Advanced bone cancer treatment with a combination of chemotherapy and immunosuppressants

Advanced bone cancer treatment with a combination of chemotherapy and immunosuppressants

A phase Ib study of metronomic cyclophosphamide and methotrexate combined with zoledronic acid and sirolimus in patients with solid tumors with bone metastasis and advanced pretreated osteosarcoma (Metzolimos).

Cancer types
  • Solid tumours
  • Bone cancer
Trial phase


ACF donation
Estimated trial cost

Why this trial?

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

The cornerstone of osteosarcoma treatment is surgery followed by chemotherapy. Upon relapse, combinations with the same chemotherapeutic drugs are recommended 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 will examine whether a specific combination of 4 drugs is safe and shows any signs of efficacy. The trial is unique and of major importance given that it seeks to affect the tumour environment: most osteosarcoma treatments tested until today have focused on affecting cancer cells directly. Tumours are surrounded by a network of blood vessels, immune cells and connective tissue, which are all involved in tumour development.

Treatment should be offered within a clinical trial, whenever possible. Clinical trials are the only way to make progress in defining the best treatment strategy. One major way to improve anticancer strategies could be to develop combined approaches that both target cancer cells as well as the tumour environment.

Why this intervention?

Researchers hypothesise that the combination of cyclophosphamide and methotrexate given with sirolimus and zoledronic acid could have a synergic effect on both the tumour environment and cancer cells.

Cyclophosphamide and methotrexate are chemotherapy drugs which will be administered at lower dose but more frequently than usual. This “metronomic” schedule affects blood vessels in the tumour environment. The combination of metronomic cyclophosphamide with methotrexate has shown activity with low-toxicity profile in breast cancer and osteosarcoma.

Zoledronic acid and sirolimus have a direct effect on cancer cells. Sirolimus is widely used in the prevention of transplant rejection. It has also recently demonstrated antitumor activity with high safety in early clinical trials, alone and in combination with antiangiogenic therapies, notably with metronomic cyclophosphamide.  Zoledronic acid protects against bone destruction.

Trial design

This phase I clinical trial consists of 2 parts. In the first part, which was 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 will be treated with the dose determined in the first part. If a regression or stabilisation of at least 6 months is observed in at least 3 patients, this combination of 4 drugs will be considered valuable and another trial will be planned to further study its anticancer activity.

For this trial, 26 patients will be recruited in total, in 4 French centres.



  • Dr. Maud Toulmonde, Institut Bergonié, Bordeaux, France (Coordinating Investigator)
  • Dr. Simone Mathoulin-Pélissier, Institut Bergonié, Bordeaux, France (Clinical Research Unit)


  • Institut Bergonié, Bordeaux, France

Our role

Financial support + Scientific input
Why we support this trial
Profit is a low priority in cancer treatment for the Anticancer Fund
Intervention has little or no commercial value
The Anticancer Fund aims at no major hurdle for clinical implementation
No major hurdle for clinical implementation
The Anticancer Fund supports a trial that benefits a population with high unmet needs
Use in a population with high unmet needs


Estimated trial cost
ACF donation
ACF internal support (2015-2020)
Questions about participation?
Questions about this trial?
The Anticancer Fund
studies [at]


More info on NCT02517918

Chou, A.J., et al. (2005). Treatment of osteosarcoma at first recurrence after contemporary therapy: the Memorial Sloan-Kettering Cancer Center experience. Cancer, 104, 2214-2221. doi:10.1002/cncr.21417

Dass C.R., et al. (2007). Zoledronic acid inhibits osteosarcoma growth in an orthotopic model. Molecular Cancer Therapeutics, 6, 3263-3270. doi:10.1158/1535-7163.MCT-07-0546

Penel, N., et al. (2012). Cyclophosphamide-based metronomic chemotherapy: after 10 years of experience, where do we stand and where are we going? Crit Rev Oncol Hematol, 82, 40-50. doi:10.1016/j.critrevonc.2011.04.009

Stiller, C.A., et al. (2006). Bone tumours in European children and adolescents, 1978-1997. Report from the Automated Childhood Cancer Information System project. Eur J Cancer, 42, 2124-2135. doi:10.1016/j.ejca.2006.05.015

Tomoda, R., et al. (2005). Low-dose methotrexate inhibits lung metastasis and lengthens survival in rat osteosarcoma. Clin Exp Metastasis, 22, 559-564. doi:10.1007/s10585-005-5377-y

Author: Kristine Beckers (Trial Manager)

Last updated: June 2018.