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Trilaciclib (G1T28), a CDK 4/6 Inhibitor, in Combination With Etoposide and Carboplatin in Extensive Stage Small Cell Lung Cancer (SCLC)

Primary Purpose

Small Cell Lung Cancer

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Carboplatin

Placebo

Trilaciclib

Etoposide

About this trial

This is an interventional treatment trial for Small Cell Lung Cancer focused on measuring Small Cell Lung Cancer, CDK 4/6 Inhibitor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Genesis Cancer Center
Highlands Oncology Group
The Oncology Institute of Hope and Innovation
Memorial Hospital - Univ. of Colorado Health
University of Colorado Health, Oncology Clinical Research Northern Region
Boca Raton Regional Hospital - Lynn Cancer Institute
Florida Cancer Specialists - South
Florida Cancer Specialists - North
Florida Cancer Specialists - East
University Cancer and Blood Center, LLC
Emory University
Norton Cancer Institute
Center For Cancer and Blood Disorders
Norris Cotton Cancer Center
University of New Mexico Comprehensive Cancer Center
Roswell Park
UNC - Lineberger Comprehensive Cancer Center
Oklahoma University - Peggy and Charles Stephenson Cancer Center
Thomas Jefferson University
Guthrie Medical Group, PC
Greenville Health System
Gibbs Cancer Center
Tennessee Cancer Specialists
Hanna Cancer Associates - University of Tennessee
Texas Oncology
Northwest Cancer Specialists, P.C.
CHU de Rennes Hopital Pontchaillou
ARENSIA Exploratory Medicine LLC
Veszprem Megyei Tudogyogyintezet
Orszagos Koranyi Tbc es Pulmonologiai Intezet, XI. Tudobelosztaly
Hetenyi Geza Korhaz
ARENSIA Exploratory Medicine Phase I Unit, The Institute of Oncology
Samodzielny Publiczny ZespAA GruAicy i ChorAb PA¿uc
Wojewodzki Szpital Zespolony im. L. Rydygiera
Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie
Hospital Regional Universitario HRU Carlos Haya Malaga
Hospital de la Santa Creu i Sant Pau
Consorcio Hospitalario Provincial
Hgu Gregorio Maranon
Fundacion Jimenez Diaz

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

trilaciclib + carboplatin/etoposide

trilaciclib/placebo + carboplatin/etoposide

Arm Description

All patients in part 1 will receive trilaciclib (G1T28) prior to standard chemotherapy- carboplatin and etoposide. Patients will have PK assessments completed on days 1 and 3 in cycle 1 only. All patents will be monitored for safety and tumor response based on RECIST version 1.1. Safety surveillance reporting of AEs and concomitant medications commences at the time that informed consent is obtained and continues through the Post Treatment Visit.

All patients enrolled in part 2 will be randomized to receive either trilaciclib (G1T28) or placebo administered prior to standard chemotherapy- carboplatin and etoposide. All patents will be monitored for safety and tumor response based on RECIST version 1.1. Safety surveillance reporting of AEs and concomitant medications commences at the time that informed consent is obtained and continues through the Post Treatment Visit.

Outcomes

Primary Outcome Measures

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

Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1

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

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

Secondary Outcome Measures

Maximum Observed Plasma Concentration (Cmax) of Trilaciclib in Cycle 1, Part 1

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

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

Time of Maximum Observed Concentration (Tmax) of Trilaciclib in Cycle 1, Part 1

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

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

AUC0-inf of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1

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

Tmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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.

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.

Duration of Grade 3/4 Neutropenia in Part 2

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.

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.

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.

Occurrence of RBC Transfusion in Part 2

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.

Occurrence of ESA Administration in Part 2

Occurrence of Platelet Transfusion in Part 2

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.

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.

Occurrence of Dose Reduction in Part 2

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.

Occurrence of Pulmonary Infection SAE in Part 2

Occurrence of IV Antibiotic Administration in Part 2

Time to First MAHE in Part 2

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.

Best Overall Tumor Response Based on BICR Assessments in Part 2

PFS Based on Assessments in Part 2

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.

Full Information

NCT ID

NCT02499770

First Posted

July 8, 2015

Last Updated

August 11, 2020

Sponsor

G1 Therapeutics, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT02499770

Brief Title

Trilaciclib (G1T28), a CDK 4/6 Inhibitor, in Combination With Etoposide and Carboplatin in Extensive Stage Small Cell Lung Cancer (SCLC)

Official Title

Phase 1b/2a Safety and Pharmacokinetic Study of G1T28 in Patients With Extensive Stage Small Cell Lung Cancer (SCLC) Receiving Etoposide and Carboplatin

Study Type

Interventional

2. Study Status

Record Verification Date

August 2020

Overall Recruitment Status

Completed

Study Start Date

June 26, 2015 (Actual)

Primary Completion Date

July 3, 2017 (Actual)

Study Completion Date

February 22, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

G1 Therapeutics, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This is a study to investigate the potential clinical benefit of trilaciclib (G1T28) in preserving the bone marrow and the immune system, and enhancing chemotherapy antitumor efficacy when administered prior to carboplatin and etoposide in first line treatment for patients with newly diagnosed extensive-stage SCLC. The study consists of 2 parts: a limited open-label, dose-finding portion (Part 1), and a randomized double-blind portion (Part 2). Both parts include 3 study phases: Screening Phase, Treatment Phase, and Survival Follow-up Phase. The Treatment Phase begins on the day of first dose with study treatment and completes at the Post-Treatment Visit. Approximately, 90 patients will be enrolled in the study; 20 patients in the Part 1 and 70 patients in the Part 2 portion.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Small Cell Lung Cancer

Keywords

Small Cell Lung Cancer, CDK 4/6 Inhibitor

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

122 (Actual)

8. Arms, Groups, and Interventions

Arm Title

trilaciclib + carboplatin/etoposide

Arm Type

Experimental

Arm Description

Arm Title

trilaciclib/placebo + carboplatin/etoposide

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Carboplatin

Other Intervention Name(s)

Paraplatin

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Type

Drug

Intervention Name(s)

Trilaciclib

Other Intervention Name(s)

G1T28

Intervention Type

Drug

Intervention Name(s)

Etoposide

Other Intervention Name(s)

VP-16, Toposar

Primary Outcome Measure Information:

Title

Number of Participants With Dose Limiting Toxicities by Cohort in Cycle 1, Part 1

Description

Time Frame

Days 1-21 of Cycle 1

Title

Incidence of Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related AEs, Related SAEs, and AEs Leading to Study Drug Discontinuation in Part 1

Description

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)

Title

Duration of Severe (Grade 4) Neutropenia in Part 2

Description

Time Frame

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

Secondary Outcome Measure Information:

Title

Maximum Observed Plasma Concentration (Cmax) of Trilaciclib in Cycle 1, Part 1

Description

Time Frame

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

Title

Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Trilaciclib in Cycle 1, Part 1

Description

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

Time Frame

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

Title

Time of Maximum Observed Concentration (Tmax) of Trilaciclib in Cycle 1, Part 1

Description

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

Time Frame

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

Title

Cmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1

Description

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)

Title

AUC0-inf of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1

Description

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)

Title

Tmax of Etoposide and Free and Total Carboplatin in Cycle 1, Part 1

Description

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)

Title

Duration of Severe (Grade 4) Neutropenia in Part 1

Description

Time Frame

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

Title

Occurrence of Severe (Grade 4) Neutropenia in Part 1

Description

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

Time Frame

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

Title

Occurrence of Febrile Neutropenia in Part 1

Description

Time Frame

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

Title

Duration of Grade 3/4 Neutropenia in Part 1

Description

Time Frame

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

Title

Occurrence of Grade 3/4 Neutropenia in Part 1

Description

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

Time Frame

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

Title

Nadir of Absolute Neutrophil Count in Cycle 1, Part 1

Description

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

Time Frame

From baseline to the end of Cycle 1

Title

Occurrence of Granulocyte-Colony Stimulating Factor (G-CSF) Administration in Part 1

Description

Time Frame

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

Title

Occurrence of Red Blood Cell (RBC) Transfusion in Part 1

Description

Time Frame

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

Title

Change From Baseline of Hemoglobin at the End of Cycle 6, Part 1

Description

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

Time Frame

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

Title

Occurrence of Erythropoietin Stimulating Agent (ESA) Administration in Part 1

Description

Time Frame

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

Title

Occurrence of Platelet Transfusion in Part 1

Description

Time Frame

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

Title

Change From Baseline of Platelet Count at the End of Cycle 6, Part 1

Description

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

Time Frame

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

Title

Change From Baseline of Lymphocyte Count at the End of Cycle 6, Part 1

Description

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

Time Frame

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

Title

Occurrence of Dose Reduction in Part 1

Description

Time Frame

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

Title

Occurrence of Infectious SAEs in Part 1

Description

Time Frame

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

Title

Occurrence of Pulmonary Infection SAE in Part 1

Description

Time Frame

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

Title

Occurrence of IV Antibiotic Administration in Part 1

Description

Time Frame

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

Title

Time to First Major Adverse Hematologic Event (MAHE) in Part 1

Description

Time Frame

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

Title

Best Overall Tumor Response Based on Assessments in Part 1

Description

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)

Title

Best Overall Tumor Response Based on Blinded Independent Central Review (BICR) Assessments in Part 1

Description

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)

Title

Progression Free Survival (PFS) Based on Assessments in Part 1

Description

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)

Title

OS in Part 1

Description

Time Frame

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

Title

Occurrence of Severe (Grade 4) Neutropenia in Part 2

Description

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

Time Frame

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

Title

Occurrence of Febrile Neutropenia in Part 2

Description

Time Frame

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

Title

Duration of Grade 3/4 Neutropenia in Part 2

Description

Time Frame

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

Title

Occurrence of Grade 3/4 Neutropenia in Part 2

Description

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

Time Frame

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

Title

Nadir of Absolute Neutrophil Count in Cycle 1, Part 2

Description

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

Time Frame

From baseline to the end of Cycle 1

Title

Occurrence of G-CSF Administration in Part 2

Description

Time Frame

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

Title

Occurrence of RBC Transfusion in Part 2

Description

Time Frame

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

Title

Change From Baseline of Hemoglobin at the End of Cycle 6, Part 2

Description

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

Time Frame

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

Title

Occurrence of ESA Administration in Part 2

Description

Time Frame

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

Title

Occurrence of Platelet Transfusion in Part 2

Description

Time Frame

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

Title

Change From Baseline of Platelet Count at the End of Cycle 6, Part 2

Description

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

Time Frame

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

Title

Change From Baseline of Lymphocyte Count at the End of Cycle 6, Part 2

Description

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

Time Frame

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

Title

Occurrence of Dose Reduction in Part 2

Description

Time Frame

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

Title

Occurrence of Infectious SAEs in Part 2

Description

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

Time Frame

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

Title

Occurrence of Pulmonary Infection SAE in Part 2

Description

Time Frame

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

Title

Occurrence of IV Antibiotic Administration in Part 2

Description

Time Frame

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

Title

Time to First MAHE in Part 2

Description

Time Frame

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

Title

Best Overall Tumor Response Based on Assessments in Part 2

Description

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)

Title

Best Overall Tumor Response Based on BICR Assessments in Part 2

Description

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)

Title

PFS Based on Assessments in Part 2

Description

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)

Title

OS in Part 2

Description

Time Frame

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male or female subjects aged ≥18 years Unequivocally confirmed diagnosis of SCLC by histology or cytology, preferably including the presence of neuroendocrine features by immunohistochemistry At least 1 target lesion that is unirradiated and measurable by RECIST, Version 1.1 Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2 Adequate organ function Exclusion Criteria: Prior chemotherapy for extensive-stage SCLC Presence of symptomatic brain metastases requiring immediate treatment with radiation therapy or steroids. Uncontrolled ischemic heart disease or uncontrolled symptomatic congestive heart failure Known history of stroke or cerebrovascular accident within 6 months prior to enrollment Other uncontrolled serious chronic disease or conditions that in the investigator's opinion could affect compliance or follow-up in the protocol Concurrent radiotherapy to any site or radiotherapy within 2 weeks prior to enrollment or previous radiotherapy to the target lesion sites (the sites that are to be followed for determination of a response) Receipt of any investigational medication within 4 weeks prior to enrollment

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Contact

Organizational Affiliation

G1 Therapeutics, Inc.

Official's Role

Study Director

Facility Information:

Facility Name

Genesis Cancer Center

City

Hot Springs

State/Province

Arkansas

ZIP/Postal Code

71913

Country

United States

Facility Name

Highlands Oncology Group

City

Rogers

State/Province

Arkansas

ZIP/Postal Code

72758

Country

United States

Facility Name

The Oncology Institute of Hope and Innovation

City

Whittier

State/Province

California

ZIP/Postal Code

90603

Country

United States

Facility Name

Memorial Hospital - Univ. of Colorado Health

City

Colorado Springs

State/Province

Colorado

ZIP/Postal Code

80909

Country

United States

Facility Name

University of Colorado Health, Oncology Clinical Research Northern Region

City

Fort Collins

State/Province

Colorado

ZIP/Postal Code

80528

Country

United States

Facility Name

Boca Raton Regional Hospital - Lynn Cancer Institute

City

Boca Raton

State/Province

Florida

ZIP/Postal Code

33486

Country

United States

Facility Name

Florida Cancer Specialists - South

City

Fort Myers

State/Province

Florida

ZIP/Postal Code

33916

Country

United States

Facility Name

Florida Cancer Specialists - North

City

Tavares

State/Province

Florida

ZIP/Postal Code

32778

Country

United States

Facility Name

Florida Cancer Specialists - East

City

West Palm Beach

State/Province

Florida

ZIP/Postal Code

33401

Country

United States

Facility Name

University Cancer and Blood Center, LLC

City

Athens

State/Province

Georgia

ZIP/Postal Code

30607

Country

United States

Facility Name

Emory University

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Facility Name

Norton Cancer Institute

City

Louisville

State/Province

Kentucky

ZIP/Postal Code

40202

Country

United States

Facility Name

Center For Cancer and Blood Disorders

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20817

Country

United States

Facility Name

Norris Cotton Cancer Center

City

Lebanon

State/Province

New Hampshire

ZIP/Postal Code

03756

Country

United States

Facility Name

University of New Mexico Comprehensive Cancer Center

City

Albuquerque

State/Province

New Mexico

ZIP/Postal Code

87106

Country

United States

Facility Name

Roswell Park

City

Buffalo

State/Province

New York

ZIP/Postal Code

14263

Country

United States

Facility Name

UNC - Lineberger Comprehensive Cancer Center

City

Chapel Hill

State/Province

North Carolina

ZIP/Postal Code

27514

Country

United States

Facility Name

Oklahoma University - Peggy and Charles Stephenson Cancer Center

City

Oklahoma City

State/Province

Oklahoma

ZIP/Postal Code

73117

Country

United States

Facility Name

Thomas Jefferson University

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19107

Country

United States

Facility Name

Guthrie Medical Group, PC

City

Sayre

State/Province

Pennsylvania

ZIP/Postal Code

18840

Country

United States

Facility Name

Greenville Health System

City

Greenville

State/Province

South Carolina

ZIP/Postal Code

29605

Country

United States

Facility Name

Gibbs Cancer Center

City

Spartanburg

State/Province

South Carolina

ZIP/Postal Code

29203

Country

United States

Facility Name

Tennessee Cancer Specialists

City

Knoxville

State/Province

Tennessee

ZIP/Postal Code

37909

Country

United States

Facility Name

Hanna Cancer Associates - University of Tennessee

City

Knoxville

State/Province

Tennessee

ZIP/Postal Code

37920

Country

United States

Facility Name

Texas Oncology

City

Tyler

State/Province

Texas

ZIP/Postal Code

75702

Country

United States

Facility Name

Northwest Cancer Specialists, P.C.

City

Vancouver

State/Province

Washington

ZIP/Postal Code

98684

Country

United States

Facility Name

CHU de Rennes Hopital Pontchaillou

City

Rennes

ZIP/Postal Code

35033

Country

France

Facility Name

ARENSIA Exploratory Medicine LLC

City

Tbilisi

ZIP/Postal Code

0112

Country

Georgia

Facility Name

Veszprem Megyei Tudogyogyintezet

City

Farkasgyepu

State/Province

Veszprem

ZIP/Postal Code

8582

Country

Hungary

Facility Name

Orszagos Koranyi Tbc es Pulmonologiai Intezet, XI. Tudobelosztaly

City

Budapest

ZIP/Postal Code

1121

Country

Hungary

Facility Name

Hetenyi Geza Korhaz

City

Szolnok

ZIP/Postal Code

5000

Country

Hungary

Facility Name

ARENSIA Exploratory Medicine Phase I Unit, The Institute of Oncology

City

Chisinau

ZIP/Postal Code

2025

Country

Moldova, Republic of

Facility Name

Samodzielny Publiczny ZespAA GruAicy i ChorAb PA¿uc

City

Olsztyn

ZIP/Postal Code

10-357

Country

Poland

Facility Name

Wojewodzki Szpital Zespolony im. L. Rydygiera

City

Torun

ZIP/Postal Code

87-100

Country

Poland

Facility Name

Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie

City

Warszawa

ZIP/Postal Code

02-781

Country

Poland

Facility Name

Hospital Regional Universitario HRU Carlos Haya Malaga

City

Malaga

State/Province

Andalucia

ZIP/Postal Code

29010

Country

Spain

Facility Name

Hospital de la Santa Creu i Sant Pau

City

Barcelona

ZIP/Postal Code

08041

Country

Spain

Facility Name

Consorcio Hospitalario Provincial

City

Castillón

ZIP/Postal Code

12002

Country

Spain

Facility Name

Hgu Gregorio Maranon

City

Madrid

ZIP/Postal Code

28009

Country

Spain

Facility Name

Fundacion Jimenez Diaz

City

Madrid

ZIP/Postal Code

28040

Country

Spain

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

34408488

Citation

Hussein M, Maglakelidze M, Richards DA, Sabatini M, Gersten TA, Lerro K, Sinielnikov I, Spira A, Pritchett Y, Antal JM, Malik R, Beck JT. Myeloprotective Effects of Trilaciclib Among Patients with Small Cell Lung Cancer at Increased Risk of Chemotherapy-Induced Myelosuppression: Pooled Results from Three Phase 2, Randomized, Double-Blind, Placebo-Controlled Studies. Cancer Manag Res. 2021 Aug 9;13:6207-6218. doi: 10.2147/CMAR.S313045. eCollection 2021.

Results Reference

derived

PubMed Identifier

34405547

Citation

Ferrarotto R, Anderson I, Medgyasszay B, Garcia-Campelo MR, Edenfield W, Feinstein TM, Johnson JM, Kalmadi S, Lammers PE, Sanchez-Hernandez A, Pritchett Y, Morris SR, Malik RK, Csoszi T. Trilaciclib prior to chemotherapy reduces the usage of supportive care interventions for chemotherapy-induced myelosuppression in patients with small cell lung cancer: Pooled analysis of three randomized phase 2 trials. Cancer Med. 2021 Sep;10(17):5748-5756. doi: 10.1002/cam4.4089. Epub 2021 Aug 18.

Results Reference

derived

PubMed Identifier

33595690

Citation

Li C, Hart L, Owonikoko TK, Aljumaily R, Rocha Lima CM, Conkling PR, Webb RT, Jotte RM, Schuster S, Edenfield WJ, Smith DA, Sale M, Roberts PJ, Malik RK, Sorrentino JA. Trilaciclib dose selection: an integrated pharmacokinetic and pharmacodynamic analysis of preclinical data and Phase Ib/IIa studies in patients with extensive-stage small cell lung cancer. Cancer Chemother Pharmacol. 2021 May;87(5):689-700. doi: 10.1007/s00280-021-04239-9. Epub 2021 Feb 17.

Results Reference

derived

PubMed Identifier

33004541

Citation

Lai AY, Sorrentino JA, Dragnev KH, Weiss JM, Owonikoko TK, Rytlewski JA, Hood J, Yang Z, Malik RK, Strum JC, Roberts PJ. CDK4/6 inhibition enhances antitumor efficacy of chemotherapy and immune checkpoint inhibitor combinations in preclinical models and enhances T-cell activation in patients with SCLC receiving chemotherapy. J Immunother Cancer. 2020 Oct;8(2):e000847. doi: 10.1136/jitc-2020-000847.

Results Reference

derived

PubMed Identifier

31504118

Citation

Weiss JM, Csoszi T, Maglakelidze M, Hoyer RJ, Beck JT, Domine Gomez M, Lowczak A, Aljumaily R, Rocha Lima CM, Boccia RV, Hanna W, Nikolinakos P, Chiu VK, Owonikoko TK, Schuster SR, Hussein MA, Richards DA, Sawrycki P, Bulat I, Hamm JT, Hart LL, Adler S, Antal JM, Lai AY, Sorrentino JA, Yang Z, Malik RK, Morris SR, Roberts PJ, Dragnev KH; G1T28-02 Study Group. Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial. Ann Oncol. 2019 Oct 1;30(10):1613-1621. doi: 10.1093/annonc/mdz278.

Results Reference

derived

Learn more about this trial

Trilaciclib (G1T28), a CDK 4/6 Inhibitor, in Combination With Etoposide and Carboplatin in Extensive Stage Small Cell Lung Cancer (SCLC)

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