(P 197) PROPRANOLOL MONOTHERAPY IN ANGIOSARCOMA - A WINDOW-OF-OPPORTUNITY STUDY (PROPANGIO)

Objective: Angiosarcoma is a rare and aggressive cancer of the endothelial cells. It has been shown that β-adrenergic signaling through the β-adrenoceptors (ADRB) 1 and 2, that are overexpressed in angiosarcoma, promotes tumor growth. Propranolol, a non-selective β-blocker, was able to initiate apoptosis in angiosarcoma cell lines and its anti-tumor activity has been demonstrated in several case reports. The aim of this window-of opportunity trial was to prospectively evaluate the anti-tumor activity of propranolol in patients with angiosarcoma.

Methods: Patients with angiosarcoma with a waiting time of 3 to 6 weeks until start of standard treatment were eligible. Propranolol was dosed 80 mg to 240 mg/day according to a dose titration schedule. The primary endpoint was clinical response rate. Clinical response was defined as either complete response (CR), partial response (PR) (according to RECIST 1.1) or stable disease (SD) with improvement of erythema, edema and thickness. Exploratory objectives included histologic response, PET response and assessment of potential biomarkers for response in tumor tissue by IHC (e.g. ADBR 1/2, immune system-based biomarkers).

Results: To date, 13 patients with a median age of 67 years (range 52-86) are enrolled and have initiated treatment. The median duration of treatment was 28 days (range 21-42 days). The median dose was 160 mg/day. Three patients showed exceptional good tolerance (blood pressure/heart rate) and could be escalated to the highest dose (240 mg/day). Two patients showed clinical response. The most common adverse event was grade 1/2 bradycardia (85%). There were no grade ≥3 adverse events. Preliminary IHC results showed ADBR2 overexpression in the majority of the tumors (12 out of 17 tumor samples, both in responders and non-responders). None of the tumors showed ADBR1 overexpression.

Conclusion: This window-of-opportunity trial did not demonstrate clinical efficacy of propranolol monotherapy in patients with angiosarcoma. Two out of 13 patients did however show clinical benefit. ADBR1 or 2 expression did not correlate with response. Translational research to better comprehend the anti-tumor activity of propranolol for adequate selection of patients in future studies is ongoing.