Despite its rarity, osteosarcoma is the most common primary bone cancer in children and adolescents, and the fifth most common cancer among adolescents and young adults aged 15 to 19.

The current cornerstone of osteosarcoma treatment is surgery followed by chemotherapy. Upon relapse, treatment consists of combinations with the same chemotherapeutic drugs, when complete surgery of the metastases is achievable. However, patients who do not respond to this strategy have a very poor prognosis and there is no standard therapy in this setting.

The Metzolimos trial, led by Dr. Toulmonde from Institut Bergonié in France, examined whether a specific combination of 4 drugs is safe and shows any signs of efficacy in this patient population. The trial is unique and of major importance given that it sought to affect the tumour environment, as opposed to the tumour cells directly: tumours are surrounded by a network of blood vessels, immune cells and connective tissue, which are all involved in tumour development.

Researchers hypothesised that the combination of the 4 drugs, sirolimus, cyclophosphamide, methotrexate and zoledronic acid, could have a synergic effect on both the tumour environment and cancer cells.

This phase I clinical trial consisted of 2 parts. In the first part, completed in August 2016, the dose of sirolimus that can be safely administered in combination with the 3 other drugs was determined. In the second part, which started in October 2016, 14 patients with osteosarcoma were treated with the dose determined in the first part.  

The study showed that combination of sirolimus at 4 mg daily with cyclophosphamide, methotrexate and zoledronic acid is safe and reached the initial targeted efficacy rate in advanced pretreated osteosarcoma patients. Further analyses are needed to understand which patients may benefit from this approach.