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.

Study Overview

• Status: Completed
• Conditions: Stage IV NSCLC
• Intervention / Treatment: Drug: Sintilimab; Radiation: stereotactic body radiation therapy; Radiation: Low Dose Radiotherapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • West China Hospital, Sichuan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Sintilimab Combined with SBRT and LDRT; Part A-Dose escalation cohort. DOSE LEVEL: Stereotactic body radiation therapy (SBRT) dose at 30 Gy/3f + Low Dose Radiotherapy (LDRT) dose from 2 Gy to 10Gy + anti-PD-1 inhibitor 200mg. Part-B - Expansion cohort. SBRT dose at 30 Gy/3f + LDRT + anti-PD-1 inhibitor 200mg, LDRT dose at MTD determined in Part A .

Drug: Sintilimab; Patients will receive treatment with Sintilimab 200mg every 3 weeks for a maximum of 24 months.; Other Names: IBI308; Radiation: stereotactic body radiation therapy; Radiation treatment utilized in this trial consists of SBRT with a standard doses to 30 Gy/3f; Other Names: SBRT; Radiation: Low Dose Radiotherapy; LDRT at dose escalation levels: 2 Gy/1f, 4 Gy/2f, 10 Gy/5f with conventional external beam radiation.; Other Names: LDRT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of participants with Adverse Events and/or Dose Limiting Toxicities as a Measurement of Safety and tolerability of Sintilimab in Combination With SBRT and LDRT	From the day the patient signs ICF until 30 days after last dose of sintilimab or 90 days after radiation, whichever occurs later

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Investigator assessed ORR using RECIST v1.1 including the all tumor, the tumor undergoing LDRT and the tumor which do not receive radiotherapy.	up to 24 months after the enrollment
Overall Survival (OS)	OS is defined as the difference (in months) between the date of study enrollment to the date death due to any cause	up to 24 months after the enrollment
Progression Free Survival (PFS)	Investigator assessed PFS according to RECIST v1.1. Progression free survival is defined as time of enrollment to first evidence of progressive disease.	up to 24 months after the enrollment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory Outcome Measure1	Circulating tumor DNA (ctDNA)	baseline, after radiation, and every 2 cycles of sintilimab, up to 24 months until end of study
Exploratory Outcome Measure2	circulating tumor cell (CTC)	baseline, after radiation, and every 2 cycles of sintilimab, up to 24 months until end of study
Exploratory Outcome Measure3	T Cell Receptor (TCR) Repertoire Diversity	baseline, after radiation, and every 2 cycles of sintilimab, up to 24 months until end of study

Collaborators and Investigators

• Sponsor: Sichuan University
• Collaborators: Innovent Biologics (Suzhou) Co. Ltd.

Publications and helpful links

General Publications

• Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015 Apr 3;348(6230):56-61. doi: 10.1126/science.aaa8172.
• Demaria S, Coleman CN, Formenti SC. Radiotherapy: Changing the Game in Immunotherapy. Trends Cancer. 2016 Jun;2(6):286-294. doi: 10.1016/j.trecan.2016.05.002.
• Kaur P, Asea A. Radiation-induced effects and the immune system in cancer. Front Oncol. 2012 Dec 17;2:191. doi: 10.3389/fonc.2012.00191. eCollection 2012.
• Bernstein MB, Krishnan S, Hodge JW, Chang JY. Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach? Nat Rev Clin Oncol. 2016 Aug;13(8):516-24. doi: 10.1038/nrclinonc.2016.30. Epub 2016 Mar 8.
• Park SS, Dong H, Liu X, Harrington SM, Krco CJ, Grams MP, Mansfield AS, Furutani KM, Olivier KR, Kwon ED. PD-1 Restrains Radiotherapy-Induced Abscopal Effect. Cancer Immunol Res. 2015 Jun;3(6):610-9. doi: 10.1158/2326-6066.CIR-14-0138. Epub 2015 Feb 19.
• Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, Mu Z, Rasalan T, Adamow M, Ritter E, Sedrak C, Jungbluth AA, Chua R, Yang AS, Roman RA, Rosner S, Benson B, Allison JP, Lesokhin AM, Gnjatic S, Wolchok JD. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012 Mar 8;366(10):925-31. doi: 10.1056/NEJMoa1112824.
• Du J, Su S, Li H, Shao J, Meng F, Yang M, Qian H, Zou Z, Qian X, Liu B. Low dose irradiation increases adoptive cytotoxic T lymphocyte migration in gastric cancer. Exp Ther Med. 2017 Dec;14(6):5711-5716. doi: 10.3892/etm.2017.5305. Epub 2017 Oct 13.
• Brooks ED, Chang JY. Time to abandon single-site irradiation for inducing abscopal effects. Nat Rev Clin Oncol. 2019 Feb;16(2):123-135. doi: 10.1038/s41571-018-0119-7.

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2019
• Primary Completion (Actual): January 31, 2022
• Study Completion (Actual): July 8, 2022

Study Registration Dates

• First Submitted: January 18, 2019
• First Submitted That Met QC Criteria: January 19, 2019
• First Posted (Actual): January 23, 2019

Study Record Updates

• Last Update Posted (Actual): July 13, 2022
• Last Update Submitted That Met QC Criteria: July 8, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Immunotherapy;SBRT; PD-L1 positive; LDRT
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: IHC-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No