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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
78
Phase I dose levels: 80 mg/m², 120 mg/m², and 160 mg/m², administered orally on Days 1 and 8 of each cycle in divided morning and evening doses. Phase II: oral paclitaxel solution at the RP2D.
An PD-1/PD-L1 inhibitor selected by the investigator according to standard of care and administered according to the approved prescribing information
SBRT at 8 Gy per fraction for 3 fractions to the primary lung tumor and selected lymph node regions.
Participants considered operable after neoadjuvant therapy are intended to undergo radical lung cancer surgery.
Participants considered inoperable after neoadjuvant therapy are intended to continue SBRT at radical dose assessed by department of radiotherapy.
Guangdong Provincial People's Hospital
Guangzhou, Guangdong, China
NOT_YET_RECRUITINGThe Affiliated Suqian Hospital of Xuzhou Medical University
Suqian, Jiangsu, China
NOT_YET_RECRUITINGShanghai Pulmonary Hospital
Shanghai, Shanghai Municipality, China
RECRUITINGZhejiang Cancer Hospital
Hangzhou, Zhejiang, China
NOT_YET_RECRUITINGLishui People's Hospital
Lishui, Zhejiang, China
NOT_YET_RECRUITINGComplete Response (CR) Rate in Phase 2
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.
Time frame: 2 weeks (±14 days) after surgery or radical radiotherapy
Incidence of Grade 3 or Higher Treatment-Related Adverse Events (TRAE) in Phase 1
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.
Time frame: First dose up to 1 week (±7 days) after neoadjuvant therapy
CR Rate in Phase 1
The percentage of participants in the Phase 1 dose-escalation cohort who achieve a CR according toRECIST v1.1. A CR is defined as the disappearance of all target lesions, with any pathological lymph nodes having a reduction in the short axis to less than 10 mm.
Time frame: 2 weeks (±14 days) after surgery
Two-Year Event-Free Survival (EFS) Rate
The percentage of participants in the Phase 1/2 who remain alive and event-free at 2 years after first dose up. An event is defined as any of the following: Disease progression that precludes planned curative-intent treatment; Local, regional, or distant disease progression or recurrence; Death from any cause. Participants without an event will be censored at the date of their last adequate disease assessment.
Time frame: 2 years
Two-Year Overall Survival (OS) Rate
The percentage of participants in the Phase 2 who are alive at 2 years after first dose. Participants who are alive or whose survival status is unknown at the data cutoff will be censored at the date they were last known to be alive.
Time frame: 2 years
Incidence of AE
The percentage of participants in Phase 2 who experience treatment-emergent adverse events (TEAE), TRAE, Grade 3 or higher AE, serious adverse events (SAE), immune-related adverse events(irAE), or radiation-related AE. Adverse events will be graded according to CTCAE 5.0. Postoperative complications occurring during the protocol-specified postoperative safety period will also be summarized.
Time frame: First dose up to 1 week (±7 days) after neoadjuvant therapy
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