On October 15, 2021 The European Organisation for Research and Treatment of Cancer (EORTC) reported that it has finished patient recruitment for the EORTC-62113-55115 trial in patients with the very rare tumour High-Grade Uterine Sarcoma (HGUtS) (Press release, EORTC, OCT 15, 2021, View Source [SID1234591427]). The randomised trial will study the effect of giving maintenance treatment* with cabozantinib after response or stabilisation further to adjuvant chemotherapy in cases of advanced stage disease, and as first-line treatment of metastatic disease (where the cancer has spread). Uterine sarcomas are aggressive tumours that occur mainly in postmenopausal women. They account for less than 1% of all gynaecological cancers and about 3-7% of all uterine malignancies, with an incidence of approximately 0.4 per 100,000 women.[1]
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The most common type of HGUtS is leiomyosarcoma (LMS), followed by endometrial stromal sarcoma (ESS), and even rarer subtypes such as undifferentiated uterine sarcoma.[2] This diversity of subtypes has led to a lack of consensus on risk factors and optimal treatment and this, combined with the rarity of the disease, has meant that outcomes for patients remain poor; there is a high risk of recurrence and most die within two years of their diagnosis.
Current treatments can include chemotherapy given after surgery for patients with a good performance status and poorly differentiated** early-stage sarcoma or in patients with advanced disease.[3] Different approaches for management of metastatic uterine sarcoma more generally include systemic chemotherapy with doxorubicin alone or in combination.[4] ‘To date, no prospective dedicated research has been conducted in uterine sarcoma, and therefore the treatment options remain limited. Considering the poor prognosis for these patients, the need to investigate new agents in this and in other rare cancers is imperative. We hope that our research will be able to improve outcomes, and also ensure that existing treatments can be used as effectively as possible’, says Prof. Isabelle Ray-Coquard of the Centre Leon Bérard in Lyon and Coordinator of this trial for the EORTC Sarcoma Group,
‘This study exemplifies the importance of multidisciplinary international collaboration, especially in the field of rare cancers, and here in particular the role of the International Rare Cancer Initiative (IRCI)’, says Prof. Nicholas Reed of the NHS Greater Glasgow & Clyde Beatson West of Scotland Cancer Centre, Co-coordinator of the trial for the EORTC Gynecological Group.
Recruitment to the trial started in February 2015 – initially dedicated to undifferentiated uterine sarcoma only, then expanded to also include High Grade LMS and High Grade adenosarcoma from 2017. As in the case of all rare cancers, enlisting the number of patients needed for the results to have the statistical power required to be reliable has been challenging. Now, more than six years later, the trial has passed its target recruitment with 58 patients (from six countries) randomised, as opposed to the 54 originally deemed to be necessary to meet the purpose of the study. This marks a crucial milestone for the trial. More broadly, this is an important step in advancing treatment optimisation, which relies on research to ensure that the right patients with rare cancers get the right medicine at the right time, thus improving safety and reducing waste.
First results from the trial are expected early 2023.
*Maintenance treatment is used to prevent or delay the cancer’s return if the cancer is in complete remission after the initial treatment. **Poorly differentiated tumours are made up of cancer cells that look very abnormal compared to normal cells.
References:
Hosh M, Antar S, Nazzal A, et al. Uterine sarcoma: analysis of 13,089 cases based on surveillance, epidemiology, and end results database. Int J Gynecol Cancer. 2016. July; 26(6): 1098-104.
Benson C & Miah AB. Uterine sarcoma – current perspectives. Int J Womens Health. 2017; 9: 597–606.
Tropé CG, Abeler VM, Kristensen GB. Diagnosis and treatment of sarcoma of the uterus. A review. 2012. Acta Oncol. 2012;51:694-705.
Giuntoli RL, Metzinger DS, DiMarco CS, et al. Retrospective review of 208 patients with leiomyosarcoma of the uterus: Prognostic indicators, surgical management, and adjuvant therapy. Gynecol Oncol. 2003;89:460-9.
About the study
The EORTC-62113-55115 trial was initiated as a collaboration between EORTC’s Soft Tissue & Bone Sarcoma Group (STBSG) and Gynaecological Cancer Group (GCG), with a protocol developed through the International Rare Cancers Initiative (IRCI) platform.
This randomised phase II double blinded trial aims to evaluate the role of maintenance therapy with cabozantinib in HGUtS, after stabilisation of the disease or response to chemotherapy following surgery, or in metastatic first-line treatment.
Cabozantinib is an oral tyrosine kinase inhibitor approved for the treatment of metastatic medullary thyroid cancer and is also being investigated in several other cancers. It is thought that this pharmaceutical could also be a beneficial maintenance treatment after chemotherapy for patients with sarcoma, as it blocks important pathways in the tumour growth process.
The primary objective of the trial is to assess – in different subtypes of HGUtS – the efficacy (measured by progression-free survival (PFS) at 4 months) of maintenance treatment with cabozantinib as compared with placebo, after clinical benefit to standard chemotherapy (doxorubicin +/- ifosfamide) (given as an adjuvant treatment after surgery, or for locally advanced or metastatic disease). Secondary endpoints include overall survival (OS), response rate (RR) and duration of response, as well as describing the safety profile of cabozantinib in the patient population studied.
Dosage of cabozantinib or placebo is set to 60 mg per day, based on results from preclinical and clinical studies. Treatment will be continued until trial completion (2 years) or occurrence of a criterion for withdrawal. Patients in the control arm (receiving placebo) will be permitted to receive cabozantinib at the time of relapse (disease progression), at the discretion of the investigators. Of note, such cross-over will not affect the selected primary endpoint (PFS).
A total of 54 patients randomised to receive either cabozantinib or placebo were required in order to detect an increase from 50% to 80% in PFS rate after 4 months.
This is an academic trial supported by the EORTC STBSG, the EORTC GCG, and a restricted educational grant from Exelixis, who supply cabozantinib for the whole duration of the trial.
About IRCI
IRCI is a joint initiative between Cancer Research UK (CRUK), the National Institute of Health Research Clinical Research Network: Cancer (NIHR CRN:Cancer), the National Cancer Institute (NCI), the European Organisation for Research and Treatment of Cancer (EORTC), the Institut National Du Cancer (INCa), Clinical Oncology Society of Australia (COSA), Japan Clinical Oncology Group (JCOG) and Canadian Cancer Trials Group. The aim of this initiative is to facilitate the development of international clinical trials for patients with rare cancers in order to boost the progress of new treatments for these patients. The initiative hopes to encourage the use of innovative methodologies to maximise the potential for answering research questions and to identify and overcome barriers to international trials to allow international collaborative trials to run smoothly.