Cancer remains the first cause of death due to disease in children and adolescents despite
important progress and 70% of the survivors present sequelae. It is therefore mandatory to
generate new and preferably less toxic treatment strategies relying on new anticancer agents,
and/or new combinations or schedules of administered compounds.
Metronomic chemotherapy (MC) consists in administrating low doses of anticancer agents on a
daily/weekly basis. MC has been showed to be a safe and effective way to administer
chemotherapy to obtain anti-cancer effects through anti-angiogenic and pro-imune effects.
Drug repositioning consist in using non-anticancer drug for which anti-cancer properties have
been unveiled. Propranolol is a non selective beta-blocker initially used to treat
hypertension but recently its anticancer properties have been discovered. The place of
Betablockers as anticancer agents is supported by both preclinical and epidemiologic data.
The investigators have showed that the use of betablockers could sensitize breast cancer,
angiosarcoma and neuroblastoma to chemotherapy in vitro and in vivo at least in part via an
anti-angiogenic mechanism. There are currently 12 clinical trials evaluating prospectively
their potential in adults with cancer but none in children so far.
The Objective is to determine the Maximal Tolerated Dose (MTD) of a combination of oral
metronomic vinorelbine and daily oral propranolol. This study is a phase I trial with a
"rolling six" design and a dose escalation with thrice weekly oral vinorelbine only plus
addition of daily oral propranolol 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 will be added Potential biomarkers (such as
beta-adrenergic receptors on the tumours, B-tubulin isotypes in the tumour) will also be
This will provide a well tolerated, all oral combination for patients with
refractory/relapsing tumours. This combination could also be then proposed as a maintenance
for instance in patients with rhabdomyosarcoma or neuroblastoma.