Trilaciclib (G1T28), a CDK 4/6 Inhibitor, in Combination With Gemcitabine and Carboplatin in Metastatic Triple Negative Breast Cancer (mTNBC)

DSN was defined as the number of days from the date of the first absolute neutrophil count (ANC) value of less than (\<) 0.5 × 10\^9 cells/liter (L) observed between Day 1 Cycle 1 and the end of Cycle 1 to the date of the first ANC value greater than or equal to (\>=) 0.5 × 10\^9/L that met the following: (1) occurred after the ANC value of \< 0.5 × 10\^9 cells/L and (2) no other ANC values \< 0.5 × 10\^9 cells/L occurred between this day and the end of Cycle 1. Severe neutropenia (SN) was set to zero for participants who did not experience severe (Grade 4) neutropenia in Cycle 1, including those who were randomized but never treated.

Time frame: From randomization to the end of Cycle 1 (Each cycle= 21 days)

Population: The ITT analysis set included all randomized participants.

Number of participants with Grade 4 SN was a binary variable. If a participants had at least 1 ANC value \< 0.5 ×10\^9/L during the treatment period, the participants was assigned as yes to the occurrence of SN. Otherwise, it was no.

Time frame: During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days

Population: The ITT analysis set included all randomized participants.

Dose reductions were not permitted for trilaciclib. Dose reductions for gemcitabine or carboplatin were collected on the dosing page. No more than 3 dose modifications for toxicity in total were allowed for any participant. All dose reductions were counted as a separate event. Discontinuations of an individual component of the chemotherapy regimen were counted as a dose reduction If the participant continued the other chemotherapy drug as a monotherapy. Event rate was calculated as the total number of cycles with an event divided by the total number of cycles.

Time frame: During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days

Population: The ITT analysis set included all randomized participants.

AUC0-t was calculated with the linear/log-trapezoidal method.

Time frame: Cycle 1 Day 1 (Group 1): Pre-dose, 0.5, 1, 2, 3.5, 5, 24 hours post-dose; Cycle 1 Day 1 (Group 2) and Cycle 1 Day 2 (Group 3): Pre-dose, 0.5, 1, 1.5, 2.5, 4, 5.5, 24 hours post-dose (Each cycle is of 21 days)

Population: The PK analysis set included all dosed participants with evaluable PK data. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

AUC0-t was calculated with the linear/log-trapezoidal method, which uses linear interpolation between data points to calculate the AUC. The linear/log-trapezoidal method will be employed for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method will be used for those arising from decreasing concentrations.

Time frame: Cycle 1 Day 1 (Group 1): Pre-dose, 0.5, 1, 2, 3.5, 5, 24 hours post-dose; Cycle 1 Day 1 (Group 2) and Cycle 1 Day 2 (Group 3): Pre-dose, 0.5, 1, 1.5, 2.5, 4, 5.5, 24 hours post-dose (Each cycle is of 21 days)

Population: The PK analysis set included all dosed participants with evaluable PK data. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure. Since, no participant received Trilaciclib in Group 1, data was not assessed and reported.

Clearance after intravenous infusion administration was calculated as: CL=Dose/AUC0-inf. AUC0-inf was calculated as: AUC0-inf=AUClast+Clast/lambdaz where Clast is the last quantifiable concentration in the terminal elimination phase.

Time frame: Cycle 1 Day 1 (Group 1): Pre-dose, 0.5, 1, 2, 3.5, 5, 24 hours post-dose; Cycle 1 Day 1 (Group 2) and Cycle 1 Day 2 (Group 3): Pre-dose, 0.5, 1, 1.5, 2.5, 4, 5.5, 24 hours post-dose (Each cycle is of 21 days)

Population: The PK analysis set included all dosed participants with evaluable PK data. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

Cumulative dose: Sum of the total doses by cycle (AUC) administered to a participant in the duration of exposure, i.e. total number of cycles received (in total prescribed AUC).

Time frame: During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days

Population: The safety analysis set included all enrolled participants who received at least 1 dose of study drug.

Cumulative dose: Sum of the total doses by cycle administered to a participant in the duration of exposure, i.e. total number of cycles received (milligram per meter square \[mg/m\^2\]).

Time frame: During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days

Population: The safety analysis set included all enrolled participants who received at least 1 dose of study drug.

Dose interruptions was defined as interruption of infusion, regardless of whether the study drug was continued after the interruption.

Time frame: During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days

Population: The safety analysis set included all enrolled participants who received at least 1 dose of study drug.

Dose modifications was summarized for each study drug based on number of cycles received during the treatment period. If the participant was unable to start a new cycle at that next visit, then the cycle is delayed, the reason entered, and the question was asked again at the next visit until the participant either starts a new cycle or discontinues treatment.

Time frame: During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days

Population: The safety analysis set included all enrolled participants who received at least 1 dose of study drug.

Dose (mg/m2) reductions were not permitted for trilaciclib. Dose reductions for carboplatin and gemcitabine were determined by comparing the planned dose on the respective drug administration pages between the current cycle and the previous cycle.

Time frame: During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days

Population: The safety analysis set included all enrolled participants who received at least 1 dose of study drug.

Dose modifications was summarized for each study drug based on skipped doses not received during the treatment period. Primary reasons for skipped doses included toxicity, investigator decision and administrative reasons (e.g., holidays).

Time frame: During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days

Population: The safety analysis set included all enrolled participants who received at least 1 dose of study drug.

Duration of exposure (days) = First dose date of study drug from the last cycle - first dose date of study drug + 21.

Time frame: During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days

Population: The safety analysis set included all enrolled participants who received at least 1 dose of study drug.

DOR is the time between first response by RECIST Version 1.1 of CR or PR and the first date that progressive disease is documented by RECIST Version 1.1, or death. Participants who do not experience PD or death was censored at the last tumor assessment date. 95% Confidence Interval (CI) was calculated using the Kaplan-Meier method.

Time frame: From date of randomization until the occurrence of progressive disease or a censoring event, assessed up to a maximum of 875 days

Population: The RE analysis set included all participants who were in the mITT analysis set, had measurable disease TLs at the baseline tumor assessment, and had (1) at least 1 post-baseline tumor assessment, (2) clinical progression (as noted by the investigator) before their first post-baseline tumor scan, or (3) died due to disease progression before their first post-baseline tumor scan. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

MAHE was a composite endpoint incorporating the measurement of several clinically meaningful aspects of myelosuppression into a single endpoint by summing of the total number of events across a set of pre-specified components.The individual components for MAHE were all-cause hospitalizations, all-cause dose reductions, febrile neutropenia, prolonged severe neutropenia (duration \> 5 days), RBC transfusion and platelet transfusion. Event rate for MAHE was calculated as the number of events/durations of treatment period divided by 7 days/1 week.

Time frame: During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days

Population: The ITT analysis set included all randomized participants.

The observed peak plasma concentration was determined from the plasma concentration-versus time data.

Time frame: Cycle 1 Day 1 (Group 1): Pre-dose, 0.5, 1, 2, 3.5, 5, 24 hours post-dose; Cycle 1 Day 1 (Group 2) and Cycle 1 Day 2 (Group 3): Pre-dose, 0.5, 1, 1.5, 2.5, 4, 5.5, 24 hours post-dose (Each cycle is of 21 days)

Population: The PK analysis set included all dosed participants with evaluable PK data. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

The observed peak plasma concentration was determined from the plasma concentration-versus time data.

Time frame: Cycle 1 Day 1 (Group 1): Pre-dose, 0.5, 1, 2, 3.5, 5, 24 hours post-dose; Cycle 1 Day 1 (Group 2) and Cycle 1 Day 2 (Group 3): Pre-dose, 0.5, 1, 1.5, 2.5, 4, 5.5, 24 hours post-dose (Each cycle is of 21 days)

Population: The pharmacokinetic (PK) analysis set included all dosed participants with evaluable PK data. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure. Since, no participant received Trilaciclib in Group 1, data was not assessed and reported.

Participants were considered to have started a cycle if they have received at least 1 dose of any study drug.

Time frame: During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days

Population: The safety analysis set included all enrolled participants who received at least 1 dose of study drug.

BOR was defined as the best response across all time points (RECIST v1.1). The best overall response was determined once all the data for the participant is known. Each participant has been assigned one of the following categories (RECIST 1.1): complete response (CR): disappearance of all target lesions; partial response (PR): \>= 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; progression disease (PD): \>= 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study); stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD); NE: not evaluable and missing.

Time frame: From date of randomization until the occurrence of progressive disease or a censoring event, assessed up to a maximum of 875 days

Population: The response-evaluable (RE) analysis set included all participants who were in the modified intent-to-treat (mITT) analysis set, had measurable disease (target lesions \[TLs\]) at the baseline tumor assessment, and had (1) at least 1 post-baseline tumor assessment, (2) clinical progression (as noted by the investigator) before their first post-baseline tumor scan, or (3) died due to disease progression before their first post-baseline tumor scan.

The occurrence during the treatment period was defined as a binary variable (Yes or No); Yes if total number of events \>=1 was observed, No for other scenarios. If a participant did not have an event, the value of 0 was assigned to that participant. The criterion to select proper records was as follows: If the chemical subgroup from WHO-DD Version September 2017 (i.e., TEXT4 for CODE4) takes value OTHER ANTIANEMIC PREPARATIONS, the medication was classified as ESAs.

Time frame: During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days

Population: The ITT analysis set included all randomized participants.

The criterion for identifying FN was if the PT was FEBRILE NEUTROPENIA the occurrence during the treatment period was defined as a binary variable (Yes or No); Yes if total number of events \>=1 was observed, No for other scenarios. If a participant did not have an event, the value of 0 was assigned to that participant.

Time frame: During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days

Population: The ITT analysis set included all randomized participants.

Hematologic toxicities events were defined as any cycle where any hematologic lab value occurs that meets the CTCAE toxicity grade criteria for \>= Grade 3 and the value is treatment emergent. The occurrence of Grade 3 and 4 hematologic toxicities was a binary endpoint. If a participant had at least 1 cycle with at least one Grade 3 or 4 hematologic toxicities during the treatment period, the participant was assigned as Yes to the occurrence of Grade 3 and 4 hematologic toxicities; otherwise, it was No. If a participant did not have an event, the value of 0 was assigned to that participant.

Time frame: During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days

Population: The ITT analysis set included all randomized participants.

Hematologic toxicities events are defined as any cycle where any hematologic lab value occurs that meets the CTCAE toxicity grade criteria for \>= Grade 3 and the value is treatment emergent. The occurrence of Grade 3 and 4 thrombocytopenia was a binary endpoint. If a participant had at least 1 cycle with at least one Grade 3 or 4 thrombocytopenia during the treatment period, the participant was assigned as Yes to the occurrence of Grade 3 and 4 thrombocytopenia; otherwise, it was No. If a participant did not have an event, the value of 0 was assigned to that participant.

Time frame: During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days

Population: The ITT analysis set included all randomized participants.

The criterion for selecting proper records is as follows: If the chemical subgroup from the World Health Organization-Drug Dictionary (WHO-DD) takes value COLONY STIMULATING FACTOR, the medication was classified as G-CSF. The occurrence during the treatment period was defined as a binary variable (Yes or No); Yes if the total number of events \>=1 was observed and No for other scenarios. If a participant did not have an event, the value of 0 will be assigned to that participant.

Time frame: During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days

Population: The ITT analysis set included all randomized participants.

Number of participants with infection SAEs during the treatment period was defined as a binary variable (Yes or No); Yes if total number of events \>=1 was observed, No for other scenarios. If a participant did not have an event, the value of 0 was assigned to that participant. The criterion for identifying the proper infection SAE records was as follows: If the system organ class (SOC) from Medical Dictionary for Regulatory Activities (MedDRA) takes value INFECTIONS AND INFESTATIONS, and the AE was a serious event.

Time frame: During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days

Population: The ITT analysis set included all randomized participants.

The criteria for identifying an IV antibiotic administration event was (1) if the Therapeutic subgroup from WHO-DD version takes value ANTIBACTERIALS FOR SYSTEMIC USE, and (2) the route of medication was intravenous or the route was other with the detailed specification as IVPB. The occurrence during the treatment period was defined as a binary variable (Yes or No); Yes if total number of events \>=1 was observed, No for other scenarios. If a participant did not have an event, the value of 0 was assigned to that participant.

Time frame: During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days

Population: The ITT analysis set included all randomized participants.

Each platelet transfusion with a unique start date during the treatment period was defined as a separate event. The occurrence during the treatment period was defined as a binary variable (Yes or No); Yes if the total number of events \>=1 was observed and No for other scenarios. If a participant did not have an event, the value of 0 will be assigned to that participant.

Time frame: During the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 542 days

Population: The ITT analysis set included all randomized participants.

Each RBC transfusion with a unique start date on/after 5 weeks on study during the treatment period was defined as a separate event. Occurrence during the treatment period was defined as a binary variable (Yes or No); Yes if the total number of events \>=1 was observed and No for other scenarios. If a participant did not have an event, the value of 0 will be assigned to that participant.

Time frame: From Day 35 through the treatment period. From date of randomization, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 508 days

Population: The ITT analysis set included all randomized participants.

Overall survival was defined as the time (months) from date of randomization to the date of death due to any cause. Participants who do not die during the study were censored at the date last known to be alive. The OS was calculated using Kaplan-Meier method.

Time frame: From date of randomization to date of death due to any cause, assessed up to a maximum of 1120 days

Population: The ITT analysis set included all randomized participants.

PFS was defined as the time (months) from date of randomization until date of documented PD or death due to any cause, whichever comes first. PD: \>= 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study). The PFS was calculated using Kaplan-Meier method.

Time frame: From date of randomization until the occurrence of disease progression, death due to any cause or a censoring event, assessed up to a maximum of 875 days

Population: The ITT analysis set included all randomized participants.

Relative dose intensity was defined as 100% times the actual dose intensity divided by the planned dose intensity. The planned dose intensity was defined as the cumulative planned dose through the study divided by (number of cycles × 3 weeks). Relative dose intensity (%) was calculated as: for gemcitabine (100 \* \[Dose intensity (mg/m2/week) / (2000/3 (mg/m2/week)\]); for carboplatin (100 \* \[Dose intensity (AUC/week)/ (4/3) (AUC/week)\]) and for trilaciclib (100 \* \[Dose intensity (mg/m2/week)/ (480 /3 (mg/m2/week)\] for Group 2 and 100 \* \[Dose intensity (mg/m2/week) / (960 /3 (mg/m2/week)\] for Group 3).

Time frame: During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 871 days

Population: The safety analysis set included all enrolled participants who received at least 1 dose of study drug.

t1/2 was calculated as 0.693 divided by lambda z. lambda z (terminal phase rate constant) was determined by linear regression of at least 3 points on the terminal phase of the log-linear plasma concentration-time curve.

Time frame: Cycle 1 Day 1 (Group 1): Pre-dose, 0.5, 1, 2, 3.5, 5, 24 hours post-dose; Cycle 1 Day 1 (Group 2) and Cycle 1 Day 2 (Group 3): Pre-dose, 0.5, 1, 1.5, 2.5, 4, 5.5, 24 hours post-dose (Each cycle is of 21 days)

Population: The PK analysis set included all dosed participants with evaluable PK data. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

t1/2 was calculated as 0.693 divided by lambda z. lambda z (terminal phase rate constant) was determined by linear regression of at least 3 points on the terminal phase of the log-linear plasma concentration-time curve, the actual body exposure to drug after administration of a dose of the drug ( in mg\*h/L).

Time frame: Cycle 1 Day 1 (Group 1): Pre-dose, 0.5, 1, 2, 3.5, 5, 24 hours post-dose; Cycle 1 Day 1 (Group 2) and Cycle 1 Day 2 (Group 3): Pre-dose, 0.5, 1, 1.5, 2.5, 4, 5.5, 24 hours post-dose (Each cycle is of 21 days)

Population: The PK analysis set included all dosed participants with evaluable PK data. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure. Since, no participant received Trilaciclib in Group 1, data was not assessed and reported.

Vss was the volume of distribution at steady state of free carboplatin was reported.

Time frame: Cycle 1 Day 1 (Group 1): Pre-dose, 0.5, 1, 2, 3.5, 5, 24 hours post-dose; Cycle 1 Day 1 (Group 2) and Cycle 1 Day 2 (Group 3): Pre-dose, 0.5, 1, 1.5, 2.5, 4, 5.5, 24 hours post-dose (Each cycle is of 21 days)

Population: The PK analysis set included all dosed participants with evaluable PK data. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

An Adverse event (AE) was any untoward medical occurrence in a participant administered a medicinal product that did not necessarily have a causal relationship with this treatment. Any AE that started on or after the first dose of study drugs was included as a TEAE. A Serious AE was defined as any AE, occurring at any dose (including after the informed consent form was signed and prior to dosing) and regardless of causality that met one, more of the following criteria: results in death, life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent, significant disability/incapacity, a congenital abnormality/birth defect, an important medical event. TEAEs included serious and non-serious TEAEs.

Time frame: During the treatment period. From date of first dose, 21 day treatment cycles continue until disease progression, unacceptable toxicity, or discontinuation by the patient or investigator, assessed up to a maximum of 1116 days

Population: The safety analysis set included all enrolled participants who received at least 1 dose of study drug.