A Single-arm, Multicenter, Exploratory Study to Evaluate the Efficacy and Safety of Nab-paclitaxel Combined With Local Therapy in Patients With Small-cell Lung Cancer Receiving Second-line or Subsequent Treatment

Patients with extensive-stage small cell lung cancer (ES-SCLC) who progress after first-line therapy have very limited second-line and subsequent treatment options. Commonly used regimens such as topotecan and lurbinectedin yield modest tumor response and survival benefits, and are often associated with prominent hematologic toxicities, especially myelosuppression. This creates a clinical dilemma of "insufficient efficacy combined with limited tolerability" and reflects a clear unmet medical need in this population.

This study explores a combined therapeutic strategy using nab-paclitaxel as the chemotherapy backbone with the addition of local radiotherapy in eligible patients. The primary objective is to evaluate whether this combination can provide clinically meaningful disease control and favorable signals for progression-free survival (PFS) and overall survival (OS), while maintaining an acceptable safety profile and manageable toxicities. Preclinical and clinical evidence suggests that nab-paclitaxel has a relatively controllable toxicity profile and convenient administration. Local therapy may exert synergistic effects by improving the tumor immune microenvironment and enhancing local tumor control, potentially supporting a more effective "chemotherapy ± local therapy" approach in the second-line setting.

Given the lack of a standardized control regimen and high patient heterogeneity in this field, a single-arm design is employed to rapidly obtain efficacy signals and define the safety boundary, which will support future larger-sample controlled studies and clinical pathway optimization.

This is a prospective, multicenter, single-arm, investigator-initiated trial (IIT) evaluating the efficacy and safety of nab-paclitaxel combined with local therapy in patients with ES-SCLC who have progressed after first-line or subsequent treatment. The study is planned to enroll 84 patients over 5 years, from January 2026 to December 2030, across two participating sites: Zhejiang Cancer Hospital (Principal Investigator: Weimin Mao) and Guangdong Provincial People's Hospital (Principal Investigator: Jiatao Zhang).

The sample size was calculated based on historical data showing a median PFS of 3 months for second-line treatment in ES-SCLC. Assuming the study regimen improves median PFS to 4.5 months, with a two-sided α of 0.05 and 80% power, 75 patients are required. Accounting for a 10% dropout rate, a total of 84 patients will be enrolled.

Eligibility Criteria Inclusion Criteria Signed written informed consent. Age 18-75 years, male or female. ECOG performance status 0 or 1. Histologically or cytologically confirmed ES-SCLC per the VALG staging system. Disease progression after at least one line of prior systemic therapy.

Asymptomatic, treated central nervous system (CNS) metastases allowed if all of the following are met:

Only supratentorial or cerebellar metastases; no brainstem, pons, medulla, or spinal cord metastases.

No ongoing corticosteroid therapy for CNS disease. No stereotactic radiotherapy within 7 days before randomization. No progression after CNS-directed therapy. New asymptomatic CNS lesions must receive radiotherapy or surgery before enrollment.

At least one measurable lesion per RECIST v1.1. Previously irradiated lesions are considered measurable only if they have progressed and are not the only lesions.

Adequate hematologic, hepatic, renal, and coagulation function within 14 days before randomization.

Availability of archival or newly obtained tumor tissue for biomarker analysis. Exclusion Criteria Active or untreated CNS metastases. Spinal cord compression not definitively treated or unstable. Leptomeningeal disease. Uncontrolled pleural, pericardial effusion, or ascites requiring frequent drainage.

Uncontrolled hypercalcemia (>1.5 mmol/L ionized calcium). History of other malignancy within 5 years except curatively treated in situ carcinoma, non-melanoma skin cancer, or localized disease with negligible risk of recurrence.

Pregnant or breastfeeding women. Severe hypersensitivity to study drugs or excipients. History of autoimmune disease requiring systemic immunosuppression. Interstitial lung disease, active pneumonitis, or severe pulmonary fibrosis. HIV infection, active hepatitis B or hepatitis C. Active tuberculosis. Severe uncontrolled infection requiring hospitalization. Significant cardiovascular disease including NYHA Class II-IV heart failure, myocardial infarction within 3 months, unstable arrhythmia or angina.

Major surgery within 28 days before randomization. Prior allogeneic bone marrow or solid organ transplantation. Prior CD137 agonist, anti-PD-1, or anti-PD-L1 therapy. Systemic immunosuppressive therapy within 14 days before randomization (except low-dose corticosteroids for specific indications).

Hypersensitivity to platinum or etoposide. Discontinuation Criteria

Patients will discontinue study treatment in cases of:

Confirmed disease progression per RECIST v1.1; Withdrawal of consent; Sponsor-initiated study termination; Death; Unacceptable toxicity; Clinical deterioration; Initiation of new anticancer therapy; Progressive disease in critical anatomical sites such as leptomeninges. Study Termination Criteria

Individual patients may be withdrawn for:

Voluntary withdrawal; Poor compliance; Treatment-related serious adverse events (SAEs); Dose-limiting toxicities (DLT) or grade ≥3 treatment-related adverse events (TRAEs) unresponsive to dose modification; Severe comorbidities; Safety concerns by the investigator or IRB. Treatment Plan Study Drug Nab-paclitaxel for injection, 100 mg, provided free of charge by Qilu Pharmaceutical (Hainan) Co., Ltd. Store at 20-30°C, protected from light, shelf life 36 months.

Regimen Nab-paclitaxel administered intravenously every 3 weeks for up to 6 cycles. Local radiotherapy may be delivered concurrently or sequentially, determined by the radiation oncologist based on performance status, disease burden, lesion location, chemotherapy tolerance, bone marrow reserve, and risk of acute toxicity.

Radiotherapy targets at least one progressive lesion, prioritizing primary lung lesions, symptomatic metastases, or lesions at risk of serious complications.

Dose and fractionation are individualized based on location, tumor size, treatment sequence, and normal tissue constraints.

Efficacy Assessment Primary Endpoint Progression-free survival (PFS), defined as time from first dose to first documented progression per RECIST v1.1 or death from any cause, whichever occurs first.

Secondary Endpoints Overall survival (OS), time from first dose to death from any cause. Objective response rate (ORR), proportion of patients with complete response (CR) or partial response (PR).

Disease control rate (DCR). Duration of response (DOR). 6-month and 12-month PFS rates. 12-month and 24-month OS rates. Timing of Evaluations Baseline imaging within 28 days before first treatment. Tumor assessment every 9 weeks (±7 days) until progression, new anticancer therapy, or withdrawal.

Survival follow-up every 12 weeks (±14 days) after progression or treatment discontinuation.

Safety Assessment Safety is evaluated throughout treatment and follow-up using NCI-CTCAE v5.0. Baseline assessment within 28 days before treatment. Cycle safety evaluations include adverse events (AEs), laboratory tests, physical examination, and vital signs.

A follow-up safety visit is performed 30 days (±7 days) after last dose. Non-resolving AEs are followed until resolution, stabilization, or study end. Adverse Events Treatment-emergent adverse events (TEAEs) are defined as any AE occurring from first dose through the post-treatment observation period. All AEs are coded using MedDRA 24.0 or higher and graded by severity. Summary tables will be generated by system organ class (SOC), preferred term (PT), severity, relatedness, and outcome.

Ethics The study will be conducted in accordance with the Declaration of Helsinki, ICH-GCP, and relevant national regulations. The protocol has been approved by the Institutional Review Board/Ethics Committee. Patient confidentiality will be strictly maintained.

Data Management All data will be recorded in case report forms consistent with source documents. Research records will be stored per local regulatory requirements. Patient identifiers will be protected and anonymized before submission to the sponsor.

Statistical Analysis Descriptive statistics will be used for baseline and demographic data. Time-to-event endpoints (PFS, OS, DOR) will be analyzed using the Kaplan-Meier method. Median values and 95% confidence intervals (CI) will be estimated. ORR and DCR will be presented as proportions with 95% CIs calculated by the Clopper-Pearson method. Safety will be summarized descriptively by frequency, severity, relatedness, and outcome. No imputation will be performed for missing data. Statistical analyses will be performed using SAS, R, or SPSS.