Stage IV NSCLC
Conditions
Keywords
Immunotherapy;SBRT; PD-L1 positive; LDRT
Brief summary
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.
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.
Interventions
DRUGSintilimab
Patients will receive treatment with Sintilimab 200mg every 3 weeks for a maximum of 24 months.
RADIATIONstereotactic body radiation therapy
Radiation treatment utilized in this trial consists of SBRT with a standard doses to 30 Gy/3f
RADIATIONLow Dose Radiotherapy
LDRT at dose escalation levels: 2 Gy/1f, 4 Gy/2f, 10 Gy/5f with conventional external beam radiation.
Sponsors
Innovent Biologics (Suzhou) Co. Ltd.
Sichuan University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events and/or Dose Limiting Toxicities of Sintilimab in Combination With SBRT and LDRT | from randomization through 30 days after last dosing, up to 24 months | Adverse Events and/or Dose Limiting Toxicity graded per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | up to 24 months after the enrollment | Investigator assessed PFS according to RECIST v1.1. Progression free survival is defined as time of enrollment to first evidence of progressive disease. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Objective Response Rate (ORR) | up to 24 months after the enrollment | Investigator assessed ORR using RECIST v1.1 including the all tumor, the tumor undergoing LDRT and the tumor which do not receive radiotherapy. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR |
| Overall Survival (OS) | up to 24 months after the enrollment | OS is defined as the difference (in months) between the date of study enrollment to the date death due to any cause |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1: 2Gy in 1 Fraction DOSE LEVEL 1: Stereotactic body radiation therapy (SBRT) dose at 30 Gy/3f + Low Dose Radiotherapy (LDRT, 2Gy/1f) + anti-PD-1 inhibitor 200mg. | 6 |
| Dose Level 2: 4Gy in 2 Fractions DOSE LEVEL 2: Stereotactic body radiation therapy (SBRT) dose at 30 Gy/3f + Low Dose Radiotherapy (LDRT, 4Gy/2f) + anti-PD-1 inhibitor 200mg. | 17 |
| Dose Level 3: 10Gy in 5 Fractions DOSE LEVEL 3: Stereotactic body radiation therapy (SBRT) dose at 30 Gy/3f + Low Dose Radiotherapy (LDRT, 10Gy/5f) + anti-PD-1 inhibitor 200mg. | 6 |
| Total | 29 |
Baseline characteristics
| Characteristic | Dose Level 1: 2Gy in 1 Fraction | Total | Dose Level 3: 10Gy in 5 Fractions | Dose Level 2: 4Gy in 2 Fractions |
|---|---|---|---|---|
| Age, Continuous | 64.3 years | 65.0 years | 64.3 years | 68.2 years |
| PD-L1 expression ≥ 50% | 2 participants | 10 participants | 1 participants | 7 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 29 Participants | 6 Participants | 17 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 6 participants | 29 participants | 6 participants | 17 participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 26 Participants | 6 Participants | 15 Participants |
| smoking history | 5 participants | 24 participants | 4 participants | 15 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 17 | 0 / 6 |
| other Total, other adverse events | 6 / 6 | 12 / 17 | 6 / 6 |
| serious Total, serious adverse events | 0 / 6 | 5 / 17 | 1 / 6 |
Outcome results
Primary
Number of Participants With Adverse Events and/or Dose Limiting Toxicities of Sintilimab in Combination With SBRT and LDRT
Adverse Events and/or Dose Limiting Toxicity graded per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time frame: from randomization through 30 days after last dosing, up to 24 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1: 2Gy in 1 Fraction | Number of Participants With Adverse Events and/or Dose Limiting Toxicities of Sintilimab in Combination With SBRT and LDRT | Any TRAE Grade ≥ 3 | 0 Participants |
| Dose Level 1: 2Gy in 1 Fraction | Number of Participants With Adverse Events and/or Dose Limiting Toxicities of Sintilimab in Combination With SBRT and LDRT | Any TRAE Grade < 3 | 6 Participants |
| Dose Level 2: 4Gy in 2 Fractions | Number of Participants With Adverse Events and/or Dose Limiting Toxicities of Sintilimab in Combination With SBRT and LDRT | Any TRAE Grade ≥ 3 | 5 Participants |
| Dose Level 2: 4Gy in 2 Fractions | Number of Participants With Adverse Events and/or Dose Limiting Toxicities of Sintilimab in Combination With SBRT and LDRT | Any TRAE Grade < 3 | 12 Participants |
| Dose Level 3: 10Gy in 5 Fractions | Number of Participants With Adverse Events and/or Dose Limiting Toxicities of Sintilimab in Combination With SBRT and LDRT | Any TRAE Grade ≥ 3 | 1 Participants |
| Dose Level 3: 10Gy in 5 Fractions | Number of Participants With Adverse Events and/or Dose Limiting Toxicities of Sintilimab in Combination With SBRT and LDRT | Any TRAE Grade < 3 | 5 Participants |
Secondary
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. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time frame: up to 24 months after the enrollment
Population: objective response rate
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1: 2Gy in 1 Fraction | Objective Response Rate (ORR) | 4 Participants |
| Dose Level 2: 4Gy in 2 Fractions | Objective Response Rate (ORR) | 10 Participants |
| Dose Level 3: 10Gy in 5 Fractions | Objective Response Rate (ORR) | 3 Participants |
Secondary
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
Time frame: up to 24 months after the enrollment
Population: overall survival
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Level 1: 2Gy in 1 Fraction | Overall Survival (OS) | NA years |
| Dose Level 2: 4Gy in 2 Fractions | Overall Survival (OS) | NA years |
| Dose Level 3: 10Gy in 5 Fractions | Overall Survival (OS) | 15.639 years |
Secondary
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. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: up to 24 months after the enrollment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Level 1: 2Gy in 1 Fraction | Progression Free Survival (PFS) | 7.228 month |
| Dose Level 2: 4Gy in 2 Fractions | Progression Free Survival (PFS) | 9.035 month |
| Dose Level 3: 10Gy in 5 Fractions | Progression Free Survival (PFS) | 4.501 month |