NSCLC (Non-small Cell Lung Cancer)
Conditions
Keywords
Elderly patients, Neoadjuvant therapy, Oral paclitaxel solution, Immune checkpoint inhibitor, SBRT, Resectable NSCLC, Pathologic complete response
Brief summary
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.
Detailed description
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.
Interventions
DRUGOral Paclitaxel Solution
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
RADIATIONStereotactic Body Radiotherapy (SBRT)
SBRT at 8 Gy per fraction for 3 fractions to the primary lung tumor and selected lymph node regions.
PROCEDURERadical Lung Cancer Surgery
Participants considered operable after neoadjuvant therapy are intended to undergo radical lung cancer surgery.
Sponsors
Shanghai Pulmonary Hospital, Shanghai, China
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase I uses a 3+3 dose-escalation design to determine the recommended Phase II dose of oral paclitaxel solution in combination with an immune checkpoint inhibitor and concurrent SBRT. Phase II is a single-arm expansion at the recommended Phase II dose to evaluate efficacy and feasibility.
Eligibility
Sex/Gender
ALL
Age
70 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 70 years or older, regardless of sex. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * 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.
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response (CR) Rate in Phase 2 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CR Rate in Phase 1 | 2 weeks (±14 days) after surgery | 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. |
| Two-Year Event-Free Survival (EFS) Rate | 2 years | 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. |
| Two-Year Overall Survival (OS) Rate | 2 years | 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. |
| Incidence of AE | First dose up to 1 week (±7 days) after neoadjuvant therapy | 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. |
Countries
China
Contacts
CONTACTXiaoling Xu, MD, PhD
PRINCIPAL_INVESTIGATORXiaoling Xu, MD, PhD
Shanghai Pulmonary Hospital, Shanghai, China
Outcome results
None listed