Trial Outcomes & Findings for Trilaciclib (G1T28), a CDK 4/6 Inhibitor, in Combination With Etoposide and Carboplatin in Extensive Stage Small Cell Lung Cancer (SCLC) (NCT NCT02499770)

Results Overview

Dose-limiting toxicities (DLTs) were drug-related toxicities defined as follows: 1. Absolute neutrophil count (ANC) \< 0.5 × 10\^9/L lasting for ≥ 7 days 2. ≥ Grade 3 neutropenic infection/febrile neutropenia 3. Grade 4 thrombocytopenia (TCP) or ≥ Grade 3 TCP with bleeding 4. Unable to start next cycle of chemotherapy due to lack of recovery to an ANC ≥ 1.5 × 10\^9/L and platelet count ≥ 100 × 10\^9/L 5. ≥ Grade 3 nonhematologic toxicity (nausea, vomiting, and diarrhea failing maximal medical management; fatigue lasting for \> 72 hours) Toxicities not clearly related to etoposide/carboplatin therapy were also considered for the purposes of determining DLTs.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

122 participants

Primary outcome timeframe

Days 1-21 of Cycle 1

Results posted on

2020-08-21

Participant Flow

The study was conducted at 71 centers in the United States of America and Europe. The first participant enrolled on 26 June 2015 and the last participant completed on 22 February 2019. For Part 1, participants were enrolled from 26 June 2015 to 30 September 2016 and for Part 2, participants were enrolled from 06 October 2016 to 25 April 2017.

Participants were screened within 14 days prior to first study drug administration. Informed consent and brain scans were obtained up to 28 days prior to first study drug administration. A total of 122 participants were enrolled (24 in Part 1 and 98 in Part 2), of which 96 were assigned to treatment.

Participant milestones

Participant milestones
Measure	Part 1: Dose Finding/Expansion The 1st cohort in Part 1 received trilaciclib 200 mg/m\^2, IV once daily on Days 1 to 3 of each 21-day E/P cycle. The 2nd cohort in the Phase 1b dose-finding portion of Part 1 \& the Phase 2a expansion cohort in Part 1 received trilaciclib 240 mg/m\^2, IV once daily on Days 1 to 3 of each 21-day E/P cycle. Participants received standard E/P chemotherapy in 21-day cycles. Carboplatin dose was calculated using the Calvert formula with a target AUC = 5 (maximum 750 mg) IV on Day 1. Etoposide 100 mg/m\^2 was given IV daily on Days 1, 2, \& 3 of each 21-day cycle. Trilaciclib was only given with E/P therapy. If E/P therapy was discontinued, trilaciclib was also to be discontinued. The interval between doses of trilaciclib on successive days was not greater than 28 hours \& between the dose of trilaciclib \& the first dose of chemotherapy on a given day (etoposide or carboplatin) not greater than 4 hours.	Part 2: Trilaciclib/Placebo IV With E/P Eligible participants were randomized (1:1) to trilaciclib or placebo administered IV once daily on Days 1 to 3 with etoposide and carboplatin on Day 1 and etoposide on Days 2 and 3 of 21-day cycles (E/P). Randomization was stratified by ECOG performance status (0 to 1 versus 2). Participants received trilaciclib 240 mg/m\^2 (recommended dose from Part 1) or placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. Participants received standard E/P chemotherapy in 21-day cycles. The carboplatin dose was calculated using the Calvert formula with a target AUC = 5 (maximum 750 mg) IV on Day 1, and 100 mg/m\^2 etoposide was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. The interval between doses of trilaciclib/placebo on successive days was not greater than 28 hours and between the dose of trilaciclib/placebo and the first dose of chemotherapy on a given day (etoposide or carboplatin) was not greater than 4 hours.
Overall Study STARTED	19	77
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	19	77

Reasons for withdrawal

Reasons for withdrawal
Measure	Part 1: Dose Finding/Expansion The 1st cohort in Part 1 received trilaciclib 200 mg/m\^2, IV once daily on Days 1 to 3 of each 21-day E/P cycle. The 2nd cohort in the Phase 1b dose-finding portion of Part 1 \& the Phase 2a expansion cohort in Part 1 received trilaciclib 240 mg/m\^2, IV once daily on Days 1 to 3 of each 21-day E/P cycle. Participants received standard E/P chemotherapy in 21-day cycles. Carboplatin dose was calculated using the Calvert formula with a target AUC = 5 (maximum 750 mg) IV on Day 1. Etoposide 100 mg/m\^2 was given IV daily on Days 1, 2, \& 3 of each 21-day cycle. Trilaciclib was only given with E/P therapy. If E/P therapy was discontinued, trilaciclib was also to be discontinued. The interval between doses of trilaciclib on successive days was not greater than 28 hours \& between the dose of trilaciclib \& the first dose of chemotherapy on a given day (etoposide or carboplatin) not greater than 4 hours.	Part 2: Trilaciclib/Placebo IV With E/P Eligible participants were randomized (1:1) to trilaciclib or placebo administered IV once daily on Days 1 to 3 with etoposide and carboplatin on Day 1 and etoposide on Days 2 and 3 of 21-day cycles (E/P). Randomization was stratified by ECOG performance status (0 to 1 versus 2). Participants received trilaciclib 240 mg/m\^2 (recommended dose from Part 1) or placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. Participants received standard E/P chemotherapy in 21-day cycles. The carboplatin dose was calculated using the Calvert formula with a target AUC = 5 (maximum 750 mg) IV on Day 1, and 100 mg/m\^2 etoposide was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. The interval between doses of trilaciclib/placebo on successive days was not greater than 28 hours and between the dose of trilaciclib/placebo and the first dose of chemotherapy on a given day (etoposide or carboplatin) was not greater than 4 hours.
Overall Study Death	17	56
Overall Study Study completion	1	10
Overall Study Withdrawal by Subject	0	7
Overall Study Lost to Follow-up	0	2
Overall Study Subject declined further treatment	1	0
Overall Study Withdrawn by PI for compassionate reason	0	1
Overall Study Randomized but not enrolled	0	1

Baseline Characteristics

BSA was only available for 75 of the 77 participants in Part 2.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1: Dose Finding/Expansion n=19 Participants The 1st cohort in Part 1 received trilaciclib 200 mg/m\^2, IV once daily on Days 1 to 3 of each 21-day E/P cycle. The 2nd cohort in the Phase 1b dose-finding portion of Part 1 \& the Phase 2a expansion cohort in Part 1 received trilaciclib 240 mg/m\^2, IV once daily on Days 1 to 3 of each 21-day E/P cycle. Participants received standard E/P chemotherapy in 21-day cycles. Carboplatin dose was calculated using the Calvert formula with a target AUC = 5 (maximum 750 mg) IV on Day 1. Etoposide 100 mg/m\^2 was given IV daily on Days 1, 2, \& 3 of each 21-day cycle. Trilaciclib was only given with E/P therapy. If E/P therapy was discontinued, trilaciclib was also to be discontinued. The interval between doses of trilaciclib on successive days was not greater than 28 hours \& between the dose of trilaciclib \& the first dose of chemotherapy on a given day (etoposide or carboplatin) not greater than 4 hours.	Part 2: Trilaciclib/Placebo IV With E/P n=77 Participants Eligible participants were randomized (1:1) to trilaciclib or placebo administered IV once daily on Days 1 to 3 of E/P therapy. Randomization was stratified by ECOG performance status (0 to 1 versus 2). Participants received trilaciclib 240 mg/m\^2 (recommended dose from Part 1) or placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. Participants received standard E/P chemotherapy in 21-day cycles. The carboplatin dose was calculated using the Calvert formula with a target AUC = 5 (maximum 750 mg) IV on Day 1, and 100 mg/m\^2 etoposide was administered IV daily on Days 1, 2, and 3 of each 21-day cycle. The interval between doses of trilaciclib/placebo on successive days was not greater than 28 hours and between the dose of trilaciclib/placebo and the first dose of chemotherapy on a given day (etoposide or carboplatin) was not greater than 4 hours.	Total n=96 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=19 Participants	0 Participants n=77 Participants	0 Participants n=96 Participants
Age, Categorical Between 18 and 65 years	7 Participants n=19 Participants	37 Participants n=77 Participants	44 Participants n=96 Participants
Age, Categorical >=65 years	12 Participants n=19 Participants	40 Participants n=77 Participants	52 Participants n=96 Participants
Sex: Female, Male Female	8 Participants n=19 Participants	23 Participants n=77 Participants	31 Participants n=96 Participants
Sex: Female, Male Male	11 Participants n=19 Participants	54 Participants n=77 Participants	65 Participants n=96 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=19 Participants	2 Participants n=77 Participants	3 Participants n=96 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	18 Participants n=19 Participants	75 Participants n=77 Participants	93 Participants n=96 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=19 Participants	0 Participants n=77 Participants	0 Participants n=96 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=19 Participants	1 Participants n=77 Participants	1 Participants n=96 Participants
Race (NIH/OMB) Asian	0 Participants n=19 Participants	1 Participants n=77 Participants	1 Participants n=96 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=19 Participants	0 Participants n=77 Participants	0 Participants n=96 Participants
Race (NIH/OMB) Black or African American	3 Participants n=19 Participants	1 Participants n=77 Participants	4 Participants n=96 Participants
Race (NIH/OMB) White	16 Participants n=19 Participants	73 Participants n=77 Participants	89 Participants n=96 Participants
Race (NIH/OMB) More than one race	0 Participants n=19 Participants	0 Participants n=77 Participants	0 Participants n=96 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=19 Participants	1 Participants n=77 Participants	1 Participants n=96 Participants
Country United States	19 Participants n=19 Participants	39 Participants n=77 Participants	58 Participants n=96 Participants
Country Non-United States	0 Participants n=19 Participants	38 Participants n=77 Participants	38 Participants n=96 Participants
Body Surface Area	1.90 m^2 STANDARD_DEVIATION 0.263 • n=19 Participants • BSA was only available for 75 of the 77 participants in Part 2.	1.90 m^2 STANDARD_DEVIATION 0.216 • n=75 Participants • BSA was only available for 75 of the 77 participants in Part 2.	NA m^2 STANDARD_DEVIATION NA • n=94 Participants • BSA was only available for 75 of the 77 participants in Part 2.

PRIMARY outcome

Timeframe: Days 1-21 of Cycle 1

Population: Safety analysis set - included all enrolled participants (i.e., signed informed consent) who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Part 1: Cohort 1 Trilaciclib 200 mg/m\^2 included 1 participant from Part 2 and 1 participant from Part 1 240 mg/m\^2 who received 200 mg/m\^2.

Dose-limiting toxicities (DLTs) were drug-related toxicities defined as follows: 1. Absolute neutrophil count (ANC) \< 0.5 × 10\^9/L lasting for ≥ 7 days 2. ≥ Grade 3 neutropenic infection/febrile neutropenia 3. Grade 4 thrombocytopenia (TCP) or ≥ Grade 3 TCP with bleeding 4. Unable to start next cycle of chemotherapy due to lack of recovery to an ANC ≥ 1.5 × 10\^9/L and platelet count ≥ 100 × 10\^9/L 5. ≥ Grade 3 nonhematologic toxicity (nausea, vomiting, and diarrhea failing maximal medical management; fatigue lasting for \> 72 hours) Toxicities not clearly related to etoposide/carboplatin therapy were also considered for the purposes of determining DLTs.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=12 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=8 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Number of Participants With Dose Limiting Toxicities by Cohort in Cycle 1, Part 1 Number of participants meeting ≥1 DLT criteria	2 Participants	1 Participants
Number of Participants With Dose Limiting Toxicities by Cohort in Cycle 1, Part 1 Grade 4 TCP or ≥Grade 3 TCP with bleeding	1 Participants	0 Participants
Number of Participants With Dose Limiting Toxicities by Cohort in Cycle 1, Part 1 Unable to start next cycle of chemotherapy	1 Participants	1 Participants

PRIMARY outcome

Timeframe: TEAEs were any AE that started on or after the first dose of study drug and up to the last dose +30 days (a minimum of 51 days up to a maximum of 374 days)

Population: Safety analysis set - included all enrolled participants (i.e., signed informed consent) who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Part 1: Cohort 1 Trilaciclib 200 mg/m\^2 included 1 participant from Part 2 and 1 participant from Part 1 240 mg/m\^2 who received 200 mg/m\^2.

An AE was defined as any untoward medical occurrence in a participant administered a medicinal product that did not necessarily have a causal relationship with this treatment. TEAEs were defined as any AE that started on or after the first dose of study drug and up to the last dose +30 days. SAEs were defined as any untoward medical occurrence that at any dose resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity or was a congenital anomaly/birth defect. Relatedness to study drug was assessed by the investigator. Related refers to those events that were Possibly, Probably, or Definitely Related. AEs with an unknown/not reported onset date were also included.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=12 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=8 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1 Any TEAE	12 Participants	8 Participants
Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1 Any SAE	4 Participants	1 Participants
Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1 TEAE related to any study drug	10 Participants	8 Participants
Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1 SAE related to any study drug	0 Participants	0 Participants
Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1 TEAE leading to discontinuation of any study drug	0 Participants	0 Participants

PRIMARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: Full analysis set (FAS) - included all randomized participants who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Severe (Grade 4) neutropenia was defined as at least 1 ANC value \<0.5 × 10\^9/L during the treatment period. Within each cycle, the duration (days) of severe neutropenia was defined as the number of days from the date of the first ANC value of \<0.5 × 10\^9/L observed between start of cycle and end of cycle to the date of the first ANC value ≥0.5 × 10\^9/L that met the following criteria: 1) occurred after the ANC value of \<0.5 × 10\^9/L and 2) no other ANC values \<0.5 × 10\^9/L occurred between this day and end of cycle. The duration of severe neutropenia only included participants who had at least 1 severe neutropenia event in the cycle, and censoring rules were applied for unresolved severe neutropenia in a cycle. For the treatment period, the overall duration of severe neutropenia was the median value among the durations from all cycles.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=16 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=2 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Duration of Severe (Grade 4) Neutropenia in Part 2	8 Days Interval 7.0 to 8.0	3 Days Interval 2.0 to 3.0

SECONDARY outcome

Timeframe: Days 1 and 3 of Cycle 1 for a 21-day cycle

Population: Pharmacokinetic (PK) analysis set - included all participants with evaluable PK profiles for both treatments and analytes.

Cmax of trilaciclib in plasma was determined from individual concentration-time data by non-compartmental analysis methods. The actual sampling times in relation to dosing were used. For estimation of Cmax, a concentration that was below the limit of quantification (BLQ) was assigned a value of zero if it occurred in a profile before the first measurable concentration. If a BLQ value occurred after a measurable concentration in a profile, and was followed by a value above the lower limit of quantification, then the BLQ was treated as missing data. If a BLQ value occurred at the end of the collection interval (after the last quantifiable concentration) it was treated as missing data. If two BLQ values occurred in succession after Cmax, the profile was deemed to have terminated at the first BLQ value and any subsequent concentrations were omitted.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=8 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=1 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Maximum Observed Plasma Concentration (Cmax) of Trilaciclib in Cycle 1, Part 1 Day 1 Cycle 1	1240 ng/mL Standard Deviation 738	1570 ng/mL Standard Deviation NA Not calculable
Maximum Observed Plasma Concentration (Cmax) of Trilaciclib in Cycle 1, Part 1 Day 3 Cycle 1	1620 ng/mL Standard Deviation 1040	2260 ng/mL Standard Deviation NA Not calculable

SECONDARY outcome

Timeframe: Days 1 and 3 of Cycle 1 for a 21-day cycle

Population: PK analysis set - included all participants with evaluable PK profiles for both treatments and analytes

AUC0-inf of trilaciclib in plasma was determined from individual concentration-time data by non-compartmental analysis methods. The actual sampling times in relation to dosing were used.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=8 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=1 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Trilaciclib in Cycle 1, Part 1 Day 1 Cycle 1	2560 h*ng/mL Standard Deviation 792	2280 h*ng/mL Standard Deviation NA Not calculable (n=1)
Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Trilaciclib in Cycle 1, Part 1 Day 3 Cycle 1	3110 h*ng/mL Standard Deviation 693	2960 h*ng/mL Standard Deviation NA Not calculable (n=1)

SECONDARY outcome

Timeframe: Days 1 and 3 of Cycle 1 for a 21-day cycle

Population: PK analysis set - included all participants with evaluable PK profiles for both treatments and analytes

Tmax of trilaciclib in plasma was determined from individual concentration-time data by non-compartmental analysis methods. The actual sampling times in relation to dosing were used.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=8 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=1 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Time of Maximum Observed Concentration (Tmax) of Trilaciclib in Cycle 1, Part 1 Day 1 Cycle 1	0.57 Hours Interval 0.45 to 0.98	0.50 Hours Not calculable (n=1)
Time of Maximum Observed Concentration (Tmax) of Trilaciclib in Cycle 1, Part 1 Day 3 Cycle 1	0.52 Hours Interval 0.47 to 1.0	0.45 Hours Not calculable (n=1)

SECONDARY outcome

Timeframe: Days 1 and 3 of Cycle 1 for a 21-day cycle (carboplatin was only dosed on Day 1 so there are no Day 3 Cmax values)

Population: PK analysis set - included all participants with evaluable PK profiles for both treatments and analytes

Cmax of etoposide and free and total carboplatin in plasma were determined from individual concentration-time data by non-compartmental analysis methods. The actual sampling times in relation to dosing were used. For estimation of Cmax, a concentration that was BLQ was assigned a value of zero if it occurred in a profile before the first measurable concentration. If a BLQ value occurred after a measurable concentration in a profile, and was followed by a value above the lower limit of quantification, then the BLQ was treated as missing data. If a BLQ value occurred at the end of the collection interval (after the last quantifiable concentration) it was treated as missing data. If two BLQ values occurred in succession after Cmax, the profile was deemed to have terminated at the first BLQ value and any subsequent concentrations were omitted.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=9 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Cmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 Etoposide Day 1 Cycle 1	21.9 μg/mL Standard Deviation 2.70	—
Cmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 Etoposide Day 3 Cycle 1	20.2 μg/mL Standard Deviation 2.40	—
Cmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 Free Carboplatin Day 1 Cycle 1	20.3 μg/mL Standard Deviation 6.83	—
Cmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 Total Carboplatin Day 1 Cycle 1	18.8 μg/mL Standard Deviation 5.45	—

SECONDARY outcome

Timeframe: Days 1 and 3 of Cycle 1 for a 21-day cycle (carboplatin was only dosed on Day 1 so there are no Day 3 AUC0-inf values)

Population: PK analysis set - included all participants with evaluable PK profiles for both treatments and analytes

AUC0-inf of etoposide and free and total carboplatin in plasma were determined from individual concentration-time data by non-compartmental analysis methods. The actual sampling times in relation to dosing were used.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=9 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
AUC0-inf of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 Etoposide Day 1 Cycle 1	131 h*μg/mL Standard Deviation 44.7	—
AUC0-inf of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 Etoposide Day 3 Cycle 1	146 h*μg/mL Standard Deviation 48.4	—
AUC0-inf of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 Free Carboplatin Day 1 Cycle 1	50.5 h*μg/mL Standard Deviation 14.4	—
AUC0-inf of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 Total Carboplatin Day 1 Cycle 1	137 h*μg/mL Standard Deviation 37.3	—

SECONDARY outcome

Timeframe: Days 1 and 3 of Cycle 1 for a 21-day cycle (carboplatin was only dosed on Day 1 so there are no Day 3 Tmax values)

Population: PK analysis set - included all participants with evaluable PK profiles for both treatments and analytes

Tmax of etoposide and free and total carboplatin in plasma was determined from individual concentration-time data by non-compartmental analysis methods. The actual sampling times in relation to dosing were used.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=9 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Tmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 Etoposide Day 1 Cycle 1	1.08 Hours Interval 0.9 to 2.67	—
Tmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 Etoposide Day 3 Cycle 1	1.00 Hours Interval 0.85 to 1.52	—
Tmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 Free Carboplatin Day 1 Cycle 1	0.52 Hours Interval 0.47 to 0.67	—
Tmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 Total Carboplatin Day 1 Cycle 1	0.52 Hours Interval 0.47 to 0.67	—

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment. No participants had severe (Grade 4) neutropenia in the 240 mg/m\^2 arm.

Severe (Grade 4) neutropenia was defined as at least 1 ANC value \<0.5 × 10\^9/L during the treatment period. Within each cycle, the duration (days) of severe neutropenia was defined as the number of days from the date of the first ANC value of \<0.5 × 10\^9/L observed between start of cycle and end of cycle to the date of the first ANC value ≥0.5 × 10\^9/L that met the following criteria: 1) occurred after the ANC value of \<0.5 × 10\^9/L and 2) no other ANC values \<0.5 × 10\^9/L occurred between this day and end of cycle. The duration of severe neutropenia only included participants who had at least 1 severe neutropenia event in the cycle, and censoring rules were applied for unresolved severe neutropenia in a cycle. For the treatment period, the overall duration of severe neutropenia was the median value among the durations from all cycles.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=4 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Duration of Severe (Grade 4) Neutropenia in Part 1	6 Days Interval 6.0 to 7.0	—

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Severe (Grade 4) neutropenia was defined as at least 1 ANC value \<0.5 × 10\^9/L during the treatment period.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=10 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=9 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Severe (Grade 4) Neutropenia in Part 1	4 Participants	0 Participants

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Each febrile neutropenia event (as defined by Common Terminology Criteria for Adverse Events \[CTCAE\]) was captured as an AE. The occurrence of febrile neutropenia was defined as at least 1 febrile neutropenia event during the treatment period. For the treatment period, the total number of febrile neutropenia events was the number of febrile neutropenia events with a unique start date.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=10 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=9 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Febrile Neutropenia in Part 1	0 Participants	0 Participants

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Grade 3/4 neutropenia was defined as at least 1 ANC value \<1.0 × 10\^9/L during the treatment period. Within each cycle, duration (days) of Grade 3/4 neutropenia was defined as the number of days from the date of the first ANC value of \<1.0 × 10\^9/L observed between start of cycle and end of cycle to the date of the first ANC value ≥1.0 × 10\^9/L that met the following criteria: 1) occurred after the ANC value of \<1.0 × 10\^9/L and 2) no other ANC values \<1.0 × 10\^9/L occurred between this day and end of cycle. The duration of Grade 3/4 neutropenia only included participants who had at least 1 Grade 3/4 neutropenia event in the cycle, and censoring rules were applied for unresolved Grade 3/4 neutropenia in a cycle. For the treatment period, the overall duration of Grade 3/4 neutropenia was the median value among the durations of Grade 3/4 neutropenia from all cycles.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=6 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=3 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Duration of Grade 3/4 Neutropenia in Part 1	8 Days Interval 6.0 to 10.0	8 Days Interval 5.0 to 9.0

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Grade 3/4 neutropenia was defined as at least 1 ANC value \<1.0 × 10\^9/L during the treatment period.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=10 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=9 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Grade 3/4 Neutropenia in Part 1	6 Participants	3 Participants

SECONDARY outcome

Timeframe: From baseline to the end of Cycle 1

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Cycle nadir was the lowest value for ANC that occurred between start of cycle and end of cycle and was less than the cycle baseline.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=10 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=9 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Nadir of Absolute Neutrophil Count in Cycle 1, Part 1	1.198 x 10^9 cells/L Standard Deviation 0.7241	1.653 x 10^9 cells/L Standard Deviation 0.7381

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Administration of G-CSF was collected with concomitant medications, which were coded using World Health Organization Drug Dictionary (WHO-DD) Version September 2017. A cycle where G-CSF was administered concurrently was identified by comparing the start and stop dates of each administration of G-CSF to the start of cycle and end of cycle. The occurrence of G-CSF administrations was defined as at least 1 cycle with G-CSF administrations during the treatment period. For the treatment period, the total number of G-CSF administrations was the number of cycles with G-CSF administrations.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=10 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=9 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Granulocyte-Colony Stimulating Factor (G-CSF) Administration in Part 1	5 Participants	3 Participants

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Within a cycle, a RBC transfusion event was defined as either 1) an actual RBC transfusion, or 2) eligible for RBC transfusion (defined as hemoglobin \<8.0 g/dL). The occurrence of RBC transfusions was defined as at least 1 cycle with RBC transfusion during the treatment period. For the treatment period, the total number of RBC transfusions was the number of cycles with RBC transfusions.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=10 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=9 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Red Blood Cell (RBC) Transfusion in Part 1	4 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Blood samples were collected for local clinical laboratory assessment of hemoglobin levels.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=5 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=7 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Change From Baseline of Hemoglobin at the End of Cycle 6, Part 1	-9.8 g/L Standard Deviation 13.27	-20.1 g/L Standard Deviation 15.21

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Administration of ESAs was collected with concomitant medications, which were coded using WHO-DD Version September 2017. A cycle where an ESA was administered concurrently was identified by comparing the start and stop dates of each administration of an ESA to the start of cycle and end of cycle. The occurrence of ESA administration was at least 1 cycle with an ESA administration during the treatment period. For the treatment period, the total number of ESA administrations was the number of cycles with ESA administrations.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=10 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=9 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Erythropoietin Stimulating Agent (ESA) Administration in Part 1	2 Participants	0 Participants

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Within a cycle, a platelet transfusion event was defined as either 1) an actual platelet transfusion, or 2) eligible for platelet transfusion (defined as a platelet count ≤10 × 10\^9/L). The occurrence of platelet transfusions was defined as at least 1 cycle with platelet transfusion during the treatment period. For the treatment period, the total number of platelet transfusions was the number of cycles with platelet transfusions.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=10 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=9 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Platelet Transfusion in Part 1	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Blood samples were collected for local clinical laboratory assessment of platelet count.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=5 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=7 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Change From Baseline of Platelet Count at the End of Cycle 6, Part 1	-72.6 x 10^9 cells/L Standard Deviation 88.38	-59.4 x 10^9 cells/L Standard Deviation 108.47

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Blood samples were collected for local clinical laboratory assessment of lymphocyte count.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=5 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=7 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Change From Baseline of Lymphocyte Count at the End of Cycle 6, Part 1	0.188 x 10^9 cells/L Standard Deviation 0.8431	0.067 x 10^9 cells/L Standard Deviation 0.4691

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: Safety analysis set - included all enrolled participants (i.e., signed informed consent) who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Part 1: Cohort 1 Trilaciclib 200 mg/m\^2 included 1 participant from Part 2 and 1 participant from Part 1 240 mg/m\^2 who received 200 mg/m\^2.

Dose reductions were not permitted for trilaciclib, per study protocol. Dose reductions for E/P were derived from changes in the protocol-specified dose on the dosing page and corresponded to the reductions for toxicity specified in the protocol. No more than 2 dose reductions of E/P in total were allowed for any participant. Simultaneous reductions in the doses of E/P were counted as 1 dose reduction. For the treatment period, the total number of dose reductions was the number of cycles where there was at least 1 dose reduction.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=12 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=8 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Dose Reduction in Part 1	2 Participants	3 Participants

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

SAEs were defined as any untoward medical occurrence that at any dose resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity or was a congenital anomaly/birth defect. An infectious SAE was a serious event in the Medical Dictionary for Regulatory Activities (MedDRA) system organ class "infections and infestations" and a preferred term of anal abscess, bacteraemia, bronchitis, candida infection, chronic sinusitis, conjunctivitis, infection, influenza, nasopharyngitis, oral candidiasis, oral herpes, pharyngitis streptococcal, pneumonia, pneumonia bacterial, respiratory tract infection, sepsis, skin infection, upper respiratory tract infection, urinary tract infection, urosepsis or viral upper respiratory tract infection.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=10 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=9 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Infectious SAEs in Part 1	2 Participants	1 Participants

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

SAEs were defined as any untoward medical occurrence that at any dose resulted in death, was life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity or was a congenital anomaly/birth defect. A pulmonary infection SAE was a serious event in the MedDRA system organ class "infections and infestations" and a preferred term of bronchitis, influenza, pneumonia, pneumonia bacterial, respiratory tract infection, upper respiratory tract infection or viral upper respiratory tract infection.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=10 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=9 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Pulmonary Infection SAE in Part 1	1 Participants	0 Participants

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Intravenous antibiotic administration was collected with concomitant medications, which were coded using WHO-DD Version September 2017. A cycle where IV antibiotic was administered concurrently was identified by comparing the start and stop dates of each administration of IV antibiotic to the start of cycle and end of cycle. The occurrence of IV antibiotic administration was defined as at least 1 cycle with IV antibiotic administration during the treatment period. For the treatment period, the total number of IV antibiotic administrations was the number of cycles with IV antibiotic administrations.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=10 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=9 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of IV Antibiotic Administration in Part 1	4 Participants	1 Participants

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

MAHE was a composite endpoint incorporating the measurement of several clinically meaningful aspects of myelopreservation into a single endpoint. The individual components for MAHE were hospitalization for a hematologic event, febrile neutropenia, death related to treatment, dose delay/reduction due to ANC or platelet counts, prolonged severe neutropenia (duration \>5 days), RBC transfusion (actual or eligible) and platelet transfusion (actual or eligible). Time to first occurrence of a MAHE event was defined as the first time to observe an interested event among all the components, starting from the first dose date of study drug administration.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=10 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=9 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Time to First Major Adverse Hematologic Event (MAHE) in Part 1	2.6 Months Interval 0.8 to Not evaluable	3.0 Months Interval 1.0 to Not evaluable

SECONDARY outcome

Timeframe: Baseline, end of every two 21-day cycles, up until disease progression to a maximum of the time at least 70% overall survival (OS) events observed (a maximum of 4 years)

Population: Response evaluable analysis set included all participants in the safety analysis set who had at least 1 post-baseline tumor assessment, or clinical progression as noted by the investigator before their first post-baseline tumor scan, or who died due to disease progression before their first post-baseline tumor scan.

Tumor response was assessed by computed tomography (CT) or magnetic resonance imaging (MRI). Overall visit response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was derived programmatically using data from target lesions (TLs), non-target lesions (NTLs), \& new lesions. Tumor response data were used to determine each participant's time point response \& best overall response (BOR). Complete response (CR) was disappearance of all TLs, any pathological lymph nodes selected as TLs must have reduced in short axis to \<10 mm. Partial response (PR) was at least a 30% decrease from baseline in the sum of diameters of TLs, as long as criteria for progressive disease (PD) were not met. PD was a ≥20% increase in the smallest sum of diameters of TLs since treatment started (including baseline) and an absolute increase of ≥5 mm. Stable disease (SD) was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=10 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=8 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Best Overall Tumor Response Based on Assessments in Part 1 CR	0 Participants	1 Participants
Best Overall Tumor Response Based on Assessments in Part 1 PR	8 Participants	7 Participants
Best Overall Tumor Response Based on Assessments in Part 1 SD	0 Participants	0 Participants
Best Overall Tumor Response Based on Assessments in Part 1 PD	1 Participants	0 Participants
Best Overall Tumor Response Based on Assessments in Part 1 Not evaluable	0 Participants	0 Participants
Best Overall Tumor Response Based on Assessments in Part 1 Unconfirmed CR	1 Participants	0 Participants
Best Overall Tumor Response Based on Assessments in Part 1 Unconfirmed PR	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline, end of every two 21-day cycles, up until disease progression to a maximum of the time at least 70% OS events observed (a maximum of 4 years)

Population: Response evaluable analysis set included all participants in the safety analysis set who had at least 1 post-baseline tumor assessment, or clinical progression as noted by the investigator before their first post-baseline tumor scan, or who died due to disease progression before their first post-baseline tumor scan.

Tumor response was assessed by CT or MRI. Overall visit response by RECIST v1.1 was determined by BICR. Tumor response data were used to determine each participant's time point response \& BOR. CR was disappearance of all TLs, any pathological lymph nodes selected as TLs must have reduced in short axis to \<10 mm. PR was at least a 30% decrease from baseline in the sum of diameters of TLs, as long as criteria for PD were not met. PD was a ≥20% increase in the smallest sum of diameters of TLs since treatment started (including baseline) and an absolute increase of ≥5 mm. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=10 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=8 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 CR	1 Participants	0 Participants
Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 PR	6 Participants	8 Participants
Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 SD	2 Participants	0 Participants
Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 PD	0 Participants	0 Participants
Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 Not evaluable	0 Participants	0 Participants
Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 Unconfirmed CR	0 Participants	0 Participants
Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 Unconfirmed PR	2 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline, end of every two 21-day cycles, up until disease progression to a maximum of the time at least 70% OS events observed (a maximum of 4 years)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Tumor response was assessed by CT or MRI. PFS was defined as the time (months) from date of first dose date of study drug for participants in Part 1 until date of documented disease progression or death due to any cause, whichever occurred first. More specifically, PFS was determined using all the assessment data up until the last evaluable visit prior to or on the date of i) disease progression as defined by RECIST 1.1 or by clinical criteria as determined by the investigator; or ii) withdrawal of consent; or iii) receiving subsequent anticancer therapy, whichever was earlier. For PFS determined using response data derived programmatically, either clinical progression or progression by RECIST (whichever came first) was considered. Median and inter-quartile range of PFS were calculated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=10 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=9 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Progression Free Survival (PFS) Based on Assessments in Part 1	5.3 Months Interval 1.5 to 6.1	6.3 Months Interval 5.9 to 9.1

SECONDARY outcome

Timeframe: Baseline up until death or a maximum of the time at least 70% OS events observed (a maximum of 4 years)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

OS was calculated as the time (months) from date of first dose of study drug for participants in Part 1 to the date of death due to any cause. Participants who did not die during the study were censored at the date last known to be alive. Participants lacking data beyond the day of first dose of study drug had their survival time censored at day of first dose of study drug. OS was not censored if a participant received other anti-tumor treatments after the study drugs. Median and inter-quartile range of OS were calculated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=10 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=9 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
OS in Part 1	10.6 Months Interval 4.9 to 25.1	12.8 Months Interval 9.5 to 13.5

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Severe (Grade 4) neutropenia was defined as at least 1 ANC value \<0.5 × 10\^9/L during the treatment period.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=38 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Severe (Grade 4) Neutropenia in Part 2	16 Participants	2 Participants

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Each febrile neutropenia event (as defined by CTCAE) was captured as an AE. The occurrence of febrile neutropenia was defined as at least 1 febrile neutropenia event during the treatment period. For the treatment period, the total number of febrile neutropenia events was the number of febrile neutropenia events with a unique start date.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=38 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Febrile Neutropenia in Part 2	3 Participants	1 Participants

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Grade 3/4 neutropenia was defined as at least 1 ANC value \<1.0 × 10\^9/L during the treatment period. Within each cycle, duration (days) of Grade 3/4 neutropenia was defined as the number of days from the date of the first ANC value of \<1.0 × 10\^9/L observed between start of cycle and end of cycle to the date of the first ANC value ≥1.0 × 10\^9/L that met the following criteria: 1) occurred after the ANC value of \<1.0 × 10\^9/L and 2) no other ANC values \<1.0 × 10\^9/L occurred between this day and end of cycle. The duration of Grade 3/4 neutropenia only included participants who had at least 1 Grade 3/4 neutropenia event in the cycle, and censoring rules were applied for unresolved Grade 3/4 neutropenia in a cycle. For the treatment period, the overall duration of Grade 3/4 neutropenia was the median value among the durations of Grade 3/4 neutropenia from all cycles.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=30 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=14 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Duration of Grade 3/4 Neutropenia in Part 2	8 Days Interval 7.0 to 13.0	8 Days Interval 6.0 to 8.0

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Grade 3/4 neutropenia was defined as at least 1 ANC value \<1.0 × 10\^9/L during the treatment period.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=38 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Grade 3/4 Neutropenia in Part 2	30 Participants	14 Participants

SECONDARY outcome

Timeframe: From baseline to the end of Cycle 1

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Cycle nadir was the lowest value for ANC that occurred between start of cycle and end of cycle and was less than the cycle baseline.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=35 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Nadir of Absolute Neutrophil Count in Cycle 1, Part 2	0.815 x 10^9 cells/L Standard Deviation 0.6385	1.899 x 10^9 cells/L Standard Deviation 1.1930

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Administration of G-CSF was collected with concomitant medications, which were coded using WHO-DD Version September 2017. A cycle where G-CSF was administered concurrently was identified bycomparing the start and stop dates of each administration of G-CSF to the start of cycle and end of cycle. The occurrence of G-CSF administrations was defined as at least 1 cycle with G-CSF administrations during the treatment period. For the treatment period, the total number of G-CSF administrations was the number of cycles with G-CSF administrations.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=38 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of G-CSF Administration in Part 2	24 Participants	4 Participants

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Within a cycle, a RBC transfusion event was defined as either 1) an actual RBC transfusion, or 2) eligible for RBC transfusion (defined as hemoglobin \<8.0 g/dL). The occurrence of RBC transfusions was defined as at least 1 cycle with RBC transfusion during the treatment period. For the treatment period, the total number of RBC transfusions was the number of cycles with RBC transfusions. If a participant did not have any RBC transfusions, they were assigned a value of 0.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=38 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of RBC Transfusion in Part 2 On/after Week 5	9 Participants	2 Participants
Occurrence of RBC Transfusion in Part 2 Overall	9 Participants	6 Participants

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Blood samples were collected for local clinical laboratory assessment of hemoglobin levels.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=22 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=20 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Change From Baseline of Hemoglobin at the End of Cycle 6, Part 2	-25.9 g/L Standard Deviation 14.63	-20.6 g/L Standard Deviation 13.83

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Administration of ESAs was collected with concomitant medications, which were coded using WHO-DD Version September 2017. A cycle where an ESA was administered concurrently was identified by comparing the start and stop dates of each administration of an ESA to the start of cycle and end of cycle. The occurrence of ESA administration was at least 1 cycle with an ESA administration during the treatment period. For the treatment period, the total number of ESA administrations was the number of cycles with ESA administrations.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=38 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of ESA Administration in Part 2	2 Participants	1 Participants

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Within a cycle, a platelet transfusion event was defined as either 1) an actual platelet transfusion, or 2) eligible for platelet transfusion (defined as a platelet count ≤10 × 10\^9/L). The occurrence of platelet transfusions was defined as at least 1 cycle with platelet transfusion during the treatment period. For the treatment period, the total number of platelet transfusions was the number of cycles with platelet transfusions.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=38 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Platelet Transfusion in Part 2	0 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Blood samples were collected for local clinical laboratory assessment of platelet count.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=22 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=20 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Change From Baseline of Platelet Count at the End of Cycle 6, Part 2	-32.7 x 10^9 cells/L Standard Deviation 100.20	-54.4 x 10^9 cells/L Standard Deviation 95.44

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Blood samples were collected for local clinical laboratory assessment of lymphocyte count.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=22 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=20 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Change From Baseline of Lymphocyte Count at the End of Cycle 6, Part 2	-0.203 x 10^9 cells/L Standard Deviation 0.4382	0.104 x 10^9 cells/L Standard Deviation 0.6320

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: Safety analysis set - included all enrolled participants (i.e., signed informed consent) who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Part 1: Cohort 1 Trilaciclib 200 mg/m\^2 included 1 participant from Part 2 and 1 participant from Part 1 240 mg/m\^2 who received 200 mg/m\^2.

Dose reductions were not permitted for trilaciclib, per study protocol. Dose reductions for E/P were derived from changes in the protocol-specified dose on the dosing page and corresponded to the reductions for toxicity specified in the protocol. No more than 2 dose reductions of E/P in total were allowed for any participant. Simultaneous reductions in the doses of E/P were counted as 1 dose reduction. For the treatment period, the total number of dose reductions was the number of cycles where there was at least 1 dose reduction.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=38 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Dose Reduction in Part 2	13 Participants	3 Participants

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

SAEs were defined as any untoward medical occurrence that at any dose resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity or was a congenital anomaly/birth defect. An infectious SAE was a serious event in the MedDRA system organ class "infections and infestations" and a preferred term of anal abscess, bacteraemia, bronchitis, candida infection, chronic sinusitis, conjunctivitis, infection, influenza, nasopharyngitis, oral candidiasis, oral herpes, pharyngitis streptococcal, pneumonia, pneumonia bacterial, respiratory tract infection, sepsis, skin infection, upper respiratory tract infection, urinary tract infection, urosepsis or viral upper respiratory tract infection.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=38 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Infectious SAEs in Part 2	2 Participants	4 Participants

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

SAEs were defined as any untoward medical occurrence that at any dose resulted in death, was life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity or was a congenital anomaly/birth defect. A pulmonary infection SAE was a serious event in the MedDRA system organ class "infections and infestations" and a preferred term of bronchitis, influenza, pneumonia, pneumonia bacterial, respiratory tract infection, upper respiratory tract infection or viral upper respiratory tract infection.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=38 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of Pulmonary Infection SAE in Part 2	1 Participants	4 Participants

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Intravenous antibiotic administration was collected with concomitant medications, which were coded using WHO-DD Version September 2017. A cycle where IV antibiotic was administered concurrently was identified by comparing the start and stop dates of each administration of IV antibiotic to the start of cycle and end of cycle. The occurrence of IV antibiotic administration was defined as at least 1 cycle with IV antibiotic administration during the treatment period. For the treatment period, the total number of IV antibiotic administrations was the number of cycles with IV antibiotic administrations.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=38 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Occurrence of IV Antibiotic Administration in Part 2	8 Participants	8 Participants

SECONDARY outcome

Timeframe: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

MAHE was a composite endpoint incorporating the measurement of several clinically meaningful aspects of myelopreservation into a single endpoint. The individual components for MAHE were hospitalization for a hematologic event, febrile neutropenia, death related to treatment, dose delay/reduction due to ANC or platelet counts, prolonged severe neutropenia (duration \>5 days), RBC transfusion (actual or eligible) and platelet transfusion (actual or eligible). Time to first occurrence of a MAHE event was defined as the first time to observe an interested event among all the components, starting from the first dose date of study drug administration.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=38 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Time to First MAHE in Part 2	1.0 Months Interval 0.5 to 2.3	NA Months Interval 3.3 to Not evaluable

SECONDARY outcome

Timeframe: Baseline, end of every two 21-day cycles, up until disease progression to a maximum of the time at least 70% OS events observed (a maximum of 4 years)

Population: Response evaluable analysis set included all participants in the safety analysis set who had at least 1 post-baseline tumor assessment, or clinical progression as noted by the investigator before their first post-baseline tumor scan, or who died due to disease progression before their first post-baseline tumor scan.

Tumor response was assessed by CT or MRI. Overall visit response by RECIST v1.1 was derived programmatically using data from TLs, NTLs, \& new lesions. Tumor response data were used to determine each participant's time point response \& BOR. CR was disappearance of all TLs, any pathological lymph nodes selected as TLs must have reduced in short axis to \<10 mm. PR was at least a 30% decrease from baseline in the sum of diameters of TLs, as long as criteria for PD were not met. PD was a ≥20% increase in the smallest sum of diameters of TLs since treatment started (including baseline) and an absolute increase of ≥5 mm. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=36 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Best Overall Tumor Response Based on Assessments in Part 2 CR	1 Participants	0 Participants
Best Overall Tumor Response Based on Assessments in Part 2 PR	19 Participants	24 Participants
Best Overall Tumor Response Based on Assessments in Part 2 SD	12 Participants	9 Participants
Best Overall Tumor Response Based on Assessments in Part 2 PD	4 Participants	1 Participants
Best Overall Tumor Response Based on Assessments in Part 2 Not evaluable	1 Participants	0 Participants
Best Overall Tumor Response Based on Assessments in Part 2 Unconfirmed CR	0 Participants	0 Participants
Best Overall Tumor Response Based on Assessments in Part 2 Unconfirmed PR	6 Participants	4 Participants

SECONDARY outcome

Timeframe: Baseline, end of every two 21-day cycles, up until disease progression to a maximum of the time at least 70% OS events observed (a maximum of 4 years)

Population: Response evaluable analysis set included all participants in the safety analysis set who had at least 1 post-baseline tumor assessment, or clinical progression as noted by the investigator before their first post-baseline tumor scan, or who died due to disease progression before their first post-baseline tumor scan.

Tumor response was assessed by CT or MRI. Overall visit response by RECIST v1.1 was determined by BICR. Tumor response data were used to determine each participant's time point response \& BOR. CR was disappearance of all TLs, any pathological lymph nodes selected as TLs must have reduced in short axis to \<10 mm. PR was at least a 30% decrease from baseline in the sum of diameters of TLs, as long as criteria for PD were not met. PD was a ≥20% increase in the smallest sum of diameters of TLs since treatment started (including baseline) and an absolute increase of ≥5 mm. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=36 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Best Overall Tumor Response Based on BICR Assessments in Part 2 CR	0 Participants	1 Participants
Best Overall Tumor Response Based on BICR Assessments in Part 2 PR	23 Participants	23 Participants
Best Overall Tumor Response Based on BICR Assessments in Part 2 SD	10 Participants	7 Participants
Best Overall Tumor Response Based on BICR Assessments in Part 2 PD	4 Participants	2 Participants
Best Overall Tumor Response Based on BICR Assessments in Part 2 Not evaluable	0 Participants	1 Participants
Best Overall Tumor Response Based on BICR Assessments in Part 2 Unconfirmed CR	0 Participants	0 Participants
Best Overall Tumor Response Based on BICR Assessments in Part 2 Unconfirmed PR	5 Participants	4 Participants

SECONDARY outcome

Timeframe: Baseline, end of every two 21-day cycles, up until disease progression to a maximum of the time at least 70% OS events observed (a maximum of 4 years)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

Tumor response was assessed by CT or MRI. PFS was defined as the time (months) from date of first dose date of study drug for participants in Part 1 until date of documented disease progression or death due to any cause, whichever occurred first. More specifically, PFS was determined using all the assessment data up until the last evaluable visit prior to or on the date of i) disease progression as defined by RECIST 1.1 or by clinical criteria as determined by the investigator; or ii) withdrawal of consent; or iii) receiving subsequent anticancer therapy, whichever was earlier. For PFS determined using response data derived programmatically, either clinical progression or progression by RECIST (whichever came first) was considered. Median and inter-quartile range of PFS were calculated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=38 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
PFS Based on Assessments in Part 2	5.0 Months Interval 3.2 to 6.8	6.1 Months Interval 4.2 to 9.5

SECONDARY outcome

Timeframe: Baseline up until death or a maximum of the time at least 70% OS events observed (a maximum of 4 years)

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

OS was calculated as the time (months) from date of first dose of study drug for participants in Part 2 to the date of death due to any cause. Participants who did not die during the study were censored at the date last known to be alive. Participants lacking data beyond the day of first dose of study drug had their survival time censored at day of first dose of study drug. OS was not censored if a participant received other anti-tumor treatments after the study drugs. Median and inter-quartile range of OS were calculated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=38 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
OS in Part 2	10.6 Months Interval 6.9 to 16.9	10.9 Months Interval 7.3 to 20.1

POST_HOC outcome

Timeframe: From baseline to the end of Cycle 1

Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.

In addition to deriving severe (Grade 4) neutropenia using the method described for the primary endpoints, an approach was applied that accounted for participants who did not experience a severe neutropenia event in Cycle 1. For the post-hoc analysis, severe neutropenia was defined as at least 1 ANC value \<0.5 × 10\^9/L during the treatment period. In Cycle 1, the duration (days) of severe neutropenia was defined as the number of days from the date of the first ANC value of \<0.5 × 10\^9/L observed between start of cycle and end of cycle to the date of the first ANC value ≥0.5 × 10\^9/L that met the following criteria: 1) occurred after the ANC value of \<0.5 × 10\^9/L and 2) no other ANC values \<0.5 × 10\^9/L occurred between this day and end of cycle. The duration of severe neutropenia was set to 0 for participants who did not experience severe neutropenia in Cycle 1. Data from unscheduled visits and the actual assessment date (rather than visit date) were included in the derivation.

Outcome measures

Outcome measures
Measure	Part 1: Cohort 1 Trilaciclib 200 mg/m^2 n=37 Participants Participants received trilaciclib 200 mg/m\^2 administered intravenously (IV) once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.	Part 1: Cohort 2 Trilaciclib 240mg/m^2 n=36 Participants Participants received trilaciclib 240 mg/m\^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle.
Duration of Severe (Grade 4) Neutropenia in Cycle 1 of Part 2	0 Days Interval 0.0 to 13.0	0 Days Interval 0.0 to 3.0

Adverse Events

Part 1: Cohort 1 Trilaciclib 200 mg/m^2

Serious events: 4 serious events

Other events: 12 other events

Deaths: 9 deaths

Part 1: Cohort 2 Trilaciclib 240mg/m^2

Serious events: 1 serious events

Other events: 8 other events

Deaths: 8 deaths

Part 2: Placebo

Serious events: 9 serious events

Other events: 36 other events

Deaths: 28 deaths

Part 2: Trilaciclib 240 mg/m^2

Serious events: 11 serious events

Other events: 37 other events

Deaths: 28 deaths

Serious adverse events

Other adverse events

Additional Information

Chandra Lovejoy

G1 Therapeutics

Phone: 001 9192991250

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The investigator will submit results communications for review by the sponsor at least 60 days prior to expected submission to the intended publisher or meeting committee. This review period may be shortened upon mutual consent. The sponsor may 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.
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Restriction type: OTHER