Trilaciclib (G1T28), a CDK 4/6 Inhibitor, in Combination With Etoposide and Carboplatin in Extensive Stage Small Cell Lung Cancer (SCLC)
Study Details
Study Description
Brief Summary
This is a study to investigate the potential clinical benefit of trilaciclib (G1T28) in preserving the bone marrow and the immune system, and enhancing chemotherapy antitumor efficacy when administered prior to carboplatin and etoposide in first line treatment for patients with newly diagnosed extensive-stage SCLC.
The study consists of 2 parts: a limited open-label, dose-finding portion (Part 1), and a randomized double-blind portion (Part 2). Both parts include 3 study phases: Screening Phase, Treatment Phase, and Survival Follow-up Phase. The Treatment Phase begins on the day of first dose with study treatment and completes at the Post-Treatment Visit. Approximately, 90 patients will be enrolled in the study; 20 patients in the Part 1 and 70 patients in the Part 2 portion.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: trilaciclib + carboplatin/etoposide All patients in part 1 will receive trilaciclib (G1T28) prior to standard chemotherapy- carboplatin and etoposide. Patients will have PK assessments completed on days 1 and 3 in cycle 1 only. All patents will be monitored for safety and tumor response based on RECIST version 1.1. Safety surveillance reporting of AEs and concomitant medications commences at the time that informed consent is obtained and continues through the Post Treatment Visit. |
Drug: Carboplatin
Other Names:
Drug: Trilaciclib
Other Names:
Drug: Etoposide
Other Names:
|
| Experimental: trilaciclib/placebo + carboplatin/etoposide All patients enrolled in part 2 will be randomized to receive either trilaciclib (G1T28) or placebo administered prior to standard chemotherapy- carboplatin and etoposide. All patents will be monitored for safety and tumor response based on RECIST version 1.1. Safety surveillance reporting of AEs and concomitant medications commences at the time that informed consent is obtained and continues through the Post Treatment Visit. |
Drug: Carboplatin
Other Names:
Drug: Placebo
Drug: Trilaciclib
Other Names:
Drug: Etoposide
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Dose Limiting Toxicities by Cohort in Cycle 1, Part 1 [Days 1-21 of Cycle 1]
Dose-limiting toxicities (DLTs) were drug-related toxicities defined as follows: Absolute neutrophil count (ANC) < 0.5 × 10^9/L lasting for ≥ 7 days ≥ Grade 3 neutropenic infection/febrile neutropenia Grade 4 thrombocytopenia (TCP) or ≥ Grade 3 TCP with bleeding 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 ≥ 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.
- 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 [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)]
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.
- Duration of Severe (Grade 4) Neutropenia in Part 2 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
Secondary Outcome Measures
- Maximum Observed Plasma Concentration (Cmax) of Trilaciclib in Cycle 1, Part 1 [Days 1 and 3 of Cycle 1 for a 21-day cycle]
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.
- Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Trilaciclib in Cycle 1, Part 1 [Days 1 and 3 of Cycle 1 for a 21-day cycle]
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.
- Time of Maximum Observed Concentration (Tmax) of Trilaciclib in Cycle 1, Part 1 [Days 1 and 3 of Cycle 1 for a 21-day cycle]
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.
- Cmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 [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)]
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.
- AUC0-inf of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 [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)]
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.
- Tmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 [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)]
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.
- Duration of Severe (Grade 4) Neutropenia in Part 1 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Occurrence of Severe (Grade 4) Neutropenia in Part 1 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
Severe (Grade 4) neutropenia was defined as at least 1 ANC value <0.5 × 10^9/L during the treatment period.
- Occurrence of Febrile Neutropenia in Part 1 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Duration of Grade 3/4 Neutropenia in Part 1 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Occurrence of Grade 3/4 Neutropenia in Part 1 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
Grade 3/4 neutropenia was defined as at least 1 ANC value <1.0 × 10^9/L during the treatment period.
- Nadir of Absolute Neutrophil Count in Cycle 1, Part 1 [From baseline to the end of Cycle 1]
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.
- Occurrence of Granulocyte-Colony Stimulating Factor (G-CSF) Administration in Part 1 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Occurrence of Red Blood Cell (RBC) Transfusion in Part 1 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Change From Baseline of Hemoglobin at the End of Cycle 6, Part 1 [Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6]
Blood samples were collected for local clinical laboratory assessment of hemoglobin levels.
- Occurrence of Erythropoietin Stimulating Agent (ESA) Administration in Part 1 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Occurrence of Platelet Transfusion in Part 1 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Change From Baseline of Platelet Count at the End of Cycle 6, Part 1 [Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6]
Blood samples were collected for local clinical laboratory assessment of platelet count.
- Change From Baseline of Lymphocyte Count at the End of Cycle 6, Part 1 [Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6]
Blood samples were collected for local clinical laboratory assessment of lymphocyte count.
- Occurrence of Dose Reduction in Part 1 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Occurrence of Infectious SAEs in Part 1 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 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. 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.
- Occurrence of Pulmonary Infection SAE in Part 1 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Occurrence of IV Antibiotic Administration in Part 1 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Time to First Major Adverse Hematologic Event (MAHE) in Part 1 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Best Overall Tumor Response Based on Assessments in Part 1 [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)]
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.
- Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 [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)]
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.
- Progression Free Survival (PFS) Based on Assessments in Part 1 [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)]
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.
- OS in Part 1 [Baseline up until death or a maximum of the time at least 70% OS events observed (a maximum of 4 years)]
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.
- Occurrence of Severe (Grade 4) Neutropenia in Part 2 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
Severe (Grade 4) neutropenia was defined as at least 1 ANC value <0.5 × 10^9/L during the treatment period.
- Occurrence of Febrile Neutropenia in Part 2 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Duration of Grade 3/4 Neutropenia in Part 2 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Occurrence of Grade 3/4 Neutropenia in Part 2 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
Grade 3/4 neutropenia was defined as at least 1 ANC value <1.0 × 10^9/L during the treatment period.
- Nadir of Absolute Neutrophil Count in Cycle 1, Part 2 [From baseline to the end of Cycle 1]
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.
- Occurrence of G-CSF Administration in Part 2 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Occurrence of RBC Transfusion in Part 2 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Change From Baseline of Hemoglobin at the End of Cycle 6, Part 2 [Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6]
Blood samples were collected for local clinical laboratory assessment of hemoglobin levels.
- Occurrence of ESA Administration in Part 2 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Occurrence of Platelet Transfusion in Part 2 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Change From Baseline of Platelet Count at the End of Cycle 6, Part 2 [Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6]
Blood samples were collected for local clinical laboratory assessment of platelet count.
- Change From Baseline of Lymphocyte Count at the End of Cycle 6, Part 2 [Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6]
Blood samples were collected for local clinical laboratory assessment of lymphocyte count.
- Occurrence of Dose Reduction in Part 2 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Occurrence of Infectious SAEs in Part 2 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 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. 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.
- Occurrence of Pulmonary Infection SAE in Part 2 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Occurrence of IV Antibiotic Administration in Part 2 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Time to First MAHE in Part 2 [From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)]
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.
- Best Overall Tumor Response Based on Assessments in Part 2 [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)]
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.
- Best Overall Tumor Response Based on BICR Assessments in Part 2 [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)]
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.
- PFS Based on Assessments in Part 2 [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)]
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.
- OS in Part 2 [Baseline up until death or a maximum of the time at least 70% OS events observed (a maximum of 4 years)]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Male or female subjects aged ≥18 years
-
Unequivocally confirmed diagnosis of SCLC by histology or cytology, preferably including the presence of neuroendocrine features by immunohistochemistry
-
At least 1 target lesion that is unirradiated and measurable by RECIST, Version 1.1
-
Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2
-
Adequate organ function
Exclusion Criteria:
-
Prior chemotherapy for extensive-stage SCLC
-
Presence of symptomatic brain metastases requiring immediate treatment with radiation therapy or steroids.
-
Uncontrolled ischemic heart disease or uncontrolled symptomatic congestive heart failure
-
Known history of stroke or cerebrovascular accident within 6 months prior to enrollment
-
Other uncontrolled serious chronic disease or conditions that in the investigator's opinion could affect compliance or follow-up in the protocol
-
Concurrent radiotherapy to any site or radiotherapy within 2 weeks prior to enrollment or previous radiotherapy to the target lesion sites (the sites that are to be followed for determination of a response)
-
Receipt of any investigational medication within 4 weeks prior to enrollment
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Genesis Cancer Center | Hot Springs | Arkansas | United States | 71913 |
| 2 | Highlands Oncology Group | Rogers | Arkansas | United States | 72758 |
| 3 | The Oncology Institute of Hope and Innovation | Whittier | California | United States | 90603 |
| 4 | Memorial Hospital - Univ. of Colorado Health | Colorado Springs | Colorado | United States | 80909 |
| 5 | University of Colorado Health, Oncology Clinical Research Northern Region | Fort Collins | Colorado | United States | 80528 |
| 6 | Boca Raton Regional Hospital - Lynn Cancer Institute | Boca Raton | Florida | United States | 33486 |
| 7 | Florida Cancer Specialists - South | Fort Myers | Florida | United States | 33916 |
| 8 | Florida Cancer Specialists - North | Tavares | Florida | United States | 32778 |
| 9 | Florida Cancer Specialists - East | West Palm Beach | Florida | United States | 33401 |
| 10 | University Cancer and Blood Center, LLC | Athens | Georgia | United States | 30607 |
| 11 | Emory University | Atlanta | Georgia | United States | 30322 |
| 12 | Norton Cancer Institute | Louisville | Kentucky | United States | 40202 |
| 13 | Center For Cancer and Blood Disorders | Bethesda | Maryland | United States | 20817 |
| 14 | Norris Cotton Cancer Center | Lebanon | New Hampshire | United States | 03756 |
| 15 | University of New Mexico Comprehensive Cancer Center | Albuquerque | New Mexico | United States | 87106 |
| 16 | Roswell Park | Buffalo | New York | United States | 14263 |
| 17 | UNC - Lineberger Comprehensive Cancer Center | Chapel Hill | North Carolina | United States | 27514 |
| 18 | Oklahoma University - Peggy and Charles Stephenson Cancer Center | Oklahoma City | Oklahoma | United States | 73117 |
| 19 | Thomas Jefferson University | Philadelphia | Pennsylvania | United States | 19107 |
| 20 | Guthrie Medical Group, PC | Sayre | Pennsylvania | United States | 18840 |
| 21 | Greenville Health System | Greenville | South Carolina | United States | 29605 |
| 22 | Gibbs Cancer Center | Spartanburg | South Carolina | United States | 29203 |
| 23 | Tennessee Cancer Specialists | Knoxville | Tennessee | United States | 37909 |
| 24 | Hanna Cancer Associates - University of Tennessee | Knoxville | Tennessee | United States | 37920 |
| 25 | Texas Oncology | Tyler | Texas | United States | 75702 |
| 26 | Northwest Cancer Specialists, P.C. | Vancouver | Washington | United States | 98684 |
| 27 | CHU de Rennes Hopital Pontchaillou | Rennes | France | 35033 | |
| 28 | ARENSIA Exploratory Medicine LLC | Tbilisi | Georgia | 0112 | |
| 29 | Veszprem Megyei Tudogyogyintezet | Farkasgyepu | Veszprem | Hungary | 8582 |
| 30 | Orszagos Koranyi Tbc es Pulmonologiai Intezet, XI. Tudobelosztaly | Budapest | Hungary | 1121 | |
| 31 | Hetenyi Geza Korhaz | Szolnok | Hungary | 5000 | |
| 32 | ARENSIA Exploratory Medicine Phase I Unit, The Institute of Oncology | Chisinau | Moldova, Republic of | 2025 | |
| 33 | Samodzielny Publiczny ZespAA GruAicy i ChorAb PA¿uc | Olsztyn | Poland | 10-357 | |
| 34 | Wojewodzki Szpital Zespolony im. L. Rydygiera | Torun | Poland | 87-100 | |
| 35 | Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie | Warszawa | Poland | 02-781 | |
| 36 | Hospital Regional Universitario HRU Carlos Haya Malaga | Malaga | Andalucia | Spain | 29010 |
| 37 | Hospital de la Santa Creu i Sant Pau | Barcelona | Spain | 08041 | |
| 38 | Consorcio Hospitalario Provincial | Castillón | Spain | 12002 | |
| 39 | Hgu Gregorio Maranon | Madrid | Spain | 28009 | |
| 40 | Fundacion Jimenez Diaz | Madrid | Spain | 28040 |
Sponsors and Collaborators
- G1 Therapeutics, Inc.
Investigators
- Study Director: Clinical Contact, G1 Therapeutics, Inc.
Study Documents (Full-Text)
More Information
Publications
None provided.- G1T28-02
- 2016-001583-11
Study Results
Participant Flow
| Recruitment Details | 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. |
|---|---|
| Pre-assignment Detail | 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. |
| Arm/Group Title | Part 1: Dose Finding/Expansion | Part 2: Trilaciclib/Placebo IV With E/P |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Period Title: Overall Study | ||
| STARTED | 19 | 77 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 19 | 77 |
Baseline Characteristics
| Arm/Group Title | Part 1: Dose Finding/Expansion | Part 2: Trilaciclib/Placebo IV With E/P | Total |
|---|---|---|---|
| Arm/Group Description | 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. | 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 of all reporting groups |
| Overall Participants | 19 | 77 | 96 |
| Age (Count of Participants) | |||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
7
36.8%
|
37
48.1%
|
44
45.8%
|
| >=65 years |
12
63.2%
|
40
51.9%
|
52
54.2%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
8
42.1%
|
23
29.9%
|
31
32.3%
|
| Male |
11
57.9%
|
54
70.1%
|
65
67.7%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
1
5.3%
|
2
2.6%
|
3
3.1%
|
| Not Hispanic or Latino |
18
94.7%
|
75
97.4%
|
93
96.9%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
1
1.3%
|
1
1%
|
| Asian |
0
0%
|
1
1.3%
|
1
1%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
3
15.8%
|
1
1.3%
|
4
4.2%
|
| White |
16
84.2%
|
73
94.8%
|
89
92.7%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
1
1.3%
|
1
1%
|
| Country (Count of Participants) | |||
| United States |
19
100%
|
39
50.6%
|
58
60.4%
|
| Non-United States |
0
0%
|
38
49.4%
|
38
39.6%
|
| Body Surface Area (m^2) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [m^2] |
1.90
(0.263)
|
1.90
(0.216)
|
NA
(NA)
|
Outcome Measures
| Title | Number of Participants With Dose Limiting Toxicities by Cohort in Cycle 1, Part 1 |
|---|---|
| Description | Dose-limiting toxicities (DLTs) were drug-related toxicities defined as follows: Absolute neutrophil count (ANC) < 0.5 × 10^9/L lasting for ≥ 7 days ≥ Grade 3 neutropenic infection/febrile neutropenia Grade 4 thrombocytopenia (TCP) or ≥ Grade 3 TCP with bleeding 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 ≥ 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. |
| Time Frame | Days 1-21 of Cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 12 | 8 |
| Number of participants meeting ≥1 DLT criteria |
2
10.5%
|
1
1.3%
|
| Grade 4 TCP or ≥Grade 3 TCP with bleeding |
1
5.3%
|
0
0%
|
| Unable to start next cycle of chemotherapy |
1
5.3%
|
1
1.3%
|
| Title | 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 |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 12 | 8 |
| Any TEAE |
12
63.2%
|
8
10.4%
|
| Any SAE |
4
21.1%
|
1
1.3%
|
| TEAE related to any study drug |
10
52.6%
|
8
10.4%
|
| SAE related to any study drug |
0
0%
|
0
0%
|
| TEAE leading to discontinuation of any study drug |
0
0%
|
0
0%
|
| Title | Duration of Severe (Grade 4) Neutropenia in Part 2 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 16 | 2 |
| Median (Inter-Quartile Range) [Days] |
8
|
3
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Part 1: Cohort 1 Trilaciclib 200 mg/m^2, Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | = 0.0097 |
| Comments | The p-value was calculated using the stratified log-rank test to account for the baseline ECOG status (0-1 vs 2) as the stratification factor. Significance level was set as two-sided 0.2. | |
| Method | Stratified log-rank test | |
| Comments | p-value calculated using stratified log-rank test with baseline ECOG status (0-1 vs 2) as stratification factor. Significance level was two-sided 0.2. | |
| Title | Maximum Observed Plasma Concentration (Cmax) of Trilaciclib in Cycle 1, Part 1 |
|---|---|
| Description | 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. |
| Time Frame | Days 1 and 3 of Cycle 1 for a 21-day cycle |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic (PK) analysis set - included all participants with evaluable PK profiles for both treatments and analytes. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 8 | 1 |
| Day 1 Cycle 1 |
1240
(738)
|
1570
(NA)
|
| Day 3 Cycle 1 |
1620
(1040)
|
2260
(NA)
|
| Title | Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Trilaciclib in Cycle 1, Part 1 |
|---|---|
| Description | 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. |
| Time Frame | Days 1 and 3 of Cycle 1 for a 21-day cycle |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK analysis set - included all participants with evaluable PK profiles for both treatments and analytes |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 8 | 1 |
| Day 1 Cycle 1 |
2560
(792)
|
2280
(NA)
|
| Day 3 Cycle 1 |
3110
(693)
|
2960
(NA)
|
| Title | Time of Maximum Observed Concentration (Tmax) of Trilaciclib in Cycle 1, Part 1 |
|---|---|
| Description | 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. |
| Time Frame | Days 1 and 3 of Cycle 1 for a 21-day cycle |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK analysis set - included all participants with evaluable PK profiles for both treatments and analytes |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 8 | 1 |
| Day 1 Cycle 1 |
0.57
|
0.50
|
| Day 3 Cycle 1 |
0.52
|
0.45
|
| Title | Cmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK analysis set - included all participants with evaluable PK profiles for both treatments and analytes |
| Arm/Group Title | Part 1: Dose Finding/Expansion |
|---|---|
| Arm/Group Description | 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 |
| Measure Participants | 9 |
| Etoposide Day 1 Cycle 1 |
21.9
(2.70)
|
| Etoposide Day 3 Cycle 1 |
20.2
(2.40)
|
| Free Carboplatin Day 1 Cycle 1 |
20.3
(6.83)
|
| Total Carboplatin Day 1 Cycle 1 |
18.8
(5.45)
|
| Title | AUC0-inf of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK analysis set - included all participants with evaluable PK profiles for both treatments and analytes |
| Arm/Group Title | Part 1: Dose Finding/Expansion |
|---|---|
| Arm/Group Description | 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 |
| Measure Participants | 9 |
| Etoposide Day 1 Cycle 1 |
131
(44.7)
|
| Etoposide Day 3 Cycle 1 |
146
(48.4)
|
| Free Carboplatin Day 1 Cycle 1 |
50.5
(14.4)
|
| Total Carboplatin Day 1 Cycle 1 |
137
(37.3)
|
| Title | Tmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK analysis set - included all participants with evaluable PK profiles for both treatments and analytes |
| Arm/Group Title | Part 1: Dose Finding/Expansion |
|---|---|
| Arm/Group Description | 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 |
| Measure Participants | 9 |
| Etoposide Day 1 Cycle 1 |
1.08
|
| Etoposide Day 3 Cycle 1 |
1.00
|
| Free Carboplatin Day 1 Cycle 1 |
0.52
|
| Total Carboplatin Day 1 Cycle 1 |
0.52
|
| Title | Duration of Severe (Grade 4) Neutropenia in Part 1 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 4 | 0 |
| Median (Inter-Quartile Range) [Days] |
6
|
| Title | Occurrence of Severe (Grade 4) Neutropenia in Part 1 |
|---|---|
| Description | Severe (Grade 4) neutropenia was defined as at least 1 ANC value <0.5 × 10^9/L during the treatment period. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 10 | 9 |
| Count of Participants [Participants] |
4
21.1%
|
0
0%
|
| Title | Occurrence of Febrile Neutropenia in Part 1 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 10 | 9 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
| Title | Duration of Grade 3/4 Neutropenia in Part 1 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 6 | 3 |
| Median (Inter-Quartile Range) [Days] |
8
|
8
|
| Title | Occurrence of Grade 3/4 Neutropenia in Part 1 |
|---|---|
| Description | Grade 3/4 neutropenia was defined as at least 1 ANC value <1.0 × 10^9/L during the treatment period. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 10 | 9 |
| Count of Participants [Participants] |
6
31.6%
|
3
3.9%
|
| Title | Nadir of Absolute Neutrophil Count in Cycle 1, Part 1 |
|---|---|
| Description | 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. |
| Time Frame | From baseline to the end of Cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 10 | 9 |
| Mean (Standard Deviation) [x 10^9 cells/L] |
1.198
(0.7241)
|
1.653
(0.7381)
|
| Title | Occurrence of Granulocyte-Colony Stimulating Factor (G-CSF) Administration in Part 1 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 10 | 9 |
| Count of Participants [Participants] |
5
26.3%
|
3
3.9%
|
| Title | Occurrence of Red Blood Cell (RBC) Transfusion in Part 1 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 10 | 9 |
| Count of Participants [Participants] |
4
21.1%
|
1
1.3%
|
| Title | Change From Baseline of Hemoglobin at the End of Cycle 6, Part 1 |
|---|---|
| Description | Blood samples were collected for local clinical laboratory assessment of hemoglobin levels. |
| Time Frame | Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 5 | 7 |
| Mean (Standard Deviation) [g/L] |
-9.8
(13.27)
|
-20.1
(15.21)
|
| Title | Occurrence of Erythropoietin Stimulating Agent (ESA) Administration in Part 1 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 10 | 9 |
| Count of Participants [Participants] |
2
10.5%
|
0
0%
|
| Title | Occurrence of Platelet Transfusion in Part 1 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 10 | 9 |
| Count of Participants [Participants] |
1
5.3%
|
0
0%
|
| Title | Change From Baseline of Platelet Count at the End of Cycle 6, Part 1 |
|---|---|
| Description | Blood samples were collected for local clinical laboratory assessment of platelet count. |
| Time Frame | Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 5 | 7 |
| Mean (Standard Deviation) [x 10^9 cells/L] |
-72.6
(88.38)
|
-59.4
(108.47)
|
| Title | Change From Baseline of Lymphocyte Count at the End of Cycle 6, Part 1 |
|---|---|
| Description | Blood samples were collected for local clinical laboratory assessment of lymphocyte count. |
| Time Frame | Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 5 | 7 |
| Mean (Standard Deviation) [x 10^9 cells/L] |
0.188
(0.8431)
|
0.067
(0.4691)
|
| Title | Occurrence of Dose Reduction in Part 1 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 12 | 8 |
| Count of Participants [Participants] |
2
10.5%
|
3
3.9%
|
| Title | Occurrence of Infectious SAEs in Part 1 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 10 | 9 |
| Count of Participants [Participants] |
2
10.5%
|
1
1.3%
|
| Title | Occurrence of Pulmonary Infection SAE in Part 1 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 10 | 9 |
| Count of Participants [Participants] |
1
5.3%
|
0
0%
|
| Title | Occurrence of IV Antibiotic Administration in Part 1 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 10 | 9 |
| Count of Participants [Participants] |
4
21.1%
|
1
1.3%
|
| Title | Time to First Major Adverse Hematologic Event (MAHE) in Part 1 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 10 | 9 |
| Median (Inter-Quartile Range) [Months] |
2.6
|
3.0
|
| Title | Best Overall Tumor Response Based on Assessments in Part 1 |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 10 | 8 |
| CR |
0
0%
|
1
1.3%
|
| PR |
8
42.1%
|
7
9.1%
|
| SD |
0
0%
|
0
0%
|
| PD |
1
5.3%
|
0
0%
|
| Not evaluable |
0
0%
|
0
0%
|
| Unconfirmed CR |
1
5.3%
|
0
0%
|
| Unconfirmed PR |
0
0%
|
0
0%
|
| Title | Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 10 | 8 |
| CR |
1
5.3%
|
0
0%
|
| PR |
6
31.6%
|
8
10.4%
|
| SD |
2
10.5%
|
0
0%
|
| PD |
0
0%
|
0
0%
|
| Not evaluable |
0
0%
|
0
0%
|
| Unconfirmed CR |
0
0%
|
0
0%
|
| Unconfirmed PR |
2
10.5%
|
0
0%
|
| Title | Progression Free Survival (PFS) Based on Assessments in Part 1 |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 10 | 9 |
| Median (Inter-Quartile Range) [Months] |
5.3
|
6.3
|
| Title | OS in Part 1 |
|---|---|
| Description | 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. |
| Time Frame | Baseline up until death or a maximum of the time at least 70% OS events observed (a maximum of 4 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 |
|---|---|---|
| Arm/Group Description | 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. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 10 | 9 |
| Median (Inter-Quartile Range) [Months] |
10.6
|
12.8
|
| Title | Occurrence of Severe (Grade 4) Neutropenia in Part 2 |
|---|---|
| Description | Severe (Grade 4) neutropenia was defined as at least 1 ANC value <0.5 × 10^9/L during the treatment period. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 37 | 38 |
| Count of Participants [Participants] |
16
84.2%
|
2
2.6%
|
| Title | Occurrence of Febrile Neutropenia in Part 2 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 37 | 38 |
| Count of Participants [Participants] |
3
15.8%
|
1
1.3%
|
| Title | Duration of Grade 3/4 Neutropenia in Part 2 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 30 | 14 |
| Median (Inter-Quartile Range) [Days] |
8
|
8
|
| Title | Occurrence of Grade 3/4 Neutropenia in Part 2 |
|---|---|
| Description | Grade 3/4 neutropenia was defined as at least 1 ANC value <1.0 × 10^9/L during the treatment period. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 37 | 38 |
| Count of Participants [Participants] |
30
157.9%
|
14
18.2%
|
| Title | Nadir of Absolute Neutrophil Count in Cycle 1, Part 2 |
|---|---|
| Description | 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. |
| Time Frame | From baseline to the end of Cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 37 | 35 |
| Mean (Standard Deviation) [x 10^9 cells/L] |
0.815
(0.6385)
|
1.899
(1.1930)
|
| Title | Occurrence of G-CSF Administration in Part 2 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 37 | 38 |
| Count of Participants [Participants] |
24
126.3%
|
4
5.2%
|
| Title | Occurrence of RBC Transfusion in Part 2 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 37 | 38 |
| Overall |
9
47.4%
|
6
7.8%
|
| On/after Week 5 |
9
47.4%
|
2
2.6%
|
| Title | Change From Baseline of Hemoglobin at the End of Cycle 6, Part 2 |
|---|---|
| Description | Blood samples were collected for local clinical laboratory assessment of hemoglobin levels. |
| Time Frame | Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 22 | 20 |
| Mean (Standard Deviation) [g/L] |
-25.9
(14.63)
|
-20.6
(13.83)
|
| Title | Occurrence of ESA Administration in Part 2 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 37 | 38 |
| Count of Participants [Participants] |
2
10.5%
|
1
1.3%
|
| Title | Occurrence of Platelet Transfusion in Part 2 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 37 | 38 |
| Count of Participants [Participants] |
0
0%
|
2
2.6%
|
| Title | Change From Baseline of Platelet Count at the End of Cycle 6, Part 2 |
|---|---|
| Description | Blood samples were collected for local clinical laboratory assessment of platelet count. |
| Time Frame | Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 22 | 20 |
| Mean (Standard Deviation) [x 10^9 cells/L] |
-32.7
(100.20)
|
-54.4
(95.44)
|
| Title | Change From Baseline of Lymphocyte Count at the End of Cycle 6, Part 2 |
|---|---|
| Description | Blood samples were collected for local clinical laboratory assessment of lymphocyte count. |
| Time Frame | Baseline, Day 1, Day 3, Day 8, Day 10, and Day 15 of a 21-day cycle x 6 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 22 | 20 |
| Mean (Standard Deviation) [x 10^9 cells/L] |
-0.203
(0.4382)
|
0.104
(0.6320)
|
| Title | Occurrence of Dose Reduction in Part 2 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 37 | 38 |
| Count of Participants [Participants] |
13
68.4%
|
3
3.9%
|
| Title | Occurrence of Infectious SAEs in Part 2 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 37 | 38 |
| Count of Participants [Participants] |
2
10.5%
|
4
5.2%
|
| Title | Occurrence of Pulmonary Infection SAE in Part 2 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21- day E/P chemotherapy cycle. |
| Measure Participants | 37 | 38 |
| Count of Participants [Participants] |
1
5.3%
|
4
5.2%
|
| Title | Occurrence of IV Antibiotic Administration in Part 2 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21- day E/P chemotherapy cycle. |
| Measure Participants | 37 | 38 |
| Count of Participants [Participants] |
8
42.1%
|
8
10.4%
|
| Title | Time to First MAHE in Part 2 |
|---|---|
| Description | 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. |
| Time Frame | From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 37 | 38 |
| Median (Inter-Quartile Range) [Months] |
1.0
|
NA
|
| Title | Best Overall Tumor Response Based on Assessments in Part 2 |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 37 | 36 |
| CR |
1
5.3%
|
0
0%
|
| PR |
19
100%
|
24
31.2%
|
| SD |
12
63.2%
|
9
11.7%
|
| PD |
4
21.1%
|
1
1.3%
|
| Not evaluable |
1
5.3%
|
0
0%
|
| Unconfirmed CR |
0
0%
|
0
0%
|
| Unconfirmed PR |
6
31.6%
|
4
5.2%
|
| Title | Best Overall Tumor Response Based on BICR Assessments in Part 2 |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 37 | 36 |
| CR |
0
0%
|
1
1.3%
|
| PR |
23
121.1%
|
23
29.9%
|
| SD |
10
52.6%
|
7
9.1%
|
| PD |
4
21.1%
|
2
2.6%
|
| Not evaluable |
0
0%
|
1
1.3%
|
| Unconfirmed CR |
0
0%
|
0
0%
|
| Unconfirmed PR |
5
26.3%
|
4
5.2%
|
| Title | PFS Based on Assessments in Part 2 |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 37 | 38 |
| Median (Inter-Quartile Range) [Months] |
5.0
|
6.1
|
| Title | OS in Part 2 |
|---|---|
| Description | 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. |
| Time Frame | Baseline up until death or a maximum of the time at least 70% OS events observed (a maximum of 4 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 37 | 38 |
| Median (Inter-Quartile Range) [Months] |
10.6
|
10.9
|
| Title | Duration of Severe (Grade 4) Neutropenia in Cycle 1 of Part 2 |
|---|---|
| Description | 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. |
| Time Frame | From baseline to the end of Cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 |
|---|---|---|
| Arm/Group Description | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. |
| Measure Participants | 37 | 36 |
| Median (Full Range) [Days] |
0
|
0
|
Adverse Events
| Time Frame | All AEs occurring from the first date of administration of trilaciclib or placebo + E/P therapy through and including 30 calendar days after the last administration of trilaciclib or placebo + E/P therapy were recorded (a minimum of 51 days up to a maximum of 374 days). | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | AEs are reported for the safety analysis set which included all enrolled participants (i.e., signed informed consent) who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the safety analysis set were conducted on the basis of the actual treatment. | |||||||
| Arm/Group Title | Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 | ||||
| Arm/Group Description | 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. One participant was screened and dosed at trilaciclib 200 mg/m^2 for Part 2 of the study without being randomized. AEs for this participant are summarized under the Part 1 trilaciclib 200 mg/m^2 cohort for the safety analysis set. One participant was enrolled in the Part 1 trilaciclib 240 mg/m^2 cohort, but dosed at trilaciclib 200 mg/m^2. AEs for this participant's are presented in the trilaciclib 200 mg/m^2 cohort for the safety analysis set. | Participants received trilaciclib 240 mg/m^2 administered IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received placebo IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | Participants received trilaciclib 240 mg/m^2 IV once daily on Days 1 to 3 of each 21-day E/P chemotherapy cycle. | ||||
All Cause Mortality |
||||||||
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 9/12 (75%) | 8/8 (100%) | 28/37 (75.7%) | 28/38 (73.7%) | ||||
Serious Adverse Events |
||||||||
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 4/12 (33.3%) | 1/8 (12.5%) | 9/37 (24.3%) | 11/38 (28.9%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Febrile neutropenia | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 1/38 (2.6%) | 1 |
| Anemia | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 2/37 (5.4%) | 3 | 0/38 (0%) | 0 |
| Anemia macrocytic | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 0/38 (0%) | 0 |
| Neutropenia | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 0/38 (0%) | 0 |
| Cardiac disorders | ||||||||
| Cardiac failure chronic | 0/12 (0%) | 0 | 1/8 (12.5%) | 1 | 0/37 (0%) | 0 | 0/38 (0%) | 0 |
| Acute myocardial infarction | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 0/38 (0%) | 0 |
| Atrial fibrillation | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 0/38 (0%) | 0 |
| Myocardial infarction | 1/12 (8.3%) | 3 | 0/8 (0%) | 0 | 0/37 (0%) | 0 | 0/38 (0%) | 0 |
| Sinus tachycardia | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 0/38 (0%) | 0 |
| Gastrointestinal disorders | ||||||||
| Diarrhea hemorrhagic | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 0/37 (0%) | 0 | 1/38 (2.6%) | 1 |
| Nausea | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 0/37 (0%) | 0 | 1/38 (2.6%) | 1 |
| Pancreatitis | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 0/37 (0%) | 0 | 1/38 (2.6%) | 1 |
| Stomatitis | 0/12 (0%) | 0 | 1/8 (12.5%) | 1 | 0/37 (0%) | 0 | 0/38 (0%) | 0 |
| General disorders | ||||||||
| Pyrexia | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 0/38 (0%) | 0 |
| Infections and infestations | ||||||||
| Pneumonia | 1/12 (8.3%) | 1 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 2/38 (5.3%) | 3 |
| Influenza | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 0/37 (0%) | 0 | 1/38 (2.6%) | 1 |
| Oral candidiasis | 0/12 (0%) | 0 | 1/8 (12.5%) | 1 | 0/37 (0%) | 0 | 0/38 (0%) | 0 |
| Upper respiratory tract infection | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 0/37 (0%) | 0 | 1/38 (2.6%) | 1 |
| Sepsis | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 0/38 (0%) | 0 |
| Urosepsis | 1/12 (8.3%) | 1 | 0/8 (0%) | 0 | 0/37 (0%) | 0 | 0/38 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||||
| Bone pain | 1/12 (8.3%) | 1 | 0/8 (0%) | 0 | 0/37 (0%) | 0 | 0/38 (0%) | 0 |
| Nervous system disorders | ||||||||
| Cerebrovascular accident | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 0/37 (0%) | 0 | 1/38 (2.6%) | 1 |
| Epilepsy | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 1/38 (2.6%) | 1 |
| Syncope | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 0/37 (0%) | 0 | 1/38 (2.6%) | 1 |
| Altered state of consciousness | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 0/38 (0%) | 0 |
| Psychiatric disorders | ||||||||
| Mental status changes | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 0/38 (0%) | 0 |
| Renal and urinary disorders | ||||||||
| Renal failure | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 0/37 (0%) | 0 | 1/38 (2.6%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Respiratory failure | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 2/38 (5.3%) | 2 |
| Hemoptysis | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 0/37 (0%) | 0 | 1/38 (2.6%) | 1 |
| Pulmonary embolism | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 0/37 (0%) | 0 | 1/38 (2.6%) | 1 |
| Chronic obstructive pulmonary disease | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 0/38 (0%) | 0 |
| Dyspnea | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 0/38 (0%) | 0 |
| Vascular disorders | ||||||||
| Deep vein thrombosis | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 0/38 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||||
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Part 2: Placebo | Part 2: Trilaciclib 240 mg/m^2 | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 12/12 (100%) | 8/8 (100%) | 36/37 (97.3%) | 37/38 (97.4%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Neutropenia | 5/12 (41.7%) | 30 | 5/8 (62.5%) | 14 | 23/37 (62.2%) | 76 | 9/38 (23.7%) | 17 |
| Thrombocytopenia | 3/12 (25%) | 18 | 2/8 (25%) | 8 | 10/37 (27%) | 35 | 10/38 (26.3%) | 12 |
| Anemia | 5/12 (41.7%) | 21 | 1/8 (12.5%) | 3 | 15/37 (40.5%) | 45 | 10/38 (26.3%) | 19 |
| Leukopenia | 5/12 (41.7%) | 29 | 0/8 (0%) | 0 | 5/37 (13.5%) | 13 | 2/38 (5.3%) | 2 |
| Gastrointestinal disorders | ||||||||
| Nausea | 5/12 (41.7%) | 13 | 4/8 (50%) | 8 | 8/37 (21.6%) | 9 | 13/38 (34.2%) | 16 |
| Constipation | 4/12 (33.3%) | 4 | 4/8 (50%) | 5 | 8/37 (21.6%) | 8 | 9/38 (23.7%) | 14 |
| Diarrhea | 3/12 (25%) | 6 | 2/8 (25%) | 3 | 7/37 (18.9%) | 10 | 6/38 (15.8%) | 11 |
| Abdominal pain upper | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 7/38 (18.4%) | 13 |
| Vomiting | 4/12 (33.3%) | 7 | 4/8 (50%) | 7 | 5/37 (13.5%) | 5 | 3/38 (7.9%) | 3 |
| Stomatitis | 0/12 (0%) | 0 | 2/8 (25%) | 4 | 1/37 (2.7%) | 1 | 2/38 (5.3%) | 2 |
| Gastroesophageal reflux disease | 0/12 (0%) | 0 | 1/8 (12.5%) | 1 | 2/37 (5.4%) | 2 | 2/38 (5.3%) | 2 |
| General disorders | ||||||||
| Fatigue | 7/12 (58.3%) | 12 | 4/8 (50%) | 10 | 6/37 (16.2%) | 6 | 16/38 (42.1%) | 21 |
| Edema peripheral | 2/12 (16.7%) | 3 | 2/8 (25%) | 4 | 2/37 (5.4%) | 2 | 3/38 (7.9%) | 4 |
| Non-cardiac chest pain | 0/12 (0%) | 0 | 0/8 (0%) | 0 | 2/37 (5.4%) | 2 | 3/38 (7.9%) | 5 |
| Asthenia | 1/12 (8.3%) | 1 | 1/8 (12.5%) | 1 | 2/37 (5.4%) | 2 | 1/38 (2.6%) | 1 |
| Pyrexia | 3/12 (25%) | 5 | 1/8 (12.5%) | 1 | 5/37 (13.5%) | 5 | 1/38 (2.6%) | 1 |
| Chills | 2/12 (16.7%) | 5 | 0/8 (0%) | 0 | 2/37 (5.4%) | 2 | 1/38 (2.6%) | 1 |
| Infections and infestations | ||||||||
| Pneumonia | 1/12 (8.3%) | 1 | 1/8 (12.5%) | 2 | 2/37 (5.4%) | 2 | 2/38 (5.3%) | 4 |
| Urinary tract infection | 0/12 (0%) | 0 | 1/8 (12.5%) | 2 | 2/37 (5.4%) | 6 | 2/38 (5.3%) | 2 |
| Injury, poisoning and procedural complications | ||||||||
| Infusion related reaction | 1/12 (8.3%) | 2 | 1/8 (12.5%) | 1 | 0/37 (0%) | 0 | 3/38 (7.9%) | 4 |
| Investigations | ||||||||
| Neutrophil count decreased | 0/12 (0%) | 0 | 3/8 (37.5%) | 3 | 9/37 (24.3%) | 32 | 3/38 (7.9%) | 9 |
| Blood creatinine increased | 1/12 (8.3%) | 4 | 2/8 (25%) | 3 | 1/37 (2.7%) | 1 | 2/38 (5.3%) | 3 |
| Platelet count decreased | 0/12 (0%) | 0 | 1/8 (12.5%) | 1 | 4/37 (10.8%) | 12 | 3/38 (7.9%) | 11 |
| Weight decreased | 1/12 (8.3%) | 1 | 1/8 (12.5%) | 1 | 3/37 (8.1%) | 3 | 2/38 (5.3%) | 2 |
| Metabolism and nutrition disorders | ||||||||
| Decreased appetite | 0/12 (0%) | 0 | 1/8 (12.5%) | 1 | 3/37 (8.1%) | 4 | 7/38 (18.4%) | 8 |
| Dehydration | 1/12 (8.3%) | 1 | 4/8 (50%) | 7 | 1/37 (2.7%) | 1 | 0/38 (0%) | 0 |
| Hyperkalemia | 0/12 (0%) | 0 | 1/8 (12.5%) | 1 | 1/37 (2.7%) | 1 | 3/38 (7.9%) | 5 |
| Hypomagnesemia | 0/12 (0%) | 0 | 2/8 (25%) | 3 | 1/37 (2.7%) | 1 | 2/38 (5.3%) | 3 |
| Hyperglycemia | 1/12 (8.3%) | 1 | 0/8 (0%) | 0 | 2/37 (5.4%) | 3 | 2/38 (5.3%) | 2 |
| Musculoskeletal and connective tissue disorders | ||||||||
| Arthralgia | 2/12 (16.7%) | 2 | 4/8 (50%) | 4 | 3/37 (8.1%) | 5 | 5/38 (13.2%) | 5 |
| Pain in extremity | 0/12 (0%) | 0 | 3/8 (37.5%) | 7 | 3/37 (8.1%) | 5 | 3/38 (7.9%) | 4 |
| Back pain | 1/12 (8.3%) | 1 | 1/8 (12.5%) | 2 | 2/37 (5.4%) | 2 | 2/38 (5.3%) | 3 |
| Neck pain | 1/12 (8.3%) | 1 | 1/8 (12.5%) | 1 | 2/37 (5.4%) | 2 | 1/38 (2.6%) | 1 |
| Bone pain | 1/12 (8.3%) | 1 | 0/8 (0%) | 0 | 4/37 (10.8%) | 4 | 0/38 (0%) | 0 |
| Nervous system disorders | ||||||||
| Dizziness | 2/12 (16.7%) | 2 | 3/8 (37.5%) | 5 | 5/37 (13.5%) | 5 | 4/38 (10.5%) | 5 |
| Headache | 4/12 (33.3%) | 12 | 0/8 (0%) | 0 | 3/37 (8.1%) | 4 | 7/38 (18.4%) | 7 |
| Dysgeusia | 0/12 (0%) | 0 | 2/8 (25%) | 2 | 4/37 (10.8%) | 4 | 3/38 (7.9%) | 3 |
| Neuropathy peripheral | 0/12 (0%) | 0 | 2/8 (25%) | 2 | 1/37 (2.7%) | 1 | 2/38 (5.3%) | 3 |
| Psychiatric disorders | ||||||||
| Anxiety | 1/12 (8.3%) | 1 | 0/8 (0%) | 0 | 2/37 (5.4%) | 2 | 3/38 (7.9%) | 3 |
| Insomnia | 2/12 (16.7%) | 2 | 1/8 (12.5%) | 1 | 3/37 (8.1%) | 3 | 1/38 (2.6%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Dyspnea | 2/12 (16.7%) | 2 | 3/8 (37.5%) | 4 | 5/37 (13.5%) | 5 | 8/38 (21.1%) | 11 |
| Cough | 1/12 (8.3%) | 1 | 2/8 (25%) | 2 | 4/37 (10.8%) | 5 | 5/38 (13.2%) | 8 |
| Oropharyngeal pain | 0/12 (0%) | 0 | 1/8 (12.5%) | 1 | 1/37 (2.7%) | 1 | 3/38 (7.9%) | 3 |
| Skin and subcutaneous tissue disorders | ||||||||
| Alopecia | 5/12 (41.7%) | 5 | 3/8 (37.5%) | 4 | 11/37 (29.7%) | 14 | 6/38 (15.8%) | 6 |
| Night sweats | 1/12 (8.3%) | 1 | 0/8 (0%) | 0 | 1/37 (2.7%) | 1 | 3/38 (7.9%) | 4 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
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.
Results Point of Contact
| Name/Title | Chandra Lovejoy |
|---|---|
| Organization | G1 Therapeutics |
| Phone | 001 9192991250 |
| clovejoy@g1therapeutics.com |
- G1T28-02
- 2016-001583-11