A Multicenter, Open-Label, Single-Arm Phase I/II Study of Oral Paclitaxel Solution Combined With an Immune Checkpoint Inhibitor and Concurrent Stereotactic Body Radiotherapy as Neoadjuvant Treatment in Older Patients With Resectable Stage IIA-IIIB Non-Small Cell Lung Cancer
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 78
- 试验地点
- 5
- 主要终点
- Complete Response (CR) Rate in Phase 2
研究概览
简要总结
his multicenter, open-label, single-arm phase I/II trial will evaluate the safety, tolerability, and preliminary efficacy of oral paclitaxel solution combined with an immune checkpoint inhibitor and concurrent stereotactic body radiotherapy (SBRT) as neoadjuvant therapy in patients aged 70 years or older with resectable stage IIA-IIIB non-small cell lung cancer (NSCLC) without sensitizing EGFR, ALK, or ROS1 alterations.
In Phase I, a 3+3 dose-escalation design will evaluate oral paclitaxel at 80, 120, and 160 mg/m² administered orally on Days 1 and 8 of each cycle, divided into morning and evening doses, in combination with an investigator-selected anti-PD-1 or anti-PD-L1 monoclonal antibody and SBRT at 8 Gy in 3 fractions. Phase II will expand enrollment at the recommended Phase II dose (RP2D). The principal efficacy outcome is pathologic complete response after surgery. Other outcomes include major pathologic response, radiographic response, event-free survival, overall survival, surgical resection and R0 resection rates, and exploratory biomarker changes.
详细描述
Older patients with NSCLC may have reduced organ reserve, more comorbidities, and a higher risk of toxicity from standard platinum-based chemotherapy, intensive radiotherapy, or multimodality treatment. The study is designed to explore a potentially lower-intensity neoadjuvant regimen that combines oral paclitaxel solution, immune checkpoint blockade, and precision radiotherapy.
Phase I will use a conventional 3+3 dose-escalation design. Oral paclitaxel solution will be evaluated at 80, 120, and 160 mg/m² on Days 1 and 8 of each cycle, administered in divided morning and evening doses. An anti-PD-1 or anti-PD-L1 monoclonal antibody will be selected by the investigator according to standard of care and administered according to the approved prescribing information. Concurrent SBRT will be delivered at 8 Gy per fraction for 3 fractions to the primary lung tumor and selected nodal regions. The Phase I objective is to evaluate safety and identify the RP2D.
Phase II will enroll additional participants at the RP2D to evaluate antitumor activity and feasibility. Participants who remain suitable for radical lung cancer surgery are intended to undergo resection after completion of neoadjuvant treatment. The study will assess pathologic response, radiographic response, surgical feasibility, event-free survival, overall survival, and changes in immune cell subsets, circulating tumor DNA, and PD-L1 expression.
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
- None
入排标准
- 年龄范围
- 70 Years 至 —（Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 70 years or older, regardless of sex.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Histologically confirmed non-small cell lung cancer, clinical stage IIA-IIIB according to the 8th edition of the AJCC staging system.
- •No evidence of distant metastasis and considered suitable for radical lung cancer surgery.
- •The primary lung lesion is suitable for stereotactic body radiotherapy.
- •No sensitizing driver alterations in EGFR, ALK, ROS1, or other tested actionable genes.
- •Adequate major organ function, including all of the following:
- •Absolute neutrophil count at least 1.5 × 10^9/L, platelet count at least 100 × 10^9/L, and hemoglobin at least 9 g/dL.
- •Total bilirubin no more than 1.5 × the upper limit of normal; alanine aminotransferase and aspartate aminotransferase no more than 2.5 × the upper limit of normal.
- •Serum creatinine no more than 1.5 × the upper limit of normal or creatinine clearance at least 60 mL/min.
- •Urine protein less than 1+; if urine protein is 1+, 24-hour urine protein must be less than 500 mg.
- •Blood glucose within the normal range or stable glycemic control in participants with diabetes.
- •Baseline forced expiratory volume in 1 second (FEV1) at least 2 L; if FEV1 is less than 2 L, the predicted postoperative FEV1 must be greater than 800 mL as assessed by a thoracic surgeon.
- •No myocardial infarction within the previous year, no unstable angina, no symptomatic severe arrhythmia, and no cardiac insufficiency.
- •The participant has been fully informed and voluntarily provides written informed consent.
排除标准
- •Prior lobectomy, thoracic radiotherapy, or systemic antitumor therapy.
- •Another concurrent malignancy or a history of another malignancy cured less than 5 years before enrollment, except adequately treated cervical carcinoma in situ or basal cell or squamous cell carcinoma of the skin.
- •Active autoimmune disease or a history of autoimmune disease requiring systemic immunosuppressive treatment.
- •Active infection requiring systemic treatment, active tuberculosis, human immunodeficiency virus infection, active hepatitis B or hepatitis C, active syphilis, or another active transmissible infection specified by the protocol.
- •Severe cardiac, hepatic, renal, or metabolic disease that precludes surgery or study treatment.
- •History of interstitial lung disease or drug-induced pneumonitis, or imaging evidence of active interstitial lung disease.
- •Uncontrolled large pleural effusion or pericardial effusion.
- •Major surgery, severe trauma, or treatment with another investigational drug within 4 weeks before enrollment.
- •Recent receipt of an anticancer vaccine or live vaccine.
- •Any other condition that, in the investigator's opinion, makes the participant unsuitable for the study or may interfere with interpretation of the study results.
研究组 & 干预措施
Phase 1 Dose-Escalation Cohort
Participants enrolled in Phase 1 will receive oral paclitaxel solution in combination with an anti-PD-1 monoclonal antibody and stereotactic body radiation therapy (SBRT). Oral paclitaxel solution will be evaluated at sequential dose levels of 80 mg/m², 120 mg/m², and 160 mg/m² using a conventional 3+3 dose-escalation design.
The primary objective of this cohort is to evaluate the safety and tolerability of the combination regimen and to determine the recommended Phase 2 dose (RP2D) of oral paclitaxel solution. Tumor response and surgical feasibility will be assessed after completion of the protocol-specified treatment.
干预措施: Oral Paclitaxel Solution (Drug)
Phase 1 Dose-Escalation Cohort
Participants enrolled in Phase 1 will receive oral paclitaxel solution in combination with an anti-PD-1 monoclonal antibody and stereotactic body radiation therapy (SBRT). Oral paclitaxel solution will be evaluated at sequential dose levels of 80 mg/m², 120 mg/m², and 160 mg/m² using a conventional 3+3 dose-escalation design.
The primary objective of this cohort is to evaluate the safety and tolerability of the combination regimen and to determine the recommended Phase 2 dose (RP2D) of oral paclitaxel solution. Tumor response and surgical feasibility will be assessed after completion of the protocol-specified treatment.
干预措施: PD-1/PD-L1 inhibitor (Drug)
Phase 1 Dose-Escalation Cohort
Participants enrolled in Phase 1 will receive oral paclitaxel solution in combination with an anti-PD-1 monoclonal antibody and stereotactic body radiation therapy (SBRT). Oral paclitaxel solution will be evaluated at sequential dose levels of 80 mg/m², 120 mg/m², and 160 mg/m² using a conventional 3+3 dose-escalation design.
The primary objective of this cohort is to evaluate the safety and tolerability of the combination regimen and to determine the recommended Phase 2 dose (RP2D) of oral paclitaxel solution. Tumor response and surgical feasibility will be assessed after completion of the protocol-specified treatment.
干预措施: Stereotactic Body Radiotherapy (SBRT) (Radiation)
Phase 1 Dose-Escalation Cohort
Participants enrolled in Phase 1 will receive oral paclitaxel solution in combination with an anti-PD-1 monoclonal antibody and stereotactic body radiation therapy (SBRT). Oral paclitaxel solution will be evaluated at sequential dose levels of 80 mg/m², 120 mg/m², and 160 mg/m² using a conventional 3+3 dose-escalation design.
The primary objective of this cohort is to evaluate the safety and tolerability of the combination regimen and to determine the recommended Phase 2 dose (RP2D) of oral paclitaxel solution. Tumor response and surgical feasibility will be assessed after completion of the protocol-specified treatment.
干预措施: Radical Lung Cancer Surgery (Procedure)
Phase 2 Cohort A - Operable Cohort
Participants enrolled in Phase 2 Cohort A will be patients considered eligible for curative-intent surgery after multidisciplinary evaluation.
Participants will receive oral paclitaxel solution at the RP2D established in Phase 1, in combination with an anti-PD-1 monoclonal antibody and SBRT. After completion of the protocol-specified neoadjuvant treatment, participants will undergo tumor response assessment and surgical evaluation. Participants who remain operable will proceed to curative-intent surgical resection.
干预措施: Oral Paclitaxel Solution (Drug)
Phase 2 Cohort A - Operable Cohort
Participants enrolled in Phase 2 Cohort A will be patients considered eligible for curative-intent surgery after multidisciplinary evaluation.
Participants will receive oral paclitaxel solution at the RP2D established in Phase 1, in combination with an anti-PD-1 monoclonal antibody and SBRT. After completion of the protocol-specified neoadjuvant treatment, participants will undergo tumor response assessment and surgical evaluation. Participants who remain operable will proceed to curative-intent surgical resection.
干预措施: PD-1/PD-L1 inhibitor (Drug)
Phase 2 Cohort A - Operable Cohort
Participants enrolled in Phase 2 Cohort A will be patients considered eligible for curative-intent surgery after multidisciplinary evaluation.
Participants will receive oral paclitaxel solution at the RP2D established in Phase 1, in combination with an anti-PD-1 monoclonal antibody and SBRT. After completion of the protocol-specified neoadjuvant treatment, participants will undergo tumor response assessment and surgical evaluation. Participants who remain operable will proceed to curative-intent surgical resection.
干预措施: Stereotactic Body Radiotherapy (SBRT) (Radiation)
Phase 2 Cohort A - Operable Cohort
Participants enrolled in Phase 2 Cohort A will be patients considered eligible for curative-intent surgery after multidisciplinary evaluation.
Participants will receive oral paclitaxel solution at the RP2D established in Phase 1, in combination with an anti-PD-1 monoclonal antibody and SBRT. After completion of the protocol-specified neoadjuvant treatment, participants will undergo tumor response assessment and surgical evaluation. Participants who remain operable will proceed to curative-intent surgical resection.
干预措施: Radical Lung Cancer Surgery (Procedure)
Phase 2 Cohort B - Inoperable Cohort
Participants enrolled in Phase 2 Cohort B will be patients considered unsuitable for curative-intent surgery after multidisciplinary evaluation.
Participants will receive oral paclitaxel solution at the RP2D established in Phase 1, in combination with an anti-PD-1 monoclonal antibody and radiotherapy. Participants will receive protocol-specified non-surgical, definitive-intent treatment and will undergo radiographic tumor response assessment and long-term survival follow-up.
干预措施: Oral Paclitaxel Solution (Drug)
Phase 2 Cohort B - Inoperable Cohort
Participants enrolled in Phase 2 Cohort B will be patients considered unsuitable for curative-intent surgery after multidisciplinary evaluation.
Participants will receive oral paclitaxel solution at the RP2D established in Phase 1, in combination with an anti-PD-1 monoclonal antibody and radiotherapy. Participants will receive protocol-specified non-surgical, definitive-intent treatment and will undergo radiographic tumor response assessment and long-term survival follow-up.
干预措施: PD-1/PD-L1 inhibitor (Drug)
Phase 2 Cohort B - Inoperable Cohort
Participants enrolled in Phase 2 Cohort B will be patients considered unsuitable for curative-intent surgery after multidisciplinary evaluation.
Participants will receive oral paclitaxel solution at the RP2D established in Phase 1, in combination with an anti-PD-1 monoclonal antibody and radiotherapy. Participants will receive protocol-specified non-surgical, definitive-intent treatment and will undergo radiographic tumor response assessment and long-term survival follow-up.
干预措施: Stereotactic Body Radiotherapy (SBRT) (Radiation)
结局指标
主要结局
Complete Response (CR) Rate in Phase 2
时间窗: 2 weeks (±14 days) after surgery or radical radiotherapy
The percentage of participants in the Phase 2 operable cohort who achieve a CR according to RECIST v1.1, at the protocol-specified preoperative tumor assessment. A CR is defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in the short axis to less than 10 mm. Participants who discontinue treatment, experience disease progression, become unable to undergo the planned response assessment, or have no evaluable post-baseline tumor assessment will be classified as not having achieved a CR.
Incidence of Grade 3 or Higher Treatment-Related Adverse Events (TRAE) in Phase 1
时间窗: First dose up to 1 week (±7 days) after neoadjuvant therapy
The percentage of participants in the Phase 1 dose-escalation cohort who experience at least one Grade 3 or higher TRAE during the safety assessment period. Adverse events will be graded according to the CTCAE 5.0. The relationship of each adverse event (AE) to oral paclitaxel solution, the anti-PD-1 antibody, radiotherapy, or the combination regimen will be assessed by the investigator.
次要结局
- CR Rate in Phase 1(2 weeks (±14 days) after surgery)
- Two-Year Event-Free Survival (EFS) Rate(2 years)
- Two-Year Overall Survival (OS) Rate(2 years)
- Incidence of AE(First dose up to 1 week (±7 days) after neoadjuvant therapy)
研究者
Xiaoling Xu
Principal Investigator, Department of Radiation Oncology
Shanghai Pulmonary Hospital, Shanghai, China