With 2 grants obtained from the PHRC-K national grants and "l’Etoile de Martin" and drugs provided by Pierre Fabre Oncology we are ready to start our latest pediatric metronomics trial that will combine oral propranolol and oral metronomic navelbine in children with refractory/relapsing solid tumours. The trial is called PROVIN and should start recruiting patients Q2 2016. Pierre Fabre has agreed to provide drugs for the trial. The trial will be opened in 10 pediatric oncology centres in France.

PROVIN : Phase I study of a propranolol (Hemangiol®) and oral metronomic vinorelbine (Navelbine®) combination for children and teenagers with refractory/relapsing solid tumors

BACKGROUND: Cancer remains the first cause of death due to disease in children and adolescents despite important progress and 70% of the survivors present one or more chronic health conditions as a result of treatment. It is therefore mandatory to generate new and preferably less toxic treatment strategies relying on new anticancer agents, and/or new combinations or new schedules of administered compounds.

Metronomic chemotherapy (MC) consists in giving low doses of anticancer agents on a daily/weekly basis. Low doses of chemotherapeutic drugs are therefore continuously administered to cancer patients. MC has been showed to be a safe and effective way to administer chemotherapy to obtain anti-cancer effects through news mechanisms of action. The higher frequency and lower dose targets distinct features of tumor biology. Thus MC has been shown to inhibit tumor angiogenesis at least in part by decreasing thrombospondin-1, VEGF and circulating endothelial progenitor cells as well as killing endothelial cells and blocking their pro-angiogenic functions. The immune system can also be stimulated through multiple mechanisms (e.g selective depletion in regulatory T cells, modulation of myeloid-derived suppressor cells or maturation of dendritic cells) (Pasquier 2010, André 2014). Some studies have also demonstrated an effect of MC on cancer stem cells (André 2014). Additionally, MC is often combined in the clinic with drug repositioning (DR). DR consists in using already approved drugs for which novel anti-cancer properties have been unveiled (Blatt 2013). Using non anticancer drugs per se allows adding more agents with at the same time very little toxicity and targeted effect like. This approach has already been used successfully in pediatric oncology and represents an interesting way to introduce medications with new mechanisms of action (Blatt 2013). Among the drugs that can be repositioned for cancer treatment, propranolol is a non selective beta-blocker initially used to treat hypertension but its potent anticancer properties have been recently uncovered The potential of beta-blockers as anticancer agents is supported both by preclinical and epidemiological data. We have shown for instance that the use of beta-blockers could sensitize breast cancer, angiosarcoma and neuroblastoma cells to chemotherapy in vitro and in vivo at least in part via anti-angiogenic mechanisms (Pasquier 2011, Pasquier 2013, Banavali 2015). Moreover, preclinical studies in breast cancer, neuroblastoma, angiosarcoma have shown synergy between betablockers and several anti-tubulin agents including vincristine, vinorelbine and paclitaxel (Pasquier 2011, Pasquier 2013, Bouche 2014) both in vitro, and in vivo. There are currently 15 clinical trials prospectively evaluating their potential in adults with cancer (Clinicaltrials.gov) but only one in children with PEComa, a rare tumor mainly affecting children with tuberous sclerosis. The therapeutic potential of beta-blockers against the most frequent and refractory childhood cancer remains however totally unexplored.

AIMS: to determine the MTD of a combination of oral metronomic vinorelbine alone and in combination with daily oral propranolol.

METHODS: Phase I trial with a “rolling six” design and a 3 levels dose escalation (10, 20 and 30 mg/m² of thrice weekly oral vinorelbine only plus addition of daily oral propranolol (1.5mg/kg/day BID) after completion of the first cycle. PK analysis of vinorelbine and propranolol will be performed. Once the recommended dose of the combination established 4 extension cohorts of 9 patients (neuroblastoma, rhabdomyosacoma, Ewing sarcoma, miscellaneous tumors) will be added. Potential biomarkers (beta-adrenergic receptors on the tumors, B-tubulin isotypes in the tumor) will also be evaluated.

IMPACT: Overall, the PROVIN project displays 3 innovative aspects: 1) Use of β-blockers as anticancer agents through drug repositioning 2) Use of oral metronomic chemotherapy 3) Genesis of a multi-targeted precision medicine treatment combining a targeted agent and broad spectrum treatment with metronomic chemotherapy. This approach aims at providing an “all oral” treatment (easy to administer, no need for hospitalization or central lines) with very little toxicity for pediatric patients. It can therefore contribute both to reduce the toxicity of anti-cancer treatments as well as to increase the quality of life of the patients. Eventually this trial will provide a well tolerated, all oral combination for patients with refractory/relapsing tumors. This combination could also be then proposed as maintenance for instance in patients with neuroblastoma or rhabdomyosarcoma or for patients living in low- and middle-income countries