There is currently no defined standard of care for chemotherapy to treat Ewing sarcoma patients for which the disease returns after initial treatment (recurrent disease), or those for which the initial treatment doesn’t work (primary refractory disease).
The rEECur clinical trial was set up to evaluate the four most used chemotherapy regimens with respect to efficacy, toxicity, acceptability to patients, and to identify the best chemotherapy backbone to which novel targeted drugs could be added for treatment.
Of the chemotherapy regimens compared so far in rEECur, high dose ifosfamide was found to be the most effective.
Multiple tyrosine kinase inhibitors (mTKIs) are a class of targeted drugs that are active against relapsed Ewing sarcomas when given alone. The rEECur trial is now testing whether Lenvatinib - a multiple tyrosine kinase inhibitor- given with chemotherapy is more effective than chemotherapy alone.
In 2022, the Bone Cancer Research Trust introduced a new funding scheme, to provide additional support to ongoing clinical trials.A Clinical Trials Support Grant has been awarded to Dr Martin MacCabe at the University of Manchester and The Christie NHS Foundation Trust.
What are the aims of this research project?
The funded project will allow the completion of 3 studies that were not funded by the original trial design and will maximise the knowledge gained from each patient recruited to the rEECur trial.
Aim 1: Pharmacokinetic study
Lenvatinib has not previously been combined with high dose ifosfamide, therefore scientists need to make sure that sufficient lenvatinib is given to patients.
Blood samples will be taken at regular intervals from patients who receive lenvatinib and analysed for lenvatinib levels, to make sure that the level of lenvatinib in the blood, when given in combination with ifosfamide, is adequate, and that ifosfamide does not interfere with the amount of lenvatinib present.
Aims 2: Biomarkers for response to treatment
To improve outcomes for patients diagnosed with recurrent and refractory Ewing sarcoma, we need better treatments, but also better ways to identify which patients are most likely to benefit from which treatments.
We know that tyrosine kinase inhibitors like lenvatinib work in some patients and do not work in others. Yet, at present, we have no way of identifying which patients are most likely to benefit.
This part of the project aims to develop biomarkers that would allow clinicians to predict who is most likely to respond to lenvatinib.
To achieve this, scientists will examine chemicals present in tumour samples and circulating proteins found in the blood of patients who receive lenvatinib and will try to identify correlations between their presence and the patients’ response to treatment.
Aim 3: Biomarkers for relapse
rEECur is the largest clinical trial in relapsed-refractory Ewing sarcoma. As such, it represents a critically important international resource of a very well-described population of patients. Tissue samples from these patients that can be used to try to identify biomarkers to predict recurrence.
Normally, a tumour sample from a patient is collected and preserved into a unique paraffin block. Each block can be finely sliced and placed onto a microscope slide for investigation under a microscope. The presence of specific proteins can them be revealed by adding certain chemicals to each microscope slide.
Tissue microarrays are prepared by extracting very small cylindrical cores from individual paraffin donor blocks and carefully placing them into a new paraffin block that now would contain samples from many patients (microarray block).
The position and full information of each sample is carefully annotated; when the microarray block is finely sliced and placed onto a microscope slide, it allows researchers to detect and compare the presence or absence of a particular protein among many different tumour samples.
Researchers will construct tissue microarrays from tumour blocks from patients recruited to rEECur in the UK.
These microarrays will be used collaboratively with microarrays produced in other countries contributing to rEECur (France, Spain, Italy, Germany) to tray to identify markers for recurrence.
How could this project improve treatment options for Ewing sarcoma patients?
This project ultimately aims to improve the outcome for patients diagnosed with recurrent and refractory Ewing sarcoma, through the addition of a novel targeted drug to their chemotherapy treatment.
By identifying the patients most likely to respond to multi tyrosine kinase inhibitor therapy (lenvatinib), it will maximise the benefit and minimise the harm to patients from this class of agents.
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