A Randomized, Double-blind, Placebo-controlled, Multi-center Phase 3 Study Evaluating Efficacy, Safety and Pharmacokinetics of Trilaciclib In Extensive-Stage Small Cell Lung Cancer Patients
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 95
- 试验地点
- 1
- 主要终点
- Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinity(AUC0-inf) for Part 1
研究概览
简要总结
A Randomized, double-blind, placebo-controlled, multi-center Phase 3 study evaluating efficacy, safety and pharmacokinetics of Trilaciclib In Extensive-Stage Small Cell Lung Cancer Patients Receiving Carboplatin combined with Etoposide or Topotecan The study consists of 2 parts: Part 1: safety run-in and pharmacokinetics evaluation of 12 ES-SCLC patients (6 each for first line and second/third line ES-SCLC patients); Part 2: randomized, double-blind, placebo-controlled efficacy confirmation study of 80 ES-SCLC patients (stratified by first line and second/third line ES-SCLC, ECOG PS [0-1 vs 2] and brain metastases.
The study includes screening period, treatment period, safety follow-up and survival follow-up.
详细描述
This is a multi-center Phase 3 clinical trial with an open-label single-arm safety run-in and PK evaluation part and a randomized double-blind, placebo controlled part in patients with ES-SCLC to evaluate the safety, efficacy, and pharmacokinetic profile of Trilaciclib based on completed clinical studies abroad.
The study consists of 2 parts. The first part, safety run-in and PK evaluation, enrolled approximately 12 patients with extensive-stage small-cell lung cancer, 6 patients each with 1st line ES-SCLC and 2nd/3rd line ES-SCLC to receive Trilaciclib in combination with carboplatin and etoposide (EC regimen) or with topotecan, and based on evaluable data from Cycle 1, evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy (prevention of myelosuppression) of Trilaciclib. The second part is a randomized double-blind, placebo-controlled efficacy validation study, and approximately 80 patients with ES-SCLC will be enrolled in Part II, stratified by 1st line vs 2nd/3rd line ES-SCLC, ECOG PS (0-1 vs 2), and presence vs absence of brain metastases, and randomized in a 1:1 ratio to Trilaciclib and placebo, in which patients with 1st line ES-SCLC receive Trilaciclib/placebo combined with EC regimen (Trilaciclib-EC group and placebo-EC group), and patients with 2nd/3rd line ES-SCLC receive Trilaciclib/placebo combined with topotecan (Trilaciclib-TPT group and placeboTPT group), and the efficacy of Trilaciclib (prevention of myelosuppression) will be evaluated with duration of severe neutropenia (DSN) in Cycle 1 as the primary endpoint. The planned dose of Trilaciclib is 240 mg/m2. If the safety data from the first part of the study suggest that the dose of Trilaciclib needs to be adjusted, 12 additional patients (6 patients each for 1st line ES-SCLC and 2nd/3rd line ESSCLC) will be enrolled in the first part of the study to explore the PK and safety of Trilaciclib 200 mg/m2. The study process includes screening period, treatment period, safety followup and survival follow-up.
The end of the study was defined as death in 75% of subjects, or 12 months after the last subject was enrolled, or the sponsor decided to terminate the study, whichever came first.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Age ≥ 18 years, male or female;
- •Histologically or cytologically confirmed extensive stage small cell lung cancer (ES-SCLC):
- •Patients scheduled to receive carboplatin plus etoposide regimen: no prior systemic therapy (eg, chemotherapy or combined with immunotherapy);
- •Patients scheduled to receive topotecan regimen: previously received 1/2 lines of chemotherapy or combined immunotherapy but not topotecan.
- •Presence of at least one radiation-naïve measurable lesion according to RECIST 1.1 criteria;
- •Hemoglobin ≥ 90 g/L;
- •Neutrophil count ≥ 1.5 × 10^9/L;
- •Platelet count ≥ 100 × 10^9/L;
- •Creatinine ≤ 15 mg/L or creatinine clearance (CrCl) ≥ 60 mL/min (Cockcroft-Gault formula);
- •Total bilirubin ≤ 1.5 × upper limit of normal (ULN);
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN or ≤ 5 × ULN (for patients with liver metastases);
- •Albumin ≥ 30 g/L;
- •ECOG PS score 0 - 2;
- •Expected survival time ≥ 3 months;
- •Contraception:
- •Females: All females of childbearing potential must have a negative serum pregnancy test at screening and must use reliable contraception from signing of informed consent through 3 months after the last dose; Male: Female partners of childbearing potential must use reliable contraception from signing the informed consent until 3 months after the last dose;
- •Understand and sign informed consent
排除标准
- •Symptomatic brain metastases requiring local radiotherapy or hormonal therapy;
- •History of other malignancies, with the following exceptions: (1) clinically cured cutaneous basal cell or squamous cell tumors; (2) cured a) cervical cancer, b) prostate cancer, c) superficial bladder cancer; or (3) other solid tumors with a clinical cure time of more than 3 years;
- •Uncontrolled ischemic heart disease or clinically significant congestive heart failure (NYHA Class III or IV);
- •Stroke or cardiovascular or cerebrovascular event within 6 months prior to enrollment;
- •Severe active infection;
- •Psychological or other social factors causing insufficient trial compliance;
- •Other uncontrolled serious chronic diseases or conditions that, in the opinion of the investigator, would make participation in the trial inappropriate;
- •Known HIV infection, active hepatitis B (defined as positive HBV DNA), and hepatitis C (positive HCV RNA);
- •Radiation therapy within 2 weeks prior to enrollment;
- •Patients who have received cytotoxic drug therapy or investigational drug therapy within 4 weeks before enrollment, or non-cytotoxic anti-tumor drug therapy within 2 weeks;
- •Subjects in the first part of the study should not take strong or moderate inducers of CYP3A4 concomitantly within 4 weeks before taking the study drug, and strong inhibitors of CYP3A4 concomitantly within 2 weeks before taking the study drug;
- •Toxicity from prior anticancer therapy has not recovered to Grade 0 or 1 (except alopecia);
- •Hypersensitivity to the study drug (Trilaciclib, etoposide, carboplatin, topotecan) or components thereof;
- •Persons who are unable to act independently due to legal restriction or legal sense;
- •Pregnant or lactating women;
- •Not suitable for participating in this study in the investigator 's opinion.
研究组 & 干预措施
Part I ( Safety run-in and PK Evaluation); Trilaciclib Group
12 patients( 6 patients are first line, 6 patients are second or third line) recieved Trilaciclib(240mg/m^2) plus chemotherapy.
干预措施: Trilaciclib, carboplatin, etoposide，or Topotecan (Drug)
Part II ( Randomized Double-blind, Placebo-controlled ), Trilaciclib Group
41 patients received trilaciclib(240mg/m^2) plus chemotherapy
干预措施: Trilaciclib, carboplatin, etoposide，or Topotecan (Drug)
Part II ( Randomized Double-blind, Placebo-controlled ), Placebo Group
42 patients received placebo plus chemotherapy
干预措施: placebo, carboplatin, etoposide，or Topotecan (Drug)
结局指标
主要结局
Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinity(AUC0-inf) for Part 1
时间窗: Day1 and Day 3( or Day 5) 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.
Duration of Severe Neutropenia in Cycle 1 (DSN)
时间窗: At the end of Cycle 1 (each cycle is 21 days)
DSN in Cycle 1 was defined as the number of days from the date of the first ANC value \< 0.5 x 10\^9/L in Cycle 1 to the date of the first ANC value ≥ 0.5 x 10\^9/L. The date of the first ANC value ≥ 0.5 x 10\^9/L should meet the following requirements: (1) occurred after the ANC value was \< 0.5 x 10\^9/L, and (2) there were no other ANC values \< 0.5 x 10\^9/L between this date and the end of Cycle 1 (otherwise, if this patient entered Cycle 2, it was counted as Day 1 of Cycle 2). DSN in Cycle 1 was scored as 0 if the patient did not experience any SN during Cycle 1.
Maximum Observed Plasma Concentration(Cmax) of Trilaciclib for Part 1
时间窗: Day1 and Day 3( or Day 5) 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.
次要结局
- Disease Control Rate (DCR)(From date of randomization , 21 day treatment cycle to the end of the treatment until (if earlier) disease progression, start of subsequent anticancer treatment, withdrawal of informed consent, or death, acessed up to a maximum of 18 months)
- Occurrence of Severe Neutropenia (SN)(From date of randomization , 21 day treatment cycle to the end of the treatment until (if earlier) disease progression, start of subsequent anticancer treatment, withdrawal of informed consent, or death, acessed up to a maximum of 12 months)
- Occurrence of Red Blood Cell Transfusion (on/After Week 5)(From week 5 to the end of the treatment until (if earlier) disease progression, start of subsequent anticancer treatment, withdrawal of informed consent, or death, acessed up to a maximum of 12 months)
- Granulocyte Colony Stimulating Factor (G-CSF) Use Rate(From date of randomization , 21 day treatment cycle to the end of the treatment until (if earlier) disease progression, start of subsequent anticancer treatment, withdrawal of informed consent, or death, acessed up to a maximum of 12 months)
- Composite Endpoints-major Hematologic AEs (Anyone of the Followings): All-cause Hospitalization; All-cause Dose Reductions; Febrile Neutropenia; SN Prolongation (Lasting > 5 Days); Red Blood Cell (RBC) Transfusions Were Performed on/After Week 5.(From date of randomization , 21 day treatment cycle to the end of the treatment until (if earlier) disease progression, start of subsequent anticancer treatment, withdrawal of informed consent, or death, acessed up to a maximum of 12 months)
- Occurrence of Grade 3 and 4 Hematological Toxicities(From date of randomization , 21 day treatment cycle to the end of the treatment until (if earlier) disease progression, start of subsequent anticancer treatment, withdrawal of informed consent, or death, acessed up to a maximum of 12 months)
- Erythropoiesis Stimulating Agent (ESA) Use Rate(From date of randomization , 21 day treatment cycle to the end of the treatment until (if earlier) disease progression, start of subsequent anticancer treatment, withdrawal of informed consent, or death, acessed up to a maximum of 12 months)
- Recombinant Human Interleukin-11 Use Rate(From date of randomization , 21 day treatment cycle to the end of the treatment until (if earlier) disease progression, start of subsequent anticancer treatment, withdrawal of informed consent, or death, acessed up to a maximum of 12 months)
- Thrombopoietin (TPO) Use Rate(From date of randomization , 21 day treatment cycle to the end of the treatment until (if earlier) disease progression, start of subsequent anticancer treatment, withdrawal of informed consent, or death, acessed up to a maximum of 12 months)
- Occurrence of Intravenous or Oral Antibiotic Administration(From date of randomization , 21 day treatment cycle to the end of the treatment until (if earlier) disease progression, start of subsequent anticancer treatment, withdrawal of informed consent, or death, acessed up to a maximum of 12 months)
- Occurrence of Infectious Serious Adverse Events(From date of randomization , 21 day treatment cycle to the end of the treatment until (if earlier) disease progression, start of subsequent anticancer treatment, withdrawal of informed consent, or death, acessed up to a maximum of 12 months)
- Occurrence of Lung Infection SAEs(From date of randomization , 21 day treatment cycle to the end of the treatment until (if earlier) disease progression, start of subsequent anticancer treatment, withdrawal of informed consent, or death, acessed up to a maximum of 12 months)
- Occurrence of Febrile Neutropenia(From date of randomization , 21 day treatment cycle to the end of the treatment until (if earlier) disease progression, start of subsequent anticancer treatment, withdrawal of informed consent, or death, acessed up to a maximum of 12 months)
- Occurrence of Platelet Transfusion(From date of randomization , 21 day treatment cycle to the end of the treatment until (if earlier) disease progression, start of subsequent anticancer treatment, withdrawal of informed consent, or death, acessed up to a maximum of 12 months)
- Objective Tumor Response Rate (ORR)(From date of randomization , 21 day treatment cycle to the end of the treatment until (if earlier) disease progression, start of subsequent anticancer treatment, withdrawal of informed consent, or death, acessed up to a maximum of 18 months)