SBRT Combination With rhGM-CSF and Tα1 for Stage IV NSCLC Patients Who Failed in Second-line Chemotherapy

A Prospective Multi-center Phase II Study: Assessment of the Safety and Abscopal Effects of SBRT Combination With rhGM-CSF and Thymosin Alpha 1 for Stage IV NSCLC Patients Who Failed in Second-line Chemotherapy

The purpose of this study is to determine whether stereotactic body radiotherapy (SBRT) combined with recombined human granulocyte-macrophage colony stimulating factor(rhGM-CSF) and Thymosin Alpha 1 is safe, effective in the treatment of stage IV NSCLC patients who failed in second-line chemotherapy.

Metastasis lesion of stage IV NSCLC will be treated with a SBRT of 50Gy/4-10F from day 1 to day 14 in one cycle. Subcutaneous injection of human recombined granulocyte-macrophage colony stimulating factor (125ug/m² per day) will be executed from day 1 to day 14 in this cycle. Another metastasis lesion will be treated likewise concurrently with rhGM-CSF in a consecutive cycle.Thymosin Alpha 1(1.6mg Biw) will be Subcutaneous injection from the fist week to the 12th weeks, Efficacy evaluation, especially abscopal effect evaluation, will be conducted at the end of therapy and every month after that. Adverse events will be recorded according to NCI-CTC version 4.03.

Inclusion Criteria:Inclusion Criteria:

1. Histologically proven non-small-cell lung cancer.

2. Stage IV according to UICC stage system(version 7,2009).

3. Progression after standard second-line chemotherapy.

4. At least Three evaluable lesions among which at least two must be suitable for SBRT.

5. ECOG performance status 0-2.

6. Expected lifespan ≥3 months.

7. Stable lab values:

   Hematological: Absolute neutrophil count (ANC) ≥1.5×109/L, Platelets ≥100×109/L, Hemoglobin ≥9 g/dL Renal: Creatinine OR Measured or calculated creatinine clearance (CrCl) (glomerular filtration rate [GFR] can also be used in place of creatinine or CrCl) ≤1.5× the upper limit of normal (ULN) OR ≥60 mL/min for patient with creatinine levels >1.5× institutional ULN Hepatic: Total bilirubin ≤1.5×ULN OR Direct bilirubin ≤ULN for patients with total bilirubin levels >1.5×ULN, Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN OR ≤5×ULN for patients with liver metastases ,globulin≥20 g/L, albumin≥30 g/L.

8. Female subjects must have a negative urine or serum pregnancy test within 72 hours prior to taking study drug if of childbearing potential.

9. Able to understand and give written informed consent and comply with study procedures.

Exclusion Criteria:

1. Any unstable systemic disease, including active infection, uncontrolled high blood pressure, unstable angina, newly observed angina pectoris within the past 3 months, congestive heart failure (New York heart association (NYHA) class II or higher), myocardial infarction onset six months before included into the group, and severe arrhythmia, liver, kidney, or metabolic disease in need of drug therapy, Including diabetes.
2. Any clinical evidence suggests moderately severe chronic obstructive pulmonary disease (COPD) - [With COPD history or related risk factors, FEV1 / FVC < 70%, FEV1 < 80% estimated value, with or without chronic cough, sputum, dyspnea symptoms), active interstitial lung disease - ILD (FEV1 / FVC < 70%, FEV1 < 80% estimated value, carbon monoxide diffusion capacity in lung - DLCO < 40%, and high resolution CT (HRCT) confirmed as the diffuse pulmonary interstitial lesions] and other active pulmonary disease.
3. Previously diagnosed with autoimmune diseases, including but not limited to systemic lupus erythematous, rheumatoid arthritis, systemic vasculitis, scleroderma, dermatomyositis, autoimmune hemolytic anemia and autoimmune liver disease, autoimmune thyroiditis.
4. Human immunodeficiency virus (HIV) infection.
5. Women in pregnancy or lactation .
6. Medicine abusers(including alcohol, drugs or other addictive drugs abusers).
7. Patients with mental illness, considered as "can't fully understand the issues of this research".
8. Cancer history within 5 years apart from NSCLC before enrollment.
9. Histologically confirmed small cell carcinoma or other non NSCLC compositions in the cancer tissue.
10. Cancer treatment within 4 weeks, including but not limited to palliative surgery ,radiotherapy, chemotherapy and target therapy.
11. Tumor related immunotherapy within 1 year, including but not limited to immune cell therapy, tumor vaccine therapy, immune check-point monoclonal antibody related treatment, and cytokines treatment except for GM-CSF.
12. Allergy of rhGM-CSF/Tα1 and its accessories.
13. Contraindications to GM-CSF/Tα1 treatment.
14. Patients with unilateral lung.