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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
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 hypothesised 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 (CP) and methotrexate (MTX) 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 (ZA) and sirolimus (SIR) 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 consisted 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 were treated with the dose determined in the first part. If a regression or stabilisation of at least 6 months was observed in at least 3 patients, this combination of 4 drugs would have been be considered valuable and another trial would've been planned to further study its anticancer activity.



From February 2015 to March 2021, 23 patients (9 in part I, 14 in part II) were included in the 3 participating centers.

The analysis concluded that combining SIR at the dosage established in the first part of the trial with CP, MTX, and ZA is well-tolerated in advanced, previously treated osteosarcoma patients. Additionally, this combination achieved the initially targeted effectiveness rate.

The full publication of the results will be available in Q2 2024.



  • 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

Intervention has little or no commercial value

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No major hurdle for clinical implementation

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Use in a population with high unmet needs

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ACF donation
Estimated trial cost

Questions about participation?

Maud Toulmonde
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Questions about this trial?

The Anticancer Fund
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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: March 2024.