Background <p>Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a novel, minimally invasive method of delivering intraperitoneal chemotherapy with promising peritoneal disease control in ovarian cancer.</p> Methods <p>This US multicenter prospective phase I trial (NCT04329494) evaluated the safety and efficacy of PIPAC cisplatin 10.5 mg/m² and doxorubicin 2.1 mg/m² (PIPAC-CD) every 6 weeks in ovarian cancer at three US centers. Primary endpoints were dose-limiting toxicities and adverse events. Secondary endpoints included response according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria, laparoscopic peritoneal carcinomatosis index, histologic peritoneal regression grading score, progression-free survival (PFS), and overall survival (OS).</p> Results <p>In total, 15 patients were enrolled. The median prior lines of therapy was 3 (range 1–10). The PIPAC completion rate (≥2 PIPACs) was 86.7%. A total of 76.9% of patients had extraperitoneal disease at baseline. One patient discontinued treatment for toxicity because of deterioration of her baseline Eastern Cooperative Oncology Group 2 performance status. There was one grade 3 abdominal pain, one grade 3 anorexia, and no grade 4 or 5 adverse events. Laparoscopic best response (peritoneal carcinomatosis index) and histologic response (peritoneal regression grading score) occurred in 30.8% and 46.2%, respectively. Radiologic best response (RECIST) was 6.7%, with one partial response and a stable disease rate of 26.7%. Median PFS and OS were 2.3 months (95% confidence interval 1.7–3.2) and 17.1 months (95% confidence interval 5.6–not reached), respectively (n=15).</p> Conclusions <p>PIPAC-CD is feasible, safe, and well tolerated at academic US centers. OS and PFS were limited in patients with heavily pretreated ovarian carcinoma who underwent PIPAC-CD. Future trials should focus on optimizing PIPAC drug combinations and determining optimal patient selection criteria for ovarian cancer.</p>