Evaluation of Durvalumab as Adjuvant Therapy in Mismatch Repair-Deficient High-Risk Endometrial Cancer Post-Surgery: A Phase III Clinical Trial

Trial ID: 2023-503267-42-00
Protocol: RAINBO MMRd-GREEN
Sponsor: Leids Universitair Medisch Centrum (LUMC)

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Diseases & Conditions

Endometrial cancer

Objectives

The primary objective of this study is to evaluate the **3-year recurrence-free survival (RFS)** in patients diagnosed with mismatch-repair deficient high-risk endometrial cancer (MMRd HREC). This objective is clinically relevant as it aims to assess the effectiveness of adjuvant treatment strategies in preventing cancer recurrence, which is crucial for improving long-term patient outcomes.

Secondary objectives include: - **Recurrence-free survival (RFS)** at median and 5 years, - **Overall survival (OS)** at median, 3 years, and 5 years, - **Vaginal RFS, pelvic RFS, and distant metastasis-free survival** at median, 3 years, and 5 years, - **Disease-specific survival** at median, 3 years, and 5 years, - **Health-related quality of life (HRQoL)**, - **Safety and tolerability** assessed by NCI-CTC grade 3-5, - **Exploratory translational research**, including PD-L1 testing using SP263 assay and TIP algorithm on biopsy or resections of endometrial cancer samples. These secondary objectives provide a comprehensive evaluation of the treatment's impact on survival, quality of life, and safety, as well as potential biomarkers for treatment response.

Participants

The clinical trial involves a total of **84 participants** who are exclusively **female** and have been diagnosed with mismatch-repair deficient high-risk endometrial cancer (MMRd HREC). The study population includes individuals aged **18 years and older**, with a focus on those who have undergone surgery with curative intent, such as hysterectomy and bilateral salpingo-oophorectomy, without signs of residual disease or distant metastases. Participants were selected based on specific histological subtypes of endometrial carcinoma, including endometrioid, serous, uterine clear cell, dedifferentiated, undifferentiated, and carcinosarcoma, among others. The trial excludes individuals with prior pelvic radiotherapy and requires adequate systemic organ function, as well as a **WHO Performance score** of 0-1. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial does not include a vulnerable population, and all participants have provided written informed consent for participation and data sharing according to local ethics committee requirements.

Plans and Procedures

The clinical trial is designed to evaluate the **recurrence-free survival** (RFS) over a three-year period in patients diagnosed with mismatch-repair deficient high-risk endometrial cancer (MMRd HREC). This Phase III trial employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The trial is expected to conclude by December 31, 2032, with recruitment having commenced on August 30, 2022. Participants will be involved in the study for a maximum treatment period of 12 months, with the primary endpoint being the time from randomization until any recurrence or death from any cause.

Study visits are structured to include an initial screening visit to confirm eligibility based on specific inclusion criteria, such as a histologically confirmed diagnosis of endometrial cancer and adequate systemic organ function. Following the screening, participants will undergo regular follow-up visits to monitor their health status and treatment response. The end-of-study visit will assess the final outcomes and gather data on the primary and secondary endpoints, including overall survival and disease-specific survival.

Participants are expected to remain in the study for the entire duration unless specific conditions necessitate early termination. These conditions include the development of significant adverse effects, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The trial involves the administration of **durvalumab** via intravenous infusion, with a maximum daily dose of 1500 mg and a total dose not exceeding 19500 mg over the treatment period. The trial's secondary endpoints include investigator-assessed five-year RFS, overall survival, and safety and tolerability, among others.

Treatment

The clinical trial involves the administration of **IMFINZI** (durvalumab), a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 50 mg/mL and is intended for intravenous (IV) infusion. The maximum daily dose of durvalumab is 1500 mg, with a total maximum dose of 19500 mg over the course of the treatment. The treatment period is set for a maximum of 12 months. Durvalumab is a protein-based therapeutic agent, specifically classified under the ATC code L01XC28, and is produced by AstraZeneca AB. The administration schedule and participant compliance will be closely monitored to ensure adherence to the dosing regimen.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the efficacy and safety of durvalumab in the context of the trial's objectives. Participants will receive the investigational product according to the specified dosing schedule, and compliance will be assessed through regular monitoring and documentation of infusion sessions. The trial aims to assess the 3-year recurrence-free survival (RFS) in patients with MMRd HREC, contributing valuable data to the understanding of durvalumab's therapeutic potential in this patient population.

Efficacy

Efficacy in the clinical trial will be assessed primarily through the measurement of **recurrence-free survival (RFS)** over a three-year period in patients with mismatch repair-deficient (MMRd) endometrial cancer (EC). RFS is defined as the time from randomization until the date of any recurrence, whether local or distant, or the date of death due to any cause. Secondary endpoints include investigator-assessed five-year RFS, overall survival (OS) at median, three-year, and five-year intervals, as well as vaginal RFS, pelvic RFS, and distant metastasis-free survival at the same intervals. Disease-specific survival will also be evaluated at median, three-year, and five-year intervals.

Additional assessments will include health-related quality of life (HRQoL) using the EORTC QLQC30 and EORTC QLQEN24 instruments, and safety and tolerability graded according to the NCI-CTC version 5.0. Exploratory translational research will involve PD-L1 testing using the SP263 assay and TIP algorithm on biopsy or resection samples of EC, with thresholds set at greater than 1% and 5%. The schedule for these assessments will align with the trial's timeline, ensuring comprehensive data collection and analysis to evaluate the efficacy of the treatment regimen.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Histologically confirmed diagnosis of EC of the following histologic subtypes: endometrioid endometrial carcinoma, serous endometrial carcinoma, uterine clear cell carcinoma, dedifferentiated and undifferentiated endometrial carcinoma, uterine carcinosarcoma, and mixed endometrial carcinomas of the aforementioned histotypes.
Full molecular classification performed following the diagnostic algorithm described in WHO 2020 (5th Edition, IARC, Lyon, 2020, adapted from Vermij et al. 2020)
TLH-BSO or TAH-BSO with or without lymphadenectomy or sentinel node biopsy, without macroscopic residual disease after surgery
No distant metastases as determined by pre-surgical or post-surgical imaging (CT/MRI scan of chest, abdomen and pelvis or PET-CT scan)
Age ≥ 18 years
Expected start of adjuvant treatment (if applicable) within 10 weeks after surgery
Patients must be accessible for treatment and follow-up
Written informed consent for participation in one of the RAINBO trials, permission for the contribution of a tissue block for translation research and permission for the use and sharing of data for the overarching research project according to the local Ethics Committee requirements.
Written informed consent
WHO Performance score 0-1
Histologically confirmed FIGO 2009 stage IB/II with substantial LVSI, stage III, or stage III ECIV with limited pelvic peritoneal involvement (FIGO 2023 stage IB with LVSI, stage II with myometrial or cervical stroma involvement and LVSI, or stage III disease)
Molecular classification: MMRd EC (Molecular classification must be performed according to the diagnostic algorithm presented in the WHO 2020 (adapted from Vermij et al., histopathology). For the MMRd-GREEN trial this means that POLE status must be determined, and must be wildtype (or non-pathogenic) for inclusion. For details on the molecular classification see section 10.4)
No prior pelvic radiotherapy
Body weight > 30 kg
Adequate systemic organ function: - Creatinine clearance (> 40 cc/min): Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance. - Adequate bone marrow function : hemoglobin >9.0 g/dl, Absolute neutrophil count (ANC) ≥1.0 x 109/l, platelet count ≥75 x 109/l. - Adequate liver function: Bilirubin ≤1.5 x institutional upper limit of normal (ULN). <> - ALT (SGPT) and/or AST (SGOT) ≤2.5 x ULN

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Exclusion Criteria

History of another primary malignancy, except for non-melanoma skin cancer, in the past 5 years
Prior pelvic irradiation
Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP
History of allogenic organ transplantation
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease,serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab
Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab. Note: Patients, if enrolled should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP
Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab with the exceptions of : - Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection). - Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent - Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
History of active primary immunodeficiency
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g.,colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome. The following are exceptions to this criterion: - Patients with vitiligo or alopecia - Patients with hypothyroidism (e.g., following Hashimoto syndrome)stable on hormone replacement - Any chronic skin condition that does not require systemic therapy - Patients without active disease in the last 5 years may be included but only after consultation with the study physician
Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen(HBsAg) result), hepatitis C, or human immuno-deficiency virus (positive HIV 1/2 antibodies). Patients with a pastor resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg)are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
Known allergy for durvalumab.
Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Recruiting	30 Aug 2022	40
Czechia	Recruiting	30 Aug 2022	34
France	Recruiting	30 Aug 2022	70
Germany	Recruiting	30 Aug 2022	48
Italy	Recruiting	30 Aug 2022	20
The Netherlands	Recruiting	30 Aug 2022	—
Netherlands	—	—	150