Phase 1b/2a Safety and Pharmacokinetic Study of G1T28 in Patients With Extensive Stage Small Cell Lung Cancer (SCLC) Receiving Etoposide and Carboplatin
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 122
- 试验地点
- 40
- 主要终点
- Number of Participants With Dose Limiting Toxicities by Cohort in Cycle 1, Part 1
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
trilaciclib + carboplatin/etoposide
All patients in part 1 will receive trilaciclib (G1T28) prior to standard chemotherapy- carboplatin and etoposide. Patients will have PK assessments completed on days 1 and 3 in cycle 1 only. All patents will be monitored for safety and tumor response based on RECIST version 1.1. Safety surveillance reporting of AEs and concomitant medications commences at the time that informed consent is obtained and continues through the Post Treatment Visit.
干预措施: Carboplatin (Drug)
trilaciclib + carboplatin/etoposide
All patients in part 1 will receive trilaciclib (G1T28) prior to standard chemotherapy- carboplatin and etoposide. Patients will have PK assessments completed on days 1 and 3 in cycle 1 only. All patents will be monitored for safety and tumor response based on RECIST version 1.1. Safety surveillance reporting of AEs and concomitant medications commences at the time that informed consent is obtained and continues through the Post Treatment Visit.
干预措施: Trilaciclib (Drug)
trilaciclib + carboplatin/etoposide
All patients in part 1 will receive trilaciclib (G1T28) prior to standard chemotherapy- carboplatin and etoposide. Patients will have PK assessments completed on days 1 and 3 in cycle 1 only. All patents will be monitored for safety and tumor response based on RECIST version 1.1. Safety surveillance reporting of AEs and concomitant medications commences at the time that informed consent is obtained and continues through the Post Treatment Visit.
干预措施: Etoposide (Drug)
trilaciclib/placebo + carboplatin/etoposide
All patients enrolled in part 2 will be randomized to receive either trilaciclib (G1T28) or placebo administered prior to standard chemotherapy- carboplatin and etoposide. All patents will be monitored for safety and tumor response based on RECIST version 1.1. Safety surveillance reporting of AEs and concomitant medications commences at the time that informed consent is obtained and continues through the Post Treatment Visit.
干预措施: Carboplatin (Drug)
trilaciclib/placebo + carboplatin/etoposide
All patients enrolled in part 2 will be randomized to receive either trilaciclib (G1T28) or placebo administered prior to standard chemotherapy- carboplatin and etoposide. All patents will be monitored for safety and tumor response based on RECIST version 1.1. Safety surveillance reporting of AEs and concomitant medications commences at the time that informed consent is obtained and continues through the Post Treatment Visit.
干预措施: Placebo (Drug)
trilaciclib/placebo + carboplatin/etoposide
All patients enrolled in part 2 will be randomized to receive either trilaciclib (G1T28) or placebo administered prior to standard chemotherapy- carboplatin and etoposide. All patents will be monitored for safety and tumor response based on RECIST version 1.1. Safety surveillance reporting of AEs and concomitant medications commences at the time that informed consent is obtained and continues through the Post Treatment Visit.
干预措施: Trilaciclib (Drug)
trilaciclib/placebo + carboplatin/etoposide
All patients enrolled in part 2 will be randomized to receive either trilaciclib (G1T28) or placebo administered prior to standard chemotherapy- carboplatin and etoposide. All patents will be monitored for safety and tumor response based on RECIST version 1.1. Safety surveillance reporting of AEs and concomitant medications commences at the time that informed consent is obtained and continues through the Post Treatment Visit.
干预措施: Etoposide (Drug)
结局指标
主要结局
Number of Participants With Dose Limiting Toxicities by Cohort in Cycle 1, Part 1
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- Maximum Observed Plasma Concentration (Cmax) of Trilaciclib in Cycle 1, Part 1(Days 1 and 3 of Cycle 1 for a 21-day cycle)
- 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))
- 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))
- 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)
- 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))
- 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))
- 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))
- 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))
- 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))
- 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)
- 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))
- 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))
- 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))
- 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))
- 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)
- 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))
- 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))
- 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))
- Nadir of Absolute Neutrophil Count in Cycle 1, Part 2(From baseline to the end of Cycle 1)
- 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))
- 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))
- 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))
- 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))
- 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)
- 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)
- 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))
- 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))
- Nadir of Absolute Neutrophil Count in Cycle 1, Part 1(From baseline to the end of Cycle 1)
- 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))
- 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)
- 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))
- 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))
- 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))
- 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)
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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)
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))