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Dose-Finding of Propranolol in combination with metronomic fixed oral cyclophosphamide based on Bivariate efficacy-tolerability outcome in patients with locally advanced or metastatic angiosarcoma : A collaborative and innovative phase I-II sequential trial

The Pr Sébastien Salas from the Adult Oncology Unit, CHU La Timone, AP-HM, Marseille, France has obtained funding for the PROPAN study (Dose-Finding of Propranolol in combination with metronomic fixed oral cyclophosphamide based on Bivariate efficacy-tolerability outcome in patients with locally advanced or metastatic angiosarcoma : A collaborative and innovative phase I-II sequential trial ).

Adrenergic processes stimulated by epinephrine and neorepinephrine drive the development of tumor growth and metastatis. Beta-adrenergic receptor (BAR) antagonists have shown efficacy against melanoma, breast cancer and prostate cancer. The non-specific BAR inhibitor propranolol has been utilized as the gold standard treatment in pediatric patients with benign infantile hemangioma which express high levels of beta adrenergic receptors potentially explaining their sensitively to propranolol. BAR have been shown to be expressed across a diverse panel of vascular tumors, with the highest expression in malignant vascular tumors including angiosarcomas. Several reports indicate positive results from beta-blockade in patients with moderately threatening vascular tumors. It remains to be determined if more malignant vascular tumor such as the angioasarcomas are susceptible to propranolol. Besides, due to the lack of adequate therapies for angiosarcomas (doxorubicin or paclitaxel and finally cyclophosphamide in third line) and to the poor prognosis of this rare and agressive tumor, there is a strong need for the development of treatments against this tumor type. Recently using a panel of angiosarcoma cell lines, Stiles et al. demonstrate that beta-adrenergic inhibition blocks cell proliferation and induces apoptosis in a dose dependent manner. Moreover, using in vivo tumor models they demonstrate that propranolol shows remarkable efficacy in reducing the growth of angiosarcoma tumors. Based on these proofs of mechanisms in vitro and in vivo and due to the well established safety propranolol in humans, we propose to determine among a wide range of propranolol dose (80 mg/d ; 120 mg/d and 160 mg/d) the optimal one based on bivariate efficacy-toxicity outcome in patients with angiosarcoma treated by cyclophosphamide. Because these these 2 agents have different pharmacological mechanisms, the aim is to determine the optimal dose of propranolol having the best systemic cardiovascular tolerability and the best potential antiangiogenic effect in addition with cyclophosphamide. Due to recent preclinical papers demonstrating the selective cytotoxicity and tumor suppressive ability of beta adrenergic inhibition on angiosarcoma in dose dependant manner, we propose here for the first time to assess the synergy of propranolol and fixed dose of oral cyclophosphamide among patients with advanced angiosarcoma, using an innovative design modeling both toxicity and efficacy outcomes (dose finding combined phase I-II sequential trial using a bivariate continual reassessment method). Because this tumor is very rare leading to a limited number of patients and because an efficient therapeutic is lacking, this design is particular of interest in order to determine more quickly the potential dose of propranolol to be tested in the pivotal phase III.

This trial will be a joint effort from the GSF/GETO, the SFCE and MGHI and will include adults and teenagers from French centers. In this dose-finding design up to 24 patients will be required to find the dose level satisfying the requirements in terms of toxicity and efficacy. The study shall be opened for recruitement by mid 2015.