Genetic-Based Adjuvant Therapy for Endometrial Cancer
Recruiting in Palo Alto (17 mi)
+60 other locations
Age: 18+
Sex: Female
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Canadian Cancer Trials Group
Disqualifiers: Prior chemotherapy, Prior radiation, Other malignancies, others
Stay on Your Current Meds
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?
This protocol tests de-escalated adjuvant treatment in patients with POLE-mutated or p53wt/NSMP (p53 wildtype/no specific molecular profile) early-stage endometrial cancer (EC). Patients may be enrolled in one of two sub-studies * EN10.A/RAINBO BLUE: POLE-mutated EC * EN10.B/TAPER: p53 wildtype / NSMP EC
Do I need to stop my current medications to join the trial?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
What data supports the effectiveness of the treatment Genetic-Based Adjuvant Therapy for Endometrial Cancer?
Recent studies have shown that using molecular profiling to guide adjuvant therapy in endometrial cancer can improve risk assessment and treatment outcomes. Specifically, adjuvant vaginal brachytherapy is recommended for high-intermediate risk endometrial cancer to enhance local control with minimal side effects, and pelvic radiotherapy is supported for high-risk cases to improve survival rates.12345
How does the observation treatment for endometrial cancer differ from other treatments?
The observation treatment for endometrial cancer, also known as watchful waiting or active surveillance, is unique because it involves closely monitoring the patient without immediate intervention, unlike other treatments that may involve surgery, chemotherapy, or radiotherapy. This approach is typically considered for patients with low-risk disease where the cancer is not expected to progress quickly, allowing for a less invasive management strategy.13678
Eligibility Criteria
This trial is for adults with early-stage endometrial cancer that's either POLE-mutated or p53 wildtype/NSMP. Participants must have had a hysterectomy, no remaining visible disease, and an ECOG performance status of 0-2. They should be able to complete questionnaires in English, French or another validated language and start treatment within 10 weeks post-surgery.Inclusion Criteria
I am 18 years old or older.
I had surgery to remove my uterus and ovaries with no visible cancer left.
I can care for myself and am up and about more than 50% of my waking hours.
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Exclusion Criteria
Clinical evidence of distant metastasis as determined by imaging
I have had cancer before, but it was either skin cancer treated successfully, cervical cancer treated without spreading, or any cancer treated over 5 years ago with no current signs of disease.
I have had chemotherapy before surgery for my current endometrial cancer.
See 1 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive tailored adjuvant therapy, which may include observation, vaginal brachytherapy, or adjuvant radiotherapy depending on the sub-study
6-8 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
12 weeks
Treatment Details
Interventions
- Adjuvant radiotherapy (EBRT +/- brachytherapy) (Radiation Therapy)
- Observation (Other)
- Vaginal brachytherapy (Brachytherapy)
Trial OverviewThe study examines de-escalated adjuvant treatments in two sub-studies: RAINBO BLUE for POLE-mutated cancer and TAPER for p53 wildtype/NSMP cancer. It compares the effects of adjuvant radiotherapy (with or without brachytherapy), vaginal brachytherapy alone, or just observation after surgery.
Participant Groups
3Treatment groups
Experimental Treatment
Group I: Sub-study A: RAINBO BLUE Cohort A1Experimental Treatment1 Intervention
Observation
Group II: Sub-Study B: TAPERExperimental Treatment2 Interventions
Observation or Vaginal Brachytherapy
Group III: Sub-Study A: RAINBO BLUE Cohort A2 ExploratoryExperimental Treatment2 Interventions
Observation or Adjuvant Radiotherapy
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University Health NetworkToronto, Canada
Cross Cancer InstituteEdmonton, Canada
London Regional Cancer ProgramLondon, Canada
BCCA - VictoriaVictoria, Canada
More Trial Locations
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Who Is Running the Clinical Trial?
Canadian Cancer Trials GroupLead Sponsor
Canadian Cancer Clinical Trials NetworkCollaborator
References
Adjuvant Treatment Recommendations in Early-Stage Endometrial Cancer: What Changes With the Introduction of The Integrated Molecular-Based Risk Assessment. [2021]Adjuvant therapy recommendations for endometrial cancer were historically based on the individual patient's risk of disease recurrence using clinicopathologic factors such as age, stage, histologic subtype, tumor grade, and lymphovascular space invasion. Despite the excellent prognosis for early stages, considerable under- and overtreatment remains. Integrated genomic characterization by the Cancer Genome Atlas (TCGA) in 2013 defined four distinct endometrial cancer subgroups (POLE mutated, microsatellite instability, low copy number, and high copy number) with possible prognostic value. The validation of surrogate markers (p53, Mismatch repair deficiency, and POLE) to determine these subgroups and the addition of other molecular prognosticators (CTNNB1, L1CAM) resulted in a practical and clinically useful molecular classification tool. The incorporation of such molecular alterations into established clinicopathologic risk factors resulted in a refined, improved risk assessment. Thus, the ESGO/ESTRO/ESP consensus in 2020 defined for the first time different prognostic risk groups integrating molecular markers. Finally, the feasibility and clinical utility of molecular profiling for tailoring adjuvant therapy in the high-intermediate-risk group is currently under investigation (NCT03469674).
Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer-Combined Analysis of the PORTEC Cohorts. [2020]Recommendations for adjuvant treatment for women with early-stage endometrial carcinoma are based on clinicopathologic features. Comprehensive genomic characterization defined four subgroups: p53-mutant, microsatellite instability (MSI), POLE-mutant, and no specific molecular profile (NSMP). We aimed to confirm the prognostic capacity of these subgroups in large randomized trial populations, investigate potential other prognostic classifiers, and integrate these into an integrated molecular risk assessment guiding adjuvant therapy.
Adjuvant therapy for endometrial cancer in the era of molecular classification: radiotherapy, chemoradiation and novel targets for therapy. [2022]Endometrial cancer is primarily treated with surgery. Adjuvant treatment strategies for endometrial cancer, such as external beam pelvic radiotherapy, vaginal brachytherapy, chemotherapy, and combined chemotherapy and radiotherapy, have been studied in several randomized trials. Adjuvant treatment is currently based on the presence of clinico-pathological risk factors. Low-risk disease is adequately managed with surgery alone. In high-intermediate risk endometrial cancer, adjuvant vaginal brachytherapy is recommended to maximize local control, with only mild side effects and without impact on quality of life. For high-risk endometrial cancer, recent large randomized trials support the use of pelvic radiotherapy, especially in stage I-II endometrial cancer with risk factors. For women with serous cancers and those with stage III disease, chemoradiation increased both recurrence-free and overall survival, while GOG-258 showed similar recurrence-free survival compared with six cycles of chemotherapy alone, but with better pelvic and para-aortic nodal control with combined chemotherapy and radiotherapy. Recent molecular studies, most notably the work from The Cancer Genome Atlas (TCGA) project, have shown that four endometrial cancer molecular classes can be distinguished; POLE ultra-mutated, microsatellite instable hypermutated, copy-number-low, and copy-number-high. Subsequent studies, using surrogate markers to identify groups analogous to TCGA sub-classes, showed that all four endometrial cancer sub-types are found across all stages, histological types, and grades. Moreover, the molecular sub-groups have proved to have a stronger prognostic impact than histo-pathological tumor characteristics. This introduces an new era of molecular classification based diagnostics and treatment approaches. Integration of the molecular factors and new therapeutic targets will lead to molecular-integrated adjuvant treatment including targeted treatments, which are the rationale of new and ongoing trials. This review presents an overview of current adjuvant treatment strategies in endometrial cancer, highlights the development and evaluation of a molecular-integrated risk profile, and briefly discusses ongoing developments in targeted treatment.
Comprehensive genomic profiling of recurrent endometrial cancer: Implications for selection of systemic therapy. [2020]To assess whether comprehensive genomic profiling (CGP) in the setting of routine clinical care allows molecular classification of recurrent endometrial cancer (EC) into the four Cancer Genome Atlas (TCGA) categories: POLE ultramutated, microsatellite instable, copy-number low, and copy-number high and whether this approach can identify genomic alterations (GAs) which inform treatment decisions.
Endometrial cancer: Molecular markers and management of advanced stage disease. [2020]Endometrial cancer is the most prevalent gynecologic cancer in the United States. Over the last 10 years, death rates from endometrial cancer have been rising about 1.4% per year. Traditionally endometrial cancer treatment has been driven by stage and histology. Recent studies have, however, shown that cancers of the same stage and histology have very distinct molecular and genomic profiles. Translational research is progressing rapidly and endometrial cancer-specific precision medicine is evolving. The first tissue agnostic therapy based on the molecular profile of the tumor was approved by the FDA this year. The approval of immune checkpoint inhibitor, pembrolizumab (anti-PD-1), for all solid tumors with defective DNA mismatch repair, could benefit 20-30% of patients with advanced endometrial cancer. Other genomic changes and molecular markers in endometrial cancer, such as hormone receptor status, could lead to more tailored therapy in the future. Pre-clinical and clinical investigations of targeted therapies suggest efficacy for some agents. Single agent targeted therapies, however, have modest activity. Identifying biomarkers that effectively determine response to targeted therapy remains a challenge. The next generation of clinical trials will focus on novel combinations and how to best utilize the advances that have been made in sequencing technology and bioinformatics. Although there is currently an immense body of data and many options for obtaining genomic characteristics of endometrial cancer, how to interpret and utilize this data is still being explored. This review will summarize the important trials that have led to the treatment options we have for advanced and/or recurrent endometrial cancer and discuss the important studies that have led to a better understanding of the distinctive molecular and genomic profiles within endometrial cancer. We will review the current status of biomarker-driven targeted therapy in endometrial cancer and the rationale behind ongoing clinical trials that are utilizing novel targeted agents.
[Molecular-integrated risk profile: An opportunity for therapeutic de-escalation in intermediate and high-intermediate risk endometrial cancer]. [2022]In Europe, endometrial cancer is the fourth most common cancer among women. The majority of patients are diagnosed at a localized stage. For these patients, the standard of care is based on an hysterectomy with salpingo oophorectomy±lymph node staging. Through the assessment of histopathologic features, risk groups are determined: low, intermediate, high-intermediate, and high risk. Adjuvant strategies are guided by these risk groups. While the prognosis of low-risk and high-risk is well known, that of intermediate and high-intermediate risk is more heterogeneous, and the therapeutic index of adjuvant treatments is more questionable. Several trials (PORTEC [Post Operative Radiation Therapy in Endometrial Carcinoma] I, GOG [Gynecologic Oncology Group] 99, ASTEC [A Study in the Treatment of Endometrial Cancer] EN.5, PORTEC II, Sorbe et al trial) have assessed observation, vaginal cuff brachytherapy and/or pelvic external beam radiotherapy in this population. Vaginal cuff brachytherapy reduces the local recurrence rate, and pelvic external beam radiotherapy the pelvic recurrence rate. However, no benefit in terms of overall survival or occurrence of distant metastases is highlighted. Compared to observation, brachytherapy and above all external beam radiotherapy are associated with an increased morbidity, and with a decreased quality of life. In order to improve the therapeutic ratio and to optimize medico-economic decisions, therapeutic de-escalation strategies, based on the molecular profiles, are emerging in clinical trials, and in the recommendations for the management of intermediate and high-intermediate risk endometrial cancers. The four main molecular profiles highlighted by the genomic analyzes of The Cancer Genome Atlas (TCGA) - POLE (polymerase epsilon) mutation, non-specific molecular profile, MMR (MisMatch repair) deficiency, and p53 mutation - but also the quantification of lymphovascular space invasion (absent, focal or substantial), and the assessment of L1CAM (L1 cell adhesion molecule) overexpression represent growing concerns. Thus, the use of molecular-integrated risk profile to determine the best adjuvant treatment represent a major way to personalize adjuvant treatment of endometrial cancers, with therapeutic de-escalation opportunity for around half of the high-intermediate risks. However, in the absence of prospective data, inclusion in clinical trials assessing molecular profile-based treatment remains the best therapeutic opportunity.
Selecting Adjuvant Treatment for Endometrial Carcinoma Using Molecular Risk Factors. [2023]To provide an overview of common molecular risk factors in endometrial cancer (EC) with the possibility to improve adjuvant treatment selection.
Improving the Management of Endometrial Cancer Patients through the Use of Liquid Biopsy Analyses: A Case Report. [2022]Endometrial cancer (EC) is the 4th most common neoplasm of the female genital tract, with 15-20% of patients being of high risk of recurrence which leads to a significant decrease in patient survival. Current therapeutic options for patients with EC are poor, being the combined therapy of carboplatin and paclitaxel the standard of care, with limited efficacy. Therefore, new therapeutic options and better monitoring tools are needed to improve the management of the disease. In the current case report, we showcase the value of liquid biopsy analyses in a microsatellite instability EC patient with initially good prognosis that however underwent rapid progression disease within 6 months post-surgery; through the study of plasma cfDNA/ctDNA dynamics to assess the tumour evolution during treatment, as well as the study of the uterine aspirate as a valuable sample that captures the intra-tumour heterogeneity that allows a comprehensive genomic profiling of the disease to identify potential therapeutic options. Furthermore, preclinical models were generated at the time of tumour progression to assess the efficacy of the identified targeted therapies.