Metzolimos, a combination of 4 repurposed drugs studied in patients with advanced solid tumor with bone metastasis and advanced pretreated osteosarcoma.

Info

Location: Institut Bergonié, Bordeaux, France
Collaboration: Dr Maud Toulmonde

 

Osteosarcoma is the most frequent type of bone tumors. It is a rare cancer type, affecting around 4 persons per million each year, mainly in the second decade of life and after 60.

The cornerstone of osteosarcoma treatment is surgery followed by chemotherapy. Because of its rarity, the treatment should be implemented by a team of specialists with experience in osteosarcomas.
The majority of patients will be cured after treatment, yet the cancer may come back in some patients. The best treatment strategy for this recurrence has yet to be defined. Treatment should be offered within a clinical trial protocol, whenever possible. A clinical trial tests how well new medical approaches work. Clinical trials are the only way to make progress in defining the best treatment strategy.

MetZolimOS will offer a new treatment to patients with osteosarcoma. This 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 primarily seeks to affect the tumor environment. The vast majority of osteosarcoma treatments tested until today have focused on affecting cancer cells directly. However, tumors are surrounded by a network of blood vessels, immune cells and connective tissue, all involved in tumor development. Thus, treating the environment might have a beneficial effect.

The combination of 4 drugs is expected to have an effect on both the tumor environment and the cancer cells. Cyclophosphamide and methotrexate are chemotherapy drugs which will be administered at lower dose but more regularly than it is usually done. This “metronomic” (referring to the regular action of administration) schedule is able to affect blood vessels in the tumor environment. Zoledronic acid and sirolimus have a direct effect on cancer cells. In addition, zoledronic acid protects against bone destruction and sirolimus might have a positive effect on the immune cells in the tumor environment.

The clinical trial consists of 2 parts. In the first part, which has been 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 according to the dose determined in the first part. If a regression of the disease or a stabilization for 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 study its anticancer activity further.

Professional info

Location: Institut Bergonié, Bordeaux, France
Collaboration: Dr Maud Toulmonde

 

Despite its rarity, osteosarcoma is the most common primary malignancy of bone in children and adolescents, and the fifth most common malignancy among adolescents and young adults aged 15 to 19. Indeed, osteosarcoma incidence rate has two peaks of about 4 per million per year, one in children and young adults ≤ 24 years, and the second after 60.

Use of chemotherapy in the neoadjuvant/adjuvant setting has dramatically improved overall survival in osteosarcoma. At relapse, combination protocols with the same drugs are favoured when complete surgery of the metastases is considered achievable. However, patients not amenable to this strategy have a very poor prognosis and there is no standard therapy in this setting.

The tumor micro-environment plays a crucial role in the development of tumors. Treatments developed so far in solid tumors - including osteosarcoma - have generally shown transient non-progression rate, because resistance eventually develops through diverse mechanisms such as up-regulation of alternate pathways. One major way to improve anticancer strategies could be to develop combined approaches that would both target cancer cells themselves and tumor-associated cells implicated in tumor angiogenesis and tumor immuno-tolerance.

"Metronomic" is the frequent and regular administration of low dose of a molecule. Metronomic cyclophosphamide combines both antiangiogenic and immunomodulatory properties that make it an interesting ‘niche’ multi-targeted therapy. Interestingly, the combination of metronomic cyclophosphamide with low-doses of methotrexate has shown activity with favourable low-toxicity profile in breast cancer and osteosarcoma, allowing to consider it as a suitable backbone for combination regimen.

Sirolimus is an mTOR inhibitor that has been widely used in the prevention of transplant rejection. It has also recently demonstrated antitumor activity with good safety in early clinical trials, alone or in combination with antiangiogenic therapies, notably with metronomic cyclophosphamide in heavily pretreated sarcoma patients. Interestingly, the mTOR pathway appears to be involved in osteosarcoma tumorigenesis and preclinical data suggest that mTOR inhibition and antiangiogenic therapy could be synergistic in osteosarcoma.

Bisphosphonates such as zoledronic acid are widely used in oncology in patients with bone metastasis. Preclinical studies support the concept that bisphosphonates have interesting activity against osteosarcoma and clinical studies combining bisphosphonates with chemotherapy are ongoing. Moreover, preclinical data suggest that zoledronic acid could have a synergic effect when combined with mTOR inhibition in osteosarcoma.

We hypothesized that the combination of metronomic cyclophosphamide and methotrexate given with sirolimus and zoledronic acid could have a synergic antiangiogenic, immunomodulatory and antitumoral effect, together with a good tolerance profile and cost-effectiveness, in patients with relapsed unresectable solid tumor with bone metastasis and more particularly in relapsed unresectable or metastatic osteosarcoma.

Because the best dosing of sirolimus given in combination with cyclophosphamide and methotrexate had never been determined, a dose-escalation was done first. Because deeper understanding of involved mechanisms of action is needed, translational research is also being done.

The first part (dose-escalation) of this trial included patients with all types of solid tumors providing there was bone involvement of the disease. This part was completed in August 2016. Because we believe there is a great interest in giving the combination of the 4 molecules to patients with relapsed unresectable or metastatic osteosarcoma, an expansion cohort is dedicated to this orphan disease and has opened in October 2016. 14 patients will be included.