SBRT Combined With PD-1 Inhibitor and Thoracic Hyperthermia for Advanced NSCLC

Study Overview
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Brief Summary
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The aim of this trial is to investigate the primary efficacy of SBRT combined with PD-1 inhibitor and thoracic hyperthermia in patients with EGFR, ALK, and ROS1 negative stage IV NSCLC patients who progressed after first-line treatment. At least one lesion (primary or metastatic) was selected for SBRT treatment, and the radiotherapy dose of each lesion was 32Gy/4Fx. SBRT was combined with thoracic hyperthermia from the first fraction, and hyperthermia was performed 6 times, twice a week. PD-1 inhibitor was used on the second day after the completion of SBRT. The PD-1 inhibitor was administered at a dose of 200mg every time, every 3 weeks for 2 years (35 times total), or until the investigators deem that the patient need to discontinue the drug because of treatment-related toxicity or disease progression. During the period, the overall response rate and toxicities were regularly evaluated.

Official Title
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An Open, Single-arm, Multicenter Phase II Trial to Evaluate SBRT Combined With PD-1 Inhibitors and Thoracic Hyperthermia for Advanced Non-Small-Cell Lung Cancer

Conditions
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Stereotactic Body Radiation Therapy; PD-1 Inhibitor; Hyperthermia; NSCLC

Intervention / Treatment
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* Radiation: SBRT combined with PD-1 inhibitors and thoracic hyperthermia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1.Age≥18. 2.ECOG PS 0-1. 3.Histopathologically confirmed stage IV non-small-cell lung cancer. 4.EGFR/ALK/ROS-1 negetive. 5.Disease progression after first-line therapy including platinum chemotherapy, but not include PD-1/L1 inhibitors. 6.Subjects with brain metastases were eligible, but only if they had no neurologic symptoms or disease stable without systemic glucocorticoid. 7.At least one lesion with a diameter of 1-5cm which could be treated with SBRT at a dose of 32Gy/4Fx, and at least one lesion which could be measured other than SBRT (RECIST1.1); Lymph nodes can be used as independent measurable lesions or receive SBRT. Brain lesions should not be used as separate SBRT lesions or as measurable lesions. 8.The subjects did not had radiotherapy before. 9.The subjects did not currently need palliative radiotherapy at any part according to the researchers. 10.It was necessary for the subjects who underwent surgery to fully recover from the toxicity and complications caused by surgical intervention prior to treatment. 11.Subjects should provide appropriate biopsy specimens before and during treatment according to the clinical trial protocol. 12.Male or female subjects agree to contraception during the trial (surgical ligation or oral contraceptive/IUD + condom). 13.Life expectancy ≥ 3 months. 14.The organ function level meet the following standards one week before enrollment: ①Bone marrow: hemoglobin ≥80g/L, white blood cell count ≥4.0*10^9/L or neutrophil count ≥1.5*10^9/L, platelet count ≥100*10^9/L. ②Liver: Serum total bilirubin level ≤1.5 upper limit of normal (ULN), when serum total bilirubin level > 1.5 ULN, direct bilirubin level must be ≤ ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ULN. ③ Kidney: serum creatinine level < 1.5 ULN or creatinine clearance rate ≥ 50ml/min, urea nitrogen ≤ 200mg/L; Serum albumin ≥ 30g/L. 15. Subjects must be able to understand and voluntarily sign informed consent. Exclusion Criteria: 1.Prior treatment with anti-PD-1 /L1 drugs or other investigational immunotherapy agent. 2.Subjects had prior radiotherapy. 3.Subjects had severe autoimmune diseases: active inflammatory bowel disease (including Crohn's disease and ulcerative colitis), rheumatoid arthritis, scleroderma, systemic lupus erythematosus, autoimmune vasculitis (such as Wegener's granuloma), etc. 4.Symptomatic interstitial lung disease or active infectious/noninfectious pneumonia. 5.Subjects had risk factors for bowel perforation: active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, abdominal cancer, or other risk factors for bowel perforation. 6.History of other malignant tumors. 7.Subjects who have current infection, heart failure, heart attack, unstable angina, or unstable arrhythmia in the last 6 months. 8.Subjects with physical examination or clinical trial findings, or other uncontrolled conditions that the investigator believes may interfere with the outcome or increase the risk of treatment complications. 9.Subjects without platinum-based combination chemotherapy included as first-line treatment. 10.The pathology reports showed a mixture of small cell lung cancer components. 11.Lactating or pregnant women. 12.Congenital or acquired immunodeficiency diseases including human immunodeficiency virus (HIV), or a history of organ transplantation, allogeneic stem cell transplantation. 13.Known hepatitis B virus (HBV), hepatitis C virus (HCV), active pulmonary tuberculosis infections. 14.Subjects had cancer vaccines other vaccines within 4 weeks before treatment initiation. (Seasonal influenza vaccines are usually inactivated and are permitted, whereas intranasal preparations are usually live attenuated vaccines and therefore are not permitted) 15.Subjects who currently use other immune agents, chemotherapy agents, other investigational drugs or long-term cortisol therapy. 16.Subjects with mental illness, substance abuse, and social problems that affected compliance were not included in the study according to doctor's evaluation. 17.Allergic or contraindicated to PD-1 inhibitors.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SBRT combined with PD-1 inhibitors and thoracic hyperthermia<br>At least one lesion (primary or metastatic) was selected for SBRT treatment, and the radiotherapy dose of each lesion was 32Gy/4Fx. SBRT was combined with thoracic hyperthermia from the first fraction, and hyperthermia was performed 6 times, twice a week. PD-1 inhibitor was used on the second day after the completion of SBRT. The PD-1 inhibitor was administered at a dose of 200mg every time, every 3 weeks for 2 years (35 times total), or until the investigators deem that the patient need to discontinue the drug because of treatment-related toxicity or disease progression. | Radiation: SBRT combined with PD-1 inhibitors and thoracic hyperthermia<br>* At least one lesion (primary or metastatic) was selected for SBRT treatment, and the radiotherapy dose of each lesion was 32Gy/4Fx. SBRT was combined with thoracic hyperthermia from the first fraction, and hyperthermia was performed 6 times, twice a week. PD-1 inhibitor was used on the second day after the completion of SBRT. The PD-1 inhibitor was administered at a dose of 200mg every time, every 3 weeks for 2 years (35 times total), or until the investigators deem that the patient need to discontinue the drug because of treatment-related toxicity or disease progression.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | The proportion of patients evaluated as complete response or partial response | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-related toxic effects | The proportion of treatment-related toxicity cases to the total number of evaluable cases assessed according to CTCAE 5.0 criteria | 2 years | 
| Objective response rate of non-irradiated lesions | The proportion of patients with non-irradiated lesions evaluated as complete response or partial response in the total enrolled patients | 2 years | 
| Overall response | The time span from the first day of enrollment until death from any cause | 2 years | 
| Progression free survival | The time span from the first day of enrollment until progression or death from any cause | 2 years |