multidrug and toxin extrusion  
mCRC 
metastatic colorectal cancer 
MOA 
mechanism of action  
mITT 
modified intent-to-treat 
MRI 
magnetic resonance imaging 
MRP 
multidrug resistance protein 
MSI 
microsatellite instable 
MSS 
microsatellite stable 
NCI 
National Cancer Institute 
NMPA 
National Medical Products Administration 
NYHA 
New York Heart Association 
OAT1 
organic anion transporter 1 
OATP1B1 
organic anion transporting polypeptide 1B1 
OATP1B3 
organic anion transporting polypeptide 1B3 
OCT2 
organic cation transporter 2 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PDX 
patient derived xenografts 
PFS 
progression-free survival 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
p-gp 
p glycoprotein 
PK 
pharmacokinetic(s) 
pMMR 
proficient mismatch repair 
PP 
Per Protocol 
PR 
partial response 
PRES 
Posterior Reversible Encephalopathy Syndrome 
PRO 
patient reported outcome 
PT 
preferred term 


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Abbreviation 
Definition 
PVG 
pharmacovigilance 
QTcF 
QTc corrected by Fridericia’s formula 
RB 
retinoblastoma 
RB1 
retinoblastoma gene 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
RP2D 
recommended phase 2 dose 
RPLS 
Reversible Posterior Leukoencephalopathy Syndrome 
S 
synthesis 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SCLC 
small cell lung cancer 
SD 
stable disease 
SN 
severe neutropenia 
SUSAR 
suspected unexpected serious adverse reactions 
t1/2 
half-life 
Tmax 
time to reach the maximum concentration 
TNBC 
triple negative breast cancer 
TTCD-fatigue 
time to first confirmed deterioration of fatigue 
ULN 
upper limit of normal 
US 
United States 
V 
volume of distribution 
VEGF 
vascular endothelial growth factor 
WHO 
World Health Organization 
WHO-DD 
World Health Organization-Drug Dictionary 
WOCBP 
women of childbearing potential 


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4. 
INTRODUCTION 
DISEASE 
Although the solid tumor cancer treatment paradigm has advanced over the last 20 years with the 
introduction of targeted therapies (e.g., vascular endothelial growth factor [VEGF] inhibitors, 
epidermal growth factor receptor [EGFR] inhibitors) and immuno-oncology agents (e.g., 
checkpoint inhibitors), chemotherapy remains the cornerstone of treatment for patients with solid 
tumor cancers in both the curative and palliative settings. Consequently, chemotherapy-related 
toxicity, including chemotherapy-induced myelosuppression (CIM), diarrhea, and stomatitis, can 
influence the risk/benefit ratio of a given chemotherapy treatment.  
CIM is a significant issue in cancer treatment; patients with myelosuppression are more likely to 
experience infections, sepsis, bleeding, and fatigue, often leading to the need for hospitalizations, 
hematopoietic growth factor support, transfusions (red blood cells [RBCs] and/or platelets) and 
even death (Caggiano, 2005; Gustinetti, 2016; Bodey, 1966; Li, 2016). Moreover, CIM 
commonly leads to dose reductions and delays, which limit therapeutic dose intensity and can 
compromise the anti-tumor efficacy benefits of chemotherapy. Chemotherapy-induced cellular 
damage to the immune system may also limit anti-tumor efficacy due to an inability of the host 
immune system to effectively mount a response against the cancer. Therefore, preserving the 
bone marrow and immune system from the cytotoxic effects of chemotherapy has the potential to 
maximize the anti-tumor activity of the chemotherapy while minimizing the consequences to the 
patient of chemotherapy-induced cellular damage. 
CHEMOTHERAPY AND TUMOR TYPE 
Globally, 1.85 million people will be diagnosed with colorectal cancer (CRC) each year and 
approximately 880,000 will die of their disease (WHO International Agency for Cancer 
Research, 2019). Multi-agent chemotherapy remains the cornerstone of treatment for metastatic 
disease and almost all patients will receive some combination of fluorouracil (5FU), oxaliplatin, 
irinotecan, a monoclonal antibody (mab) targeting the VEGF pathway and, for those with KRAS 
wild type disease, a mab targeting the EGFR pathway. How these drugs are combined with one 
another and administered to patients depends on a variety of factors including physician 
preference, patient preference, and patient characteristics. Geographic differences in practice 
patterns also influence the choice of therapies and how they are administered. In general, until 
relatively recently, the standard of care focused on the use of either FOLFOX (5FU, leucovorin, 
oxaliplatin) or FOLFIRI (5FU, leucovorin, irinotecan) in the first line setting to which a mab 
(anti-VEGF or anti-EGFR) would be added. Upon progression on this therapy, the patient then 
received the alternative therapy. For example, if a patient started on FOLFOX/mab, they would 
switch to FOLFIRI/mab upon progression on FOLFOX/mab. However, recent studies combining 
all four drugs (FOLFOXIRI) indicate that four drugs are better than three with respect to anti-
tumor efficacy in metastatic colorectal cancer (mCRC). 
In the TRIBE trial, patients on FOLFOXIRI/bevacizumab had a median progression free survival 
(PFS) of 12.1 months compared to those receiving FOLFIRI/bevacizumab who had a median 
PFS of 9.7 months (hazard ratio [HR]: 0.75); and a median overall survival (OS) of 29.8 months 
compared to 25.8 months in the FOLFIRI/bevacizumab arm (HR: 0.8) (Loupakis, 2014; 
Cremolini, 2015). In VISNU-1, in a subset of mCRC patients with a poor prognosis being treated 
in the first line setting, FOLFOXIRI/bevacizumab was statistically significantly better than 


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FOLFOX/bevacizumab at prolonging median PFS (12.4 months vs 9.3 months) (Sastre, 2019). 
Unfortunately, the improvements in PFS and OS have come at the expense of increased 
chemotherapy-induced toxicity as would be expected when the chemotherapy regimen is 
intensified by adding additional cytotoxic agents (Montagnani, 2011). For example, in the 
TRIBE study, patients receiving FOLFOXIRI/bevacizumab had higher rates of Grade 3 or 4 
neutropenia (50% vs 20.5%, febrile neutropenia (8.8% vs 6.3%) diarrhea (18.8% vs 10.6%), and 
stomatitis (8.8% vs 4.3%) compared to FOLFIRI/bevacizumab (Loupakis, 2014). Similarly, in 
VISNU-1, rates of ≥ Grade 3 neutropenia, febrile neutropenia and diarrhea were all significantly 
higher in patients receiving FOLFOXIRI/bevacizumab (35%, 9%, 21%) than in those receiving 
FOLFOX/bevacizumab (26%, 2%, 6%). Mucositis was also numerically higher in the 
FOLFOXIRI arm at 9% as compared to 4% in the FOLFOX arm in VISNU-1 (Sastre, 2019).  
One significant challenge when considering the FOLFOXIRI/bevacizumab published literature is 
that these trials were primarily designed to demonstrate anti-tumor efficacy and not designed to 
provide detailed assessments of CIM, as demonstrated by limited number of timepoints for blood 
counts and less frequent testing for blood counts. In addition, application of supportive care 
measures were left flexible and not regulated during these trials. For these reasons, the published 
literature likely underestimates the actual degree and rate of myelosuppression of FOLFOXIRI, 
which is hypothesized to be similar to that seen with the small cell lung cancer (SCLC) 
chemotherapy regimens studied in the trilaciclib program. 
As a result of the increased toxicity associated with FOLFOXIRI, the use of FOLFOXIRI is 
frequently limited to younger patients with fewer comorbidities and in need of aggressive 
cytoreduction. In fact, most trials where FOLFOXIRI is being evaluated specifically exclude 
patients over 70 with an Eastern Cooperative Oncology Group (ECOG) performance status other 
than 0. In the United States (US), the median age for colon cancer detection is 68 in men and 
72 in women suggesting that a substantial portion of those diagnosed are not considered for the 
FOLFOXIRI/bevacizumab regimen (ACS, 2019). In addition, some members of the oncology 
community believe that using all of the most active drugs together in the first line setting is 
inferior to a sequential approach. While recent data show no advantage to a sequential approach 
and suggest that patients should ideally receive the triple drug combination in the first line 
setting (Cremolini, 2019), the issue of increased chemotherapy-induced toxicity remains.  
Currently, there are no approved treatments to prevent the chemotherapy-induced cellular 
damage that leads to chemotherapy-induced toxicities like CIM, diarrhea, and stomatitis. 
Although some therapies may help to address CIM once they have occurred (eg, transfusions, 
growth factors), there are currently no available options that provide patients with the means to 
effectively protect hematopoietic stem and progenitor cells (HSPCs). HSPC protection would 
help to limit reductions in therapeutic dose intensity as well as off-target lymphocyte depletion 
that decreases host anti-tumor immunity (Lyman, 2006; Smith, 2006). Introducing a therapy that 
can protect the host from chemotherapy-induced cellular damage has the potential to minimize 
chemotherapy-induced toxicity while optimizing anti-tumor activity.  
CYCLIN-DEPENDEINT KINASES 4/6 PATHWAY AND COLORECTAL CANCER 
Cyclin-dependent kinases (CDKs) are a family of enzymes that regulate the cell cycle by binding 
to cyclins A-E and activating transcription factors that regulate cellular transition from gap 1 
(G1) (growth phase) to synthesis (S) (deoxyribonucleic acid [DNA] replication) and gap 2 (G2) 
(growth phase) to M (mitosis) (Asghar, 2015). Specifically, in G1, association of cyclin D with 


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CDK4 and/or CDK6 (CDK4/6) forms a complex that results in the activation of CDK4/6. The 
activated CDK4/6 complex phosphorylates the retinoblastoma (RB) protein leading to 
transcription of genes required for the G1/S transition and subsequent cell cycle progression. 
Similarly, other cyclin-CDK complexes (cyclin E-CDK2, cyclin A-CDK2, cyclin A-CDK1 and 
cyclin B-CDK1) regulate the transition through G1/S and the other phases of the cell cycle (S, 
G2, M).  
While CDK4/6 has been shown to orchestrate a variety of complex biological processes, all are 
associated with cell division including (1) cellular senescence (Anders, 2011) (2) cell 
differentiation (He, 2017; Sicinski, 1995; Lazarov, 2002; Shen, 2006; Fujimoto, 2007) (3) 
metabolism (Sakamaki, 2006; Wang, 2006) and (4) DNA repair (Cook, 2015; Hashizume, 2016). 
In addition to these normal cellular processes, dysregulation of the CDK4/6 pathway described 
above leads to uncontrolled tumor proliferation including loss of retinoblastoma gene (RB1) and 
increased p16INK4a expression (George, 2015; Herschkowitz, 2008; Subhawong, 2009). In 
addition to cell cycle regulation, CDK4/6 inhibition has been shown to regulate anti-tumor 
immunity through increased antigen presentation in tumor cells, (Goel, 2017; Schaer, 2018; 
Teo, 2017; G1 data not shown), reduced intra-tumoral frequency of T regulatory cells, and 
increased tumor infiltration and activation of cluster of differentiation (CD)4+ and CD8+ T cells 
(Deng, 2018; Schaer, 2018; Lai, 2018). 
While the data evaluating the role of the CDK4/6 pathway in CRC is relatively limited, the 
available nonclinical (in vivo and in vitro) and clinical data indicate that CRC is largely 
insensitive to CDK4/6 inhibitors (including trilaciclib); thereby suggesting that normal cell cycle 
controls mediated by the CDK4/6 pathway have been dysregulated (Lai, 2018; Sorrentino, 2017; 
Pek, 2017; Lee, 2016; Shapiro, 2013; O’ Hara, 2015). In addition, the observation that CRC is a 
chemosensitive tumor, and that loss of CDK4/6 pathway function correlates with increased 
tumor proliferation and improved tumor response to chemotherapy in a variety of cancer types, 
also indirectly indicates that CRC is generally CDK4/6 independent (Socinski, 2009; 
Herschkowitz, 2008; Ertel, 2010; Witkiewicz, 2012). Lastly, applying a DNA signature analysis 
algorithm to the cBioportal dataset to characterize CRC tumors as CDK4/6 dependent, 
independent or indeterminate, only 7.5% of microsatellite stable (MSS) CRC would be classified 
as CDK4/6 dependent (Gao, 2013; Cerami, 2012). 
4.1. 
Study Rationale 
Trilaciclib is a highly potent and selective, reversible, CDK4/6 inhibitor that is administered 
intravenously (IV) prior to chemotherapy and is designed to preserve HSPCs during 
chemotherapy (myelopreservation) and enhance anti-tumor immunity (anti-tumor efficacy). Both 
HSPC and lymphocyte populations are dependent on CDK4/6 activity (Kozar, 2004; 
Malumbres, 2004; Ramsey, 2007; Horsley, 2008) for proliferation and become arrested in the G1 
phase of the cell cycle upon exposure to trilaciclib (He, 2017). This transient, drug-induced, cell 
cycle arrest by trilaciclib has been demonstrated to provide protection from chemotherapy-
induced cell damage by preventing HSPCs from proliferating in the presence of cytotoxic 
chemotherapy and to favorably alter the tumor immune microenvironment through transient 
T cell inhibition when combined with chemotherapy (He, 2017; Bisi, 2016, Lai, 2020). 
Whereas current treatments for CIM are lineage specific, used after the damage to HSPCs has 
occurred, and place patients at risk for additional toxicities, trilaciclib improves the overall 


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chemotherapy experience for patients by the prevention of damage to HSPCs and therefore CIM, 
thus resulting in an overall improved safety profile and reduced utilization of available SOC 
treatments (Figure 1). 
Figure 1: 
Comparison of Trilaciclib and Current Myelosuppression Therapies 
 
ESA=erythropoiesis stimulating agent; G-CSF=granulocyte colony-stimulating factor. 
Three randomized, double-blind Phase 2 clinical trials evaluating trilaciclib/placebo administered 
prior to chemotherapy in patients with SCLC have demonstrated in a variety of clinical settings 
(first, second, third line SCLC treated with several different classes of chemotherapy) that 
trilaciclib can prevent CIM as measured by multiple endpoints (Weiss, 2019; Hart, 2019; 
Daniel, 2019). Analysis of the exploratory patient reported outcome (PRO) endpoints in these 
patients suggested that trilaciclib administered prior to chemotherapy may offer potential benefit 
in multiple aspects of health-related quality of life with a greater magnitude of effect observed 
for fatigue and anemia symptoms and functional limitations (Weiss, 2019). In an analysis of 
integrated data from all three studies, the delivery of trilaciclib prior to chemotherapy results in a 
4-day reduction in the duration of severe neutropenia in Cycle 1 and an approximately 76% 
reduction (52.9% placebo to 11.4% trilaciclib) in the occurrence of severe neutropenia during 
chemotherapy treatment. The occurrence of RBC transfusions on or after 5 weeks on study was 
reduced by almost half from 26.1% in those treated with placebo to 14.6% in those receiving 
trilaciclib with an associated 31.9% to 20.3% reduction in the rates of Grade 3 or 4 anemia. 
Grade 3 or 4 thrombocytopenia was decreased from 36.1% to 19.5% with the addition of 
trilaciclib and diarrhea was decreased from 17.8% to 13.1%. An analysis of integrated fatigue 
subscale data from Functional Assessment of Cancer Therapy – Anemia (FACT-An) in the three 
studies showed that trilaciclib delayed the median time to deterioration by approximately 5 
months for fatigue (7.03 months in the trilaciclib group vs 2.33 months in the placebo group, 
HR: 0.56 [0.37, 0.85]). In addition, these myelopreservation benefits were observed in the setting 


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of stable PFS and OS as evidenced by hazard ratios < 1.0 in almost all clinical settings for 
trilaciclib compared to placebo.  
In February 2021, the FDA approved trilaciclib (COSELA™) as a treatment to decrease the 
incidence of chemotherapy-induced myelosuppression in adult patients when administered prior 
to a platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage 
small cell lung cancer (ES-SCLC). 
In contrast, addition of trilaciclib to chemotherapy in patients with triple negative breast cancer 
(TNBC) in a fourth randomized, Phase 2 trial did not result in the striking statistically significant 
effects on CIM observed in the SCLC trials but did substantially impact anti-tumor efficacy as 
measured by OS (median OS in control 12.6 months vs 17.8 months or 20.1 months in the two 
trilaciclib groups) (Tan, 2019). The differences between the observed results in the SCLC trials 
and those in the TNBC trial, are hypothesized to result from differences in the key variables 
between the two clinical situations, ie, chemotherapy type, chemotherapy schedule, trilaciclib 
schedule, tumor type and host.  
Based on the mechanism of action (MOA) of trilaciclib, the effects of trilaciclib on CIM are 
predicted to be primarily influenced by the host, chemotherapy type and schedule, and trilaciclib 
schedule; the tumor type should be irrelevant since myelosuppression is not normally influenced 
by the type of solid tumor. Evaluation of these variables in the two clinical settings highlights an 
important observation: SCLC chemotherapy is delivered over sequential days (1-3 for 
etoposide/carboplatin or 1-5 for topotecan) in a cyclical fashion while in the TNBC trial, the 
chemotherapy (gemcitabine/carboplatin) was delivered intermittently (Days 1 and 8) in a cyclical 
fashion. This difference in chemotherapy schedule is hypothesized to be the key explanation for 
the differences in the magnitude of the effects on CIM in these settings. With sequential day 
chemotherapy, the HSPCs are relatively quiescent in their natural unstimulated state when 
chemotherapy begins. With the first dose of chemotherapy, the HSPCs and peripheral blood cells 
are damaged, which is hypothesized to signal the HSCPs to begin proliferating to repair the 
damage and replenish the peripheral blood counts. If chemotherapy continues to be administered 
for several days after that first stimulus, the HSPCs are predicted to be damaged further as they 
increase proliferation (Wang, 2006). In contrast, if proliferation is paused in G1 by trilaciclib, the 
HSPCs do not begin proliferating while chemotherapy is present and are predicted not to be 
damaged. Hence, with sequential day chemotherapy (eg, SCLC), trilaciclib prevents CIM. In 
contrast, with intermittent chemotherapy (e.g., TNBC trial), the chemotherapy is hypothesized to 
be delivered in a situation where the HSPCs are not fully protected from damage by trilaciclib. 
Unlike CIM, the effects of trilaciclib on anti-tumor efficacy are predicted to be primarily driven 
by the tumor type, chemotherapy type and host, ie, (1) the tumor type must be sufficiently 
responsive to chemotherapy such that maintenance of chemotherapy dose intensity is beneficial, 
(2) the tumor must be sufficiently immunogenic and sensitive to the host cytolytic efforts as to 
see improvement in anti-tumor endpoints like OS, (3) the chemotherapy should promote immune 
activation, and (4) the host must be able to tolerate the standard of care chemotherapy dose 
intensity and (5) the host must be able to mount an effective cytolytic response against the tumor. 
In the SCLC trials, the addition of trilaciclib to the standard of care therapies provided modest 
improvement, to neutral effects, on measures of anti-tumor efficacy including objective response 
rate (ORR), PFS and OS. These results are not surprising considering that SCLC is one of the 
most aggressive solid tumors, relapses quickly after completion of chemotherapy, has been 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1_ 1 5 Dece m ber 2 0 2 2  
 
2 6  
s h o w n t o be relati vel y i nse nsiti ve t o m ulti ple atte m pts t o i nte nsif y t he c he m ot hera p y re gi me n 
be y o n d t he c urre nt S O C , a n d is n ot partic ularl y i m m u n o ge nic or se nsiti ve t o i m m u ne 
m o d ulati o n. I n c o ntr ast, s o me T N B C o utc o mes ca n be i m pr o ve d wit h mai nte na nce of d ose 
i nte nsit y (i m pr o ve d O S wit h d ose de nse a dria m yci n a n d c ycl o p h os p ha mi d e [A C ] c o m pare d t o 
tra diti o nal sc he d ule A C) (Citr o n , 2 0 0 3 ; L oi bl  2 0 1 1 ), a n d T N B C has bee n s h o w n t o be 
i m m u n o ge nic a n d m ore s e nsiti ve t o i m m u ne m o d ulati o n c o m pare d t o S C L C (Se me n o va , 2 0 1 5 ; 
He , 2 0 1 7 ; Car vajal -Ha us d orf , 2 0 1 9 , Li u , 2 0 1 8 ). He nce, trila cicli b a d de d t o sta n dar d of care 
t hera p y i n T N B C a p peare d t o i m pr o ve  a nti-t u m or efficac y o utc o mes. 
I n s u m mar y, t he ma g nit u de of be nefit pr o vi de d b y trilacicli b f or t he pre ve nti o n or miti gati o n of 
CI M a n d/ or i m pr o vi n g a nti -t u m or efficac y is h y p ot hesize d t o de pe n d o n t h e c he m ot hera p y t y pe 
a n d sc he d ule, h ost i m m u ne s yste m, a n d t u m or t y pe. P R E S E R V E 1  has bee n desi g ne d t o 
u n dersta n d h o w t hes e varia bles i nfl ue nce t h e ma nifestati o n of trilacicli b be nefits (i .e., pre v e nt 
CI M, i m pr o ve a nti -t u m or effic ac y or b ot h) b y c o m bi ni n g trilacicli b wit h a c he m ot hera p y 
re gi me n wit h a se q u e ntial da y sc he d ule t hat is i nter me diate bet w ee n t hat e v al uate d i n t he S C L C 
a n d T N B C trial ( F O L F O XI RI/ be vaci z u ma b wit h 4 8 h o urs i nf usi o nal -5 F U). I n a d diti o n, 
e nr oll me nt of patie nts wit h pr oficie nt mis matc h re pair  (p M M R) /M S S  C R C, w hic h has n ot bee n 
res p o nsi ve t o si n gle a ge nt c hec k p oi nt i n hi bit ors i n t he cli nic (R os , 2 0 1 8 ; Her mel , 2 0 1 9 ), will 
e x pl ore t he e xt e nt t o w hic h  t he i m m u ne micr oe n vir o n me nt of t he t u m or, al o ne or i n c o m bi nati o n 
wit h i nte nsificati o n of c h e m ot hera p y, pla ys a r ole i n t he a bilit y of trilacicli b t o be nefit  patie nts 
wit h i m pr o ve me nt i n a nti -t u m or effic ac y. 
F O L F O XI RI is a f o ur -dr u g re gi me n c o m p ose d of i nf usi o nal -5 F U, o xali plati n, iri n oteca n a n d 
le uc o v ori n a d mi nistere d f or a ma xi m u m of 1 2 I n d ucti o n c ycles (e ver y 1 4 d a ys) f oll o we d b y 
Mai nte na nce c o nsisti n g of i nf usi o nal -5 F U a n d le uc o v ori n a d mi nistere d i n 1 4 -da y c ycl es u ntil 
disease pr o gressi o n, u nacce pta ble t o xicit y etc . F O L F O XI RI was c h os e n as t he c he m ot hera p y 
bac k b o ne f or t his trial (c o m pare d t o F O L F O X or F O L FI RI) f or a m ultit u de of reas o ns i ncl u di n g:  
•  F O L F O XI R I is t he m ost m yel os u p pressi ve of t he 5 F U -b ase d re gi me ns. Patie nts 
recei vi n g t his re gi me n will recei ve t he m a xi mal be nefit fr o m t he a bilit y of trilacicli b 
t o pre ve nt or miti gate CI M.  
•  F O L F O XI RI is m ore effi caci o us t ha n eit her F O L F O X or F O L FI RI s uc h t hat if  
patie nts c o ul d recei ve t his re gi me n safel y at t he sta n dar d of care d ose a n d s c he d ule, 
t he y w o ul d deri ve m ore be nefit. 
•  Beca use of t h e c he m ot hera p y -i n d uce d t o xicit y ass ociate d wit h F O L F O XI RI, its use is 
li mite d t o y o u n ger patie nts wit h a p o orer pr o g n osis; pre ve nti o n or miti gati o n of t h ose 
t o xicities c o ul d lea d t o e x pa nsi o n of its use t o m ore patie nts w h o c o ul d b e nefit fr o m 
its a bilit y t o deli ver s u peri or o utc o mes.  
p M M R/ M S S m C R C was c h ose n beca use it is t he m ost c o m m o n t u m or t y pe treate d wit h 
F O L F O XI RI a n d i t has b ee n s h o w n t o be se nsiti ve t o c he m ot hera p y i nte nsificati o n, ie, t he f o ur 
dr u g re gi me n is m ore effi caci o us t ha n t he t hree dr u g re gi me ns, s o t here is a p ote ntial f or patie nts 
t o be nefit fr o m de crease d CI M lea di n g t o mai nte na nce of st a n dar d of care c he mot hera p y d os e 
a n d sc he d ule.  
T his st u d y will e nr oll patie nts wit h u nresecta ble disease. H o we ver, patie nts wit h metastases 
c o nfi ne d t o t he li ver ha ve bee n s h o w n t o ha v e hi g her rat es of c urati ve i nte nt s ur gical res ecti o n 
wit h F O L F O XI RI/ be v aci z u ma b  (Gr u e n ber ger , 2 0 1 5). S uc h patie nts ac hie vi n g gr oss t otal 


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resection have longer PFS and OS (Cremolini, 2017). Patients enrolled in this study who may 
become eligible for and proceed to surgical resection will be appropriately managed both 
clinically and with respect to analysis of their study data (see Section 12). 
While preventing or mitigating CIM is the primary objective of this trial, there are other cells in 
the host that are dependent on CDK4/6 for proliferation and that suffer from chemotherapy-
induced damage similar to HSPCs and lymphocytes. Examples include the stem cells of hair 
follicles and the stem and progenitor cells of the intestinal crypts (Purba, 2019; Yu, 2008; 
Wei, 2016; Yang, 2007). In a manner similar to what is seen with protection of HSPCs and 
lymphocytes, it is possible that protection of these cell populations could lead to improvements 
in chemotherapy-induced alopecia, stomatitis and diarrhea. This possibility is supported by 
results from the integrated analysis of the SCLC trials where, although the rates of stomatitis 
were low in both arms as expected with the chemotherapy regimens utilized, trilaciclib 
administered prior to chemotherapy resulted in a decreased percentage of patients experiencing 
diarrhea (13.1% vs 17.8%) and alopecia (13.1% vs 25.4%) compared to placebo.  
4.2. 
Background 
4.2.1. 
Summary of Nonclinical Data 
A summary of the trilaciclib nonclinical data is presented in the Trilaciclib Investigator’s 
Brochure (IB).  
Nonclinical data related to FOLFOXIRI/bevacizumab are provided in the prescribing 
information (Section 17.5 and Section 17.6). 
4.2.1.1. 
Pharmacology Studies 
Trilaciclib-induced G1 arrest of HSPCs has been shown to be transient and readily reversible in 
both in vitro and in vivo models. In mice treated with a single dose of 5FU, the rapid depletion of 
various cellular lineages (neutrophils, red blood cells, lymphocytes, platelets) is not prevented 
with the administration of trilaciclib, but animals that received trilaciclib + 5FU demonstrate a 
faster rate of recovery and improved survival compared with the 5FU alone group. In accordance 
with the single-dose study, trilaciclib administration with all cycles of 5FU maintained the 
protective effect against 5FU-induced DNA damage in HSPCs over multiple cycles, leading to 
an effect that persisted and was greater following multiple cycles of trilaciclib + 5FU compared 
with 5FU alone. In addition, bone marrow obtained from mice that received trilaciclib in 
combination with 5FU for a total of 4 cycles was more robust at hematopoietic reconstitution of 
lethally irradiated mice compared with bone marrow obtained from mice that received 4 cycles 
of 5FU alone, suggesting that trilaciclib administered with chemotherapy can preserve stem cell 
function. Additionally, when a separate cohort of 5FU ± trilaciclib-treated mice was analyzed 
13 months after the last dose of 5FU (in the absence of bone marrow transplantation), 
trilaciclib-treated mice demonstrated significantly higher peripheral blood lymphoid-to-myeloid 
cell ratios compared to 5FU only treated mice, further supporting trilaciclib’s long-term 
protection of hematopoietic stem cell function (He, 2017) following 5FU based chemotherapy. 
As a consequence of trilaciclib’s MOA, there is a hypothetical risk that administration of 
trilaciclib prior to chemotherapy could decrease chemotherapy efficacy by pausing 
CDK4/6-dependent tumor cells in G1 in the presence of chemotherapy; however, nonclinical 


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data suggest this risk is not clinically significant. To understand why trilaciclib should not 
antagonize chemotherapy treatment, the baseline proliferation rates of hematopoietic stem and 
progenitor cells (HSPCs), bone marrow, and patient derived xenografts (PDX) were examined 
using flow cytometric analysis of the cell cycle. A bar graph depicting mean percentage of cells 
in S/G2/M demonstrates there are a higher proportion of cells cycling in tumor cells when 
compared to bone marrow/HSPCs. Specifically, < 4% of human HSPCs are cycling, while in 
breast tumors an average of ~40% of cells were cycling (Figure 2, left). These results illustrate 
why tumor cells are more susceptible to chemotherapy-induced damage compared to HSPCs, 
since chemotherapy treatment is predominantly effective in the S/G2/M phases of the cell cycle. 
To evaluate the effects of trilaciclib on HSPCs and CDK4/6 dependent tumor cells, MCF7 
tumor-bearing mice were given a single dose of trilaciclib, and bone marrow and MCF7 tumor 
cell proliferation was evaluated. MCF7 tumors are a well-established estrogen receptor (ER)+ 
breast cancer model known to be CDK4/6 dependent (Hafner, 2019). After treatment, trilaciclib 
inhibits proliferation (% 5-ethynyl-2´-deoxyuridine [EdU]+ cells) at a faster rate and more 
completely in bone marrow than tumor cells (Figure 2, right). The differences in inhibition rates 
between HSPCs and MCF7 tumors cells after trilaciclib treatment creates a therapeutic window 
for the selective protection of bone marrow compared to CDK4/6-dependent tumor cells from 
the cytotoxic effects of chemotherapy. 
Figure 2: 
Proliferation Kinetics Are Different Between Bone Marrow and Tumor Cells 
 
A) Mean differences in baseline proliferation rates of hematopoietic stem cells (HSCs), hematopoietic stem and 
progenitor cells (HSPCs), bone marrow (BM), and patient derived xenograft (PDX) tumor cells in mice and humans, 
were examined using flow cytometric analysis of the cell cycle (He, 2017). Error bars represent the minimum and 
maximum. B) MCF7 tumor-bearing mice were treated with a single dose of trilaciclib (intraperitoneal [IP], 
100 mg/kg) or vehicle control. 4, 12, 24, and 48 hours post-treatment. Animals were pulsed with 5 ethynyl-2′ -
deoxyuridine (EdU; IP, 200 mg) and tumors and femurs were harvested after 4 hours of EdU dosing. HSPC in bone 
marrow is defined as cell populations negative for lineage markers Mac-1, Gr-1, Ter119, B220, CD4, and CD8. 
Proliferations was measured by % EdU incorporated. ****p≤ 0.0001, **p≤ 0.01, *p≤ 0.05 
To test whether trilaciclib could decrease chemotherapy efficacy in CDK4/6 dependent tumor 
models, two different models were treated with chemotherapy and trilaciclib. To confirm 
CDK4/6 dependence in MCF7 tumors, two alternative CDK4/6 inhibitors (palbociclib and 
lerociclib) were administered continuously to MCF7 tumor-bearing mice for 28 days, with 
tumors regressing when on treatment. MCF7 tumor-bearing mice were treated with docetaxel 
(IV, 5 mg/kg) +/- trilaciclib once weekly for three doses. Although weekly trilaciclib treatment 
caused some tumor growth inhibition, administering trilaciclib with docetaxel did not alter the 


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effects of chemotherapy (Figure 3, top right). Next, MDA-MB231 tumor-bearing mice were 
treated with daily trilaciclib (intraperitoneal [IP], 100 mg/kg) for 28 days to confirm CDK4/6 
dependence. Continuous treatment with trilaciclib caused stable disease in MDA-MB231 tumor-
bearing mice (Figure 3, bottom left). MDA-MB231 tumor-bearing mice were then treated with 
eribulin (IV, 0.5 mg/kg) +/- trilaciclib once weekly for three doses. Similar to the MCF7 model, 
the addition of trilaciclib to eribulin treatment did not impact chemotherapy efficacy (Figure 3, 
bottom right). These experiments demonstrate that transient CDK4/6 inhibition prior to 
chemotherapy (eribulin, docetaxel) does not antagonize the intended anti-tumor effects of the 
chemotherapy in these CDK4/6-dependent tumor models. 
Figure 3:  
CDK4/6 Inhibition Does Not Antagonize Anti-Tumor Efficacy of 
Chemotherapy in CDK4/6 Dependent Xenograft Models 
 
 
4.2.1.2. 
Pharmacokinetic Studies 
In vitro analyses of direct and time-dependent inhibition suggest that drug interactions based on 
inhibition of cytochrome P450 (CYP)1A2-, 2B6-, 2C8-, 2C9-, 2C19-, and 2D6-mediated 
metabolic pathways are unlikely at clinical doses, however, the studies do suggest that drug 
interactions via trilaciclib-mediated inhibition of CYP3A4 metabolic pathways are possible. A 
clinical DDI study using the index CYP3A substrate midazolam indicated that trilaciclib had no 
impact on CYP3A activity. Two clinical DDI studies using a strong CYP3A inhibitor 
itraconazole were also conducted. No clinically significant changes in exposure were observed 
for trilaciclib when co-administered with itraconazole. In vitro induction studies of the 3 major 
inducible CYP enzymes (CYP1A2, CYP3A4, and CYP2B6) in human hepatocytes suggest that 
trilaciclib mediated induction is unlikely. 
In vitro inhibition studies with membrane transporter model systems also suggest trilaciclib is 
unlikely to cause a drug-drug interaction (DDI) based on inhibition of breast cancer resistance 
protein (BCRP)-, bile salt export pump (BSEP)-, organic anion transporter 1 (OAT1)-, organic 
anion transporter 3 (OAT3)-, organic anion transporting polypeptide 1B1 (OATP1B1), 


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p glycoprotein (p-gp), multidrug resistance protein (MRP) 1, MRP2, organic cation transporter 1 
(OCT1), or organic anion transporting polypeptide 1B3 (OATP1B3) mediated transport. 
However, in vitro, trilaciclib is a potent inhibitor of multidrug and toxin extrusion 1 (MATE1), 
multidrug and toxin extrusion 2-K (MATE2-K), organic cation transporter 1 (OCT1), and 
organic cation transporter 2 (OCT2). Clinical data from the evaluation of trilaciclib administered 
prior to topotecan (Study G1T28-03) suggests that drugs that are substrates of multidrug and 
toxin extrusion (MATE)1 and MATE2 do not pose a clinically relevant risk of DDIs when 
administered concomitantly with trilaciclib. In an additional clinical DDI assessment, trilaciclib 
increased metformin (MATE1, MATE2-K and OCT2 substrate) exposure by 65%, in healthy 
subjects, compared to administration of metformin alone. Avoid concomitant use of trilaciclib 
with certain OCT2, MATE1, and MATE2-K substrates (e.g., dofetilide, dalfampridine) where 
minimal concentration changes may lead to serious or life-threatening toxicities. Refer to the 
prescribing information for these concomitant medications for assessing the benefit and risk of 
concomitant use with trilaciclib. 
Study G1T28-11 was a single ascending dose study, with both placebo and positive control 
groups, with the objective to evaluate potential effects of trilaciclib on ECG parameters, 
including concentration-QTc (C-QTc) analysis. Trilaciclib transiently increased heart rate by 
approximately 10 beats per minute. At the clinical dose of 240 mg/m2, trilaciclib did not have a 
clinically relevant effecton QTc (i.e., > 10 msec).  
Irinotecan is converted by enzymes into its active metabolite SN-38. SN-38 is inactivated by the 
enzyme UGT1A1 via glucuronidation. The inhibition of UGT1A1 could potentially elevate the 
SN-38 exposure causing toxicity. The inhibitory effect of trilaciclib on UGT1A1 was tested in 
vitro using 17ß-Estradiol as a substrate. The estimated half maximal inhibitory concentration 
(IC50) was 20 µM. The highest concentration of trilaciclib observed in the clinical studies was 
~1800 ng/mL (~4 µM) at recommended dose of 240 mg/m2. The unbound fraction of trilaciclib 
in human plasma is ~30%. By assuming inhibitory constant (Ki)=IC50/2, the R1 value 
recommended by the Food and Drug Administration (FDA) is calculated to be 1.12 which is 
slightly higher than the 1.02 threshold proposed by FDA for clinical assessment. Given trilaciclib 
showed a three-compartment pharmacokinetic (PK) profile with an alpha phase half-life (t1/2) of 
0.25 hour, the concentration of trilaciclib will drop below the 1.02 threshold approximately 40 
minutes after reaching the maximum concentration (Tmax). Therefore, the overall impact on the 
SN-38 exposure via UGT1A1 inhibition by trilaciclib is regarded to be minimal.  
Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via 
displacement of the labile oxalate ligand. There is no evidence of cytochrome P450-mediated 
metabolism in vitro. The major route of platinum elimination is renal excretion. In addition, 
oxaliplatin does not inhibit P450 enzymes in vitro. Hence, a PK drug-drug interaction between 
trilaciclib and oxaliplatin is not expected. 
5FU is a prodrug and it has a narrow therapeutic range. In humans, the majority of 5FU dosage is 
degraded by dihydropyrimidine dehydrogenase. Approximately 60 to 90% of the administered 
dose is excreted in the urine within 24 hours, primarily as alpha-fluoro-beta-alanine. 5FU inhibits 
CYP2C9. However, triaciclib is not a substrate of CYP2C9. Therefore, a PK DDI between 
trilaciclib and 5FU is not expected. 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1_ 1 5 Dece m ber 2 0 2 2  
 
3 1  
4. 2. 2.  
S u m m ar y of Cli nic al D at a  
4. 2. 2. 1.  
Tril acicli b  
A s u m mar y of t he cli nical st u d y res ults wit h trilacicli b is a vaila ble i n t he Trilacicli b I B. Res ults 
rele va nt t o t his cli nical st u d y are s u m marize d bel o w. 
T he safet y a n d eff icac y of a d mi nisteri n g trilacicli b pri or t o  c he m ot hera p y was teste d i n o ne 
c o m plete d a n d o ne o n g oi n g P hase 1 b/ 2 st u d y ( G 1 T 2 8 -0 2 a n d G 1 T 2 8 -0 3) a n d 2 c o m plete d P hase 
2 st u dies ( G 1 T 2 8 -0 5 a n d G 1 T 2 8 -0 4) i n patie nts wit h S C L C or T N B C. T he P hase 2 p orti o ns of 
St u dies G 1 T 2 8 -0 2 , G 1 T 2 8 -0 3 a n d St u d y G 1 T 2 8 -0 5 were ra n d o mize d, d o u ble bli n d a n d place b o -
c o ntr olle d. St u d y G 1 T 2 8 -0 4 was r a n d o mize d a n d i ncl u de d a c o ntr ol ar m b ut was n ot d o u ble -
bli n de d.  
•  St u d y G 1 T 2 8 -0 2 e xa mi ne d o nce -d ail y I V a d mi nistrati o n of eit her trilaci cli b  or 
place b o o n D a ys 1 t o 3 of eac h 2 1 -da y et o p osi de pl us car b o plati n ( E/ P ) c h e m ot hera p y 
c ycle i n patie nts wit h treat me nt naï ve e xte nsi ve -sta ge S C L C.  
•  St u d y G 1 T 2 8 -0 3 e xa mi ne d o nce -d ail y I V a d mi nistrati o n of trilacicli b or pl ace b o o n 
Da ys 1 t o 5 of eac h 2 1 -d a y t o p oteca n c he m ot hera p y c ycle i n patie nts wit h pre vi o usl y 
treate d e xt e nsi ve-sta ge S C L C.  
•  St u d y G 1 T 2 8 -0 5 e xa mi ne d o nce -d ail y I V a d mi nistrati o n of trilacicli b or pl ace b o o n 
Da ys 1  t o 3 f or a m a xi m u m of f o ur 2 1-da y c ycles of E/ P a n d atez oliz u ma b, f oll o we d 
b y m o n ot hera p y ate z oliz u ma b, i n patie nts wit h treat me nt naï ve e xte nsi ve -sta ge 
S C L C.  
•  St u d y G 1 T 2 8 -0 4 e xa mi ne d o nce -d ail y I V a d mi nistrati o n of trilacicli b  pri or t o  
ge mcita bi ne a n d car b o pl ati n i n patie nts wit h meta static T N B C. Patie nts recei ve d 1) 
ge mcita bi ne pl us car b o plati n ( G/ C ) t hera p y o nl y o n D a ys 1 a n d 8 of a 2 1 -d a y c ycle, 
2) trilacicli b a n d G/ C o nce dail y o n Da ys 1 a n d 8 of eac h 2 1 -da y c ycle, O R 3) 
trilacicli b o n Da ys 1, 2, 8 a n d 9 wit h G/ C o n Da ys 2 a n d 9 of eac h 2 1 -d a y c ycle.  
At t he rec o m me n d e d p hase 2 d ose ( R P 2 D) of 2 4 0 m g/ m 2, acr oss all t hree S C L C trials, trilacicli b 
a d mi nistere d pri or t o c h e m ot hera p y statisticall y si g nifica ntl y re d uce d t he d urati o n of se vere 
ne utr o pe nia [ S N] i n C ycle 1 a n d occ urre nce of S N ( pri mar y e n d p oi nts) c o m pare d wit h  place b o. 
A n i nte grate d dat a a nal ysis of t he t hree S C L C st u dies f or 8 of t he m ost rel e va nt 
m yel os u p pressi o n e n d p oi nts ( ne utr o p hils, R B Cs a n d platelets) is s u m marize d i n Ta ble  2 . Base d 
o n t his p o ole d S C L C a nal ysis, statisticall y si g nifica nt, a n d cli nicall y mea ni n gf ul, i m pr o ve me nts 
f or trilacicli b o ver a vaila ble t hera pies is de m o nstrate d i n 6 of 8 e n d p oi nts acr oss m ulti ple 
li nea ges. I m p orta ntl y, t hese m yel o preser vati o n be n efits c o me wit h a n o verall i m pr o ve d safet y 
pr ofile c o m pare d t o a vail a ble t hera p y, as e vi de nce d b y re d uce d hi g h gra de treat me nt-e mer ge nt 
A Es acr oss all S C L C st u dies, a n d n o detri me nt t o a nti -t u m or efficac y res ults.  


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32 
Table 2: 
Integrated Analysis for Myelopreservation Efficacy in SCLC (Studies 
G1T28-02, G1T28-03, and G1T28-05) 
Placebo 
+Chemo 
Trilaciclib 
+Chemo 
2-sided p-value 
ITT Set  
119 
123 
 
Neutrophils 
DSN [days] in Cycle 1 – Mean (SD)a 
4 (5.1) 
0 (1.8) 
<0.0001 
Occurrence of SN (Yes, %)b 
64 (52.9)  
14 (11.4)  
<0.0001 
RBCs 
Occurrence of Grade 3/4 hemoglobin decreased 
(anemia) (Yes, %)b 
38 (31.9) 
25 (20.3) 
0.0279 
Occurrence of RBC transfusion on/after 5 weeks 
(Yes, %)b 
31 (26.1) 
18 (14.6) 
0.0252 
Cumulative incidence of RBC transfusion on/after 5 
weeks - Event rate (per 100 weeks) c 
 3.1 
1.5 
0.0027 
Platelets 
Occurrence of Grade 3/4 platelet count decreased 
(thrombocytopenia) (Yes, %) b 
43 (36.1) 
24 (19.5) 
0.0067 
Occurrence of platelet transfusion (Yes, %)b 
11 (9.2) 
10 (8.1) 
0.9564 
Cumulative incidence of platelet transfusion - Event 
rate (per 100 weeks)c 
1.7 
1.1 
0.5169 
ANC=absolute neutrophil count; Chemo=chemotherapy; DSN=duration of severe (Grade 4) neutropenia; 
ECOG=Eastern Cooperative Group; ITT=intent to treat; SN=severe (Grade 4) neutropenia which is defined as ANC 
< 500/mm3; RBC=red blood cells, SCLC=small cell lung cancer; SD=standard deviation. 
Chemo=etoposide + platinum in G1T28-02, etoposide + platinum + atezolizumab in G1T28-05, and topotecan in 
G1T28-03. Standard supportive care interventions were allowed for all arms.  
a. p-value was obtained from a nonparametric analysis of covariance (ANCOVA).  
b. p-value was obtained from a modified Poisson model. 
c. p-value was obtained from a negative binomial model. All three models contained fixed effect of treatment, 
ECOG performance status (0/1 vs. 2), Presence of brain metastases (Y/N), and study (G1T28-02, G1T28-03, or 
G1T28-05). Corresponding baseline assessment was also included as a covariate. 
Results from Study G1T28-04 demonstrated that although the addition of trilaciclib to GC did 
not statistically significantly improve CIM as measured by the neutrophil-based primary 
endpoints of duration of severe (Grade 4) neutropenia (DSN) in Cycle 1 and occurrence of SN, 
there were trends toward improvement in RBC and platelet-based measures. In addition, anti-
tumor efficacy results demonstrated a clinically meaningful improvement in PFS and most 
importantly OS with HR: 0.31 (median OS: not reached [NR]; 95% confidence interval [10.2, 
NR]) and 0.40 ([median OS: 17.8 months; 95% confidence interval [12.9, 32.7]) for the two 
trilaciclib arms, respectively (see Trilaciclib IB). This meaningful anti-tumor efficacy was 
observed across multiple subgroups and in both of the trilaciclib groups compared with the 
control group.  
As mentioned in Section 4.2.1.1, there is a hypothetical risk that administration of trilaciclib 
prior to chemotherapy could decrease chemotherapy efficacy by pausing CDK4/6-dependent 


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33 
tumor cells in G1 in the presence of chemotherapy. This hypothetical risk is countered by the 
results observed in Study G1T28-04 which suggested that the addition of trilaciclib improves the 
anti-tumor efficacy of gemcitabine and carboplatin regardless of the CDK4/6 status of the TNBC 
tumor. Although TNBC tumors are predominantly classified as CDK4/6 independent (ie, their 
replication is not sensitive to CDK4/6 inhibition), there is a small subset of patients whose 
tumors are classified as either CDK4/6 indeterminate or CDK4/6 dependent. When the TNBC 
population enrolled in Study G1T28-04 is divided into these subsets, evaluation of the anti-tumor 
efficacy in patients whose tumors are classified as CDK4/6 indeterminate or CDK4/6 dependent 
suggests that trilaciclib does not antagonize the anti-tumor effects of gemcitabine and 
carboplatin. Specifically, PFS and OS did not decrease when trilaciclib was added to 
gemcitabine and carboplatin in the most CDK4/6 dependent population (see Trilaciclib IB). 
4.2.2.2. 
FOLFOXIRI/Bevacizumab 
4.2.2.2.1. FOLFOXIRI 
FOLFOXIRI is a combination of 5FU, leucovorin, oxaliplatin, and irinotecan commonly used in 
the treatment of mCRC (NCCN, 2019). Complete prescribing information for each component is 
provided in Section 17.5. 
4.2.2.2.2. Bevacizumab 
Bevacizumab has been tested in clinical studies and is currently approved by the US FDA for the 
treatment of mCRC, in combination with fluorouracil-based chemotherapy for first- or 
second-line treatment (Avastin®, 2020; Avastin®, 2019). Complete prescribing information is 
provided in Section 17.6.  
4.2.3. 
Risks 
4.2.3.1. 
Trilaciclib 
Reproductive/embryo-fetal effects is an important potential risk of trilaciclib. Both nonclinical 
toxicology studies with trilaciclib, and clinical studies with other compounds with a similar 
MOA, report effects on either the reproductive system or embryo/fetus. Since this clinical study 
will focus on trilaciclib administered prior to cytotoxic chemotherapy (which carries its own risk 
of reproductive/embryo-fetal toxicity), the risks specific to trilaciclib are consistent with those 
experienced with chemotherapy. In addition, female patients will be monitored for pregnancy 
and eligibility criteria describing specific birth control methods are incorporated. Dose 
discontinuation recommendations for female patients who become pregnant while receiving 
trilaciclib are also provided in the protocol. Detailed information regarding all important 
identified and important potential risks of trilaciclib administration can be found in the 
Trilaciclib IB. 
Adverse events of special interest (AESIs) identified for trilaciclib are described below. Rates 
reported below reflect those observed in the integrated safety summary from the four Phase 2 
oncology trials conducted with trilaciclib to date (G1T28-02 [database lock: 05 May 2019], 
G1T28-03 [data cutoff: 31 May 2019], G1T28-05 [data cutoff: 28 June 2019], and G1T28-04 
[data cutoff: 28 June 2019]). Some AESIs have been infrequently reported (or not reported) in 
the trilaciclib clinical program to date but are considered to be potential class effects of CDK4/6 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1_ 1 5 Dece m ber 2 0 2 2  
 
3 4  
i n hi bit ors. H o we ver,  as trilacicli b is gi ve n i ntra ve n o usl y a n d o nl y w he n c he m ot hera p y  is 
a d mi nistere d, t he safet y pr ofile of trilacicli b a p pears t o be differe nt fr o m t hat of t he oral, 
c hr o nicall y -d ose d m e m bers of its p har mac ol o gic class. All patie nts w ill be m o nit ore d f or t hese 
e ve nts a n d d ose m o dificati o n a n d disc o nti n uati o n g ui deli nes are pr o vi d e d i n Secti o n  9. 5 .  
Tril acicli b A E SIs : 
1.  I njecti o n Site Re acti o n/ P hle bitis/ T hr o m b o p hle bitis:  I nf usi o n of trilacicli b ma y res ult 
i n l ocal irritati o n ma nifesti n g as er yt he ma, pai n, a n d s welli n g; a n d i n a s u bset of patie nts, 
t he irritati o n ma y ca use p hle bitis/t hr o m b o p hle bitis. I njecti o n site reacti o ns ha ve bee n 
o b ser ve d i n a p pr o xi matel y 1 5 t o 2 0 % of patie nts r ecei vi n g trilacicli b a n d t h e e ve nts ha v e 
bee n Gra de 1 or 2. P hle bitis/t hr o m b o p hle bitis has bee n n ote d i n a p pr o xi mat el y 5 t o 1 0 % 
of patie nts recei vi n g trilacicli b a n d t he e ve nts were pri maril y Gra d e 1 or 2. S u p p orti ve 
care i nter ve nti o ns s uc h as  sl o wi n g t he i nf usi o n rate, fl us hi n g t he i nf usi o n li ne wit h a 
mi ni m u m of 2 0 ml n or mal sali ne or 5 % de xtr ose, r otati n g I V cat h eter sites or  re m o vi n g 
t he I V (w h e n gi ve n peri p herall y ) f oll o wi n g eac h trilacicli b i nf usi o n ca n decrease t h e 
fre q ue n c y a n d se v erit y of t hese e ve nts. I n a d diti o n, if s y m pt o ms are o bser ve d wit h 
n or mal sali ne as dil ue nt/fl us h, use of 5 % de xtr ose as a n alter nati ve ma y decrease t h e 
s y m pt o ms. Ce ntral access ma y als o be c o nsi dere d.  
2.  Ac ute D r u g H y perse nsiti vit y R e acti o n: Trilacicli b a d mi nistrati o n ma y ca use ac ute dr u g 
h y perse nsiti vit y reacti o n c haracteri ze d b y s y m pt o ms li ke facial e de m a, pr uritis, a n d 
urticaria. T h ese e v e nts ha ve bee n re p orte d i n a p pr o xi matel y 6 % of pati e nts r ecei vi n g 
trilacicli b c o m pare d wit h a p pr o xi matel y 3 % i n patie nts recei vi n g place b o, a n d were 
classifie d as Gra de 1 a n d 2. O nl y o ne cas e of gra d e 2 a na p h yla xis was  o bser ve d , w hic h 
occ urre d  4 da ys after  t he prece di n g d os e of trilaci cli b, res ol ve d o n t he sa me da y, was n ot 
seri o us, a n d di d n ot res ult i n disc o nti n uati o n of treat me nt.  
3.  P ne u m o nitis/ I nterstiti al L u n g Dise ase (I L D): A rare ( 1 t o 3 %) b ut seri o us class effect 
( < 1 % fatal) ass o ciate d wit h C D K 4/ 6 i n hi bit ors. S y m pt o ms i ncl u de h y p o xia, c o u g h, 
d ys p nea , or i nterstitial i nfiltrates o n ra di ol o gic e x a ms i n patie nts i n w h o m i nfecti o us, 
ne o plastic or ot her ca uses ha ve bee n e xcl u de d. T h e o nl y case of p ne u m o nitis re p orte d i n 
patie nts w h o recei ve d  tril acicli b was o bser ve d i n a patie nt i n w h o m trilacicli b ha d bee n 
disc o nti n ue d f or t w o m o nt hs a n d w h o ha d bee n recei vi n g atez oliz u ma b ( k n o w n t o ca use 
p ne u m o nitis) as m o n ot hera p y. T he p n e u m o nitis e ve nt was Gra de 3 a n d c o nsi dere d b y t he 
In v esti gat or t o be relate d t o atez oliz u ma b.  
4.  He p at ot o xicit y : B ot h n o ncli nical t o xic o l o g y st u dies wit h trilacicli b, a n d cli nical st u dies 
wit h ot her c o m p o u n ds wit h a si milar M O A,  re p ort re versi ble ele vati o ns i n tr a nsa mi nases 
wit h c o nti n u o us d osi n g. T here h as bee n o nl y 1 i nsta nce of Gra de 4 ala ni ne 
a mi n otra nsferase ( A L T ) i ncreas e i n a patie nt r ecei vi n g trilacicli b, n o Gra de 4 as partate 
a mi n otra nsferase ( A S T ) i ncreas es, a n d n o cases of H y’s la w re p orte d i n patie nts 
recei vi n g trilaci cli b. H o we ver, ge nerall y l o w gra de a n d tra nsie nt i ncreas es i n A S T, A L T 
or bilir u bi n ha ve bee n o bser ve d i n a s mall n u m ber of patie nts ( ~ 5 %) recei vi n g trilacicli b 
pri or t o  c he m ot hera p y. Patie nts wit h mil d h e patic i m pair me nt ha ve bee n treate d wit h 
trilacicli b wit h o ut a cli nicall y si g nifica nt i ncrease i n e x p os ure or t he fre q u e nc y/se verit y 
of A Es.   


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1_ 1 5 Dece m ber 2 0 2 2  
 
3 5  
5.  E m b olic a n d T hr o m b otic E ve nts, V e n o us : T he C D K 4/ 6 i n hi bit or a be macicli b has bee n 
ass ociate d wit h a n i ncrease d ris k  f or ve n o us t hr o m b oe m b olis m w he n c o m bi ne d wit h 
e n d ocri ne t hera p y i n pati e nts wit h breast ca n cer. T his sa me ris k has n ot bee n re p ort e d f or 
t he ot her a p pr o ve d C D K 4/ 6 i n hi bit ors (ri b ocicli b a n d pal b ocicli b); t heref ore, it is n ot 
clear if t his is a cl ass effec t. A p pr o xi matel y 3 % of ca ncer patie nts t hat recei ve d trilacicli b 
pri or t o  c he m ot hera p y e x perie nce d a ve n o us t hr o m b oe m b olic e ve nt a n d h alf of t h ose 
e ve nts ( 3/ 6) w ere Gra d e 3 or 4. N o Gra d e 5 e v e nts were re p orte d. A p pr o xi matel y 2 % of 
patie nts recei vi n g c he m o t hera p y al o ne or wit h place b o re p orte d a n e m b olic or t hr o m b otic 
e ve nt, 1  of 3 s uc h e ve nts was Gra d e 3.   
4. 2. 3. 2.  
F O L F O XI RI/ Be v aciz u m a b  
4. 2. 3. 2. 1.  F O L F O XI RI  
4. 2. 3. 2. 1. 1.  Fl u or o ur acil  
Per War ni n gs a n d Preca uti o ns i n t he prescri bi n g i nf or mati o n f or fl u or o uracil ( Secti o n  1 7. 5. 1 ), 
t he f oll o wi n g are i m p orta nt ris ks relate d t o fl u or o uracil use: 
•  I n crease d Ris k of Seri o us or Fatal A d verse R eacti o ns i n Patie nts wit h L o w or A bse nt 
d i p yri mi di ne d e h y dr o ge n ase ( D P D) Acti vit y. N o fl u or o uracil d ose has b ee n pr o ve n 
safe i n patie nts wit h a bse nt D P D acti vit y.  
•  Car di ot o xicit y: Fl u or o uracil ca n ca use car di ot o xi cit y, i ncl u di n g a n gi na, m y ocar dial 
i nfarcti o n/isc he mia, arr h yt h mia, a n d heart fail ure. 
•  H y pera m m o ne mic E n ce p hal o pat h y: Altere d me ntal stat us, c o nf usi o n, dis orie ntati o n, 
c o ma, or ata xi a wit h ele v ate d ser u m a m m o nia le v el ca n occ ur wit hi n 7 2 h o urs of 
i nitiati o n of fl u or o uracil. 
•  Ne ur ol o gic T o xicit y: Fl u or o uracil ca n ca use ac ute cere b ellar s y n dr o m e, c o nf usi o n, 
dis orie ntati o n, ata xia, or vis ual dist ur ba nces.  
•  Diarr hea (se v ere) . 
•  Pal mar -Pla ntar Er yt hr o d ysest hesia ( Ha n d -F o ot S y n dr o me; H F S): S y m pt o ms of H F S 
i ncl u de a ti n gli n g se nsati o n, pai n, s welli n g, a n d er yt he ma wit h te n der ness, a n d 
des q ua mati o n.  
•  M yel os u p pressi o n (se vere a n d p ote ntiall y fatal) . 
•  M uc ositis (se vere) . 
•  I n crease d Ris k of Ele vat e d i nter nati o nal n or malize d rati o (I N R) wit h Warfari n: 
C o nc urre nt a d mi nistrati o n wit h warfari n ca n res ult i n cli nicall y si g nifica nt i ncreas es 
i n c oag ulati o n para m eters .  
•  E m br y ofetal T o xicit y: Fl u or o uracil ca n ca use fetal har m.  
Please refer t o t he f ull fl u or o uracil prescri bi n g i nf or mati o n ( Secti o n  1 7. 5. 1 ) f or s pecifi c 
i nf or mati o n o n a d vers e reacti o ns a n d ma na ge me nt of t o xicit y.  


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1_ 1 5 Dece m ber 2 0 2 2  
 
3 6  
4. 2. 3. 2. 1. 2.  Le uc o v ori n  
Per War ni n gs a n d Preca uti o ns i n t he prescri bi n g i nf or mati o n f or le uc o v ori n ( Secti o n  1 7. 5. 2 ), t he 
f oll o wi n g are i m p orta nt ris ks relate d t o le uc o v ori n use: 
•  T hera p y wit h le u c o v ori n a n d 5 F U m ust n ot be i nitiate d or c o nti n ue d i n pati e nts w h o 
ha ve s y m pt o ms of gastr oi ntesti nal t o xicit y of a n y se verit y, u ntil t h ose s y m pt o ms ha ve 
c o m pletel y res ol ve d.  
•  Seiz ures a n d/ or s y n c o pe ha ve bee n re p orte d rarel y i n ca ncer patie nts recei vi n g 
le uc o v ori n, us uall y i n ass ociati o n wit h ﬂu or o p yri mi di ne a d mi nistrati o n, a n d m ost 
c o m m o nl y i n t h ose wit h ce ntral ner v o us s yste m metastases or ot her pre dis p osi n g 
fact ors, h o w e ver, a ca usal relati o ns hi p has n ot bee n esta blis he d.  
•  Le uc o v ori n e n h a nces t he t o xicit y of 5 F U . 
Please refer t o t he f ull le uc o v ori n pres cri bi n g i nf or mati o n ( Secti o n  1 7. 5. 2 ) f or s pecifi c 
i nf or mati o n o n a d vers e reacti o ns a n d ma na ge me nt of t o xicit y.  
4. 2. 3. 2. 1. 3.  O x ali pl ati n  
Per War ni n gs a n d Preca uti o ns i n t he prescri bi n g i nf or mati o n f or o xali plati n ( Secti o n  1 7. 5. 3 ), t he 
f oll o wi n g are i m p orta nt ris ks relate d t o o xali plati n use: 
•  A na p h ylactic reacti o ns t o o xali plati n ha ve bee n re p orte d, ca n b e fat al, a n d ma y occ ur 
wit hi n mi n utes of o xali plati n a d mi nistrati o n.  
•  O xali plati n is ass ociate d wit h t w o t y pes of ne ur o pat h y:  
− A n ac ute, re versi ble, pri maril y peri p heral, se ns or y ne ur o pat h y t hat  is of earl y 
o nset, occ urri n g wit hi n h o urs or o ne t o t w o da ys of d osi n g, t hat res ol ves wit hi n 
1 4  da ys, a n d t hat fre q ue ntl y rec urs wit h f urt her d osi n g.  
− A persiste nt ( >  1 4 d a ys), pri maril y peri p heral, se ns or y ne ur o pat h y t hat is us uall y 
c haracteri ze d b y pares t hesias, d ysest hesias, h y p oest hesias, b ut ma y als o i ncl u de 
deficits i n pr o pri oce pti o n t hat ca n i nterfere wit h dail y acti vities ( e g, writi n g, 
b utt o ni n g, s wall o wi n g, a n d diffic ult y wal ki n g fr o m i m paire d pr o pri oce pti o n).  
•  Re versi ble P osteri or Le u k oe nce p h al o pat h y S y n dr o me ( R P L S, als o k n o w n as P R E S, 
P osteri or Re versi ble E nce p hal o pat h y S y n dr o me) has bee n o bser ve d i n cli nical trials 
( < 0. 1 %) a n d p ost  mar keti n g e x perie nce.  
•  Se vere ne utr o pe nia ( Gra de 3 or 4).  
•  O xali plati n has bee n ass o ciate d wit h p ul m o nar y fi br osis ( <  1 % of st u d y patie nts), 
w hic h ma y be fatal. I n case of u ne x plai ne d res pirat or y s y m pt o ms s uc h as n o n -
pr o d ucti ve c o u g h, d ys p n ea, crac kles, or ra di ol o gi cal p ul m o nar y i nfiltrates, 
E L O X A TI N s h o ul d b e disc o nti n ue d u ntil f urt her p ul m o nar y i n vesti gati o n e xcl u des 
interstitial l u n g disease or p ul m o nar y fi br osis.  
•  He pat ot o xicit y, as e vi de n ce d i n t he a dj u va nt st u d y b y i ncreas e i n tra nsa mi n ases a n d 
al kali ne p h os p hatase, was o bser ve d m ore c o m m o nl y i n t he o xali plati n c o m bi nati o n 
ar m t ha n i n t he c o ntr ol ar m.  


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1_ 1 5 Dece m ber 2 0 2 2  
 
3 7  
•  Q T pr ol o n gati o n  a n d ve ntric ular arr h yt h mias i ncl u di n g fatal t orsa de d e p oi ntes ha ve 
bee n re p orte d i n p ost  mar keti n g e x perie n ces f oll o wi n g o xali plati n a d mi nistrati o n.  
•  O xali plati n ma y ca use fetal har m w he n a d mi nistere d t o a pre g n a nt w o ma n.  
Please refer t o t he f ull o x ali pl ati n prescri bi n g i nf or mati o n ( Secti o n  1 7. 5. 3 ) f or s pecific 
i nf or mati o n o n a d vers e reacti o ns a n d ma na ge me nt of t o xicit y. O xali plati n is als o ass ociate d wit h 
hi g h rates of gastr oi ntesti nal t o xicit y s uc h as na usea/ v o miti n g, diarr hea, a b d o mi nal pai n a n d 
st o matitis. T o xicit y s h o ul d be ma na ge d as per pac ka ge i nsert a n d i nstit uti o nal g ui deli nes.  
4. 2. 3. 2. 1. 4.  Iri n otec a n 
Per War ni n gs a n d Preca uti o ns i n t he prescri bi n g i nf or mati o n f or iri n oteca n ( Secti o n  1 7. 5. 4 ), t he 
f oll o wi n g are i m p orta nt ris ks relate d t o iri n oteca n use: 
•  Earl y a n d late f or ms of diarr hea ca n o cc ur. Earl y diarr hea ma y be acc o m p a nie d b y 
c h oli ner gic s y m pt o ms. Late diarr h ea ca n be life t hreate ni n g .  
•  Se vere m yel os u p pr essi o n ma y occ ur.  
•  I n di vi d uals w h o are h o m oz y g o us f or t he U G T 1 A 1 * 2 8 allele ( U G T 1 A 1 7/ 7 ge n ot y pe) 
are at i ncrease d ris k f or ne utr o p e nia.  
•  H y perse nsiti vit y reacti o ns i ncl u di n g se vere a n a p h ylactic or a n a p h ylact oi d reacti o ns 
ha ve bee n o bser ve d.  
•  Re nal i m pair me nt a n d ac ute re nal f ail ure ha v e bee n i de ntifie d, us uall y i n patie nts w h o 
beca me v ol u me d e plete d fr o m se vere v o miti n g a n d/ or diarr hea . 
•  I nterstitial P ul m o nar y Disease-li ke e ve nts, i ncl u di n g fatalities, ha ve o cc urre d i n 
patie nts recei vi n g Iri n oteca n (i n c o m bi nati o n a n d as m o n ot hera p y).  
•  Iri n oteca n h y dr oc hl ori de ca n ca use fetal har m w h e n a d mi nistere d t o a pre g n a nt 
w o ma n.  
•  He patic i m pair me nt : T he use of C A M P T O S A R i n patie nts wit h si g nifica nt he patic 
i m pair me nt has n ot bee n esta blis he d.  
Please refer t o t he f ull iri n oteca n prescri bi n g i nf or mati o n ( Secti o n  1 7. 5. 4 ) f or s pecific 
i nf or mati o n o n a d vers e reacti o ns a n d ma na ge me nt of t o xicit y.  
4. 2. 3. 2. 2.  Be v aciz u m a b  
Per War ni n gs a n d Preca uti o ns i n t he prescri bi n g i nf or mati o n f or be v aciz u m a b ( Secti o n  1 7. 6 ), t he 
f oll o wi n g are i m p orta nt ris ks relate d t o be vaciz u m a b use: 
•  Seri o us, a n d s o meti mes fatal, gastr oi ntesti nal perf orati o n occ urre d at a hi g her 
i nci de nce i n patie nts r ecei vi n g be vaciz u ma b c o m pare d wit h c o ntr ols. T h e maj orit y of 
cases occ urre d wit hi n t he first 5 0 da ys of i nitiati o n of be vaci z u ma b . Seri o us a n d 
s o meti mes fatal n o n-gastr oi ntesti nal fist ula f or mati o n i n v ol vi n g trac he o -es o p ha geal, 
br o nc h o ple ural, biliar y, va gi nal a n d bla d der sites occ urs at a hi g her i nci de n ce i n 
be vaciz u m a b -treate d patie nts c o m pare d t o c o ntr ols. M ost e ve nts occ urre d wit hi n t he 
first 6 m o nt hs of be vaciz u ma b t hera p y. 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1_ 1 5 Dece m ber 2 0 2 2  
 
3 8  
•  T he i nci de nce of w o u n d heali n g c o m plicati o ns, i ncl u di n g seri o us a n d fat al 
c o m plicati o ns, was 1 5 % i n patie nts wit h m C R C w h o u n der we nt s ur g er y w hile 
recei vi n g be v aciz u m a b a n d 4 % i n patie nts w h o di d n ot recei ve be vaciz u ma b.  
•  Be vaciz u m a b ca n res ult i n t w o disti nct patter ns of blee di n g: mi n or he m orr h a ge, 
w hic h is m ost c o m m o nl y Gra de 1 e pista xis, a n d seri o us he m orr ha g e, w hic h i n s o me 
cases has b ee n fatal. Acr oss i n dicati o ns, t he i nci de nce of Gra d e ≥ 3 he m orr ha gic 
e ve nts a m o n g patie nts rec ei vi n g be vaciz u ma b  ra n ge d fr o m 1. 2 t o 4. 6 %.  
•  Seri o us, s o meti mes fatal, arterial t hr o m b oe m b olic e ve nts i ncl u di n g cere bral 
i nfarcti o n, tra nsie nt isc h e mic attac ks, m y ocar dial i nfarcti o n, a n d a n gi na, occ urre d at a 
hi g her i nci de nce i n patie nts recei vi n g be v aciz u ma b c o m pare d wit h c o ntr ols.  
•  Se vere h y perte nsi o n occ urre d at a hi g her i nci de n ce i n patie nts recei vi n g be vaciz u ma b 
as c o m pare d t o c o ntr ols.  
•  R P L S has bee n re p orte d wit h a n i nci de nce of <  0. 1 % i n cli nical st u dies.  
•  T he i nci de nce a n d se v erit y of pr otei n uria was hi g her i n patie nts recei vi n g 
be vaciz u m a b as c o m pare d wit h c o ntr ols.  
•  I nf usi o n-relat e d reacti o ns re p orte d acr oss cli nical st u dies a n d p ost-mar keti n g 
e x perie n ce i ncl u de h y p erte nsi o n, h y perte nsi ve crises ass ociate d wit h ne ur ol o gic si g ns 
a n d s y m pt o ms, w hee zi n g, o x y ge n desat ur ati o n, Gra de 3 h y perse nsiti vit y, c hest pai n, 
hea dac hes, ri g ors, a n d dia p h oresis.  
•  Be vaciz u ma b ma y ca us e fetal har m w h e n a d mi nistere d t o pr e g na nt w o me n.  
Please refer t o t he f ull be vaciz u ma b prescri bi n g i nf or mati o n ( Secti o n  1 7. 6 ) f or i m p orta nt d ose 
ma na ge me nt i nf or m ati o n s pecific t o a d verse reacti o ns.  
4. 3.  
Be nefit/ Ris k Assess me nt  
Trilacicli b ca n pr o vi de p atie nt be nefit b y ma ki n g c he m ot her a p y s afer a n d all o wi n g patie nts t o 
recei v e t he f ull be nefit of t heir c he m ot hera p y treat me nt, ie, at t he sta n dar d of care d oses a n d 
sc he d ule i n t he setti n g of a n i m m u ne s yste m pr otecte d fr o m c h e m ot hera p y -i n d uce d cell ular 
da ma ge. T hes e be n efits are pr o vi de d i n t he c o nte xt of mi ni mal t o xicit y (l o w gra de i njecti o n site 
reacti o ns/ p hle bitis/t hr o m b o p hle bitis) bei n g  a d de d t o t heir ca ncer treat me nt. M ore s pecifi call y, 
trilacicli b has t he p ote ntial t o ma ke F O L F O XI RI safer a n d t o i ncrease t he patie nt p o p ulati o n t o 
w hi c h F O L F O XI RI ca n be a d mi nistere d s o t hat m ore patie nts ca n h a ve access t o a c he m ot hera p y 
re gi me n wit h s u peri or o utc o mes c o m pare d t o w hat t he y w o ul d n or mall y be gi ve n.  
Trilacicli b is n ot e x pecte d t o ha ve si g nifica nt o verla p pi n g t o xicit y wit h t he c o m p o ne nts  of t he 
sta n dar d of care re gi me n of F O L F O XI RI/ b e vaciz u ma b. S pecificall y, n o o verla p pi n g t o xicit y 
bet wee n 5 F U a n d l e uc o v ori n wit h trilacicli b is a ntici pate d. I n fact, trilacicli b is e x pecte d t o ha v e 
a fa v ora ble i m pact o n s p ecific fl u or o uracil c o m plicati o ns s uc h as m yel os u p pressi o n a n d 
p ote ntiall y o n gastr oi ntesti nal ( GI ) relate d si de effects.  
B ot h trilacicli b a n d o xali plati n ca n be ass o ciate d wit h ac ute h y perse nsiti vit y reacti o ns. I n 
a d diti o n, o xali plati n has bee n ass oci ate d wit h p ul m o nar y fi br osis a n d he p at ot o xicit y, a n d 
c hr o nicall y d ose d oral C D K 4/ 6 i n hi bit ors ha ve bee n ass ociate d wit h I L D/ p n e u m o nitis a n d 
he pat ot o xicit y. Trilacicli b ( w hic h is d ose d i nter mitte ntl y) has n ot bee n ass o ciate d wit h a n 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
39 
increased risk of pulmonary toxicity or hepatotoxicity. Patients will be carefully observed during 
infusions, followed closely for signs of laboratory abnormalities and for signs of pulmonary 
toxicity. Appropriate actions are described in the dose modifications section (Section 9.5). No 
overlapping neurologic toxicity is anticipated with trilaciclib, and trilaciclib is expected to 
decrease the rates of myelosuppression. QT prolongation and ventricular arrhythmias have been 
reported with Oxaliplatin. No clinically relevant effect on QTc prolongation was observed with 
trilaciclib at the clinical dose of 240 mg/m2. As a result, no clinically significant overlapping 
toxicity is anticipated.  
Both trilaciclib and irinotecan can be associated with acute hypersensitivity reactions. In 
addition, irinotecan and chronically dosed oral CDK4/6 inhibitors have been associated with 
ILD/pneumonitis. Trilaciclib (which is dosed intermittently) has not been associated with an 
increased risk of pulmonary toxicity. Patients will be carefully observed during infusions and 
will be followed for signs of pulmonary toxicity. Appropriate actions are described in the dose 
modifications section (Section 9.5). Otherwise, overlapping toxicity is not anticipated and 
trilaciclib is expected to decrease the rates of myelosuppression.  
As with multiple drugs in the FOLFOXIRI regimen, bevacizumab has also been associated with 
GI toxicity including nausea, diarrhea, and stomatitis as well as bone marrow suppression. 
Overlapping toxicity with trilaciclib is not anticipated. However, bevacizumab is known to have 
potential impacts on cardiac toxicity, primarily mediated through thromboembolic events. 
Though this is not an established risk for trilaciclib to date, thromboembolic events are an 
adverse event of special interest for trilaciclib and will be monitored closely. Management 
should proceed according to the bevacizumab package insert, institutional guidelines and dose 
modification tables (Section 9.5). 
Trilaciclib has been successfully combined at the RP2D with all the major chemotherapy classes 
included in the FOLFOXIRI regimen (e.g., alkylating agents, antimetabolites, topoisomerase 
inhibitors). Based on the PK results described in Section 4.2.1.2, the risk for clinically relevant 
DDI is low and is not predicted to impact the benefit/risk assessment. 
As described in Section 4.2.1.1, there is a hypothetical risk that administration of trilaciclib prior 
to chemotherapy could decrease chemotherapy efficacy by pausing CDK4/6-dependent tumor 
cells in G1 in the presence of chemotherapy. However, at this time there is no nonclinical 
(Section 4.2.1.1) or clinical (Section 4.2.2.1) evidence to support this theoretical risk. In addition, 
since sensitivity to CDK4/6 inhibitors is a surrogate marker for CDK4/6 dependence, and the 
oral, chronically-dosed CDK4/6 inhibitors have shown minimal anti-tumor activity in solid 
tumors other than ER+ breast cancer (Baghdadi, 2019; Goldman, 2014; Goldman, 2018; 
Gopalan, 2014; Infante, 2016; Karasic, 2018; Rose, 2018), these results suggest that the majority 
of solid tumor cancers are not CDK4/6 dependent and not susceptible to this hypothetical risk.  
Given the potential benefit to patients with mCRC from the addition of trilaciclib to 
FOLFOXIRI/bevacizumab and the limited potential for significant trilaciclib-related toxicity, the 
benefit/risk assessment is positive for this combination.  
A COVID-19 risk assessment has been performed, documented, and is provided as a separate 
document (as needed). 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1_ 1 5 Dece m ber 2 0 2 2  
 
4 0  
5.  
O B J E C TI V E S A N D E N D P O I N T S 
T he o bjecti ves of t his st u d y are t o assess t h e m yel o preser vati o n a n d a nti -t u m or efficac y of 
trilacicli b a d mi nistere d pri or t o  F O L F O XI RI/ b e vaciz u ma b i n patie nts recei vi n g treat me nt f or 
m C R C.  O bjecti ves a n d e n d p oi nts are descri be d i n Ta ble  3 . 
T a ble  3 : 
O bjecti ves a n d E n d p oi nts  
O bjecti ves  
E n d p oi nts  
Pri mar y O bjecti ves  
•  
T o assess t he effects of trilacicli b o n t he 
ne utr o p hil li nea ge c o m pare d wit h  place b o 
i n patie nts recei vi n g  
F O L F O XI RI/ be vaciz u ma b f or 
p M M R/ M S S m C R C . 
•  
D urati o n of se vere ( Gra de 4) ne utr o pe nia i n 
C ycle  1  –  4  
•  
Occ urre nce of se vere ne utr o pe nia d uri n g 
In d ucti o n  
Ke y Sec o n dar y O bjecti ves  
 
•  
T o assess t he effect of trilacicli b o n O S  
c o m pare d wit h  place b o i n patie nts 
recei vi n g F O L F O XI RI/ be vaciz u ma b  f or 
p M M R/ M S S m C R C.  
•  
O S  
Sec o n dar y  Efficac y  O bjecti ves : 
T he occ urre n ce a n d n u m ber of e v e nts d uri n g I n d u cti o n f or eac h of t he f oll o wi n g e n d p oi nts will 
be e val uat e d e xce pt as n ote d.  
•  
T o assess t he effects of trilacicli b o n 
a d diti o nal meas ures of t he ne utr o p hil 
li nea ge c o m pare d wit h place b o i n patie nts 
recei vi n g F O L F O XI RI/ be vaciz u ma b f or 
p M M R/ M S S m C R C  
•  
S N ( n u m ber of e ve nts o nl y)  
•  
G -C S F a d mi nistrati o n  
•  
F N A Es  
•  
T o assess t he effects of trilacicli b o n t he 
R B C li nea ge c o m pare d wit h  place b o i n 
patie nts recei vi n g  
F O L F O XI RI/ be vaciz u ma b  f or 
p M M R/ M S S m C R C . 
•  
Gra de 3 or 4 decrease d he m o gl o bi n 
la b orat or y val ues  
•  
R B C tra nsf usi o ns o n or aft er Wee k  5  
•  
E S A a d mi nistrati o n  
•  
T o assess t he effects of trilacicli b o n t he 
platelet li nea ge  c o m pare d wit h  place b o i n 
patie nts recei vi n g  
F O L F O XI RI/ be vaciz u ma b f or 
p M M R/ M S S m C R C . 
•  
Gra de 3 or 4 decrease d platelet c o u nt 
la b orat or y val ues  
•  
P latelet tra nsf usi o ns  
•  
T o assess t he effects of trilacicli b o n 
m ulti ple li nea ges c o m pare d wit h place b o 
i n patie nts recei vi n g 
F O L F O XI RI/ be vaciz u ma b  f or 
p M M R/ M S S m C R C . 
•  
Gra de 3 or 4 he mat ol o gic la b val ues  


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1_ 1 5 Dece m ber 2 0 2 2  
 
4 1  
O bjecti ves  
E n d p oi nts  
•  
T o assess t he effects of trilacicli b o n 
sta n dar d of care d osi n g c o m pare d wit h 
place b o i n patie nts recei vi n g 
F O L F O XI RI/ be vaciz u ma b f or 
p M M R/ M S S m C R C  
•  
All -ca use d ose re d ucti o ns or c ycle dela ys  
•  
Relati ve d ose i nte nsit y f or 
F O L F O XI RI/ be vaciz u ma b  
•  
T o assess t he effects of trilacicli b o n  
healt hcare utilizati o n  c o m pare d wit h  
place b o i n patie nts recei vi n g  
F O L F O XI RI/ be vaciz u ma b  f or 
p M M R/ M S S m C R C.  
•  
H os pitalizati o ns  
• 
All ca use  
• 
Fe brile ne utr o pe nia/ 
ne utr o pe nia  
• 
A ne mia/ R B C tra nsf usi o ns 
• 
T hr o m b oc yt o pe nia/ blee di n g  
• 
I nfecti o ns 
•  
A nti bi otic use  
• 
I V 
• 
Oral  
• 
Oral a n d I V  
•  
T o e val uate t he a nti -t u m or acti vit y of 
trilacicli b c o m pare d wit h  place b o i n 
patie nts recei vi n g  
F O L F O XI RI/ be vaciz u ma b  f or 
p M M R/ M S S m C R C.  
•  
B O R a n d  o bjecti ve res p o nse ( C R or P R) per 
R E CI S T v 1. 1  
•  
D O R   
•  P F S ( per R E CI S T 1. 1) as assesse d b y 
I n v esti gat or  
 
•  
T o  assess t he effects of trilacicli b o n 
c he m ot hera p y -i n d uce d fati g ue c o m pare d 
wit h place b o i n patie nts recei vi n g 
F O L F O XI RI/ be vaciz u ma b f or 
p M M R/ M S S m C R C.  
•  
T T C D -fati g ue d uri n g In d ucti o n , as 
meas ure d b y t he F A CI T -F  
Safet y O bjecti ves  
•  
T o assess t he safet y a n d t olera bilit y of 
trilacicli b c o m pare d wit h place b o i n 
patie nts recei vi n g  
F O L F O XI RI/ be vaciz u ma b  f or 
p M M R/ M S S m C R C . 
•  
Occ urre nce a n d se verit y of A Es b y 
N CI -C T C A E v 5 i ncl u di n g diarr h oea , 
st o matitis, a n d he mat ol o gic A Es 
( ne utr o pe nia, a ne mia, t hr o m b oc yt o pe nia) 
•  
C ha n ges i n la b orat or y para meters 
( he mat ol o g y, c he mistr y, uri nal ysis), vital 
si g ns a n d E C G para meters 
•  
Gra de 3 or 4 a b n or malities i n  c he mistr y  
la b orat or y para meters  
•  
Trilacicli b A E SIs  
•  
Trilacicli b i nf usi o n i nterr u pti o ns  
•  
C he m ot hera p y i nf usi o n i nterr u pti o ns  
•  
St u d y treat me nt disc o nti n uati o n d ue t o A Es  


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1_ 1 5 Dece m ber 2 0 2 2  
 
4 2  
O bjecti ves  
E n d p oi nts  
E x pl orat or y O bjecti ves  
•  
T o assess t he a nti -t u m or efficac y of 
trilacicli b i n patie nts wit h m C R C t u m ors 
wit h differe nt le vels of relia nce o n t he 
C D K 4/ 6 pat h wa y.  
O R R ( per R E CI S T v 1. 1), P F S, a n d O S i n patie nts 
wit h eac h of t he f oll o wi n g C D K 4/ 6 de pe n de nce 
si g nat ures: 
•  
C D K 4/ 6 de pe n de nt  
•  
C D K 4/ 6 i n de pe n de nt  
•  
C D K 4/ 6 i n deter mi na nt 
•  
T o c haracterize t he p o p ulati o n P K of 
trilacicli b a n d i de ntif y i m p orta nt 
deter mi na nts of varia bilit y.  
•  
Ex p os ur e -r es p o ns e r el ati o ns hi p b et w e e n 
tril acicli b as w ell as a n y m et a b olit es a n d 
r es p o ns e or s af et y e n d p oi nts 
•  
T o assess t he effects of tri lacicli b o n 
CI M  -relate d s y m pt o ms a n d f u ncti o nal 
li mitati o ns c o m pare d wit h place b o i n 
patie nts recei vi n g  
F O L F O XI RI/ be vaciz u ma b  f or 
p M M R/ M S S m C R C . 
C ha n ge fr o m baseli ne a n d/ or ti me t o deteri orati o n 
i n: 
•  
F A C T -G d o mai n sc ores ( p h ysical, 
s ocial/fa mil y, e m oti o nal, a n d f u ncti o nal 
well -bei n g)  
•  
F A C T -A n: A ne mia  
•  
F A C T -C (c ol orectal ca ncer): C ol orectal 
Ca ncer S u bscale  
•  
E Q -5 D -5 L  
 
Perce nt of patie nts re p orti n g deteri orati o n a n d 
i m pr o ve me nt usi n g: 
•  
P GI C fati g ue ite m  
•  
P GI S fati g ue ite m  
•  
T o assess t he ef fects of trilacicli b o n t he 
recei pt of s u bse q ue nt a nti-ca ncer 
t hera p y(ies) c o m pare d wit h place b o i n 
patie nts recei vi n g  
F O L F O XI RI/ be vaciz u ma b f or 
p M M R/ M S S m C R C . 
•  
N u m ber of patie nts w h o recei ve s yste mic 
a nti-ca ncer t hera p y after disc o nti n ui n g 
st u d y dr u g 
•  
T y p es a n d n u m b er of li n es of 
tr e at m e nts p ati e nts r ec ei v e aft er 
disc o nti n ui n g st u d y dr u g  
A E =a d verse e v e nt; B O R = b est o verall res p o nse; C D K =c ycli n -de pe n de nt ki nase; CI M =c he m ot hera p y -i n d uce d 
m yel os u p pressi o n; C R =c o m plete res p o nse; C T C A E = C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts; 
D O R = d urati o n of o bjecti ve res p o nse; E C G =electr ocar di o gra m; E S A =er yt hr o p oiesis -sti m ulati n g a ge nts; 
E Q -5 D -5 L = 5 -le vel E Q-5 D;  F A C T -A n = F u ncti o nal Assess me nt of Ca ncer T hera p y -A ne mia; F A C T C = F u ncti o nal 
Assess me nt of Ca n cer T hera p y -C ol orectal; F A C T -G = F u ncti o nal Assess me nt of Ca ncer T hera p y -Ge n eral; 
G -C S F = gra n ul oc yte -c ol o n y sti m ulati n g fact or; p M M R/ M S S m C R C = pr oficie nt mis matc h re pair/ micr osatellite sta ble 
metastatic c ol orectal ca ncer; N CI = N ati o nal Ca ncer I nstit ute; O S = o verall s ur vi val; P F S = pr o gressi o n free s ur vi val; 
P GI C = Patie nt Gl o bal I m pressi o n of C ha n ge; P GI S = Patie nt Gl o bal I m pressi o n of Se verit y; P K = p har mac o ki netic(s); 
P R = p artial res p o nse; R B C =re d bl o o d cell; R E CI S T = Res p o nse E val uati o n C riteria i n S oli d T u m ors; 
T T C D -fati g ue =ti me t o first c o nfir me d deteri orati o n of fati g ue. 


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5.1. 
Rationale for Primary and Key Secondary Endpoints 
5.1.1. 
Myelopreservation Efficacy 
Patients experiencing CIM often face severe clinical consequences (e.g., febrile neutropenia [FN] 
predisposes patients to serious infections and even death). For those patients with neutropenia 
requiring hospitalization, the estimated inpatient mortality rates ranged from 3.4% to 10.5% 
depending on tumor type in 1 study, with an overall mortality rate of 6.8% (Caggiano, 2005). In 
another analysis, the overall in hospital rate of death was 9.5%, with rates for solid tumor cancer 
patients ranging from 3.6% for breast cancer patients to 13.4% for lung cancer patients 
(Kuderer, 2006). Because both the severity and duration of neutropenia correlate with the risk of 
FN and infections (Bodey, 1966; Li, 2016; Gustinetti, 2016), a reduction in the occurrence and 
duration of will decrease the risk of these events and provide an improved patient experience 
while receiving chemotherapy (Padilla, 2005). 
The measurement of DSN is limited to Cycle 1 – 4 because the risk of FN is highest in Cycle 1 – 
4 in patients treated with FOLFOXIRI/bevacizumab (Rossini, 2021).  Rossini et al describes the 
occurrence as well as the time course for Grade 3/4, and FN in patients randomized on the 
TRIBE and TRIBE 2 studies to FOLFOXIRI+B, which is the identical treatment regimen 
utilized in PRESERVE 1. The TRIBE study randomized 508 patients with mCRC to receive up 
to 12 cycles of FOLFOXIRI+B or FOLFIRI+B followed by maintenance therapy for both 
groups.  In TRIBE 2, 679 patients were randomized to up to 8 cycles of FOLFOXIRI+B versus 
mFOLFOX6+B followed by maintenance treatment in both arms.  At the time of progression, 8 
additional cycles of the randomized regimen could be delivered, again followed by maintenance.  
The pooled data on these 2 studies (N= 1,155), revealed 51% of patients receiving the 
FOLFOXIRI+B regimen experienced adverse events of Grade 3/4 neutropenia and 8% 
experienced FN.  In these same patients, the median time to the onset of neutropenia was 0.7 
months (i.e., during Cycle 2), suggesting that neutropenic events in this patient population occur 
later and are not concentrated in Cycle 1. In total, 78.5% of the Grade 3/4 neutropenia events 
occurred during the first 2 months (or 4 cycles) of treatment. Measuring DSN during the 
timeframe of occurrence of the majority of SN, i.e., Cycle 1 through 4, will allow an assessment 
of the risk of FN during the time of greatest clinical risk to patients. 
 
5.1.2. 
Anti-tumor Efficacy 
Measurement of OS is standard in oncology solid tumor trials to measure effects of study 
treatment on the underlying malignant disease.  
5.1.3. 
Safety 
Assessment of AEs, changes in laboratory parameters, vital signs, and ECOG status are all 
standard assessments used in oncology trials to measure patient safety. 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1_ 1 5 Dece m ber 2 0 2 2  
 
4 4  
6.  
I N V E S TI G A TI O N A L P L A N 
6. 1.  
O ver all St u d y Desi g n  
T his is a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, gl o bal, m ultice nter, P hase 3 trial 
e val uati n g t he i m pact of trilacicli b o n m yel o preser vati o n a n d a nti -t u m or efficac y w he n 
a d mi nistere d pri or t o  F O L F O XI RI/ b e vaci z u ma b i n patie nts wit h p M M R/ M S S m C R C w h o ha ve 
n ot recei ve d s yste mic t h era p y f or met astatic diseas e. I ncl usi o n/e xcl usi o n criteria a re o utli ne d i n 
Secti o n  7. 1  a n d Secti o n  7. 2 . 
A p pr o xi matel y 3 2 6  patie nts will be ra n d o ml y assi g ne d ( 1: 1) t o recei ve place b o or trilacicli b o n 
Da ys 1 a n d 2 a d mi nistere d I V pri or t o  F O L F O XI RI/ be vaciz u m a b i n 1 4 -da y c ycles f or u p t o 
1 2  c ycles (I n d ucti o n). T h ere will be t hr ee stratificati o n fact ors f or ra n d o mizati o n: c o u ntr y, pri or 
t hera p y i n a dj u va nt/ ne o a dj u va nt setti n g, a n d prese nce of B R A F V 6 0 0 E m utati o n. Wit hi n eac h 
c o u ntr y, patie nt ra n d o mi zati o n will be stratifie d b y hist or y of s yste mic c yt ot o xic t hera p y i n t he 
a dj u va nt/ ne oa dj u va nt setti n g ( yes/ n o) a n d t he prese nce of a B R A F V 6 0 0 E m uta ti o n ( yes/ n o). 
St u d y dr u gs a d mi nistere d d uri n g I n d u cti o n are as f oll o ws:  
•  Trilacicli b ( 2 4 0 m g/ m 2) or place b o–  a d mi nistere d as a 3 0 -mi n ute I V i nf usi o n n o m ore 
t ha n 4 ho urs pri or t o c he m ot hera p y o n eac h da y c he m ot hera p y is a d mi nistere d. T h e 
sec o n d d ose of trilacicli b/ place b o s h o ul d be a d mi nistere d as a 3 0 -mi n ute i nf usi o n o n 
Da y 2 .  
•  Iri n oteca n 1 6 5 m g/ m2 –  I V, Da y 1  
•  O xali plati n 8 5 m g/ m 2 –  I V, Da y 1  
•  Le uc o v ori n 4 0 0  m g/ m 2 –  I V, Da y 1; L E V Ole uc o v ori n 2 0 0  m g/ m 2 is a n acce pta ble 
alter nati ve  
•  Fl u or o uracil 2 4 0 0 –  3 2 0 0 m g/ m 2 –  c o nti n u o us i nf usi o n ( CI ) o v er 4 6 –  4 8 h o urs 
be gi n ni n g o n Da y 1 ; t his d ose ra n ge is pr o vi d e d t o reflect ge o gra p hi c variati o ns i n 
prescri be d 5 F U d os e, h o we ver, t he s a me d ose s h o ul d be c o nti n ue d t hr o u g h o ut t he 
st u d y f or eac h patie nt, e x ce pt w here d ose m o dificati o ns are re q uire d f or t o xicit y 
ma na ge me nt.  
•  Be vaciz u ma b 5 m g/ k g –  I V, Da y 1  
T h o u g h t here is n o re q uir e me nt f or a mi ni m u m n u m ber of c h e m ot hera p y c yc les d uri n g 
I n d u cti o n, patie nts s h o ul d c o nti n ue wit h In d u cti o n t hera p y (i n t he a bse nce of disease 
pr o gressi o n) as l o n g as it is t olerate d. H o we v er, if a patie nt is u na ble t o c o m plete t he ma xi m u m 
n u m ber of 1 2 I n d u cti o n c ycles beca use of t o xicit y, a n d t he tre ati n g p h ysicia n feels t he patie nt 
will recei ve a d diti o nal cli nical be nefit b y tra nsiti o ni n g t o Mai nte na nce, t he patie nt will be 
all o we d t o disc o nti n ue o xali plati n a n d iri n oteca n, a n d c o nti n ue o n Mai nte n a nce t hera p y as 
descri be d b el o w.  
F oll o wi n g c o m pleti o n of I n d u cti o n, patie nts will c o nti n ue i n Mai nte na nce , w here t he y will 
c o nti n ue t o recei ve trilaci cli b or place b o p er ra n d o mizati o n all ocati o n at st u d y e ntr y. 
Trilacicli b/ place b o will b e  a d mi nistere d pri or t o  i nf usi o nal-5 F U/ le uc o v ori n/be vaciz u m a b at t he 
sa me d ose a n d s c he d ule use d d uri n g I n d ucti o n. T he patie nt ma y c o nti n ue t o recei v e treat me nt o n 
st u d y u ntil disease pr o gressi o n, u nacce pta ble t o xi cit y, wit h dra wal of c o nse nt, disc o nti n uati o n b y 


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45 
Investigator, or the end of the trial, whichever occurs first. Treatment cycles will occur 
consecutively without interruption, except when necessary to manage toxicities or for 
administrative reasons. 
Figure 4: 
Study Schema 
 
CI=continuous infusion; DC=discontinued; FU=fluorouracil; LCV= leucovorin; Bev= bevacizumab; 
PD=progressive disease; PI=Principal Investigator; WD=withdrawal. 
Upon discontinuation of study treatment, patients will be followed for survival, ie, patients or 
their caregivers will be contacted approximately every 2 months until the end of the trial (or 
death) to record their status (alive or dead) as well as details of any subsequent systemic 
anti-cancer therapy initiated. The study will be completed when the criteria outlined in 
Section 10.4 have been met, or upon Sponsor termination of the study. 
6.2. 
Rationale for Dose and Schedule of Study Treatment 
6.2.1. 
Trilaciclib 
The RP2D of trilaciclib is 240mg/m2. This dose was chosen based on (1) a mechanistic 
PK/pharmacodynamic model informed by nonclinical and human PK and pharmacodynamics 
and (2) PK and myelopreservation efficacy results from cancer patient studies evaluating 
trilaciclib administered prior to chemotherapy. In the FIH study (Study G1T28-1-01), assessment 
of bone marrow aspirates 24 hours after administration of a single dose of trilaciclib at the 
biologically effective dose (BED) of 192 mg/m2 revealed a significant decrease in the number of 
HSPCs in the S/G2/M phases of the cell cycle (ie, an increase in the proportion of cells in G1 
arrest). Recovery of the total bone marrow with resumption of proliferation of the bone marrow 
progenitor subsets was observed by 32 hours post dose, thereby indicating that the arrest was 
transient and reversible (He, 2017). 
When trilaciclib was administered prior to chemotherapy to cancer patients, doses of 200 
(rounded up from 192), 240, and 280 mg/m2 were evaluated. Trilaciclib exposures in cancer 
patients were slightly lower compared to healthy subjects, such that the dose of 240 mg/m2 
(rather than 200 mg/m2) more closely matched the BED dose of 192 mg/m2. In addition, the dose 
of 240 mg/m2 demonstrated maximal myelopreservation efficacy benefits (compared to 200 and 
280 mg/m2) as measured by a variety of myelosuppression endpoints. The myelopreservation 
effect at 240 mg/m2 was further evaluated and confirmed in three randomized controlled phase 2 
trials in SCLC patients. See the Trilaciclib IB for details.  


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In all trials enrolling cancer patients, trilaciclib is always administered prior to systemic 
chemotherapy on each day of chemotherapy administration. Since the infusional-5FU component 
of FOLFOXIRI/bevacizumab is administered over 46 – 48 hours, trilaciclib is planned to be 
administered on both Day 1 and Day 2 of each 14-day cycle. The Day 2 infusion of trilaciclib is 
being administered to ensure that synchronization and release of the HSPC G1 arrest (~24-32 
hours after a single dose of trilaciclib) does not occur while 5FU is at sufficient concentrations 
such that 5FU-related myelosuppression is exacerbated rather than mitigated.  
Although the Maintenance regimen of infusional-5FU/leucovorin/bevacizumab is not 
particularly myelosuppressive, 5FU does cause chemotherapy-induced damage to the host 
leading to other side effects like diarrhea. In a manner similar to the protection of HSPCs, 
trilaciclib may protect other cell populations that are dependent on CDK4/6 for proliferation. In 
the integrated data analysis from the 3 randomized SCLC trials, trilaciclib administered prior to 
chemotherapy resulted in a decreased percentage of patients experiencing diarrhea (13.1% vs 
17.8%) compared to placebo. In addition, prolonged exposure to any cytotoxic chemotherapy 
can lead to cumulative bone marrow toxicity and myelosuppression that can limit the ability to 
deliver subsequent lines of therapy at the standard of care doses and schedule. Therefore, 
continuation of trilaciclib has the potential to prevent this damage leading to decreases in GI side 
effects and facilitating maintenance of dose intensity in subsequent lines of therapy; both of 
which could lead to improved patient outcomes.  
6.2.2. 
FOLFOXIRI/bevacizumab 
The doses of FOLFOXIRI/bevacizumab are described in Section 6.1. They are consistent with 
standard of care as established in multiple clinical trials (Loupakis, 2014; Cremolini, 2019; 
Sastre, 2019) and the approved labeling for those products. The range of allowable 
infusional-5FU doses (2400-3200 mg/m2) reflects differences in practice patterns between 
different geographic regions and physician preference. The variability in this dose range is not 
expected to significantly influence the magnitude of CIM or anti-tumor efficacy observed as 
enrollment will be stratified by country.  
Trilaciclib has been successfully combined at the RP2D with all the major chemotherapy classes 
included in the FOLFOXIRI regimen (e.g., alkylating agents, antimetabolites, topoisomerase 
inhibitors) in 4 completed or ongoing clinical trials in cancer patients. Integrated safety data from 
those 4 trials (338 patients) demonstrates that the addition of trilaciclib actually decreases the 
rate of high-grade AEs associated with the underlying chemotherapy regimen. There is no 
evidence to suggest that a different result would be expected from the combination of trilaciclib 
with FOLFOXIRI/bevacizumab. In addition, trilaciclib has a limited toxicity profile and minimal 
overlapping toxicities are expected with FOLFOXIRI/bevacizumab (Section 4.2.3). The primary 
AEs anticipated with trilaciclib are low grade injection site reactions including 
phlebitis/thrombophlebitis. These infusion reactions have generally been mild and occur in 
association with drug delivery through peripheral access. Central access is likely to 
reduce/eliminate these issues. The remainder of the trilaciclib AESIs to date have been 
uncommon and for most, the percentage of patients experiencing these AESIs is not clearly 
increased in patients receiving trilaciclib compared to placebo. Based on these results a dose-
finding study is not needed. 


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6.3. 
Rationale for Supportive Care Interventions (Growth Factors and 
Transfusions) 
Primary prophylactic G-CSF will be prohibited in Cycle 1; however therapeutic G-CSF 
(administered in response to a febrile neutropenia event) in Cycle 1 and secondary prophylactic 
G-CSF beginning in Cycle 2 and for all subsequent cycles (i.e., after a precipitating event in a 
prior cycle of therapy) will be allowed per growth factor/neutropenia management guidelines and 
physician discretion (Aapro, 2010; Smith, 2015). In the clinical trials evaluating FOLFOXIRI, 
primary prophylactic G-CSF (ie, in Cycle 1) was specifically not recommended per protocol; and 
in this setting the rates of febrile neutropenia ranged from 3 to 10% and the rates of SN AEs 
(Grade 4) were approximately 15 to 20%. Based on these data, FOLFOXIRI would be predicted 
to have an intermediate FN risk of between 10 and 20% which would not require primary 
prophylactic G-CSF in Cycle 1 per growth factor/neutropenia management guidelines 
(Cremolini, 2018; Hashimoto, 2016; Loupakis, 2014; Fornaro, 2013; Falcone, 2007; Souglakis, 
2006).  
Prohibiting primary prophylactic G-CSF in Cycle 1 in order to facilitate an unbiased evaluation of 
trilaciclib activity in Cycle 1 is permissible as long as the risk to placebo patients is minimized by 
(1) allowing therapeutic use of G-CSF in Cycle 1, and (2) allowing Investigators to only enroll 
those patients whose safety (as assessed by the treating physician) is not substantially 
compromised by this approach. In Cycle 2 and beyond, secondary prophylaxis is permitted in order 
to reduce the risk of subsequent neutropenia events in patients who have already demonstrated an 
increased propensity for such events, particularly for the patients enrolled in the placebo arm.  
However, evaluation of DSN in Cycle 2 – 4 and occurrence of SN in Cycle 2 – 12 could be 
confounded by the potential use of secondary G-CSF prophylaxis.    
In the pooled TRIBE data, only 6% of patients in the FOLFOXIRI+B group experienced a 
second episode of Grade 3/4 neutropenia while receiving G-CSF as secondary prophylaxis.  This 
finding suggests that the majority of the 78.5% of SN episodes that were reported by Rossini 
2021 et al in the first 4 cycles were first occurrences of the event, not recurrent events, and 
therefore would not be impacted by secondary G-CSF prophylaxis.  Further, in the integrated 
efficacy analysis for the 3 trilaciclib SCLC Phase 2 studies, a consistent treatment effect for 
trilaciclib compared to placebo in DSN and occurrence of SN was observed in patients who 
received G-CSF and in those that did not, at each Cycle for Cycle 1 to 4.  For example, in Cycle 
1, where G-CSF could only be utilized therapeutically in response to an episode of FN, the large 
reduction in occurrence of SN seen with trilaciclib (5.6% occurrence) compared to placebo 
(41.3% occurrence) in those that did not receive G-CSF was also observed in those that were 
treated with G-CSF (trilaciclib 16.7% occurrence vs placebo 80% occurrence). Similarly, in 
Cycle 2-4 where G-CSF could be utilized prophylactically as well as therapeutically, the benefit 
of trilaciclib, albeit smaller, persisted.   In Cycle 2, an absolute 14% decrease in the occurrence 
of SN was seen with trilaciclib (compared to placebo) for patients who received G-CSF and an 
identical absolute decrease was seen with trilaciclib compared to placebo in patients where G-
CSF was not utilized. In Cycle 3, the absolute decrease was 10-12% with or without G-CSF and 
in Cycle 4, approximately 8%. Treatment-by-subgroup interaction was tested for occurrence of 
SN at Cycle 1 and Cycle 2, respectively, and both showed no statistically significant interaction 
between treatment effect and the usage of G-CSF. Statistical testing for treatment-by-subgroup 
interaction was not conducted for Cycle 3 or Cycle 4 given the small total event numbers at 


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Cycle 3 or 4.  A decrease in DSN was also observed with trilaciclib relative to placebo in Cycle 1 
in patients receiving G-CSF (7 day decrease for the trilaciclib group); and in patients not 
receiving G-CSF (4 day decrease for the trilaciclib group).  A smaller, but persistent benefit was 
observed in Cycle 2 – 4, where patients who received G-CSF, and those who did not, 
experienced a 1 – 2-day improvement in DSN with trilaciclib relative to placebo, respectively. 
These analytic results and consistent numerical reduction of DSN and the proportion of patients 
with SN in cycles where G-CSF could be used both prophylactically and therapeutically (Cycle 2 
– 4) demonstrate that even in the context of G-CSF use, the beneficial effects of trilaciclib for 
CIN reduction can still be observed.   
Erythropoiesis-stimulating agent (ESA) administration and RBC or platelet transfusions will be 
allowed per Investigator discretion based on guidelines detailed in Section 9.6.2 and 
Section 9.6.3. While these interventions may confound analysis of the supportive secondary 
myelopreservation efficacy endpoints, allowing physicians to provide appropriate supportive 
care to patients will facilitate patient safety.  
6.4. 
Rationale for Stratification Factors 
As outlined in Section 6.1, randomization will be stratified by country, prior therapy in 
adjuvant/neoadjuvant setting, and presence of BRAF V600E mutation. Within each country, 
patient randomization will be stratified by history of systemic cytotoxic therapy in the 
adjuvant/neoadjuvant setting (yes/no) and the presence of a BRAF V600E mutation (yes/no). 
These factors were chosen because they are predicted to have an impact on the primary 
myelopreservation efficacy endpoints or the key secondary anti-tumor efficacy endpoint such 
that if there is an imbalance in these factors, interpretation of the results of the study could be 
compromised.  
Country was chosen as a stratification factor to account for the geographic differences in patient 
populations, treatment patterns including use of different doses of infusional-5FU within 
FOLFOXIRI and access to subsequent anti-cancer therapy, practice patterns including use of 
G-CSF and ESAs, and criteria for RBC and platelet transfusions; all of which could influence the 
primary and key secondary endpoint outcomes. 
Prior therapy in adjuvant/neoadjuvant setting was chosen because results observed in the Phase 2 
SCLC trials indicate that exposure to prior therapy, and presumably chemotherapy-induced 
damage to the HSPCs, can influence the magnitude of the effect size observed for the primary 
endpoints of DSN in Cycle 1 and occurrence of SN. For example, in Study G1T28-05 (1st line 
SCLC), the occurrence of SN for the placebo group was 49.1% compared with 1.9% for 
trilaciclib; in Study G1T28-03 (2nd/3rd line SCLC), the occurrence of SN for the placebo group 
was 75.9% compared with 40.6% for the trilaciclib group. While the chemotherapy backbones 
on these two trials were different (as reflected by the occurrence of SN rates in the placebo 
groups), the results suggest that exposure to prior therapy in adjuvant/neoadjuvant setting 
impacts the ability of trilaciclib to prevent or mitigate SN.  
And finally, BRAF mutation status was chosen because patients with BRAF V600E mutations 
have a significantly worse prognosis than patients without this mutation, and the frequency of 
this mutation in patients with CRC is low. In one analysis of 2282 patients with CRC, the median 
OS for BRAF mutation-positive patients was 22.5 months, which was significantly worse than 
that for patients with wild-type (wt) KRAS and BRAF (49.2 months) (Wang, 2018). While 


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patients with KRAS mutant CRC also have a poor prognosis compared with patients with wt 
KRAS tumors, the prognosis is not as poor as BRAF mutant patients (median OS: 36.2 months) 
and the frequency of KRAS mutations in CRC is much higher than that observed for BRAF 
mutant patients (KRAS = 47.3%; BRAF = 7.0%) (Wang, 2018). The higher frequency of KRAS 
mutations means that the two treatment groups are more likely to be balanced for this prognostic 
factor.  


Pr ot oc ol  
 
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5 0  
7.  
S T U D Y P O P U L A TI O N  
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr oll me nt criteria, als o k n o w n as 
pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.  
7. 1.  
I ncl usi o n Criteri a 
Patie nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all of t he f o ll o wi n g criteria a p pl y: 
1.  A ge ≥ 1 8  years of a g e  at t he ti me of si g ni n g t he i nf or me d c o nse nt. Patie nts >  7 0 years of 
a ge m ust ha ve a G 8 Healt h State Scree ni n g T o ol ( geriatric scree ni n g t o ol) sc ore >  1 4.  
2.  Pr oficie nt mis matc h re pair/ micr osatellite sta ble ( p M M R/ M S S ), hist ol o gicall y or 
c yt ol o gicall y -c o nfir me d a de n ocarci n o ma of t he c ol o n or rect u m . Patie nts wit h a n y B R A F 
or K R A S m utati o n stat us (wil d t y pe or m uta nt) are eli gi ble.  If hist orical p M M R/ M S S 
a n d/ or B R A F V 6 0 0 E m utati o nal stat us are n ot k n o w n, a t u m or s peci me n (arc hi val or 
fres h bi o ps y) m ust be se nt f or testi n g a n d res ults m ust be a vaila ble at t he ti me of 
ra n d o mizati o n i n i nteracti ve we b res p o ns e s yste m (I W R S). If testi n g ca n n ot be c o m plete d 
usi n g a sta n dar d cli nical assa y perf or me d i nstit uti o nall y/l oc all y, t he t u m or s peci me n ma y 
be se nt t o t he S p o ns or’s desi g nate d ce ntral la b orat or y f or a nal ysis ; o nl y hist orical K R A S 
m utati o nal stat us will be c ollecte d (ie, n o t esti n g re q uire d pri or t o st u d y e ntr y) . N ote:  A ny 
s a m ple se nt f or M S S/ B R A F a n alysis will be i n a d diti o n t o t h at re q uire d per I ncl usi o n 
Criteri o n  5 . 
3.  U nresecta ble a n d m eas ur a ble or e v al ua ble metastatic c ol orectal ca ncer  per R E CI S T v 1. 1  
4.  E C O G perf or ma nce stat us of 0 t o 1  
5.  A f or mali n -fi xe d p araffi n-e m be d de d ( F F P E) t u m or s peci me n (fr o m arc hi val or fresh 
bi o ps y) wit h a n ass ociate d pat h ol o g y re p ort d oc u me nti n g p M M R/ M S S m C R C m ust be 
c o nfir me d t o be a vaila ble t o se n d t o t he S p o ns or f or pla n ne d retr os pecti ve bi o mar ker 
a nal yses (tiss ue re q uire m e nts are pr o vi d e d i n t he ass ociate d la b orat or y ma n ual).  
6.  He m o gl o bi n ≥ 9. 0 g/ d L i n t he a bse nce of R B C tra nsf usi o n or E S A a d mi nistrati o n wit hi n 
1 4  da ys pri or t o first d os e of trilacicli b / place b o 
7.  A bs ol ute ne utr o p hil c o u nt ( A N C ) ≥ 1. 5 × 1 0 9/ L 
8.  Platelet c o u nt ≥ 1 0 0 × 1 0 9/ L 
9.  Esti mate d gl o mer ular filtrati o n rate (e G F R) ≥ 3 0 m L/ mi n ute / 1. 7 3 m2 
1 0.  T otal bilir u bi n ≤ 1. 5 × u p per li mit of n or mal ( U L N)  
1 1.  A S T, A L T , a n d al kali ne p h os p hatase ≤ 3 × U L N  f or patie nts wit h o ut li ver or b o ne 
metastases; A S T, A L T a n d al kali ne p h os p hatase  ≤ 5 × U L N i n  t he pres e nce of li ver 
metastases ; A S T a n d A L T ≤ 3 x U L N a n d al kali n e p h os p hatase ≤ 5 × U L N i n t he 
prese nce of b o ne m etastases  
1 2.  Res ol uti o n of n o n he mat ol o gic t o xicities fr o m pri or t hera p y or s ur gical pr o ce d ures t o 
≤ Gra de 1 or baseli ne (e x ce pt al o pecia)  
1 3.  Uri ne di pstic k pr otei n <  2 +. If ≥ 2 + at Scree ni n g, t he n a 2 4 -h o ur uri ne c oll ecti o n m ust be 
d o ne t o de m o nstrate ≤ 1 g of pr otei n/ 2 4 h o urs  


Pr ot oc ol  
 
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5 1  
1 4.  C o ntrace pti ve use b y me n or w o me n s h o ul d be c o nsiste nt wit h l ocal re g ulati o ns 
re gar di n g t he m et h o ds of c o ntrace pti o n f or t h ose p artici pati n g i n cli nical st u dies. Please 
see Secti o n  1 7. 4  f or d etaile d i nstr ucti o ns o n met h o ds of c o ntrace pti o n re q uire me nts. 
1 5.  Ca pa bl e of gi vi n g si g ne d i nf or me d c o nse nt w hic h i ncl u des c o m plia nce wit h t he 
re q uire me nts a n d restricti o ns liste d i n t he i nf or me d c o nse nt f or m (I C F) a n d i n t his 
pr ot oc ol . 
7. 2.  
E xcl usi o n Criteri a  
Patie nts are e x cl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:  
1.  Pri or s yste mic t hera p y f or m C R C. Patie nts w h o recei ve d a dj u v a nt/ ne oa dj u va nt t hera p y 
(ie, treat me nt wit h c urati ve i nte nt) f or c ol orectal ca ncer are eli gi ble if it has bee n 
≥ 6  m o nt hs bet wee n t he l ast d ose of s yste mic c he m ot hera p y a n d t he dat e of i nf or me d 
c o nse nt.  
2.  A n y ra di ot hera p y, c he m ot hera p y, i m m u n ot hera p y, bi ol o gic, i n vesti gati o nal, or h or m o nal 
t hera p y f or ca n cer treat m e nt (e xce pt f or a dj u v a nt h or m o nal t hera p y f or breast  ca ncer or 
pr ostate ca n cer d efi ne d as  M 0 disease or P S A persiste nce/r ec urre n ce wit h o ut metastatic 
disease ) wit hi n 3 wee ks pri or t o t he first d ose of trilacicli b/ place b o.  
3.  Recei pt of a n y l o w -d os e s yste mic c he m ot hera p e utic a ge nt ( e.g ., l o w-d ose met h otre xate 
f or r he u mat oi d art hritis) a d mi nistere d f or a n o n o n c ol o gic p ur p ose withi n 3 wee ks pri or t o 
t he first d ose of trilaci cli b/ place b o.  
4.  Prese nce of ce ntral ner v o us s yste m ( C N S ) metastases/le pt o me ni n geal disease re q uiri n g 
i m me diate treat me nt wit h ra diati o n t hera p y or ster oi ds (i.e., patie nt m ust be off ster oi ds 
a d mi nistere d f or br ai n metastases f or at least 1 4 d a ys pri or t o t he first d ose of 
trilacicli b/ place b o). 
5.  Q Tc F i nter val >  4 5 0 msec ( males) or >  4 7 0 msec (fe males) at scree ni n g (c o nfir me d o n 
re peat). F or patie nts wit h ve ntric ular pace ma kers, Q Tc F > 5 0 0 msec. 
6.  Pers o nal or fa mil y hist or y of l o n g Q T s y n dr o me  
7.  S y m pt o matic peri p heral ne ur o pat h y  
8.  Hist or y of i nterstitial l u n g disease (I L D)  
9.  U nc o ntr olle d h y pert e nsi o n ( bl o o d press ure ≥ 1 5 0/ 9 0 m m H g)  
1 0.  Cli nicall y si g nifica nt (i .e., acti ve) car di o vas c ular disease at t he ti me of si g ni n g t he 
i nf or me d c o nse nt; f or e x a m ple cere br o vasc ular acci de nts ( ≤ 6 m o nt hs bef ore t he first 
d ose of trilacicli b/ place b o), m y ocar dial i nfarcti o n ( ≤ 6 m o nt hs bef ore t he first d ose of 
trilacicli b/ place b o), u nsta ble a n gi na, seri o us car diac arr yt h mia re q uiri n g me dicati o n, or 
u nc o ntr olle d s y m pt o matic c o n gesti ve heart fail ure [ Class II or hi g her as defi ne d b y t he 
Ne w Y or k Heart Ass ociati o n [ N Y H A] f u ncti o nal classificati o n s yste m ])  
1 1.  Seri o us, n o n -heali n g w o u n d, ulcer, or b o n e fract ure   
1 2.  Maj or s ur gical pr o ce d ure, o pe n bi o ps y , or si g nifica nt tra u matic i nj ur y wit hi n 2 8 da ys 
pri or t o st u d y treat me nt start, or a ntici pati o n of t he nee d f or m aj or s ur gical pr oce d ure 
d uri n g t he c o urse of t he st u d y.  


Pr ot oc ol  
 
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Versi o n 6 . 1_ 1 5 Dece m ber 2 0 2 2  
 
5 2  
1 3.  K n o w n seri o us acti ve i nf ecti o n (e .g ., h u ma n i m m u n o deficie nc y vir us [ HI V], he patitis B 
or C, t u berc ul osis, etc. )  
1 4.  K n o w n Gil bert’s S y n dr o me or h o m oz y g o us f or t h e U G T 1 A 1 * 2 8 allele. U G T 1 A 1 
ge n ot y pi n g is n ot re q uire d f or t his st u d y.  
1 5.  Patie nts wit h c o m plete a bse nce of di h y dr o p yri mi di ne de h y dr o ge n ase ( D P D) acti vit y as 
e vi de nce d b y  t h e pres e nce of certai n ge n etic m utati o ns  or p ol y m or p his ms  i n t he DY P D 
ge ne or  bl o o d ur acil le vel ≥1 5 0 n g/ m L (see Secti o n 1 7. 2  f or assa y re q uire m e nts). 
1 6.  C hr o nic i nfla m mat or y b o wel disease a n d/ or acti ve i ntesti nal o bstr ucti o n.  Patie nts s h o ul d 
n ot be treate d u ntil t he i ntesti nal o bstr ucti o n has res ol ve d.  
1 7.  Pre vi o us hist or y of si g nifica nt /se vere he m orr h a ge, wit hi n 1 m o nt h bef ore ra n d o mizati o n . 
Hist or y of pre vi o us a b d o mi nal  fist ula or gastr oi ntesti nal  perf orati o n wit hi n 6 m o nt hs 
bef ore ra n d o mizati o n  
1 8.  K n o w n hist or y  of blee di n g diat hesis or c oa g ul o pat h y  
1 9.  I N R > 1. 5 wit hi n 1 4  da ys pri or t o starti n g st u d y treat me nt. E X E M P TI O N: p atie nts o n f ull 
a ntic oa g ulati o n m ust ha ve a n i n -ra n ge I N R (us uall y bet wee n 2  t o 3 ) if I N R is use d f or 
m o nit ori n g . A n y a ntic oa g ulati o n t hera p y m ust be at sta ble d osi n g pri or t o e nr oll me nt  
2 0.  O n g oi n g or a ntici pate d tr eat me nt wit h p ote nt c yt oc hr o me i n hi bit ors C Y P 4 5 0 3 A 4 (s uc h 
as ket oc o naz ole) or i n d u cers (s u c h as rifa m pici n, car ba m aze pi n e, p he n o bar bital, 
p he n yt oi n or St. J o h n's w ort).  Iri n oteca n s h o ul d n ot be deli vere d c o nc urre ntl y. 
2 1.  Patie nts wit h o n g oi n g or a ntici pate d treat me nt wit h s ori v u di ne or its c he micall y relate d 
a nal o g ues, s uc h as bri v u di ne . 
2 2.  C hr o nic, dail y  treat me nt wit h hi g h-d ose as piri n ( >  3 2 5 m g/ da y)   
2 3.  Pri or all o ge neic or a ut ol o g o us he mat o p oietic ste m cell or b o ne marr o w tra ns pla ntati o n  
2 4.  Recei pt of a n y li ve atte n uate d vacci ne s wit hi n 4  wee ks pri or t o first d ose of st u d y 
treat me nt 
2 5.  K n o w n h y perse nsiti vit y t o a n y of t he dr u gs use d i n t his st u d y   
2 6.  Pre g na nt or lact ati n g w o me n   
2 7.  Le gal i nca p acit y or li mite d le gal ca pacit y  
2 8.  Ot her u nc o ntr olle d seri o us c hr o nic diseas e or ps yc hiatric c o n diti o n t hat i n t he 
In v esti gat or’s o pi ni o n c o ul d affect patie nt safet y, c o m plia nce, or f oll o w -u p i n t he 
pr ot oc ol  
2 9.  A n y c o ntrai n dicati o ns t o t he a d mi nistrati o n of F O L F O XI RI a n d be v aciz u m a b  at t he 
discreti o n of t he i n vesti g at or.  


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8. 
SCHEDULE OF ASSESSMENTS 
The procedures and assessments to be performed during the study are outlined in Table 4 
(Screening and Cycle 1) and Table 5 (Cycle 2 through End of Study). The timing and number of 
samples collected for PK and biomarker testing may be altered based on emerging data without 
requiring an amendment if the blood volume per day or overall does not increase and the patient 
is not required to have additional clinic visits or prolongation of a clinic visit, i.e., the risk-benefit 
profile for the patient does not worsen.  
Study visits are outlined in the Schedule of Assessments. Unless otherwise specified, 
assessments are to be completed within ± 1 day of the scheduled visit date. When there are 
multiple procedures at the same or overlapping time points, order of events should be: patient 
reported outcome measures, ECGs, vitals, blood draw. Unscheduled assessments and visits to 
manage patient safety may occur at the Investigator’s discretion. Study procedures performed at 
unscheduled visits should be recorded in the appropriate electronic case report form (eCRF). 
 


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Table 4: 
Schedule of Assessments: Screening and Induction Cycle 1 
Assessment 
Screening 
Rand 
Induction Cycle 1 (14-day cycle) 
Day 
-28 to -1 
-3 to -1a 
1 
2 
4  
(±1 day) 
6  
(±1 day) 
8  
(±1 day) 
10  
(±1 day) 
12  
(±1 day) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History and CRC Historyb 
X 
 
 
 
 
 
 
 
 
MMR/MSS and BRAF V600E statusc 
X 
 
 
 
 
 
 
 
 
Eligibility Evaluation and Randomization 
X 
X 
 
 
 
 
 
 
 
G8 Health Status Screening Tool  
(Patients > 70yrs only) 
X 
 
 
 
 
 
 
 
 
Archived tumor sample 
X 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
 
X 
 
 
 
 
 
 
Physical Examd 
X 
 
X 
 
 
 
 
 
 
Height, Weight 
Xe 
 
X 
 
 
 
 
 
 
Vital Signs 
X 
 
Xf 
 
 
 
 
 
 
12-lead Electrocardiogram 
Xg 
 
Xg 
Xg 
 
 
 
 
 
Clinical Chemistry 
X 
 
Xh 
 
 
 
 
 
 
DPD testingi  
X 
 
 
 
 
 
 
 
 
Hematology 
X 
 
Xj 
X 
X 
X 
X 
X 
X 
INR/aPTT 
X 
 
 
 
 
 
 
 
 
Urinalysis (dipstick) 
X 
 
X 
 
 
 
 
 
 
Pregnancy test (WOCBP)k 
 
X 
 
 
 
 
 
 
 
Tumor Assessment by RECIST v1.1l 
X 
 
 
 
 
 
 
 
 
Trilaciclib or Placebom 
 
 
X 
X 
 
 
 
 
 


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Assessment 
Screening 
Rand 
Induction Cycle 1 (14-day cycle) 
Day 
-28 to -1 
-3 to -1a 
1 
2 
4  
(±1 day) 
6  
(±1 day) 
8  
(±1 day) 
10  
(±1 day) 
12  
(±1 day) 
Irinotecan 
 
 
X 
 
 
 
 
 
 
Oxaliplatin 
 
 
X 
 
 
 
 
 
 
Leucovorin 
 
 
X 
 
 
 
 
 
 
Fluorouracil 
 
 
X 
X 
 
 
 
 
 
Bevacizumab 
 
 
X 
 
 
 
 
 
 
FACT-An (includes FACIT-F), FACT-C,  
PGIS, and PGICn 
 
 
X 
 
 
 
X 
 
 
EQ-5D-5L 
 
 
X 
 
 
 
X 
 
 
Blood sample for PKo 
 
 
X 
X 
 
 
 
 
 
Blood sample for Immunologic and 
Hematologic Markers 
 
 
X 
 
 
 
 
 
 
AEs 
 
 
X 
Concomitant Medications 
Xb 
Xb 
X 
AE=adverse event; aPTT=activated partial thromboplastin time; β-hCG=beta human chorionic gonadotropin; CRC=colorectal cancer; CT=computed 
tomography; ECOG=Eastern Cooperative Oncology Group; EQ-5D-5L=5-level EQ-5D; FACT-An=Functional Assessment of Cancer Therapy – Anemia; 
FACIT-F=Functional Assessment of Chronic Illness Therapy – Fatigue; FACT-C=Functional Assessment of Cancer Therapy – Colorectal; FACT-G=Functional 
Assessment of Cancer Therapy – General; INR=international normalized ratio; IWRS=interactive web response system; MMR=mismatch repair; MRI=magnetic 
resonance imagining; MSI=microsatellite instable; PE=physical exam; PGIC=Patient Global Impression of Change; PGIS=Patient Global Impression of 
Severity; PK=pharmacokinetic; pMMR/MSS=proficient mismatch repair/microsatellite stable; RECIST=Response Evaluation Criteria in Solid Tumors; 
yrs=years; WOCBP=women of childbearing potential. 
a Patients can be randomized and receive Cycle 1 Day 1 on the same day. When required by institutional procedures, randomization will be allowed up to 7 days 
prior to dosing without a protocol deviation. Screening procedures must be completed prior to randomization and the screening window remains 28 days. 
b Including medical and surgical history, documentation of CRC diagnosis and prior CRC therapy, and prior medications (current and those taken within 14 days 
of informed consent). 
c Documentation of BRAF V600E and pMMR/MSS is required; patients with deficient MMR/MSI-high or MSI-low CRC are not eligible for this study. If 
historical pMMR/MSS and/or BRAF V600E mutational status are not known, a tumor specimen (archival or fresh biopsy) must be sent for testing and results 
must be available at the time of randomization in IWRS. If testing cannot be completed using a standard clinical assay performed institutionally/locally, the 
tumor specimen may be sent to the Sponsor’s designated central laboratory for analysis. If institutional/local testing is unavailable, please contact your CRA.  
d Full PE at Screening, brief PE at all other timepoints. 


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e Height measured only at Screening; weight measured at Screening and Day 1 of each cycle in Induction and Maintenance. 
f Vitals (BP, HR, temperature) should be taken 15 minutes (± 10 minutes) before and after the trilaciclib/placebo infusion. 
g Perform triplicate ECGs at Screening and on Day 1 of Cycle 1 at the following timepoints: predose (trilaciclib/placebo) at any time prior to dosing, within 30 
minutes following the end of the trilaciclib/placebo infusion, and at 3 hours after the start of trilaciclib/placebo infusion (± 30 minutes). Triplicate ECGs should 
also be performed on Day 2 of Cycle 1 at the following timepoints: predose (trilaciclib/placebo) at any time prior to dosing and within 30 minutes following the 
end of the trilaciclib/placebo infusion. Additional ECGs during the study may be performed as clinically indicated. Any ECG with a QTc value of > 500 or any 
other clinically significant abnormal finding should be repeated every 5 minutes for a total of three ECGs to confirm this finding, if not already recorded in 
triplicate. 
h Clinical chemistry and urinalysis may be obtained up to 3 calendar days prior to dosing.  
i Patients with complete absence of dihydropyrimidine dehydrogenase (DPD) activity as evidenced by the presence of certain genetic mutations or 
polymorphisms in the DYPD gene or blood uracil level ≥150ng/mL must be excluded. Fluorouracil dose modification should be considered for those with 
partial DPD deficiency as evidenced by certain genetic mutations/polymorphisms in the DYPD gene or blood uracil values >16 but <150 ng/mL (Section 9.5). 
j Hematology may be obtained up to 1 calendar day prior to dosing. 
k Female patients of childbearing potential: serum β-hCG at enrolment (eg, signed consent and during window allowing randomization in IWRS; results should 
be available prior to randomization).  
l Initial staging should include, at a minimum, CT or MRI of chest, abdomen and pelvis. IV contrast should be used unless contraindicated. Oral contrast can be 
used at the Investigator’s discretion. 
m Trilaciclib or placebo will be administered as a 30-minute IV infusion prior to FOLFOXIRI/bevacizumab chemotherapy on Day 1 and on Day 2 of every cycle. 
Chemotherapy cannot be administered until after completion of the trilaciclib or placebo infusion on Day 1. The interval between the dose of trilaciclib or 
placebo and the first dose of chemotherapy on Day 1 should not be greater than 4 hours. The second dose of trilaciclib/placebo should be administered on 
Day 2. Trilaciclib or placebo will only be administered if chemotherapy is also to be administered on that day. 
n FACT-An, FACT-C, PGIS, and EQ-5D-5L will be administered on Days 1 and 8 of Cycle 1. PGIC will only be administered on Day 8 of Cycle 1. FACIT-F is 
embedded within the FACT-An. Patient-reported outcome questionnaires may be administered up to 1 calendar day prior to the first dose of each cycle; 
questionnaires administered on Day 8 may be obtained ±1 day of scheduled visit; NOTE: questionnaires should be completed on the same day blood sample is 
collected for hematology assessment. Questionnaires must be completed prior to the administration of any study drug and should be administered prior to the 
conduct of any study procedures at visit. 
o Four blood samples for PK analysis of trilaciclib and any metabolites will be collected: on Cycle 1 Day 1 at the end of trilaciclib/placebo infusion (within 5 
minutes prior to the end of the infusion), and at 25 to 45 minutes and 4-6 hours post the end of the trilaciclib/placebo infusion, as well as predose 
(trilaciclib/placebo) on Cycle 1 Day 2. Three samples will be collected for PK analysis of irinotecan and its metabolite (SN-38): on Cycle 1 Day 1 at the end of 
irinotecan infusion (within 5 minutes prior to the end of the infusion) and at 4-6 hours post the end of the irinotecan infusion as well as predose 
(trilaciclib/placebo) on Cycle 1 Day 2. 
 
 
 


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Table 5: 
Schedule of Assessments: Induction (Cycle 2-12), Maintenance, and Survival Follow-up 
Assessment 
Induction (14-day cycles) 
[Maximum 12 cycles] 
Last 
Induction 
Cycle only if 
no 
Maintenance 
Maintenance 
(14-day cycles) 
Post 
Treatment 
Visit 
Survival 
Follow 
Up 
Day 
1 
2 
8 
(±1 day) 
15 
(±1 day) 
1 
2 
30 ±7d 
post last 
dose 
 
ECOG Performance Status 
X 
 
 
 
X 
 
X 
 
Physical Exam [Odd cycles only in both 
Induction and Maintenance, eg, C1, 3, 5, 
etc) 
X 
 
 
 
X 
 
X 
 
Weight 
X 
 
 
 
X 
 
X 
 
Vital Signsa 
X 
 
 
 
X 
 
X 
 
12-lead Electrocardiogram 
Xb 
[C2 only] 
Xb 
[C2 
only] 
 
 
 
 
 
 
Clinical Chemistryc 
X 
 
 
 
X 
 
X 
 
Hematologyd 
X 
 
X 
[C2-4 only] 
X 
X 
 
X 
 
INR/aPTT  
(as clinically indicated during the study) 
 
 
 
 
 
 
 
 
Urinalysisc (dipstick) 
X 
 
 
 
X 
 
 
 
Pregnancy test (WOCBP, q month)e 
X 
 
 
 
X 
 
X 
 
Tumor Assessment by RECIST v1.1 
Xf (q8 weeks regardless of dosing) 
 
Xf (q12 
weeks) 
 
Xg 
Xg 
Trilaciclib or placeboh 
X 
X 
 
 
X 
X 
 
 
Irinotecan 
X 
 
 
 
 
 
 
 


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Assessment 
Induction (14-day cycles) 
[Maximum 12 cycles] 
Last 
Induction 
Cycle only if 
no 
Maintenance 
Maintenance 
(14-day cycles) 
Post 
Treatment 
Visit 
Survival 
Follow 
Up 
Day 
1 
2 
8 
(±1 day) 
15 
(±1 day) 
1 
2 
30 ±7d 
post last 
dose 
 
Oxaliplatin 
X 
 
 
 
 
 
 
 
Leucovorin 
X 
 
 
 
X 
 
 
 
Fluorouracil 
X 
X 
 
 
X 
X 
 
 
Bevacizumab 
X 
 
 
 
X 
 
 
 
FACT-An (includes FACIT-F), FACT-C,  
PGIS, PGICi 
X 
 
X 
[C2-4 only] 
Xj 
X 
 
X 
 
EQ-5D-5L 
X 
 
X 
[C2-4 only] 
Xj 
X 
 
X 
 
Blood sample for Immunologic and 
Hematologic Markers 
X 
[C2, C5, 
only] 
 
 
 
X  
[C1 only] 
 
 
 
AEs 
X 
 
Concomitant Medications 
X 
 
Survival Follow-up Contact  
(every other month) 
 
 
 
 
 
 
 
Xk 
AE=adverse event; aPTT=activated partial thromboplastin time; β-hCG=beta human chorionic gonadotropin; C=cycle; ECOG=Eastern Cooperative Oncology 
Group; EQ-5D-5L=5-level EQ-5D; FACT-An=Functional Assessment of Cancer Therapy – Anemia; FACIT-F=Functional Assessment of Chronic Illness 
Therapy-Fatigue; FACT-C=Functional Assessment of Cancer Therapy – Colorectal; FACT-G=Functional Assessment of Cancer Therapy – General; 
INR=international normalized ratio; IWRS=interactive web response system; PE=physical exam; PGIC=Patient Global Impression of Change; PGIS=Patient 
Global Impression of Severity; RECIST=Response Evaluation Criteria in Solid Tumors; WOCBP=women of childbearing potential. 
a Vitals (blood pressure, heart rate, temperature) should be taken 15 minutes (± 10 minutes) before and after the trilaciclib/placebo infusion. 
b Perform triplicate ECGs on Day 1 of Cycle 2 at the following timepoints: predose (trilaciclib/placebo) at any time prior to dosing, within 30 minutes following 
the end of the trilaciclib/placebo infusion, and 3 hours after the start of trilaciclib/placebo infusion (± 30 minutes). Triplicate ECGs should also be performed on 
Day 2 of Cycle 2 at the following timepoints: predose (trilaciclib/placebo) at any time prior to dosing and within 30 minutes of the end of the trilaciclib/placebo 


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infusion. Additional ECGs during the study may be performed as clinically indicated. Any ECG with a QTc value of > 500 or any other clinically significant 
abnormal finding should be repeated every 5 minutes for a total of three ECGs to confirm this finding, if not already recorded in triplicate .  
c Clinical chemistry and urinalysis may be obtained up to 3 calendar days prior to dosing. 
d Hematology may be obtained up to 1 calendar day prior to dosing. If the initiation of the next cycle is delayed due to an AE, the patient should have (at least) 
weekly visits, including CBCs if the AE is hematologic, to follow the AE. Clinical laboratory assessments should be completed on the scheduled Day 1 as well 
as on the actual first dosing day of that delayed cycle. 
e Female patients of childbearing potential: serum or urine pregnancy testing every 2nd cycle (eg, every month) during treatment (Induction and Maintenance) 
and at the post-treatment visit. 
f Tumor assessments of chest, abdomen, and pelvis using the same imaging modality as at baseline should be performed every 8 weeks ± 7 days during 
Induction and every 12 weeks ± 14 days during Maintenance. IV contrast should be used unless contraindicated. Oral contrast can be used at the Investigator’s 
discretion. Timing of scans should be regardless of dosing (e.g. from date of first dose). Additional scans may be performed during the study if clinically 
indicated. 
g Perform tumor assessments at the Post Treatment Visit (30 +7d after last dose of study drug) only for patients who have not progressed at the time of study 
drug discontinuation. For those patients being followed for survival who have not progressed at the time of study drug discontinuation, tumor assessments will 
be repeated every 12 weeks ± 14 days until the occurrence of disease progression, withdrawal of consent, initiation of subsequent anti-cancer therapy, or study 
completion. Tumor assessments of chest, abdomen, and pelvis using the same imaging modality as at baseline should be performed. IV contrast should be used 
unless contraindicated; oral contrast can be used at the Investigator's discretion. 
h Trilaciclib or placebo will be administered as a 30-minute IV infusion prior to chemotherapy on Day 1 and on Day 2 of every cycle during Induction and 
Maintenance. Chemotherapy cannot be administered until after completion of the trilaciclib or placebo infusion on Day 1. The interval between the dose of 
trilaciclib or placebo and the first dose of chemotherapy on Day 1 should not be greater than 4 hours. The second dose of trilaciclib/placebo should be 
administered on Day 2. Trilaciclib or placebo will only be administered if chemotherapy is also to be administered on that day.  
i FACIT-F is embedded in the FACT-An. Patient reported outcome questionnaires should be completed at the following timepoints: Induction Cycles 2 to 4 
(Days 1 and 8), Induction Cycle 5-12 (Day 1), Day 1 of each cycle in Maintenance, and at the post-treatment visit. If a cycle is delayed, the patient should still 
complete the questionnaires on the scheduled Day 1 of that cycle, as well as the actual first dosing day of that cycle. PRO questionnaires may be administered 
up to 1 calendar day prior to the first dose of each cycle; questionnaires administered on Day 8 may be obtained ±1 day of scheduled visit. NOTE: 
questionnaires should be completed on the same day blood sample is collected for hematology assessment. Questionnaires must be completed prior to the 
administration of any study drug and should be administered prior to conduct of any study procedure at that visit. 
j Administer PRO questionnaires on Day 15 of last induction cycle only if patient does not continue with Maintenance therapy. When patient does not continue 
in Maintenance, questionnaires do not need to be repeated at both Post Treatment Visit and Day 15 of last induction cycle if < 3 weeks between these 
2 timepoints. 
k If a patient withdraws consent for further study treatment and/or procedures, the site should clarify if the patient remains open to survival contact and associated 
data collection. See Section 11.12 for details of information to be collected during Survival Follow-up. 
 


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9. 
STUDY TREATMENT 
9.1. 
Study Drugs Administered 
Study drugs are defined as any investigational agent(s), marketed product(s), or placebo intended 
to be administered to a study patient according to the study protocol. Study drugs used in this 
protocol are described in Table 6. 
 


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Table 6: 
Study Drugs 
Name 
Trilaciclib  
Placebo 
FOLFOXIRI 
Bevacizumab 
Type  
Active Drug  
Placebo 
SOC Therapy 
SOC Therapy 
Dose Formulation 
Single-use, sterile powder to 
be reconstituted with 250 mL 
of dextrose 5% in water or 
normal saline (sodium 
chloride solution 0.9%) per 
the Pharmacy Manual 
250 mL of dextrose 5% 
in water or normal saline 
(sodium chloride 
solution 0.9%) 
Descriptions of the formulations are 
provided in the current prescribing 
information (Section 17.5)  
Description of the 
formulation is provided in 
the current prescribing 
information (Section 17.6) 
Unit Dose Strength(s) 
300 mg/20 mL  
N/A 
See Section 17.5 
See Section 17.6 
Dosage Level(s) 
240 mg/m2 administered on 
Days 1 and 2 over 30 minutes 
N/A – administered on 
Days 1 and 2 to match 
trilaciclib 
Irinotecan 165 mg/m2 (Day 1) 
Oxaliplatin 85 mg/m2 (Day 1) 
Leucovorin 400 mg/m2 (Day 1); 
LEVOleucovorin 200 mg/m2 is an 
acceptable alternative 
Fluorouracil 2400 – 3200 mg/m2 
(continuous infusion over 48 hours; 
Days 1 and 2); actual dose to be 
determined by the Investigator 
Bevacizumab 5 mg/kg  
(Day 1) 
Route of 
Administration 
IV 
IV 
IV 
IV 
Use 
Experimental 
Placebo 
SOC 
SOC 
Sourcing 
Provided by the Sponsor  
Prepared locally at the 
study site 
Commercially available; may be 
supplied by study site or Sponsor 
Commercially available; 
may be supplied by study 
site or Sponsor 
Packaging and 
Labeling 
Study Intervention will be 
provided in flint glass vials. 
Each vial will be labeled as 
required per country 
requirements. 
Placebo may be provided 
by the study site. 
SOC may be supplied by the study 
site in the commercially available 
packaging or by the Sponsor. 
SOC may be supplied by the 
study site in the 
commercially available 
packaging or by the 
Sponsor. 
 
IV=intravenous; N/A=not applicable; SOC=standard of care; USP=United States Pharmacopeia. 


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9.1.1. 
Dose, Dosing Regimen, and Route 
9.1.1.1. 
Trilaciclib 
Trilaciclib for injection, (300 mg/vial, also referred to as “Trilaciclib Sterile Powder” for 
concentrate for solution for IV infusion, 300 mg/vial) 240 mg/m2 diluted in 250 mL of dextrose 
5% in water (D5W) or sodium chloride solution 0.9% is to be administered by IV infusion over 
30 (±10) minutes by peripheral or central access. During sequential drug administration (e.g., 
Day 1 infusions), trilaciclib can be delivered through the same access point through which 
chemotherapy/bevacizumab will be delivered. However, when trilaciclib is given concurrently 
with another infusion (e.g., during Day 2 5FU infusion), trilaciclib must be delivered through 
either a separate peripheral line or through central access that is designed for delivery of 
incompatible medications. Following trilaciclib administration in either scenario, flushing the 
infusion line with a minimum of 20 ml of 5% dextrose or normal saline is recommended. In 
addition, for peripheral access delivery, rotating the IV catheter sites and starting a new IV with 
each day of trilaciclib infusion can decrease the frequency and severity of local reactions. 
Administration of trilaciclib infusion by central access may be considered to limit these local 
reactions.  
Actual body weight (not ideal body weight) should be utilized for dose calculations. At a 
minimum, if there is a change in body weight of > 10% relative to the weight at the time of the 
last dose calculation, doses should be recalculated. Recalculation of the dose more frequently per 
local institutional guidelines is permitted. Dose recalculation to adjust for changes in body 
weight will not be considered a dose reduction.  
If there is any study drug remaining in the infusion bag at the end of the 30 minutes, the infusion 
should be continued at the same rate until the entire contents of the bag have been administered 
to ensure patients receive the full dose. Details regarding the reconstitution and dilution of 
trilaciclib vials is detailed in the Pharmacy Manual. 
The infusion rate may be decreased to manage an infusion-related AE; for example, if a patient 
experiences a burning sensation during infusion, the infusion may be increased to 45 minutes (or 
longer if clinically indicated) to alleviate the symptoms.  
9.1.1.2. 
Placebo 
The placebo formulation of 250 mL of D5W or sodium chloride solution 0.9% will be 
administered by IV infusion over 30 (±10) minutes by peripheral or central access. If there is any 
volume remaining in the infusion bag at the end of the 30 minutes, the infusion should be 
continued at the same rate until the entire contents of the bag have been administered to ensure 
patients receive the full dose. 
9.1.1.3. 
FOLFOXIRI/bevacizumab 
FOLFOXIRI/bevacizumab will be administered IV in accordance with the prescribing 
information (see Section 17.5 and Section 17.6) and according to the study site’s standard 
practice. Fluorouracil 2400 – 3200 mg/m2 (continuous infusion over 48 hours; Days 1 and 2) will 
be administered, with the actual dose to be determined by the Investigator at the beginning of 
Induction (e.g., Cycle 1 Day 1). The same dose of 5FU must be administered to a given patient 


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63 
throughout the study (Induction and Maintenance) except when dose modification for toxicity is 
necessary. If a bevacizumab biosimilar is used, the biosimilar must be approved for use by the 
FDA, European Commission, or the China National Medical Products Administration (NMPA). 
At a minimum, if there is a change in body weight of > 10% relative to the weight at the time of 
the last dose calculation, doses should be recalculated. Recalculation of the dose more frequently 
per local institutional guidelines is permitted. Dose recalculation to adjust for changes in body 
weight will not be considered a dose reduction.  
9.1.2. 
Preparation, Handling, Storage, and Accountability 
The Investigator or designee, institution, or the head of the medical institution (where applicable) 
is responsible for study medication accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). Further guidance and information are 
provided in the Pharmacy Manual. 
9.1.3. 
Treatment Compliance 
The Investigator or designee will dispense the study drugs, via an unblinded 
Pharmacist/Designee, only for use by patients enrolled in the study as described in this protocol. 
The study drugs are not to be used for reasons other than those described in this protocol. The 
clinical study site will maintain records of study drugs’ receipt, preparation, and dispensing, 
including the applicable lot numbers; patient’s height, body weight, and body surface area; date 
and time of the start and end of each trilaciclib or placebo, FOLFOXIRI, and bevacizumab 
infusion; and total drug administered in milligrams. Any discrepancy between the calculated 
dose and dose administered and the reason for the discrepancy (e.g., interruption of infusion 
without restarting) will be recorded on eCRF and in the source documents. 
9.2. 
Induction 
During Induction, all patients will receive trilaciclib 240 mg/m2 or placebo IV on Day 1 and Day 
2 of each 14-day Induction cycle (up to 12 cycles in total). On Day 1, trilaciclib/placebo will be 
administered no more than 4 hours prior to the start of chemotherapy administration; the second 
dose of trilaciclib/placebo should be administered on Day 2. FOLFOXIRI/bevacizumab should 
not be administered until after the completion of the trilaciclib or placebo infusion on Day 1. 
Patients should meet the requirements outlined in Section 9.4 before initiation of Cycle 2 and 
each subsequent Induction cycle. Criteria for study drug discontinuation are outlined in 
Section 10.1. 
Since individual drugs may be discontinued for toxicity, Induction refers to any cycles of therapy 
where 5FU and either oxaliplatin or irinotecan is also being administered, e.g., 5FU + oxaliplatin 
+ bevacizumab; 5FU+ irinotecan + bevacizumab; 5FU + oxaliplatin; or 5FU + irinotecan. 
9.3. 
Maintenance 
Patients who complete Induction without radiographic or clinical disease progression and remain 
eligible to receive 5FU/leucovorin/bevacizumab will continue with Maintenance therapy. These 
patients include those who were able to complete the maximum of 12 Induction cycles as well as 
those who were unable to complete 12 cycles due to toxicity (without documented disease 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n  6 . 1_ 1 5 Dece m ber  2 0 2 2  
 
 
6 4  
pr o g ressi o n) w h e n  t he treati n g p h ysicia n feels t he patie nt will recei ve a d diti o nal cli nical be nefit  
b y tra nsiti o ni n g t o Mai nte na nce . Patie nts will recei ve trilacicli b or place b o  ( per sa me 
ra n d o mizati o n all ocati o n at st u d y e ntr y) pri or t o  i nf usi o nal-5 F U/ le uc o v ori n/be vaciz u m a b at t he 
sa me d ose a n d s c he d ule i n eac h 1 4-d a y c y cle d uri n g Mai nte na nce. I nf usi o nal -
5 F U/ le uc o v ori n/be vaciz u ma b s h o ul d n ot be a d mi nistere d o n Da y 1  u ntil aft er t he c o m pleti o n of 
a d mi nistrati o n of t he trilacicli b or place b o i nf usi o n.  Patie nts s h o ul d meet t he re q uir e me nts 
o utli ne d i n Secti o n  9. 4  bef ore i nitiati o n of eac h M ai nte na nce c ycle. Criteria f or st u d y dr u g 
disc o nti n uati o n are o utli ne d i n Secti o n  1 0. 1 . 
Si nce i n di vi d ual dr u gs ma y be disc o nti n ue d f or t o xicit y, Mai nte na nce refers t o a n y c ycles of 
t hera p y w here at least  5 F U is a d mi nistere d.  
9. 4.  
Criteri a f or St arti n g C ycle 2 a n d E ac h S u bse q ue nt C ycle i n 
I n d ucti o n or M ai nte n a nce 
F oll o w i n g c o m pleti o n of C ycle 1, patie nts m ust meet all t he f oll o wi n g mi ni m u m criteria t o 
recei v e t he Da y 1 d os e of st u d y treat me nt f or C ycl e 2 a n d eac h s u bse q ue nt c ycle d uri n g 
I n d u cti o n or Mai nte na n ce:  
•  A N C ≥ 1. 0  × 1 0 9/ L,  
•  P latelet c o u nt ≥ 7 5 × 1 09/ L, a n d  
•  N o n h e mat ol o gic dr u g -rel ate d t o xicities m ust be ≤ Gra de 1. H o we v er, Gra d e 2 
t o xicities n ot s pecificall y n ote d i n Ta ble  9  as re q uiri n g a d ose dela y u ntil t o xicit y 
res ol ves t o < G 1 (e x. ne ur o pat h y, m uc ositis, pal mar-pla ntar er yt hr o d ys est hesia) ca n 
be ma na ge d acc or di n g t o l ocal sta n dar d of care i n c o ns ultati o n wit h  t he Me dical 
M o nit or.  
If t he i nitiati o n of t he ne xt c ycle is dela ye d d u e t o a n A E, t he patie nt s h o ul d ha ve (at least) 
wee kl y visits, i ncl u di n g C B Cs if t he A E is he mat ol o gic, t o m o nit or t he t o xicit y u ntil treat me nt 
criteria d escri be d a b o ve are met or u ntil t he y disc o nti n ue treat me nt (e. g., if m ore t ha n 4 wee ks 
ela pse fr o m t he l ast c he m ot hera p y d ose).  T he patie nt s h o ul d still c o m plete t he cli nical la b orat or y 
assess me nts a n d t he P R O q uesti o n naires o n t he sc he d ule d Da y 1 (e ntere d as U nsc he d ule d 
assess me nts i n E D C) as well as o n t he act u al first d osi n g da y of t hat c ycle.  
T here s h o ul d be n o m or e t ha n 4 wee ks (f or t o xicit y a n d/ or a d mi nistrati ve reas o ns) bet w ee n d oses 
of c he m ot hera p y; h o we v er d osi n g dela ys > 4 wee ks ma y be per mitte d o n a case b y -case b asis 
wit h t he  d oc u me nte d a p pr o val of t he In v esti gat or a n d M e dical M o nit or.  
L ocal treat me nt of s y m pt o matic lesi o n(s) wit h palliati ve t hera p y (e x. s ur ger y, ra di ot hera p y, 
ra di ofre q u e nc y a blati o n, e m b olizati o n) is per mitte d  at t he I n vesti gat or’s dis creti o n t o c o ntr ol 
disea se s y m pt o ms. H o we ver, use of tec h ni q ues t hat i nc or p orate s yste mic t h era p y, i ncl u di n g l ocal 
a d mi nistrati o n, is n ot per mitte d  (see Secti o n  9. 7 ). Patie nts re q uiri n g palliati ve t hera p y ma y 
c o nti n ue recei vi n g st u d y dr u g u ntil d oc u me nte d disease pr o gressi o n (ra di o gra p hic or cli nical)  if, 
i n t he I n v esti gat or’s o pi ni o n, t he patie nt is c o nti n ui n g t o recei ve cli nical be nefit a n d t he y meet 
t he re q uire m e nts descri b e d a b o ve.   
Patie nts wit h metastases c o nfi ne d t o t he li ver w h o e x perie n ce a r o b ust res p o nse t o c he m ot hera p y 
ma y als o pr ocee d wit h c urati ve i nte nt s ur gical r esecti o n at t he In vesti gat or ’s discreti o n. I n t hat 


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event, study treatment in this trial will be considered complete and patients will enter into 
Survival Follow-up. Tumor assessments will continue as directed for survival follow-up (Table 
5, footnote g). For the time-to-event endpoints, except OS, these patients are considered to be 
censored at the date of surgery. Any anti-cancer therapy for colorectal cancer that is initiated 
post-surgical resection is at the discretion of the Investigator and will be recorded as subsequent 
anti-cancer therapy in the EDC.  
9.5. 
Toxicity Management and Dose Modifications 
All dose reductions for hematologic or non-hematologic toxicity management will only be made 
on Day 1 of a cycle. All dose reductions for an individual patient are permanent and no dose 
increases will occur following a dose reduction. Recommended dose levels for reduction of 
irinotecan, oxaliplatin and 5FU are described in Table 7.  
Table 7: 
Recommended Chemotherapy Dose Modifications 
 
IRIN 
OXALI 
5FU 
LCV 
Starting Dose 
165 mg/m2 
85 mg/m2 
2400-3200 mg/m2 
(actual dose to be 
determined by 
Investigator) 
400 mg/m2; 
LEVOleucovorin at 
200 mg/m2 is an 
accepted alternative 
Dose Level -1 
125 mg/m2  
(~75% of starting 
dose) 
65 mg/m2  
(~75% of starting 
dose) 
1800-2400 mg/m2 
(75% of starting 
dose) 
No dose adjustment 
(per package insert) 
Dose Level -2 
80 mg/m2  
(~50% of starting 
dose) 
40 mg/m2  
(~50% of starting 
dose) 
1200-1600 mg/m2 
(50% of starting 
dose) 
5FU=fluorouracil; IRIN=irinotecan; OXALI=oxaliplatin; LCV=leucovorin. 
No dose modification is permitted for trilaciclib. 
*In case of partial DPD deficiency as evidenced by certain genetic mutations/polymorphisms in the DYPD gene or 
blood uracil levels <150 ng/mL but >16 ng/mL, consideration should be given to modifying the starting dose of 
5FU, taking into account the specific mutation/polymorphism or blood uracil level as well as the individual patient 
risk factors for bone marrow toxicity. Depending on treatment-related toxicity, a therapeutic dose adjustment may be 
required in Cycle 2.  
 
The recommended dose modification procedures for hematologic toxicities are described in 
Table 8, non-hematologic toxicities are described in Table 9 and those for bevacizumab toxicities 
are described in Table 10. Recommendations for hepatobiliary toxicity management are in 
Section 9.5.2. All recommendations are intended as a minimum guideline for toxicity 
management and are not a replacement for independent medical judgement tailored to specific 
circumstances with an individual patient. Please also refer to the individual package inserts 
(Section 17.5) for additional information and recommendations. 
Note that dose modifications (specifically dose reductions/discontinuations) are recommended 
for those events considered related to drug (i.e., toxicities) such that decreasing the dose or 
stopping the drug will lead to improved patient safety. If an event is not thought to be related to 
study drug by the Investigator, dose reduction/discontinuation is not required since decreasing 
the dose or stopping the drug would not be expected to alter the risk of the event occurring again; 


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rather the Investigator should consider if treatment should be delayed until the event recovers to 
≤ Grade 1 or baseline before resumption of treatment. Decreased neutrophil, platelet counts or 
hemoglobin values that occur in isolation (e.g., at nadir) that do not result in a dosing delay, 
febrile neutropenia, serious adverse event (SAE) or other consequence, do not require dose 
modification. 
Dose modifications for drug-related toxicity should be done according to the organ system 
showing the greatest degree of drug-related toxicity (e.g., modify dose of the suspect drug) and 
may be independent of other drugs in the regimen. If drug-related toxicity requires 
discontinuation of both oxaliplatin and irinotecan, Induction will be considered complete and 
Maintenance therapy with 5FU, leucovorin and bevacizumab may continue per the clinical 
judgment of the Investigator.  
If fluorouracil is discontinued during Induction or Maintenance, then the patient must 
permanently discontinue all study drugs (e.g., End of Treatment) and should complete the Post 
Treatment Visit and enter Survival Follow-up.  
9.5.1. 
Trilaciclib and FOLFOXIRI 
The dose of trilaciclib will not be modified and will remain at 240 mg/m2 throughout the study. 
The interval between the dose of trilaciclib or placebo and the first dose of chemotherapy on 
Day 1 should not be greater than 4 hours. The second dose of trilaciclib/placebo should be 
administered on Day 2.  
Trilaciclib or placebo will only be administered with FOLFOXIRI/bevacizumab therapy. If 
administration of chemotherapy/bevacizumab is held or discontinued, trilaciclib or placebo 
will also be held or discontinued. Conversely, if trilaciclib or placebo is held on Day 1 of 
any given cycle, chemotherapy/bevacizumab will not be administered until 
trilaciclib/placebo can be given on the same day.  
 


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Table 8: 
Dose Modifications for Drug-related Hematologic Toxicity 
 
 
Action Taken 
Event, 
CTCAE 
Grade or Lab 
Value 
Frequency 
Trilaciclib 
IRIN 
OXAL 
5FU 
LCV 
Toxicity 
Management 
Hematologic toxicity on scheduled Day 1 in Cycle 2 and all subsequent cycles resulting in delay of treatment 
ANC  
< 1.0 x 109/L 
(≥ G3) 
1st episode 
Hold drug until 
ANC criteria for 
dosing reached. 
No change in 
dose. 
Hold drug until ANC criteria for dosing reached. No change 
in dose. 
Hold drug until 
ANC criteria for 
dosing reached. 
No change in 
dose. 
Administer 
prophylactic G-CSF 
with each 
subsequent cycle of 
chemotherapy. 
2nd, 3rd and 
4th episode 
Hold drug until 
ANC criteria for 
dosing reached. 
No change in 
dose. 
Hold drug until ANC criteria for dosing reached. Reduce dose 
of one drug by one dose level and resume dosing; Investigator 
discretion as to which drug is reduced. 
Hold drug until 
ANC criteria for 
dosing reached. 
No change in 
dose. 
Continue 
prophylactic G-CSF 
with each 
subsequent cycle of 
chemotherapy. 
Prolonged severe 
myelosuppression 
should prompt 
evaluation for 
dihydropyrimidine 
dehydrogenase 
deficiency. 
5th episode 
Permanently discontinue 
Platelets  
< 75 x 109/L 
(≥ G2) 
1st, 2nd and 
3rd episode 
Hold drug until 
platelet criteria 
for dosing 
reached. No 
change in dose. 
Hold drug until platelet criteria for dosing reached. Reduce 
dose of one drug by one dose level and resume dosing; 
Investigator discretion as to which drug is reduced. 
Hold drug until 
platelet criteria 
for dosing 
reached. No 
change in dose. 
Monitor for signs 
and symptoms of 
bleeding. 
 
Consider treatment 
as clinically 
indicated. 
4th episode 
Permanently discontinue.  


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
 
68 
 
 
Action Taken 
Event, 
CTCAE 
Grade or Lab 
Value 
Frequency 
Trilaciclib 
IRIN 
OXAL 
5FU 
LCV 
Toxicity 
Management 
Hematologic toxicity at any point during study treatment 
Febrile 
neutropenia 
(G3 or 4) 
OR 
G4 
neutropenia 
lasting 
> 5 days 
1st episode 
Hold drug until 
ANC criteria for 
dosing reached. 
No change in 
dose. 
Hold drug until ANC criteria for dosing reached. Consider 
reducing one drug by one dose level. 
Hold drug until 
ANC criteria for 
dosing reached. 
No change in 
dose. 
Administer 
prophylactic G-CSF 
with each 
subsequent cycle of 
chemotherapy. 
Prolonged severe 
myelosuppression 
should prompt 
evaluation for 
dihydropyrimidine 
dehydrogenase 
deficiency 
2nd episode 
Hold drug until 
ANC criteria for 
dosing reached. 
No change in 
dose. 
Hold drug until ANC criteria for dosing reached. Reduce dose 
of one drug by two dose levels OR the dose of two drugs by 
one dose level each and resume dosing; Investigator 
discretion as to which option is selected. 
Hold drug until 
ANC criteria for 
dosing reached. 
No change in 
dose. 
Continue 
prophylactic G-CSF 
with each 
subsequent cycle of 
chemotherapy. 
Prolonged severe 
myelosuppression 
should prompt 
evaluation for 
dihydropyrimidine 
dehydrogenase 
deficiency  
3rd episode 
Permanently discontinue. 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
 
69 
 
 
Action Taken 
Event, 
CTCAE 
Grade or Lab 
Value 
Frequency 
Trilaciclib 
IRIN 
OXAL 
5FU 
LCV 
Toxicity 
Management 
Symptomatic 
thrombocytope
nia (≥ G3 with 
bleeding) 
1st and 2nd 
episode 
Hold drug until 
ANC criteria for 
dosing reached. 
No change in 
dose. 
Hold drug until ANC criteria for dosing reached. Reduce dose 
of one drug by one dose level and resume dosing; Investigator 
discretion as to which drug is reduced. 
Hold drug until 
ANC criteria for 
dosing reached. 
No change in 
dose. 
Consider treatment 
as clinically 
indicated. 
 
3rd episode 
Permanently discontinue. 
ANC=absolute neutrophil count; CTCAE=Common Terminology Criteria for Adverse Events; G=Grade; G-CSF=granulocyte colony-stimulating factor;5FU= 
fluorouracil; IRIN=irinotecan; OXALI=oxaliplatin; LCV=leucovorin. 
 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
 
70 
Table 9: 
Dose Modification for Drug-related Non-hematologic Toxicity 
 
 
Action Taken 
Event, CTCAE 
Grade 
Frequency 
Trilaciclib 
IRIN 
OXAL 
5FU 
LCV 
Toxicity Management 
Acute drug 
hypersensitivity 
reaction G1 
(defined as mild; 
asymptomatic or 
mild symptoms; 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated).  
Any 
occurrence. 
No change in 
dose.  
No change in dose.  
No change in 
dose.  
Initiate appropriate 
medical therapy and 
monitor as clinically 
indicated. 
Acute drug 
hypersensitivity 
reaction G2 
(defined as 
moderate; minimal, 
local or 
noninvasive 
intervention 
indicated; limiting 
age-appropriate 
instrumental ADL). 
1st episode 
Stop infusion 
and hold drug 
until toxicity 
resolves to ≤ G1 
or baseline. No 
change in dose. 
Stop infusion and hold drug until toxicity resolves 
to ≤G1 or baseline. No change in dose. 
Stop infusion 
and hold drug 
until toxicity 
resolves to ≤ G1 
or baseline. No 
change in dose. 
Acute drug 
hypersensitivity 
reaction G3-4 
(defined as severe 
or life-threatening 
consequences) 
2nd episode G2 
or any 
occurrence  
G3-4 
Permanently discontinue 
Diarrhea G1 
Any 
occurrence. 
No change in 
dose.  
No change in dose; continue dosing and consider 
starting anti-diarrheal therapy. 
No change in 
dose.  
Manage with appropriate 
antidiarrheal therapy per 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
 
71 
 
 
Action Taken 
Event, CTCAE 
Grade 
Frequency 
Trilaciclib 
IRIN 
OXAL 
5FU 
LCV 
Toxicity Management 
Diarrhea G2 
Any 
occurrence. 
No change in 
dose. 
Hold drug until toxicity resolves to ≤ G1 or 
baseline. Resume dosing at the same dose and 
consider starting anti-diarrheal therapy. 
No change in 
dose. 
institutional standards. 
Encourage patients to take 
plenty of oral fluids. 
Diarrhea G3  
1st and 2nd 
episode 
Hold drug until 
toxicity resolves 
to ≤ G1 or 
baseline. No 
change in dose. 
Hold drug until toxicity resolves to ≤ G1 or 
baseline. Reduce dose of one drug by one dose 
level and resume dosing; Investigator discretion as 
to which drug is reduced. 
Hold drug until 
toxicity 
resolves to ≤ G1 
or baseline. No 
change in dose. 
Severe diarrhea should 
prompt evaluation for 
dihydropyrimidine 
dehydrogenase 
deficiency. 
Consider referral to 
dietician for dietary 
management. 
Consider antidiarrheal 
therapy such as 
loperamide with titration 
to effect. 
Consider work-up for 
infectious cause if clinical 
signs of infection or 
unresponsive to 
conservative 
management. 
 
 3rd episode 
Permanently discontinue. 
Diarrhea G4  
1st episode 
Hold drug until 
toxicity resolves 
to ≤ G1 or 
baseline. No 
change in dose. 
Hold drug until toxicity resolves to ≤ G1 or 
baseline. Reduce dose of one drug by two dose 
levels OR the dose of two drugs by one dose level 
each and resume dosing: Investigator discretion as 
to which option is selected. 
Hold drug until 
toxicity 
resolves to ≤ G1 
or baseline. No 
change in dose. 
2nd episode 
Permanently discontinue. 
Hepatobiliary 
toxicity 
See Section 9.5.2 
Hy’s Law 
[ALT and/or 
AST 
≥3×ULN, 
ALP 
≤2×ULN, and 
total bilirubin 
≥2×ULN] 
Permanently discontinue. 
See Section 9.5.2 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
 
72 
 
 
Action Taken 
Event, CTCAE 
Grade 
Frequency 
Trilaciclib 
IRIN 
OXAL 
5FU 
LCV 
Toxicity Management 
Injection site 
reactions including 
phlebitis and 
thrombophlebitis 
G1  
(defined as 
tenderness with or 
without symptoms 
[e.g. warmth, 
erythema, itching]) 
Any 
occurrence 
Pause or slow 
the infusion.  
No change in dose.  
No change in 
dose.  
Initiate supportive care 
interventions. Upon 
completion of infusion, 
flush line/cannula with at 
least 20 ml sterile 5% 
dextrose or normal saline. 
If normal saline is being 
used as a diluent/flush, 
consider changing to 5% 
dextrose as appropriate 
for subsequent infusions. 
Central access may also 
be considered. 
Injection site 
reactions including 
phlebitis and 
thrombophlebitis 
G2  
(defined as pain; 
lipodystrophy; 
edema; phlebitis) 
Any 
occurrence 
Pause infusion. 
If pain not 
severe, follow 
instructions for 
G1. Otherwise, 
stop infusion in 
extremity and 
rotate site of 
infusion to 
site in 
alternative 
extremity.  
No change in dose.  
No change in 
dose. 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
 
73 
 
 
Action Taken 
Event, CTCAE 
Grade 
Frequency 
Trilaciclib 
IRIN 
OXAL 
5FU 
LCV 
Toxicity Management 
Injection site 
reactions including 
phlebitis and 
thrombophlebitis 
G3-4  
(G3 defined as 
ulceration or 
necrosis; severe 
tissue damage; 
operative 
intervention 
required; G4 
defined as life-
threatening 
consequences 
including need for 
urgent 
intervention) 
Any 
occurrence 
Permanently discontinue. 
Interstitial lung 
disease 
/pneumonitis G1 
(asymptomatic) 
Any 
occurrence 
No change in 
dose. 
No change in dose. 
No change in 
dose. 
Initiate appropriate 
medical therapy and 
monitor as clinically 
indicated. 
Interstitial lung 
disease 
/pneumonitis G2 
(symptomatic) 
1st episode 
Hold drug until 
toxicity resolves 
to ≤G1 or 
baseline. No 
change in dose.  
Hold drug until toxicity resolves to ≤ G1 or 
baseline. No change in dose.  
Hold drug until 
toxicity 
resolves to ≤ G1 
or baseline. No 
change in dose. 
2nd episode 
Permanently discontinue. 
Interstitial lung 
disease 
/pneumonitis 
G3-4 
Any 
occurrence 
Permanently discontinue. 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
 
74 
 
 
Action Taken 
Event, CTCAE 
Grade 
Frequency 
Trilaciclib 
IRIN 
OXAL 
5FU 
LCV 
Toxicity Management 
Mucositis G1-2 
Any 
occurrence 
No change in 
dose  
No change in dose  
No change in 
dose  
Manage with appropriate 
oral care per institutional 
standards. 
Mucositis G3 
1st and 2nd 
episode 
Hold drug until 
toxicity resolves 
to ≤ G1 or 
baseline. No 
change in dose. 
Hold drug 
until toxicity 
resolves to 
≤ G1 or 
baseline. No 
change in 
dose. 
Hold drug 
until toxicity 
resolves to 
≤ G1 or 
baseline. No 
change in 
dose. 
Hold drug 
until toxicity 
resolves to 
≤ G1 or 
baseline. 
Reduce dose 
by one level 
and resume 
dosing.  
Hold drug until 
toxicity 
resolves to ≤ G1 
or baseline. No 
change in dose. 
In addition to oral care, 
consider use of topical or 
systemic analgesia 
Severe mucositis should 
prompt evaluation of 
dihydropyrimidine 
dehydrogenase 
deficiency. 
3rd episode 
Permanently discontinue This toxicity is associated with 5FU infusion such that per 
protocol, if 5FU is permanently discontinued, then all study drugs should also be 
discontinued. 
Mucositis G4 
1st episode 
Hold drug until 
toxicity resolves 
to ≤ G1 or 
baseline. No 
change in dose. 
Hold drug 
until toxicity 
resolves to 
≤ G1 or 
baseline. No 
change in 
dose. 
Hold drug 
until toxicity 
resolves to 
≤ G1 or 
baseline. No 
change in 
dose. 
Hold drug 
until toxicity 
resolves to 
≤ G1 or 
baseline. 
Reduce dose 
by two dose 
levels and 
resume dosing.  
Hold drug until 
toxicity 
resolves to ≤ G1 
or baseline. No 
change in dose. 
2nd episode 
Permanently discontinue This toxicity is associated with 5FU infusion such that per 
protocol, if 5FU is permanently discontinued, then all study drugs should also be 
discontinued. 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
 
75 
 
 
Action Taken 
Event, CTCAE 
Grade 
Frequency 
Trilaciclib 
IRIN 
OXAL 
5FU 
LCV 
Toxicity Management 
Myocardial 
ischemia, OR 
hyperammonemic 
encephalopathy, 
OR CNS toxicity 
including acute 
cerebellar 
syndrome, 
confusion, 
disorientation, 
ataxia, or visual 
disturbances 
Any 
occurrence 
Permanently discontinue. These toxicities are associated with 5FU infusion such that if 
they are experienced by a patient and considered related to 5FU, 5FU should be 
discontinued. Per protocol, if 5FU is permanently discontinued, then all study drugs 
should also be discontinued. 
Manage per institutional 
standards 
Palmar-plantar 
erythrodysesthesia 
(hand-foot 
syndrome) 
G1-2 
Any 
occurrence 
No change in 
dose.  
No change in dose.  
No change in 
dose.  
Manage with appropriate 
supportive care per 
institutional standards 
Palmar-plantar 
erythrodysesthesia 
(hand-foot 
syndrome) 
G3 
1st episode 
Hold drug until 
toxicity resolves 
to ≤ G1 or 
baseline. No 
change in dose. 
Hold drug 
until toxicity 
resolves to 
≤ G1 or 
baseline. No 
change in 
dose. 
Hold drug 
until toxicity 
resolves to 
≤ G1 or 
baseline. No 
change in 
dose. 
Hold drug 
until toxicity 
resolves to 
≤ G1 or 
baseline. 
Reduce dose 
by two dose 
levels and 
resume dosing.  
Hold drug until 
toxicity 
resolves to ≤ G1 
or baseline. No 
change in dose. 
Symptoms may be 
managed using topical 
wound care, cold 
compresses, topical 
corticosteroids and or 
topical or systemic 
analgesics. 
2nd episode 
Permanently discontinue This toxicity is associated with 5FU infusion such that per 
protocol, if 5FU is permanently discontinued, then all study drugs should also be 
discontinued. 
Peripheral sensory 
neuropathy G1-2 
Any 
occurrence 
No change in 
dose.  
No change in dose.  
No change in 
dose.  
Manage with appropriate 
supportive care per 
institutional standards 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
 
76 
 
 
Action Taken 
Event, CTCAE 
Grade 
Frequency 
Trilaciclib 
IRIN 
OXAL 
5FU 
LCV 
Toxicity Management 
Peripheral sensory 
neuropathy G2 
lasitng > 14 days  
Any 
occurrence 
No change in 
dose 
No change in 
dose 
Consider 
reducing dose 
by one dose 
level and 
resume dosing 
No change in 
dose 
No change in 
dose 
Consider use of systemic 
analgesics, particularly 
those utilized for 
neuropathic pain. 
Peripheral sensory 
neuropathy 
 
OR 
G3 lasting < 14 
days 
1st episode 
Hold drug until 
toxicity resolves 
to ≤ G2 or 
baseline. No 
change in dose. 
Hold drug 
until toxicity 
resolves to 
≤ G2 or 
baseline. No 
change in 
dose. 
Hold drug 
until toxicity 
resolves to 
≤ G2 or 
baseline. 
Reduce dose 
by two dose 
levels and 
resume dosing.  
Hold drug 
until toxicity 
resolves to 
≤ G2 or 
baseline. No 
change in 
dose. 
Hold drug until 
toxicity 
resolves to ≤ G2 
or baseline. No 
change in dose. 
Peripheral sensory 
neuropathy  
2nd G3 <14 
days OR any 
occurrence of 
G3 lasting ≥ 
14 days 
OR any 
occurrence of 
G4 
 
 No change in 
dose.  
No change in 
dose. 
Permanently 
discontinue. 
No change in 
dose. 
No change in 
dose. 
Any other G1-2 
non-hematologic 
toxicity 
Any 
occurrence 
No change in 
dose.  
No change in dose.  
No change in 
dose.  
Supportive care as 
appropriate. 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
 
77 
 
 
Action Taken 
Event, CTCAE 
Grade 
Frequency 
Trilaciclib 
IRIN 
OXAL 
5FU 
LCV 
Toxicity Management 
Any other G3 non-
hematologic 
toxicity 
1st and 2nd 
episode 
 Hold drug until 
toxicity resolves 
to ≤ G1 or 
baseline. No 
change in dose. 
Hold drug until toxicity resolves to ≤ G1 or 
baseline. Reduce dose of one drug by one dose 
level and resume dosing; Investigator discretion as 
to which drug is reduced. 
 Hold drug until 
toxicity 
resolves to ≤ G1 
or baseline. No 
change in dose. 
3rd episode 
Permanently discontinue. 
Any other G4 non-
hematologic 
toxicity 
1st episode 
Hold drug until 
toxicity resolves 
to ≤ G1 or 
baseline. No 
change in dose. 
Hold drug until toxicity resolves to ≤ G1 or 
baseline. Reduce dose of one drug by two dose 
levels or the dose of two drugs by one dose level 
and resume dosing: Investigator discretion as to 
which drug is reduced. 
Hold drug until 
toxicity 
resolves to ≤ G1 
or baseline. No 
change in dose. 
2nd episode 
Permanently discontinue. 
CNS=central nervous system; CTCAE=Common Terminology Criteria for Adverse Events; G=Grade; G-CSF=granulocyte colony-stimulating factor; 
5FU=fluorouracil; IRIN=irinotecan; OXALI=oxaliplatin; LCV=leucovorin. 
 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
7 8  
9. 5. 2.  
He p at o bili ar y T o xicit y M a n a ge me nt  
A b n or mal val ues i n A S T a n d/ or A L T c o n c urre nt wit h a b n or mal ele vati o ns i n t otal bilir u bi n t hat 
meet t he criteri a o utli ne d bel o w i n t he a bse nce of ot her ca us es of li ver i nj ur y are c o nsi d ere d 
p ote ntial cases of dr u g -i n d uce d li ver i nj ur y ( p ote ntial H y’s La w cases) a n d s h o ul d al wa ys be 
c o nsi dere d i m p orta nt me dical e ve nts.  
T he t hres h ol d of la b orat or y a b n or malities f or a p ote ntial case of dr u g -i n d uce d li ver i nj ur y 
de pe n ds o n t he patie nt’s i n di vi d ual baseli ne val ues a n d u n derl yi n g c o n diti o ns.  Patie nts w h o 
prese nt wit h t he f oll o wi n g la b orat or y a b n or malities s h o ul d be e val uate d f urt her t o defi niti vel y 
deter mi ne t he eti ol o g y of t he a b n or mal la b orat or y val ues:  
•  Patie nts wit h A S T or A L T a n d t otal bilir u bi n baseli ne val ues wit hi n t he n or mal ra n ge 
w h o s u bse q ue ntl y prese nt wit h A S T or A L T ≥3 ti mes t he u p per li mit of n or mal ( X 
U L N) c o n c urre nt wit h a t otal bilir u bi n ≥2 X U L N wit h n o e vi de nce of he m ol ysis a n d 
a n al kali ne p h os p hatas e ≤2 X U L N or n ot a vaila ble.  
•  F or patie nts wit h pree xisti n g A L T O R A S T O R t otal bilir u bi n val ues a b o ve t he u p per 
li mit of n or mal, t he f oll o wi n g t hres h ol d val ues s h o ul d be use d i n t he defi niti o n 
me nti o ne d a b o ve:  
− F or patie nts wit h pre -e xisti n g A S T or A L T baseli ne val ues a b o v e t he n or m al 
ra n ge: A S T or A L T ≥2 ti mes t he baseli ne val u es a n d ≥3 X U L N, or ≥8 X U L N 
( w hic he ver is s maller). 
C o nc urre nt wit h  
− F or patie nts wit h pre -e xisti n g val ues of t otal bilir u bi n a b o ve t he n or mal ra n ge: 
T otal bilir u bi n i ncrease d b y t w o ti mes t he baseli ne val ue  O R ≥3 ti mes t he u p per 
li mit of n or mal ( w hic he v er is s maller). 
T he patie nt  s h o ul d ret ur n t o t he i n vesti gati o nal site a n d be e val uate d as s o o n as p ossi ble, 
prefera bl y wit hi n 4 8 h o urs fr o m a w are n ess of t he a b n or mal res ults. T his e v al uati o n s h o ul d 
i ncl u de la b orat or y t ests, detaile d hist or y a n d p h ysical assess me nt. I n a d diti o n t o repeati n g A S T 
a n d A L T, la b orat or y tests s h o ul d i ncl u de al b u mi n, creati ne ki n ase, t otal bilir u bi n, direct a n d 
i n direct bilir u bi n, ga m ma-gl uta m yl tra nsferase, acti vate d partial t hr o m b o plasti n ti me 
(a P T T)/pr ot hr o m bi n ti me ( P T)/I nt er nati o nal N or malize d Rati o (I N R), a n d al kali ne p h os p hatase. 
A detaile d hist or y, i ncl u di n g rele va nt i nf or mati o n, s uc h as re vie w of et h a n ol, aceta mi n o p he n, 
recreati o nal dr u g a n d s u p ple me nt c o ns u m pti o n, fa mil y hist or y, occ u pati o nal e x p os ure, se x u al 
hist or y, tra vel hist or y, hist or y of c o nt act wit h a ja u n dice d patie nt, s ur ger y, bl o o d tra nsf usi o n, 
hist or y of li ver or aller gi c disease, a n d w or k e x p os ure, s h o ul d be c ollect e d. F urt her t esti n g f or 
ac ute he p atitis A, B, or C i nfecti o n a n d li ver i ma gi n g (e g, biliar y tract) ma y be warra nte d. All 
cases c o nfir me d o n re peat testi n g as meeti n g t he la b orat or y criteria defi ne d a b o ve, wit h n o ot her 
ca use f or li ver f u n cti o n test ( L F T) a b n or malities i de ntifie d at t he ti me s h o ul d be c o nsi dere d 
p ote ntial H y’s La w cases irres pecti ve of a v aila bilit y of all t he re s ults of t he i n vesti gati o ns 
perf or me d t o d eter mi ne eti ol o g y of t he a b n or mal L F Ts. S uc h p ote ntial H y’s La w cas es s h o ul d be 
re p orte d as S A Es. 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
7 9  
9. 5. 3.  
Be v aciz u m a b  
T here are n o rec o m me n d e d d ose re d u cti o ns f or be vaciz u ma b, p er pac ka ge i nsert. I n cas es w here 
be vaciz u m a b  is per ma n e ntl y disc o nti n ue d, c o nti n uati o n of c he m ot hera p y ma y  be c o nsi dere d.  If 
a d mi nistrati o n of c he m ot hera p y is hel d or disc o nti n ue d, be vaciz u ma b  will als o be hel d or 
disc o nti n ue d  (e.g ., be v aciz u ma b s h o ul d n ot be a d mi nistere d i n is olati o n). 
T a ble  1 0 : 
D ose M o dific ati o n f or Be v aciz u m a b -rel ate d T o xicit y M a n a ge me nt at A n y 
P oi nt D uri n g t he St u d y  
A d verse E ve nt  
C T C A E 
Gr a de  
Be v aciz u m a b 
D ose 
M o dific ati o n  
T o xicit y M a n a ge m e nt  
H y perte nsi o n  
3  
H ol d or 
Disc o nti n ue  
Disc o nti n ue if n ot c o ntr olle d wit h tri ple -dr u g 
me dicati o n . 
4  
Disc o nti n ue  
 
He m orr ha ge  
≥ 2  
[ p ul m o nar y 
or C N S]  
Disc o nti n ue  
 
3  
[ n o n-
p ul m o nar y 
a n d n o n -
C N S]  
H ol d  
H ol d be vaciz u ma b u ntil all of t he f oll o wi n g 
criteria are met, a n d t he n res u me d osi n g:  
•  
Blee di n g has res ol ve d a n d he m o gl o bi n is 
sta ble. 
•  
T here is n o blee di n g diat hesis t hat w o ul d 
i ncrease t he ris k of t hera p y. 
•  
T here is n o a nat o mic or pat h ol o gic 
c o n diti o n t hat si g nifica ntl y i ncreases t he 
ris k of he m orr ha ge rec urre nce. 
4  
Disc o nti n ue  
 
Ve n o us t hr o m b osis  
3 or 4  
Disc o nti n ue  
 
Arterial t hr o m b oe m b olic 
e v e nt 
A n y Gra d e  
Disc o nti n ue  
 
C o n gesti ve heart fail ure  
3  
H ol d  
H ol d be vaciz u ma b u ntil ≤ Gra de 2; res u me 
d osi n g . 
4  
Disc o nti n ue  
 
Pr otei n uria  
≥ 2 +  
[ uri ne 
di pstic k]  
H ol d  
Assess wit h 2 4 -h o ur uri ne c ollecti o n.  
H ol d be vaciz u ma b f or ≥ 2 g/ 2 4 -h o ur uri ne 
c ollecti o n; res u me d osi n g w he n pr otei n uria is 
<  2  g/ 2 4 h o urs.  
ne p hr otic 
s y n dr o me 
Disc o nti n ue  
 
GI perf orati o n  
- 
Disc o nti n ue  
 
N o n -G I fist ulas 
- 
Disc o nti n ue  
 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
 
80 
Adverse Event 
CTCAE 
Grade 
Bevacizumab 
Dose 
Modification 
Toxicity Management 
Bowel obstruction 
1 
Continue dosing 
Patients who experience partial obstruction not 
requiring medical intervention may continue on 
bevacizumab. 
2 
Hold 
Hold bevacizumab in patients who experience 
partial obstruction requiring medical 
intervention. 
Resume dosing upon complete resolution of 
event. 
3 or 4 
Discontinue 
 
Infusion reactions  
(ex. hypertension, 
hypertensive crises 
associated with 
neurologic signs and 
symptoms, wheezing, 
oxygen desaturation, 
Grade 3 hypersensitivity, 
chest pain, headaches, 
rigors, and diaphoresis) 
3 or 4 
Discontinue 
Administer appropriate medical therapy. 
Reversible posterior 
leukoencephalopathy 
syndrome (RPLS) 
- 
Discontinue 
 
Wound dehiscence 
- 
Discontinue 
Bevacizumab should be discontinued 28 days 
prior to elective surgery. 
Other unspecified 
bevacizumab-related 
adverse events 
3 
Hold 
Hold bevacizumab until ≤ Grade 1; resume 
dosing. 
4 
Discontinue 
 
CNS=central nervous system; CTCAE=Common Terminology Criteria for Adverse Events; GI=gastrointestinal. 
9.6. 
Supportive Care Interventions 
9.6.1. 
Colony Stimulating Factor Usage 
Use of primary prophylactic colony stimulating factors (e.g., G-CSF; granulocyte-macrophage 
colony-stimulating factor [GM-CSF]) during Cycle 1 is not allowed; therapeutic use of 
G-CSF/GM-CSF is permitted in any cycle, including Cycle 1, as described below. In subsequent 
cycles (Cycle 2 and beyond), secondary prophylactic colony stimulating factors are allowed as 
outlined in regional guidelines or consensus (e.g., American Society of Clinical Oncology 
[ASCO], European Society for Medical Oncology [ESMO], Chinese Anti-Cancer Association) 
and package inserts. G-CSF products (i.e., Neupogen or biosimilars) may be administered 
starting 24 to 48 hours after chemotherapy is complete on Day 2 and must be stopped 48 hours 
prior to study drug administration in the next cycle. Similarly, Neulasta (or biosimilars) or other 
long half-life GCSF (ex. macapegfilgrastim) may be administered up to 48 hours after 


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c he m ot hera p y b ut d u e t o its pr ol o n ge d half -life s h o ul d be a d mi nistere d as s o o n as cli nicall y 
acce pta ble a n d s h o ul d n ot be re peate d wit hi n t hat c ycle.  
If i n a n y c y cle (i ncl u di n g C ycle 1), a patie nt e x perie nces fe brile ne utr o p e ni a a n d is at hi g h ris k 
f or i nfecti o n-ass ociate d c o m plicati o ns O R has pr o g n ostic fact ors t hat are pre dicti ve of p o or 
cli nical o utc o mes ( Ta bl e  1 1 ), G-C S F/ G M -C S F ma y be use d t o treat t he fe brile ne utr o pe nia e v e nt 
per re gi o n al g ui deli nes a n d pac ka g e i nsert (i .e., t her a pe utic use of G -C S F).  
T a ble  1 1 : 
P atie nt Ris k F act ors f or P o or Cli nic al O utc o mes Res ulti n g fr o m Fe brile 
Ne utr o pe ni a or I n fecti o n 
Ris k F act or  
Se psis s y n dr o me  
A ge > 6 5 years  
Pr of o u n d ne utr o pe nia (a bs ol ute ne utr o p hil c o u nt < 0. 1 × 1 0 9/ L) 
Ne utr o pe nia e x pect e d t o last > 1 0 da ys  
P ne u m o nia  
I n v asi ve f u n g al i nfecti o n 
Ot her cli nicall y d oc u me nte d i nfecti o ns  
H os pitalizati o n at ti me of fe ver  
Pri or e pis o de of fe brile n e utr o pe nia  
S o urce: Ta ble recreate d fr o m Ta ble 2 of t h e A S C O g ui d eli nes ( S mit h , 2 0 1 5; S mit h , 2 0 0 6). 
9. 6. 2.  
Er yt hr o p oiesis -Sti m ul ati n g A ge nt  Us a ge  
If a patie nt e x perie n ces a he m o gl o bi n le vel < 1 0. 0 g/ d L or s y m pt o matic a ne mia d uri n g st u d y 
treat me nt, E S As ma y be use d per t he c urre nt pres cri bi n g i nf or mati o n ( B o hli us , 2 0 1 9 ) 
(Pr ocrit ® , 2 0 1 7 ; Ara nes p ® , 2 0 1 1 ). 
9. 6. 3.  
Tr a nsf usi o ns  
Re d Bl o o d Cells  
Base d o n t he N C C N Cli nical Practice G ui deli nes i n O nc ol o g y f or He mat o p oietic Gr o wt h Fact ors 
Versi o n 2. 2 0 2 0 a n d t he A A B B Cli nical Practice G ui deli nes, t he f oll o wi n g R B C tra nsf usi o n 
t hres h ol ds are rec o m me n de d (Cars o n , 2 0 1 6 ; G oel , 2 0 1 7 ); h o we ver, t h e pati e nt’s cli nical sit uati o n 
s h o ul d al wa ys be t he pri mar y g ui di n g fact or w h e n deci di n g t o tra nsf use.  
•  Tra nsf usi o n is n ot i n dicate d u ntil t he he m o gl o bi n le vel is ≤ 7 g/ d L f or h os pitalize d 
a d ult patie nts w h o are h e m o d y na micall y sta ble . 
•  A n R B C tra nsf usi o n t hres h ol d of ≤ 8 g/ d L is rec o m me n de d f or patie nts u n der g oi n g 
ort h o pe dic s ur ger y, car diac s ur ger y, a n d t h ose wit h pree xisti n g car di o v asc ular 
d isease.  
•  Patie nts wit h s y m pt o matic a ne mia s h o ul d be tr a nsf use d per t he In vesti gat or discreti o n 
re gar dl ess of he m o gl o bi n le vels. 


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PLATELETS 
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) (Kaufman, 2015; Schiffer, 2017). 
9.7. 
Prior/Concomitant Medications 
Any medication (including over-the-counter or prescription medicines, vitamins, herbal 
supplements, growth factors, blood products, and/or parenteral nutrition) that the patient has 
received within 14 days prior to date of informed consent or receives during the study and 
through 30 days after the last dose of study drug must be recorded in the eCRF. During the study, 
prescription and commercially available products, including traditional Chinese medications, 
with known or suspected immunomodulatory properties should be used with caution or avoided 
entirely. 
Supportive care as described in Section 9.6, including the administration of colony stimulating 
factors or ESA and RBC or platelet transfusions, must be recorded in the eCRF. 
Trilaciclib is a time-dependent inhibitor of CYP3A4 and is a substrate for CYP3A4. No 
clinically meaningful change in trilaciclib exposure was observed when co-administered with a 
CYP3A4 inhibitor or inducer. Trilaciclib is not expected to affect the exposure of CYP3A 
substrates following coadministration. 
Avoid concomitant use of trilaciclib with certain OCT2, MATE1, and MATE2-K substrates 
(e.g., dofetilide, dalfampridine) where minimal concentration changes may lead to serious or life-
threatening toxicities. Refer to the prescribing information for these concomitant medications for 
assessing the benefit and risk of concomitant use of trilaciclib (Section 4.2.1.2). 
Refer to the current, regional package insert of fluorouracil for recommendations on monitoring 
for INR or prothrombin time in patients receiving concomitant coumarin-derivative 
anticoagulants such as warfarin (e.g. low dose as prophylaxis for port) in order to adjust the 
anticoagulant dose accordingly. Administration of aspirin doses > 325 mg/day is not permitted. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.  
Administration of other systemic concomitant non-protocol anti-cancer therapies prior to 
progression is not permitted while on this study with the exception of adjuvant endocrine therapy 
for breast cancer or prostate cancer defined as M0 disease or PSA persistence/recurrence without 
metastatic disease.  
Local treatment of symptomatic lesion(s) with palliative therapy (ex. surgery, radiotherapy, 
radiofrequency ablation, embolization) is permitted at the Investigator’s discretion to control 
disease symptoms. However, use of techniques that incorporate systemic therapy, including local 
administration, is not permitted. If the lesion(s) treated is being followed for evaluation by 
RECIST (target or nontarget lesion), then “not evaluable” should be reported in EDC for this 
lesion at subsequent disease assessments following palliative treatment. Patients requiring 
palliative therapy may continue receiving study drug until documented disease progression 
(radiographic or clinical) if, in the Investigator’s opinion, the patient is continuing to receive 
clinical benefit and they meet the requirements described in Section 9.4. However, for patients 


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who have not had disease progression at the time of the need for palliative treatment, the 
requirement for intervention will be regarded as disease progression in the study’s analyses and 
will be entered as such in the EDC.  
Patients with metastases confined to the liver who experience a robust response to chemotherapy 
may also proceed with curative intent surgical resection at the Investigator’s discretion. In that 
event, study treatment in this trial will be considered complete and patients will enter into 
Survival Follow-up. Tumor assessments will continue as directed for survival follow-up. Any 
anti-cancer therapy for colorectal cancer that is initiated post-surgical resection is at the 
discretion of the Investigator, and will be recorded as subsequent anti-cancer therapy in the EDC.  
Administration of other concomitant investigational agents for any indication or any live 
attenuated vaccines is not permitted while on this study. Necessary supportive care (antiemetics, 
antidiarrheals, etc.) per the standard of care at the study center will be permitted.  
9.8. 
Measures to Minimize Bias: Randomization and Blinding 
The study will be randomized and double-blind. Patients meeting all inclusion and exclusion 
criteria will be randomized 1:1 by an IWRS according to a randomization schedule generated by 
an unblinded external statistician. Each patient will be assigned a unique randomization number, 
which will not be reused. There will be three stratification factors for randomization: country, 
prior therapy in adjuvant/neoadjuvant setting, and presence of BRAF V600E mutation. Within 
each country, patients will be stratified by systemic cytotoxic therapy in the 
adjuvant/neoadjuvant setting (yes/no) and BRAF V600E mutation (yes/no).  
Each site will have an unblinded Pharmacist/Designee, who will have access to the treatment 
assignment. Because the active drug product trilaciclib has a faint yellow color when 
reconstituted and diluted, additional procedures will be implemented to ensure the blind is 
maintained for the patient, Investigator, Research Nurse, Study Coordinator, and other blinded 
site personnel. Details regarding the preparation and administration of trilaciclib/placebo in a 
manner to maintain the blinding will be included in the Pharmacy Manual. 
The patients, Investigators, other site staff involved in the clinical care of the patients, and the 
Sponsor or Designees involved in the conduct of the study will not be aware of the treatment 
group to which a particular patient has been randomized. If an Investigator determines that a 
patient’s assignment should be unblinded for reasons of safety, this should be discussed with the 
study Medical Monitor prior to unblinding, unless an urgent and immediate intervention is 
required that precludes this discussion. If unblinding of the treatment assignment is necessary, 
the Investigator or Designee will obtain the treatment assignment details from the IWRS. 
Unblinding of personnel should be limited to the minimum needed for mitigation of safety 
concern. Following unblinding, patient continuation on study will be determined on a case by 
case basis. Any unplanned unblinding must be communicated to the Project Manager, Study 
Statistician, and Sponsor for documentation in the study files and the clinical study report. 


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9.9. 
Intervention after End of Study Treatment 
Following completion of study treatment on the study, patients will receive standard of care 
treatment as determined by their healthcare provider. During Survival Follow-up, patients and 
their caregivers will be contacted to record their status (alive or dead) as well as details of any 
subsequent systemic anti-cancer therapy initiated (see Section 11.12). 


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DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D 
P A TI E N T DI S C O N TI N U A TI O N/ WI T H D R A W A L  
1 0. 1.  
Disc o nti n u ati o n of St u d y Tre at me nt  
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 In vesti gat or, S p o ns or, or M e dical 
M o nit or, prese nts a n u nacce pta bl e ris k t o t he patie nt  
•  Ge neral or s pecific c h a 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 In vesti gat or, are u n acce 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 n c y  d uri n g t he st u d y  
•  Si g nifica nt n o nc o m plia nce wit h pr ot oc ol r e q uire me nts  
•  T he  S p o ns or or le gal r e 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 d oc u me nte d disease pr o gressi o n  (ra di o gra p hic or cli nical pr o gressi o n). 
See Secti o n  9. 7  f or det ails re gar di n g palliati ve t hera p y a n d c urati ve i nte nt s ur gical 
resecti o n. 
•  W here p er ma n e nt disc o nti n uati o n of all st u d y dr u gs is i n dicate d i n t he t o xicit y 
ma na ge me nt rec o m me n d ati o ns  
At t he ti me of st u d y dr u g disc o nti n uati o n, a P ost -treat me nt V isit s h o ul d be c o m plete d wit h 
assess me nts perf or me d as s h o w n i n t he Sc he d ule of Assess me nts ( Ta ble  5 ). T he In vesti gat or or 
D esi g nee will d oc u me nt t he reas o n f or st u d y dr u g disc o nti n uati o n o n t he a p plica ble e C R F. W h e n 
disc o nti n uati o n is d ue t o a S A E or a Gra de 3 or 4 t o xicit y c o nsi dere d t o be relate d t o st u d y 
me dicati o n, t he In vesti gat or s h o ul d f oll o w t he e ve nt u ntil res ol uti o n, ret ur n t o baseli ne, or it is 
dee me d t hat f urt her rec o ver y is u nli kel y. Data o n t hese e ve nts s h o ul d be c ollecte d o n t he A E 
e C R F. I n t he e v e nt a pati e nt disc o nti n ues d ue t o pre g na nc y, t h e In vesti gat or or desi g nee s h o ul d 
n otif y t he M e dical M o nit or b y tele p h o ne wit hi n 2 4 h o urs of pre g n a nc y c o nfir mati o n  (see 
Secti o n  1 7. 4 ). 
1 0. 2.  
Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y 
A patie nt ma y wit h dra w fr o m t he st u d y at a n y ti me at his/ her o w n re q uest or ma y be wit h dra w n 
at a n y ti me at t he discreti o n of t he In vesti gat or f or safet y, be ha vi oral, c o m plia nce, or 
a d mi nistrati ve reas o ns. At t he ti me of disc o nti n ui n g fr o m t he st u d y, if patie nt has n ot alrea d y 
disc o nti n ue d st u d y i nter ve nti o n, a P ost -treat me nt V isit s h o ul d be c o m plete d wit h assess me nts 
perf or me d as s h o w n i n t h e Sc he d ule of Assess me nts  (Ta ble  5 ).  
If t he patie nt wit h dra ws c o nse nt f or discl os ure of f ut ure i nf or mati o n, t he S p o ns or ma y retai n a n d 
c o nti n ue t o use a n y data c ollecte d bef ore s u c h a wit h dra wal of c o ns e nt.  
If a patie nt wit h dra ws fr o m t he st u d y, he/s he ma y re quest destr u cti o n of a n y sa m ples ta ke n a n d 
n ot teste d, a n d t he In vesti gat or or desi g nee m ust d oc u me nt t his i n t he site st u d y rec or ds.  


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If a patie nt wit h dra ws c o nse nt f or f urt h er st u d y pr oce d ures, t h e site s h o ul d clarif y if t he p atie nt 
re mai ns o pe n t o s ur vi val c o ntact a n d ass ociate d data c ollecti o n. 
1 0. 3.  
L ost t o F oll o w U p  
A patie nt will be c o nsi dere d l ost t o f oll o w -u p if he or s he re peat e dl y fails t o ret ur n f or sc he d ule d 
visits a n d is u na ble t o be c o ntacte d b y t he st u d y sit e.  
T he f oll o wi n g acti o ns s h o ul d be ta ke n i f a p atie nt fails t o ret ur n t o t he cli nic f or a re q uir e d st u d y 
visit:  
•  T he site m ust atte m pt t o c o ntact t he patie nt a n d resc he d ule t he misse d visit as s o o n as 
p ossi ble a n d c o u nsel t he patie nt o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit 
sc he d ule a n d ascertai n w het her or n ot t he p atie nt wis hes t o a n d/ or s h o ul d c o nti n ue i n 
t he st u d y. 
•  Bef ore a p atie nt is dee me d l ost t o f oll o w u p, t he In vesti gat or or D esi g ne e s h o ul d 
ma ke e ver y eff ort t o re g ai n c o ntact wit h t he patie nt per i nstit uti o nal practice . T hese 
c o ntact atte m pts s h o ul d be d oc u me nte d i n t he p atie nt’s me dical r ec or d.  
•  S h o ul d t he patie nt c o nti n ue t o be u nreac ha bl e, he/s he will be c o nsi dere d t o ha ve 
wit h dra w n fr o m t he st u d y.  
1 0. 4.  
St u d y a n d Site St art a n d Cl os ure  
T he st u d y start date is t he date o n w hi c h t h e first site is o pe n f or recr uit me nt of patie nts.  
T he S p o ns or’s desi g nee reser ves t he ri g ht t o cl ose t he st u d y site or ter mi nate t he st u d y at a n y 
ti me f or a n y reas o n at t he s ole discreti o n of t he S p o ns or. St u d y sites will be cl ose d u p o n st u d y 
c o m plet i o n. A st u d y site is c o nsi dere d cl ose d w he n all re q uire d d o c u me nts a n d st u d y s u p plies 
ha ve bee n c ollecte d, a st u d y -site cl os ure visit has bee n perf or me d, a n d t he site has cl ose d all 
re g ulat or y acti vities wit h t he I nstit uti o nal Re vie w B oar d (I R B)/I n de p e n de nt Et hics C o m mittee 
(I E C). 
T he In vesti gat or ma y b e re q ueste d t o i nitiate st u d y -site cl os ure at a n y ti me, pr o vi de d t here is 
reas o na bl e ca us e a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d t er mi nati o n. S h o ul d 
t his occ ur wit h patie nts recei vi n g st u dy dr u g , t he patie nts will tra nsiti o n t o recei v e sta n dar d of 
care treat me nt b y t heir h ealt hcare pr o vi der o utsi de of t his st u d y.  
Reas o ns f or t he earl y cl os ure of a st u d y site b y t he S p o ns or or In v esti gat or ma y i ncl u de b ut are 
n ot li mite d t o:  
•  Fail ure of t he In vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uir e me nts of t he 
I R B/I E C or l ocal h ealt h a ut h orities, t he S p o ns or's pr oce d ures, or G o o d Cli nical 
Practice ( G C P ) g ui deli nes  
•  I n a de q uat e recr uit me nt of patie nts b y t he In vesti g at or  
•  Disc o nti n uati o n of f urt her de vel o p me nt of trilacicli b  


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If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the patient and 
should assure appropriate patient therapy and/or follow-up. 


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11. 
STUDY ASSESSMENTS 
Study procedures and their timing are summarized in the Schedule of Assessments (Table 4 and 
Table 5). Adherence to the study design requirements, including those specified in the Schedule 
of Assessments, is essential and required for study conduct. Immediate safety concerns should be 
discussed with the study Medical Monitor upon occurrence or awareness to determine if the 
patient should continue or discontinue study intervention. 
The Investigator or Designee will maintain a screening log to record details of all patients 
screened and to confirm eligibility or record reasons for screening failure, as applicable. The 
following information for screening failures should be recorded into appropriate eCRFs: patient 
identification (ID), demographic data, and reason for failing the screening process. Patients may 
only be rescreened one time at the discretion of the Investigator. For abnormal laboratory values, 
a second test to confirm the first is permitted. If a patient is rescreened, they should receive a 
new patient ID. Procedures conducted as part of the patient’s routine clinical management (e.g., 
hematology, clinical chemistry) and obtained before signing of the ICF may be utilized for 
screening or baseline purposes provided the procedures met the protocol-specified criteria and 
are performed within 28 days prior to Cycle 1 Day 1.  
For the patients who undergo curative intent surgical resection, no additional myelosuppression, 
or PRO data will be collected following surgery. However, tumor assessments will continue as 
directed in survival follow-up.  
11.1. 
Randomization 
Eligibility should be determined prior to randomization and the start of study treatment. Eligible 
patients will be instructed on all protocol requirements, including any restrictions on concomitant 
medication usage. 
Randomization will be performed via IWRS within 3 days prior to the first dose of trilaciclib or 
placebo + FOLFOXIRI/bevacizumab therapy, following confirmation that the patient is eligible 
for the study. Patients can be randomized and receive Cycle 1 Day 1 on the same day. 
11.2. 
Myelopreservation Efficacy Assessments 
Myelosuppression will be assessed based on hematology assessments, severe AEs, supportive 
care interventions (including transfusions), dose modifications, and PROs. 
11.2.1. 
Hematology Sampling Schedule 
Trilaciclib has been shown in SCLC patients to prevent the myelosuppressive effects of 
chemotherapy across multiple cellular lineages, including neutrophils, RBCs, and platelets, by 
protecting HSPCs. In order to adequately characterize the myelopreservation benefit of 
trilaciclib, more frequent hematology lab assessments will be done during Cycle 1, as outlined in 
the Schedule of Assessments (Table 4 and Table 5). The frequent assessments will only be done 
during Cycle 1 because the data collected in Cycle 1 won’t be subject to bias due to primary 
prophylactic G-CSF administration, and more frequent monitoring in subsequent cycles would 
be an unreasonable burden on the patient.  


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11.3. 
Anti-tumor Efficacy Assessment 
Tumor response criteria will be based on RECIST v1.1 (Eisenhauer, 2009).  
Initial staging studies should include computed tomography (CT) or magnetic resonance imaging 
(MRI) of the chest, abdomen, pelvis at a minimum. IV contrast should be used unless 
contraindicated. Oral contrast can be used at the Investigator’s discretion. Post-baseline tumor 
assessment using the same imaging modality and region(s) as at baseline should be performed as 
outlined in the Schedule of Assessments (Table 4 and Table 5) until the occurrence of disease 
progression, withdrawal of consent, the initiation of subsequent anti-cancer therapy, or study 
completion. These assessments should be done regardless of the timing of study drug 
administration, e.g. if cycles are delayed. 
Any CT, MRI, or other staging study obtained as standard of care prior to signing the informed 
consent will not need to be repeated if performed within 28 days prior to Cycle 1 Day 1 as long 
as it meets the requirements above. Additional scans may be obtained at the discretion of the 
Investigator during the course of the study, if clinically indicated. 
For those patients who have not progressed at the time of study drug discontinuation and enter 
into Survival Follow-up, radiological tumor assessments should continue, utilizing the same 
imaging modality as used at screening as outlined in the Schedule of Assessments (Table 4 and 
Table 5) until progression, withdrawal of consent, initiation of subsequent anti-cancer therapy, or 
study completion. 
For definitions of tumor response per RECIST v1.1 see Section 17.7. 
During the course of this trial, scans may be collected and sent to Sponsor or Designee for 
storage. Centralized storage is intended for possible blinded independent central review (BICR) 
of disease assessments. At the discretion of the Sponsor, BICR of all scans by RECIST v1.1 may 
be conducted retrospectively. The blinded review will include all patients with available images. 
However, the raw images for patients enrolled in China cannot be stored outside of China and 
therefore these images will be stored in the server in China for central imaging review if 
approved by the related authority. If needed, guidelines for imaging collection and storage will 
be provided in a separate document. The clinical management of patients will be based solely 
upon the results of the assessment conducted by the Investigator based on RECIST v1.1 per 
protocol. 
11.4. 
Safety Assessments 
11.4.1. 
Demographics 
Age, gender, race and ethnicity will be collected during the Screening period. 
11.4.2. 
Medical History and Colorectal Cancer Disease History 
Medical and surgical history, including past and current conditions, will be collected. 
Concomitant medications taken within 14 days of signing the informed consent will be recorded. 
Documentation of CRC history, including date of diagnosis as well as BRAF V600E (required) 
and KRAS (as available) mutational status, will be collected. Patients will be stratified based on 
a locally available BRAF mutation test result that has been performed in a Clinical Laboratory 


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I m pr o v e me nt A me n d me nts ( C LI A)-certifie d la b orat or y ( U S sites) or a n accre dite d la b orat or y 
(sites o utsi de of t he U S). A li q ui d bi o ps y is acce pta ble t o c o nfir m B R A F V 6 0 0 E m utati o nal 
stat us if tiss ue ca n n ot be utilize d. If hist orical B R A F V 6 0 0 E m utati o nal st at us is n ot k n o w n, a 
t u mor s peci me n (arc hi val , fres h, or bi o ps y) m ust b e se nt f or testi n g. If  a p pr o priate testi n g ca n n ot 
be perf or me d at t he l oc al i nstit uti o n, a t u m or s peci me n (arc hi val or fres h tiss ue o nl y) ma y be se nt 
t o t he S p o ns or’s desi g nate d ce ntr al la b orat or y f or a nal ysis. Res ults m ust be a vaila ble at t he ti me 
of ra n d o mizati o n i n I W R S. A n y t u m or sa m ple se nt f or a nal ysis of B R A F will be i n a d diti o n t o 
t hat re q uire d f or t he retr os pecti ve bi o mar ker a nal ysis descri be d i n Secti o n  1 1. 8. 1 .  
D oc u me ntati o n of p M M R/ M S S is als o re q uire d; patie nts wit h deficie nt M M R/ micr osatellite 
i nsta ble (M SI )-hi g h  or M SI -l o w C R C are n ot eli gi ble f or t his st u d y. Patie nts wit h M SI -hi g h 
t u m ors ha ve a m ore fa v ora ble pr o g n osis t ha n t h os e wit h M S S or M SI-l o w t u m ors 
(Ma lesci, 2 0 0 7 ; H utc hi ns , 2 0 1 1; Si nicr o pe , 2 0 1 3; Zaa na n , 2 0 1 8) a n d ha v e bee n s h o w n t o ha v e 
l o n ger pr o gressi o n-free s ur vi val wit h t he a d diti o n of i m m u n ot hera p y t o c o m m o n c ol orectal 
c he m ot hera p y re gi me ns  (Hel wic k , 2 0 2 0). T h e clinical be ha vi or of M SI -l o w t u m ors is 
i nc o m pletel y c haracteri ze d b ut has bee n ass ociate d wit h w orse o utc o mes relati ve t o M SI-hi g h 
a n d M S S t u m ors  (K o h o ne n -C o ris h, 2 0 0 5; Wri g ht , 2 0 0 5; M ojara d , 2 0 1 6). B eca use M SI-l o w 
t u m ors ma ke up o nl y 3 -1 0 % of a n u nsel ecte d c ol orectal ca ncer p o p ulati o n (de la C ha pelle , 2 0 1 0) 
a n d c o ul d ha ve a ne g ati ve i m pact o n pr o g n osis, stratificati o n s h o ul d be c o nsi dere d if t hese 
s u bjects are i ncl u d e d. At t he pla n ne d sa m ple siz e f or t his st u d y, a n a d diti o nal stratificati on fact or 
is n ot o pti mal a n d t heref ore, o nl y patie nts wit h M S S disease will be eli gi ble. Patie nts will be 
eli gi ble base d o n a l oc all y a vaila ble p M M R/ M S S test res ult t hat has bee n p erf or me d i n a 
C LI A -certifie d la b orat or y ( U S sites) or a n accre dite d la b orat or y (sites o utsi de of t he U S). If 
hist orical p M M R/ M S S stat us is n ot k n o w n, a t u m or s peci me n (arc hi v al or fres h bi o ps y) m ust be 
se nt f or testi n g. If a p pr o priate testi n g ca n n ot be perf or me d at t he l o cal i nstit uti o n, t he t u m or 
s peci me n ma y be s e nt t o t he S p o ns or’s desi g nate d ce ntral la b orat or y f or a n al ysis. Res ults m ust 
be a vaila ble at t he ti me of ra n d o mizati o n i n I W R S . A n y t u m or sa m ple se nt f or a nal ysis of 
p M M R/ M S S  will be i n a d diti o n t o t hat re q uire d f or t he retr os p ecti ve bi o m ar ker a nal ysis 
descri be d i n Secti o n  1 1. 8. 1 .  
Pri or ra diati o n, s ur ger y, a n d s yste mic c he m ot hera p y f or C R C will als o be rec or de d.   
1 1. 4. 3.  
Vit al Si g ns  
T he f oll o wi n g will be c ollecte d per t h e Sc he d ule of Assess me nts  (Ta ble  4  a n d Ta ble  5 ): 
•  B o d y te m perat ure, p ulse rate, bl o o d press ure ( diast olic a n d s yst olic)  
− Bl o o d press ure a n d p ulse meas ure me nts s h o ul d be assesse d i n t he s u pi ne p ositi o n.  
− Bl o o d press ure a n d p ulse meas ure me nts s h o ul d be prece d e d b y at least 5 mi n utes 
of rest f or t he patie nt i n a q uiet setti n g wit h o ut distracti o ns (e .g ., tel e visi o n, cell 
p h o nes).  
•  Hei g ht i n ce nti meters ( Scree ni n g visit o nl y) a n d b o d y wei g ht i n kil o gra ms  


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11.4.4. 
Physical Examination 
Full physical examination evaluations at screening should include general appearance, skin, 
neck, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and 
neurological examinations. Subsequent physical exams should include body systems as 
appropriate (e.g., brief physical exam). 
Information about the physical examination must be present in the source documentation at the 
study site. Clinically relevant findings observed prior to the start of study drug, should be 
recorded as medical history. Clinically relevant findings observed after the start of study drug, 
which meet the definition of an AE, must be recorded on the AE eCRF. 
11.4.5. 
Electrocardiogram 
Triplicate 12-lead single electrocardiograms (ECGs) will be performed as outlined in the 
Schedule of Assessments (Table 4 and Table 5). Patients should rest for 5 minutes prior to the 
ECG assessment. Additional ECGs during the study may be performed as clinically indicated.  
Any ECG with a QTc value of > 500 or any other clinically significant abnormal finding should 
be repeated every 5 minutes for a total of three ECGs to confirm this finding, if not already 
recorded in triplicate. The QTc value should also be confirmed via manual read.  
The Investigator or qualified designee should review the ECGs for any abnormalities as 
compared with the baseline ECG. 
11.4.6. 
Clinical Safety Laboratory Assessments 
Hematology, clinical chemistry, coagulation (INR, activated partial thromboplastin time 
[aPTT]), and urinalysis will be performed at the site’s local certified laboratory per the schedule 
outlined in the Schedule of Assessments (Table 4 and Table 5). Clinical laboratory samples may 
be collected from patients at a different location that the Investigator’s clinic following approval 
by the Medical Monitor. A list of clinical laboratory tests to be performed is provided in 
Section 17.2. Clinical chemistry and hematology results should be reviewed before dosing. 
Laboratory toxicities will be assessed using the National Cancer Institute-Common Terminology 
Criteria for Adverse Events (NCI-CTCAE), v5.0. 
An abnormal laboratory value is not an AE unless it is considered to be clinically significant. 
Laboratory parameters for which clinically significant values are noted will be re-measured on 
the appropriate clinical follow-up arranged by the Investigator. Any laboratory value that 
remains abnormal at the end of the study and that is considered clinically significant should be 
followed according to accepted medical standards for up to 30 days or until the values return to 
normal or baseline or are no longer considered clinically significant by the Investigator. If such 
values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified, and the Medical Monitor notified.  
If a subsequent cycle is delayed for toxicity, the patient should still complete the clinical 
laboratory assessments on the scheduled Day 1 (entered as an Unscheduled assessment in EDC) 
as well as on the actual first dosing day of that cycle. If the delay is secondary to hematologic 
toxicity, weekly repeat hematology assessments should continue until the finding has returned to 
baseline or is deemed not clinically significant by the Investigator. 


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If laboratory values from non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory as part of the monitoring of an SAE, then the results should be 
provided to the Pharmacovigilance group as part of the safety reporting.  
11.5. 
Geriatric 8 Health Status Screening Tool 
In prior studies, the administration of FOLFOXIRI has generally been limited to patients 
< 75 years of age because of concerns regarding the potential risks of chemotherapy-induced 
toxicities like CIM. However, the evolving field of geriatric oncology has demonstrated that 
chronologic age is not necessarily the best measure of a patient’s physiologic age and the ability 
to tolerate more intensive chemotherapy regimens (Soto Perez de Celis, 2018). Therefore, rather 
than implementing an arbitrary chronologic age cutoff for enrollment in this trial, the G8 
(geriatric 8) Health Status screening tool will be used to evaluate a prospective patient’s fitness 
for treatment. This tool has been shown to predict outcomes and AEs during the management of 
the elderly with cancer (Bellera, 2012; Kenis, 2014). The G8 Health Status screening tool will be 
completed by the Investigator or designee. 
The G8 consists of 8 items concerning nutritional status, weight loss, body mass index, motor 
skills, psychological status, number of medications, self-perception of health, and age (< 80, 80 
to 85, > 85). Scores range from 17 (not impaired) to 0 (heavily impaired). A score of > 14 is 
suggestive of a geriatric cancer patient able to tolerate standard treatment without major 
modification; low G8 scores have been associated with functional decline and poorer survival 
(Kenis, 2014). The G8 Health Status screening tool will be completed by the Investigator or 
designee once during Screening only for patients > 70 years old.  
11.6. 
Patient Reported Outcomes 
11.6.1. 
Functional Assessment of Cancer Scales 
The Functional Assessment of Cancer Therapy – Colorectal (FACT-C) and FACT-An are 
validated instruments that will be administered to patients by a designated trained study site staff 
member. The instruments will be administered on the days outlined in the Schedule of 
Assessments (Table 4 and Table 5). If the cycle is delayed, the patient should still complete the 
PRO on the scheduled Day 1 (entered as an Unscheduled assessment), as well as on the actual 
first dosing day of that cycle. The PROs will be administered electronically during a protocol-
specified clinic visit; if a hematology assessment is performed at the visit then the questionnaires 
should be completed on the same day a blood sample is collected for that assessment. 
Questionnaires must be administered prior to administration of any study drug and should be 
administered prior to conduct of any study procedure at that visit.  
A core general questionnaire (FACT-G) that measures physical, social/family, emotional, and 
functional well-being is embedded in both the FACT-C and FACT-An instruments. The FACT-
C has an additional subscale to measure aspects of health-related quality of life that are specific 
to colorectal cancer patients. The FACT-An includes the FACIT-F, a 13-item subscale that 
measures fatigue severity and the impact of fatigue on functioning (Yellen, 1997). The core 
general questionnaire (FACT-G) is the same for both instruments; as such, at each assessment, 
the core questionnaire will be administered only once along with the condition-specific 
colorectal and anemia subscales, including the FACIT-F. 


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11.6.2. 
Patient Global Impression of Change and Patient Global Impression of Severity 
The Patient Global Impression of Change (PGIC) and Patient Global Impression of Severity 
(PGIS) items will be administered to patients by a designated trained study site staff member. 
The instruments will be administered on the days outlined in the Schedule of Assessments 
(Table 4 and Table 5). The PGIC item will ask the patient to rate the change in their fatigue since 
taking study medication on a 7-point scale ranging from -3 (very much worse) to 3 (very much 
better). The PGIS item, will ask the patient to rate the overall severity of their fatigue over the 
past week on a 5-point scale ranging from 0 (none) to 4 (severe).  
PGIC and PGIS will be administered electronically during a protocol-specified clinic visit; if a 
hematology assessment is performed at the visit then the questionnaires should be completed on 
the same day a blood sample is collected for that assessment. The questionnaires must be 
administered prior to administration of any study drug and should be administered prior to 
conduct of any study procedure at that visit.  
11.6.3. 
5-Level EQ-5D 
The 5-level EQ-5D (EQ-5D-5L) is a standardized instrument by which treatment effects can be 
assessed by measuring health status at different points in time, e.g., before and after treatment, 
and then investigating the gains (or losses) in reported health status. The EQ-5D-5L consists of 
the EQ-5D descriptive system and the EQ visual analogue scale (EQ-VAS). For the EQ-5D, 
respondents will rate their health on each of 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression. Each dimension has 5 levels: no problems, slight problems, 
moderate problems, severe problems, and extreme problems. The patient will be asked to 
indicate his/her health state by ticking the box next to the most appropriate statement in each of 
the five dimensions. This decision results in a 1-digit number that expresses the level selected for 
that dimension. The digits for the five dimensions can be combined into a 5-digit number that 
describes the patient’s health state. The EQ-VAS records the patient’s self-rated health on a 
vertical visual analogue scale, where the endpoints are labelled “The best health you can 
imagine” and “The worst health you can imagine”. The VAS can be used as a quantitative 
measure of health outcome that reflect the patient’s own judgement.  
The EQ-5D-5Lwill be administered to patients by a designated trained study site staff member 
on the days outlined in the Schedule of Assessments (Table 4 and Table 5). It will be 
administered electronically during a protocol-specified clinic visit; if a hematology assessment is 
performed at the visit then the EQ-5D-5L should be completed on the same day a blood sample 
is collected for that assessment. The questionnaire must be administered prior to administration 
of any study drug and should be administered prior to conduct of any study procedure at that 
visit. 
11.7. 
Pharmacokinetics 
Blood samples for PK analysis will be collected at the time points indicated in the Schedule of 
Assessments (Table 4 and Table 5) from all patients. Four blood samples for PK analysis will be 
collected for trilaciclib and any metabolites and three samples will be collected for PK analysis 
of irinotecan and its metabolite (SN-38. The actual date and time of each blood sample 
collection, the scheduled timepoint of collection, and the time of dose administration prior to the 


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p har mac o ki netic s a m ple will be rec or de d. Det ails of P K  bl o o d sa m ple c ollecti o n i ncl u di n g 
v ol u me t o be c ollecte d, ti mi n g of sa m ples, pr ocessi n g, st ora ge , a n d s hi p pi n g pr oce d ures are 
pr o vi de d i n t he st u d y pr oce d ure m a n ual.  
1 1. 8.  
Bi o m ar kers ( C D K 4/ 6 Si g n at ure)  
1 1. 8. 1.  
R ati o n ale f or Arc hi v al T u m or C ollecti o n  
Beca use trilacicli b  mai ntai ns G 1 arrest i n C D K 4/ 6 de pe n de nt cells, t here is a h y p ot hetical ris k 
t hat trilacicli b c o ul d a nta g o nize t he a nti-t u m or efficac y of c yt ot o xic c he m ot hera p y b y 
mai ntai ni n g a G 1 cell c y cle arrest of C D K 4/ 6 de pe n de nt t u m or cells d uri n g c he m ot hera p y. W hil e 
t he c urre ntl y a vaila ble n o ncli nical a n d cli nical dat a i n dicate t hat t his ris k re mai ns h y p ot hetical 
a n d d oes n ot i nfl ue nce t he o verall be n efit/ris k assess me nt f or c o m bi ni n g trilacicli b wit h 
c he m ot hera p y, t his st u d y will e val uate i n a retr os p ecti ve fas hi o n  t he relati o ns hi p bet wee n 
C D K 4/ 6 stat us a n d meas ures of a nti -t u m or efficac y; t he pla n ne d statistical a nal yses are des cri be d 
i n Secti o n  1 2. 4. 5. 1 .  
T o s u p p ort t hese a nal yses, pri or t o si g ni n g t he i nf or me d c o nse nt, a F F P E arc hi val t u m or 
s peci me n wit h a n ass oci ate d pat h ol o g y re p ort d oc u me nti n g p M M R/ M S S C R C f or eac h p atie nt 
m ust be c o nfir me d t o be a vaila ble t o se n d t o t he S p o ns or f or pla n ne d retr os pecti ve bi o mar ker 
a nal yses. T u m or tiss ue m ust c o nsist of 2 0 ( 1 5 mi ni m u m) fres hl y c ut u nstai n e d sli des , 4 -6 
micr o ns i n t hic k ness fr o m a serial secti o n cl os e t o t he secti o n of t he bl oc k ta ke n f or l ocal H & E 
assess me nt. If secti o ni n g is n ot feasi ble, a n F F P E t u m or b l oc k, 1 0 0 micr o ns preferre d ( or 7 5 
micr o ns at t he mi ni m u m) is a n acce pta ble alter nati ve. If arc hi val tiss ue is n ot a vaila ble, a fres h 
bi o ps y m ust be o btai ne d. Acce pt a ble sa m ples i ncl u de c ore n ee dle bi o psies, t u m or tiss ue - 
e xcisi o nal or i ncisi o nal, p u nc h, or f orce ps bi o psies f or c uta ne o us, s u b c uta ne o us, or m uc osal 
lesi o ns. Fi ne-nee dle as pir ati o n, br us hi n g, cell pellet fr o m ple ural eff usi o n, b o ne metastases, a n d 
la va ge sa m ples are n ot a cce pta ble. A d diti o nal g ui d a nce is pr o vi de d i n t he l a b orat or y ma n ual. 
A n y re mai ni n g t u m or tiss ue f oll o wi n g t he descri b e d a nal yses will be b a n ke d a n d ma y be 
a nal yze d f or rele va nt D N A, ri b o n ucleic aci d ( R N A), or pr otei n bi o mar k ers a n d t heir r ole i n 
ca ncer, i ncl u di n g t o better u n dersta n d i m m u ne -rel ate d mec h a nis ms. N ote: N o t u m or ti ss ue will 
be arc hi v e d f or st u d y ce nters i n C hi na . 
1 1. 8. 2.  
Descri pti o n of C D K 4/ 6 Si g n at ure  
I n or der t o c h aracteri ze t his h y p ot hetical ris k i n a t u m or t y pe wit h o ut a clear C D K 4/ 6 res p o nse 
p he n ot y pe, arc hi val t u m or tiss ue will be c ollecte d fr o m patie nts’ m ost rece nt bi o ps y (c ol orectal 
pri mar y or metastatic site) a n d s u bjecte d t o a ge netic si g nat ure a n al ysis base d o n p u blis he d 
literat ure i n a n eff ort t o c haract erize patie nt t u m ors i nt o o ne of t he f oll o wi n g t hree gr o u ps 
(S ha pir o , 2 0 1 7 ; G o n g , 2 0 1 7 ):  
•  C D K 4/ 6 i n de pe n de nt : As t he ca n o nical d o w nstrea m tar get of C D K 4/ 6, t he R B 1 ge ne 
a n d e x pressi o n of its ge n e pr o d uct ( R B  pr otei n) h as bee n well st u die d as a mar ker of 
resista nce a n d se nsiti vit y t o C D K 4/ 6 i n hi bit ors. R B 1 is c o m m o nl y d ysre g ulate d i n 
ca ncer cells t hr o u g h deleti o n, m utati o n or e pi ge netic m o dificati o n res ulti n g i n l oss of 
R B e x pressi o n, as well as b y a berra nt C D K ki nas e acti vit y lea di n g t o e xcessi ve 
p h os p h or ylati o n a n d i nacti vati o n of  R B  f u ncti o n (C he n , 2 0 1 9 ; S herr , 2 0 0 2 ). 
C C N E 1/ 2 (c ycli n E) is part of a p arallel pat h w a y t hat pr o vi des f u ncti o nal r e d u n da nc y 


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wit h C D K 4/ 6 a n d hel ps t o tra nsiti o n cells fr o m t he G 1 t o S p hase. O vere x pressi o n 
will decreas e t he relia nce o n t he C D K 4/ 6 pat h wa y lea di n g t o C D K 4/ 6 i n de pe n de nce 
(T ur ner , 2 0 1 9 ). T heref ore, a t u m or wit h eit her C C N E 1/ 2 a m plificati o n or RB  l oss 
will be classifie d as “ C D K 4/ 6 i n de pe n de nt”.  
•  C D K 4/ 6 de pe n de nt : Atte m pts t o i de ntif y mar kers of C D K 4/ 6 de pe n de n ce h a ve 
e val uate d i ncreas e d e x pressi o n of C D K 4/ 6 acti vat ors (c ycli n D). I n P A L O M A -1, 
w he n t he C ycli n D 1 ge ne (C C N D 1 ) a m plificati o n a n d l oss of p 1 6I N 4a were 
e val uate d i n patie nts r ecei vi n g pal b ocicli b pl us  letr oz ole, a nti-t u m or efficac y was 
i m pr o ve d re gar dless of C C N D 1 or p 1 6I N K 4 a stat us (Fi n n , 2 0 1 9 ); t here b y s h o wi n g 
t he f utilit y of t his a p pr oac h. O ne e x pl a nati o n of t his result is t hat assess me nt of 
c ycli n D 1 al o ne is i ns uffi cie nt t o pre dict C D K 4/ 6 se nsiti vit y. Le n di n g s u p p ort t o t his 
h y p ot hesis is a n o ncli nical st u d y e val uati n g a br o a der set of d -t y pe c y cli n acti vati n g 
feat ur es ( D C A F) —  i ncl u di n g C C N D 1 tra nsl ocati o n, C C N D 1-3  3’ U T R l oss, a n d 
a m plificati o n of C C N D 2 or C C N D 3  —  w hic h were s h o w n t o pre dict i n vitr o 
se nsiti vit y t o a be macicli b treat me nt (G o n g , 2 0 1 7 ). T heref ore, after e xcl u di n g t u mors 
t hat are “ C D K 4/ 6 i n de pe n de nt”, a n y re mai ni n g t u m ors t hat are W T f or RB  a n d 
C C N E 1/ 2 as well as ha ve o ne of t he D C A F descri be d a b o ve will be classifie d as 
“ C D K 4/ 6 de pe n d e nt”.   
•  C D K 4/ 6 i n deter mi nate : A n y re mai ni n g t u m or will be classifie d as “ C D K 4/ 6 
i n deter mi nate” si nc e t he y ca n n ot be c o nfir me d as C D K 4/ 6 de pe n de nt or i n de pe n de nt. 
T he e val uati o n of t h e rel ati o ns hi p bet wee n C D K 4/ 6 stat us  a n d a nti -t u m or o utc o mes will be 
perf or me d w he n t he O S a nal ysis is perf or me d, t h at is, w he n t he pre di cte d dea t h e ve nts are 
o bser ve d . T he use of mat ure O S data, i n a d diti o n t o t he O R R a n d P F S data, will all o w f or a m ore 
r o b ust i nter pretati o n of t he relati o ns hi p bet wee n C D K 4/ 6 stat us a n d a nti-t u m or o utc o mes wit h o ut 
t he c o m plicati o n of tr yi n g t o dra w c o n cl usi o ns with i na de q uate i nf or m ati o n (ie , i m mat ure a nti-
t u m or efficac y data).  
T his ti mi n g is c o nsi dere d t o be a p pr o priat e si nce all c urre ntl y a vaila ble data i n dicate t hat if t here 
is a ris k, it is n ot cli nicall y rele va nt; t heref ore, waiti n g u ntil mat ure O S data d oes n ot p ose a 
si g nifica nt hazar d t o t he e nr olle d patie nts, partic ul arl y si nce t he perce nta ge of patie nts at ris k f or 
a p ote ntial ne gati ve o utc o me (i .e., w h o ha v e C D K 4/ 6 de pe n de nt t u m ors) is pre dicte d t o be 
<  1 0 %  (Secti o n  4 ).  
I n a d diti o n t o t his pres pecifie d retr os p ecti ve a n al ysis of C D K 4/ 6 stat us a n d res p o nse w h e n O S 
data are mat ure , d uri n g t he st u d y a n u n bli n de d D M C  (Secti o n  1 1. 1 1 ) will als o re vie w t he 
res p o nse rate of t he o v erall p o p ulati o n (e g, wit h o ut s u bsets of C D K 4/ 6 stat us) t o m o nit or a n y 
p ote ntial detri me nt i n c he m o t hera p y efficac y i n t h ose patie nts recei vi n g trilacicli b vers us 
place b o . S p o ns or, I n v esti gat ors, a n d patie nts will re mai n bli n de d. Ti mi n g of t his re vie w a n d 
details of t he ass ociat e d a nal ysis pla n will be i ncl u de d i n t he D M C C harter.  
1 1. 9.  
I m m u n ol o gic a n d He m at ol o gic M ar kers 
C he m ot hera pe utic a ge nts ma y elicit part of t heir a nti -t u m or efficac y b y m o d ulati n g t he i m m u ne 
s yste m t o e n ha nce a nti ge n prese ntati o n, u pta ke, a n d pr ocessi n g; pri me t he i m m u ne res p o nse 
t hr o u g h i m m u n o de pleti o n; i n hi bit re g ulat or y cells; a n d sti m ulate i m m u ne effect or cells 
(Zit v o gel , 2 0 0 8 ; Mc D o n nell , 2 0 1 1 ; Bracci , 2 0 1 4 ). C o n versel y, i m m u n os u p pressi o n fr o m direct 


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cytotoxicity to the bone marrow and immune system over repeated cycles of chemotherapy may 
counterbalance the positive immunostimulatory effects of chemotherapy. Therefore, therapeutic 
approaches to maintain bone marrow health and immune system function should enhance the 
immune-mediated anti-tumor activity. 
To evaluate the impact of trilaciclib administration on chemotherapy-induced changes of the 
immune and hematopoietic system, immunophenotypic and hematologic changes will be 
compared (as data warrant) between patients receiving FOLFOXIRI/bevacizumab therapy with 
either placebo or trilaciclib. To assess these changes, peripheral blood will be collected per the 
timepoints in the Schedule of Assessments (Table 4 and Table 5). At each time point (Cycle 1 
Day 1, Cycle 2 Day 1, Cycle 5 Day 1, and Maintenance Cycle 1 Day 1), collection should occur 
prior to trilaciclib dosing. These blood samples will be banked and may be analyzed for relevant 
DNA, RNA, or protein biomarkers and their role in cancer. Note: No blood will be archived for 
study centers in China. 
11.10. 
Adverse and Serious Adverse Events 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up, as applicable, AEs that are serious, considered related to the study drugs or study procedures, 
or that caused the patient to discontinue the study or study drugs (see Section 10.1). Patients 
should be encouraged to report AEs spontaneously or in response to general, nondirected 
questioning. Adverse events should be reported on the appropriate page of the eCRF.  
11.10.1. 
Time Period and Frequency for Collecting Adverse and Serious Adverse Event 
Information 
All AEs and SAEs will be collected from the day of first dose of any study drug until 30 days 
after the last dose of study drug. Any SAE occurring between the date the patient signs informed 
consent and the first dose of any study drug, and which the investigator feels is related to a study 
specific procedure (i.e. would not have occurred unless the patient was on the study), should also 
be reported. 
All SAEs will be recorded and reported to G1 Therapeutics pharmacovigilance (PVG) or 
designee immediately and under no circumstance should this exceed 24 hours after becoming 
aware of the event, as indicated in Section 17.3. The Investigator or designee will submit any 
updated SAE data to G1 Therapeutics PVG within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE information after 30 days following 
the last dose of study drugs on this study. However, if the Investigator learns of any SAE, 
including a death, at any time after a patient has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, the 
Investigator or designee must promptly notify G1 Therapeutics PVG or designee. 
11.10.2. 
Method of Detecting Adverse and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 17.3. 


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Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the patient is the preferred method to inquire about AE 
occurrences. 
11.10.3. 
Follow-up of Adverse and Serious Adverse Events 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All AEs (both serious and nonserious) will be followed in accordance 
with good medical practice until resolution, return to baseline, or it is deemed that further 
recovery is unlikely. All measures required for AE management and the ultimate outcome of the 
AE will be recorded in the source document and reported to G1 Therapeutics PVG or designee. 
All SAEs will be followed until resolution, stabilization, the event is otherwise explained, or the 
patient is lost to follow-up (as defined in Section 10.3). Further information on follow-up 
procedures is provided in Section 17.3. 
11.10.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification of G1 Therapeutics PVG or designee by the Investigator (or designee) of a 
SAE is essential so that legal obligations and ethical responsibilities towards the safety of 
patients and the safety of a study intervention under clinical investigation are met. 
G1 Therapeutics has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. G1 
Therapeutics will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and Investigators. 
For all studies, except those utilizing medical devices, Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and G1 Therapeutics policy and forwarded to Investigators as necessary. 
An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from G1 Therapeutics or designee will 
review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
11.10.5. 
Pregnancy 
Details of all pregnancies in female patients and female partners of male patients will be 
collected after the start of study intervention and until 3 weeks and 3 months respectively, after 
the last dose of study drug. 
If a pregnancy is reported, the Investigator or designee should inform G1 Therapeutics PVG or 
designee within 24 hours of learning of the pregnancy and should follow the procedures outlined 
in Section 17.4. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 


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11.10.6. 
Adverse Events of Special Interest  
All Grade 3 or Grade 4 trilaciclib AESIs should be reported as SAEs using the procedures 
outlined in Section 11.10.1 to Section 11.10.4. For a list of trilaciclib AESIs, please see 
Section 4.2.3.1. 
11.11. 
Data Monitoring Committee 
An unblinded, independent data monitoring committee (DMC) will monitor accumulating safety 
and disposition data with the first meeting planned for when approximately 30 patients have 
enrolled and completed at least 2 cycles of study treatment. The meetings will continue 
approximately every 4 months while patients are on study treatment depending upon the 
enrollment rate. Additional reviews may occur based on DMC requests.  
A DMC charter will define the roles and responsibilities of the DMC and its members. 
Additional details regarding the committee’s composition, scope, objectives, procedures and 
policies, including data to be reviewed and strategy for maintaining study blind for the Sponsor, 
Investigators and patients, are described in the DMC charter. The DMC will monitor 
accumulating safety and disposition data entirely independent of the conduct of the study. 
In addition to its periodic review of all available safety data, the DMC will also review at one 
meeting the response data of the overall population to monitor any potential detriment in 
chemotherapy efficacy in those patients receiving trilaciclib. Sponsor, Investigators, and patients 
will remain blinded. Timing of this review and details of the associated analysis plan will be 
included in the DMC Charter. 
11.12. 
Survival Follow-up 
When a patient permanently discontinues study treatment (End of Treatment [EOT]), the patient 
should complete a Post-treatment follow-up visit as outlined in Table 5. The patient will then 
continue in the study in Survival Follow-up. If a patient withdraws consent for further study 
treatment and/or procedures, the site should clarify if the patient remains open to survival contact 
and associated data collection. 
During Survival Follow-up, patients will be followed for survival, i.e., patients or their 
caregivers will be contacted approximately every 2 months until the end of the trial (or death) to 
record their status (alive or dead). In addition, details of any subsequent systemic anti-cancer 
therapy initiated, including name(s) of agent(s), dates (start/stop) administered, best response to 
the treatment, and date of progression should also be reported in EDC. As available, results of 
CBC performed prior to the start of each regimen of subsequent systemic anti-cancer therapy 
should also be reported in the EDC. Provided that the patient has not withdrawn consent for 
follow up contact, information from medical records may be substituted for phone or other 
contact, provided that records are available as source documentation. Public records may be used 
to verify survival status if permitted by institutional or country guidance.  
For those patients who have not progressed at the time of study drug discontinuation and enter 
into Survival Follow-up, radiological tumor assessments should continue as outlined in Table 5 
until progression, withdrawal of consent, initiation of the first subsequent anti-cancer therapy, or 


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study completion (see Section 11.3). Results of these scans should be assessed by RECIST 1.1 
and data entered in EDC in the corresponding tumor assessment forms. 
For those patients who undergo curative intent surgical resection during this trial, the patient will 
discontinue study treatment at the time of resection and continue in Survival Follow-up. Tumor 
assessments will continue as directed for survival follow-up. Any anti-cancer therapy for 
colorectal cancer that is initiated post-surgical resection is at the discretion of the Investigator. 
Details of subsequent anti-cancer therapy received post-surgical resection (even if a continuation 
of the study regimen), including name(s) of agent(s), dates (start/stop) administered, best 
response to the treatment, and date of progression should also be reported in EDC. Subsequent 
anti-cancer therapy data following curative intent surgical resection will be summarized 
separately from subsequent anti-cancer therapy data reported following disease progression. 


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12. 
STATISTICAL CONSIDERATIONS 
Full details on the statistical analyses to be performed will be provided in a separate statistical 
analysis plan (SAP). 
12.1. 
Sample Size Determination 
The primary and key secondary objectives of this study are to evaluate the myelopreservation 
and anti-tumor efficacy of trilaciclib administered prior to FOLFOXIRI/bevacizumab (referred to 
as trilaciclib hereafter) compared with placebo administered prior to FOLFOXIRI/bevacizumab 
(referred to as placebo hereafter). To ensure strong control of family-wise type I error rate at the 
level of 2-sided 0.05 when performing statistical analyses for the two primary myelosuppression 
endpoints, and key secondary anti-tumor efficacy endpoint, the overall 2-sided α of 0.05 will be 
split between the analyses of the primary endpoints (using 𝛼1 = 0.04 ) and analysis for OS 
(using 𝛼2 = 0.01).  
The sample size is determined to support primary efficacy analysis on the two primary efficacy 
endpoints.  
To detect the assumed treatment effect of an absolute reduction of 15% on the proportion of 
patients who have SN in Induction at the significance level of 2-sided 0.04 with 90% power, 
assuming the event rate for placebo is 25%, a sample size of 282 (141 per group) is needed using 
a Chi-square test without continuity correction.  
The sample size needed to detect a treatment effect on DSN in Cycle 1 – 4 (refer to Section 
12.4.4.1 for definition) is estimated through simulations to detect a treatment effect of 2.4 days 
reduction for DSN. In derivation of this endpoint, duration of 0 will be assigned to patients who 
do not experience any SN in Cycle 1 – 4 (see details in Section 12.4.4.1). With a large proportion 
of 0 values, the variable of DSN in Cycle 1– 4 does not follow a normal distribution but 
approximately a Poisson distribution with the mean parameter as -log (proportion of patients 
without any SN at Cycle 1– 4). Assuming approximately 80% of SN that occurs during Induction 
will take place in the first 4 cycles of Induction as reported in (Rossini, 2021) and assuming that 
trilaciclib will have an effect of 15% absolute reduction on SN in the first 4 cycles, , it is 
estimated that the proportion of patients with SN in Cycle 1 – 4 is 20% for placebo and 5% for 
the trilaciclib group, respectively. Hence, the Poisson means are estimated to be 0.2231 and 
0.0513 for placebo and trilaciclib groups, respectively. 10,000 trials were simulated based on the 
Poisson distributions to obtain DSN in Cycle 1– 4. Treatment group difference is evaluated using 
the Mann-Whitney-Wilcoxon test, and the power is estimated by the proportion of the trials that 
have achieved a 2-sided p-value ≤ 0.04 over 10,000 simulated trials. From the simulation results, 
a sample size of 200 patients (100 per group) can achieve an empirical power of 91%.  
Overall, 282 patients (141 per group) are needed to detect the assumed treatment effect for each 
of the two co-primary myelosuppression endpoints with 90% power at the 2-sided significance 
level of 0.04. Assuming 5% of randomized patients will not have any post-baseline data, a total 
of 296 patients (148 per group) will be required for the study.  
Although the number of patients is determined to ensure adequate power for the evaluation of the 
myelopreservation efficacy of trilaciclib, statistical comparisons for anti-tumor efficacy will also 
be conducted and the statistical significance is set to be 0.01 for testing the treatment effect on 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 0 1  
O S. A  t otal of 1 5 7 deat hs  are esti mate d  t o b e o bser ve d d uri n g 52 -m o nt h of st u d y d urati o n  base d 
o n t he f oll o wi n g ass u m pti o ns: 1 8 m o nt hs of accr ual wit h  3 4 m o nt hs f oll o w u p after t he l ast 
patie nt is ra n d o mize d, a m o nt hl y dr o p -o ut rate of 0. 0 0 2 9 (ass u mi n g a n e x p o ne ntial distri b uti o n ), 
a n d t he me dia n O S of 3 1 m o nt hs f or place b o gr o u p ( patie nts recei vi n g F O L F O XI RI/ b e vaci z u ma b 
pl us place b o)  (L o u p a kis , 2 0 1 4). It is als o ass u me d t hat t he hazar d rati o (trilacicli b vs. place b o) is 
0. 7 5.   
A t otal of 4 4 patie nts fr o m U krai ne were ra n d o mize d t o t he st u d y as of 2 4 Fe br uar y 2 0 2 2. T o 
miti gate t he p ote ntial i m pact of R ussia n -U krai ne war o n data i nte grit y a n d e ns ure t he o bjecti ves 
of P R E S E R V E -1 will n ot be c o m pr o mise d, patie nts w h o were ra n d o mize d fr o m U krai ne pri or t o 
0 9 Se pte m ber 2 0 2 1 will be i ncl u de d i n efficac y a nal yses w hile all ra n d o mize d patie nts fr o m 
U krai ne will be i ncl u de d i n t he safet y e val uati o n. T heref ore, a t otal of 3 0 ra n d o mize d patie nts 
fr o m U kraine will be e xcl u de d fr o m efficac y e val uati o n. T o preser ve t he st u d y p o wer as it was 
ori gi nall y desi g ne d, a d diti o nal 3 0 patie nts will be ra n d o mize d i n c o u ntries ot her t ha n U krai ne. 
As s uc h, t he t otal sa m ple size f or t his st u d y will be 3 2 6, wit h 2 9 6 patie nts  i ncl u de d i n t he mI T T 
p o p ulati o n f or t he pri mar y effic ac y a n al yses. T he reas o n t hat 0 9 Se pte m ber 2 0 2 1 was c h ose n is 
beca use p atie nts ra n d o mi ze d pri or t o t his date s h o ul d ha ve c o m plete d or h a d t he o p p ort u nit y t o 
c o m plete I n d ucti o n peri o d per pr ot oc ol (a p pr o xi m atel y 2 4 wee ks), pri or t o t he start of t he war 
( 2 4 Fe br uar y 2 0 2 2). 
1 2. 2.  
A n al ysis P o p ul ati o n  
T he i nte nt -t o-treat (I T T) p o p ulati o n i ncl u des all ra n d o mize d patie nts. A nal yses f or t he I T T 
p o p ulati o n will be c o n d ucte d base d o n t he ra n d o ml y assi g ne d treat me nt r e g a r dless of w h et her 
t he patie nt recei ve d st u d y treat me nt or was c o m plia nt  wit h t he pr ot oc ol.  
T o acc o u nt f or  t he data i nte grit y iss ues res ulti n g fr o m t he war i n U krai ne, a m o difie d i nte nt -t o-
treat ( mI T T) p o p ulati o n will be utilize d as  t he pri mar y a nal ysis p o p ulati o n f or all efficac y 
e val uati o ns. T he criteria f or t he mI T T p o p ulati o n are as f oll o ws:   
•  All patie nts ra n d o mize d i n c o u ntries ot her t ha n t he U krai ne.  
•  All patie nts i n t he U krai n e w h o were ra n d o mize d pri or t o 0 9 Se pte m ber 2 0 2 1.  T his 
gr o u p s h o ul d ha ve c o m pl ete d, or ha d t he o p p ort u nit y t o c o m plete, I n d u cti o n peri o d 
per pr ot oc ol (a p pr o xi mat el y 2 4 wee ks) pri or t o t he start of t he war ( 2 4  Fe b r uar y 
2 0 2 2).  
As a s u bs et of I T T p o p ulati o n, t he a n al yses perf or me d o n mI T T will be c o nsiste nt wit h t he I T T 
pri nci ple, t hat is, data will be a nal yze d b ase d o n t he ra n d o ml y assi g ne d tr eat me nt re g ar dless of 
w het her t he p atie nt recei ve d st u d y treat me nt or was c o m plia nt wit h t he pr ot oc ol.   
A per -pr ot oc ol ( P P) p o p ulati o n is t he s u bset of t he mI T T  p o p ulati o n t hat i ncl u des o nl y t h ose 
patie nts w h o ha ve n o ke y pr ot oc ol de viati o ns (e .g ., a s u bset of maj or pr ot oc ol de viati o ns t hat 
mi g ht si g nifica ntl y affect t he acc urac y of t he st u d y efficac y dat a) a n d w h o recei v e at least o n e 
d ose of t he ra n d o ml y assi g ne d st u d y treat me nt. T h e P P p o p ulati o n will  be use d t o a nal yze 
selecte d e n d p oi nts t o e v al uate t he r o b ust ness of t h e effi cac y fi n di n gs o bser ve d i n t he mI T T  
p o p ulati o n . A nal yses o n t he P P p o p ulati o n will be base d o n t he ra n d o ml y assi g ne d treat me nt. 
T he criteri a f or p atie nts t o be i ncl u de d i n t he P P p o p ulati o n will be f ull y defi ne d a n d d oc u me nt e d 


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prior to database lock, unblinding and performing the analysis of myelopreservation efficacy 
endpoints.  
The response evaluable (RE) population will include patients in the mITT population who have a 
measurable lesion (target) at the baseline tumor assessment, and either (i) have at least 
1 post-dose tumor assessment, or (ii) do not have post-dose tumor assessment but have clinical 
progression as noted by the Investigator, or (iii) have died due to disease progression before their 
first post-dose tumor scan. RE population will be the primary analysis set to evaluate tumor 
response and the data will be analyzed based on real received treatment. 
The safety population includes all enrolled patients who received at least 1 dose of study drug. 
Analyses conducted on the safety population will be based on the actual treatment received. All 
safety analyses will be conducted using the safety population. 
The PK population will include all dosed patients with evaluable PK data. 
12.3. 
Timing of Planned Analyses 
12.3.1. 
First Planned Analysis – Evaluation of Myelopreservation Efficacy  
The first planned analysis will be conducted at the time that all randomized patients have 
finished 12 cycles of Induction treatment or discontinued during Induction. Trilaciclib’s effects 
on myelopreservation will be evaluated in this analysis. The clinical trial database will be locked 
to support this first planned analysis. 
This analysis is estimated to occur approximately 24 months from the date of the first patient 
randomized in the study. At the time of performing this analysis, the Sponsor will be unblinded; 
however, Investigators and patients will remain blinded.  
Analysis for tumor response data will also be performed at this time. 
12.3.2. 
Second Planned Analysis - Analysis for Progression Free Survival  
The planned second analysis of the study is to perform the PFS analysis around the time that is 
35 months post first randomization. 
12.3.3. 
Third Analysis – Analysis for Overall Survival 
At the time when 157 death events are observed or at 52 months after the date of first 
randomization, whichever comes first, the study will be concluded, and the final study database 
will be locked to perform the OS analysis. 
PFS analysis will also be performed at this time along with other endpoints that will be analyzed 
based on the final study database lock, such as safety endpoints. 
12.4. 
Statistical Analysis Methods 
An SAP will be developed and finalized prior to the first planned database lock and will include 
more details related to the statistical analysis of this study’s data. This section is a summary of 
the key aspects of the planned statistical analyses. 


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12.4.1. 
General Considerations 
All statistical analyses will be performed using SAS® v9.4 or higher. 
Data will be summarized descriptively by treatment group. The descriptive summary for the 
categorical variables will include counts and percentages. The descriptive summary for the 
continuous variables will include means, medians, standard deviations, 25% and 75% 
percentiles, and minimum and maximum values.  
There are three stratification factors for randomization: country, prior therapy in 
adjuvant/neoadjuvant setting, and BRAF V600E mutational status. Within each country, patient 
randomization will be stratified by history of prior therapy in the adjuvant/neoadjuvant setting 
(yes/no) and BRAF V600E mutational status (“BRAF status”; yes/no). The countries will be 
grouped into the factor of “region” with four different entries of US, Eastern Europe, Western 
Europe, and China. The factor “region” will be used instead of “country” in the statistical 
analysis models to account for regional differences in clinical practice. It is anticipated that all 
three factors (region, prior therapy in adjuvant/neoadjuvant setting and BRAF status) would have 
an impact on patients’ anti-tumor efficacy outcome, but only region and prior therapy in 
adjuvant/neoadjuvant setting would have an impact on myelosuppression measures. Therefore, 
region and prior therapy in adjuvant/neoadjuvant setting will be included as the factors in 
statistical analysis models evaluating trilaciclib myelopreservation efficacy, while all three 
factors are included in the statistical analysis models to assess trilaciclib’s anti-tumor efficacy. 
Unless otherwise specified, the strata information as entered in IWRS at the time of 
randomization except for “region” will be used as the factors for all stratified statistical analyses. 
For the patients who undergo curative intent surgical resection, myelosuppression and tumor 
assessments collected prior to the date of surgery will be included in the efficacy analyses, while 
all safety data will be included in the safety evaluation.  
12.4.2. 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the ITT population 
descriptively by treatment and overall.  
12.4.3. 
Prior and Subsequent Anti-cancer Therapies 
Prior and subsequent anti-cancer therapy verbatim terms will be coded to Anatomical 
Therapeutic Classification (ATC) and preferred term (PT) using the most recent World Health 
Organization-Drug Dictionary (WHO-DD). For the ITT population, summary statistics will be 
provided for prior or subsequent systemic anti-cancer therapies by treatment group and overall. 
For the subsequent systemic anti-cancer therapies, the lines of therapy, response to each 
treatment regimen, and disease progression status will also be summarized by treatment group 
and overall. 
For patients who undergo surgical resection with curative intent, surgery will be recorded as a 
subsequent surgery/procedure. The number and percentage of these patients will be summarized 
by treatment group and overall. Any post-surgical resection systemic anti-tumor therapy will be 
recorded on the subsequent anti-cancer therapy eCRF. Subsequent anti-cancer therapy data 
following curative intent surgical resection will be summarized separately from subsequent 
anti-cancer therapy reported following disease progression.  


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 0 4  
1 2. 4. 4.  
Effic ac y A n al yses  
U nless ot her wise s pecifie d, all effic ac y a n al ys es will be perf or me d o n  t he mI T T  p o p ul ati o n . 
U nless ot her wise s pecifie d, m yel o preser vati o n  effi cac y will be e val uate d b ase d o n t he data  t hat 
are c ollecte d  d uri n g I n d u cti o n  as of t he data c ut off date of t he first pla n n e d a nal ysis . Treat me nt 
effects o n P F S a n d O S will be e val uate d bas e d o n t he esti mate d n u m ber of e ve nts a n d will n ot be 
li mite d t o w here t he patie nt is i n t he st u d y (e.g ., I n d ucti o n, Mai nte na nce or S ur vi val F oll o w-U p).  
T o e ns ure str o n g c o ntr ol of fa mil y -wise T y pe I err o r rate at t he le vel of 2-si de d 0. 0 5 w he n 
perf or mi n g statistical a nal yses f or t he t w o pri mar y m yel os u p pressi o n e n d p oi nts ( D S N i n C ycle  1  
–  4  a n d occ urre n ce of S N d uri n g  I n d u cti o n) a n d  O S, t he o verall 2-si de d α of 0. 0 5 will be s plit 
bet wee n t w o gr o u ps of a n al ysis: t he a nal yses of t he pri mar y e n d p oi nts ( usi n g α  =  0. 0 4 ), a n d t he 
a nal ys is f or O S ( usi n g α =  0. 0 1). Testi n g strate gies wit hi n eac h gr o u p  a n d t he rec y cli n g 
al g orit h m fr o m t he first gr o u p t o t he ne xt are descri be d i n Secti o n 1 2. 4. 4. 2  a n d Secti o n 
1 2. 4. 4. 3. 1 , res pecti vel y.  
1 2. 4. 4. 1.  A n al yses of Pri m ar y M yel os u p pressi o n E n d p oi nts: D S N i n C ycle  1 –  4  a n d 
Occ urre nce of S N d uri n g I n d ucti o n  
Se vere ne utr o pe nia  ( S N) is defi ne d as a n A N C of < 0. 5 × 1 0 9/ L ( Gra d e 4). He mat ol o g y 
la b orat or y ass ess me nts o btai ne d at sc he d ule d a n d n o n -sc he d ule d visits will all be i ncl u de d t o 
i de ntif y S N e ve nts a n d i n t he D S N deri vati o n.  
T he c o -pri mar y e n d p oi nt D S N i n C ycle 1 –  4, is defi ne d as t he n u m b er of d a ys of t he first S N 
e ve nt t hat occ urre d i n t he first 4 c ycles of I n d ucti o n . S pecificall y, for patie nts wit h at least 1  S N  
e ve nt i n I n d ucti o n i n C ycle 1, 2, 3 or 4, D S N is cal c ulate d f or t h e first occ urre nce of t he e v e nt 
f oll o wi n g t he r ules descri be d bel o w. 
•  F or patie nts w h ose S N is res ol ve d ( defi n e d as a n A N C ≥ 0. 5 × 1 0 9/ L at a date after t he 
i nitial S N occ urre n ce a n d mai ntai ne d u ntil t he e n d of t he cycle), D S N will be deri ve d 
as t he n u m ber of da ys fr o m t he date of t he first S N occ urre n ce t o t he d ate of S N 
res ol uti o n.  
•  F or p atie nts w h o wit h dra w fr o m t he st u d y wit h u nres ol ve d n e utr o pe nia, D S N will be 
deri ve d as t he n u m ber of da ys fr o m t he date of t he first S N occ urre nce t o t he date of 
wit h dra wal (i.e., t h e last date i n t he st u d y).  
F or patie nts wit h o ut a n y S N i n C y cle 1–  4 of I n d u cti o n, or t h ose w h o ra n d o mize d b ut w h o di d 
n ot recei ve a n y st u d y dr u g,  D S N will be set t o 0 .  
D S N is a c o nti n u o us ra n d o m varia ble b ut is n ot n or mall y distri b ute d gi ve n t hat a bi g pr o p orti o n 
of t he val ues are set as 0 per t he defi niti o n desc ri b e d a b o ve.  
Treat me nt effect o n D S N i n C ycle  1  –  4  will be e val uate d usi n g n o n para metric a nal ysis of 
c o varia n ce ( A N C O V A) ( Q ua de , 1 9 6 7 ). I n t his a nal ysis, t he ra n k-tra nsf or me d ( wit hi n eac h 
strat u m) D S N val ues are a nal yze d b y a n A N C O V A m o del wit h t he ter ms of treat me nt, r e gi o n 
( U S, Easter n E ur o p e, Wester n E ur o pe, a n d C hi na ), a n d pri or t hera p y i n t he a dj u va nt/ ne oa dj u va nt 
setti n g ( Yes or N o) wit h t he ra n k-tr a nsf or me d bas eli ne A N C ( wit hi n eac h strat u m) as a 
c o variate. I n a d diti o n, t he mea n differe n ce (trilaci cli b –  place b o), t he st a n d ar d err or a n d t h e 9 6 % 
c o nfi de nce i nter val  for t h e differe nce ge nerate d fr o m a Sattert h waite t -test will be prese nte d.  


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 0 5  
T he occ urre n ce of S N d uri n g I n d u cti o n  is defi ne d as ha vi n g S N i n at least o ne c ycle i n I n d u cti o n 
a n d t h us  is a bi nar y vari a ble T he treat me nt effect f or occ urre nce of S N will be e val uat e d usi n g 
m o difie d P oiss o n re gressi o n ( Z o u , 2 0 0 4 ). T he m o del will i ncl u de t he treat me nt, re gi o n, a n d pri or 
t hera p y i n t he a dj u va nt/ n e oa dj u va nt setti n g ( yes/ n o) as t he fi xe d effect wit h baseli ne A N C val ue 
as a c o variate . T h e l o g -tr a nsf or me d n u m ber of c y cles will be use d as t he offset i n t he m o del t o 
acc o u nt f or t he vari a ble d urati o n d uri n g I n d ucti o n f or eac h patie nt. T he 2 -si de d p-val ue, a dj uste d 
relati ve ris k ( a R R) (trilacicli b vs place b o) a n d its 9 6 % c o nfi de n ce i nter val  will be calc ulate d.  
  
1 2. 4. 4. 2.  M ulti plicit y C o ntr ol  f or t he Pri m ar y M yel os u p pressi o n E n d p oi nts 
F or eac h of t h e  pri mar y e n d p oi nts , t he treat me nt effect will be teste d at 2 -si de d 𝛼1 = 0 .0 4  le vel. 
T hat is, t he statisticall y si g nifica nt treat me nt effect f or D S N i n C ycle 1 –  4 will be  esta blis he d if 
t he 2-si de d p-val ue fr o m n o n -para m etric A N C O V A m o del ( Secti o n  1 2. 4. 4. 1 ) is ≤ 0. 0 4, a n d t he 
statisticall y si g nifica nt treat me nt effect f or S N d uri n g I n d ucti o n will be est a blis he d if t he 2 -si de d 
p -val ue fr o m  t he m o difi e d P oiss o n m o del (Secti o n  1 2. 4. 4. 1 ) is ≤ 0. 0 4.  W he n t he statisticall y 
si g nifica nt treat me nt effects are esta blis he d f or b ot h pri mar y e n d p oi nts, t he pri mar y o bjecti ve of 
t he st u d y is met. 
1 2. 4. 4. 3.  A n al ys is of Ke y Sec o n d ar y A nti-T u m or Effic ac y E n d p oi nt:  O ver all S ur vi v al  
O S will be calc ulate d as t he ti me ( m o nt hs)  fr o m t he date of ra n d o mizati o n t o t he date of deat h 
d ue t o a n y ca us e. Patie nts w h o d o n ot die d uri n g t he st u d y will be ce ns ore d at t he date last 
k n o w n t o be ali ve. Patie nts lac ki n g data be y o n d t h e date of ra n d o mizati o n will ha ve t heir 
s ur vi val ti me ce ns ore d at t he date of ra n d o mizati o n. O S will n ot be ce ns ore d if a patie nt recei ves 
s u bse q ue nt a nti-ca n cer treat me nts after disc o nti n uati o n of t he st u d y dr u gs.  
1 2. 4. 4. 3. 1.  St atistic al Si g nific a nce Le vel a n d Testi n g Str ate g y f or Testi n g Tre at me nt Effect 
o n O ver all S ur vi v al  
As descri be d i n Secti o n  1 2. 4. 4 , a T y pe I err or rate of 2-si de d 𝛼2 = 0 .0 1  is ori gi nall y assi g ne d t o 
t he a nal ysis f or O S wit h 𝛼1 = 0 .0 4  bei n g use d f or test i n g treat me nt effect o n t he pri m ar y 
e n d p oi nts ( D S N i n C ycle 1 –  4  a n d occ urre n ce of S N i n I n d ucti o n). If t he statisticall y si g nifica nt 
treat me nt effect are esta blis he d at 0. 0 4 le vel f or t h e t w o pri mar y e n d p oi nts, t he n 𝛼1 = 0 .0 4  will 
be a d de d o nt o t o 𝛼2 = 0 .0 1  t o all o w a f ull α of 2-si de d 0. 0 5 t o test t he treat me nt effects o n O S 
f oll o wi n g t he fall bac k pr oce d ure (Wie ns , 2 0 0 3 ). T hat is, t here are t w o sce nari os f or statistical 
si g nifica nce le v el i n testi n g O S:  
•  Sce n ari o 1 : If o ne of t he pri mar y e n d p oi nts  fails t o esta blis h t he statistical 
si g nifica nce, O S will be t este d at 2-si de d 0. 0 1 le v el. 
•  Sce n ari o 2 : If t he statistical si g nifica nce f or D S N i n C ycle  1  –  4 , a n d occ urre nce of 
S N are esta blis he d at t he le vel of 2 -si de d 0. 0 4, O S will be teste d at 2 -si de d 0. 0 5 le vel. 
1 2. 4. 4. 3. 2.  St atistic al A n al ysis M o dels  
T he  Ka pla n -Meier pl ot will be pr o d uce d a n d t he wit hi n -gr o u p me dia n, 2 5 % a n d 7 5 % perce ntile 
of ti me -t o-e ve nt will be esti mate d usi n g t he Ka pla n -Meier met h o d wit h t heir c orres p o n di n g 9 5 % 
c o nfi de nce i nter val , w hi c h are calc ulate d base d o n t he met h o d b y Br o o k me yer  a n d Cr o wl e y 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 0 6  
(1 9 8 2 ). A d diti o nall y, Ka pla n-Meier esti mates will be pr o vi de d f or t he s ur vi val pr o ba bilit y al o n g 
wit h t heir 9 5 % c o nfi de n ce i nter val s (K al bfleisc h , 1 9 8 0 ) at select e d la n d mar ks, f or e x a m ple, at 
1 2, 2 4, a n d 3 6 m o nt hs.  
T he  treat me nt effect will be e val uat e d usi n g a stratifie d l o g-ra n k test acc o u nti n g f or fact ors of 
re gi o n, pri or t hera p y i n t he a dj u va nt/ ne oa dj u v a nt setti n g, a n d B R A F stat us . T he H R bet wee n t he 
2 treat me nt gr o u ps (trila cicli b vs place b o), t o get her wit h its ( 1 -α) x 1 0 0 % c o nfi de nce i nter val s, 
will be calc ulate d fr o m a C o x pr o p orti o nal hazar d m o del  wit h t he sa me fact ors as i ncl u de d i n t he 
stratifie d l o g-ra n k test.  
1 2. 4. 4. 4.  A n al ysis f or Sec o n d ar y M yel os u p pressi o n E n d p oi nts  
T he detaile d deri vati o n f or t hese e n d p oi nts al o n g wit h t heir a nal ysis met h o ds will be i ncl u de d i n 
t he S A P. T he m yel os u p pressi o n e n d p oi nts will be use d t o e val uate t he p ot e ntial of trilacicli b t o 
pre ve nt or miti gate CI M b y assessi n g effects o n m ulti ple li nea ges (e.g ., ne utr o p hils, R B Cs, 
platelets) a n d c urre nt sta n dar d of care i nter ve nti o ns t o treat CI M  (e.g ., G-C S F a d mi nistrati o n, 
E S A a d mi nistrati o n, R B C or platelet tra nsf usi o n , a n d d ose re d u cti o ns ).  
I n g e neral, a bi nar y res p o nse varia ble, e g, occ urre nce of  F N a d v erse e ve nts  or  Gra d e 3 or 4 
decrease d h e m o gl o bi n la b orat or y val ues ( meas ure d b y he m o gl o bi n la b orat or y val ue < 8. 0 g/ d L) 
i n I n d ucti o n, will be a n al yze d usi n g t he m o difie d P oi ss o n re gressi o n m o del  (Z o u , 2 0 0 4 ) as 
o utli ne d i n Secti o n  1 2. 4. 4. 1  wit h t he c orres p o n di n g baseli ne la b orat or y val ue as a c o v ariat e . A 
c o u nti n g varia ble, e .g ., n u m ber of R B C tra nsf usi o ns o n/after Wee k 5 , will be a nal yze d usi n g a 
ne gati ve bi n o mial re gressi o n m o del . T he m o del c o ntai ns t he sa me ter ms as i ncl u de d i n t he 
m o difie d P oiss o n m o del.  I n b ot h t he m o difie d P oiss o n a n d ne gati ve bi n o mial m o dels, t he 
varia ble d urati o n of I n d u cti o n f or eac h patie nt  will be a dj uste d i n assessi n g treat me nt effect b y 
usi n g t he l o g -tra nsf or me d c ycles ( or wee ks) as t h e offset varia ble i n the m o del. I n a d diti o n, 
baseli ne vari ati o n of t he c orres p o n di n g la b orat or y val ues will als o be a dj uste d b y i ncl u di n g 
baseli ne val ue as a c o v ari ate i n t he m o del . F or b ot h m o dels, t he  2 -si de d p-v al ue, a R R (trilacicli b 
vs  place b o), a n d 9 5 % c o nfi de nce i nter val  will be ge nerat e d a n d prese nte d.  
1 2. 4. 4. 5.  A n al ysis f or Sec o n d ar y A nti -t u m or Effic ac y E n d p oi nts   
Sec o n dar y a nti -t u m or e n d p oi nts  will i ncl u de t he f oll o wi n g:   
•  O bjecti ve res p o ns e ( c o m plete res p o nse [ C R ] or partial res p o nse [ P R ]) 
•  Best o verall res p o nse ( B O R)  
•  D urati o n of o bjecti ve res p o nse ( D O R)  
At eac h t u m or ass ess me nt visit, a n o verall ti me p oi nt res p o nse b y R E CI S T v 1. 1 will be 
deter mi ne d pr o gra m maticall y usi n g t he meas ure m e nts pr o vi de d b y t he In vesti gat or f or tar get 
lesi o ns, n o n-tar get lesi o ns, a n d ne w lesi ons c ollect e d i n t he e C R F. Best o verall res p o nse ( B O R ) 
will be deter mi ne d usi n g all visit res p o nses pri or t o or o n t he date of (i) ra di o gra p hic disease 
pr o gressi o n; (ii) wit h dra wal of c o nse nt t o o btai n sca ns; (iii) deat h; (i v) l ost t o f oll o w -u p; or ( v) 
i nitiati o n of s u bse q ue nt a nti-ca ncer t hera p y ot her t ha n t he st u d y dr u gs, w hi c he ver is earlier.   
O bjecti ve res p o ns e rat e ( O R R) al o n g wit h its e xact 9 5 % t w o -si de d c o nfi de nce i nter val usi n g t he 
Cl o p per -Pears o n met h o d will be c o m p ute d f or eac h treat me nt gr o u p. T he treat me nt effect o n  
O R R  will be e val uate d  usi n g a stratifie d C oc hra n – Ma ntel – Hae ns zel ( C M H) met h o d t o acc o u nt 


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for the factors of region, prior therapy in the adjuvant/neoadjuvant setting, and BRAF status. The 
adjusted proportion difference (trilaciclib vs placebo) and its 95% confidence intervals will be 
calculated using Cochran–Mantel–Haenszel (CMH) weight (as described in Kim, 2013). 
DOR is the time between first objective response of CR or PR and the first date that progressive 
disease is objectively documented or death, whichever comes first. Patients who do not 
experience objective CR or PR will not be included in the analysis. For patients with objective 
response of CR or PR but (i) withdrew consent to obtain scans; (ii) is considered lost to follow 
up; (iii) initiated subsequent anti-cancer therapy other than the study drugs, or (iv) died, the DOR 
of this patient will be censored at the earliest date among these four.  
The Kaplan-Meier method will be used to estimate the median, 25% and 75% percentile of DOR 
for each treatment group, along with the 95% confidence interval which is calculated using the 
method by Brookmeyer and Crowley (1982).  
The analysis for objective response, BOR, and DOR will be based on response evaluable 
population, unless otherwise specified.  
12.4.4.6. Analysis of Secondary Endpoint – Progression Free Survival 
PFS is defined as the time (number of months) from date of randomization until date of 
documented radiologic disease progression per RECIST v1.1 or death due to any cause, 
whichever comes first. More specifically, PFS will be determined using all data until the last 
evaluable visit prior to or on the date of (i) radiographic disease progression per RECIST v1.1; 
(ii) withdrawal of consent to obtain additional scans on study; or (iii) initiation of subsequent 
anti-cancer therapy other than the study drugs whichever is earlier. Death is always categorized 
as a confirmed progressive disease (PD) event. Censoring rules for patients who do not 
experience PD or death will be described in the study SAP. 
PFS analysis will be performed twice in this study. The first time is around the time point of 35 
months post first randomization and the second time at the end of the study.  
The Kaplan-Meier plots will be produced and the within-group median, 25% and 75% percentile 
of time-to-event will be estimated using the Kaplan-Meier method with their corresponding 95% 
confidence interval, which are calculated based on the method by Brookmeyer and Crowley 
(1982).  
The treatment effect will be evaluated using a stratified log-rank test accounting for factors of 
region, prior therapy in the adjuvant/neoadjuvant setting, and BRAF status. The HR between the 
2 treatment groups (trilaciclib vs placebo), together with its (1-α) x100% confidence intervals, 
will be calculated from a Cox proportional hazard model with the same factors as included in the 
stratified log-rank test. 
12.4.4.7. Analysis of Secondary Endpoint - Time to Confirmed Deterioration of Fatigue 
The secondary endpoint, TTCD-fatigue, is calculated from the patient reported outcome FACIT-
F. Time (months) to the first deterioration of fatigue (confirmed at the next visit) is calculated as 
the duration of time from date of randomization to the date of first deterioration which is 


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confirmed at the next visit. Patients who do not experience confirmed deterioration will be 
censored at the date of the last instrument completion (i.e., date of the last non-missing value).  
For time to first deterioration of fatigue, the Kaplan-Meier plots will be produced and the 
median, 25% and 75% percentile of TTCD-fatigue will be estimated using Kaplan-Meier method 
with their corresponding 95% confidence interval, which are calculated based on the method by 
Brookmeyer and Crowley (1982). Treatment group difference in TTCD-fatigue will be evaluated 
using a stratified log-rank test to account for the factors of region and prior therapy in the 
adjuvant/neoadjuvant setting. The HR between the 2 treatment groups (trilaciclib vs placebo), 
together with its 95% confidence intervals, will be calculated from a Cox proportional hazard 
model with the same terms as used in the stratified log-rank test. 
12.4.4.8. Analysis of Exploratory Endpoints 
The FACT (FACT-An and FACT-C), EQ-5D-5L, and PGIC/PGIS instruments will be used to 
assess the impact of trilaciclib on various quality of life measures. The analysis will be based on 
the mITT population. 
12.4.5. 
Safety Analyses 
Summaries of safety data will be performed using the safety population. Adverse event data will 
be coded to system organ class and preferred term using MedDRA (Version 23 or later). The 
number and percentage of patients experiencing any AE overall, and by system organ class and 
preferred term will be tabulated for each treatment group. Adverse events considered by the 
Investigator to be related to treatment will also be summarized by the treatment to which it is 
attributed (e.g., trilaciclib/placebo, chemotherapy, bevacizumab) for each treatment group. 
Severity of AEs will be tabulated based on greatest severity observed for each patient. In the 
tabulation of grade and causality, if the same AE occurs on multiple occasions, the highest grade 
and strongest relationship to study drug will be used in a summary. AESIs for trilaciclib, AEs 
leading to study drug discontinuation, dose reductions, cycle delays, and use of concomitant 
medications to treat AEs will be tabulated separately. 
Observed values and change (including maximum and minimum values) from baseline to each 
visit in vital signs, ECG intervals, and laboratory assessments of hematology, clinical chemistry, 
urinalysis, and liver function parameters will be tabulated, as appropriate. Toxicity grades for 
clinical lab parameters (e.g., hematology, chemistry) will be characterized according to 
NCI-CTCAE, Version 5.0, when possible. Shifts in toxicity grades from baseline to each visit, 
and from baseline to the worst grade during the study, will be summarized. Both scheduled and 
unscheduled data will be included in the safety evaluation. Graphical presentations of safety data 
will be presented as is deemed appropriate. 
Relative dose intensity of chemotherapy (fluorouracil, leucovorin, irinotecan, oxaliplatin, 
bevacizumab), dose modifications, dose reduction, dose interruptions, chemotherapy delay, 
compliance, and patient exposure will be summarized for each study therapy component, where 
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12.4.5.1. Analysis of Anti-tumor Endpoints by CDK4/6 Biomarker Signature 
In addition to summarizing the distribution of CDK4/6 signature by treatment groups as 
described in Section 11.8.2, selected anti-tumor endpoints (ORR, PFS, and OS) will be evaluated 
by subgroup of patients with different CDK 4/6 signature status (i.e., CDK4/6 independent, 
CDK4/6 dependent, and CDK4/6 indeterminate). Within each type of signature, the analysis 
methods for PFS and OS will follow the approaches as outlined in Section 12.4.4.3.2, and 
method for ORR will follow the approach as outlined in Section 12.4.4.5. 
The planned timing of the analysis is detailed in Section 12.3. The evaluation of CDK4/6 status 
will be performed retrospectively when final OS results are available.  
12.4.6. 
Pharmacokinetic Analyses 
The pharmacokinetics of trilaciclib and any metabolites will be determined using a non-linear 
mixed effects modeling approach. Population pharmacokinetic parameters including CL, V, and 
other parameters will be estimated as data permit. Alternatively, if population pharmacokinetic 
models already exist, the predictability of the model to describe trilaciclib (and any metabolites) 
concentration obtained in this study will be evaluated. Population pharmacokinetic modeling will 
be performed using the non-linear mixed effects software such as NONMEM (ICON 
Development Solutions, Ellicott City, MD) or other similar software. Further details of 
population pharmacokinetic analyses will be described in the population 
pharmacokinetic/pharmacodynamic analysis plan.  
12.4.7. 
Pharmacokinetic/Pharmacodynamic Analyses 
If data warrant, exploratory analyses may be performed to examine the relationship(s) between 
exposure to trilaciclib (and any metabolites) and pharmacodynamic endpoints or other clinical 
and safety endpoints. Further details of population PK/pharmacodynamic analyses will be 
described in a separate population PK/pharmacodynamic analysis plan. 


Pr ot oc ol  
 
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Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 1 0  
1 3.  
E T HI C S  
1 3. 1.  
Et hics Re vie w  
T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, I B, a n d ot her rele va nt d oc u me nts (e .g ., a d vertise me nts) 
m ust be s u b mitte d t o a n I R B/I E C b y t he In vesti gat or a n d re vi e we d a n d  a p pr o ve d b y t he I R B/I E C 
bef ore t h e st u d y is i nitiate d.  
A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of 
c ha n ges ma d e t o t he st u d y desi g n, e xce pt f or c ha n ges necess ar y t o eli mi nat e a n i m me diate 
hazar d t o st u d y patie nts . 
T he In vesti gat or will be res p o nsi ble f or t he f oll o wi n g:  
•  Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y t o t he I R B/I E C a n n uall y or 
m ore fre q u e ntl y i n acc or da nce wit h t he re q uire m e nts, p olicies, a n d pr oce d ures 
esta blis he d b y t he I R B/I E C  
•  N otif yi n g t he I R B/I E C of S A Es or ot her si g nifica nt safet y fi n di n gs as re q uire d b y 
I R B/I E C pr oce d ures 
•  Pr o vi di n g o versi g ht of t he c o n d uct of t he st u d y at t he site a n d a d here nce t o 
re q uire me nts of 2 1 C o de of Fe d eral Re g ulati o ns ( C F R), I nter n ati o nal C o u ncil f or 
Har m o nisa ti o n (I C H) g ui deli nes, t he I R B/I E C, E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 f or 
cli nical st u dies (if a p plica ble), a n d all ot her a p plica ble l ocal r e g ulati o ns  
1 3. 2.  
Et hic al C o n d uct of t he St u d y  
T his st u d y will be c o n d ucte d i n acc or da n ce wit h t he pr ot oc ol a n d wit h t he f oll o wi n g:  
•  C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he 
Declarati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical 
Scie nces I nter nati o nal Et hical G ui deli nes  
•  A p plica ble I C H G o o d G C P G ui deli nes  
•  A p plica ble la ws  a n d re g ulati o ns  
1 3. 3.  
Writte n I nf or me d C o nse nt  
T he Pri nci pal I n vesti gat or(s) at e ac h ce nter will e ns ure t hat t he patie nt is gi ve n f ull a n d a de q u ate 
oral a n d writte n i nf or mati o n a b o ut t he nat ure, p ur p ose, p ossi ble ris k a n d b e nefit of t he st u d y. 
Patie nts m ust als o be n otifie d t hat t he y are free t o disc o nti n ue fr o m t he st u d y at a n y ti me. T he 
patie nt s h o ul d be gi ve n t he o p p ort u nit y t o as k q uesti o ns a n d all o we d ti me t o c o nsi der t he 
i nf or mati o n pr o vi de d. 
T he patie nt’s si g ne d a n d date d i nf or me d c o nse nt m ust be o btai ne d  bef ore c o n d ucti n g a n y st u d y 
pr oce d ures.  
T he Pri nci pal I n vesti gat or(s) m ust mai ntai n t he ori gi nal, si g ne d I nf or me d C o nse nt F or m. A c o p y 
of t he si g ne d I nf or me d C o nse nt F or m m ust be gi v e n t o t he patie nt.  
Rec o m me n dati o ns f or t h e i nf or me d c o ns e nt pr ocess are pr o vi de d i n Secti o n  1 7. 1 . 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 1 1  
1 4.  
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 4. 1.  
D at a Pr otecti o n  
Patie nts will be assi g ne d a u ni q ue i de ntifier b y t he S p o ns or. A n y patie nt rec or ds or datasets t hat 
are tr a nsferre d t o t he S p o ns or will c o ntai n t he i de ntifier o nl y; patie nt na mes or a n y i nf or mati o n 
w hic h w o ul d ma ke t he p atie nt i de ntifia ble will n ot be tra ns ferre d.  
T he patie nt m ust be i nf or me d t hat his/ her pers o nal st u d y -relate d dat a will be use d b y t he S p o ns or 
i n acc or da nce wit h l ocal data pr otecti o n la w. T he le vel of discl os ure m ust als o be e x plai ne d t o 
t he patie nt w h o will be re q uire d t o gi ve c o nse nt f or t heir data t o be us e d as descri be d i n t he 
i nf or me d c o nse nt.  
T he patie nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y b e e x a mi ne d b y Cli nical Q ualit y 
Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y t he S p o ns or, b y a p pr o priate 
I R B/I E C me mbers, a n d b y i ns pect ors fr o m re g ulat or y a ut h orities.  
1 4. 2.  
D at a Q u alit y Ass ur a nce  
•  All patie nt data relati n g t o t he st u d y will be rec or de d o n e C R F u nless tra ns mitte d t o 
t he S p o ns or or D esi g nee electr o nicall y. T he In vesti gat or is res p o nsi ble f or verif yi n g 
t hat data e ntries are acc urate a n d c orrect b y p h ysicall y or electr o nicall y si g ni n g t he 
eC R F.  
•  T he In vesti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce dat a) t hat s u p p orts 
t he i nf or mati o n e ntere d i n t he eC R F.  
•  T he In vesti gat or m ust per mit st u d y -relate d m o nit ori n g, a u dits, I R B/I E C re vie w, a n d 
re g ulat or y a g e nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce data d oc u me nts.  
•  M o nit ori n g details descri bi n g strate g y (e .g ., ris k-b ase d i nitiati ves i n o perati o ns a n d 
q ualit y s uc h as Ris k Ma na ge me nt a n d Miti gati o n Strate gies a n d A nal ytical Ris k 
Base d M o nit ori n g), met h o ds, res p o nsi bilities a n d re q uire me nts, i ncl u di n g h a n dli n g of 
n o nc o m plia nce iss ues a n d m o nit ori n g tec h ni q ues (ce ntr al, re m ote, or o n -site 
m o nit ori n g) are pr o vi de d i n t he M o nit ori n g Pla n.  
•  T he S p o ns or or D esi g nee is res p o nsi ble f or t he dat a ma na ge m e nt of t his st u d y 
i ncl u di n g q ualit y c hec ki n g of t he data.  
•  St u d y M o nit ors will perf or m o n g oi n g s o urce data verificati o n at t he fre q u e ncies a n d 
S D V e xte nt as o utli ne d i n t he M o nit ori n g Pla n t o c o nfir m t hat data e ntere d i nt o t he 
eC R F b y a ut h orize d site pers o n nel are acc urate, c o m plete, a n d verifi a ble fr o m s o urce 
d oc u me nts; t hat t he safet y a n d ri g hts of patie nts are bei n g pr otect e d; a n d t h at t he 
st u d y is bei n g c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y 
ot her st u d y a gree me nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire m e nts.  
•  Rec or ds a n d d o c u me nts, i ncl u di n g si g ne d I C Fs, p ertai ni n g t o t he c o n d uct of t his 
st u d y are re q uire d t o be mai ntai ne d u n der t his part f or a peri o d of 2 years f oll o wi n g 
t he date a mar keti n g a p plicati o n is a p pr o ve d f or t he dr u g f or t he i n dicati o n f or w hic h 
it is bei n g i n vesti gate d; or, if n o a p plicati o n is t o be file d or if t he a p plicati o n is n ot 
a p pr o ve d f or s uc h i n dicati o n, u ntil 2 years after t h e i n vesti gati o n is disc o nti n ue d  a n d 


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FDA is notified. However, if required by local regulation that these documents should 
be retained for a longer period, then Retention of Documentation will abide by local 
regulation, no records will be destroyed without the written consent of the Sponsor, if 
applicable. It is the responsibility of the Sponsor to inform the investigator when 
these documents no longer need to be retained. 
A study-specific COVID-19 Assessment Plan will be utilized for any necessary modifications 
and/or mitigation to the data collection, monitoring or other associated activities during this 
study due to the COVID-19 pandemic. 
14.3. 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site.  
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
14.4. 
Audits and Inspections 
Authorized representatives of G1 Therapeutics, a regulatory authority, an IEC or IRB may visit 
the site to perform audits or inspections, including source data verification. The purpose of an 
audit or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, GCP guidelines of the ICH, and any 
applicable regulatory requirements. The Investigator should contact G1 Therapeutics 
immediately if contacted by a regulatory agency about an inspection. 


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15. 
PUBLICATION POLICY 
By signing the study protocol, the Investigator and his or her institution agree that the results of 
the study may be used by G1 Therapeutics 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. G1 Therapeutics reserves the right to request modification of any publication, 
presentation or use by the Investigator if such activity may jeopardize a patent application, an 
existing patent, or other proprietary rights. G1 Therapeutics shall determine order of authorship 
of any publication combining all clinical results of this trial. 


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Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 2 3  
1 7.  
A P P E N DI C E S  
1 7. 1.  
I nf or me d C o nse nt Pr ocess Rec o m me n d ati o ns 
•  T he In vesti gat or or his/ h er re prese nt ati ve will e x plai n t he nat ure of t h e st u d y t o t he 
patie nt a n d a ns wer all q u esti o ns re gar di n g t he st u d y.  
•  Patie nts m ust be i nf or me d t hat t h eir partici pati o n is v ol u ntar y. Patie nts or t heir le gall y 
a ut h orize d re pres e ntati ve will be re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat 
meets t he re q uir e me nts of 2 1 C F R 5 0, l ocal re g ul ati o ns, I C H g ui deli nes, Healt h 
I ns ura nce P orta bilit y a n d Acc o unta bilit y Act ( HI P A A) re q uire me nts, w here 
a p plica ble, a n d t h e I R B/I E C or st u d y ce nter.  
•  T he me dical r ec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o ns e nt was 
o btai ne d bef ore a n y st u d y relate d pr oce d ures  i n t he st u d y were p erf or me d  a n d t he 
date t he writte n c o ns e nt was o btai ne d. T he a ut h orize d pers o n o btai ni n g t he i nf or me d 
c o nse nt m ust als o si g n t he I C F.  
•  Patie nts m ust be re -c o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g t heir 
partici pati o n i n t he st u d y.  
•  A c o p y of t he I C F(s) m ust be pr o vi d e d t o t he pati e nt or t he patie nt’s le gall y 
a ut h orize d re pres e ntati ve.  
 
 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 2 4  
1 7. 2.  
Cli nic al L a b or at or y Tests  
•  T he  ti mi n g a n d la b orat or y tests detaile d i n Sc he d ule of Assess me nts ( Ta bl e  4  a n d 
Ta ble  5 ) will be perf or m e d b y a l ocal la b orat or y.  
•  Pr ot oc ol -s pecific re q uire me nts f or i ncl usi o n or e x cl usi o n of patie nts are d etaile d i n 
Secti o n  7  of t he pr ot oc ol.  
•  A d diti o nal tests ma y be perf or me d at a n y ti me d uri n g t he st u d y as deter mi ne d 
necessar y b y t he In v esti gat or or re q uire d b y l ocal re g ulati o ns  
T a ble  1 2 : 
Pr ot oc ol -s pecifie d S afet y L a b or at or y Assess m e nts 
L a b or at or y 
Assess me nt  
P ar a meters  
He m at ol o g y  
Platelet C o u nt  
He m o gl o bi n  
 
C o m plete Bl o o d C o u nt ( C B C) wit h Differe ntial ( % a n d/ or a bs ol ute val ues):  
ne utr o p hils, m o n oc ytes, l y m p h oc ytes  
Cli nic al 
C he mistr y  
Bl o o d Urea 
Nitr o ge n ( B U N) 
o r Urea  
Ser u m Creati ni ne  
Lactate 
De h y dr o ge nase  
Al b u mi n  
As partate 
A mi n otra nsferase 
( A S T) 
Ala ni ne 
A mi n otra nsferase 
( A L T) 
Al kali ne 
P h os p hatase  
T otal Bilir u bi n  
P otassi u m  
S o di u m  
Calci u m  
C hl ori de  
I n or ga nic 
P h os p h or o us  or 
P h os p hate  
T otal Pr otei n  
Gl uc ose  
( n o n-fasti n g) 
 
C o a g ul ati o n  
I nter nati o nal N or malize d Rati o  
(I N R) 
Acti vate d Partial T hr o m b o plasti n Ti me 
(a P T T) 
Uri n al ysis  
Se mi q ua ntitati ve di pstic k: s pecific gra vit y, p H, e val uati o n of gl uc ose, pr otei n, 
bilir u bi n, ket o nes, le u k oc ytes, a n d he m o gl o bi n  
Micr osc o pic e xa mi nati o n (i ncl u di n g R B C, W B C, a n d casts) will be perf or me d, if 
cli nicall y warra nte d  
Ot her Tests  
Ser u m or uri ne h u ma n c h ori o nic g o na d otr o pi n ( h C G) pre g na nc y test (f or w o me n 
of c hil d beari n g p ote ntial o nl y)  
ser u m F S H f or p ost me n o pa usal fe males  ( Scree ni n g o nl y) 
D P D testi n g –  ge netic testi n g or bl o o d uracil le vel ( Scree ni n g o nl y)  
 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 2 5  
T o g uara nte e t he relia bilit y of bl o o d uracil res ults, t he f oll o wi n g c o n diti o ns are rec o m me n d e d:  
•  use of t u bes wit h o ut se parati n g gel a n d wit h a ntic o a g ula nt t o carr y o ut t he sa m pli n g 
(restricti o n of sa m pli n g ti mes n ot ma n dat or y); 
•  ti me bet wee n sa m pli n g a n d ce ntrif u gati o n of 1 h 3 0 if t he sa m ple is st ore d at r o o m 
te m perat ur e a n d 4 h if it is place d at + 4° C; 
•  ce ntrif u gati o n prefera bl y at + 4° C t he n i m me diate freezi n g of t he o btai ne d plas ma;  
•  tra ns p ort m ust res pect t h e c ol d c hai n. 
Fail ure t o c o m pl y wit h t h ese c o n diti o ns m ust lea d t o a re p ort of n o n -c o m plia nce br o u g ht t o t he 
atte nti o n of t he cli nicia n as s o o n as p ossi ble s o t hat a ne w sa m ple ca n be s e nt t o t he la b orat or y 
q uic kl y.  
 
 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 2 6  
1 7. 3.  
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g  
1 7. 3. 1.  
Defi niti o n of A E  
A E Defi niti o n  
•  
A n A E is a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical st u d y patie nt, te m p orall y 
ass ociate d wit h t he use of st u d y i nter ve nti o n, w het her or n ot c o nsi dere d relate d t o t he st u d y 
i nter ve nti o n. 
•  
N O T E: A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), s y m pt o m, or disease ( ne w or e xacer bate d) te m p orall y ass ociate d wit h t he use 
of st u d y i nter ve nti o n.  
E ve nts Meeti n g  t he A E Defi niti o n  
•  
A n y a b n or mal la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) or ot her safet y 
assess me nts (e .g ., E C G, ra di ol o gical sca ns, vital si g ns meas ure me nts), i ncl u di n g t h ose t hat w orse n 
fr o m baseli ne, c o nsi dere d cli nicall y si g nifica nt a n d r e q uire cli nical i nter ve nti o n or f urt her 
i n vesti gati o n ( be y o n d or deri n g a re peat [c o nfir mat or y] test) i n t he me dical a n d scie ntific j u d g me nt 
of t he In vesti gat or (i .e., n ot relate d t o pr o gressi o n of u n derl yi n g disease) u nless t he y are ass ociate d 
wit h a n alre a d y re p orte d cli nical e ve nt, e .g . ele vate d li ver e nz y mes i n a patie nt wit h ja u n dice . 
•  
E xacer bati o n of a c hr o nic or i nter mitte nt pre -e xisti n g c o n diti o n i ncl u di n g eit her a n i ncrease i n 
fre q ue nc y a n d/ or i nte nsit y of t he c o n diti o n. 
•  
Ne w c o n diti o ns detecte d or di a g n ose d after st u d y i nter ve nti o n a d mi nistrati o n e ve n t h o u g h it ma y 
ha ve bee n prese nt bef ore t he start of t he st u d y.  
•  
Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y i nter ve nti o n or a 
c o nc o mita nt me dicati o n. O ver d ose per se will n ot be re p orte d as a n A E/ S A E u nless it is a n 
i nte nti o nal o ver d ose ta ke n wit h p ossi ble s uici dal/self-har mi n g i nte nt. S uc h o ver d oses s h o ul d be 
re p orte d re gar dless of se q uelae. 
E ve nts N O T  Meeti n g t he A E Defi niti o n  
•  
A n y cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs or ot her a b n or mal safet y assess me nts w hic h 
are ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d b y t he In vesti gat or t o be m ore se vere t ha n 
e x pecte d f or t he patie nt’s c o n diti o n.  
•  
T he disease/ dis or d er bei n g st u die d or e x pecte d pr o gressi o n, si g ns, or s y m pt o ms of t he 
disease/ dis or der bei n g st u die d, u nless m ore se vere t ha n e x pecte d f or t he patie nt’s c o n diti o n.  
•  
Me dical or s ur gical pr oce d ure (e .g ., e n d osc o p y, a p pe n dect o m y): t he c o n diti o n t hat lea ds t o t he 
pr oce d ure is t he A E.  
•  
Sit uati o ns i n w hic h a n u nt o war d me dical occ urre nce di d n ot occ ur (s ocial a n d/ or c o n ve nie nce 
a d missi o n t o a h os pital).  
•  
A ntici pate d da y -t o-da y fl uct uati o ns of pre -e xisti n g disease(s) or c o n diti o n(s) prese nt or detecte d at 
t he start of the st u d y t hat d o n ot w orse n.  


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 2 7  
1 7. 3. 2.  
Defi niti o n of S A E  
If a n e v e nt is n ot a n A E per defi niti o n a b o ve, t h e n it ca n n ot be a n S A E e v e n if seri o us c o n diti o ns 
are met (e.g ., h os pitalizati o n f or si g ns/s y m pt o ms of t he disease u n d er st u d y, deat h d ue t o 
pr o gressi o n of dis eas e).  
A S A E is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y d ose:  
1.  Res ults i n de at h  
2.  Is life-t hre ate ni n g 
T he ter m 'life -t hreate ni n g' i n t he defi niti o n of 'seri o us' refers t o a n e ve nt i n w hic h t he patie nt was at ris k 
of deat h at t he ti me of t he e ve nt. It d oes n ot refer t o a n e ve nt, w hic h h y p ot heticall y mi g ht ha ve ca use d 
deat h, if it were m ore se vere.  
3.  Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n  
I n ge neral, h os pitalizati o n si g nifies t hat t he patie nt has bee n detai ne d ( us uall y i n v ol vi n g at least a n 
o ver ni g ht sta y) at t he h os pital or e mer ge nc y war d f or o bser vati o n a n d/ or treat me nt t hat w o ul d n ot ha ve 
bee n a p pr o priate i n t he p h ysicia n’s office or o ut patie nt setti n g. C o m plicati o ns t hat occ ur d uri n g 
h os pitalizati o n  are A Es. If a c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y ot her seri o us criteria, 
t he e ve nt is seri o us. 
H os pitalizati o n f or electi ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot w orse n fr o m baseli ne is 
n ot c o nsi dere d a n A E.  
4.  Res ults i n per siste nt dis a bilit y/i nc a p acit y 
•  
T he ter m disa bilit y mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life 
f u ncti o ns. 
•  
T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical si g nifica nce 
s uc h as u nc o m plicate d hea dac he, na usea, v o miti n g, diarr hea, i nfl ue nza, a n d acci de ntal tra u ma 
(e.g ., s prai ne d a n kle) w hic h ma y i nterfere wit h or pre ve nt e ver y da y life f u ncti o ns b ut d o n ot 
c o nstit ute a s u bsta ntial disr u pti o n.  
5.  Is a c o n ge nit al a n o m al y/ birt h defect 
6.  Ot her sit u ati o ns : 
•  
Me dical or scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E re p orti n g is 
a p pr o priate i n ot her sit uati o ns s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life -
t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he patie nt or ma y re q uire 
me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d i n t he a b o ve 
defi niti o n. T hese e ve nts s h o ul d us uall y be c o nsi dere d seri o us.  
•  
E xa m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca ncers, i n te nsi ve treat me nt i n a n 
e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d yscrasias or c o n v ulsi o ns t hat d o 
n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g de pe n de nc y or dr u g a b use.  
 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 2 8  
1 7. 3. 3.  
Rec or di n g a n d F oll o w -U p of A E a n d/ or S A E  
A E a n d S A E Rec or di n g  
•  
W he n a n A E/ S A E occ urs, it is t he res p o nsi bilit y of t he In vesti gat or t o re vie w all d oc u me ntati o n 
(e.g ., h os pital pr o gress n otes, la b orat or y re p orts, a n d dia g n ostics re p orts) relate d t o t he e ve nt. 
•  
T he In vesti gat or will t he n rec or d all rele va nt A E/ S A E i nf or mati o n i n t he eC R F.  
•  
It is n ot acce pta ble f or t he In vesti gat or t o se n d p h ot oc o pies of t he patie nt’s me dical rec or ds t o G 1 
T hera pe utics ( or desi g nee) i n lie u of c o m pleti o n of t he A E/ S A E eC R F pa ge.  
•  
T here ma y be i nsta nces w he n c o pies of me dical rec or ds f or  certai n cases are re q ueste d b y 
G 1  T hera pe utics ( or desi g nee). I n t his case, all patie nt i de ntifiers, wit h t he e xce pti o n of t he patie nt 
n u m ber, will be re dacte d o n t he c o pies of t he me dical rec or ds bef ore s u b missi o n t o G 1 
T hera pe utics ( or desi g nee).  
•  
T he In vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, s y m pt o ms, a n d/ or 
ot her cli nical i nf or mati o n. W he ne ver p ossi ble, t he dia g n osis ( n ot t he i n di vi d ual si g ns/s y m pt o ms) 
will be d oc u me nte d as t he A E/ S A E.  
•  
A ll S A Es s h o ul d be re p orte d t o G 1 T hera pe utics  P V G ( or desi g nee) wit hi n 2 4 h o urs of n otificati o n 
o n a S A E F or m  i n t he e C R F. A n y rele va nt s o urce data relate d t o t he S A E t hat ca n n ot be e ntere d i n 
t he E D C s h o ul d be e maile d or fa xe d t o G 1 T hera pe utics P V G ( or desi g nee): 
G 1 T her a pe utics P h ar m ac o vi gil a nce  
E mail: safet yre p orti n g @ g 1t hera pe utics.c o m 
Fa x: + 1 -9 8 4 -2 8 5 -7 1 3 1  
Assess me nt of I nte nsit y 
I nte nsit y will be ass esse d usi n g N CI-C T C A E v 5. 0 criteria, as f oll o ws:  
•  
Gra de 1: Mil d; as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns o nl y; 
i nter ve nti o n n ot i n dicate d. 
•  
Gra de 2: M o derate; mi ni mal, l ocal or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g a ge -a p pr o priate 
i nstr u me ntal acti vities of dail y li vi n g. 
•  
Gra de 3: Se vere or me dicall y si g nifica nt b ut n ot i m me diatel y life -t hreate ni n g; h os pitalizati o n or 
pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g self -care acti vities of dail y li vi n g. 
•  
Gra de 4: Life -t hreate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d. 
•  
Gra de 5: Deat h relate d t o A E.  


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 2 9  
A E a n d S A E Rec or di n g  
Assess me nt of C a us alit y  
•  
T he In vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y i nter ve nti o n a n d eac h 
occ urre nce of eac h A E/ S A E.  
•  
A “reas o na ble p ossi bilit y” of a relati o ns hi p c o n ve ys t hat t here are facts, e vi de nce, a n d/ or 
ar g u me nts t o s u g gest a ca usal relati o ns hi p, rat her t ha n a relati o ns hi p ca n n ot be r ule d o ut.  
•  
T he In vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p.  
•  
Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k fact ors, as 
well as t he te m p oral relati o ns hi p of t he e ve nt t o st u d y i nter ve nti o n a d mi nistrati o n will be 
c o nsi dere d a n d i n vesti gate d.  
•  
T he In vesti gat or will als o c o ns ult t he I B a n d/ or Pr o d uct I nf or mati o n, f or mar kete d pr o d ucts, i n 
his/ her assess me nt.  
•  
F or eac h A E/ S A E, t he In vesti gat or m ust  d oc u me nt i n t he me dical n otes t hat he/s he has re vie we d 
t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usalit y. 
•  
T here ma y be sit uati o ns i n w hic h a n S A E has occ urre d a n d t he In vesti gat or has mi ni mal 
i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o G 1 T hera peutics  P V G  ( or desi g nee). H o we ver, it is 
ver y i m p orta nt t hat t he In vesti gat or al wa ys ma ke a n assess me nt of ca usalit y f or e ver y e ve nt bef ore 
t he i nitial tra ns missi o n of t he S A E data t o G 1 T hera pe utics P V G  ( or desi g nee). 
•  
T he In vesti gat or ma y c ha n ge his/ her o p i ni o n of ca usalit y i n li g ht of f oll o w-u p i nf or mati o n a n d 
se n d a S A E f oll o w-u p re p ort wit h t he u p date d ca usalit y assess me nt.  
•  
T he ca usalit y assess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y re p orti n g 
re q uire me nts. 
F oll o w -u p of A Es a n d S A Es  
•  
T he In vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal meas ure me nts 
a n d/ or e val uati o ns as me dicall y i n dicate d or as re q ueste d b y G 1 T hera pe utics  P V G  ( or desi g nee) t o 
el uci date t he nat ure a n d/ or ca usalit y of t he A E or S A E as f u ll y as p ossi ble. T his ma y i ncl u de 
a d diti o nal la b orat or y tests or i n vesti gati o ns, hist o pat h ol o gical e xa mi nati o ns, or c o ns ultati o n wit h 
ot her healt h care pr ofessi o nals.  
•  
Ne w or u p date d i nf or mati o n will be rec or de d i n t he ori gi nall y c o m plete d eC R F.  
•  
T he In vesti gat or will s u b mit a n y  ne w or  u p date d S A E data t o G 1 T hera pe utics  P V G  ( or desi g nee) 
wit hi n 2 4 h o urs of recei pt of t he i nf or mati o n : 
G 1 T her a pe utics P h ar m ac o vi gil a nce  
E m ail: s afet yre p orti n g @ g 1t her a pe utics.c o m 
F a x: + 1 -9 8 4 -2 8 5 -7 1 3 1  
 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 3 0  
1 7. 3. 4.  
Re p orti n g of S A Es  
S A E Re p orti n g t o G 1 T her a pe utics ( or desi g nee) vi a a n Electr o nic D at a C ollecti o n T o ol  
•  
T he pri mar y mec ha nis m f or re p orti n g a n S A E t o G 1 T hera pe utics ( or desi g nee) will be t he 
electr o nic data c ollecti o n t o ol ( E D C). 
•  
If t he electr o nic s yste m is u na vaila ble, t he n t he site will use t he pa per S A E Re p ort F or m  i n or der t o 
re p ort t he e ve nt wit hi n 2 4 h o urs via e mail or fa x  (see bel o w f or S A E re p orti n g c o ntact 
i nf or mati o n). 
•  
T he site will e nter t he S A E data i nt o t he electr o nic s yste m as s o o n as it bec o mes a vaila ble.  
•  
After t he st u d y is c o m plete d at a gi ve n site, t he electr o nic data c ollecti o n t o ol will be ta ke n off -li ne 
t o pre ve nt t he e ntr y of ne w data or c ha n ges t o e xisti n g data. 
•  
If a site recei ves a re p ort of a ne w S A E fr o m a st u d y patie nt or recei ves u p date d data o n a 
pre vi o usl y re p orte d S A E after t he electr o nic data c ollecti o n t o ol has bee n ta ke n off -li ne, t he n t he 
site s h o ul d re p ort t his i nf or mati o n o n a pa per S A E Re p ort f or m or n otif y  the M e dical M o nit or b y 
tele p h o ne. 
•  
C o ntact f or S A E re p orti n g : 
G 1 T her a pe utics P h ar m ac o vi gil a nce  
E m ail: s afet yre p orti n g @ g 1t her a pe utics.c o m 
F a x: + 1 -9 8 4 -2 8 5 -7 1 3 1   
 
 
 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 3 1  
1 7. 4.  
C o ntr ace pti ve G ui d a nce a n d C ollecti o n of Pre g n a nc y I nf or m ati o n  
W O C B P Defi niti o n  
W o m a n of C hil d be ari n g P ote nti al  
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc h e a n d u ntil bec o mi n g p ost -me n o pa usal u nless 
per ma ne ntl y sterile (see bel o w).  
If fertilit y is u nclear (e.g ., a me n orr hea i n a d oles ce nts or at hletes), a d diti o nal e val uati o n s h o ul d be 
c o nsi dere d.  
W o me n i n t he f oll o wi n g c ate g ori es are n ot c o nsi dere d W o m a n of C hil d be ari n g P ote nti al  
1.  Pre me narc hal  
N ote: D oc u me ntati o n ca n c o me fr o m t he site pers o n nel’s re vie w of t he pati e nt’s me dical 
rec or ds, me di cal e x a mi nati o n, or me dical hist or y i nter vie w.  
2.  Pre me n o pa usal f e male wit h 1 of t he f oll o wi n g acce pta ble s ur gical sterilizati o n 
tec h ni q ues: c o m plete or partial h ysterect o m y, bilateral t u bal li gati o n or occl usi o n wit h 
s ur ger y at least 6 m o nt hs pri or t o d osi n g, or bilateral o o p h orect om y wit h s ur ger y at least 
2 m o nt hs pri or t o d osi n g.  
3.  P ost me n o pa usal fe male: defi ne d as s p o nta n e o us a me n orr hea f or >  1 2 m o nt hs pri or t o 
scree ni n g wit h o ut alter n ati ve ca use (e.g ., i m pla nta ble c o ntrace pti ve, si de effect of 
me dicati o n, etc .) a n d a ser u m f ollicle sti m ulati n g h or m o ne (F S H ) wit hi n t he la b orat or y’s 
refere nce ra n ge f or p ost me n o pa usal fe m ales. 
•  W o me n ta ki n g h or m o ne re place me nt t hera p y ( H R T ) m ust disc o nti n ue H R T at least 
2 -4 wee ks pri or t o scree ni n g f or acc urate assess me nt of F S H (t h o u g h e xact i nter val 
w ill de pe n d o n t he t y pe a n d d osa ge of H R T a n d s h o ul d be deter mi ne d b y t h e 
pri nci pal In vesti gat or).  
C o ntr ace pti o n G ui d a nce  
C o ntrace pti ve use b y me n or w o me n s h o ul d be c o nsiste nt wit h l ocal re g ulati o ns re gar di n g t he 
met h o ds of c o ntrace pti o n f or t h ose partici p ati n g i n cli nical st u dies.  
•  Male patie nts: Males m ust be s ur gicall y sterile pri or t o scree ni n g wit h a p pr o priate 
d oc u me ntati o n (a bse n ce of s per m i n ejac ul ate 6 m o nt hs after pr o ce d ure) or ha ve a 
fe male part ner(s) w h o is eit her p ost me n o pa usal, s ur gicall y sterile, or usi n g 2 f or ms of 
c o nc urre nt c o ntrace pti o n as defi ne d b el o w. I n a d diti o n, males m ust als o refrai n fr o m 
s per m d o nati o n d uri n g t he st u d y a n d utilize a barri er met h o d wit h i nterc o urse d uri n g 
a n d f or 6  m o nt hs f oll o wi n g disc o nti n uati o n of c he m ot hera p y. 
•  Fe male p atie nts: All fe males of c hil d beari n g p ote ntial m ust ha ve a ne gati v e ser u m 
beta h u ma n c h ori o nic g o na d otr o pi n ( β -h C G) test res ult at scree ni n g, a n d ne gati ve 
ser u m or uri ne pre g na n c y test res ults a p pr o xi matel y e ver y m o nt h at t he st art of a 
c ycle d uri n g I n d u cti o n a n d M ai nte na nce a n d at t h e p ost -treat me nt visit.  


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 3 2  
•  Fe males m ust be eit her p ost me n o pa usal, s ur gicall y sterile, or a gree t o use 2 
c o nc urre nt f or ms of c o ntrace pti o n d uri n g t he st u d y a n d f or 6 m o nt hs  f oll o wi n g last 
d ose of c he m ot hera p y . A cce pta bl e f or ms of c o ntrace pti o n i ncl u de:  
− Esta blis he d use of oral, i njecte d or i m pla nte d h or m o nal met h o ds of c o ntrace pti o n 
(sta ble d ose at least 3 m o nt hs pri or t o d osi n g) 
− I ntr a uteri ne d e vice or i ntra uteri ne s yste m 
− Barrier met h o ds of c o ntr ace pti o n: c o n d o m or occ l usi ve ca p ( dia p hra g m or 
cer vical/ va ult ca ps) wit h s per mici dal f oa m/ gel/fil m/crea m/s u p p osit or y. Barrier 
met h o ds al o ne ( wit h o ut s per mici de) are n ot acce pta ble met h o ds. Li ke wise, 
s per mici de al o ne is n ot a n acce pta ble met h o d 
− Male sterilizati o n pri or t o scree n i n g wit h t he a p pr o priate p ost-vasect o m y 
d oc u me ntati o n (a bse n ce of s per m i n t he ejac ulate 6 m o nt hs after pr oce d ure). F or 
fe male patie nts o n t he st u d y, t he vasect o mize d m ale part ner s h o ul d be t he s ole 
part ner f or t hat patie nt  
− Tr ue a bsti ne nce w he n t his is i n li ne wit h t he preferre d a n d us ual lifest yle of t he 
patie nt. Peri o dic a bsti ne n ce (e .g ., cale n dar, o v ulati o n, s y m pt ot her mal, p ost-
o v ulati o n met h o ds) a n d wit h dra wal are n ot acce pta ble met h o ds of c o ntrace pti o n  
•  F or patie nts w h o are e xcl usi vel y i n sa me -se x rel ati o ns hi ps, c o ntrace pti ve 
re q uire me nts d o n ot a p pl y. If a patie nt w h o is i n a sa me-se x relati o ns hi p at t he ti me of 
si g ni n g t he I C F b ec o mes e n ga ge d i n a heter os e x ual relati o ns hi p, t he y m ust a gree t o 
use c o ntrace pti o n as des cri be d pre vi o usl y. If a pati e nt w h o is a bsti ne nt at t he ti me of 
si g ni n g t he I C F b ec o mes se x uall y acti ve, t he y m ust a gree t o use c o ntrace pti o n as 
descri be d a b o ve.  
C ollecti o n of Pre g n a nc y I nf or m ati o n  
M ale p artici p a nts wit h p art ners w h o bec o me pre g n a nt  
•  T he In vesti gat or or d esi g nee will atte m pt t o c ollect pre g na nc y i nf or mati o n o n a n y 
male patie nt’s fe m ale part ner w h o bec o m es pre g n a nt w hile t he male patie nt is i n t his 
st u d y. T his a p plies o nl y t o males w h o recei ve st u d y i nter ve nti o n.  
•  After o btai ni n g t he necessar y si g ne d i nf or me d c o nse nt fr o m t he pr e g n a nt fe male 
part ner directl y, t he In v esti gat or or desi g nee will rec or d pre g na n c y i nf or mati o n o n t he 
Pre g na nc y Re p orti n g a n d O utc o me F or m a n d s u b mitte d t o G 1 T hera pe utics P V G or 
desi g nee wit hi n 2 4 h o urs of lear ni n g of t he part ner’s pre g n a nc y. T h e fe mal e part ner 
will als o be f oll o we d t o deter mi ne t he o utc o me of t he pre g na n c y. I nf or mati o n o n t he 
stat us of t he m ot her a n d c hil d will be f or war de d t o G 1 T hera p e utics P V G or desi g nee . 
Ge nerall y, t he f oll o w -u p will be n o l o n ger t ha n 1 2  wee ks f oll o wi n g t he esti mate d 
deli ver y date. A n y t er mi nati o n of t he pre g n a nc y will be re p orte d re gar dless of fetal 
stat us ( prese n ce or a bse n ce of a n o m alies) or i n dicati o n f or t he pr oce d ure.  


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 3 3  
Fe m ale P atie nts w h o bec o me  pre g n a nt  
•  T he In vesti gat or or d esi g nee will c ollect pr e g na nc y i nf or mati o n o n a n y fe m ale patie nt 
w h o bec o mes pre g na nt w hile partici pati n g i n t his st u d y. T he i nitial I nf or mati o n will 
be rec or de d o n t he Pr e g n a nc y Re p orti n g a n d O ut c o me F or m a n d s u b mitte d t o G 1  
P V G or desi g nee wit hi n 2 4 h o urs of lear ni n g of a patie nt’s pre g na n c y wit hi n 2 4 h o urs 
of lear ni n g of a patie nt’s pre g na nc y.  
•  T he patie nt will be f oll o we d t o deter mi ne t he o ut c o me of t he pre g na n c y. T he 
In v esti gat or or desi g ne e will c ollect f oll o w -u p i nf or ma ti o n o n t he patie nt a n d t he 
ne o nate a n d t h e i nf or mati o n will be f or war de d t o G 1 T hera p e utics  P V G or desi g nee . 
Ge nerall y, f oll o w -u p will n ot be re q uire d f or l o n ger t ha n 1 2  wee ks be y o n d t he 
esti mate d deli ver y date. A n y ter mi nati o n of pre g n a nc y will be re p orte d, re gar dless of 
fetal stat us ( pres e nce or a bse nce of a n o malies) or i n dicati o n f or t he pr oce d ure. 
•  W hile pre g na n c y itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na n c y 
c o m plicati o n or electi ve t er mi nati o n of a pre g na nc y f or me dical r eas o ns will be 
re porte d as a n A E or S A E. A s p o nta ne o us a b orti o n ( occ urri n g at <  2 2 wee ks 
gestati o nal a ge) or still birt h ( occ urri n g at >  2 2 wee ks gestati o nal a ge) is al wa ys 
c o nsi dere d t o be a n S A E a n d will be re p ort e d as s uc h. A n y p ost -st u d y pre g na nc y 
relate d S A E c o nsi dere d reas o na bl y r elate d t o t he st u d y i nter ve nti o n b y t he 
In v esti gat or will be re p orte d t o G 1 T hera p e utics P V G or desi g ne e . W hile t he 
In v esti gat or is n ot o bli gate d t o acti vel y see k t his i nf or mati o n i n f or mer st u d y patie nts, 
he or s he ma y lear n of a n S A E t hr o u g h  s p o nta ne o us re p orti n g. 
•  A n y fe male p atie nt w h o bec o mes pre g na nt w hile partici pati n g i n t he st u d y will 
disc o nti n ue st u d y i nter ve nti o n.  
 
 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
 
134 
17.5. 
FOLFOXIRI Components Package Inserts 
Links to US package inserts in this section are provided for reference only. Please refer to the 
inserts with the product(s) available at your individual center for the most current and region-
specific information. 
17.5.1. 
Fluorouracil 
US package insert: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012209s040lbl.pdf 
17.5.2. 
Leucovorin 
US package insert: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/040347s010lbl.pdf 
17.5.3. 
Oxaliplatin 
US package insert: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021492s011,021759s009lbl.pdf 
17.5.4. 
Irinotecan  
US package insert: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020571s048lbl.pdf 
 
 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
 
135 
17.6. 
Bevacizumab Package Insert 
The following link to the US package insert is provided for reference only. Please refer to the 
insert with the product available at your individual center for the most current and region-
specific information. 
US package insert: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125085s319lbl.pdf 
 
 


Pr ot oc ol  
 
G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
Versi o n 6 . 1 _1 5 Dece m ber  2 0 2 2  
 
 
1 3 6  
1 7. 7.  
Defi niti o ns of T u m or Res p o nse a n d Dise ase Pr o gressi o n ( per 
R E CI S T v 1. 1)  
T he deter mi nati o n of t u m or res p o nse a n d pr o gressi o n will be base d o n t he R E CI S T  v 1. 1 criteria 
(Eise n ha uer , 2 0 0 9 ). T u m or lesi o ns will be cate g orize d as f oll o ws:  
Me as ur a ble lesi o ns : t u m or lesi o ns wit h a l o n gest dia meter ( meas ure d i n at least 1 di me nsi o n) 
wit h a mi ni m u m size as f oll o ws:  
•  1 0 m m b y C T or M RI ( wit h a sca n slice t hic k ness of n o great er t h a n 5 m m)  
•  Meas ura ble l y m p h n o des m ust be ≥ 1 5 m m o n t he s h ort a xis b y C T or M RI ( wit h a 
sca n slice t hic k ness of n o greater t ha n 5 m m); o nl y t he s h ort a xis is t o be meas ure d at 
baseli ne a n d f oll o w -u p.   
•  L ytic b o ne lesi o ns or mi xe d l ytic -blastic lesi o ns wit h a  s oft tiss ue c o m p o ne nt meeti n g 
t he defi niti o n of meas ur a bilit y a b o ve ca n be c o nsi dere d meas ura ble l esi o ns.  
•  C ystic lesi o ns re prese nti n g c ystic metastases t hat meet t he defi niti o n of meas ura bilit y 
descri be d a b o ve ca n be c o nsi dere d meas ura ble lesi o ns. If pre se nt, n o n-c ystic lesi o ns 
s h o ul d be selecte d as tar g et lesi o ns f or t his st u d y. 
•  A t u m or lesi o n t hat has bee n pre vi o usl y irra diate d ma y be c o nsi dere d meas ura ble if 
u ne q ui v ocal gr o wt h of t h e lesi o n has bee n d e m o nstrate d.  
T ar get lesi o ns : At baseli ne, u p t o 5 meas ura bl e t u m or lesi o ns/l y m p h n o des ( wit h a ma xi m u m of 
2 lesi o ns per or ga n) s h o ul d be i de ntifie d as tar g et lesi o ns. Lesi o ns wit h t he l o n gest dia meter, t hat 
are re pres e ntati ve of all i n v ol ve d or ga ns, a n d f or w hic h re pr o d uci ble re p eate d meas ure m e nts ca n 
be o btai ne d s h o ul d be sel ecte d as t he t ar get lesi o ns.  Mali g na nt l y m p h n o de is c o nsi dere d a n 
or ga n i n t his st u d y, t heref ore o nl y 2 mali g na nt l y m p h n o des (re g ar dless of l ocati o n) ma y be 
selecte d as t ar get lesi o ns a n d all ot hers s h o ul d be e ntere d as n o ntar get les i o ns. 
N o n -me as ur a ble lesi o ns: t u m or lesi o ns wit h a l o n gest dia meter < 1 0 m m, l y m p h n o des wit h 
≥ 1 0 t o < 1 5 m m s h ort a xis, or n o n -meas ura ble lesi o ns s uc h as le pt o me ni n geal disease, ascites, 
ple ural or pericar dial eff usi o n, i nfla m mat or y breast disease, l y m p ha n gitic i n v ol ve me nt of s ki n or 
l u n g, or a b d o mi nal masses/a b d o mi nal or ga n o me gal y i de ntifie d b y p hysical e xa m t hat is n ot 
meas ura ble b y C T sca n or M RI.  
N o nt ar get lesi o ns : All ot her lesi o ns ( or sites of disease) i de ntifi e d at baseli ne s h o ul d be 
i de ntifie d as n o ntar get lesi o ns a n d rec or de d i n t he e C R F. Meas ure me nts of t hese lesi o ns are n ot 
re q uire d, b ut t he prese n ce, a bse nce, or u n e q ui v ocal pr o gressi o n of eac h n o ntar get lesi o n s h o ul d 
be rec or de d i n t he e C R F at eac h f oll o w u p ti me p oi nt. M ulti ple n o ntar get lesi o ns i n t he sa me 
or ga n ma y be n ote d as a si n gle ite m o n t he e C R F.  
E v al u ati o n of T ar get Lesi o ns  
T he defi niti o ns f or t u m or res p o nse f or t he tar g et lesi o n per R E CI S T v 1. 1 are as f oll o ws:  
C o m plete Res p o nse : Disa p peara nce of all tar g et lesi o ns. A n y pat h ol o gical l y m p h n o des ( w het her 
tar get or n o n-tar get) m ust ha ve re d u cti o n i n s h ort a xis t o < 1 0 m m ( <  1 c m).  
Partial Res p o nse : At least a 3 0 % decreas e i n t he s u m of t he dia meters of t ar get lesi o ns, ta ki n g as 
refere nce t he bas eli ne s u m dia meters. 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
 
137 
Progressive Disease: At least a 20% increase in the sum of the diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm (0.5 cm). (Note: the appearance of one or more new lesions is also 
considered progression). 
Stable Disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
Evaluation of Non-Target Lesions 
Complete Response: Disappearance of all non-target lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological in size (< 10 mm [< 1 cm] short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease: Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. ‘Unequivocal progression’ represents a substantial increase in overall 
tumor burden such that treatment should be discontinued even in the setting of stable disease 
(SD) or PR in the target disease. Although a clear progression of “non-target” lesions only is 
rare, the opinion of the treating physician should prevail in such circumstances. 
Appearance of New Lesions 
The appearance of new lesion(s) is considered PD according to RECIST v1.1.  
Timepoint Response 
Patients with Measurable Disease (i.e., Target ± Non-Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-CR/Non-PD/NE 
No 
PR 
SD 
Non-CR/Non-PD/NE 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PDa 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response; NE=not evaluable; PD: progressive disease; PR=partial response; SD=stable disease. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort should 
be made to document the objective progression even after discontinuation of treatment. 
a Unequivocal progression in non-target lesions may be accepted as disease progression. 
 


Protocol 
 
G1T28-207_PRESERVE 1 
Version 6.1_15 December 2022 
 
 
138 
Patients with Evaluable or Non-Measurable Disease Only (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR=complete response; NE=not evaluable; PD: progressive disease; SD=stable disease. 
a Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised. 


C o nfi de ntial  
Pa ge 1  of 2  
 
Cli nic al St u d y Pr ot oc ol G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
A P h ase 3 R a n d o mize d, D o u ble -bli n d Tri al of Tril acicli b vers us Pl ace b o i n P atie nts R ecei vi n g 
F O L F O XI RI/ Be v aciz u m a b f or Met ast atic C ol orect al C a ncer  
 
S u m m ar y of C h a n ges  
A me n d me nt Versi o n 6 .1   
Date : 1 5  Dece m ber  2 0 2 2  
R ati o n ale of 
C h a n ges:  
Herei n is a s u m mar y of t he c ha n ges ma de t o A me n d me nt Versi o n 5 .1  of t he st u d y date d 2 1  N o ve m ber  
2 0 2 2  a n d reflecte d i n ame n d me nt versi o n 6 .1  date d 1 5  Dece m ber  2 0 2 2 .  C ha n ges are clearl y 
i de ntifie d i n t he trac k c h a n ges versi o n of t he a me n d me nt. Mi n or a d mi nistrati ve c ha n ges are n ot 
descri be d bel o w.  T his a me n d me nt is c o nsi dere d a n o n -s u bsta ntial a me n d me nt.  
 
C ha n ge s t o k e y sec o n dar y o bjecti ve a n d e n d p oi nt : 
1.  S y n o psis : T he ke y sec o n dar y o bjecti ve of pr o gressi o n free s ur vi val ( P F S) was delete d 
beca use t his o bjecti ve is n o l o n ger c o nsi dere d a ke y sec o n dar y o bjecti ve f or t his st u d y.   
2.  Secti o n 5 : P F S was re m o ve d as a ke y sec o n dar y o bjecti ve/e n d p oi nt a n d was a d d e d as a  
sec o n dar y objecti ve  a n d e n d p oi nt t o e val uate a nti -t u m or acti vit y.   
3.  Secti o n 5. 1:  T he rati o nale f or t he P F S as a n a nti -t u m or efficac y e n d p oi nt i n t he st u d y was 
delete d si nce P F S is n o l o n ger a ke y sec o n dar y e n d p oi nt  i n t he st u d y. 
4.  Secti o n 1 2 : P F S was delete d i n e ver y me nti o n as a n o bjecti ve  a n d e n d p oi nt si nce t his is n o 
l o n ger c o nsi dere d a ke y sec o n dar y e n d p oi nt a n d it was clarifie d t hat O S is t he o nl y ke y 
sec o n dar y e n d p oi nt i n t he st u d y. 
 
C ha n ges t o t he sa m ple size deter mi nati o n a n d ti mi n g of pla n ne d a nal yses : 
5.  S y n o psis : P F S was delete d fr o m t he sa m ple size j ustificati o n as it is n o l o n ger a ke y 
sec o n dar y o bjecti ve.  
6.  S y n o psis : Ass u m pti o ns f or t he n u m ber of P F S e ve nts were delete d as P F S is n o l o n ger a ke y 
sec o n dar y e n d p oi nt.  T he ti mi n g of t he fi nal data b ase l oc k f or O S a nal ysis was a d de d t o t he 
S y n o psis.  
7.  Secti o n 1 2. 1 : Ass u m pti o ns ar o u n d t he accr ual of P F S e ve nts were delete d as P F S is n o 
l o n ger a ke y sec o n dar y e n d p oi nt.  W or di n g ar o u n d t he ass u m pti o ns f or O S e ve nts were 
u p date d t o reflect t hat O S is t he o nl y ke y sec o n dar y e n d p oi nt.    
8.  Secti o n 1 2. 3. 2:  O S was re m o ve d as a p ote ntial a nal ysis t o occ ur at t he ti me of t he sec o n d 
pla n ne d a nal ysis.  T he sec o n d a nal ysis will n o w be f or P F S a n d occ ur ar o u n d t he ti me t hat is 
3 5 m o nt hs p ost first ra n d o mizati o n.   
9.  S ecti o n 1 2. 3. 3:  T he t hir d a nal ysis was u p date d t o re m o ve “ o pti o nal ,” a n d te xt was a d de d t o 
s pecif y t hat t he fi nal data b ase l oc k f or t he O S a nal ysis will occ ur “at t he ti me w he n 1 5 7 
deat h e v e nts are o bser ve d or at 5 2 m o nt hs after t he date of first ra n d o miza ti o n, w hic he v er 
c o mes first. ”  P F S a nal ysis at t he ti me of t he fi nal st u d y data base l oc k was a d de d.    
 
C ha n ges t o t he statistical a nal ysis met h o d f or pri mar y a n d sec o n dar y e n d p oi nts : 
1 0.  S y n o psis : P F S  was delete d  fr o m t he testi n g strate g y a n d a nal ysis secti o ns  si nce it is n o 
l o n ger a ke y sec o n dar y e n d p oi nt.  I nstea d, O S will be  t he o nl y ke y sec o n dar y e n d p oi nt. 
1 1.  S y n o psis : The a n al ysis secti o n was u p date d wit h t he a d diti o n of t he f oll o wi n g te xt t o reflect 
t he ti mi n g of t he a nal ysis as f oll o ws: “ At t he ti me w he n 1 5 7 deat h e ve nts are o bser ve d or at 
5 2 m o nt hs after t he date of first ra n d o mizati o n, w hic he ver c o mes first, t he st u d y will be 
c o ncl u de d, a n d t he fi nal st u d y data b ase will be l oc ke d t o perf or m t he O S a nal ysis.”  
1 2.  Secti o n 1 2. 4. 4. 3: P F S, t he defi niti o n of P F S a n d  t he met h o d of deter mi ni n g P F S were delete d 
as P F S was re m o ve d as a ke y sec o n dar y e n d p oi nt.  
1 3.  Secti o n 1 2. 4. 4. 3. 1:  T his e ntire secti o n, ' Ti mi n g f or P F S a n d O S a nal y sis’ w as delete d , as t h e 
ti mi n g of t he fi nal O S a nal ysis is descri be d i n ot her secti o ns.  
1 4.  Sect i o n 1 2. 4. 4. 3. 2.:  L a n g ua ge re gar di n g t he hierarc hical testi n g strate g y f or P F S a n d O S 
was d elete d as it is n o l o n ger a p plica ble wit h t he re m o val of P F S as a ke y sec o n dar y 
e n d p oi nt a n d O S as t he o nl y ke y sec o n dar y e n d p oi nt.  


S u m mar y of C ha n ges  
Cli nical Pr ot oc ol G 1 T 2 8 -2 0 7 _ P R E S E R V E 1  
C O N FI D E N TI A L  
Pa ge 2  of 2  
 
1 5.  Secti o n 1 2. 4. 4. 6:  Secti o n was a d de d t o reflect P F S as a sec o n dar y e n d p oi nt.  A d de d t o t his 
secti o n were t he defi niti o n of P F S, t he ti mi n g of t he t w o P F S a nal yses, descri pti o n of t he 
Ka pla n -Meier pl ots a n d ass ociate d calc ulati o ns, a n d e val uati o n of t he tre at me nt effect.   
 

SAP_001.pdf: 
Oﬃcial Title: 
PRESERVE 1: A Phase 3 Randomized, Double-blind Trial of Trilaciclib versus 
Placebo in PaƟents Receiving FOLFOXIRI/Bevacizumab for MetastaƟc Colorectal 
Cancer 
NCT Number: 
 
NCT04607668 
Document Date: 
09-Jan-2023 


 
1 
  
                              
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
PRESERVE 1: A Phase 3 Randomized, Double-blind 
Trial of Trilaciclib versus Placebo in Patients 
Receiving FOLFOXIRI/Bevacizumab for Metastatic 
Colorectal Cancer 
Protocol Version 
6.0 
Protocol Number: 
G1T28-207 
Compound: 
Trilaciclib for Injection, 300 mg/vial 
Study Phase: 
Phase 3 
Study Name: 
PRESERVE 1 
Sponsor: 
G1 Therapeutics, Inc. 
Legal Registered Address: 
700 Park Offices Dr. Suite 200 
PO Box 110341  
Research Triangle Park, NC 27709 
Regulatory Agency Identifier 
Numbers: 
IND: 119254 
EudraCT: 2019-003826-25 
Statistical Analysis Plan 
Version: 
V 3.0 
Document Completion: 
19 Dec 2022 
Approval Date: 
09 Jan 2023 
 
 
 


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Statistical Analysis Plan for Protocol G1T28-207 
Version 3.0   
 
 
 
 
G1 Therapeutics 
3 
CONFIDENTIAL 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................1 
1. 
INTRODUCTION ......................................................................................................11 
1.1. 
Study Design ...............................................................................................................11 
1.2. 
Study Objectives .........................................................................................................13 
1.3. 
Sample Size Consideration .........................................................................................13 
2. 
THE NUMBER OF PLANNED ANALYSES ...........................................................16 
2.1. 
First Planned Analysis – Evaluation of Myeloprotection Efficacy and Effects 
on Patient Reported Outcome .....................................................................................16 
2.2. 
Second Planned Analysis - Analysis for Progression Free Survival ..........................16 
2.3. 
Third Analysis – Analysis for Overall Survival .........................................................16 
3. 
ANALYSIS POPULATIONS ....................................................................................17 
3.1. 
The Intent-to-treat Population .....................................................................................17 
3.2. 
The Modified Intent-to-treat Population .....................................................................17 
3.3. 
The Per-protocol Population .......................................................................................17 
3.4. 
The Response Evaluable Population ..........................................................................17 
3.5. 
The Safety Population .................................................................................................18 
4. 
GENERAL CONSIDERATIONS FOR DATA SUMMARY AND 
DISPLAY ...................................................................................................................19 
4.1. 
Treatment Group Descriptions and Display in Table, Listings and Figures ..............19 
4.2. 
Data Summary and Precision......................................................................................20 
4.3. 
Definitions for Analysis Related Timepoint and Time Interval .................................21 
4.4. 
Study Day ...................................................................................................................22 
4.5. 
General Principles of Missing Data Handling ............................................................22 
5. 
DISPOSITION AND BASELINE CHARACTERISTICS ........................................23 
5.1. 
Patient Disposition ......................................................................................................23 
5.2. 
Demographics and Baseline Disease Characteristics .................................................25 
5.3. 
Medical History and Ongoing Conditions ..................................................................25 
5.4. 
Prior and Concomitant Medications ...........................................................................26 
5.5. 
Summary of Protocol Deviations................................................................................27 
5.5.1. 
Definitions and Process for Identifying Protocol Deviations .....................................27 
5.5.2. 
Summary of Protocol Deviations................................................................................27 


Statistical Analysis Plan for Protocol G1T28-207 
Version 3.0   
 
 
 
 
G1 Therapeutics 
4 
CONFIDENTIAL 
6. 
CLASSIFICATION OF PRIOR, CONCOMITANT, AND SUBSEQUENT 
ANTICANCER THERAPIES ....................................................................................29 
6.1. 
Prior Anticancer Therapies .........................................................................................29 
6.2. 
Concomitant Anticancer Therapies ............................................................................29 
6.3. 
Subsequent Anticancer Treatments ............................................................................30 
7. 
STUDY DRUG EXPOSURE, DOSE INTENSITY AND MODIFICATION ...........32 
7.1. 
Duration of Study Drug Exposure ..............................................................................32 
7.1.1. 
Duration of Study Drug Exposure in Induction ..........................................................32 
7.1.2. 
Duration of Study Drug Exposure in Maintenance and in the Study .........................32 
7.2. 
Cumulative Dose and Dose Intensity .........................................................................33 
7.3. 
Study Drug Modifications ..........................................................................................35 
7.4. 
Duration of Total Follow-up .......................................................................................36 
8. 
EFFICACY ANALYSIS ............................................................................................37 
8.1. 
Definitions of Efficacy Endpoints ..............................................................................37 
8.1.1. 
Primary Efficacy Endpoints – Duration of Severe Neutropenia in Cycle 1-4 
and Occurrence of Severe Neutropenia during Induction ..........................................37 
8.1.2. 
Key Secondary Efficacy Endpoint – Overall Survival ...............................................38 
8.1.3. 
Secondary Endpoints – Other Myelosuppression Endpoints......................................38 
8.1.3.1. 
Neutrophil-Related Endpoints ....................................................................................39 
8.1.3.2. 
RBC-Related Endpoints ..............................................................................................40 
8.1.3.3. 
Platelet-Related Endpoints..........................................................................................41 
8.1.3.4. 
All Three Lineages .....................................................................................................41 
8.1.3.5. 
Chemotherapy Modifications .....................................................................................42 
8.1.4. 
Secondary Endpoints – Healthcare Utilization ...........................................................42 
8.1.5. 
Secondary Endpoint – Progression Free Survival ......................................................44 
8.1.6. 
Secondary Endpoints – Tumor Response and Duration of Objective 
Response .....................................................................................................................45 
8.1.7. 
Secondary Endpoint - Time to First Confirmed Deterioration of Fatigue ..................46 
8.2. 
Statistical Analysis Methods.......................................................................................47 
8.2.1. 
General Considerations for Efficacy Analysis ...........................................................47 
8.2.2. 
Overarching Statistical Approaches to Ensure Strong Control of Family-wise 
Type I Error Rate among Statistical Analysis for Two Primary and One Key 
Secondary Efficacy Endpoint .....................................................................................48 


Statistical Analysis Plan for Protocol G1T28-207 
Version 3.0   
 
 
 
 
G1 Therapeutics 
5 
CONFIDENTIAL 
8.2.3. 
Primary Analysis and Statistical Inferences for Primary Efficacy Endpoints ............48 
8.2.3.1. 
Statistical Approaches Ensuring Strong Control of Family-wise Type I Error 
Rate of 2-sided α1 = 0.04 ............................................................................................48 
8.2.3.2. 
Primary Analysis for Primary Efficacy Endpoints .....................................................48 
8.2.4. 
Primary Analysis and Statistical Inferences for Key Secondary Endpoint -  
Overall Survival ..........................................................................................................48 
8.2.4.1. 
Timing for Overall Survival Analysis ........................................................................48 
8.2.4.2. 
Statistical Significance Level for Analysis of Overall Survival .................................49 
8.2.4.3. 
Statistical Analysis Models for Overall Survival .......................................................49 
8.2.5. 
Estimand Framework and Sensitivity Analysis for Primary and Key Efficacy 
Endpoints ....................................................................................................................49 
8.2.5.1. 
Estimand Framework and Sensitivity Analysis for DSN in Cycle 1-4 ......................50 
8.2.5.2. 
Estimand Framework and Sensitivity Analysis for Occurrence of SN ......................50 
8.2.5.3. 
Estimand Framework for OS ......................................................................................51 
8.2.6. 
Analysis for Secondary Endpoints - Other Myelosuppression Endpoints..................52 
8.2.6.1. 
Analysis for Binary Myelosuppression Endpoints .....................................................52 
8.2.6.2. 
Analysis for Counting Myelosuppression Endpoints .................................................52 
8.2.7. 
Analysis for Secondary Endpoints - Healthcare Utilization Endpoints ......................53 
8.2.8. 
Analysis for Secondary Endpoints - Other Anti-tumor Efficacy Endpoints ..............53 
8.2.8.1. 
Analysis for Secondary Endpoint - Progression Free Survival ..................................53 
8.2.8.2. 
Analysis for Secondary Endpoints - Tumor Response and Duration of 
Objective Response ....................................................................................................54 
8.2.9. 
Exploratory Analysis - Anti-tumor Endpoints by CDK4/6 Biomarker 
Signature .....................................................................................................................55 
8.2.10. 
Exploratory Analysis - Myelosuppression Endpoints during Overall 
Treatment Period ........................................................................................................55 
8.3. 
Handling of Missing Data ...........................................................................................55 
8.4. 
Efficacy Endpoints to Analyzed on Per-protocol Population .....................................55 
8.5. 
Subgroup Analysis ......................................................................................................56 
8.5.1. 
Subgroup Analysis for DSN in Cycle 1-4 and Occurrence of SN in Induction .........56 
8.5.2. 
Subgroup Analysis for PFS and OS ............................................................................57 
9. 
SAFETY ANALYSIS ................................................................................................58 
9.1. 
General Consideration of Safety Analysis ..................................................................58 
9.2. 
Adverse Events ...........................................................................................................58 


Statistical Analysis Plan for Protocol G1T28-207 
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9.2.1. 
Definition and Classification of Adverse Events ........................................................58 
9.2.2. 
Imputation Rules for Missing Start or Stop Date for Adverse Events .......................59 
9.2.3. 
Analysis for Adverse Events ......................................................................................60 
9.3. 
Clinical Laboratory Data ............................................................................................61 
9.3.1. 
Laboratory Parameters ................................................................................................61 
9.3.2. 
Analysis for Laboratory Parameters ...........................................................................62 
9.4. 
Vital Signs ..................................................................................................................63 
9.4.1. 
Vital Sign Parameters .................................................................................................63 
9.4.2. 
Analysis for Vital Signs ..............................................................................................64 
9.5. 
ECOG Performance Status .........................................................................................64 
9.6. 
12-lead Electrocardiograms ........................................................................................64 
9.6.1. 
Electrocardiograms Parameters ..................................................................................64 
9.6.2. 
Analysis for Electrocardiograms Parameters ..............................................................65 
10. 
CHANGES FROM THE PROTOCOL ......................................................................67 
11. 
REFERENCES ...........................................................................................................68 
12. 
APPENDICES ............................................................................................................69 
 


Statistical Analysis Plan for Protocol G1T28-207 
Version 3.0   
 
 
 
 
G1 Therapeutics 
7 
CONFIDENTIAL 
LIST OF TABLES 
Table 1: 
Primary and Key Secondary Objectives and Endpoints .............................................13 
Table 2: 
Descriptions of Treatment Groups in Protocol, SAP, and Their Orders of 
Appearance in Table/Listing/Figures .........................................................................20 
Table 3: 
Definitions for Timepoints, Timepoint Related Assessments and Time 
Intervals ......................................................................................................................21 
Table 4: 
Dose Administration Parameters for Study G1T28-207 ............................................34 
Table 5: 
Protocol Permitted Dose Reduction by Study Drug ...................................................35 
Table 6: 
Other Myelosuppression Endpoints ............................................................................39 
Table 7: 
PFS Calculation and Censoring Rules ........................................................................44 
Table 8: 
The Intercurrent Events and Handling Strategies for DSN in Cycle 1-4 ...................50 
Table 9: 
The Intercurrent Events and Handling Strategies for Occurrence of SN ...................51 
Table 10: The Intercurrent Events and Handling Strategies for OS ...........................................52 
Table 11: Endpoints to be Analyzed in the Per-protocol Population ..........................................56 
Table 12: Hematologic Preferred Terms to be Collapsed ...........................................................59 
Table 13: Laboratory Categories and Parameters .......................................................................62 
Table 14: Criteria for Potentially Clinically Significant Vital Signs ..........................................64 
Table 15: Criteria for Potentially Clinically Significant ECG Findings .....................................65 
Table 16: Schedule of Assessments: Screening and Induction Cycle 1 .....................................70 
Table 17: Schedule of Assessments: Induction (Cycles 2-12), Maintenance, and 
Survival Follow-up .....................................................................................................73 
 
 
LIST OF FIGURES 
Figure 1: 
G1T28-07 Study Design Diagram ..............................................................................12 
 
 
 


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LIST OF ABBREVIATIONS  
Abbreviation  
 Term 
5FU 
Fluorouracil 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ANCOVA 
Analysis of covariance 
aRR 
Adjusted relative risk 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
BOR 
Best overall response 
CBC 
Complete blood count 
CDK 
Cyclin dependent kinase 
CI 
Confidence interval 
CIM 
Chemotherapy-induced-myelosuppression 
CMH 
Cochran–Mantel–Haenszel 
CR 
Complete response 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic blood pressure 
DCO 
Data cut-off 
DOR 
Duration of response 
DSN 
Duration of severe neutropenia 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ESA 
Erythropoiesis-stimulating agent 
FACIT-F 
Functional Assessment of Chronic Illness Therapy - Fatigue 


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Abbreviation  
 Term 
FACT-An 
Functional Assessment of Cancer Therapy - Anemia 
FDA 
Food and Drug Administration 
GCSF 
Granulocyte colony stimulating factor 
Hgb 
Hemoglobin 
HR 
Hazard ratio 
ICE 
Intercurrent event 
ICH 
International Council for Harmonisation 
ID 
Identification 
ITT 
Intent-to-treat 
IV 
Intravenous 
IWRS 
Interactive Wed Response System 
mCRC 
Metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-treat 
NCI 
National Cancer Institute 
NE 
Not evaluable 
ORR 
Objective response rate 
OS 
Overall survival 
PCS 
Potentially clinically significant 
PD 
Progressive disease 
PFS 
Progression free survival 
PK 
Pharmacokinetic(s) 
pMMR/MSS 
Proficient mismatch repair/microsatellite stable 
PP 
Per-protocol 
PR 
Partial response 
PRO 
Patient-reported outcomes 
PT 
Preferred term 
PTV 
Post Treatment Visit 
RBC 
Red blood cell 
RE 
Response evaluable 
RECIST 
Response Evaluable Criteria in Solid Tumors 


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Abbreviation  
 Term 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAT 
Subsequent anticancer treatment 
SBP 
Systolic blood pressure 
SD 
Stable disease 
SE 
Standard error 
SI 
Standard international 
SN 
Severe neutropenia 
SOC 
System organ class 
SPSD 
Statistical Programming Supportive Documents 
TLF 
Tables, listings, and figures 
TOC 
Table of contents 
TTCD 
Time to confirmed deterioration 
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 
WHO-DD 
World Health Organization Drug Dictionary 
 
 


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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides the detailed statistical methods, variable definitions 
and derivations, and data handling that will be applied to analyze clinical trial data (except 
patient-reported outcomes [PRO] and pharmacokinetics [PK] data) collected from 
Study G1T28-207, “PRESERVE 1: A Phase 3 Randomized, Double-blind Trial of Trilaciclib 
versus Placebo in Patients Receiving FOLFOXIRI/Bevacizumab for Metastatic Colorectal 
Cancer” protocol version 6.0. 
If there are differences between the statistical analysis approaches described in the SAP and 
those in the protocol, the methods and approaches in the SAP will supersede those in the 
protocol.  
Statistical Programming Supportive Documents (SPSD) will be developed based on the SAP to 
serve as companion documents of the SAP to guide programming realization of the SAP. SPSD 
contain three separate documents: the table of contents (TOC) for planned analyses (in Excel 
Spreadsheet), reporting conventions (in Word), and shells or specificities for tables, listings, and 
figures (TLFs) generation (in Word). 
Statistical software SAS® (SAS Institute Inc., Cary, NC) Version 9.4 or later will be used to 
perform data analyses following the plan as laid out in this SAP.  
Changes and additions to the last signed off version of the SAP will be documented with 
corresponding rationale in the clinical study report (CSR).  
The SAP for PRO data collected in Study G1T28-207 will be written as a separate document, as 
will the SAP for PK data collected in this study.  
1.1. 
Study Design 
This is a randomized, double-blind, placebo-controlled, global, multicenter, Phase 3 trial 
evaluating the impact of trilaciclib on myeloprotection and anti-tumor efficacy when 
administered prior to FOLFOXIRI/bevacizumab in patients with proficient mismatch 
repair/microsatellite stable (pMMR/MSS) metastatic colorectal cancer (mCRC) who have not 
received systemic therapy for metastatic disease. Patients will be randomly assigned (1:1) to 
receive placebo or trilaciclib on Days 1 and 2 administered intravenously (IV) prior to 
FOLFOXIRI/bevacizumab in 14-day cycles for up to 12 cycles (Induction). There will be three 
stratification factors for randomization: country, prior therapy in adjuvant/neoadjuvant setting, 
and presence of BRAF V600E mutation. Within each country, patient randomization will be 
stratified by history of systemic cytotoxic therapy in the adjuvant/neoadjuvant setting (yes/no) 
and BRAF V600E mutational status (yes/no). Study drugs administered during Induction are as 
follows: 
• Trilaciclib (240 mg/m2) or placebo – administered as a 30-minute IV infusion no 
more than 4 hours prior to chemotherapy on each day chemotherapy is administered. 
The second dose of trilaciclib/placebo should be administered as a 30-minute infusion 
on Day 2.  
• Irinotecan 165 mg/m2 –IV, Day 1 


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• Oxaliplatin 85 mg/m2 – IV, Day 1  
• Leucovorin 400 mg/m2 – IV, Day 1; LEVOLeucovorin 200 mg/m2 is an acceptable 
alternative 
• Fluorouracil 2400 – 3200 mg/m2 – continuous infusion over 46 – 48 hours beginning 
on Day 1; this dose range is provided to reflect geographic variations in prescribed 
fluorouracil (5FU) dose; however, the same dose should be continued throughout the 
study for each patient, except where dose modifications are required for toxicity 
management. 
• Bevacizumab 5 mg/kg – IV, Day 1 
Though there is no requirement for a minimum number of chemotherapy cycles during 
Induction, patients should continue with Induction therapy (in the absence of disease 
progression) as long as it is tolerated. However, if a patient is unable to complete the maximum 
number of 12 Induction cycles because of toxicity, and the treating physician feels the patient 
will receive additional clinical benefit by transitioning to Maintenance, the patient will be 
allowed to discontinue oxaliplatin and irinotecan and continue on Maintenance therapy as 
described below. 
Following completion of Induction, patients will continue in Maintenance, where they will 
receive trilaciclib or placebo per randomization allocation at study entry. Trilaciclib/placebo will 
be administered prior to infusional-5FU/leucovorin/bevacizumab at the same dose and schedule 
used during Induction. The patient may continue to receive treatment on study until disease 
progression, unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the 
end of the study, whichever occurs first. Treatment cycles will occur consecutively without 
interruption, except when necessary to manage toxicities or for administrative reasons.  
Upon discontinuation of study treatment, patients will be followed for survival, ie, patients or 
their caregivers will be contacted approximately every 2 months until the end of the study (or 
death) to record their status (alive or dead) as well as details of any subsequent systemic 
anti-cancer therapy initiated.  
The general design of the study, including study drugs administration in Induction and 
Maintenance, is depicted in the design diagram below (Figure 1). 
Figure 1: 
G1T28-07 Study Design Diagram 
 


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1.2. 
Study Objectives  
Primary: 
To assess the effects of trilaciclib on the neutrophil lineage compared with placebo in patients 
receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC. 
Key Secondary: 
• To assess the effect of trilaciclib on overall survival (OS) compared with placebo in 
patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC. 
Specifically, the primary and key secondary objectives and their associated endpoints are 
described in Table 1.  
Table 1: 
Primary and Key Secondary Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objectives  
• 
To assess the effects of trilaciclib on the 
neutrophil lineage compared with placebo 
in patients receiving 
FOLFOXIRI/bevacizumab for 
pMMR/MSS mCRC. 
• 
Duration of severe (Grade 4) neutropenia 
in Cycle 1– 4 of Induction 
• 
Occurrence of severe neutropenia during 
Induction  
Key Secondary Objective 
• 
To assess the effect of trilaciclib on OS 
compared with placebo in patients 
receiving FOLFOXIRI/bevacizumab for 
pMMR/MSS mCRC. 
• 
OS 
mCRC=metastatic colorectal cancer; OS=overall survival; pMMR/MSS=proficient mismatch repair/microsatellite 
stable 
Other objectives and endpoints of the study can be found in Section 5 of the protocol.  
1.3. 
Sample Size Consideration  
The primary and key secondary objectives of this study are to evaluate the myeloprotection and 
anti-tumor efficacy of trilaciclib administered prior to FOLFOXIRI/bevacizumab (referred to as 
trilaciclib hereafter) compared with placebo administered prior to FOLFOXIRI/bevacizumab 
(referred to as placebo hereafter). To ensure strong control of family-wise Type I error rate at the 
level of 2-sided 0.05 when performing statistical analyses for the two primary myelosuppression 
endpoints and the anti-tumor efficacy endpoint, the overall 2-sided α of 0.05 will be split 
between the analyses of the primary endpoints (using 𝛼𝛼1 = 0.04 ) and analysis for OS (using 
𝛼𝛼2 = 0.01).  
The sample size is determined to support the primary efficacy analysis on the two primary 
efficacy endpoints. To detect the assumed treatment effect of an absolute reduction of 15% on 
the proportion of patients who have severe neutropenia (SN) in Induction at the significance 


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level of 2-sided 0.04 with 90% power, assuming the event rate for placebo is 25%, a sample size 
of 282 (141 per group) is needed using a Chi square test without continuity correction.  
The sample size needed to detect a treatment effect on duration of SN (DSN) in Cycle 1-4 is 
estimated through simulations to detect a treatment effect of 2.4 days reduction for DSN in 
Cycle 1-4. In derivation of this endpoint, a duration of 0 will be assigned to patients who do not 
experience any SN in Cycle 1-4 (see details in Section 8.1.1). With a large proportion of 
0 values, the variable of DSN in Cycle 1-4 does not follow a normal distribution but 
approximately a Poisson distribution with the mean parameter as -log (proportion of patients 
without any SN at Cycle 1-4). Assuming that approximately 80% of the SN occurring in 
Induction will take place in the first 4 cycles of Induction as reported in Rossini et al (Rossini, 
2021) and assuming that trilaciclib will have an effect of 15% absolute reduction on SN in the 
first 4 cycles, it is estimated that the proportion of patients with SN in Cycle 1-4 is 20% for 
placebo and 5% for the trilaciclib group, respectively. Hence, the Poisson means are estimated to 
be 0.2231 and 0.0513 for placebo and trilaciclib groups, respectively. 10,000 trials were 
simulated based on the Poisson distributions to obtain the DSN in Cycle 1-4. Treatment group 
difference is evaluated using the Mann-Whitney-Wilcoxon test, and the power is estimated by 
the proportion of the trials that have achieved a 2-sided p-value ≤ 0.04 over 10,000 simulated 
trials. From the simulation results, a sample size of 200 patients (100 per group) can achieve an 
empirical power of 91%.  
Overall, 282 patients (141 per group) are needed to detect the assumed treatment effect for each 
of the two co-primary myelosuppression endpoints with 90% power at the 2-sided significance 
level of 0.04. Assuming 5% of randomized patients will not have any post-baseline data, a total 
of 296 patients (148 per group) will be required for the study.  
Although the number of patients is determined to ensure adequate power for the evaluation of the 
myeloprotection efficacy of trilaciclib, statistical comparisons for anti-tumor efficacy will also be 
conducted and the statistical significance is set to be 0.01 for testing treatment effect on OS. A 
total of 157 deaths are estimated to be observed during 52-months of study duration based on the 
following assumptions: 18 months of accrual and total duration of study of 52 months 
(34 months follow-up after the last patient is randomized), a hazard rate of 0.0029 for lost-to-
follow up during the study, and the median OS of 31 months for placebo group (patients 
randomized to receive FOLFOXIRI/bevacizumab plus  placebo) (Loupakis 2014). It is also 
assumed that the hazard ratio (trilaciclib vs. placebo) is 0.75 for OS. 
A total of 44 patients from the Ukraine were randomized to the study as of February 2022. To 
mitigate the potential impact of the Russian-Ukraine war on data integrity and ensure the 
objectives of PRESERVE-1 will not be compromised, patients randomized from Ukraine prior to 
09 September 2021 will be included in the efficacy analyses while all randomized patients from 
Ukraine will be included in the safety evaluation. As noted in the Protocol Amendment 4.0, there 
are 14 patients from Ukraine who have been randomized prior to 09 September 2021. That 
implies a total of 30 randomized patients from Ukraine will be excluded from the efficacy 
evaluation. To preserve the study power as it was originally designed, an additional 30 patients 
will be randomized in countries other than Ukraine. As such, the total sample size for this study 
will be 326. The reason that 09 September 2021 was chosen is because patients randomized prior 


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to this date would have completed or had the opportunity to complete the Induction per protocol 
(approximately 24 weeks), prior to the start of the war (24 February 2022). 
 


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2. 
THE NUMBER OF PLANNED ANALYSES 
2.1. 
First Planned Analysis – Evaluation of Myeloprotection Efficacy and 
Effects on Patient Reported Outcome  
As the protocol specifies, the first planned analysis would be conducted at the time when all 
randomized patients have finished up to 12 cycles of Induction treatment or discontinued during 
Induction. Trilaciclib’s effects of myeloprotection and its effect on the PRO endpoints will be 
evaluated in this analysis. In addition, tumor responses will be assessed and safety data collected 
during Induction will also be analyzed at this time. The clinical study database will be locked to 
support this planned analysis.  
At the time when all 326 patients have been randomized, the date when these patients will 
complete a maximum of 12 cycles Induction will be projected, and this projected date will be 
used as the data cutoff date (DCO) to determine inclusion of data elements to be locked in the 
study database. However, due to the possibility of cycle delays, the last few patients randomized 
might still be in later cycles (eg, Cycle 9 -12) of the Induction Period. In that event, the database 
will still be locked using the projected DCO to include all data collected in Induction as of the 
DCO, including the data from these patients who might still be ongoing in Induction.  
At the time of performing the first planned analysis, the Sponsor will be unblinded to the results. 
However, Investigators and patients will remain blinded to individual patient’s treatment 
assignment until the study is completed and the final study database is locked.  
2.2. 
Second Planned Analysis - Analysis for Progression Free Survival  
The second planned analysis of the study is to perform the PFS analysis around the time point 
that is 35 months post first randomization. This analysis will be performed based on a data 
snapshot.   
2.3. 
Third Analysis – Analysis for Overall Survival 
At the time when 157 death events are observed or at 52 months after the date of first 
randomization, whichever comes first, the study will be concluded, and the final study database 
will be locked to perform the OS analysis. 
PFS analysis will also be performed at this time, as well as analyses of anti-tumor endpoints by 
cyclin-dependent kinase (CDK)4/6 biomarker signature as described in Section 8.2.9. Safety data 
will also be summarized at this time.  
 
 


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3. 
ANALYSIS POPULATIONS 
3.1. 
The Intent-to-treat Population 
The Intent-to-treat (ITT) Population includes all randomized patients. Analyses for the ITT 
population will be conducted based on the randomly assigned treatment regardless of whether 
the patient received any study treatment or was compliant with the protocol.  
3.2. 
The Modified Intent-to-treat Population 
To account for potential data integrity issues resulting from the war in Ukraine, a modified 
intent-to-treat (mITT) population will be utilized as the primary analysis population for all 
efficacy evaluations.  
The criteria for the patients in the ITT population to be included in the mITT population are as 
follows:   
• All patients randomized in countries other than the Ukraine. 
• All patients in the Ukraine who were randomized prior to 09 September 2021. This 
group should have completed, or had the opportunity to complete, Induction per 
protocol (approximately 24 weeks) prior to the start of the war (24 February 2022).  
As a subset of the ITT population, the analyses performed on mITT will be consistent with the 
ITT principle, that is, data will be analyzed based on the randomly assigned treatment regardless 
of whether the patient received study treatment or was compliant with the protocol.  
3.3. 
The Per-protocol Population 
The Per-protocol (PP) Population is the subset of the mITT population that includes only those 
patients who have no major protocol deviations (that could significantly affect the accuracy of 
the study efficacy results) and who receive at least one dose of the randomly assigned study 
treatment. The PP population will be used to analyze selected critical myelosuppression 
endpoints whose outcomes are particularly susceptible to major protocol violations. Analyses on 
the PP population will be based on the randomly assigned treatment.  
The criteria for major protocol deviations that will be used to justify the exclusion from the PP 
population will be fully defined and documented prior to the first study database lock. In 
addition, those randomized patients who will not be included in the PP population will be 
identified and documented with details prior to database lock.  
3.4. 
The Response Evaluable Population 
The Response Evaluable (RE) population includes those patients who are in the mITT population 
and received at least one dose of any study drug, have measurable (target) tumor lesion(s) at 
baseline tumor assessment, and have one of the following: (1) at least 1 post-baseline tumor 
assessment; (2) discontinued treatment because of clinical progression prior to their first 
post-baseline tumor scan; (3) died due to disease progression prior to their first post-baseline 
tumor scan. Analyses using the RE population will be conducted on the basis of the randomly 
assigned treatment. It will be the primary analysis population for tumor response evaluation. 


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3.5. 
The Safety Population 
The Safety Population includes all randomized patients who received at least one dose of any 
study drug. Analyses using the Safety Population will be conducted on the basis of the actual 
treatment received. Unless otherwise specified, all safety data analyses will be performed on the 
Safety Population. 


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4. 
GENERAL CONSIDERATIONS FOR DATA SUMMARY AND 
DISPLAY 
4.1. 
Treatment Group Descriptions and Display in Table, Listings and 
Figures 
As described in Section 1.1, patients meeting entry criteria will be randomized at a 1:1 ratio to 
the treatment group of Placebo + FOLFOXIRI/bevacizumab or Trilaciclib + 
FOLFOXIRI/bevacizumab and thereafter enter the treatment phase of Induction. FOLFOXIRI 
stands for the set of chemotherapies of fluorouracil, leucovorin, oxaliplatin, and irinotecan and 
will be used in combination with the vascular endothelial growth factor (VEGF) inhibitor 
bevacizumab. If not discontinued from study treatment during Induction, patients will enter the 
Maintenance phase of treatment and continue receiving trilaciclib or placebo per their 
randomization allocation at study entry, which will be administered prior to infusional-
5FU/leucovorin/bevacizumab at the same dose and schedule used during Induction. That is, the 
background treatments used in Maintenance are a continuation of the treatments used in 
Induction, with the exception of the two chemotherapies oxaliplatin and irinotecan. Study drugs 
in Maintenance will continue until one of the following conditions is met: disease progression, 
unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the 
study, whichever occurs first.  
Treatment cycles will occur consecutively within Induction, within Maintenance, as well as from 
Induction to Maintenance, without interruption except when necessary to manage toxicities or 
for administrative reasons. 
An overview of treatment group descriptions by treatment phase that will be used in the SAP and 
TFLs with their corresponding descriptions in the protocol is provided in Table 2. In addition, 
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Table 2: 
Descriptions of Treatment Groups in Protocol, SAP, and Their Orders of 
Appearance in Table/Listing/Figures 
Data included in 
the Analysis 
Description in protocol 
Description 
in SAP  
Description in TLF  
Order in 
TLF 
Display  
Induction  
Placebo + 
FOLFOXIRI/bevacizumab 
Placebo 
Placebo + FOLFOXIRI/B 
1 
Trilaciclib + 
FOLFOXIRI/bevacizumab 
Trilaciclib 
Trilaciclib + FOLFOXIRI/B 
2 
Maintenance 
Placebo + 
5FU/leucovorin/bevacizumab 
Placebo 
Placebo + 5FU/L/B 
1 
Trilaciclib + 
5FU/leucovorin/bevacizumab 
Trilaciclib 
Trilaciclib + 5FU/L/B 
2 
Overall treatment 
period (Induction 
and Maintenance) 
OR 
During the study 
NA 
Placebo 
Placebo + Chemo/B 
1 
 
NA 
Trilaciclib 
Trilaciclib + Chemo/B 
2 
FOLFOXIRI=fluorouracil, leucovorin, oxaliplatin, and irinotecan; B=bevacizumab, 5FU=fluorouracil, 
L=leucovorin. Chemo=fluorouracil, leucovorin, oxaliplatin, and irinotecan during Induction and fluorouracil and 
leucovorin during Maintenance. 
4.2. 
Data Summary and Precision 
General Principles of Data Summary 
Data will be summarized by treatment group in table format. Tables summarizing disposition, 
demographics and baseline characteristics will include an overall column for patients pooled 
from all treatment groups. In general, continuous variables will be summarized based on number 
of patients with non-missing data (indicated by n), mean, standard deviation, median, Q1, Q3, 
minimum, and maximum values. Categorical variables will be summarized by number (n) and 
percentage of patients in each category.  
General Principles of Data Listings 
All collected data and derived variables will be included in patient data listings. An indicator will 
be provided for any imputed data element (e.g., imputed adverse event [AE] onset date). 
Columns in listings will be ordered by treatment group, country, study site, patient identification 
(ID), visit, and assessment or event date, if applicable, and then the data elements. The treatment 
group presented in listings will be based on the randomly assigned treatment, unless otherwise 
noted.  
General Principles of Precision for Summary Statistics and Calculated Statistical 
Quantities 
The precision of summary statistics for continuous variables, including mean, median, Q1, Q3 
minimum, and maximum, will be consistent with the precision of the variable as collected unless 
the collected data are integers. When the collected data are integers (whole numbers), the 
summary statistics of mean, median, Q1 and Q3 will be presented in the format with an 
additional digit after the decimal point. Calculated quantities of variability (e.g., standard 


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deviation, standard error [SE]) will be presented with one more decimal place than the precision 
of the variable that is collected. The boundaries of a confidence interval (CI) will keep the same 
precision as the point estimate. The estimated adjusted relative risk will be reported with two 
decimal places.  
For percentages, the total digits will be 3. That is, when the percentage has 2 digits prior to the 
decimal point, there will only be 1 decimal place (e.g., 30.5%); while for a percentage that has 
only 1 digit prior to the decimal point, 2 digits places will be presented after the decimal point 
(e.g., 0.16%).  
P-values, in general, will be displayed in 3 decimal places,  with the exception of when a p-value 
is less than < 0.001, it will be presented as “<0.001”. If a p-value is greater than 0.999, it will be 
displayed as “>0.999”.  
Rounding will take place after all calculation steps are completed prior to result display. 
4.3. 
Definitions for Analysis Related Timepoint and Time Interval 
Efficacy and safety data collected from this study will be summarized by Induction, during the 
overall treatment period (including Induction and Maintenance), or during the study 
(i.e., regardless of whether the patient was in Induction, Maintenance or Survival follow-up), 
depending on the category of the data to be summarized. For each specific category of data, the 
time interval by which the data will be analyzed or summarized will be specified in the 
respective section in which the data analysis plan is described.  
The maximum duration for Induction is 12 cycles, which is equal to 168 days or 24 weeks or 
5.54 months under the assumption that there are no cycle delays or treatment interruptions.  
To clarify data inclusion for each time interval of interest and baseline or end values for each 
given time interval, Table 3 presents definitions for timepoints, timepoint related assessments, 
and time intervals involved in statistical data analysis or summary.  
Table 3: 
Definitions for Timepoints, Timepoint Related Assessments and Time 
Intervals 
Term 
Definition 
Start of study (date) 
Date of randomization  
Study baseline 
(assessment) 
The last non-missing value prior to or on the date of the first dose of any 
study drug at the time that is before the time of the first study drug 
administration.  
Day 1 of Cycle X (date) 
The date when the first dose of any study drug for Cycle X is administered. 
End of cycle (date) 
Day 1 of the subsequent cycle if there is a subsequent cycle, allowing 
crossing from Induction to Maintenance. For two special cases, 1) for the 
last Induction cycle and the patient did not enter Maintenance and 2) the 
last Maintenance cycle, the End of cycle is defined as the date of the Post 
Treatment Visit (PTV) as collected on the SCHEDULED VISITS CRF 
page. If the PTV does not occur for a patient, the End of cycle for the 
patient will be defined as 30 days post the last dose of any study drugs in 
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Term 
Definition 
Duration of a cycle 
(days) 
Total number of days from Day 1 of the cycle to End of the cycle, that is, 
End of the cycle – Day 1 of the cycle + 1. 
Duration of study drug 
exposure in Induction 
(weeks)  
Total number of weeks from Day 1 of Cycle 1 in Induction to the End of 
last Induction cycle. That is, (End of last Induction cycle – Day 1 of 
Cycle 1 + 1)/7. 
Duration of overall study 
drug exposure (weeks)  
The total number of weeks from Day 1 of Cycle 1 in Induction to the End 
of the last cycle in the study (could be in Induction or in Maintenance). 
That is, (End of the last cycle in the study – Day 1 of Cycle 1 + 1) / 7.  
Duration of total  
follow-up (months) 
The total number of months from date of randomization to either the date 
of death or last contact date in the study known as alive. That is, duration 
of total follow-up = (date of death or date of last contact date known as 
alive – date of randomization + 1) /30.4375. 
4.4. 
Study Day 
Study Day will be calculated for an event date or an assessment date to provide additional 
information for interpretation of the event occurrence. Study Day is calculated as:  
• The start date of the event (visit date, onset date of an event, assessment date etc.) − 
the date of randomization + 1, if the event occurred on or after the reference date.  
• The start date of the event (visit date, onset date of an event, assessment date etc.) − 
the date of randomization, if the event occurred prior to the reference date.  
4.5. 
General Principles of Missing Data Handling 
For primary and secondary efficacy endpoints (including key secondary), handling of missing 
data is described in Section 8.3.  
For all other data analyses, in general, the observed data are used for analyses or data summary. 
That is, no missing imputation will be performed. However, imputation of missing onset or stop 
dates for AEs and medications/therapies will be adapted to determine the status of each AE and 
the prior/concomitant/subsequent status of each non-study treatment medication/treatment. 
Please refer to Section 9.2.2 for the rules of imputation of missing AE onset or stop date and 
Section 5.4 for the rules of imputation of missing medication onset or stop dates. 
For demographic and baseline characteristics, continuous variables will be summarized based on 
non-missing observations with the sample size of patients with non-missing data indicated. For a 
categorical variable with missing data, a category of “Missing” will be included as one of the 
components of the variable for the summary. That is, the number and percentage of patients in 
each category of the variable (including “Missing”) will be summarized and reported with the 
randomized patient number as the denominator for the percentage calculation.  


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5. 
DISPOSITION AND BASELINE CHARACTERISTICS 
5.1. 
Patient Disposition  
A summary of patient disposition will be generated for each planned analysis using all 
accumulated data as of the data cutoff date for the respective analysis that will be conducted.  
In general, patient disposition summary will include the following 4 major sections:  
1. Disposition of all screened patients who signed informed consent  
2. Study drug disposition for patients who received at least one dose of any study drug 
3. Study disposition for patients who were randomized 
4. Deaths among patients who were randomized  
For Categories 2 and 3, the contents to be summarized and reported differ slightly among the 
three planned analyses. Therefore, details are provided for each planned analysis. Specific details 
for each section are described below.  
1. Disposition of all screened patients  
The total number of screened patients who signed informed consent will be presented as two 
mutually exclusive groups: those who were screen failures and those who were randomized. For 
those who were randomized, patients who received at least one dose of an Induction treatment 
and those who did not receive any dose of any study drug are further presented by treatment 
group and overall. The number of randomized patients in each respective group will be the 
denominator for calculating percentages of patients in each of the categories.  
2. Study drug disposition 
For the first planned analysis 
For each study drug prescribed in Induction (trilaciclib/placebo, fluorouracil, leucovorin, 
oxaliplatin, irinotecan, and bevacizumab), the number and percentage of patients who were 
ongoing with the treatment during the Induction or discontinued the treatment during the 
Induction will be summarized by treatment group. In addition, for each of the 4 study drugs that 
could be continued from Induction to Maintenance per protocol (trilaciclib/placebo, fluorouracil, 
leucovorin, and bevacizumab), the number and percentage of patients who continued with the 
study drug at Maintenance Cycle 1 will also be summarized by treatment group. The number of 
patients who received the respective study drug in each treatment group at Day 1 of Cycle 1 in 
Induction will be the denominator for the percentage calculation. Primary reasons for study drug 
discontinuation will be presented with the percentage of patients in each reason being calculated 
based on the number of patients who discontinued the study drug in Induction.  
For the second planned analysis  
At the time of performing the 2nd planned analysis, all patients should have finished Induction. 
For each of the 4 study drugs that could be prescribed in Maintenance (trilaciclib/placebo, 
fluorouracil, leucovorin, and bevacizumab) per protocol, the number and percentage of patients 
who were ongoing with the study drug in Maintenance or discontinued from the study drug 
during the study as of the DCO for performing the second planned analysis will be summarized 


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by treatment group. The number of patients who received the respective study drug in each 
treatment group at Day 1 of Maintenance Cycle 1 will be the denominator for the percentage 
calculation. Primary reasons for study drug discontinuation will also be presented with the 
percentage of patients in each reason being calculated based on the number of patients who 
discontinued the study drug in Maintenance.  
For the final analysis  
For each of the 6 study drugs (trilaciclib/placebo, fluorouracil, leucovorin, oxaliplatin, irinotecan, 
and bevacizumab), the number and percentage of patients who were discontinued from the study 
drug during the study will be summarized by treatment group. The number of patients who 
received the respective study drug in each treatment group at Day 1 of Induction Cycle 1 will be 
the denominator for the percentage calculation. Primary reasons for study drug discontinuation 
will also be presented with the percentage of patients in each reason being calculated based on 
the number of patients who discontinued the study drug during the study. 
3. Study disposition  
For the first planned analysis  
Out of those who entered Induction (i.e., who were randomized and had at least one dose of any 
study drug, the Safety Population), the number and percentage of patients in the following 
mutually exclusive categories will be summarized by treatment group and overall: entered 
Maintenance, entered Survival follow-up without going through Maintenance, or discontinued 
from the study during Induction. The number of randomized patients who had at least one dose 
of any study drug in Induction in each respective group will be the denominator for calculating 
percentages of patients in each of the categories. The primary reason for study discontinuation 
will also be summarized by treatment group and overall, and the number of patients who 
discontinued in the respective treatment group will be the denominator for the percentage 
calculation for each reason of discontinuation. 
For the secondary planned analysis 
The number and percentage of patients who are ongoing in the study or discontinued from the 
study will be summarized by treatment group and overall for patients in the Safety Population. 
The number of patients who were randomized and had at least one dose of any study drug will be 
the denominator for the percentage calculation. The primary reason for study discontinuation 
will also be summarized by treatment group and overall, and the number of patients who 
discontinued in each group will be the denominator for the percentage calculation for each 
reason of discontinuation. 
For the final analysis 
The primary reasons for study discontinuation will be summarized by treatment group and 
overall for patients in the Safety Population. The number of patients who were randomized and 
had at least one dose of any study drug in the respective group will be the denominator for the 
percentage calculation.  
4. Death 
The number and percentage of patients who died as of the DCO for the respective analysis 


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(i.e., the first planned analysis, the second analysis, or the final analysis) will be summarized by 
treatment group and overall for all randomized patients along with the primary reason of death 
(Progressive Disease, AE, Other). The number of randomized patients in each respective group 
will be the denominator for calculating percentages of death, and the number of patients who 
died will be the denominator for calculating the percentage of patients for each reason of death. 
Study drug and study disposition information will be provided in data listings for all randomized 
patients.  
5.2. 
Demographics and Baseline Disease Characteristics 
Demographics and baseline disease characteristics will only be summarized for the first planned 
analysis on the ITT and mITT population.  
Demographics will be summarized descriptively by treatment group and overall. Demographics 
include age (at screening), age group (≥18 to <65, or ≥ 65; ≥ 18 to <70, or ≥ 70), gender, race, 
ethnicity, region, country.  
Baseline disease characteristics will also be summarized descriptively by treatment group and 
overall. Baseline disease characteristics to be summarized include stage at screening, site of the 
primary tumor, primary tumor site laterality, Eastern Cooperative Oncology Group (ECOG) 
status, prior systemic therapy in adjuvant/neoadjuvant setting (abbreviated as Prior therapy 
hereafter), BRAF V600E mutation status (abbreviated as BRAF status hereafter), pMMR/MSS 
status with the methods used to determine pMMR/MSS status, and KRAS mutation status. All 
these baseline disease characteristics are categorical. For patients >70 years old, the total score 
from the G8 Health Status Screening Tool will also be summarized by treatment group and 
overall as a continuous variable.  
Prior therapy and BRAF status are stratification factors and patients’ status was entered into 
Interactive Web Response System (IWRS) at the time of randomization. These two factors were 
also entered into the electronic data capture (EDC) system. Therefore, Prior therapy and BRAF 
status as recorded in the IWRS and in the EDC will both be summarized and reported as baseline 
disease characteristics. However, as protocol specified, the status recorded in the IWRS will be 
used as the stratification factors for being included in statistical models to evaluate treatment 
effect unless otherwise specified.  
Data listings for demographics and baseline disease characteristics for the ITT population will be 
produced, respectively. A separate data listing will be generated to present demographics 
collected for screen failures.  
5.3. 
Medical History and Ongoing Conditions 
Medical history and ongoing conditions at the Screening Visit will be summarized at the first 
planned analysis on the ITT population.  
Non-cancer medical history and ongoing medical conditions collected at the Screening Visit will 
be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 24.1 or later, 
and then summarized by treatment group and overall. Medical history and ongoing conditions 
will be presented by system organ class (SOC) and preferred term (PT), with SOC and PT all 


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sorted in descending frequency based on the overall column. A patient will only be counted once 
within a particular SOC (or PT) even if the patient had multiple conditions/diseases in the same 
SOC (or PT). 
In addition, a data listing for medical history and ongoing medical conditions collected at the 
Screening Visit will be provided for ITT population. 
5.4. 
Prior and Concomitant Medications  
A summary of concomitant medications will be generated for the first planned analysis and the 
final analysis based on ITT population. Prior medications will be presented in a data listing.  
Concomitant medications are those medications that were given during the time interval from the 
first dose of any study drug to the end of last cycle for the respective analysis. Medications 
collected through electronic case report forms (eCRFs) will be coded to Anatomical Therapeutic 
Classification (ATC) and PT, where applicable, using the most recent World Health 
Organization Drug Dictionary (WHO-DD) version WHODrug-Global-B3 202109.  
Concomitant medications will be summarized by ATC and PT and presented in a descending 
order of frequency for ATC and PT within an ATC based on the overall group. If a patient took 
multiple medications within the same ATC, the patient will only be counted once for that ATC. 
Similar logic applies to PT summaries. The number and percentage of patients receiving any 
prior/concomitant medications will be summarized by treatment group and overall, respectively. 
Handling of Missing Start and/or End Date for Medications Entered into EDC 
Medications with incomplete start and/or end dates will be imputed according to the 
specifications described below. Those with incomplete start and/or end dates will be assumed to 
be concomitant if it cannot be shown that the medication was not taken outside the treatment 
period.  
For completely missing or partially missing start dates: 
• If the start date has month and year but day is missing, the first dose date will be used 
if the month and year is the same as the first dose date, otherwise, the first day of the 
month will be used. 
• If the start date has year, but day and month are missing, then the first dose date will 
be used if the year is the same as the first dose date, otherwise January 1st will be 
used. 
• If the start date is completely missing, then it will be imputed as the first dose date of 
study drug. 
After the imputation, the imputed start date will be compared with corresponding stop date, if 
available. If the imputed start date is later than the stop date, the start date will be imputed with 
the stop date instead. 


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For completely missing or partially missing stop dates for concomitant medications that are not 
ongoing at the time of data cutoff: 
• If the stop date has month and year but day is missing, the last day of the month will 
be used. 
• If the stop date has year, but day and month are missing, December 31st will be used.  
• If the stop date is completely missing, the last dose date will be used.  
After the imputation, the imputed stop date will be compared against the death date for patients 
who died. If the date is later than the death date, the date of death will be used to impute the stop 
date instead. 
Prior and concomitant medications will be listed with an indicator for prior or concomitant for 
the ITT population.  
5.5. 
Summary of Protocol Deviations  
5.5.1. 
Definitions and Process for Identifying Protocol Deviations  
A protocol deviation refers to situations where a patient’s eligibility for study entry or a specific 
data collection deviate from the entry criteria or study procedure as specified in the protocol. 
Protocol deviation cases at the patient level with specific data elements of concern need to be 
summarized and reported in the CSR. Protocol deviations will be categorized as major or minor. 
Major protocol deviations are those that could affect the integrity of the data or adversely affect 
the ability of assessing efficacy and safety of the investigational drug. Criteria that define major 
or minor protocol deviations will be specified, documented, and signed off prior to study 
database lock. Specifically, a protocol deviation specifications document that describes the 
criteria defining major and minor protocol deviations, the categories of major protocol 
deviations, and the list of patients who had at least one protocol deviation case with the 
classification of major or minor will be created and signed off prior to study database lock to 
perform the unblinded statistical analysis.  
The deviation of receiving a treatment that was not randomly assigned will be the only exception 
to the process described above. It will only be recognized after database lock and unblinding. 
These cases will impact on the composition of the Safety population and a data listing for these 
patients will be provided and included in the CSR.  
5.5.2. 
Summary of Protocol Deviations   
A protocol deviation summary will be generated for the first planned analysis (including protocol 
deviations occurring during Induction) and for the final analysis (including all protocol 
deviations occurred since Induction).  
The number and percentage of patients in the ITT population with protocol deviations will be 
tabulated for each of the following categories by treatment group and overall.  
• Patients with at least one protocol deviation (major or minor) 
• Patients with at least one major protocol deviation 


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• Patients with at least one protocol deviation in each of the major deviation categories 
Protocol deviations will be listed with details and flags for major or minor for the ITT 
population. 


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6. 
CLASSIFICATION OF PRIOR, CONCOMITANT, AND 
SUBSEQUENT ANTICANCER THERAPIES 
Prior anticancer therapies refers to those anticancer treatments that patients received prior to the 
Screening Visit, including medications, surgical procedures, or radiotherapy treatments. 
Concomitant anticancer therapies refer to those treatments, other than study drugs, that could be 
utilized concurrently with study drug(s) as specified in the protocol. That is, the treatments that 
were given in the time interval from the first dose of any study drug to the end of last cycle in the 
respective analysis. Subsequent anticancer therapies refer to anticancer treatments received 
following investigational study drug discontinuation while the patient was still in the study 
(i.e., in the Survival Follow-up period).  
The rules of imputation of missing onset or stop dates for medications described in Section 5.4 
are, in general, applicable for missing onset or stop dates imputation for anticancer therapies in 
any format (medications, surgical procedures, or radiotherapy treatments). 
6.1. 
Prior Anticancer Therapies 
Summaries of prior anticancer therapies will only be generated for the first planned analysis and 
based on the ITT population.  
The number and percentage of patients with any prior anticancer therapies will be summarized 
by treatment group and overall. Prior systemic anticancer medications will be further 
summarized based on ATC and PT and presented in a descending order of frequency for ATC 
and PT withing an ATC based on the overall group.  
The number and percentage of patients with any prior surgical procedures that were related to 
colorectal cancer and radiotherapies will be summarized by treatment group and overall, 
respectively. 
Data listings will be produced for all prior anticancer therapies, including detailed information 
related to prior systemic anticancer therapies such as setting, regimen, start/stop dates, and 
detailed information related to surgical procedures and radiotherapies for the ITT population. 
6.2. 
Concomitant Anticancer Therapies 
Summaries for concomitant anticancer therapies will be generated at the first planned analysis 
and at the final analysis for the ITT population.  
The number and percentage of patients receiving any concomitant anticancer surgical procedures 
or radiotherapies will be summarized by treatment groups and overall, respectively.  
Detailed information for surgical procedures and radiotherapies will be included in the data 
listing for ITT population. 
Summary of Palliative Therapies Administered While on Study Treatments 
The study protocol allowed patients to receive palliative therapies (through radiotherapy or 
surgeries/procedures) during the study. Palliative therapies will be summarized at the first 
planned analysis and at the final analysis for the mITT population.  


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Patients with palliative therapy administrations will be identified based on blinded Sponsor 
medical review of details entered into the eCRF pages of “Concurrent radiotherapy”, 
“Concurrent surgeries/procedures”, “Subsequent radiotherapy” or “Subsequent 
surgeries/procedures”. A palliative therapy for a patient will be included in the first analysis if 
the date of the administration is less than or equal to the last date in Induction for that patient, 
regardless of whether it is entered to a concomitant or subsequent page of the eCRF. This is 
because the end date of Induction is defined as the date of PTV, if it exists, or 30 days post the 
last dose date of any study drugs in Induction.  Palliative therapies used during the time interval 
from last dose of any study drugs to the last date in Induction were entered to subsequent 
(radiotherapy or surgeries/procedures) eCRF pages.   
The number and percentage of patients who have had any palliative therapies (either through 
radiotherapy or surgeries/procedures) during the reporting interval will be summarized by 
treatment group and overall. In this summary, a patient who has more than one administration of 
palliative therapies (including radiotherapy or surgeries/procedures) will only count once. In 
addition, the number and percentage of patients receiving radiotherapy or surgeries/procedures 
for palliative purposes during the reporting interval will also be summarized by treatment group 
and overall.  
6.3. 
Subsequent Anticancer Treatments 
Subsequent anticancer treatments (SAT) will be summarized at the final analysis based on the 
ITT population. 
The number and percentage of patients receiving at least one SAT in any modality (systemic 
anticancer therapies, surgical procedure, or radiotherapy) as well as for each of the modalities 
will be summarized by treatment group and overall.  
For the subsequent systemic anticancer therapies, the total number of lines of therapy will be 
summarized by treatment group and overall as a continuous variable, and the number and 
percentage of patients who had 1, 2, .. maximum lines of systemic anticancer therapies will also 
be summarized. The number of patients who had at least one dose of any systemic anticancer 
therapies will be the denominator to calculate the percentage for the respective group. 
Furthermore, subsequent systemic anticancer therapies will be summarized by treatment group 
based on ATC and PT and presented in a descending order of frequency for ATC and PT within 
an ATC based on the overall group. The best overall response to each treatment regimen and 
disease progression status as collected will be presented in data listings.  
Analysis for Patients who Undergo Curative Intent Surgical Procedure during the Study 
Patients with metastases confined to the liver who experience a robust response to chemotherapy 
may also proceed with curative intent surgical resection at the Investigator’s discretion. In that 
event, study drugs will be discontinued before they undergo such surgery. If choosing to stay 
with the study after the surgery, these patients would enter the Survival Follow-up period of the 
study. These patients will be identified based on blinded Sponsor medical review of the terms 
provided in the eCRF pages of “Subsequent surgery” . The number and percentage of patients 
with curative intent surgical procedure will be summarized by treatment group and overall for 
the ITT population. Because this patient population has a better prognosis for tumor response 


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outcomes, the SAT received by this patient group will not be included in the above stated SAT 
summaries.  
Subsequent anticancer treatment in any format (systemic anticancer therapies, surgical 
procedure, or radiotherapy) for this group of patients will be presented in data listings. If this 
group contains at least 10% of all randomized patients in the study, their SAT will be 
summarized separately in a similar manner as described above.  
Corresponding data listings will be provided for ITT population.  


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7. 
STUDY DRUG EXPOSURE, DOSE INTENSITY AND 
MODIFICATION  
7.1. 
Duration of Study Drug Exposure  
Analyses described in this section will be based on the Safety population unless otherwise 
specified.  
7.1.1. 
Duration of Study Drug Exposure in Induction 
Duration of study drug exposure (weeks) in Induction is defined as the duration from Day 1 of 
Cycle 1 in Induction to the End of cycle for the last cycle in Induction. That is, duration of study 
drug exposure in Induction (weeks) = (End of cycle for the last Induction cycle – Day 1 of 
Induction Cycle 1 + 1)/7, where the definitions for End of cycle and Day 1 of Cycle 1 can be 
found in Section 4.3. 
The duration of study drug exposure in Induction will be summarized by treatment group and 
overall. For each treatment group, the total number of cycles that a patient received will be 
summarized as a continuous variable, as well as a categorical variable. That is, descriptive 
summary statistics will be provided for the total number of cycles that patients received, and the 
number and percentage of patients that received exactly 0, 1, 2,…, up to the maximum number of 
cycles will also be summarized. 
Corresponding data listings will be provided.  
7.1.2. 
Duration of Study Drug Exposure in Maintenance and in the Study 
Two additional variables will be calculated to report study drug exposure: the duration of study 
drug exposure in Maintenance and the duration of total study drug exposure (i.e., Induction and 
Maintenance combined exposure). These will be calculated and reported at the second planned 
analysis and the final analysis. Specifically:   
• Duration of study drug exposure in Maintenance (weeks) is defined as (End of cycle 
for the last cycle in Maintenance – Day 1 of Maintenance Cycle 1 + 1)/7; 
• Duration of total study drug exposure (Induction and Maintenance combined) (weeks) 
is defined as (End of cycle for the last cycle in the study – Day 1 of Induction Cycle 1 
+ 1)/7.  
The definitions for End of cycle and Day 1 of Cycle 1 can be found in Section 4.3. 
For the patients in the Safety population who enter Maintenance, the duration of study drug 
exposure in Maintenance will be calculated and summarized by treatment group and overall. For 
each treatment group, the total number of cycles that a patient received will be summarized as a 
continuous variable, as well as a categorical variable. 
Similarly, based on the Safety population, the duration of total study drug exposure will be 
summarized by treatment group and overall. For each treatment group, the total number of cycles 
that a patient received will be summarized as a continuous variable, as well as a categorical 
variable. 


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Corresponding data listings will be provided.  
7.2. 
Cumulative Dose and Dose Intensity 
Dose administration parameters will be summarized for Induction and the overall treatment 
period, respectively. That is, the analyses described in this section will be performed at the first 
planned analysis, the second planned analysis, and the final analysis, respectively.  
At each specified analysis time, the dose administration during the respective time interval 
(Induction, or overall treatment period) as defined in Table 3 (Section 4.3) will be used to 
calculate dose intensity. 
The definitions for cumulative delivered dose, delivered dose intensity, relative cumulative dose, 
and relative dose intensity at the patient level, along with other parameters involved in the 
calculation of these variables are presented in Table 4. All collected dose information will be 
used in the calculation. 
The calculated cumulative delivered dose, delivered dose intensity, relative cumulative dose, and 
relative dose intensity will be summarized by treatment group as continuous variables.  
All variables described in Table 4 will be included in the data listing except for the study drug 
administration schedule. 


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Table 4: 
Dose Administration Parameters for Study G1T28-207 
Parameter 
Meaning  
Trilaciclib  
Fluorouracil 
Leucovorin 
Oxaliplatin 
Irinotecan  
Bevacizumab 
Study drug 
administration 
schedule   
Drug dose and 
schedule per 
protocol 
240 mg/m2 IV on 
Days 1 and 2 of a 
14-day cycle 
2400 – 3200 mg/m2 
IV given via 
46-48 hour  
continuous infusion 
beginning on Day 1of 
a 14-day cycle 
400 mg/m2 IV on 
Days 1 of a 14-day 
cycle; 200 mg/m2 is 
also acceptable  
85 mg/m2 IV on 
Day 1 of a 14-day 
cycle 
165 mg/m2 IV on 
Day 1 of a 14-day 
cycle 
5 mg/kg IV on 
Day 1 of a 14-day 
cycle 
Cumulative 
delivered dose 
(mg/m2 or mg/kg) 
Sum of doses 
over the duration 
of the study drug 
administration  
Sum of doses over 
the duration of 
trilaciclib/placebo 
administration 
(mg/m2) 
Sum of doses over the 
duration of 
fluorouracil 
administration 
(mg/m2) 
Sum of doses over 
the duration of 
leucovorin 
administration 
(mg/m2) 
Sum of doses over 
the duration of 
oxaliplatin 
administration 
(mg/m2) 
Sum of doses over 
the duration of 
irinotecan 
administration 
(mg/m2) 
Sum of doses over 
the duration of 
bevacizumab 
administration 
(mg/kg) 
Delivered Dose  
Intensity 
(mg/m2/week or 
mg/kg/week) 
Cumulative dose 
administered per 
week  
Cumulative dose 
(mg/m2) / duration 
of study drug 
exposure in weeks 
[(mg/m2/week)] 
Cumulative dose 
(mg/m2) / duration of 
study drug exposure in 
weeks 
[(mg/m2/week)] 
Cumulative dose 
(mg/m2) / duration 
of study drug 
exposure in weeks 
[(mg/m2/week)] 
Cumulative dose 
(mg/m2) / duration of 
study drug exposure 
in weeks 
[(mg/m2/week)] 
Cumulative dose 
(mg/m2) / duration 
of study drug 
exposure in weeks 
[(mg/m2/week)] 
Cumulative dose 
(mg/kg) / duration 
of study drug 
exposure in weeks 
[(mg/kg/week)] 
Relative 
cumulative dose 
(%) 
Cumulative 
delivered dose 
over cumulative 
prescribed dose   
[Cumulative 
delivered dose 
(mg/m2) / (240 × 2 × 
number of cycles) 
(mg/m2)]*100 
[Cumulative 
delivered dose 
(mg/m2) / (starting 
dose  × number of 
cycles) (mg/m2)] *100 
[Cumulative 
delivered dose 
(mg/m2) / (starting 
dose × number of 
cycles) (mg/m2)] * 
100 
[Cumulative 
delivered dose 
(mg/m2) / (85 × 
number of cycles) 
(mg/m2)] * 100 
[Cumulative 
delivered dose 
(mg/m2) / (165 × 
number of cycles) 
(mg/m2)] * 100 
[Cumulative 
delivered dose 
(mg/kg) / (5 × 
number of cycles 
(mg/kg)] * 100 
Relative dose 
intensity (%) 
Delivered dose 
intensity over 
prescribed dose 
intensity  
[Delivered dose 
intensity/480/2]*100 
[Delivered dose 
intensity / starting 
dose /2)]*100 
[Delivered dose 
intensity / (starting 
dose/ 2)]*100 
[Delivered dose 
intensity / 
(85 /2)]*100 
[Delivered dose 
intensity / (165 / 
2)]*100 
[Delivered dose 
intensity / (5/2) 
]*100 
IV = intravenous. 


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7.3. 
Study Drug Modifications 
Study drug modifications will be summarized for Induction and for the overall treatment period, 
respectively. That is, the analyses described in this section will be performed at the first planned 
analysis and the final analysis, respectively.  
There are three types of study drug modification: dose reduction, cycle delay or infusion 
interruption. Protocol permitted dose reductions for each study drug are summarized in Table 5.  
Table 5: 
Protocol Permitted Dose Reduction by Study Drug 
Study Drug 
Number of Dose Reductions Allowed 
Trilaciclib/placebo 
0 
Fluorouracil 
2 
Leucovorin 
0 
Oxaliplatin 
2 
Irinotecan 
2 
Bevacizumab 
0 
Study drug modifications will be summarized by treatment group based on the Safety population 
in each of the following categories: chemotherapy dose reduction, treatment cycle delay, and 
infusion interruption. The number and percentage of patients who had any chemotherapy dose 
reduction, any cycle delay, cycle delay due to hematological toxicity, or any infusion interruption 
will be summarized by treatment group.  
In addition, more detailed summaries outlined below will be provided. 
Dose reduction for a specific chemotherapy. Three chemotherapies (fluorouracil, oxaliplatin, 
and irinotecan) can have dose reduction per protocol (Table 5). Of these, only fluorouracil is 
used during the entire treatment period. Dose reduction is counting for all the reductions across 
these three chemotherapies during the reporting period. Although the protocol specified up to 
2 reductions for each of the three chemotherapies, there were protocol deviations of additional 
reductions. All of these will be included in the summary of dose reductions. The number and 
percentage of patients who had at least one dose reduction will be summarized by treatment 
group. In addition, the number and percentage of patients will be summarized by treatment group 
in the following mutually exclusive categories: no chance to have any dose reduction (Cycle 1 
treatment only), 0, 1, 2, up to the maximum number of reductions for the drug. The reasons for 
dose reduction as collected in the eCRF will also be summarized for each of these 
chemotherapies by treatment group.  
Cycle delay. Information regarding whether a cycle was delayed was collected in the eCRF for 
each cycle. The number of cycles that have been delayed will be summarized as a continuous 
variable by treatment group. In addition, the number and percentage of patients in each of the 
following mutually exclusive categories will be summarized by treatment group: no chance to 
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The reasons for cycle delay collected in eCRF are as follows:  
Absolute neutrophil count (ANC) value < 1.0 × 109/L, platelet counts < 75 x 109/L, Other 
hematologic toxicity, Non-hematologic toxicity, or Other. Patients with reasons entered under 
the “Other” category will be further classified based on medical review of comments collected 
on the eCRFs into the following categories:  
• Administrative 
• Concurrent Illness or Procedure 
• 
COVID-19 Infection or Site Closure  
• Patient’s Decision 
• Principal Investigator’s Decision 
• Other 
• Missing 
 
All these categories (eCRF collected and further classified) will be reported by treatment group. 
The percentage of patients in each of the categories will be calculated based on the number of 
patients in the respective treatment group in the Safety population. 
Infusion interruption. Infusion interruption was captured in the eCRF for each respective study 
drug with the reasons. In addition to summarizing the number and percentage of patients who 
had at least one infusion interruption for any study treatment, the summary statistics for the total 
number of infusion interruptions and the number and percentage of patients in each of the 
following mutually exclusive categories will be summarized by treatment group: 0, 1, 2, …, up 
to maximum number of interruptions. The number of interruptions is the sum of infusion 
interruptions for all study drugs for which the interruption occurred at least once during the 
infusion across all cycles in Induction. Multiple interruptions for a drug during an infusion will 
only be counted once. The reasons for infusion interruption as collected in the eCRF will also be 
summarized by treatment group. 
Furthermore, trilaciclib/placebo infusion interruption and the reasons will also be summarized in 
the similar manner described above. 
Corresponding data listings will be provided.  
7.4. 
Duration of Total Follow-up 
Duration of total follow-up will be summarized for the final analysis.  
Duration of total follow-up (months) refers to the time interval that a patient participated in this 
clinical study starting from the date of randomization. It will be calculated based on the 
definition provided below.  
Duration of total follow-up (months) = (date of death or date of last contact date known as alive 
– date of randomization + 1) /30.4375. 
The summary statistics for this variable will be included in the summary table for the OS 
analysis, and the patient level data will be included in the data listing described in 
Section 8.2.4.3.  


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8. 
EFFICACY ANALYSIS 
Trilaciclib’s myeloprotection efficacy and its effect on PRO endpoints will be evaluated based 
on the data collected during Induction. Data for the PRO instrument Functional Assessment of 
Chronic Illness Therapy – Fatigue (FACIT-F) collected as of the DCO determined for the first 
study database lock will be included in the first study database to derive the key secondary 
endpoint, time to deterioration of fatigue. Trilaciclib’s effect on tumor response will be evaluated 
on data collected during Induction in the first planned analysis, and it will also be assessed at the 
time when PFS is analyzed in the cumulative manner.  
Treatment effects on PFS and OS will be event-driven. When the number of events as specified 
in Sample Size Consideration (Section 1.3) are observed for PFS and OS, the clinical database 
will be locked accordingly to support the analysis of PFS and OS, either at the same time or at 
two separate times (see Section 2.2 and Section 2.3). 
For the patients who will undergo curative intent surgical resection due to response to study 
treatments, study drugs will be discontinued before the surgery per protocol. As such, there will 
be no myelosuppression assessments or PRO data collection following the curative intent surgery 
procedure. After the surgery, these patients can continue with the study in the Survival Follow-
up period, and they might have continued tumor assessments as specified in the protocol for all 
who entered the Survival Follow-up period. However, tumor assessments collected after the date 
of curative intent surgical procedure will be excluded from derivation of tumor response status, 
duration of response, and PFS for these patients. On the other hand, the status of this procedure 
will not impact on the derivation of OS for these patients.  
8.1. 
 Definitions of Efficacy Endpoints 
Efficacy endpoints defined in this section will be derived for patients in the mITT population.  
8.1.1. 
Primary Efficacy Endpoints – Duration of Severe Neutropenia in Cycle 1-4 and 
Occurrence of Severe Neutropenia during Induction 
Severe neutropenia is defined as an ANC value < 0.5 × 109/L (Grade 4 neutropenia per National 
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] criteria, 
Version 5.0).  
The co-primary endpoint DSN in Cycle 1-4, is defined as the days of the first SN event that 
occurred in the first 4 cycles of Induction. Specifically, for patients with at least 1 SN event in 
Induction Cycle 1, 2, 3 or 4, DSN in Cycle 1-4 is calculated for the first occurrence of the event 
following the rules described below. 
• For patients whose SN is resolved (defined as an ANC value ≥ 0.5 × 109/L at a date 
after the initial SN occurrence, and maintained until the end of the cycle), DSN will 
be derived as the number of days from the date of the first SN occurrence to the date 
of SN resolution.  
• For patients who withdraw from the study with unresolved neutropenia, DSN will be 
derived as the total number of days from the date of the first SN occurrence to the 
date of withdrawal (the last day of the study).  


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For patients without any SN in the first 4 cycles of Induction or those who were in the mITT 
population but who did not receive any study drug, DSN in Cycle 1-4 will be set to 0.  
In Cycle 1, hematology laboratory parameters, including ANC, will be collected at Day 1 (prior 
to dosing), Days 2, 4, 6, 8, 10, 12 and at the End of Cycle 1 (See Table 3 in Section 4.3 for End 
of cycle definition). In Cycle 2 to 4, ANC will be collected at Day 1 and Day 8 of each cycle. For 
the patients who experienced SN in a treatment cycle, unscheduled assessments of ANC must be 
obtained in that cycle to evaluate the status of SN resolution, since the event must be resolved 
before the patient could start next cycle’s treatment. All scheduled and unscheduled ANC 
assessments obtained in Cycle 1, 2, 3, or 4 will be used to calculate the DSN in Cycle 1-4 for 
those patients with at least 1 SN event in the first 4 cycles of Induction.  
DSN in Cycle 1-4 is a continuous random variable but is not normally distributed given that a 
proportion of the values are set as 0 per definition described above.  
Occurrence of SN during Induction (also referred to as occurrence of SN in the SAP) for a 
patient is defined as having as least one ANC value < 0.5 × 109/L among all ANC measurements 
during Induction regardless of scheduled or unscheduled visits. Occurrence of SN is a binary 
random variable (Yes or No).  
8.1.2. 
Key Secondary Efficacy Endpoint – Overall Survival 
OS is defined as the time (months) from the date of randomization to the date of death for 
patients who died in the study regardless of cause, or to the last contact date known to be alive 
for those who survived as of the date for final database lock (censored cases). Patients lacking 
data beyond the date of randomization will have their survival time censored at the date of 
randomization. OS will not be censored even if a patient receives subsequent anticancer 
treatments or undergoes curative intent surgical resection. 
8.1.3. 
Secondary Endpoints – Other Myelosuppression Endpoints 
Secondary myelosuppression endpoints that are defined to assess trilaciclib’s effect on multiple 
lineage protection in Induction are described in Table 6 by lineage (i.e., neutrophils, red blood 
cells [RBCs] and platelets). Endpoints that evaluate trilaciclib’s impact on administration of 
current standard of care interventions to treat chemotherapy-induced-myelosuppression (CIM),  
as well as evaluate trilaciclib’s impact on chemotherapy delivery in Induction are also described 
in Table 6.  
Unless otherwise specified, all endpoints described in Table 6 are derived based on data 
collected through scheduled and unscheduled visits during Induction. 


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Table 6: 
Other Myelosuppression Endpoints 
 
Lineage  
Endpoint 
Type of 
Variable 
Neutrophils 
Number of cycles with severe neutropenia (event rate per 100 cycles) 
Counting 
Occurrence of febrile neutropenia 
Binary 
Occurrence of GCSF administration 
Binary 
Number of cycles with GCSF administrations (event rate per 100 cycles) 
Counting 
Occurrence of Grade 3 or 4 neutropenia 
Binary 
RBCs 
Occurrence of Grade 3 or 4 decreased hemoglobin  
Binary 
Occurrence of RBC transfusion on/after Week 5 
Binary 
Number of RBC transfusions on/after Week 5 (event rate per 100 weeks) 
Counting 
Occurrence of ESA administration 
Binary 
Platelets  
Occurrence of Grade 3 or 4 decreased platelet counts 
Binary 
Occurrence of platelet transfusion 
Binary 
Number of platelet transfusions (event rate per 100 weeks) 
Counting 
All three lineages 
Occurrence of Grade 3 or 4 hematologic laboratory values 
Binary 
Chemotherapy 
Modifications 
Occurrence of chemotherapy dose reduction (all causes) 
Binary 
Number of chemotherapy dose reductions (event rate per 100 cycles) 
Counting 
Occurrence of cycle delay due to toxicity  
Binary 
Number of cycle delays due to toxicity (event rate per 100 cycles) 
Counting 
ESA=erythropoiesis-stimulating agents; GCSF=granulocyte colony stimulating factor; RBC=red blood cell 
8.1.3.1. 
Neutrophil-Related Endpoints 
Number of Cycles with Severe Neutropenia 
The number of cycles with SN in Induction for a patient is the total number of cycles in 
Induction where the patient had at least one SN event. For patients who did not have any SN 
during Induction and those who were in the mITT population but did not receive any study 
treatment, the value of 0 will be assigned. Number of cycles with SN is a counting random 
variable and the summary statistics for this variable is event rate per 100 cycles. 
Occurrence of Febrile Neutropenia 
FN is an AE as reported by the Investigator and captured in the eCRF. A PT term of FEBRILE 
NEUTROPENIA is used to identify a FN event. The occurrence of FN for a patient is defined as 
having at least one FN event in Induction and is a binary random variable (Yes or No). 
Occurrence and Number of Granulocyte Colony Stimulating Factor (GCSF) Administrations 
Administration of GCSF is collected throughout Induction. Cycles where GCSF was 
administered will be identified by comparing the start and stop dates of each administration of 
GCSF to cycle interval. If any of the time intervals in which GCSF was administered overlapped 
with any dates between the start of a cycle and the end of the cycle, that cycle will be considered 


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as having a GCSF administration. Data handling conventions for missing start and stop dates are 
described in Section 5.4. 
The occurrence of GCSF administration during Induction for a patient is defined as having at 
least one cycle in which GCSF was administrated for the patient during Induction. It is a binary 
random variable (Yes or No).  
The number of cycles with GCSF administrations in Induction for a patient is the total number 
cycles in Induction where the patient received at least one dose of GCSF. If a dose of GCSF was 
administrated on Day 1 of Cycle X (> 1), the following counting rules will apply:  
• If the start date and stopped date both were on Cycle X Day 1, it will be counted an 
occurrence in Cycle X – 1 only (assuming the trigger event occurred in Cycle X-1). 
• If the start date was on Cycle X Day 1 and stop date was within the same cycle or in a 
later cycle, Cycle X-1 will be included in the total count of cycles in which GCSF was 
administrated  as the triggering event is considered to have occurred in Cycle X-1.  
• If the start date was in the middle of Cycle X-1 (that is, any day other than Cycle X-1 
Day 1 or end of Cycle X-1), and the stopped date was on Day 1 of Cycle X, it will only 
be counted an occurrence in Cycle X-1.  
For patients who did not have any GCSF use during Induction and those who were in the mITT 
population but did not receive any study treatment, the value of 0 will be assigned. Number of 
cycles with GCSF administrations is a counting random variable and the summary statistics for 
this variable is event rate per 100 cycles. 
Occurrence of Grade 3 or Grade 4 Neutropenia 
Occurrence of Grade 3 or Grade 4 neutropenia during Induction for a patient is defined as having 
as least one ANC value < 1.0 × 109/L among all ANC measurements during Induction regardless 
of scheduled or unscheduled visits. Occurrence of SN is a binary random variable (Yes or No). 
8.1.3.2. 
RBC-Related Endpoints 
Occurrence of Grade 3 or 4 Decreased Hemoglobin  
Occurrence of Grade 3 or 4 decreased hemoglobin (Hgb) in Induction for a patient is defined as 
having at least one Hgb value that was < 8.0 g/dL among all scheduled or unscheduled 
assessments during Induction. It is a binary random variable (Yes or No).  
Occurrence and Number of RBC Transfusion on/after Week 5 
The following endpoints will be derived for those patients who had at least 4 weeks of study 
drug exposure, which is equivalent to having at least 29 days exposure in Induction. 
Occurrence of RBC transfusions on/after Week 5 for a patient is defined as having at least one 
RBC transfusion on or after Week 5 (relative to Day 1 of Cycle 1) during Induction. Occurrence 
of RBC transfusions on/after Week 5 is a binary random variable (Yes or No). 
The number of RBC transfusions on/after Week 5 for a patient is defined as the total number of 
RBC transfusions the patient had on/after Week 5 during Induction. Transfusions with a unique 
start date were counted as different events. For patients who did not have any RBC transfusion 


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on/after Week 5 in Induction and those who were in the mITT population but did not receive any 
study treatment, a value of 0 will be assigned. Number of RBC transfusions on/after Week 5 is a 
counting random variable and the summary statistics for this variable is event rate per 
100 weeks. 
Occurrence of Erythropoiesis-Stimulating Agent (ESA) Administration 
Administration of ESA is collected throughout Induction. Cycles where ESA was administered 
will be identified by comparing the start and stop dates of each administration of ESA to cycle 
interval. If any of the time interval in which ESA was administered overlapped with any dates 
between the start of a cycle and the end of the cycle, that cycle will be considered as having an 
ESA administered. Data handling conventions for missing start and stop dates are described in 
Section 5.4. 
The occurrence of ESA administration during Induction for a patient is defined as having at least 
one cycle in which ESA was administrated for the patient during Induction. It is a binary random 
variable (Yes or No). 
8.1.3.3. 
Platelet-Related Endpoints 
Occurrence of Grade 3 or 4 Decreased Platelet Counts 
Occurrence of Grade 3 or 4 decreased platelet counts for a patient is defined as having at least 
one platelet count value that was < 50.0 x 109/L among all scheduled or unscheduled assessments 
during Induction. Occurrence of Grade 3 or 4 decreased platelet counts is a binary random 
variable (Yes or No). 
Occurrence and Number of Platelet Transfusions 
Occurrence of platelet transfusion for a patient is defined as having at least one platelet 
transfusion during Induction. It is a binary random variable (Yes or No). 
The number of platelet transfusions for a patient is defined as the total number of platelet 
transfusions the patient had during Induction. Transfusions with a unique start date during 
Induction were counted as different events. For patients who did not have any platelet 
transfusion in Induction and those who were in the mITT population but did not receive any 
study treatment, the value of 0 will be assigned. Number of platelet transfusions is a counting 
random variable and the summary statistics for this variable is event rate per 100 weeks. 
8.1.3.4. 
All Three Lineages 
Occurrence of Grade 3 or 4 Hematologic Laboratory Values 
Occurrence of Grade 3 or 4 hematologic laboratory values (abbreviated as occurrence of Grade 3 
or 4 hem-labs) for a patient is defined as having at least one ANC < 1.0 x 109/L, Hgb <8.0 g/dL, 
or platelets < 50.0 x 109/L based on the CTCAE toxicity criteria among all scheduled or 
unscheduled assessments during Induction. It is a binary random variable (Yes or No). 


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8.1.3.5. 
Chemotherapy Modifications 
Occurrence and Number of Chemotherapy Dose Reduction  
The occurrence of a chemotherapy dose reduction for a patient is defined as having at least one 
dose reduction in a cycle during Induction (regardless of which chemotherapy). Chemotherapies 
that allow dose reduction and the maximum number of reductions in Induction can be found in 
Section 7.3. Occurrence of chemotherapy dose reduction is a binary random variable (Yes or 
No). 
Number of chemotherapy dose reductions for a patient is defined as the total counts of 
chemotherapy dose reductions across the 3 chemotherapies for which dose reduction was 
allowed per protocol (Table 5) during Induction. In addition, chemotherapy that was stopped due 
to toxicity will be also counted as a dose reduction event. The value of 0 will be assigned to 
those patients who did not have any chemotherapy dose reductions during Induction and those 
who were in the mITT population but did not receive any study treatment. Number of chemo-
dose reductions is a counting random variable and the summary statistics for this variable is 
event rate per 100 cycles. 
Occurrence and Number of Cycle Delays Due to Hematologic Toxicity 
Occurrence of cycle delays and the associated reason is collected in detail in the eCRF with the 
following mutually exclusive categories: ANC value < 1.0 × 109/L, platelet counts < 75 x 109/L , 
Other hematologic toxicity, Non-hematologic toxicity, or Other. A cycle that was marked as 
delayed with the reason of ANC value < 1.0 × 109/L, platelet counts < 75 x 109/L , or Other 
hematologic toxicity is considered a delay due to hematologic toxicity.  
Occurrence of cycle delays due to hematologic toxicity for a patient is defined as having at least 
one cycle delay due to hematologic toxicity during Induction and is a binary random variable 
(Yes or No). The number of cycle delays due to hematologic toxicity for a patient is defined as 
the total number of cycles that were delayed due to such reason for the patient during Induction. 
For patients who did not have any cycle delays due to hematologic toxicity in Induction and 
those who were in the mITT population but did not receive any study treatment, the value of 0 
will be assigned. Number of cycle delays due to toxicity is a counting random variable and the 
summary statistics for this variable is event rate per 100 cycles. 
8.1.4. 
 Secondary Endpoints – Healthcare Utilization 
Secondary endpoints that are defined to assess trilaciclib’s impact on healthcare utilization are 
listed below. 
• Occurrence of all-cause hospitalizations 
• Occurrence and number of hospitalizations due to CIM, Sepsis or Other Serious 
Infections 
• Occurrence of intravenous antibiotic administration 
Occurrence of All-cause Hospitalizations 
Hospitalization is collected as one of the serious adverse events (SAEs) in eCRF along with the 
cause of the hospitalization, which are captured in PTs. If a patient was hospitalized and several 


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PTs were attributed to that hospitalization with the same start date, there will be just one count 
for the corresponding hospital event. 
Occurrence of all-cause hospitalization for a patient is defined as having at least one 
hospitalization regardless of cause during Induction. It is a binary random variable (Yes or No). 
Occurrence and Number of Hospitalizations due to CIM, Sepsis or Other Serious Infections   
Myelosuppression events that were related to chemotherapy are grouped in three categories: 
Neutropenia (including PT terms of Nneutropenia, Neutrophil count decreased, and Febrile 
neutropenia), Anemia (including PT terms of Anemia, Anaemia, Anaemia macrocytic, Red 
blood cell count decreased, Hemoglobin decreased, and Pancytopenia), and Thrombocytopenia 
(including PT terms of Thrombocytopenia and Platelet count decreased).  
Hospitalization that was caused by any of these events is defined as hospitalizations due to CIM.  
The criterion for identifying the proper infection SAE records is as follows: if the SOC from 
MedDRA (Version 24.1) takes value “INFECTIONS AND INFESTATIONS”, and the AE is a 
serious event. 
Occurrence of hospitalization due to CIM, sepsis or other serious infections for a patient is 
defined as having at least one hospitalization due to CIM, sepsis or other serious infections 
during Induction. It is a binary random variable (Yes or No). 
Number of hospitalizations due to CIM, sepsis or other serious infections for a patient is defined 
as the total number of hospitalizations due to any of these causes during Induction. In deriving 
the total number of hospitalizations, if a hospitalization start date is after the discharge date of 
previous hospitalization which was caused by the same AE, it will be counted as a new 
hospitalization event. The value of 0 will be assigned to those patients who did not have any 
hospitalizations due to CIM, sepsis or other serious infections during Induction and those who 
were in the mITT population but did not receive any study treatment. Number of hospitalizations 
due to CIM, sepsis or other serious infections is a counting random variable and the summary 
statistics for this variable is event rate per 100 cycles. 
Occurrence of Intravenous Antibiotic Administration 
IV antibiotic administration is collected as concomitant medications which are coded using 
WHO-DD version WHODrug-Global-B3 202109. The criteria for identifying an IV antibiotic 
administration event are: 
• If the Therapeutic subgroup from WHO-DD (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”. 
Occurrence of IV antibiotic administration for a patient is defined as having at least one IV 
antibiotic administration during Induction, and it is binary random variable (Yes or No).  


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8.1.5. 
Secondary Endpoint – Progression Free Survival 
Progressive disease (PD) and tumor response status are programmatically determined according 
to Response Evaluable Criteria in Solid Tumors (RECIST) v1.1 based on the radiographic tumor 
assessment data recorded on the eCRF by the Investigator for target lesions, the Investigator 
assessment of non-target lesions, and the status of new lesions. For a patient, the status of PD 
will be determined using all radiographic tumor scan data assessed prior to or on the date of the 
data cutoff to conduct the analysis for PFS. In the situation where PD and withdrawal of consent 
or PD and initiation of subsequent anticancer therapy occurred on the same day for a patient, the 
PD status will be assumed for that patient.  
PD and death due to any cause are referred to as PFS events. The observation of PFS events is 
not limited to a specific treatment phase (Induction, Maintenance, or Survival Follow-up).  
PFS is defined as the time (months) from date of randomization to the date of the first 
documented disease progression, or death in the absence of PD for those who had a PFS event, 
and the time from randomization to the censoring date for those who did not have a PFS event. 
Specifically, PFS is calculated as (date of PFS event or censoring – date of randomization + 1)/ 
30.4375.  
Details for PFS calculation and censoring rules can be found in Table 7.  
Table 7: 
PFS Calculation and Censoring Rules 
Situation 
Date of Event or Censoring 
Outcome 
Disease progression per 
RECIST v 1.1 
Date of the first documented progression 
PFS event 
Death without a PD 
Date of death 
PFS event 
Incomplete or no baseline 
tumor assessments 
Date of randomization 
Censored 
Lacking information beyond 
randomization 
Date of randomization 
Censored 
No progression 
Date of the last adequate radiological 
tumor assessment with no documented 
disease progression 
Censored 
Subsequent anticancer 
treatment started prior to 
documented disease 
progression 
Date of last adequate radiologic 
assessment prior to or the date of 
initiation of subsequent anticancer 
treatment 
Censored 
Underwent curative intent 
surgical procedure during the 
treatment period of the study 
Date of last adequate radiologic 
assessment prior to the date of surgery 
Censored 
Required palliative therapies 
Date of last adequate radiologic 
assessment prior to the date of the first 
palliative therapy 
Censored 
 
 


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8.1.6. 
Secondary Endpoints – Tumor Response and Duration of Objective Response  
Secondary anti-tumor efficacy endpoints include the following, which will be calculated and 
reported twice during the study: at the first planned analysis (including all tumor assessments 
collected in Induction) and at the time when PFS is analyzed (including all tumor assessments 
collected as of the DCO for the analysis if it is not final).  
For the patients who underwent a curative intent surgical procedure due to response to study 
treatments, study drugs will be discontinued before the surgery per protocol. After the surgery, 
these patients can continue with the study in the Survival Follow-up period. As such, they might 
have continued tumor assessments as the protocol specified for all who entered the Survival 
Follow-up period. However, tumor assessments collected after the date of curative intent surgical 
procedure will be excluded from derivation of tumor response status and duration of response. 
For patients who required palliative treatment concomitantly while on study drugs, tumor 
assessments after the date of first palliative treatment administration will be excluded from tumor 
response evaluation.  
Tumor scan data collected in Induction are the basis to classify tumor response status for being 
analyzed in the first planned analysis, and the tumor scan data collected as of DCO for the PFS 
analysis are the basis to classify tumor response status for being analyzed in the second planned 
analysis. 
• Best overall response (BOR) 
• Objective response rate (ORR) 
• Duration of objective response (DOR) 
At each tumor assessment visit, an overall time point response status based on RECIST v1.1 will 
be determined programmatically using the measurements recorded on the eCRF by the 
Investigator for target lesions, the Investigator assessment of non-target lesions, and records of 
new lesions.  
Tumor assessments collected in Induction (for the first analysis) or by the DCO (for the second 
analysis) will be used to determine response status, with the following rules of exclusion: 
(i) assessments obtained after radiographic disease progression; (ii) assessments obtained after 
initiation of any subsequent anti-cancer therapy, including undergoing curative intent surgical 
procedure; (iii) assessments obtained after the first dose of palliative therapies.  
Best Overall Response  
BOR categorizes a patient’s tumor response status into one of following mutually exclusive 
categories per RECIST v1.1: Complete Response (CR), Partial Response (PR), Stable Disease 
(SD), PD, and Not Evaluable (NE). The minimum duration of stable disease must be 7 weeks 
starting from the date of randomization (the protocol scheduled tumor assessments is every 
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Objective Response Rate 
Achieving an objective response for a patient is defined as having a complete response (CR) or 
partial response (PR) as the BOR. ORR is defined as the proportion of the patients who achieved 
objective response based on the RE population.  
Confirmed Objective Response Rate 
Confirmed CR or PR will be derived based on the principle described in RECIST v1.1. In the 
derivation, the minimum interval for confirmation of CR or PR is 4 weeks, and the minimum 
duration of treatment is 7 weeks (the protocol scheduled tumor assessments is every 8 weeks ± 
1 week). Confirmed ORR (confirmed CR or PR) is defined as the proportion of the patients who 
achieved confirmed objective response based on the RE population. 
Duration of Confirmed Objective Response  
DOR is calculated for patients who achieved confirmed CR or PR as the BOR status. It is 
defined as the time (months) from the date when the objective response of CR or PR was first 
documented to the date that radiographic progressive disease is documented, or death, whichever 
comes first. That is, DOR = (Date of documented disease progression or death – date of first 
documented CR or PR + 1)/30.4375.  
Censored DOR follows the same rules as the censoring rules for PFS (see Section 8.1.5).  
8.1.7. 
Secondary Endpoint - Time to First Confirmed Deterioration of Fatigue 
The secondary PRO efficacy endpoint is time to confirmed deterioration (TTCD)-fatigue, 
where fatigue is the total score calculated from the PRO instument FACIT-F (13 item subscale 
of the Functional Assessment of Cancer Therapy – Anemia [FACT-An]). The confirmed 
clinically meaningful deterioration for fatigue in Induction is defined as such an event where 
the fatigue score obtained in Induction was at least 7 units worse compared with the baseline, 
and it was confirmed by the fatigue score collected at the next scheduled visit (which can go 
beyond Induction). Of note, the value of 7, defining the threshold of clinically meaningful 
deterioration of fatigue in this patient population, was determined by the anchor analysis 
conducted on the pooled, blinded data at the time when 50% of the randomized patients had 
finished Induction. The SAP for the anchor analysis as a separate document were submitted to 
the Food and Drug Administration (FDA) via the Sponsor response to a Type C Written 
Response Only, dated 10-Aug-2021; and the results from anchor analysis were submitted to the 
FDA on 16-Sep-2022 as the Background Materials to support a Type C teleconference held 
with FDA on 27-Oct-2022. 
If the patient discontinued from the study (including death) or missed all PRO assessments 
after the first deterioration was observed, the one-time observation of deterioration will be 
classified as a confirmed event. All FACIT-F data collected as of the data cutoff date for the 
first study database lock will be included in the TTCD-fatigue derivation following the rules 
described above.  
For the patients with one confirmed clinically meaningful deterioration for fatigue, 
TTCD-fatigue (months) will be calculated as the time from the date of randomization to the 
date of the first confirmed clinically meaningful deterioration in the unit of months. That is, 
TTCD-fatigue (months) = (Date of assessment when the first confirmed clinically meaningful 


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deterioration was observed – Date of randomization + 1)/30.4375. 
For patients who did not experience a confirmed clinically meaningful deterioration prior to 
the data cutoff date for the first planned analysis, the censored TTCD-fatigue will be calculated 
using the date of the last available PRO assessment (i.e., the assessment with last non-missing 
value) as the end date. Patients with no baseline assessment, with no post-baseline assessments, 
or whose baseline scores did not allow for further deterioration will be censored at the date of 
randomization.  
8.2. 
 Statistical Analysis Methods  
8.2.1. 
General Considerations for Efficacy Analysis 
Unless otherwise specified, all efficacy analyses will be performed on the mITT population.  
Unless otherwise specified, the treatment effect on myelosuppression endpoints will be evaluated 
based on the data collected during Induction, and the treatment effect on PRO endpoints will be 
evaluated using all available data as of the DCO for the first database lock. The first planned 
analysis is to evaluate trilaciclib’s myeloprotection effect and its effect on PRO endpoints 
compared with placebo for patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS 
mCRC. The analysis for PFS or OS will not be included in the first planned analysis since the 
expected number of events for either PFS or OS (see Section 1.3) will not be reached at the DCO 
for the first study database lock.  
Stratification Factors and Factored to Be Included in Statistical Models for Analysis 
There are three stratification factors for randomization: country, prior therapy in 
adjuvant/neoadjuvant setting, and BRAF V600E mutational status. Within each country, patient 
randomization will be stratified by history of prior therapy in the adjuvant/neoadjuvant setting 
(Yes or No) and BRAF V600E mutational status (Yes or No). History of prior therapy in the 
adjuvant/neoadjuvant setting will be abbreviated as “Prior chemotherapy” and BRAF V600E 
mutational status will be abbreviated as “BRAF status” hereafter. Countries will be grouped into 
the factor of “Region” with four different entries of US, Eastern Europe, Western Europe, and 
China. The factor “Region” will be used instead of “country” in the statistical analysis models to 
account for regional differences in clinical practice.  
It is anticipated that all three factors (Region, Prior chemotherapy and BRAF status) will have an 
impact on patients’ anti-tumor efficacy outcomes, but only Region and Prior chemotherapy will 
have an impact on myeloprotection efficacy. Therefore, Region and Prior chemotherapy will be 
included as the factors in statistical analysis models evaluating trilaciclib’s effect on 
myeloprotection and trilaciclib’s effect on PRO endpoints, while all three factors will be 
included in the statistical analysis models to assess trilaciclib’s anti-tumor efficacy. Unless 
otherwise specified, the strata information as entered in IWRS at the time of randomization 
except for “region” will be used as the factors for all stratified statistical analyses. 
Family-wise Type 1 Error Rate Control and Nominal P-values 
As described in the protocol and further detailed in the sections below, the family-wise Type 1 
error rate of 2-sided 0.05 is strongly controlled among statistical analyses for primary and key 
secondary endpoints. For secondary efficacy endpoints, nominal p-value and 95% CI will be 


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generated as the reference for judging strength of the evidence and the precision of point 
estimation.  
8.2.2. 
Overarching Statistical Approaches to Ensure Strong Control of Family-wise 
Type I Error Rate among Statistical Analysis for Two Primary and One Key 
Secondary Efficacy Endpoint 
To ensure strong control of family-wise Type I error rate at the level of 2-sided 0.05 when 
performing statistical analyses for the two primary myelosuppression endpoints (DSN in 
Cycle 1-4 and occurrence of SN during Induction) and OS, the overall 2-sided α of 0.05 will be 
split between the analyses of the primary endpoints and using 2-sided 𝛼𝛼1 = 0.04 and the 
analyses for key secondary endpoint of OS using 2-sided 𝛼𝛼2 = 0.01.  
8.2.3. 
Primary Analysis and Statistical Inferences for Primary Efficacy Endpoints  
8.2.3.1. 
Statistical Approaches Ensuring Strong Control of Family-wise Type I Error 
Rate of 2-sided α1 = 0.04 
The treatment effect for DSN in Cycle 1-4 and occurrence of SN in Induction will be both tested 
at the 2-sided 0.04 level based on the primary analysis models specified in Section 8.2.3.2.  
8.2.3.2. 
Primary Analysis for Primary Efficacy Endpoints 
Treatment effect on DSN in Cycle 1-4 will be evaluated using nonparametric analysis of 
covariance (ANCOVA) (Quade 1967). In this analysis, the rank-transformed (within each 
stratum) DSN values will be analyzed by an ANCOVA model with the terms of treatment, 
Region and Prior chemotherapy. Rank-transformed baseline ANC (within each stratum) will be 
included as a covariate in the model. In addition, the group-difference in DSN in Cycle 1-4 
(trilaciclib – placebo), its standard error and 96% CI will be generated and reported from a 
Satterthwaite t-test and presented.  
The treatment effect for occurrence of SN will be evaluated using modified Poisson regression 
model (Zou 2004). The model will include treatment, Region and Prior chemotherapy as the 
fixed effect with baseline ANC value as a covariate. The log-transformed number of cycles will 
be used as the offset in the model to account for the variable duration among patients. The 
2-sided p-value, adjusted relative risk (aRR) (trilaciclib vs placebo) and its 96% CI will be 
generated from the model and reported. 
Data listings will include all collected ANC values during Induction, derived DSN in Cycle 1-4, 
and indicator for occurrence of SN by cycle during Induction.  
8.2.4. 
Primary Analysis and Statistical Inferences for Key Secondary Endpoint -  
Overall Survival 
8.2.4.1. 
Timing for Overall Survival Analysis 
At the time when 157 death events are observed or at 52 months after the date of first 
randomization, whichever comes first, the study will be concluded, and the final study database 
will be locked to perform the OS analysis. 


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8.2.4.2. 
Statistical Significance Level for Analysis of Overall Survival 
As described in Section 8.2.2, a Type I error rate of 2-sided 𝛼𝛼2 = 0.01 is originally assigned to 
the analysis for OS with 𝛼𝛼1 = 0.04 being used for testing treatment effect on the primary 
endpoints. If the statistically significant treatment effect is established at the 0.04 level for DSN 
at Cycle 1-4 and occurrence of SN as outlined in Section 8.2.3, 𝛼𝛼1 = 0.04 will be added onto to 
𝛼𝛼2 = 0.01 to allow a full α of 2-sided 0.05 to test the treatment effect on OS following the 
fallback procedure (Wiens 2003).  
In summary, there are two possible scenarios with respect to statistical significance level when 
testing treatment effect on OS:  
• Scenario 1: If one of the tests in the fixed sequence procedure for DSN in Cycle 1-4 
and occurrence of SN fails to establish the statistical significance, OS will be tested at 
2-sided 0.01 level. 
• Scenario 2: If the statistical significance for DSN in Cycle 1-4 and occurrence of SN 
are established at the level of 2-sided 0.04, OS will be tested at 2-sided 0.05 level. 
8.2.4.3. 
Statistical Analysis Models for Overall Survival 
The number and percentage of patients who died or are censored will be summarized by 
treatment group. In addition, duration of total follow-up will also be summarized by treatment 
group. 
The treatment effect for OS will be primarily evaluated using a stratified log-rank test accounting 
for the factors of Region, Prior chemotherapy, and BRAF status. The magnitude of treatment 
effect, HR (trilaciclib vs. placebo) along with its (1-α) x100% CI will be estimated using a Cox 
proportional hazard model controlling for the same factors as included in the stratified log-rank 
test.  
For each treatment group, the Kaplan-Meier plots will be generated and the median, 25% and 
75% percentile of OS will be estimated using the Kaplan-Meier method with their corresponding 
95% CI calculated based on the method by Brookmeyer  and Crowley (1982). Additionally, 
Kaplan-Meier estimates will be provided for the survival probability along with their 95% CIs 
(Kalbfleisch, 1980) at selected landmarks of 24, 36, and 48 months for OS. 
Data listings will be generated for OS. The duration of total follow-up will be included in the OS 
data listing along with detailed information supporting the calculation of OS, the censoring 
indicator, and reasons for censoring.  
8.2.5. 
Estimand Framework and Sensitivity Analysis for Primary and Key Efficacy 
Endpoints 
The complete framework of estimands for the primary and key secondary endpoints following 
International Council for Harmonisation (ICH) E9 (R1) (2020) are presented in Appendix 2. The 
identified intercurrent event (ICE) and the strategies for ICE classification with the justifications 
are also elaborated for each of the estimands in the appendix.  
In this section, ICEs and strategies for ICE handling cited from Appendix 2 will be presented for 
each estimand and the corresponding sensitivity analysis, if warranted, will be described.  


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8.2.5.1. 
Estimand Framework and Sensitivity Analysis for DSN in Cycle 1-4 
The identified ICEs for one of the primary estimands, DSN in Cycle 1-4, the strategies for the 
primary analysis (Section 8.2.3) and the strategies for the sensitivity analyses are presented in 
Table 8.  
The justifications for the strategies from primary to sensitivity can be found in Appendix 2.  
Table 8: 
The Intercurrent Events and Handling Strategies for DSN in Cycle 1-4 
ICE 
Primary 
Sensitivity 
1. Patients who randomized but not 
dosed by any study drug 
Treatment Policy Strategy 
Principal Stratum Strategy 
2. Treatment discontinuation prior to 
any SN in Cycle 1-4 
Treatment Policy Strategy 
None 
3. Receipt of GCSF administration in 
Cycle 1-4 
Treatment Policy Strategy 
Hypothetical Strategy 
To address the potential impact of ICE 1 and 3 on the treatment effect for this estimand and 
based on the identified policy for sensitivity analysis, DSN in Cycle 1-4 will be derived using 
two alternative definitions:  
• Not to assign 0 for DSN for those patients who were in the mITT population but did not 
receive any study drug. These patients will then be automatically excluded from the 
analysis model.  
• Consider the first SN event that occurred after a dose of GCSF was administrated in 
Cycle 1, 2, 3, or 4 as non-event, and then re-derive the DSN based on rules described in 
Section 8.1.1. 
For the two alternatively derived DSN in Cycle 1-4, the treatment effect will be evaluated using 
the same statistical model as described in Section 8.2.3.2.  
In addition, treatment effect on DSN in Cycle 1-4 will be evaluated after adjusting for the 
potential impact of GCSF use in the first 4 cycles of Induction. In that analysis, the status of 
GCSF use in Cycle 1-4 (Yes or No) will be added to the primary analysis model for DSN in 
Cycle 1-4 as described in Section 8.2.3. Subgroup analysis for DSN in Cycle 1-4 for patients 
with or without GCSF use in the first 4 cycles of Induction will also be performed (see 
Section 8.5.1).  
8.2.5.2. 
Estimand Framework and Sensitivity Analysis for Occurrence of SN  
The identified ICEs for one of the primary estimands, occurrence of SN, the strategies for the 
primary analysis (Section 8.2.3) and the strategies for the sensitivity analyses are presented in 
Table 9.  
The justifications for the strategies from primary to sensitivity can be found in Appendix 2. 


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Table 9: 
The Intercurrent Events and Handling Strategies for Occurrence of SN 
ICE 
Primary 
Sensitivity 
1. Patients who randomized but not 
dosed by any study drug 
Treatment Policy Strategy 
Principal Stratum Strategy 
2. Treatment discontinuation from 
Induction prior to any SN 
Treatment Policy Strategy 
None 
3. Receipt of GCSF administration 
during Induction 
Treatment Policy Strategy 
Hypothetical Strategy 
To address the potential impact of ICE 1 and 3 on the treatment effect for this estimand and 
based on the identified policy for sensitivity analysis, the following sensitivity analyses will be 
performed for occurrence of SN. 
• Exclude those patients who were in the mITT population but did not receive any study 
drug from the analysis population, and then evaluate the treatment effect using the 
modified Poisson model as described in Section 8.2.3.2.  
• Re-define the binary variable of occurrence of SN by considering any SN events that 
occurred after a dose of GCSF administration as “No”, and then evaluate the treatment 
effect using the modified Poisson model as described in Section 8.2.3.2.  
In addition, treatment effect on occurrence of SN in Induction will be evaluated after adjusting 
for the potential impact of GCSF use during Induction. In that analysis, the status of GCSF use in 
Induction (Yes or No) will be added to the primary analysis model for occurrence of SN in 
Induction as described in Section 8.2.3. Subgroup analysis for occurrence of SN for patients with 
or without GCSF use in Induction will also be performed (see Section 8.5.1).  
To facilitate the understanding of GCSF administration in Induction and to provide information 
for the above stated sensitivity analysis, the first occurrence of SN in Induction, in Cycle 1 to 
Cycle 4, in Cycle 5 to Cycle 8, and in Cycle 9 to Cycle 12 will be tabulated by treatment group. 
In addition, the first occurrence of SN in Induction will also be tabulated by cycle for each 
treatment group.   
Furthermore, a logistic regression model with the terms of treatment, Prior chemotherapy, 
Region, baseline ANC values, and log-transformed duration of cycles in Induction as covariate 
will be used to evaluate treatment effect on occurrence of SN. The odds ratio, its 96% CI and the 
p-value will be generated and reported. A stratified Cochran-Mantel-Haenszel test with the 
stratum of Prior chemotherapy and Region will also be used to assess treatment effect on 
occurrence of SN in Induction. Model-adjusted relative risk, its 96% CI and p-value will be 
generated and reported.   
8.2.5.3. 
Estimand Framework for OS 
The identified ICEs for the key secondary estimand OS along with the corresponding strategies 
for the primary analysis (Section 8.2.4) are presented in Table 10. The justifications for the 
strategies from primary analysis and none for sensitivity analysis can be found in Appendix 2. 


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Table 10: 
The Intercurrent Events and Handling Strategies for OS 
ICE 
Primary 
Sensitivity 
1. Subsequent anticancer therapy  
Treatment Policy Strategy 
None 
2. Study discontinuation including lost-
to-follow up 
Treatment Policy Strategy 
None 
3. Curative intent surgical resection 
Treatment Policy Strategy 
None 
8.2.6. 
Analysis for Secondary Endpoints - Other Myelosuppression Endpoints 
Statistical analysis methods for other myelosuppression endpoints derived based on data 
collected in Induction (Section 8.1.3) are described in this section. Corresponding data listings 
will be provided.  
8.2.6.1. 
Analysis for Binary Myelosuppression Endpoints 
For each binary myelosuppression endpoint as specified in Table 6 in Section 8.1.3, the number 
and percentage of patients with at least one occurrence during Induction will be summarized by 
treatment group.  
The treatment effect will be evaluated using a modified Poisson regression model (Zou, 2004). 
The model includes the factors of Region and Prior chemotherapy as the fixed effect with 
corresponding baseline value as a covariate when applicable. The variable duration of Induction 
among patients will be adjusted by using the log-transformed duration of Induction (in the unit of 
cycles or weeks) as the offset variable in the model. A 2-sided p-value, aRR (trilaciclib versus 
placebo) and its 95% CI will be generated from the modified Poisson regression model and 
reported.  
Baseline value to be used as a covariate in the model is determined by the lineage of the endpoint 
(Table 6 in Section 8.1.3) and they are paired in the following manner: baseline ANC for 
neutrophil-related endpoints, baseline hemoglobin for RBC-related endpoints, and baseline 
platelet for platelet-related endpoints.  
The duration of Induction that is used to construct an offset variable in the model is the number 
of cycles in Induction for all binary endpoints but two: occurrence of RBC transfusion on/after 
Week 5 and occurrence of platelet transfusion. For these two endpoints, the total number of 
weeks in Induction that is the same as the duration of study drug exposure in Induction (defined 
in Table 3, Section 4.3) will be used as the duration variable.  
Additionally, the proportion of patients with Grade 3 or 4 neutropenia in Cycles 1 – 4, Cycles 5 – 
8, and Cycles 9 – 12 will be tabulated by treatment group.  
8.2.6.2. 
Analysis for Counting Myelosuppression Endpoints 
For the counting myelosuppression endpoints as specified in Table 6 (Section 8.1.3), the total 
number of the events, the duration of Induction (in the unit of cycles or weeks), and raw event 
rate per 100 units (weeks or cycles) will be summarized by treatment group.  


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The treatment group difference in the event rate will be assessed by a negative binomial model. 
The model includes the two factors of Region and Prior chemotherapy as the fixed effect with 
corresponding baseline value as a covariate when applicable. The various duration among 
patients will be adjusted in assessing treatment effect by using the log-transformed duration of 
Induction as the offset variable in the model. A 2-sided p-value, aRR (trilaciclib versus placebo) 
and its 95% CI will be generated from the negative binomial model and reported. 
Baseline value to be used as a covariate in the model is determined by the lineage of the endpoint 
(Table 6 in Section 8.1.3) and they are paired in the following manner: baseline ANC for 
neutrophil-related endpoint, baseline hemoglobin for RBC-related endpoints, and baseline 
platelet for platelet-related endpoints.  
The duration of Induction (used to calculate the raw event rate and to construct an offset variable 
in the model) is the number of cycles in Induction for the endpoints of number of GCSF 
administrations and number of dose reductions, and it is the number of weeks in Induction for 
the two other counting random variables: number of RBC transfusions on/after Week 5 and 
number of platelet transfusions. The total number of weeks in Induction (the same as the duration 
of study drug exposure in Induction) is defined in Table 3 (Section 4.3).  
8.2.7. 
Analysis for Secondary Endpoints - Healthcare Utilization Endpoints 
For the binary healthcare utilization endpoints (occurrence of hospitalizations due to any cause, 
occurrence of hospitalizations due to CIM, occurrence of hospitalizations due to sepsis or serious 
infections, and occurrence of IV antibiotic administration), the number and percentage of 
patients with at least one occurrence during Induction will be summarized by treatment group. 
The treatment effect will be evaluated using a modified Poisson regression model (Zou, 2004). 
The model includes the factors of Region and Prior chemotherapy as the fixed effect. The 
variable duration of Induction among patients will be adjusted by using the log-transformed 
cycles as the offset variable in the model. A 2-sided p-value, aRR (trilaciclib versus placebo) and 
its 95% CI will be generated from the modified Poisson regression model.  
For the counting endpoint, number of hospitalizations due to CIM, the total number of events, 
the total number of cycles in Induction, and raw event rate per 100 cycles will be summarized by 
treatment group. The treatment group difference in the event rate will be assessed by a negative 
binomial model. The model includes the two factors of Region and Prior chemotherapy as the 
fixed effect. The variable duration of Induction among patients will be adjusted by using the 
log-transformed number of cycles as the offset variable in the model. A 2-sided p-value, aRR 
(trilaciclib versus placebo) and its 95% CI will be generated from the negative binomial model.  
Corresponding data listings will be provided.  
8.2.8. 
Analysis for Secondary Endpoints - Other Anti-tumor Efficacy Endpoints 
8.2.8.1. 
Analysis for Secondary Endpoint - Progression Free Survival 
PFS analysis will be performed twice in this study. The first time is around the time point of 
35 months post first randomization and the second time at the end of the study. 


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The number and percentage of patients with a PFS event (radiographic disease progression or 
died due to any cause) or censored will be summarized by treatment group along with the 
reasons for censoring. Furthermore, the number and percentage of patients with disease 
progression or who died due to any cause will be summarized by treatment group with the 
number of PFS events as the denominator for percentage calculation.  
The treatment effect for PFS will be primarily evaluated using a stratified log-rank test 
accounting for the factors of Region, Prior chemotherapy, and BRAF status. The magnitude of 
treatment effect, HR (trilaciclib vs. placebo) along with its (1-α) x100% CI will be estimated 
using a Cox proportional hazard model controlling for the same factors as included in the 
stratified log-rank test.  
For each treatment group, the Kaplan-Meier plots will be generated and the median, 25% and 
75% percentile of PFS will be estimated using the Kaplan-Meier method with their 
corresponding 95% CI calculated based on the method by Brookmeyer  and Crowley (1982).  
Data listings will be generated. Tumor scan data will be included in the PFS data listing. The 
detailed information supporting the calculation of PFS along with the censoring indicator, and 
reasons for censoring will also be included.  
8.2.8.2. 
Analysis for Secondary Endpoints - Tumor Response and Duration of Objective 
Response 
The analysis for BOR and ORR (see variable definitions in Section 8.1.5) will be based on the 
RE population.  
Tumor response status classified by BOR will be tabulated by treatment group with the number 
and percentage of patients in each category of CR, PR, stable disease (SD), PD, or not evaluable 
(NE), where the percentages are calculated based on the number of patients in the RE population 
for the respective group.  
ORR along with its exact 95% two-sided CI using the Clopper-Pearson method will be computed 
for each treatment group. The treatment effect on ORR will be evaluated using a Cochran–
Mantel–Haenszel (CMH) test accounting for the factors of Region, Prior chemotherapy and 
BRAF status. The adjusted proportion difference (trilaciclib vs placebo) and its 95% CI will be 
calculated using CMH weight (as described in Kim, 2013). 
Confirmed ORR will be summarized and analyzed using the same methods as are used for the 
ORR. 
For patients who achieved confirmed CR or PR as BOR status, DOR will be calculated and 
analyzed. The Kaplan-Meier method will be used to estimate the median, 25% and 75% 
percentile of DOR for each treatment group, along with its 95% CI calculated using the method 
by Brookmeyer and Crowley (1982).  
Data listings will include tumor scan data, Investigator determined timepoint responses and 
BOR, programmatically derived tumor response status, and confirmed tumor response status.  


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8.2.9. 
Exploratory Analysis - Anti-tumor Endpoints by CDK4/6 Biomarker Signature 
Analyses described in this section will be performed at the time of final analysis.  
The distribution of CDK4/6 signature by treatment group will be tabulated for the mITT 
population. A Chi-square test will be used to assess the difference in distribution of patients’ 
CDK4/6 signature status (i.e., CDK4/6 independent, CDK4/6 dependent, and CDK4/6 
indeterminate) between the two treatment groups. 
Anti-tumor endpoints (ORR, PFS, and OS) will be evaluated by subgroup of patients with 
different CDK 4/6 signature status in the mITT population. Within each type of signature, 
treatment group difference in ORR and its 95% CI will be generated using the same methods as 
described in Section 8.2.8. The treatment effect for PFS (or OS) will be estimated by a hazard 
ratio (HR) and its 95% CI generated from a Cox proportional hazard model with the same terms 
as described in Section 8.2.4.3.  
Data listings include CDK 4/6 signature status and above-mentioned anti-tumor endpoints.  
8.2.10. 
Exploratory Analysis - Myelosuppression Endpoints during Overall Treatment 
Period 
The overall treatment period includes Induction and Maintenance (Section 4.3) with fluorouracil, 
leucovorin, and bevacizumab continued from Induction to Maintenance.  
Definitions for occurrence of SN and other myelosuppression endpoints as described in Table 6 
in Section 8.1.3 can all be extended to include data collected up to the end of last cycle in 
Maintenance. Similarity, such extension of definition can be made to healthcare utilization 
endpoints (Section 8.1.4).  
Myelosuppression endpoints and healthcare utilization endpoints during the overall treatment 
period will be summarized with appropriate summary statistics by treatment group. Treatment 
group difference for each of these endpoints will be quantified by a point estimate and its 
95% CI using the similar model as outlined in Section 8.2.6 and Section 8.2.7. No testing of 
treatment group difference will be conducted.  
Corresponding data listings will be provided.  
8.3. 
Handling of Missing Data 
Since all scheduled and unscheduled laboratory assessments will be included in deriving 
myelosuppression endpoints (Section 8.1.1 and Section 8.1.3) and the patients must have 
demonstrated the following before continuing the study treatment from one cycle to the next: 
ANC < 1.0 x 109/L, Hgb <8.0 g/dL, or platelets < 50.0 x 109/L based on the CTCAE toxicity 
criteria. As such, the potential risk of missing complete blood count (CBC) data collection to 
derive the primary endpoints and other myelosuppression endpoints is at minimum.  
Missing data impact on other endpoints are in general managed by derivation rules (Section 8.1).  
8.4. 
Efficacy Endpoints to Analyzed on Per-protocol Population 
The definition for the PP population is provided in Section 3.3.  


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Since the treatment effect on the primary efficacy endpoints along with other neutrophil-related 
endpoints (Table 11) can be relatively more easily impacted by inappropriate use of supportive 
care, like GCSF, these endpoints will be analyzed in PP population using the same statistical 
models as described in Section 8.2.3.2 and Section 8.2.8.  
Table 11: 
Endpoints to be Analyzed in the Per-protocol Population 
Lineage  
Endpoint 
Neutrophils 
DSN in Cycle 1-4 
Occurrence of severe neutropenia  
Occurrence of GCSF administration 
Number of GCSF administrations (event rate per 100 cycle) 
Occurrence of Grade 3 or 4 neutropenia 
DSN=duration of severe neutropenia; GCSF=granulocyte colony stimulating factor 
8.5. 
Subgroup Analysis 
Subgroup analysis for the primary efficacy endpoints will be performed in the first planned 
analysis, whereas subgroup analysis for PFS and OS will be conducted when PFS and OS are 
analyzed, respectively.  
8.5.1. 
Subgroup Analysis for DSN in Cycle 1-4 and Occurrence of SN in Induction 
DSN in Cycle 1-4 and occurrence of SN in Induction will be the dependent variables to perform 
the subgroup analysis for each of the following subgroups: 
1. Age group (< 65 or ≥ 65) 
2. Gender (male or female) 
3. Region (US, Eastern Europe, Western Europe, and China) 
4. Prior chemotherapy (yes or no) 
5. GCSF administration (see below for different definitions of this subgroup for DSN in 
Cycle 1-4 and occurrence of SN) 
DSN at Cycle 1-4 and occurrence of SN in Induction will be tabulated within each stratum of a 
subgroup by treatment group. Within each stratum of each subgroup, the group mean difference 
for DSN in Cycle 1-4 will be generated from a Satterthwaite t-test along with its SE and 95% CI.  
Within each stratum of Age and Gender, the aRR and its 95% CI for occurrence of SN in 
Induction will be generated using a modified Poisson model as outlined in Section 8.2.3. The 
treatment-by-subgroup interaction will be tested by a different modified Poisson model with 
additional terms of subgroup and treatment-by-subgroup interaction. Statistically significant 
interaction is judged by an interaction p-value that is < 0.20. 
To generate aRR and its 95% CI for occurrence of SN with the stratum of subgroup Region or 
Prior chemotherapy, the same factor will be eliminated from the modified Poisson model. There 
will be no treatment-by-subgroup interaction testing for these two subgroups since they were 


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either created from a randomization stratification factor or were chosen as a randomization 
stratification factor.  
GCSF use in the first 4 cycles of Induction (Yes or No) will be used as the subgroup to perform 
the subgroup analysis for DSN in Cycle 1-4, while GCSF in Induction (Yes or No) will be used 
as the subgroup to perform the analysis for occurrence of SN.  
Subgroup analysis results across all subgroups will be graphically displayed by forest plot for 
DSN in Cycle 1-4 and occurrence of SN, respectively. For DSN at Cycle 1-4, the mean 
difference in DSN and its 95% CI for each stratum of a subgroup will be displayed; for 
occurrence of SN, the aRR and its 95% CI for each stratum of a subgroup will be displayed.  
8.5.2. 
Subgroup Analysis for PFS and OS 
The following subgroups have been identified to assess whether treatment effect on PFS and OS, 
respectively, are consistent for each of the identified subgroups.  
1. Age group (< 65 or ≥ 65) 
2. Gender (male or female) 
3. Baseline ECOG Status (0 or 1) 
4. Region (US, Eastern Europe, Western Europe, and China) 
5. Prior chemotherapy (yes or no) 
6. BRAF status (yes or no) 
Within each stratum of Age, Gender, Race, and ECOG, a Cox proportional hazard model with 
the terms of treatment, Region, Prior chemotherapy and BRAF status will be used to estimate the 
HR (trilaciclib over placebo) and its 95% CI for PFS and OS, respectively. Treatment-by-
subgroup interaction will be tested by a different Cox model with additional terms of the 
subgroup and the treatment-by-subgroup interaction. Statistically significant interaction is judged 
by an interaction p-value that is < 0.20. 
To generate the HR and its 95% CI within each stratum for the subgroup Region, Prior 
chemotherapy or BRAF status, the same factor will be eliminated from the Cox model to 
estimate the HR and its 95% CI. Treatment-by-subgroup interaction for these subgroups will not 
be tested, since these three were either chosen as randomization stratification factors or obtained 
from a randomization stratification factor because of the anticipated impact on the outcome of 
PFS or OS. 
A forest plot for HR and its 95% CI across all subgroups will be produced for PFS and OS, 
respectively. 
In addition, the number and percentage of patients who died among those patients who 
underwent curative intent surgical resection during the study will be summarized. If the number 
of patients who underwent curative intent surgical resection is sufficient to allow the application 
of a Cox proportional regression model, the HR and its 95% CI for OS will be generated from a 
Cox regression model with the term of treatment.  


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9. 
SAFETY ANALYSIS 
9.1. 
General Consideration of Safety Analysis 
Safety data summaries will be on based the Safety Population as defined in Section 3.4 of this 
SAP.  
Unless otherwise specified, all safety data collected in Induction (i.e., from Day 1 of Cycle 1 in 
Induction to the end of last cycle in Induction) will be summarized in the first planned analysis. 
At the time of final analysis, all safety data collected during the study will be summarized. Safety 
variable definitions and the data analysis plan as described in this section will be applied to both 
analyses unless otherwise specified. As such, the phrase “during the analysis period” refers to the 
respective analysis period of interest (i.e., the first planned analysis or the final analysis). All 
safety data collected through scheduled or non-scheduled visits during the analysis period will be 
included in the safety data analyses. 
Safety data will be summarized using descriptive statistics by treatment group and for overall 
patients when appropriate. No inferential statistical comparisons for between-group differences 
will be made.  
Missing safety data will generally not be imputed, unless otherwise specified.  
Baseline assessment is, in general, defined as the last non-missing observation prior to receiving 
the first dose of any study drug.  
9.2. 
Adverse Events  
9.2.1. 
Definition and Classification of Adverse Events 
AEs are defined as those AEs occurring on or worsening in severity after the first dose of any 
study drug (i.e., the conventional treatment-emergent AEs). Only AEs as described above are 
collected in the study database. All AEs are reported since the first dose of any study drug until 
30 days after the last dose of study drug. SAEs thought to be related to a study specific procedure 
are also collected between the time the patient signs the informed consent and the first dose of 
any study drug.  
AEs will be coded from verbatim text to PT and grouped by primary SOC according to 
MedDRA version 24.1. The severity (toxicity grades 1-5) of AEs will be graded according to the 
NCI CTCAE version 5.0 by the Investigator.  
Hematologic Adverse Events 
AEs related to hematologic toxicity will be collapsed based on the PTs from MedDRA 
version 24.1 and will be summarized separately (see Section 9.2.3). Table 12 outlines those PTs 
that will be collapsed.  


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Table 12: 
Hematologic Preferred Terms to be Collapsed 
Term presented in the Output  
Preferred Term 
Neutropenia 
Neutropenia 
Neutrophil count decreased 
Anemia 
Anemia 
Anaemia 
Red blood cell count decreased 
Hemoglobin decreased 
Thrombocytopenia 
Thrombocytopenia 
Platelet count decreased 
Lymphocytopenia 
Lymphocytopenia 
Lymphopenia 
Lymphocyte count decreased 
Leukopenia 
Leukopenia 
White blood cell count decreased 
Trilaciclib Adverse Events of Special Interest 
AEs of special interest (AESI) for trilaciclib have been identified, reflecting either the findings in 
the AEs from the previous studies of trilaciclib or class effects for CDK 4/6 inhibitors. AESI for 
trilaciclib will be identified by searching MedDRA PTs based on the Customized MedDRA 
Queries as detailed in Appendix 2.  
Specifically, trilaciclib AESI include the following 6 categories: 
• Phlebitis/Thrombophlebitis 
• Injection site reaction 
• Acute drug hypersensitivity reaction 
• Hepatotoxicity 
• Interstitial lung disease /Pneumonitis 
• Embolic and thrombotic events, venous 
9.2.2. 
Imputation Rules for Missing Start or Stop Date for Adverse Events 
AEs with start/stop dates that are partially or completely missing that are not ongoing at the time 
of data cutoff will be imputed according to the specifications below in order to classify AEs. 


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For completely missing or partially missing AE start date: 
• If the start date has month and year but day is missing, the first dose date will be used 
if the month and year is the same as the first dose date, otherwise, the first day of the 
month will be used. 
• If the start date has year, but day and month are missing, then the first dose date will 
be used if the year is the same as the first dose date, otherwise January 1st will be 
used. 
• If the start date is completely missing, then it will be imputed as the first dose date of 
study drug. 
After the imputation, the imputed start date will be compared with AE stop date, if available. If 
the imputed start date is later than the stop date, the start date will be imputed with the stop date 
instead. 
For completely missing or partially missing AE stop dates: 
• If the stop date has month and year but day is missing, the last day of the month will 
be used. 
• If the stop date has year, but day and month are missing, December 31st will be used.  
• If the stop date is completely missing, the date of PTV will be used; if PTV does not 
exist, then the last dose date + 30 days will be used. 
After the imputation, the imputed AE stop date will be compared against the death date for 
patients who died. If the date is later than the death date, the date of death will be used to impute 
the stop date instead. 
Every attempt will be made to obtain complete information for AEs regarding severity 
(i.e., CTCAE Grade) and relationship to drug. However, in the rare case of missing data, the 
following conservative approach will be taken for summary purpose. The non-imputed raw data 
will be presented in AE listings. 
• Missing AE grade will be classified as ‘Grade 3’  
• Missing AE relationship will be classified as “Related”  
9.2.3. 
Analysis for Adverse Events 
AEs will be summarized by number and percentage of patients having at least one occurrence at 
the PT and SOC level by treatment group and overall. Patients with more than one occurrence of 
the same SOC (PT) will be counted only once within the SOC (PT) categorization. In general, 
the percentage of patients with an event will be calculated using the number of patients in the 
safety population as the denominator either by each treatment group or overall.  
AEs will also be summarized by CTCAE grade and relationship to study drug (to any study 
drugs and to each individual study drug). Should a patient experience more than one occurrence 
of the same SOC (PT), the patient’s worst occurrence (highest grade or highest related causality) 
will be used for the analysis and reporting.  


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In AE summaries, the SOC and PT within a SOC will be presented in descending order based on 
the incidence from all patients. If the incidence for two or more PTs is equal, these PTs will be 
presented in alphabetical order.  
An overall AE summary table will be generated to present general information related to AEs 
including the following categories: number and percentage of patients with any AE, Serious 
AEs, AEs with CTCAE Grade ≥ 3 or 4, AEs leading to discontinuation of any study drug, AEs 
leading to death, AEs related to study drug (to any study drug, to trilaciclib/placebo, and to each 
other study drug), and AESI for trilaciclib/placebo.  
At the time of performing final analysis, in addition to generating the overall AE summary table 
for the data collected during entire the entire treatment period, an overall AE summary table will 
also be generated for the AEs collected during Maintenance. That is, AEs reported after the first 
dose in Cycle 1 of Maintenance to the end of last cycle in Maintenance (Table 3 in Section 4.3). 
In addition, the following summary tables will be generated, and they will be, in general, 
presented by SOC and PT unless otherwise specified.  
1. AEs by decreasing frequency of PT 
2. AEs by SOC, PT, and CTCAE Grade 
3. AEs with CTCAE Grade 3 or 4 by SOC and PT 
4. AEs leading to discontinuation of any study drug  
5. AEs leading to death 
6. AEs related to any and each study drug  
7. Hematological AEs by collapsed PT and CTCAE grade  
8. Serious AEs 
9. Serious AEs related to any and each study drug  
10. AESI for trilaciclib will be summarized.  
In the above, hematological AEs will be reported as they are with the exception of item 7 
(Hematological AEs by collapsed PT and CTCAE grade), for which the collapsed terms as 
specified in Table 12 (Section 9.2.1) will be reported by the descending order of frequency based 
on the overall group.  
Corresponding AE listings will be provided to clearly indicate, at the patient level, the AE and 
SAE occurrence, start/stop date, relative study days to onset or stop, grade and causality for each 
AE. AESI for trilaciclib/placebo will also be listed with a similar level of detail.  
9.3. 
Clinical Laboratory Data 
9.3.1. 
Laboratory Parameters 
Blood and urine samples for the determination of clinical chemistry, hematology, and urinalysis 
laboratory variables described in Table 13 will be measured according to Schedule of 
Assessments in Appendix 1. 


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Table 13: 
Laboratory Categories and Parameters 
Lab Category 
Lab Parameters 
Chemistry 
albumin, alkaline phosphatase (ALP), total bilirubin, calcium, chloride, creatinine, 
glucose, inorganic phosphorus, potassium, total protein, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), sodium, 
blood urea nitrogen (BUN) 
Hematology 
hemoglobin, white blood cell (WBC), platelet counts, absolute neutrophil count 
(ANC), absolute lymphocyte count (ALC) 
Urinalysis 
semiquantitative dipstick: specific gravity, pH, evaluation of glucose, protein, 
bilirubin, ketones, leukocytes, and hemoglobin microscopic examination, including 
red blood cell (RBC), white blood cell (WBC), and casts will be performed, if 
necessary 
Lab = laboratory.  
For hematology parameters, if absolute counts are not provided, those values will be derived 
from the differential counts by multiplying differential value with leukocyte value from the same 
sample. The normal ranges will be left missing in those cases.  
Clinical chemistry and hematology assessments will be graded according to NCI CTCAE 
criteria, Version 5.0 or later. The determination of CTCAE grade for each measurement will be 
based on the collected laboratory values and will not involve clinical judgement. For laboratory 
parameters that CTCAE toxicity grade are not available, they will not be included in the analyses 
in which toxicity grades are reported. Instead, these parameter results will be classified and 
reported by the low/normal/high based on the laboratory normal reference ranges.  
Abnormal Hepatic Laboratory Values 
Abnormal hepatic laboratory values are defined in the following categories including any 
occurrence among all on-treatment, post-baseline assessments including scheduled and 
unscheduled values.  
• Hy’s Law: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
> 3x the upper limit of normal (ULN), alkaline phosphatase (ALP) < 2x ULN, and 
total bilirubin ≥ 2x ULN 
• AST:  > 3 and ≤ 5x ULN, > 5 and ≤ 8x ULN, > 8 and ≤ 10x ULN, > 10 and ≤ 20x 
ULN, and > 20x ULN; AST > 5x ULN for more than 5 weeks. 
• ALT:  >3 and ≤ 5x ULN, > 5 and ≤ 8x ULN, > 8 and ≤ 10x ULN, > 10 and ≤ 20x 
ULN, and > 20x ULN; ALT > 5x ULN for more than 5 weeks. 
• Total bilirubin > 1.5xULN and < 2xULN, ≥ 2xULN  
 
9.3.2. 
Analysis for Laboratory Parameters  
Laboratory data from all central and local laboratories will be included in analyses. Different 
laboratories are likely using slightly different normal reference ranges, which should not affect 
the planned analysis since they are all categorical and reported based on CTCAE toxicity grade 
or relationship to the normal ranges. The default convention for reporting of laboratory units will 


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be standard international (SI) units. If a lab value is reported using an inequality symbol e.g., less 
than (<) a certain value, or greater than (>) a certain value, the given numeric value will be used 
in the summary. Data will be presented in listings with their inequality symbol.  
For each parameter in the clinical chemistry and hematology laboratory group, respectively, 
CTCAE toxicity grading is used to classify patients into a toxicity grade from 1 to 4 for each 
timepoint assessment. The number and percentage of patients with highest grade during the 
treatment period will be summarized for each grade from 1 to 4 and Grade 3-4 by treatment 
group, along with such summary for the value collected at baseline.  
For the laboratory parameters that cannot be classified by CTCAE grade, the number and 
percentage of patients in the categories of treatment-emergent low or treatment-emergent high 
based on the normal reference range associated with the parameter will be summarized by 
treatment group.  
In addition, shift in CTCAE grade from baseline to the worst post-baseline value during 
treatment period will be produced for each treatment group. The shift tables will include patients 
who had non-missing baseline and at least one non-missing post-baseline value for the parameter 
of interest.  
The number and percentage of patients in each category of abnormal hepatic laboratory values 
will be summarized by treatment group. 
Laboratory parameters will be listed by the group of chemistry, hematology, and urinalysis. In 
addition, coagulate laboratory parameters as collected for some patients as part of the entry 
criteria will also be presented in the data listing. In the data listing, flags that indicate the 
corresponding CTCAE grades and the classifications relative to the laboratory reference ranges 
will be included. In addition, a separate listing will be prepared for patients who met Hy’s law.  
9.4. 
Vital Signs  
9.4.1. 
Vital Sign Parameters 
Vital signs including heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP), 
weight, height, and body temperature will be measured according to Schedule of Assessments in 
Appendix 1.  
Baseline vital signs refers to the measurements taken at the Screening visit. Post-baseline 
assessments refer to the measurements taken after the first dose of any study drug and during 
treatment period. Change from baseline to the highest/lowest value across all post-baseline 
measurements for each vital sign parameter will be calculated. Patients with who had a 
non-missing baseline and at least one non-missing measurement post-first dose for a given 
parameter will be included in the calculation.  
Patients are classified with respect to the criteria of potentially clinically significant (PCS) 
findings of vital signs, which are defined by the highest/lowest value among post-baseline 
assessments and/or the change from baseline to the highest/lowest observed value. Details of 
PCS criteria for vital signs can be found in Table 14.  


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Table 14: 
Criteria for Potentially Clinically Significant Vital Signs 
 Parameter   
Direction  
Highest/Lowest Observed 
Value   
Change from Baseline to the 
Highest/Lowest Observed Value 
 SBP   
High 
 
 ≥180 mmHg   
 Increase ≥40 mmHg   
    
Low 
 
 ≤ 90 mmHg   
 Decrease ≥40 mmHg   
 DBP   
High 
 
 ≥105 mmHg   
 Increase ≥ 20 mmHg   
    
Low 
 
 ≤ 50 mmHg   
 Decrease ≥20 mmHg   
 Heart Rate 
High 
 
 ≥ 120 bpm   
 Increase ≥40 bpm   
    
Low 
 
  ≤ 50 bpm   
 Decrease ≥40 bpm  
 Weight   
High 
 
--   
 Increase ≥10%   
 
Low 
 
 -- 
 Decrease ≥10% 
bpm=beats per minute; DBP-diastolic blood pressure; SBP=systolic blood pressure 
9.4.2. 
Analysis for Vital Signs   
The number and percentage of patients who meet any PCS criteria for each vital sign parameter 
as well as for each criterion will be summarized by treatment group.  
All observed vital sign values, change from baseline at each post-first dose assessment, and PCS 
flag will be listed. 
9.5. 
ECOG Performance Status  
ECOG performance status was assessed at the Screening Visit and at Day 1 of each treatment 
cycle during the study.  
A shift table that tabulates ECOG status at baseline and the worst status post first dose of any 
study drug during the treatment period will be generated for each treatment group. Patients 
missing baseline or without any post baseline ECOG score will be excluded from the analysis.  
All ECOG data will be included in a data listing.  
9.6. 
12-lead Electrocardiograms 
9.6.1. 
Electrocardiograms Parameters 
The standard 12-lead Electrocardiogram (ECG) will collect heart rate, PR interval, QRS interval, 
RR interval, and QT interval at the frequency according to Schedule of Assessments in 
Appendix 1. Investigator’s clinical interpretation of 12-lead ECG results by normal or abnormal 
will also be collected. 
Since either QTcF or QTcB could be collected by different study sites, QTcF (using Fridericia's 
method) will be calculated from the QT and RR (converted from collected ms to sec) intervals 
based on the formula:  


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QTcF = Uncorrected QT/ (RR Interval)^1/3, if QT and/or RR are missing, the QTcF will be left 
as missing.  
Change from baseline to the highest/lowest value across all post-baseline measurements for 
QTcF will be calculated. Patients with who had a non-missing baseline and at least one 
non-missing measurement post-first dose will be included in the calculation.  
The potentially clinically significant ECG findings are defined by the highest/lowest value across 
all post-baseline assessments while during the treatment period for all parameters except for 
QTcF, for which both observed values and change scores are used to define the PCS findings 
(Table 15). For QTcF, a total of 5 different criteria are defined with some of these are mutually 
exclusive and some cumulative (denoted by Criterion Index in Table 15). 
Table 15: 
Criteria for Potentially Clinically Significant ECG Findings 
ECG Parameter  
Direction or 
Criterion Index 
Highest/Lowest 
Observed Value   
Change from Baseline to 
the Highest/Lowest 
Observed Value 
RR Interval   
High 
> 1200 ms   
-- 
 
Low 
< 500 ms   
-- 
PR Interval   
High 
≥ 210 ms   
-- 
QRS Interval   
High 
≥ 120 ms   
-- 
    
Low 
≤ 50 ms   
-- 
QT Interval   
High 
≥ 500 ms   
-- 
    
Low 
≤ 300 ms   
-- 
QTcF  
Index 1  
(mutually exclusive) 
≥ 500 msec 
-- 
 
 
≥ 480 and < 500 msec 
-- 
 
 
≥ 450 and < 480 msec 
-- 
 
 
≤ 300 msec 
-- 
 
Index 2  
≥ 480 msec 
-- 
 
Index 3 
≥ 450 msec 
-- 
 
Index 4  
(mutually exclusive) 
-- 
Increase ≥ 60  
 
 
-- 
Increase ≥ 30 and < 60 ms 
 
Index 5 
-- 
Increase ≥ 30 ms 
9.6.2. 
Analysis for Electrocardiograms Parameters 
For each ECG parameter in Table 15, the number and percentage of patients who met each 
potentially clinically significant criterion will be summarized by treatment group.  


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Investigator’s clinical interpretation of the 12-lead ECG results (normal or abnormal) will be 
tabulated to present shift from baseline to the worst case post-dose during the treatment period 
by treatment group. Similarly, a shift table from baseline to the last post-baseline assessment 
during the treatment period will be generated for each treatment group.  
All ECG parameters as collected along with corrected values of QTcF will be included in the 
data listing. In the listing, the flag of meeting a PCS criterion and the flag indicating 
investigator’s determined abnormality are also included.  
 


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10. 
CHANGES FROM THE PROTOCOL 
• In the protocol Section 5, it stated that occurrence and number of events will be evaluated 
for each of the secondary myelosuppression endpoints. Several of these endpoints are 
expected to have low repeated counts or the summaries of number of events are expected 
to be non-informative, therefore, the following endpoints will only be analyzed for 
occurrence but not for the number of events:  
Febrile neutropenia AEs, Grade 3 or 4 decreased hemoglobin laboratory values, ESA 
administration, Grade 3 or 4 decreased platelet count laboratory values, Grade 3 or 4 
hematologic lab values, number of all-cause hospitalizations, oral or oral + IV antibiotic 
use. 
• In the SAP, an additional endpoint of Grade 3 or 4 neutropenia derived from the 
laboratory parameter ANC has been added to evaluate the extent of clinically relevant 
neutropenia more fully. While Grade 4 neutropenia during Induction and the duration of 
Grade 4 neutropenia in Cycle 1-4 are used as the primary endpoints, both Grade 3 and 
Grade 4 neutropenia are important attributors to dose reductions, cycle delays, and 
subsequent use of prophylactic GCSF. Therefore, it is believed that evaluating treatment 
effect on this endpoint will be clinically meaningful.  
 


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11. 
REFERENCES  
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 
1982;29-41.  
ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on 
statistical principles for clinical trials, February 17, 2020. 
Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. New York: John 
Wiley & Sons. 1980 
Kim Y, Won S. (2013) Adjusted proportion difference and confidence interval in stratified 
randomized trials. PharmaSUG; Paper SP-04. 
Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI and bevacizumab for 
metastatic colorectal cancer. N Engl J Med. 2014;371(17):1609-18. 
Quade. Rank analysis of covariance. Journal of the American Statistical Association 
1967;62:1187-1200. 
Rossini D, Boccaccino A, Sbrana A, et al. Clinical impact of neutropenia and febrile neutropenia 
in metastatic colorectal cancer patients treated with FOLFOXIRI/bevacizumab: a pooled analysis 
of TRIBE and TRIBE2 studies by GONO. (2021) ESMO Open. Vol 6, Issue 6.  
Wiens BL. A fixed sequence Bonferroni procedure for testing multiple endpoints. 
Pharmaceutical Statistics. 2003;2:211-15. 
Zou G. A modified Poisson regression approach to prospective studies with binary data. Am J 
Epidemiol. 2004;159(7):702-6. 
 


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12. 
APPENDICES  


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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Table 16: 
Schedule of Assessments: Screening and Induction Cycle 1 
Assessment 
Screening 
Rand. 
Induction Cycle 1 (14-day cycle) 
Day 
-28 to -1 
-3 to -1a 
1 
2 
4  
(±1 day) 
6  
(±1 day) 
8  
(±1 day) 
10  
(±1 day) 
12  
(±1 day) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History and CRC Historyb 
X 
 
 
 
 
 
 
 
 
MMR/MSS and BRAF V600E statusc 
X 
 
 
 
 
 
 
 
 
Eligibility Evaluation and Randomization 
X 
X 
 
 
 
 
 
 
 
G8 Health Status Screening Tool  
(Patients > 70yrs only) 
X 
 
 
 
 
 
 
 
 
Archived tumor sample 
X 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
 
X 
 
 
 
 
 
 
Physical Examd 
X 
 
X 
 
 
 
 
 
 
Height, Weight 
Xe 
 
X 
 
 
 
 
 
 
Vital Signs 
X 
 
Xf 
 
 
 
 
 
 
12-lead Electrocardiogram 
Xg 
 
Xg 
Xg 
 
 
 
 
 
Clinical Chemistry 
X 
 
Xh 
 
 
 
 
 
 
Hematology 
X 
 
Xi 
X 
X 
X 
X 
X 
X 
INR/aPTT 
X 
 
 
 
 
 
 
 
 
Urinalysis (dipstick) 
X 
 
X 
 
 
 
 
 
 
Pregnancy test (WOCBP)j 
 
X 
 
 
 
 
 
 
 


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Assessment 
Screening 
Rand. 
Induction Cycle 1 (14-day cycle) 
Day 
-28 to -1 
-3 to -1a 
1 
2 
4  
(±1 day) 
6  
(±1 day) 
8  
(±1 day) 
10  
(±1 day) 
12  
(±1 day) 
Tumor Assessment by RECIST v1.1k 
X 
 
 
 
 
 
 
 
 
Trilaciclib or Placebol 
 
 
X 
X 
 
 
 
 
 
Irinotecan 
 
 
X 
 
 
 
 
 
 
Oxaliplatin 
 
 
X 
 
 
 
 
 
 
Leucovorin 
 
 
X 
 
 
 
 
 
 
Fluorouracil 
 
 
X 
X 
 
 
 
 
 
Bevacizumab 
 
 
X 
 
 
 
 
 
 
FACT-An (includes FACIT-F), FACT-C,  
PGIS, and PGICm 
 
 
X 
 
 
 
X 
 
 
EQ-5D-5L 
 
 
X 
 
 
 
X 
 
 
Blood sample for PKn 
 
 
X 
X 
 
 
 
 
 
Blood sample for Immunologic and 
Hematologic Markers 
 
 
X 
 
 
 
 
 
 
AEs 
 
 
X 
Concomitant Medications 
Xb 
Xb 
X 
AE=adverse event; aPTT=activated partial thromboplastin time; β-hCG=beta human chorionic gonadotropin; CRC=colorectal cancer; CT=computed 
tomography; ECOG=Eastern Cooperative Oncology Group; EQ-5D-5L=5-level EQ-5D; FACT-An=Functional Assessment of Cancer Therapy – Anemia; 
FACIT-F=Functional Assessment of Chronic Illness Therapy – Fatigue; FACT-C=Functional Assessment of Cancer Therapy – Colorectal; FACT-G=Functional 
Assessment of Cancer Therapy – General; INR=international normalized ratio; IWRS=interactive web response system; MMR=mismatch repair; MRI=magnetic 
resonance imagining; MSI=microsatellite instable; PE=physical exam; PGIC=Patient Global Impression of Change; PGIS=Patient Global Impression of 
Severity; PK=pharmacokinetic; pMMR/MSS=proficient mismatch repair/microsatellite stable; RECIST=Response Evaluation Criteria in Solid Tumors; 
yrs=years; WOCBP=women of childbearing potential. 
a Patients can be randomized and receive Cycle 1 Day 1 on the same day. When required by institutional procedures, randomization will be allowed up to 7 days 
prior to dosing without a protocol deviation. Screening procedures must be completed prior to randomization and the screening window remains 28 days. 
b Including medical and surgical history, documentation of CRC diagnosis and prior CRC therapy, and prior medications (current and those taken within 14 days 
of informed consent). 


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c Documentation of BRAF V600E and pMMR/MSS is required; patients with deficient MMR/MSI-high or MSI-low CRC are not eligible for this study. If 
historical pMMR/MSS and/or BRAF V600E mutational status are not known, a tumor specimen (archival or fresh biopsy) must be sent for testing and results 
must be available at the time of randomization in IWRS. If testing cannot be completed using a standard clinical assay performed institutionally/locally, the 
tumor specimen may be sent to the Sponsor’s designated central laboratory for analysis. If institutional/local testing is unavailable, please contact your CRA.  
d Full PE at Screening, brief PE at all other timepoints. 
e Height measured only at Screening; weight measured at Screening and Day 1 of each cycle in Induction and Maintenance. 
f Vitals (BP, HR, temperature) should be taken 15 minutes (± 10 minutes) before and after the trilaciclib/placebo infusion. 
g Perform triplicate ECGs at screening and on Day 1 of Cycle 1 at the following timepoints: predose (trilaciclib/placebo) at any time prior to dosing, within 
30 minutes following the end of the trilaciclib/placebo infusion, and at 3 hours after the start of trilaciclib/placebo infusion (± 30 minutes). Triplicate ECGs 
should also be performed on Day 2 of Cycle 1 at the following timepoints: predose (trilaciclib/placebo) at any time prior to dosing and within 30 minutes 
following the end of the trilaciclib/placebo infusion. Additional ECGs during the study may be performed as clinically indicated. Any ECG with a QTc value of 
> 500 or any other clinically significant abnormal finding should be repeated every 5 minutes for a total of three ECGs to confirm this finding, if not already 
recorded in triplicate.  
h Clinical chemistry and urinalysis may be obtained up to 3 calendar days prior to dosing. 
i Hematology may be obtained up to 1 calendar day prior to dosing. 
j Female patients of childbearing potential: serum β-hCG at enrolment (eg, signed consent and during window allowing randomization in IWRS; results should 
be available prior to randomization).  
k Initial staging should include, at a minimum, CT or MRI of chest, abdomen and pelvis. IV contrast should be used unless contraindicated. Oral contrast can be 
used at the Investigator’s discretion. 
l Trilaciclib or placebo will be administered as a 30-minute IV infusion prior to FOLFOXIRI/bevacizumab chemotherapy on Day 1 and on Day 2 of every cycle. 
Chemotherapy cannot be administered until after completion of the trilaciclib or placebo infusion on Day 1. The interval between the dose of trilaciclib or 
placebo and the first dose of chemotherapy on Day 1 should not be greater than 4 hours. The second dose of trilaciclib/placebo should be administered on 
Day 2. Trilaciclib or placebo will only be administered if chemotherapy is also to be administered on that day. 
m FACT-An, FACT-C, PGIS, and EQ-5D-5L will be administered on Days 1 and 8 of Cycle 1. PGIC will only be administered on Day 8 of Cycle 1. FACIT-F is 
embedded within the FACT-An. Patient-reported outcome questionnaires may be administered up to 1 calendar day prior to the first dose of each cycle; 
questionnaires administered on Day 8 may be obtained ±1 day of scheduled visit; NOTE: questionnaires should be completed on the same day blood sample is 
collected for hematology assessment. Questionnaires must be completed prior to the administration of any study drug and should be administered prior to the 
conduct of any study procedures at that visit. 
n Four blood samples for PK analysis of trilaciclib and any metabolites will be collected: on Cycle 1 Day 1 at the end of trilaciclib/placebo infusion (within 5 
minutes prior to the end of the infusion), and at 25 to 45 minutes and 4-6 hours post the end of the trilaciclib/placebo infusion, as well as predose 
(trilaciclib/placebo) on Cycle 1 Day 2. Three samples will be collected for PK analysis of irinotecan and its metabolite (SN-38): on Cycle 1 Day 1 at the end of 
irinotecan infusion (within 5 minutes prior to the end of the infusion) and at 4-6 hours post the end of the irinotecan infusion as well as predose 
(trilaciclib/placebo) on Cycle 1 Day 2. 
 
 


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Table 17: 
Schedule of Assessments: Induction (Cycles 2-12), Maintenance, and Survival Follow-up 
Assessment 
Induction (14-day cycles) 
[Maximum 12 cycles] 
Last Induction 
Cycle only if 
no 
Maintenance 
Maintenance 
(14-day cycles) 
Post 
Treatment 
Visit 
Survival 
Follow 
Up 
Day 
1 
2 
8 
(±1 day) 
15 
(±1 day) 
1 
2 
30 ±7d 
post last 
dose 
 
ECOG Performance Status 
X 
 
 
 
X 
 
X 
 
Physical Exam (Odd cycles only in 
both Induction and Maintenance, eg, 
C1, 3, 5, etc) 
X 
 
 
 
X 
 
X 
 
Weight 
X 
 
 
 
X 
 
X 
 
Vital Signsa 
X 
 
 
 
X 
 
X 
 
12-lead Electrocardiogram 
Xb 
[C2 only] 
Xb 
[C2 only] 
 
 
 
 
 
 
Clinical Chemistryc 
X 
 
 
 
X 
 
X 
 
Hematologyd 
X 
 
X 
[C2-4 only] 
X 
X 
 
X 
 
INR/aPTT  
(as clinically indicated during the 
study) 
 
 
 
 
 
 
 
 
Urinalysisc (dipstick) 
X 
 
 
 
X 
 
 
 
Pregnancy test (WOCBP, q month)e 
X 
 
 
 
X 
 
X 
 
Tumor Assessment by RECIST v1.1 
Xf (q8 weeks regardless of dosing) 
 
Xf (q12 weeks) 
 
Xg 
Xg 
Trilaciclib or placeboh 
X 
X 
 
 
X 
X 
 
 
Irinotecan 
X 
 
 
 
 
 
 
 
Oxaliplatin 
X 
 
 
 
 
 
 
 


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Assessment 
Induction (14-day cycles) 
[Maximum 12 cycles] 
Last Induction 
Cycle only if 
no 
Maintenance 
Maintenance 
(14-day cycles) 
Post 
Treatment 
Visit 
Survival 
Follow 
Up 
Day 
1 
2 
8 
(±1 day) 
15 
(±1 day) 
1 
2 
30 ±7d 
post last 
dose 
 
Leucovorin 
X 
 
 
 
X 
 
 
 
Fluorouracil 
X 
X 
 
 
X 
X 
 
 
Bevacizumab 
X 
 
 
 
X 
 
 
 
FACT-An (includes FACIT-F), 
FACT-C, PGIS, PGICi 
X 
 
X 
[C2-4 only] 
Xj 
X 
 
X 
 
EQ-5D-5L 
X 
 
X 
[C2-4 only] 
Xj 
X 
 
X 
 
Blood sample for Immunologic and 
Hematologic Markers 
X 
[C2, C5, only] 
 
 
 
X  
[C1 only] 
 
 
 
AEs 
X 
 
Concomitant Medications 
X 
 
Survival Follow-up Contact  
(every other month) 
 
 
 
 
 
 
 
Xk 
AE=adverse event; aPTT=activated partial thromboplastin time; β-hCG=beta human chorionic gonadotropin; C=cycle; ECOG=Eastern Cooperative Oncology 
Group; EQ-5D-5L=5-level EQ-5D; FACT-An=Functional Assessment of Cancer Therapy – Anemia; FACIT-F=Functional Assessment of Chronic Illness 
Therapy-Fatigue; FACT-C=Functional Assessment of Cancer Therapy – Colorectal; FACT-G=Functional Assessment of Cancer Therapy – General; 
INR=international normalized ratio; IWRS=interactive web response system; PE=physical exam; PGIC=Patient Global Impression of Change; PGIS=Patient 
Global Impression of Severity; RECIST=Response Evaluation Criteria in Solid Tumors; WOCBP=women of childbearing potential. 
a Vitals (blood pressure, heart rate, temperature) should be taken 15 minutes (± 10 minutes) before and after the trilaciclib/placebo infusion. 
b Perform triplicate ECGs on Day 1 of Cycle 2 at the following timepoints: predose (trilaciclib/placebo) at any time prior to dosing, within 30 minutes following 
the end of the trilaciclib/placebo infusion, and 3 hours after the start of trilaciclib/placebo infusion (± 30 minutes). Triplicate ECGs should also be performed on 
Day 2 of Cycle 2 at the following timepoints: predose (trilaciclib/placebo) at any time prior to dosing and within 30 minutes of the end of the trilaciclib/placebo 
infusion. Additional ECGs during the study may be performed as clinically indicated. Any ECG with a QTc value of > 500 or any other clinically significant 
abnormal finding should be repeated every 5 minutes for a total of three ECGs to confirm this finding, if not already recorded in triplicate.  
c Clinical chemistry and urinalysis may be obtained up to 3 calendar days prior to dosing. 


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d Hematology may be obtained up to 1 calendar day prior to dosing. If the initiation of the next cycle is delayed due to an AE, the patient should have (at least) 
weekly visits, including CBCs if the AE is hematologic, to follow the AE. Clinical laboratory assessments should be completed on the scheduled Day 1 as well 
as on the actual first dosing day of that delayed cycle. 
e Female patients of childbearing potential: serum or urine pregnancy testing every 2nd cycle (e.g., every month) during treatment (Induction and Maintenance) 
and at the post-treatment visit. 
f Tumor assessments of chest, abdomen, and pelvis using the same imaging modality as at baseline should be performed every 8 weeks ± 7 days during 
Induction and every 12 weeks ± 14 days during Maintenance. IV contrast should be used unless contraindicated. Oral contrast can be used at the Investigator’s 
discretion. Timing of scans should be regardless of dosing (e.g., from date of first dose). Additional scans may be performed during the study if clinically 
indicated. 
g Perform tumor assessments at the Post Treatment Visit (30 +7d after last dose of study drug) only for patients who have not progressed at the time of study 
drug discontinuation. For those patients being followed for survival who have not progressed at the time of study drug discontinuation, tumor assessments will 
be repeated every 12 weeks ± 14 days until the occurrence of disease progression, withdrawal of consent, initiation of subsequent anti-cancer therapy, or study 
completion. Tumor assessments of chest, abdomen, and pelvis using the same imaging modality as at baseline should be performed. IV contrast should be used 
unless contraindicated; oral contrast can be used at the Investigator's discretion. 
h Trilaciclib or placebo will be administered as a 30-minute IV infusion prior to chemotherapy on Day 1 and on Day 2 of every cycle during Induction and 
Maintenance. Chemotherapy cannot be administered until after completion of the trilaciclib or placebo infusion on Day 1. The interval between the dose of 
trilaciclib or placebo and the first dose of chemotherapy on Day 1 should not be greater than 4 hours. The second dose of trilaciclib/placebo should be 
administered on Day 2. Trilaciclib or placebo will only be administered if chemotherapy is also to be administered on that day.  
i FACIT-F is embedded in the FACT-An. Patient reported outcome questionnaires should be completed at the following timepoints: Induction Cycles 2 to 4 
(Days 1 and 8), Induction Cycles 5-12 (Day 1), Day 1 of each cycle in Maintenance, and at the post-treatment visit. If a cycle is delayed, the patient should still 
complete the questionnaires on the scheduled Day 1 of that cycle, as well as the actual first dosing day of that cycle. PRO questionnaires may be administered 
up to 1 calendar day prior to the first dose of each cycle; questionnaires administered on Day 8 may be obtained ±1 day of scheduled visit. NOTE: 
questionnaires should be completed on the same day blood sample is collected for hematology assessment. Questionnaires must be completed prior to the 
administration of any study drug and should be administered prior to conduct of any study procedure at that visit. 
j Administer PRO questionnaires on Day 15 of last induction cycle only if patient does not continue with Maintenance therapy. When patient does not continue 
in Maintenance, questionnaires do not need to be repeated at both Post Treatment Visit and Day 15 of last induction cycle if < 3 weeks between these 
2 timepoints. 
k If a patient withdraws consent for further study treatment and/or procedures, the site should clarify if the patient remains open to survival contact and associated 
data collection. See Section 11.12 of the protocol for details of information to be collected during Survival Follow-up. 
 


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APPENDIX 2. 
ESTIMANDS FRAMEWORK FOR PRIMARY AND KEY 
SECONDARY ENDPOINTS FOR STUDY G1T28-207 
In this document, the primary and key secondary endpoints defined in the protocol are described 
in the estimand framework following ICH E9 (R1)  (2020). The strategies for ICE classification 
in the primary and sensitivity settings are also elaborated for each of the estimands.  
Primary Estimands 
To assess the myeloprotective effect of trilaciclib on the neutrophil lineage compared with 
placebo. 
DSN in Cycle 1-4 
Population:  
 
 
The mITT population as defined in Section 3.1 
Treatment:  
 
 
Trilaciclib versus placebo administered prior to FOLFOXIRI/bevacizumab 
Variable:   
 
 
See Section 8.1.1 
Summary measure:  Treatment difference from the nonparametric ANCOVA model (see 
Section 8.2.3.2) 
Occurrence of SN during Induction 
Population:  
 
 
The mITT population 
Treatment:  
 
 
Trilaciclib versus placebo administered prior to FOLFOXIRI/bevacizumab 
Variable:   
 
 
See Section 8.1.1 
Summary measure:  The adjusted relative risk from the modified Poisson model (see 
Section 8.2.3.2) 
Handling of Intercurrent Events for Primary Estimands 
DSN in Cycle 1-4 
The following ICEs were identified: 
• Patients who were randomized but not dosed with any study drug 
• Treatment discontinuation in Cycle 1-4 
• Receipt of GCSF administration in Cycle 1-4 


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The following strategies will be used for each of the above ICEs: 
ICE 
Primary 
Sensitivity 
1. Patients who were randomized but 
not dosed with any study drug 
Treatment Policy Strategy 
Principal Stratum Strategy 
2. Treatment discontinuation prior to 
any SN in Cycle1-4 
Treatment Policy Strategy 
None 
3. Receipt of GCSF administration in 
Cycle 1-4 
Treatment Policy Strategy 
Hypothetical Strategy 
 
Justification for Primary and Sensitivity Strategies of ICE  
1. Patients who were randomized but not dosed with any study drug 
As DSN in Cycle 1-4 was designed as one of the primary endpoint to assess the myeloprotective 
effect of trilaciclib on the neutrophil lineage compared with placebo, if a patient does not take 
any study drug, that implies that the patient was discontinued from study between the time of 
randomization and entering the first cycle of treatment in Induction, and thus there was no 
neutrophil count data collection for the patient. However, following the ITT principle to include 
this type of patients in the analysis, a value of 0 for DSN in Cycle 1-4 was assigned to these 
patients (Section 8.1.1). In this approach, the treatment policy strategy was used (i.e., the 
occurrence of the ICE was ignored).  The impact of this ICE on the analysis outcome is that the 
number of such patients might not be balanced between two treatment groups, thus, assigning a 
value of 0 to DSN in Cycle 1-4 could introduce bias to the results. To account for the impact of 
this ICE to the evaluation of treatment effect on DSN in Cycle1-4, the principal stratum strategy 
will be used as a sensitivity analysis, in which patients who were randomized but not dosed with 
any study drug will be excluded from the analysis for DSN in Cycle 1-4.  
2. Treatment discontinuation prior to any SN in Cycle 1-4 
Treatment discontinuation prior to any SN in Cycle 1-4 may potentially prevent SN from being 
reported. The treatment policy strategy (i.e., the occurrence of the ICE was ignored) will be used 
for this ICE in the primary analysis of DSN in Cycle 1-4. However, there is no rational way to 
predict if the patient may or may not develop SN after treatment discontinuation; therefore, no 
sensitivity analysis will be performed for this ICE.  
3. Receipt of GCSF administration in Cycle 1-4 
The treatment policy strategy (i.e., the occurrence of the ICE was ignored) will be used for this 
ICE in the primary analysis of DSN in Cycle 1-4. Despite that primary prophylactic GCSF will 
be prohibited in Cycle 1, therapeutic GCSF (administered in response to a neutropenic event) in 
Cycle 1 and secondary prophylactic GCSF beginning in Cycle 2 and for all subsequent cycles 
(i.e., after a precipitating event in a prior cycle of therapy) will be allowed per growth 
factor/neutropenia management guidelines and physician discretion. This GCSF use would 
potentially boost the neutrophil counts and thus prevent SN from occurring. The imbalance of 
GCSF use between the treatment group may potentially bias the between-treatment comparison 


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of DSN. Therefore, the hypothetical strategy (data after ICE will not be used) will be used for a 
sensitivity analysis.  
Occurrence of SN during Induction 
The following ICEs were identified: 
• Patients who were randomized but not dosed with any study drug 
• Treatment discontinuation from Induction 
• Receipt of GCSF administration during Induction 
The following strategies will be used for each of the above ICEs: 
ICE 
Primary 
Sensitivity 
1. Patients who were randomized but 
not dosed with any study drug 
Treatment Policy Strategy 
Principal Stratum Strategy 
2. Treatment discontinuation from 
Induction prior to any SN 
Treatment Policy Strategy 
None 
3. Receipt of GCSF administration 
during Induction 
Treatment Policy Strategy 
Hypothetical Strategy 
Justification for Primary and Sensitivity Strategies of ICE  
1. Patients who were randomized but not dosed with any study drug 
As the occurrence of SN during Induction was designed as one of the primary endpoint to assess 
the myeloprotective effect of trilaciclib on the neutrophil lineage compared with placebo, if a 
patient does not take any study drug, that implies that the patient was discontinued from study 
between the time of randomization and entering the first cycle of treatment in Induction, and thus 
there was no neutrophil count data collection for the patient. However, following the ITT 
principle to include this type of patients in the analysis, a value of 0 for the occurrence of SN 
during Induction was assigned to these patients (Section 8.1.1). In this approach, the treatment 
policy strategy was used (i.e., the occurrence of the ICE was ignored).  The impact of this ICE on 
the analysis outcome is that the number of such patients might not be balanced between two 
treatment groups, thus, assigning a value 0 to the occurrence of severe neutropenia during 
Induction could introduce bias to the results. To account for the impact of this ICE to the 
evaluation of treatment effect on the occurrence of SN during Induction, the principal stratum 
strategy will be used as sensitivity analysis, in which patients who were randomized but not 
dosed with any study drug will be excluded from the analysis for the occurrence of SN during 
Induction.  
2. Treatment discontinuation from Induction prior to any SN  
Treatment discontinuation from Induction prior to any SN may potentially prevent SN from 
being reported. The treatment policy strategy (i.e., the occurrence of the ICE was ignored) will 
be used for this ICE in the primary analysis of the occurrence of SN during Induction. However, 
there is no rational way to predict if the patient may or may not develop SN after treatment 
discontinuation; therefore, no sensitivity analysis will be performed for this ICE.  


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3. Receipt of GCSF administration during induction 
The treatment policy strategy (i.e., the occurrence of the ICE was ignored) will be used for this 
ICE in the primary analysis of the occurrence of severe neutropenia during Induction. Despite 
that primary prophylactic GCSF will be prohibited in Cycle 1, therapeutic GCSF (administered 
in response to a neutropenic event) in Cycle 1 and secondary prophylactic GCSF beginning in 
Cycle 2 and for all subsequent cycles (i.e., after a precipitating event in a prior cycle of therapy) 
will be allowed per growth factor/neutropenia management guidelines and physician discretion. 
This GCSF use would potentially boost the neutrophil counts and thus prevent SN from 
occurring. The imbalance of GCSF use between the treatment group may potentially bias the 
between-treatment comparison of the occurrence of SN during Induction. Therefore, the 
hypothetical strategy (data after ICE will not be used) will be used for a sensitivity analysis.  
Key Secondary Estimand 
Overall Survival 
To evaluate the effect of trilaciclib on OS compared with placebo. 
Population:  
 
 
The mITT population 
Treatment:  
 
 
Trilaciclib versus placebo administered prior to FOLFOXIRI/bevacizumab 
Variable:    
 
 
See Section 8.1.2  
Summary measure:  HR from stratified Cox proportional hazard model with the fixed term of 
treatment and stratification factors at randomization 
Handling of Intercurrent Events for Key Secondary Estimand 
Overall Survival 
Overall survival is considered the most reliable cancer endpoint when studies can be conducted 
to adequately assess survival. It is usually the preferred endpoint (FDA Guidance Dec. 2018, 
EMA/CHMP Guidance Sept. 2017). As mentioned in the FDA Guidance, the disadvantages of 
using OS as an endpoint include the following: (1) noncancer deaths are included; (2) may be 
affected by switch-over of control to treatment or subsequent therapies; (3) requires longer 
follow-up. 
In this study, OS includes all deaths observed in the study regardless of cause (i.e., noncancer 
deaths as well as cancer-related deaths) for all randomized patients (the ITT population). The 
switch-over of control to treatment is not allowed in this study so it will not be considered as an 
ICE. Therefore, the following ICEs are identified for the primary estimand: 
• Subsequent anticancer therapy  
• Study discontinuation including lost to follow-up 
• Curative intent surgical resection 


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The following strategies will be used for each of the above ICEs: 
ICE 
Primary 
Sensitivity 
1. Subsequent anticancer therapy  
Treatment Policy Strategy 
None 
2. Study discontinuation including lost-
to-follow up 
Treatment Policy Strategy 
None 
3. Curative intent surgical resection 
Treatment Policy Strategy 
None 
Justification for Primary and Sensitivity Strategies of ICE  
1. Subsequent anticancer therapy 
For the SAT, the treatment policy strategy is planned for the primary analysis of OS, in which all 
survival data collected over the course of the study are included regardless of the use of SAT. 
Treating SAT as a potential composite event for death would put two events with vastly different 
impacts on patients at the same level; therefore, there will be no sensitivity analysis for survival. 
2. Study discontinuation 
It is acknowledged that there are various reasons for patients to discontinue from the study which 
will potentially impact the estimate of treatment effect on OS in the situation that dropouts are 
not at random but associated with the treatment received in the study (i.e., the censoring is 
informative). However, there is no formal way to identify whether censorings are non-
informative or informative. Therefore, the treatment policy strategy (i.e., the occurrence of the 
ICE was ignored) will be used as the primary analysis. Similarly, treating study discontinuation 
as a potential composite event for death would put two events with vastly different impacts on 
patients at the same level; therefore, there will be no sensitivity analysis for this ICE.  
3. Curative intent surgical resection 
For OS, this ICE will be treated similarly as SAT. Therefore, treatment policy strategy (i.e., the 
occurrence of the ICE was ignored) is planned for the primary analysis of OS, and there will be 
no sensitivity analysis for OS. 


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APPENDIX 3. CUSTOMIZED MedDRA QUERIES FOR TRILACICLIB 
AESIs 
AESI Categories 
Preferred Terms 
Injection Site 
Reaction/ 
Phlebitis/ 
Thrombophlebitis 
 
Administration site phlebitis 
Periphlebitis 
Application site phlebitis 
Phlebitis 
Catheter site phlebitis 
Phlebitis deep 
Chemical phlebitis 
Phlebitis infective 
Infusion site phlebitis 
Septic phlebitis 
Infusion site thrombosis 
Thrombophlebitis 
Injection site phlebitis 
Thrombophlebitis septic 
Injection site thrombosis 
Thrombophlebitis superficial 
  
Vascular access site thrombosis 
Administration related reaction 
Infusion site erythema 
Administration site dermatitis 
Infusion site hypersensitivity 
Administration site 
hypersensitivity 
Infusion site pain 
Administration site pain 
Infusion site rash 
Administration site rash 
Infusion site reaction 
Administration site recall 
reaction 
Infusion site recall reaction 
Administration site urticaria 
Infusion site urticaria 
Administration site vasculitis 
Infusion site vasculitis 
Application site dermatitis 
Injection related reaction 
Application site hypersensitivity 
Injection site dermatitis 
Application site pain 
Injection site erythema 
Application site rash 
Injection site hypersensitivity 
Application site recall reaction 
Injection site pain 
Application site urticaria 
Injection site rash 
Application site vasculitis 
Injection site reaction 
Catheter site dermatitis 
Injection site recall reaction 
Catheter site hypersensitivity 
Injection site urticaria 
Catheter site pain 
Injection site vasculitis 
Catheter site rash 
Installation site urticaria 
Catheter site urticaria 
instillation site hypersensitivity 
Catheter site vasculitis 
instillation site pain 
Immediate post-injection reaction instillation site rash 
Infusion related reaction 
Skin reaction 
Infusion site dermatitis 
Vessel puncture site rash 
  
Vessel puncture site vesicles 


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


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


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