PropAngio study protocol: a neoadjuvant trial on the efficacy of propranolol monotherapy in cutaneous angiosarcoma—a proof of principle study

Abstract

IntroductionAngiosarcoma is a rare and aggressive malignancy with a high metastatic potential and recurrence rate. Despite optimal treatment with surgery, with or without radiation, the prognosis remains poor and, therefore, new treatment strategies are warranted. Recently, propranolol has effectively been repurposed for the treatment of infantile haemangioma. Propranolol is a β3-sparing antagonist of the β-adrenergic receptor. In infantile haemangioma, the β1, β2 and β3 receptors are highly expressed. Angiosarcoma has several similarities with haemangioma, including its high β-adrenergic receptor expression and the supposedly important role of vascular endothelial growth factor in malignant growth. As a result, propranolol has been administered small scale in individual angiosarcoma cases with promising results. The precise effect of propranolol, however, is not yet established.Methods and analysisThe goal of this neoadjuvant window of opportunity study is to prospectively evaluate the activity of propranolol monotherapy in patients with cutaneous angiosarcoma. The neoadjuvant setting provides a good opportunity to rapidly evaluate both the clinical response and histological response, without a significant delay in standard anticancer treatment. Fourteen patients with primary, recurrent or metastatic cutaneous angiosarcoma will be included. Propranolol will be administered orally in an escalating dose during 3–6 weeks, before the initiation of standard treatment. The primary endpoint is clinical response according to Response Evaluation Criteria in Solid Tumours, as measured on consecutive coloured photographs or CT/MRI. The histological response will be determined as secondary endpoint, comparing the difference in proliferation index before and after propranolol by measuring the change in immunohistochemistry staining of Ki-67. The study will be considered positive when at least three patients have a response to propranolol.Ethics and disseminationEthical approval was obtained from the Medical Ethical Committee of the Netherlands Cancer Institute. Independent of the outcome, results of this study will be shared and submitted for publication in an international peer-reviewed journal.Trial registration numberNL8118; registry through the Netherlands Trial Register.

New molecular targets in canine hemangiosarcoma—Comparative review and future of the precision medicine

“…257 In fact, a current huge PropAngio clinical trial is recruiting participants with cAS to estimate effectiveness of propranolol as a neoadjuvant monotherapy. 258 The newest study showed that HSAs overexpress three β-AR subtypes: ADRB1, ADRB2 and ADRB3, 259 thus, β-AR antagonists could be used as adjunct drugs to current therapeutic strategies, especially to overcome DOX-resistance. 252 Repurposing of propranolol with weak base chemotherapeutics, such as DOX, in a canine cohort is supported by studies conducted by Saha et al 252 in which increased cytotoxicity and reduction of the drug resistance has been achieved without significant AEs.…”

The Role of Propranolol as a Repurposed Drug in Rare Vascular Diseases

“…Two very similar phase 2 clinical trials, in the EU (EudraCT: 2019-002947-41) and in the USA (NCT04518124), developed by the Netherlands Cancer Institute, are active and ongoing during the writing of this review [68]. The clinical response to oral propranolol as monotherapy in patients with angiosarcoma will be evaluated as primary endpoint and histological response as secondary endpoint (Ki-67 as biomarker).…”

Beta-adrenergic receptor blockade in angiosarcoma: Which beta-blocker to choose?

“…Hence, propranolol obtained the orphan designation by the European Commission for the treatment of soft tissue sarcomas ( 6 , 7 ). Furthermore, the effect of β-receptor blockade with propranolol on angiosarcoma is currently being studied in two clinical trials: The PropAngio trial (NCT04518124, study start date December 2019, status ongoing) and the PROPAN trial (NCT02732678, study start date May 2016, status unknown) ( 8 – 10 ). The aim of the PropAngio trial is to prospectively assess the anti-proliferative effect of neoadjuvant propranolol as monotherapy in primary, recurrent and metastatic angiosarcoma.…”