254TiP A phase I clinical trial testing the dose escalation and expansion of pressurized intrathoracic hyperthermic aerosol cisplatin administration (PITHAC) for the management of pleural carcinosis

Pleural carcinosis originates from various cancers. Its management consists in systemic palliative therapies combined to dyspnea relief procedures. Prior studies have shown limited activity of normo/hypethermic intrathoracic chemotherapy to treat pleural carcinosis. These approaches could not be generalized because of restricted cytostatic penetration in tumors and local toxicity. Preclinical data demonstrate that hyperthermia combined to local pleural chemotherapy induces an immunogenic response directed against cancer that could be further enhanced by immunotherapy. Recently, pressurized intraperitoneal aerosol chemotherapies (PIPAC) have shown high cytostatic penetration in abdominal carcinosis with low drug concentration requirements and a good safety profile. This approach was tested in small number of patients with pleural carcinosis but never combined with hyperthermia. Pressurized IntraThoracic Hyperthermic Aerosol Cisplatin (PITHAC) is an open-label phase I trial. Patients with proven pleural carcinosis sensitive to cisplatin, a good performance status (ECOG 0-2) and a planned surgical management of their pleural effusion (chemical pleurodesis or indwelling catheter placement by video assisted thoracoscopy) are eligible. Chemotherapy (Cisplatin Teva®) heated at 39 ± 1°C is delivered in the thoracic cavity at a pressure of 8 mmHg for 30 minutes before the surgical effusion management. The first part consists in a dose escalation study (3+3 design) of four cisplatin doses (7.5 – 12.5 – 35 and 70 mg/m2 of body surface). The primary endpoint is the maximum tolerated dose of cisplatin administered by PITHAC. The secondary endpoints are safety as well as, dyspnea and pleural effusion index evaluation after PITHAC. The translational endpoints consist in the blood pharmacokinetics and tumor distribution of cisplatin as well as the immune response landscape (effector T cells directed against tumor neoantigens) after PITHAC. The second part is an expansion phase at the RP2D cisplatin dose on an additional 15 patients. Phase I clinical trial testing the dose escalation and expansion of Pressurized IntraThoracic Hyperthermic Aerosol Cisplatin administration (PITHAC) for the management of pleural carcinosis (BASEC number 2023-00099). Centre Hospitalier Universitaire Vaudois. Fondation chercher trouver.