Refining Adjuvant treatment IN endometrial cancer Based On molecular features, TransPORTEC platform trials – p53abn - RED Randomized phase III trial testing maintenance olaparib versus observation after adjuvant chemoradiation for p53abn endometrial cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Not possible to specify

Trial duration

10 Jun 2024 → ongoing

Decision date (initial)

2023-12-12

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Diagnosis, Dose response, Others, Therapy, Efficacy, Safety

To assess whether maintenance therapy with olaparib improves recurrence-free survival (RFS), as compared to observation after chemoradiotherapy in patients with p53abn HREC

Secondary objectives 1

1. To assess the differences between maintenance therapy with olaparib and observation after chemo-radiotherapy in patients with p53abn HREC on: Overall survival (OS) , Disease-specific survival , Vaginal recurrence-free survival , Pelvic recurrence-free survival , Distant recurence-free survival

Conditions and MedDRA coding

Patients with a histological diagnosis of p53abn HREC, treated with curative intent, after surgery (hysterectomy and bilateral salpingooophorectomy, with or without lymphadenectomy or sentinel node biopsy), without signs of residual disease or distant metastases

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. Histologically confirmed diagnosis of EC (all grades and the following histologic subtypes : endometrioid, serous, clear cell, de- /undifferentiated carcinomas, and uterine carcinosarcoma).
2. WHO Performance score 0-1
3. Histologically confirmed Stage I to III EC with myometrial invasion
4. Molecular classification: p53abn EC*
5. Body weight > 30 kg
6. 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
7. 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
8. 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.
9. Patients must be affiliated to a social security system or beneficiary of the same
10. Molecular classification performed following the diagnostic algorithm described in WHO 2020 (adapted from Vermij et al.)
11. TLH-BSO or TAH-BSO with or without lymphadenectomy or sentinel node biopsy, without macroscopic residual disease after surgery
12. No distant metastases as determined by pre-surgical or postsurgical imaging (CT scan of chest, abdomen and pelvis or PETCT scan)
13. Written informed consent prior to any study specific procedures
14. Age >= 18 years
15. Patients must have a life expectancy ≥ 16 weeks
16. Patients must be accessible for treatment and follow-up
17. Written informed consent for one of the RAINBO trials and the overarching research project according to the local Ethics Committee requirements
18. 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)
19. 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 26

1. 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.
2. Patient with severe hepatic impairment
3. Any previous treatment with a PARP inhibitor, including olaparib
4. History of active primary immunodeficiency
5. History or evidence of hemorrhagic disorders within 6 months prior to randomization
6. Patients with myelodysplastic syndrome/acute myeloid leukemia history or with features suggestive of MDS/AML.
7. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
8. 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.
9. 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
10. 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.
11. FIGO Stage IV disease of any histology even if there is no evidence of disease after surgery
12. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
13. 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.
14. Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent
15. Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
16. Treatment with an unlicensed or investigational product within 4 weeks of trial entry.
17. Prior pelvic irradiation
18. 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.
19. History of allogenic organ transplantation
20. 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
21. 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
22. Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia
23. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
24. 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
25. Significant traumatic injury within 4 weeks of the first dose of olaparib.
26. Breastfeeding patients

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Recurrence free survival (RFS) in patients with p53abn EC, as assessed by the investigator. RFS is defined as time from randomization until date of any recurrence (local or distant) or date of death due to any cause

Secondary endpoints 1

1. Overall survival (OS) ,Disease-specific survival , Vaginal recurrence-free survival , Pelvic recurrence-free survival , Distant recurrence-free survival

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Aqsa YAR

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Aqsa YAR

Locations

1 EU/EEA country · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications