A Single-Arm, Prospective, Exploratory Phase II Clinical Study of Quad Shot Radiotherapy Combined With Tislelizumab and Platinum-Based Doublet Chemotherapy as Neoadjuvant Treatment for Stage II-III Non-Small Cell Lung Cancer
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Pathological Complete Response (pCR) Rate
研究概览
简要总结
This study aims to evaluate a new pre-surgery (neoadjuvant) treatment for patients with stage II-III non-small cell lung cancer (NSCLC). Currently, standard pre-surgery treatment involves immunotherapy combined with chemotherapy. While effective, many patients still have residual tumor cells after this standard treatment.
Radiation therapy can not only kill tumor cells but also help the immune system recognize and fight cancer. The type of radiation used in this study is called "Quad Shot" (QS) radiotherapy. It is a short, high-dose, cyclical treatment designed to boost the effects of immunotherapy with less toxicity than standard daily radiation.
Patients in this study will receive 3 cycles of QS radiotherapy combined with Tislelizumab (an immunotherapy drug) and standard platinum-based chemotherapy before surgery. The main goal of this study is to see if this combined approach can make the tumor completely disappear under a microscope (called pathological complete response, or pCR). Researchers will also monitor the safety of the treatment, side effects, and how well patients tolerate the treatment before undergoing surgery. Approximately 12 patients will be enrolled in this study.
详细描述
Background:
Neoadjuvant immune checkpoint inhibitor (ICI) combined with platinum-based chemotherapy has become a standard of care for resectable stage II-III NSCLC, as demonstrated by phase III trials such as CheckMate-816, KEYNOTE-671, and RATIONALE-315. However, a significant proportion of patients still fail to achieve deep pathological responses due to mechanisms such as poor antigen release, impaired antigen presentation, and an immunosuppressive tumor microenvironment (TME).
Radiotherapy possesses immunomodulatory properties, inducing immunogenic cell death and promoting antigen release. However, traditional continuous fractionated radiotherapy may deplete circulating lymphocytes and cause normal tissue damage. The "Quad Shot" (QS) regimen is a cyclical hypofractionated radiotherapy approach (14-14.8 Gy in 4 fractions over 2 days) that has shown low toxicity in palliative settings. Its cyclical, pulsatile nature may provide repeated immune stimulation and TME remodeling, making it a promising partner for immunotherapy.
Study Design:
This is a single-arm, prospective, exploratory phase II clinical study. Patients with histologically or cytologically confirmed, untreated, resectable stage II-IIIB NSCLC (including T3-4N2 IIIB, AJCC 9th edition) will be enrolled.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18-75 years, either gender.
- •Histologically or cytologically confirmed, untreated stage II-IIIB non-small cell lung cancer (NSCLC) (including T3-4N2 IIIB, AJCC 9th edition). Baseline staging must include PET/CT (or chest + upper abdomen contrast-enhanced CT + whole body bone scan) + brain MRI. Stage III patients will be further subdivided into IIIA and IIIB per AJCC 9th edition for separate recording, evaluation, and analysis.
- •Evaluated as resectable by a multidisciplinary team including thoracic surgeons.
- •At least one evaluable target lesion per RECIST v1.
- •ECOG Performance Status 0-
- •Adequate major organ function: Neutrophils ≥ 1.5×10^9/L; Platelets ≥ 100×10^9/L; Hemoglobin > 9.0 g/dL; Serum creatinine ≤ 1.5×ULN or Creatinine Clearance (CrCl) ≥ 40 mL/min; AST/ALT ≤ 3×ULN; Total bilirubin ≤ 1.5×ULN; INR/APTT within normal range; FEV1 ≥ 1.2L or > 40% predicted.
- •Signed written informed consent prior to any study-related procedures.
- •Investigator judges that the patient is able to comply with the study protocol, willing and able to follow visit schedules, treatment plans, laboratory tests, and other study procedures.
- •Negative pregnancy test at screening (for women of childbearing potential). Subjects of childbearing potential (male and female) must agree to use effective contraception from screening until 180 days after the last dose.
排除标准
- •Known or suspected autoimmune disease (except vitiligo, Type I diabetes, or hypothyroidism requiring only hormone replacement therapy with no signs of recurrence).
- •Requires systemic corticosteroid therapy (>10 mg/day prednisolone or equivalent) or other immunosuppressive drugs within 14 days prior to enrollment (inhaled or topical steroids, and physiological replacement doses of adrenal corticosteroids are allowed).
- •History of thoracic radiotherapy.
- •Active bleeding before treatment.
- •Severe heart, lung, liver, or kidney dysfunction, hematopoietic system disease, cachexia, or other conditions that make the patient unable to tolerate chemoradiotherapy.
- •History of diabetes for more than 10 years with unsatisfactory blood glucose control.
- •History of interstitial lung disease or non-infectious pneumonitis.
- •NSCLC patients with EGFR sensitizing mutations or ALK fusion genes.
- •Prior or concurrent other malignancies (except cured non-melanoma skin cancer and carcinoma in situ; or malignancies in complete remission for ≥ 2 years without requiring additional anti-tumor therapy during the study period).
- •Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, or other drugs targeting T-cell costimulatory or immune regulatory pathways.
- •Active hepatitis B (HBV DNA ≥ 2000 IU/mL or 10^4 copies/mL) or hepatitis C (HCV antibody positive and HCV-RNA above the lower limit of detection).
- •HIV positive or diagnosed with acquired immunodeficiency syndrome (AIDS).
- •Received live vaccine within 4 weeks prior to the start of study treatment.
- •Known or suspected allergy to the study drugs or any related drugs in this trial.
- •Pregnant or breastfeeding women.
- •Investigator considers that the patient has other factors that may prevent completion of the study or affect subject safety or data collection.
研究组 & 干预措施
Neoadjuvant Quad Shot Radiotherapy + Tislelizumab + Chemotherapy
Patients receive 3 cycles of neoadjuvant therapy (every 21 days). Each cycle consists of:
- Quad Shot radiotherapy (14-14.8 Gy/4 fractions on Day 1-2)
- Tislelizumab (200 mg, Day 3)
- Platinum-based doublet chemotherapy (Day 3): Carboplatin (AUC 5) or Cisplatin (75 mg/m²), combined with Pemetrexed (500 mg/m² for non-squamous) or Paclitaxel (175 mg/m² for squamous).
Surgery is performed 4-6 weeks (±7 days) after the third cycle. Postoperative adjuvant therapy is administered at the investigator's discretion according to NCCN and CSCO guidelines.
干预措施: Quad Shot Radiotherapy (Radiation)
Neoadjuvant Quad Shot Radiotherapy + Tislelizumab + Chemotherapy
Patients receive 3 cycles of neoadjuvant therapy (every 21 days). Each cycle consists of:
- Quad Shot radiotherapy (14-14.8 Gy/4 fractions on Day 1-2)
- Tislelizumab (200 mg, Day 3)
- Platinum-based doublet chemotherapy (Day 3): Carboplatin (AUC 5) or Cisplatin (75 mg/m²), combined with Pemetrexed (500 mg/m² for non-squamous) or Paclitaxel (175 mg/m² for squamous).
Surgery is performed 4-6 weeks (±7 days) after the third cycle. Postoperative adjuvant therapy is administered at the investigator's discretion according to NCCN and CSCO guidelines.
干预措施: Pemetrexed or Paclitaxel (Drug)
Neoadjuvant Quad Shot Radiotherapy + Tislelizumab + Chemotherapy
Patients receive 3 cycles of neoadjuvant therapy (every 21 days). Each cycle consists of:
- Quad Shot radiotherapy (14-14.8 Gy/4 fractions on Day 1-2)
- Tislelizumab (200 mg, Day 3)
- Platinum-based doublet chemotherapy (Day 3): Carboplatin (AUC 5) or Cisplatin (75 mg/m²), combined with Pemetrexed (500 mg/m² for non-squamous) or Paclitaxel (175 mg/m² for squamous).
Surgery is performed 4-6 weeks (±7 days) after the third cycle. Postoperative adjuvant therapy is administered at the investigator's discretion according to NCCN and CSCO guidelines.
干预措施: Carboplatin or cisplatin (Drug)
Neoadjuvant Quad Shot Radiotherapy + Tislelizumab + Chemotherapy
Patients receive 3 cycles of neoadjuvant therapy (every 21 days). Each cycle consists of:
- Quad Shot radiotherapy (14-14.8 Gy/4 fractions on Day 1-2)
- Tislelizumab (200 mg, Day 3)
- Platinum-based doublet chemotherapy (Day 3): Carboplatin (AUC 5) or Cisplatin (75 mg/m²), combined with Pemetrexed (500 mg/m² for non-squamous) or Paclitaxel (175 mg/m² for squamous).
Surgery is performed 4-6 weeks (±7 days) after the third cycle. Postoperative adjuvant therapy is administered at the investigator's discretion according to NCCN and CSCO guidelines.
干预措施: Tislelizumab (Drug)
结局指标
主要结局
Pathological Complete Response (pCR) Rate
时间窗: After completion of neoadjuvant therapy and surgery (approximately 4-6 weeks after the last dose of neoadjuvant therapy)
The proportion of patients with no residual viable tumor cells in the resected primary tumor and regional lymph nodes, as assessed by pathological review. Patients who do not undergo surgery will be considered as not achieving pCR.
次要结局
- Major Pathological Response (MPR) Rate(After completion of neoadjuvant therapy and surgery (approximately 4-6 weeks after the last dose of neoadjuvant therapy))
- R0 Resection Rate(At time of surgery)
- Objective Response Rate (ORR) per RECIST v1.1(Up to 14 days before surgery)
- Event-Free Survival (EFS) and 2-Year EFS Rate(Up to 60 months after enrollment)
- Overall Survival (OS) and 2-Year OS Rate(Up to 60 months after enrollment)
- Incidence and Severity of Adverse Events (AEs), Serious Adverse Events (SAEs), and Immune-Related Adverse Events (irAEs)(From informed consent to 90 days after the last dose of study treatment)
- Feasibility (Completion Rate of Neoadjuvant Therapy and Surgery)(Up to 4-6 weeks after the last dose of neoadjuvant therapy)
- QS Radiotherapy-Related Toxicity(Up to 90 days after the last dose of radiotherapy)