Phase III Randomized Trial of Maintenance Olaparib Versus Observation Post-Adjuvant Chemoradiation in p53abn Endometrial Carcinoma
- Trial ID
- 2023-503886-44-00
- Protocol
- CSET 2023/3603
- Sponsor
- Institut Gustave Roussy
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate whether maintenance therapy with **olaparib** improves recurrence-free survival (RFS) compared to observation after chemoradiotherapy in patients with p53abn high-risk endometrial cancer (HREC). This is clinically relevant as it aims to determine the efficacy of olaparib in prolonging the period without disease recurrence, which is crucial for improving patient outcomes in this high-risk population.
Secondary objectives include assessing the differences between maintenance therapy with olaparib and observation after chemoradiotherapy in terms of:
- Overall survival (OS)
- Disease-specific survival
- Vaginal recurrence-free survival
- Pelvic recurrence-free survival
- Distant recurrence-free survival
Participants
The clinical trial involves a study population consisting exclusively of **female** participants, as the trial is focused on patients with a histological diagnosis of p53abn high-risk endometrial cancer (HREC). The age range of participants is 18 years and older, with no upper age limit specified. Participants are required to have a **WHO Performance score** of 0-1, indicating they are in relatively good health with adequate systemic organ function. The trial does not provide information on the total number of participants, as the sponsor has not disclosed this data. Selection criteria include a histologically confirmed diagnosis of endometrial cancer (EC) with specific histologic subtypes and stages, and participants must have undergone surgery with no signs of residual disease or distant metastases. Lifestyle considerations such as diet and physical activity are not specified, but participants must have a body weight greater than 30 kg and meet certain organ function criteria. The trial population is selected based on these medical and health criteria, ensuring participants are suitable for the study's objective of assessing the efficacy of maintenance therapy with olaparib in improving recurrence-free survival.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy of maintenance therapy with **olaparib** in improving recurrence-free survival (RFS) in patients with p53abn endometrial cancer (EC) following adjuvant chemoradiotherapy. The trial is structured as a phase III study, with participants randomly assigned to receive either olaparib or observation. The trial is expected to span from November 2023 to November 2031, with the recruitment phase commencing in November 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of EC, adequate organ function, and a WHO performance score of 0-1. Following randomization, participants will attend regular follow-up visits to monitor their health status and treatment response. These visits will include assessments of recurrence-free survival, overall survival, and other secondary endpoints such as disease-specific survival and recurrence-free survival at various anatomical sites. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.
The expected length of participant involvement is up to 24 months, corresponding to the maximum treatment period with olaparib. Conditions that may lead to early termination from the study include the occurrence of unacceptable adverse events, withdrawal of consent, or any significant protocol deviations. Participants must be able to comply with study visits and procedures as outlined in the protocol. The study aims to provide valuable insights into the potential benefits of olaparib as a maintenance therapy in this patient population.
Treatment
The clinical trial involves the administration of **Lynparza** (olaparib) as the experimental medication. Lynparza is available in two formulations: 150 mg and 100 mg film-coated tablets. The active substance in both formulations is olaparib, a chemical compound. The pharmaceutical form is a film-coated tablet, and the route of administration is oral. The maximum daily dose for both formulations is 600 mg, with a total maximum treatment period of 24 months. Participants will be instructed to take the medication as per the dosing schedule, which will be monitored for compliance throughout the study duration.
In addition to the experimental treatment, the study includes a comparator group that will undergo observation following adjuvant chemoradiation therapy for p53abn endometrial cancer. This group will not receive any additional medication, serving as a control to evaluate the efficacy of maintenance therapy with olaparib. The trial aims to assess whether olaparib improves recurrence-free survival compared to observation alone. Compliance with the treatment regimen will be closely monitored to ensure adherence to the study protocol.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the measurement of **recurrence-free survival (RFS)** in patients with p53abn endometrial cancer. 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. This primary endpoint will be evaluated by the investigator to determine the effectiveness of maintenance therapy with olaparib compared to observation following chemoradiotherapy.
Secondary endpoints include overall survival (OS), disease-specific survival, vaginal recurrence-free survival, pelvic recurrence-free survival, and distant recurrence-free survival. These parameters will provide additional insights into the efficacy of the treatment regimen. The trial is designed to monitor these outcomes over a specified period, with data collection occurring at predetermined intervals throughout the study duration.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically confirmed diagnosis of EC (all grades and the following histologic subtypes : endometrioid, serous, clear cell, de- /undifferentiated carcinomas, and uterine carcinosarcoma).
- WHO Performance score 0-1
- Histologically confirmed Stage I to III EC with myometrial invasion
- Molecular classification: p53abn EC*
- Body weight > 30 kg
- Adequate systemic organ function: Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below: Creatinine clearance (> 50 cc/min): Patients must have creatinine less than 1.5 ULN or calculated creatinine clearance estimated of ≥ 51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test. Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F) / serum creatinine (mg/dL) x 72 Adequate bone marrow function : hemoglobin ≥10.0 g/dl with no blood transfusion in the past 28 days, Absolute neutrophil count (ANC) ≥1.5 x 109/l, platelet count ≥ 100 x 109/l. Adequate liver function: bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician. ALT (SGPT) and/or AST (SGOT) ≤2.5 x ULN
- Molecular classification must be performed according to the diagnostic algorithm presented in the WHO 2020 (Vermij et al. 2020). For the p53abn-RED trial this means that MMR and POLE status must be determined, and must be pMMR and POLE wildtype (or non-pathogenic) for inclusion. For details on the molecular classification see 7.1: Diagnostic algorithm for molecular classification
- Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol.
- Patients must be affiliated to a social security system or beneficiary of the same
- Molecular classification performed following the diagnostic algorithm described in WHO 2020 (adapted from Vermij et al.)
- 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 postsurgical imaging (CT scan of chest, abdomen and pelvis or PETCT scan)
- Written informed consent prior to any study specific procedures
- Age >= 18 years
- Patients must have a life expectancy ≥ 16 weeks
- Patients must be accessible for treatment and follow-up
- Written informed consent for one of the RAINBO trials and the overarching research project according to the local Ethics Committee requirements
- Patient must receive or have received a sequential radiotherapy and chemothe-rapy preferably given according to the PORTEC-3 regimen and should be started within 6 to 8 weeks after surgery and no later than 10 weeks: two cycles of intrave-nous cisplatin 50mg/m² in the first and fourth week of the pelvic external beam ra-diotherapy (EBRT) +/- vaginal brachytherapy followed by four cycles of intrave-nous carboplatin AUC 5 and paclitaxel 175 mg/m² at 21-day intervals. However the sequence of chemotherapy , number of cycles and inclusion of cisplatin may be altered according to local practice at the investigator's discretion. This may include; · 4 cycles carboplatin & paclitaxel before or after radiotherapy with 2 cycles cisplatin · 4 cycles carboplatin & paclitaxel before or after radiotherapy (no cisplatin) · 6 cycles carboplatin & paclitaxel before or after radiotherapy (no cisplatin)
- Patients registered after their standard treatment must: - Provide a tumor assessment performed within the 4 weeks before the start of RT/CT. This will be considered as the M0. - have started RT/CT 6 to 8 weeks after surgery. A maximum gap of 10 weeks is accepted. - be randomized within two weeks before maintenance or observation
Exclusion Criteria
- 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.
- Patient with severe hepatic impairment
- Any previous treatment with a PARP inhibitor, including olaparib
- History of active primary immunodeficiency
- History or evidence of hemorrhagic disorders within 6 months prior to randomization
- Patients with myelodysplastic syndrome/acute myeloid leukemia history or with features suggestive of MDS/AML.
- Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
- 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 past or 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.
- Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks
- Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
- FIGO Stage IV disease of any histology even if there is no evidence of disease after surgery
- Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
- 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.
- Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent
- Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
- Treatment with an unlicensed or investigational product within 4 weeks of trial entry.
- Prior pelvic irradiation
- Major surgical procedure (as defined by the Investigator) within 2 weeks prior randomization and patients must have recovered from any effects of any major surgery.
- History of allogenic organ transplantation
- Other malignancy unless curatively treated with no evidence of disease for ≥5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma
- Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome
- Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia
- Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
- Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent
- Significant traumatic injury within 4 weeks of the first dose of olaparib.
- Breastfeeding patients
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 15 Nov 2023 | 150 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Lynparza 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 600 | 24 | PRD6163466 |
Lynparza 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 600 | 24 | PRD6152224 |