Phase 3 Study Evaluating Efficacy, Safety and Pharmacokinetics of Trilaciclib In Small Cell Lung Cancer Patients

Phase 3

Completed

Conditions: Extensive-stage Small-cell Lung Cancer

Interventions: Drug: Trilaciclib, carboplatin, etoposide，or Topotecan
Drug: placebo, carboplatin, etoposide，or Topotecan

Registration Number: NCT04902885

Lead Sponsor: Jiangsu Simcere Pharmaceutical Co., Ltd.

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 95

Inclusion Criteria

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

Exclusion Criteria

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part I ( Safety run-in and PK Evaluation); Trilaciclib Group	Trilaciclib, carboplatin, etoposide，or Topotecan	12 patients( 6 patients are first line, 6 patients are second or third line) recieved Trilaciclib(240mg/m\^2) plus chemotherapy.
Part II ( Randomized Double-blind, Placebo-controlled ), Trilaciclib Group	Trilaciclib, carboplatin, etoposide，or Topotecan	41 patients received trilaciclib(240mg/m\^2) plus chemotherapy
Part II ( Randomized Double-blind, Placebo-controlled ), Placebo Group	placebo, carboplatin, etoposide，or Topotecan	42 patients received placebo plus chemotherapy

Primary Outcome Measures

Name	Time	Method
Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinity(AUC0-inf) for Part 1	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)	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	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.

Secondary Outcome Measures

Name	Time	Method
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	DCR was performed based on the Response Evaluation Analysis Set (RES). Based on the assessments at each visit, the number and percentage of patients with best response of CR, PR, SD, PD and NE will be summarized by treatment group when CR/PR confirmation is not required and CR/PR confirmation is required, respectively . In particular, SD BOR requires at least 35 days or more after enrollment. DCR was calculated based on the number of patients with best response of CR PR or SD.
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	Severe (Grade 4) neutropenia was defined as at least 1 ANC value \<0.5 × 10\^9/L during the treatment period.
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	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.
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	Administration of G-CSF was collected with concomitant medications, which were coded using World Health Organization Drug Dictionary (WHO-DD) . 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.
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	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). Event rate per week， calculated as the total number of events divided by duration of in weeks.
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	Occurrence of Grade 3 and 4 hematological toxicities was defined according to CTCAE 5.0 during the treatment period.
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	Administration of ESA was collected with concomitant medications, which were coded using WHO-DD . 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.
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	Administration of interleukin-11 was collected with concomitant medications, which were coded using WHO-DD Version. A cycle where interleukin-11 was administered concurrently was identified by comparing the start and stop dates of each administration of interleukin-11 to the start of cycle and end of cycle. The occurrence of interleukin-11 administration was at least 1 cycle with interleukin-11 administration during the treatment period.
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	Administration of TPO was collected with concomitant medications, which were coded using WHO-DD Version. A cycle where TPO was administered concurrently was identified by comparing the start and stop dates of each administration of TPO to the start of cycle and end of cycle. The occurrence of TPO administration was at least 1 cycle with TPO administration during the treatment period.
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	Administration of intravenous or oral antibiotic was collected with concomitant medications, which were coded using WHO-DD Version. A cycle where intravenous or oral antibiotic was administered concurrently was identified by comparing the start and stop dates of each administration of intravenous or oral antibiotic to the start of cycle and end of cycle. The occurrence of intravenous or oral antibiotic administration was at least 1 cycle with intravenous or oral antibiotic administration during the treatment period.
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	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 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	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 lung 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 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	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.
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	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.
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	ORR was performed based on the Response Evaluation Analysis Set (RES). Based on the assessments at each visit, the number and percentage of patients with best response of CR, PR, SD, PD and NE will be summarized by treatment group when CR/PR confirmation is not required and CR/PR confirmation is required, respectively . In particular, SD BOR requires at least 35 days or more after enrollment.ORR was calculated based on the number of patients with best response of CR or PR.