Trial Design - Patients with stage IV non-small cell lung cancer are randomized to nivolumab/ipilimumab plus either sequential or concurrent stereotactic body radiotherapy (SBRT). - The primary endpoint is the phase I safety endpoint of SBRT dose for each body site. - The same starting SBRT dose levels are used in each arm. If two or more patients experience a dose-limiting toxicity (DLT) at the starting dose level, then the reduced dose level will be used (Section 7.1-Page 72). - DLT is defined as any grade ≥3 toxicity possibly, likely, or definitely related to SBRT plus nivolumab/ipilimumab (the combination and not the individual components). - Irradiated metastases will be grouped into one of five locations, which have different SBRT doses, and the DLTs will be attributed to the relevant organ system. - The starting and decreased SBRT dose levels are found in Table 2 (Page 20). - SBRT will be delivered in 3-5 fractions over the course of 1-1.5 weeks. - Patients in the sequential arm will begin immunotherapy between 1-7 days after completion of SBRT - Given the accrual data for IRB15-1130, the investigators anticipate that approximately 1/3 of patients will contribute metastasis to 2 locations. Since there are 2 arms, and 5 metastasis locations with 6 patients per location for the starting dose level, this translates to 40 patients for the starting dose level, and another 40 patients should each of the 5 locations require de-escalation to the lower dose level. - Secondary endpoints include comparisons of efficacy and toxicity between the arms, as well as interrogation of changes in the immune microenvironment induced by the two approaches.
Name: Nivolumab
Name: Ipilimumab
Name: Stereotactic body radiation therapy
Description: To determine the recommended SBRT dose to various metastatic locations in patients with stage IV NSCLC when delivered prior to or concurrently with nivolumab and ipilimumab.
Measure: Number of serious adverse events Time: Up to 4 yearsDescription: To estimate and compare rates of ≥ grade 3-4 adverse events, by organ system, by CTCAEv4.0 that occur within 3 months from the start of SBRT when given prior to or concurrently with nivolumab/ipilimumab.
Measure: Number of adverse events of grade 3-4 or higher Time: Up to 4 yearsDescription: To estimate and compare the rates of long-term adverse events (after 3 months) from the end of SBRT when given prior to or concurrently with nivolumab/ ipilimumab.
Measure: Rate of long term adverse events Time: Up to 4 yearsDescription: Summarize and compare the response rate to determine the progression-free survival at 6 months with SBRT given either prior to or concurrently with nivolumab/ipilimumab.
Measure: Rate of response Time: From the start of treatment until the date of first documented progression or date of death from any cause, whichever comes first, up to 100 monthsDescription: To determine and compare the control of lesion(s) (SBRT treated and non-treated) when given either prior to or concurrently with nivolumab/ipilimumab.
Measure: Rate of lesion control Time: Up to 4 yearsDescription: To evaluate and compare changes in the tumor microenvironment induced by radiation when given prior to or concurrently with nivolumab/ipilimumab.
Measure: Rate of change in tumor microenvironment Time: Up to 4 yearsDescription: To evaluate whether response to therapy correlates with PD-L1 expression levels among patients treated with nivolumab/ipilimumab either concurrently or sequential to SBRT.
Measure: Rate of PD-L1 expression levels response Time: Up to 4 yearsDescription: To explore whole PBMC by measuring peripheral blood cell T cell subset IFNγ ELISPOT levels throughout the study course and correlate with response to treatment.
Measure: Measure of peripheral blood cell T cell levels Time: From the start of treatment, not to exceed 4 yearsDescription: To explore peripheral blood T cell receptor deep sequencing quantification of T cell receptor (TCR) repertoire changes throughout the study course and how TCR repertoire may correlate with progression free survival and/or overall survival.
Measure: Quantification of T cell receptor Time: From the start of treatment until the date of first documented progression or date of death from any cause, whichever comes first, up to 100 monthsAllocation: Randomized
Parallel Assignment
There is one SNP
- 12. Patients whose tumors known to harbor an exon 19 deletion or exon 21 L858R EGFR mutation must have progressed on or had intolerance to an EGFR TKI. --- L858R ---