Clinical trial NCT03812549
Conditions: Stage IV NSCLC
Keywords: Immunotherapy;SBRT; PD-L1 positive; LDRT
Sponsor: Sichuan University
Start date: 2019-01-18; Completion date: 2022-07-08
Enrollment: 29 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: Period 1-Dose escalation cohort. Dose Level 1: Stereotactic body radiation therapy (SBRT) dose at 30 Gy/3f + Low Dose Radiotherapy (LDRT, 2 Gy in 1 fraction) + anti-PD-1 inhibitor 200mg.

Dose Level 2: Stereotactic body radiation therapy (SBRT) dose at 30 Gy/3f + Low Dose Radiotherapy (LDRT, 4 Gy in 2 fractions) + anti-PD-1 inhibitor 200mg.

Dose Level 3: Stereotactic body radiation therapy (SBRT) dose at 30 Gy/3f + Low Dose Radiotherapy (LDRT, 10 Gy in 5 fractions) + anti-PD-1 inhibitor 200mg.

Period 2 - Expansion cohort. SBRT dose at 30 Gy/3f + LDRT + anti-PD-1 inhibitor 200mg, LDRT dose at RDE determined in Period 1.
Interventions: intervention 1: Sintilimab intervention 2: stereotactic body radiation therapy intervention 3: Low Dose Radiotherapy
Intervention descriptions: intervention 1: Patients will receive treatment with Sintilimab 200mg every 3 weeks for a maximum of 24 months. intervention 2: Radiation treatment utilized in this trial consists of SBRT with a standard doses to 30 Gy/3f intervention 3: LDRT at dose escalation levels: 2 Gy/1f, 4 Gy/2f, 10 Gy/5f with conventional external beam radiation.

Protocol documents:
Prot_SAP_000.pdf: 
IHC-001: Safety and Tolerability Evaluation of Sintilimab in Combination With
Radiation in Stage IV NSCLC Patients
NCT number: NCT03812549
Date: 2018.08.19
Version:1.0
Study population
Eligible patients had histologically or cytologically confirmed stage IV NSCLC; were
negative for mutations of EGFR\ALK\ROS1; were aged 18 to 75; never received any
systematic treatment (including immunotherapy, chemotherapy and targeted therapy);
had an Eastern Cooperative Oncology Group (ECOG) performance status 0–1; PD-L1
positive (TPS ≥1%); had an expected survival time ≥3 months; and presented no
major organ dysfunction Patients were excluded if they had active brain metastases,
uncontrolled
hypertension,
severe
cardiovascular
diseases,
or
coagulation
abnormalities. This study was reviewed and approved by the Institutional Review
Board of West China Hospital, Sichuan University. Written informed consent was
obtained from all participants.
This study is registered with ClinicalTrials.gov, number NCT03812549
Study design
This study is a dose-finding, phase I trial of IBI308 in combination with radiotherapy,
including dose-escalation and dose-expansion parts. Patients with untreated advanced
NSCLC will receive SBRT for small lesions, LDRT for large lesions, and IBI308
treatment every three weeks. Tumors of enrolled patients must be PD-L1 positive.
The dose-escalation part during the dose-escalation phase trial includes the
determination of DLT, MTD, and RDE for LDRT, and preliminary assessment of
safety and tolerability. The dose-expansion part of dose-expansion phase includes
continuing to expand to 17 patients based on MTD/RDE, and further observing the
safety and efficacy of this dose.
Assessments
Primary objectives:
To evaluate the safety and preliminary efficacy of IBI308 combined with radiotherapy
in the treatment of patients with stage IV PD-L1 positive NSCLC.
1.As the dose-escalation stage, dose-escalation phase mainly serves to evaluate the
safety of IBI308 combined with radiotherapy and to determine the LDRT dose.
2.Dose-expansion phase further evaluates the safety and objective response rate (ORR)
of IBI308 combined with radiotherapy.
To evaluate the safety of IBI308 combined with radiotherapy for first-line treatment
of PD-L1-positive stage IV NSCLC, including incidences of all adverse events (AEs)
and serious adverse events (SAEs), treatment-related adverse events (TRAEs), and
their severity.
Secondary objectives:


To evaluate the efficacy of IBI308 combined with radiotherapy for first-line treatment
of PD-L1-positive stage IV NSCLC, including median ORR, progression-free
survival (PFS), overall survival (OS).
Statistical analysis
All analyses were performed using R software33 (version 4.02) or Prism (version 9.0;
GraphPad Software, San Diego, CA, USA). Unless otherwise noted, two-sided 95%
confidence intervals will be adopted. Continuous variables will be summarized using
descriptive statistics including number of cases, mean, median, standard deviation,
and maximum and minimum. The numbers and percentages of cases will be described
by categories. Statistical analyses will be further explained in the statistical analysis
plan (SAP). SAP will be finalized before database lock.