Systemic immune checkpoint blockade and intraperitoneal chemo-immunotherapy in recurrent ovarian cancer: An interim analysis (317)

Objectives: Increasing levels of tumor-infiltrating lymphocytes (TIL) correlate with improved outcomes in ovarian cancer. Singleagent immune therapies have had limited clinical success due to the several immune suppressive mechanisms of the tumor microenvironment (TME). Consequently, the objective of this study was to use combination immunotherapy to overcome those immune suppressive mechanisms for improved tumor response. The primary clinical endpoint was the objective response at 13 weeks. The secondary endpoint was the increase in CD3+ and CD8+ TIL in tumor and/or intraperitoneal washes. Methods: This ongoing, investigator-initiated phase II, single-arm, trial (NCT03734692) combines intraperitoneal (IP) chemotherapy (cisplatin) with dual agent immunotherapy using IV pembrolizumab (anti-PDl) and IP rintatolimod (dsRNA acting as toll-like receptor 3 -TLR-3- agonist) in platinum-sensitive ovarian cancer patients. Patients received a total of six treatment cycles at 3-week intervals, with interval cytoreduction of residual tumor after four cycles, at the provider’s discretion. Each treatment cycle includes: day 1 IP cisplatin 50mg/m2 , day 2 IV pembrolizumab 200mg followed by IP rinta- tolimod 200mg. The objective response rate was measured by RECIST 1.1 criteria at 13 weeks (CT imaging performed at seven weeks and 13 weeks). Tumor tissue was collected at IP port placement and at the time of debulking surgery. IP washes were collected pretreatment (Day 1), before pembrolizumab, after pembrolizumab, and after rintatolimod (Day 2), and on Day 3. Blood samples were collected on each day of treatment. Correlative translational biospecimens analysis focuses on cytokine/chemokine measurements (via the Meso Scale Discovery- MSD - platform), multispectral imaging of immune infiltrates (using ChipCytometry), and immune gene expression changes (via NanoString). Results: To date, 17 patients have been enrolled in the trial (goal enrollment of 45 patients). Of the 17 patients enrolled, there were three screen failures. Thirteen patients are off the trial, and one patient is currently undergoing treatment. Six patients completed all six cycles (46.2%), one patient completed only three cycles (7.6%), and six patients completed four cycles (46.2%). Of those patients that are off the trial, there were two (15.4%) patients with complete responses (CR), three (23.1%) patients with partial responses (PR), three (23.1%) patients with stable disease (SD), and five (38.4%) patients with progressive disease (PD). This translates into a clinical benefit rate (CR+PR+SD) of 61.6%. The most common grade 1 and 2 toxicities were anemia, fatigue, nausea, hypertension, and decreased lymphocyte count. Two patients developed immune-mediated reactions (new-onset type I diabetes and Steven’s Johnson syndrome) and were taken off the trial. Both patients remain in remission (PFI 24 and 25 months). Two patients experienced grade 3 gastrointestinal obstructions (15.4%). One patient had a catheter-related infection (7.1%). Over 25 tumor samples, 205 blood samples, and 185 IP wash samples have been so far collected and cryopreserved. Interim results from MSD, chip cytometry, and NanoString profiling are currently pending. Conclusions: We present an interim analysis on phase II clinical trial NCT03734692. Overall, the treatment regimen has been well-tolerated, with mostly grade 1 and grade 2 toxicities. Treatment response shows several patients achieving remission with prolonged progression-free survival. Objectives: Increasing levels of tumor-infiltrating lymphocytes (TIL) correlate with improved outcomes in ovarian cancer. Singleagent immune therapies have had limited clinical success due to the several immune suppressive mechanisms of the tumor microenvironment (TME). Consequently, the objective of this study was to use combination immunotherapy to overcome those immune suppressive mechanisms for improved tumor response. The primary clinical endpoint was the objective response at 13 weeks. The secondary endpoint was the increase in CD3+ and CD8+ TIL in tumor and/or intraperitoneal washes. Methods: This ongoing, investigator-initiated phase II, single-arm, trial (NCT03734692) combines intraperitoneal (IP) chemotherapy (cisplatin) with dual agent immunotherapy using IV pembrolizumab (anti-PDl) and IP rintatolimod (dsRNA acting as toll-like receptor 3 -TLR-3- agonist) in platinum-sensitive ovarian cancer patients. Patients received a total of six treatment cycles at 3-week intervals, with interval cytoreduction of residual tumor after four cycles, at the provider’s discretion. Each treatment cycle includes: day 1 IP cisplatin 50mg/m2 , day 2 IV pembrolizumab 200mg followed by IP rinta- tolimod 200mg. The objective response rate was measured by RECIST 1.1 criteria at 13 weeks (CT imaging performed at seven weeks and 13 weeks). Tumor tissue was collected at IP port placement and at the time of debulking surgery. IP washes were collected pretreatment (Day 1), before pembrolizumab, after pembrolizumab, and after rintatolimod (Day 2), and on Day 3. Blood samples were collected on each day of treatment. Correlative translational biospecimens analysis focuses on cytokine/chemokine measurements (via the Meso Scale Discovery- MSD - platform), multispectral imaging of immune infiltrates (using ChipCytometry), and immune gene expression changes (via NanoString). Results: To date, 17 patients have been enrolled in the trial (goal enrollment of 45 patients). Of the 17 patients enrolled, there were three screen failures. Thirteen patients are off the trial, and one patient is currently undergoing treatment. Six patients completed all six cycles (46.2%), one patient completed only three cycles (7.6%), and six patients completed four cycles (46.2%). Of those patients that are off the trial, there were two (15.4%) patients with complete responses (CR), three (23.1%) patients with partial responses (PR), three (23.1%) patients with stable disease (SD), and five (38.4%) patients with progressive disease (PD). This translates into a clinical benefit rate (CR+PR+SD) of 61.6%. The most common grade 1 and 2 toxicities were anemia, fatigue, nausea, hypertension, and decreased lymphocyte count. Two patients developed immune-mediated reactions (new-onset type I diabetes and Steven’s Johnson syndrome) and were taken off the trial. Both patients remain in remission (PFI 24 and 25 months). Two patients experienced grade 3 gastrointestinal obstructions (15.4%). One patient had a catheter-related infection (7.1%). Over 25 tumor samples, 205 blood samples, and 185 IP wash samples have been so far collected and cryopreserved. Interim results from MSD, chip cytometry, and NanoString profiling are currently pending. Conclusions: We present an interim analysis on phase II clinical trial NCT03734692. Overall, the treatment regimen has been well-tolerated, with mostly grade 1 and grade 2 toxicities. Treatment response shows several patients achieving remission with prolonged progression-free survival.