Safety and Tolerability Evaluation of Sintilimab in Combination With Radiation in Stage IV NSCLC Patients

Multi-center Phase I Study of Sintilimab in Combination With Radiotherapy in Treatment Naive PD-L1 Positive Stage IV Non-small Cell Lung Cancer (NSCLC)

This pilot phase I trial aims to investigate the safety and tolerability of anti-programmed cell death-1 (PD-1) monoclonal antibody Sintilimab (also called IBI308) in combination with concurrent stereotactic body radiation therapy (SBRT) and low dose radiotherapy (LDRT) in treating patients with stage IV non-small cell lung cancer (NSCLC).

At least 29 participants will be enrolled in this study. All will take part at West China Hospital, Sichuan University.

This exploratory phase I study will be conducted in two steps:

Step A: A low dose radiotherapy (LDRT) dose escalation, 6 patients per cohort (a total of 18 patients) will be enrolled to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended dose for expansion (RDE) for lung LDRT.

Step B: A lung LDRT dose expansion

All eligible patients will receive lung SBRT dosed at 30 Gy in 3 fractions, in combination with LDRT at different dose levels (decried as below) starting from the 2nd day of SBRT, followed by sintilimab monotherapy starting within 7 days after radiation completed. Sintilimab will be given at 200mg every 3 weeks until disease progression, unacceptable toxicities, the patient withdraws informed consent, or sintilimab reaches a maximum of up to 24 months.

Patients in the dose escalation will receive lung LDRT at 3 cohorts with increasing dose levels: 2 Gy in 1 fraction in dose level 1, 4 Gy in 2 fractions in dose level 2, 10Gy in 5 fractions in dose level 3.

A cohort of 17 patients will receive lung LDRT at the RDE determined during the dose escalation phase in combination with SBRT and Sintilimab to obtain additional safety and response data.

Inclusion Criteria:

1. Patients with histologically or cytologically confirmed stage IV NSCLC.
2. Enough tumor tissue samples.
3. No previous radiation, chemotherapy, immunotherapy. Patients who have received neoadjuvant or adjuvant chemotherapy 12 months before enrollment is permitted.
4. At least three measurable disease according to RECIST 1.1 that meet SBRT and LDRT radiation requirement as protocol defined
5. PD-L1 expression positive (TPS >1%)
6. Be ≥18 years of age on day of signing informed consent and ≤75 years old.
7. ECOG 0-1.
8. Patients must have normal organ and marrow function as defined below: Total bilirubin </= 1.5 mg/dL. Aminotransferase (AST) Serum Glutamic Oxaloacetic Transaminase (SGOT)/ Alanine Aminotransferase (ALT) Serum Glutamic-Pyruvic Transaminase (SGPT) <2.5 X institutional upper limit of normal (patients with liver involvement will be allowed </= 5.0 X institutional upper normal limit) *WBC >/= 3500/uL, ANC >/= 1500/uL *Platelets >/= 90K *Hemoglobin >/= 9g/dL *Creatinine </= 1.5 x ULN.
9. Be willing and able to provide written informed consent/assent for the trial.
10. Patients should be able to tolerate a course of radiotherapy as assessed by the investigator.
11. No contradiction to radiation per radio-oncologists' judgments
12. Life expectancy of > 6 months.

Exclusion Criteria:

1. EGFR/ALK/ROS-1 mutation or mutation status unknown.
2. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
3. Subjects with coronary bypass operation.
4. Subjects with insufficient heart function, liver function and kidney function.
5. Subjects with severe uncontrollable psychotic symptoms.
6. Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, anti-tumor necrosis factor agents) within 4 weeks prior to enrollment or anticipated requirement for systemic immunosuppressive medications during the trial.
7. Subjects with active, known or suspected autoimmune disease such as interstitial pneumonia, uveitis, Crohn's disease, autoimmune thyroiditis. Subjects with cured childhood asthma, type I diabetes mellitus only requiring hormone replacement.
8. Known history of allogeneic organ or allogeneic hemopoietic stem cell transplantation.
9. Known hypersensitivity or allergy to monoclonal antibody.
10. Subjects with a history of interstitial lung disease.
11. Uncontrolled concomitant disease, including but not limited to :

1)Active or poorly controlled severe infection 2)Human Immunodeficiency Virus (HIV) infection (HIV antibody positive) 3)Known acute or chronic active hepatitis B (HBV DNA positive) infection or acute or chronic active hepatitis C (HCV antibody positive and HCV RNA positive) infection 4)Active tuberculosis 5)Symptomatic congestive heart failure (New York Heart Association grade III-IV) or symptomatic, poorly controlled arrhythmia 6)Uncontrolled hypertension (SBP ≥ 160mmHg or DBP ≥ 100mmHg) 7)Prior arterial thromboembolism event, including myocardial infarction, unstable angina, stroke and transient ischemic attack, within 6 months of enrollment 8)Concomitant disease needs anticoagulant therapy 9)Uncontrolled hypercalcemia（Ca2+>1.5mmol/L or Ca >12mg/dl or corrected Serum Calcium >ULN），or Symptomatic hypercalcemia during diphosphonate therapy

12. Other primary malignancy, with the exception of: (radical Non-melanoma skin cancer or cured cervical in-situ carcinoma;).

13. Subjects with other diseases or abnormal Lab test results which might increase the risk of enrollment and treatment or Interfere with the interpretation of study results could be excluded according to the judgments of investigator.

14. Pregnant or lactating women.