Small Cell Lung Cancer
Conditions
Keywords
Small Cell Lung Cancer, CDK 4/6 Inhibitor
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.
Interventions
DRUGCarboplatin
DRUGPlacebo
DRUGTrilaciclib
DRUGEtoposide
Sponsors
G1 Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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: 1. Absolute neutrophil count (ANC) \< 0.5 × 10\^9/L lasting for ≥ 7 days 2. ≥ Grade 3 neutropenic infection/febrile neutropenia 3. Grade 4 thrombocytopenia (TCP) or ≥ Grade 3 TCP with bleeding 4. Unable to start next cycle of chemotherapy due to lack of recovery to an ANC ≥ 1.5 × 10\^9/L and platelet count ≥ 100 × 10\^9/L 5. ≥ Grade 3 nonhematologic toxicity (nausea, vomiting, and diarrhea failing maximal medical management; fatigue lasting for \> 72 hours) Toxicities not clearly related to etoposide/carboplatin therapy were also considered for the purposes of determining DLTs. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
France, Georgia, Hungary, Moldova, Poland, Spain, United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Dose Finding/Expansion The 1st cohort in Part 1 received trilaciclib 200 mg/m\^2, IV once daily on Days 1 to 3 of each 21-day E/P cycle. The 2nd cohort in the Phase 1b dose-finding portion of Part 1 & the Phase 2a expansion cohort in Part 1 received trilaciclib 240 mg/m\^2, IV once daily on Days 1 to 3 of each 21-day E/P cycle. Participants received standard E/P chemotherapy in 21-day cycles. Carboplatin dose was calculated using the Calvert formula with a target AUC = 5 (maximum 750 mg) IV on Day 1. Etoposide 100 mg/m\^2 was given IV daily on Days 1, 2, & 3 of each 21-day cycle. Trilaciclib was only given with E/P therapy. If E/P therapy was discontinued, trilaciclib was also to be discontinued. The interval between doses of trilaciclib on successive days was not greater than 28 hours & between the dose of trilaciclib & the first dose of chemotherapy on a given day (etoposide or carboplatin) not greater than 4 hours. | 19 |
| Part 2: Trilaciclib/Placebo IV With E/P Eligible participants were randomized (1:1) to trilaciclib or placebo administered IV once daily on Days 1 to 3 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. | 77 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 17 | 56 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Randomized but not enrolled | 0 | 1 |
| Overall Study | Study completion | 1 | 10 |
| Overall Study | Subject declined further treatment | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 7 |
| Overall Study | Withdrawn by PI for compassionate reason | 0 | 1 |
Baseline characteristics
| Characteristic | Part 1: Dose Finding/Expansion | Part 2: Trilaciclib/Placebo IV With E/P | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 40 Participants | 52 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 37 Participants | 44 Participants |
| Body Surface Area | 1.90 m^2 STANDARD_DEVIATION 0.263 | 1.90 m^2 STANDARD_DEVIATION 0.216 | NA m^2 |
| Country Non-United States | 0 Participants | 38 Participants | 38 Participants |
| Country United States | 19 Participants | 39 Participants | 58 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 75 Participants | 93 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 16 Participants | 73 Participants | 89 Participants |
| Sex: Female, Male Female | 8 Participants | 23 Participants | 31 Participants |
| Sex: Female, Male Male | 11 Participants | 54 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 12 | 8 / 8 | 28 / 37 | 28 / 38 |
| other Total, other adverse events | 12 / 12 | 8 / 8 | 36 / 37 | 37 / 38 |
| serious Total, serious adverse events | 4 / 12 | 1 / 8 | 9 / 37 | 11 / 38 |
Outcome results
Primary
Duration of Severe (Grade 4) Neutropenia in Part 2
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)
Population: Full analysis set (FAS) - included all randomized participants who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Duration of Severe (Grade 4) Neutropenia in Part 2 | 8 Days |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Duration of Severe (Grade 4) Neutropenia in Part 2 | 3 Days |
p-value: =0.0097Stratified log-rank test
Primary
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
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)
Population: Safety analysis set - included all enrolled participants (i.e., signed informed consent) who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib).~Part 1: Cohort 1 Trilaciclib 200 mg/m\^2 included 1 participant from Part 2 and 1 participant from Part 1 240 mg/m\^2 who received 200 mg/m\^2.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1 | Any SAE | 4 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1 | SAE related to any study drug | 0 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1 | TEAE related to any study drug | 10 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1 | TEAE leading to discontinuation of any study drug | 0 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1 | Any TEAE | 12 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1 | TEAE leading to discontinuation of any study drug | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1 | Any TEAE | 8 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1 | Any SAE | 1 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1 | TEAE related to any study drug | 8 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1 | SAE related to any study drug | 0 Participants |
Primary
Number of Participants With Dose Limiting Toxicities by Cohort in Cycle 1, Part 1
Dose-limiting toxicities (DLTs) were drug-related toxicities defined as follows: 1. Absolute neutrophil count (ANC) \< 0.5 × 10\^9/L lasting for ≥ 7 days 2. ≥ Grade 3 neutropenic infection/febrile neutropenia 3. Grade 4 thrombocytopenia (TCP) or ≥ Grade 3 TCP with bleeding 4. Unable to start next cycle of chemotherapy due to lack of recovery to an ANC ≥ 1.5 × 10\^9/L and platelet count ≥ 100 × 10\^9/L 5. ≥ Grade 3 nonhematologic toxicity (nausea, vomiting, and diarrhea failing maximal medical management; fatigue lasting for \> 72 hours) Toxicities not clearly related to etoposide/carboplatin therapy were also considered for the purposes of determining DLTs.
Time frame: Days 1-21 of Cycle 1
Population: Safety analysis set - included all enrolled participants (i.e., signed informed consent) who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib).~Part 1: Cohort 1 Trilaciclib 200 mg/m\^2 included 1 participant from Part 2 and 1 participant from Part 1 240 mg/m\^2 who received 200 mg/m\^2.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Number of Participants With Dose Limiting Toxicities by Cohort in Cycle 1, Part 1 | Unable to start next cycle of chemotherapy | 1 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Number of Participants With Dose Limiting Toxicities by Cohort in Cycle 1, Part 1 | Number of participants meeting ≥1 DLT criteria | 2 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Number of Participants With Dose Limiting Toxicities by Cohort in Cycle 1, Part 1 | Grade 4 TCP or ≥Grade 3 TCP with bleeding | 1 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Number of Participants With Dose Limiting Toxicities by Cohort in Cycle 1, Part 1 | Number of participants meeting ≥1 DLT criteria | 1 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Number of Participants With Dose Limiting Toxicities by Cohort in Cycle 1, Part 1 | Grade 4 TCP or ≥Grade 3 TCP with bleeding | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Number of Participants With Dose Limiting Toxicities by Cohort in Cycle 1, Part 1 | Unable to start next cycle of chemotherapy | 1 Participants |
Secondary
Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Trilaciclib in Cycle 1, Part 1
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
Population: PK analysis set - included all participants with evaluable PK profiles for both treatments and analytes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Trilaciclib in Cycle 1, Part 1 | Day 1 Cycle 1 | 2560 h*ng/mL | Standard Deviation 792 |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Trilaciclib in Cycle 1, Part 1 | Day 3 Cycle 1 | 3110 h*ng/mL | Standard Deviation 693 |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Trilaciclib in Cycle 1, Part 1 | Day 1 Cycle 1 | 2280 h*ng/mL | — |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Trilaciclib in Cycle 1, Part 1 | Day 3 Cycle 1 | 2960 h*ng/mL | — |
Secondary
AUC0-inf of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1
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)
Population: PK analysis set - included all participants with evaluable PK profiles for both treatments and analytes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | AUC0-inf of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 | Etoposide Day 1 Cycle 1 | 131 h*μg/mL | Standard Deviation 44.7 |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | AUC0-inf of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 | Etoposide Day 3 Cycle 1 | 146 h*μg/mL | Standard Deviation 48.4 |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | AUC0-inf of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 | Free Carboplatin Day 1 Cycle 1 | 50.5 h*μg/mL | Standard Deviation 14.4 |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | AUC0-inf of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 | Total Carboplatin Day 1 Cycle 1 | 137 h*μg/mL | Standard Deviation 37.3 |
Secondary
Best Overall Tumor Response Based on Assessments in Part 1
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)
Population: Response evaluable analysis set included all participants in the safety analysis set who had at least 1 post-baseline tumor assessment, or clinical progression as noted by the investigator before their first post-baseline tumor scan, or who died due to disease progression before their first post-baseline tumor scan.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 1 | SD | 0 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 1 | Not evaluable | 0 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 1 | PR | 8 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 1 | Unconfirmed CR | 1 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 1 | PD | 1 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 1 | Unconfirmed PR | 0 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 1 | CR | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 1 | Unconfirmed PR | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 1 | CR | 1 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 1 | PR | 7 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 1 | SD | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 1 | PD | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 1 | Not evaluable | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 1 | Unconfirmed CR | 0 Participants |
Secondary
Best Overall Tumor Response Based on Assessments in Part 2
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)
Population: Response evaluable analysis set included all participants in the safety analysis set who had at least 1 post-baseline tumor assessment, or clinical progression as noted by the investigator before their first post-baseline tumor scan, or who died due to disease progression before their first post-baseline tumor scan.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 2 | Unconfirmed PR | 6 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 2 | PR | 19 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 2 | Not evaluable | 1 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 2 | SD | 12 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 2 | CR | 1 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 2 | PD | 4 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 2 | Unconfirmed CR | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 2 | PD | 1 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 2 | Not evaluable | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 2 | Unconfirmed CR | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 2 | Unconfirmed PR | 4 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 2 | CR | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 2 | PR | 24 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Assessments in Part 2 | SD | 9 Participants |
Secondary
Best Overall Tumor Response Based on BICR Assessments in Part 2
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)
Population: Response evaluable analysis set included all participants in the safety analysis set who had at least 1 post-baseline tumor assessment, or clinical progression as noted by the investigator before their first post-baseline tumor scan, or who died due to disease progression before their first post-baseline tumor scan.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on BICR Assessments in Part 2 | SD | 10 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on BICR Assessments in Part 2 | Not evaluable | 0 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on BICR Assessments in Part 2 | PR | 23 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on BICR Assessments in Part 2 | Unconfirmed CR | 0 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on BICR Assessments in Part 2 | PD | 4 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on BICR Assessments in Part 2 | Unconfirmed PR | 5 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on BICR Assessments in Part 2 | CR | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on BICR Assessments in Part 2 | Unconfirmed PR | 4 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on BICR Assessments in Part 2 | CR | 1 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on BICR Assessments in Part 2 | PR | 23 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on BICR Assessments in Part 2 | SD | 7 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on BICR Assessments in Part 2 | PD | 2 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on BICR Assessments in Part 2 | Not evaluable | 1 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on BICR Assessments in Part 2 | Unconfirmed CR | 0 Participants |
Secondary
Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1
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)
Population: Response evaluable analysis set included all participants in the safety analysis set who had at least 1 post-baseline tumor assessment, or clinical progression as noted by the investigator before their first post-baseline tumor scan, or who died due to disease progression before their first post-baseline tumor scan.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 | Unconfirmed PR | 2 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 | CR | 1 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 | PR | 6 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 | SD | 2 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 | PD | 0 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 | Not evaluable | 0 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 | Unconfirmed CR | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 | Unconfirmed PR | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 | PD | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 | CR | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 | Unconfirmed CR | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 | PR | 8 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 | Not evaluable | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1 | SD | 0 Participants |
Secondary
Change From Baseline of Hemoglobin at the End of Cycle 6, Part 1
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
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Change From Baseline of Hemoglobin at the End of Cycle 6, Part 1 | -9.8 g/L | Standard Deviation 13.27 |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Change From Baseline of Hemoglobin at the End of Cycle 6, Part 1 | -20.1 g/L | Standard Deviation 15.21 |
Secondary
Change From Baseline of Hemoglobin at the End of Cycle 6, Part 2
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
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Change From Baseline of Hemoglobin at the End of Cycle 6, Part 2 | -25.9 g/L | Standard Deviation 14.63 |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Change From Baseline of Hemoglobin at the End of Cycle 6, Part 2 | -20.6 g/L | Standard Deviation 13.83 |
Secondary
Change From Baseline of Lymphocyte Count at the End of Cycle 6, Part 1
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
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Change From Baseline of Lymphocyte Count at the End of Cycle 6, Part 1 | 0.188 x 10^9 cells/L | Standard Deviation 0.8431 |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Change From Baseline of Lymphocyte Count at the End of Cycle 6, Part 1 | 0.067 x 10^9 cells/L | Standard Deviation 0.4691 |
Secondary
Change From Baseline of Lymphocyte Count at the End of Cycle 6, Part 2
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
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Change From Baseline of Lymphocyte Count at the End of Cycle 6, Part 2 | -0.203 x 10^9 cells/L | Standard Deviation 0.4382 |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Change From Baseline of Lymphocyte Count at the End of Cycle 6, Part 2 | 0.104 x 10^9 cells/L | Standard Deviation 0.632 |
Secondary
Change From Baseline of Platelet Count at the End of Cycle 6, Part 1
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
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Change From Baseline of Platelet Count at the End of Cycle 6, Part 1 | -72.6 x 10^9 cells/L | Standard Deviation 88.38 |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Change From Baseline of Platelet Count at the End of Cycle 6, Part 1 | -59.4 x 10^9 cells/L | Standard Deviation 108.47 |
Secondary
Change From Baseline of Platelet Count at the End of Cycle 6, Part 2
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
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Change From Baseline of Platelet Count at the End of Cycle 6, Part 2 | -32.7 x 10^9 cells/L | Standard Deviation 100.2 |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Change From Baseline of Platelet Count at the End of Cycle 6, Part 2 | -54.4 x 10^9 cells/L | Standard Deviation 95.44 |
Secondary
Cmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1
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)
Population: PK analysis set - included all participants with evaluable PK profiles for both treatments and analytes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Cmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 | Etoposide Day 1 Cycle 1 | 21.9 μg/mL | Standard Deviation 2.7 |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Cmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 | Etoposide Day 3 Cycle 1 | 20.2 μg/mL | Standard Deviation 2.4 |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Cmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 | Free Carboplatin Day 1 Cycle 1 | 20.3 μg/mL | Standard Deviation 6.83 |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Cmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 | Total Carboplatin Day 1 Cycle 1 | 18.8 μg/mL | Standard Deviation 5.45 |
Secondary
Duration of Grade 3/4 Neutropenia in Part 1
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Duration of Grade 3/4 Neutropenia in Part 1 | 8 Days |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Duration of Grade 3/4 Neutropenia in Part 1 | 8 Days |
Secondary
Duration of Grade 3/4 Neutropenia in Part 2
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Duration of Grade 3/4 Neutropenia in Part 2 | 8 Days |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Duration of Grade 3/4 Neutropenia in Part 2 | 8 Days |
Secondary
Duration of Severe (Grade 4) Neutropenia in Part 1
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment. No participants had severe (Grade 4) neutropenia in the 240 mg/m\^2 arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Duration of Severe (Grade 4) Neutropenia in Part 1 | 6 Days |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Trilaciclib in Cycle 1, Part 1
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
Population: Pharmacokinetic (PK) analysis set - included all participants with evaluable PK profiles for both treatments and analytes.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of Trilaciclib in Cycle 1, Part 1 | Day 1 Cycle 1 | 1240 ng/mL | Standard Deviation 738 |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of Trilaciclib in Cycle 1, Part 1 | Day 3 Cycle 1 | 1620 ng/mL | Standard Deviation 1040 |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of Trilaciclib in Cycle 1, Part 1 | Day 1 Cycle 1 | 1570 ng/mL | — |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of Trilaciclib in Cycle 1, Part 1 | Day 3 Cycle 1 | 2260 ng/mL | — |
Secondary
Nadir of Absolute Neutrophil Count in Cycle 1, Part 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.
Time frame: From baseline to the end of Cycle 1
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Nadir of Absolute Neutrophil Count in Cycle 1, Part 1 | 1.198 x 10^9 cells/L | Standard Deviation 0.7241 |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Nadir of Absolute Neutrophil Count in Cycle 1, Part 1 | 1.653 x 10^9 cells/L | Standard Deviation 0.7381 |
Secondary
Nadir of Absolute Neutrophil Count in Cycle 1, Part 2
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
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Nadir of Absolute Neutrophil Count in Cycle 1, Part 2 | 0.815 x 10^9 cells/L | Standard Deviation 0.6385 |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Nadir of Absolute Neutrophil Count in Cycle 1, Part 2 | 1.899 x 10^9 cells/L | Standard Deviation 1.193 |
Secondary
Occurrence of Dose Reduction in Part 1
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)
Population: Safety analysis set - included all enrolled participants (i.e., signed informed consent) who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib).~Part 1: Cohort 1 Trilaciclib 200 mg/m\^2 included 1 participant from Part 2 and 1 participant from Part 1 240 mg/m\^2 who received 200 mg/m\^2.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Dose Reduction in Part 1 | 2 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Dose Reduction in Part 1 | 3 Participants |
Secondary
Occurrence of Dose Reduction in Part 2
Dose reductions were not permitted for trilaciclib, per study protocol. Dose reductions for E/P were derived from changes in the protocol-specified dose on the dosing page and corresponded to the reductions for toxicity specified in the protocol. No more than 2 dose reductions of E/P in total were allowed for any participant. Simultaneous reductions in the doses of E/P were counted as 1 dose reduction. For the treatment period, the total number of dose reductions was the number of cycles where there was at least 1 dose reduction.
Time frame: From randomization to the end of the treatment period (a minimum of 51 days up to a maximum of 379 days)
Population: Safety analysis set - included all enrolled participants (i.e., signed informed consent) who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib).~Part 1: Cohort 1 Trilaciclib 200 mg/m\^2 included 1 participant from Part 2 and 1 participant from Part 1 240 mg/m\^2 who received 200 mg/m\^2.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Dose Reduction in Part 2 | 13 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Dose Reduction in Part 2 | 3 Participants |
Secondary
Occurrence of Erythropoietin Stimulating Agent (ESA) Administration in Part 1
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Erythropoietin Stimulating Agent (ESA) Administration in Part 1 | 2 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Erythropoietin Stimulating Agent (ESA) Administration in Part 1 | 0 Participants |
Secondary
Occurrence of ESA Administration in Part 2
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of ESA Administration in Part 2 | 2 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of ESA Administration in Part 2 | 1 Participants |
Secondary
Occurrence of Febrile Neutropenia in Part 1
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Febrile Neutropenia in Part 1 | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Febrile Neutropenia in Part 1 | 0 Participants |
Secondary
Occurrence of Febrile Neutropenia in Part 2
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Febrile Neutropenia in Part 2 | 3 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Febrile Neutropenia in Part 2 | 1 Participants |
Secondary
Occurrence of G-CSF Administration in Part 2
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of G-CSF Administration in Part 2 | 24 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of G-CSF Administration in Part 2 | 4 Participants |
Secondary
Occurrence of Grade 3/4 Neutropenia in Part 1
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Grade 3/4 Neutropenia in Part 1 | 6 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Grade 3/4 Neutropenia in Part 1 | 3 Participants |
Secondary
Occurrence of Grade 3/4 Neutropenia in Part 2
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Grade 3/4 Neutropenia in Part 2 | 30 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Grade 3/4 Neutropenia in Part 2 | 14 Participants |
Secondary
Occurrence of Granulocyte-Colony Stimulating Factor (G-CSF) Administration in Part 1
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Granulocyte-Colony Stimulating Factor (G-CSF) Administration in Part 1 | 5 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Granulocyte-Colony Stimulating Factor (G-CSF) Administration in Part 1 | 3 Participants |
Secondary
Occurrence of Infectious SAEs in Part 1
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Infectious SAEs in Part 1 | 2 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Infectious SAEs in Part 1 | 1 Participants |
Secondary
Occurrence of Infectious SAEs in Part 2
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Infectious SAEs in Part 2 | 2 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Infectious SAEs in Part 2 | 4 Participants |
Secondary
Occurrence of IV Antibiotic Administration in Part 1
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of IV Antibiotic Administration in Part 1 | 4 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of IV Antibiotic Administration in Part 1 | 1 Participants |
Secondary
Occurrence of IV Antibiotic Administration in Part 2
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of IV Antibiotic Administration in Part 2 | 8 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of IV Antibiotic Administration in Part 2 | 8 Participants |
Secondary
Occurrence of Platelet Transfusion in Part 1
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Platelet Transfusion in Part 1 | 1 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Platelet Transfusion in Part 1 | 0 Participants |
Secondary
Occurrence of Platelet Transfusion in Part 2
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Platelet Transfusion in Part 2 | 0 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Platelet Transfusion in Part 2 | 2 Participants |
Secondary
Occurrence of Pulmonary Infection SAE in Part 1
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Pulmonary Infection SAE in Part 1 | 1 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Pulmonary Infection SAE in Part 1 | 0 Participants |
Secondary
Occurrence of Pulmonary Infection SAE in Part 2
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Pulmonary Infection SAE in Part 2 | 1 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Pulmonary Infection SAE in Part 2 | 4 Participants |
Secondary
Occurrence of RBC Transfusion in Part 2
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of RBC Transfusion in Part 2 | On/after Week 5 | 9 Participants |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of RBC Transfusion in Part 2 | Overall | 9 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of RBC Transfusion in Part 2 | Overall | 6 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of RBC Transfusion in Part 2 | On/after Week 5 | 2 Participants |
Secondary
Occurrence of Red Blood Cell (RBC) Transfusion in Part 1
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Red Blood Cell (RBC) Transfusion in Part 1 | 4 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Red Blood Cell (RBC) Transfusion in Part 1 | 1 Participants |
Secondary
Occurrence of Severe (Grade 4) Neutropenia in Part 1
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Severe (Grade 4) Neutropenia in Part 1 | 4 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Severe (Grade 4) Neutropenia in Part 1 | 0 Participants |
Secondary
Occurrence of Severe (Grade 4) Neutropenia in Part 2
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Occurrence of Severe (Grade 4) Neutropenia in Part 2 | 16 Participants |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Occurrence of Severe (Grade 4) Neutropenia in Part 2 | 2 Participants |
Secondary
OS in Part 1
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | OS in Part 1 | 10.6 Months |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | OS in Part 1 | 12.8 Months |
Secondary
OS in Part 2
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | OS in Part 2 | 10.6 Months |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | OS in Part 2 | 10.9 Months |
Secondary
PFS Based on Assessments in Part 2
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | PFS Based on Assessments in Part 2 | 5.0 Months |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | PFS Based on Assessments in Part 2 | 6.1 Months |
Secondary
Progression Free Survival (PFS) Based on Assessments in Part 1
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Progression Free Survival (PFS) Based on Assessments in Part 1 | 5.3 Months |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Progression Free Survival (PFS) Based on Assessments in Part 1 | 6.3 Months |
Secondary
Time of Maximum Observed Concentration (Tmax) of Trilaciclib in Cycle 1, Part 1
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
Population: PK analysis set - included all participants with evaluable PK profiles for both treatments and analytes
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Time of Maximum Observed Concentration (Tmax) of Trilaciclib in Cycle 1, Part 1 | Day 1 Cycle 1 | 0.57 Hours |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Time of Maximum Observed Concentration (Tmax) of Trilaciclib in Cycle 1, Part 1 | Day 3 Cycle 1 | 0.52 Hours |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Time of Maximum Observed Concentration (Tmax) of Trilaciclib in Cycle 1, Part 1 | Day 1 Cycle 1 | 0.50 Hours |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Time of Maximum Observed Concentration (Tmax) of Trilaciclib in Cycle 1, Part 1 | Day 3 Cycle 1 | 0.45 Hours |
Secondary
Time to First MAHE in Part 2
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Time to First MAHE in Part 2 | 1.0 Months |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Time to First MAHE in Part 2 | NA Months |
Secondary
Time to First Major Adverse Hematologic Event (MAHE) in Part 1
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)
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Time to First Major Adverse Hematologic Event (MAHE) in Part 1 | 2.6 Months |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Time to First Major Adverse Hematologic Event (MAHE) in Part 1 | 3.0 Months |
Secondary
Tmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1
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)
Population: PK analysis set - included all participants with evaluable PK profiles for both treatments and analytes
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Tmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 | Etoposide Day 1 Cycle 1 | 1.08 Hours |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Tmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 | Etoposide Day 3 Cycle 1 | 1.00 Hours |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Tmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 | Free Carboplatin Day 1 Cycle 1 | 0.52 Hours |
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Tmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1 | Total Carboplatin Day 1 Cycle 1 | 0.52 Hours |
Post Hoc
Duration of Severe (Grade 4) Neutropenia in Cycle 1 of Part 2
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
Population: The FAS included all randomized patients who received at least 1 dose of study drug (etoposide, carboplatin, or trilaciclib). Analyses using the FAS were conducted on the basis of the assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort 1 Trilaciclib 200 mg/m^2 | Duration of Severe (Grade 4) Neutropenia in Cycle 1 of Part 2 | 0 Days |
| Part 1: Cohort 2 Trilaciclib 240mg/m^2 | Duration of Severe (Grade 4) Neutropenia in Cycle 1 of Part 2 | 0 Days |