RAINBO: Refining Adjuvant treatment IN endometrial cancer Based On molecular features, TransPORTEC platform trials (MMRd-GREEN)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Leiden University Medical Center

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Jun 2022 → ongoing

Decision date (initial)

2023-11-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

KWF and AstraZeneca

External identifiers

EU CT number

2023-503267-42-00

EudraCT number

2021-000518-40

ClinicalTrials.gov

NCT05255653

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

3 year recurrence free survival (RFS), in patients with MMRd HREC

Secondary objectives 7

1. RFS (median and at 5 years)
2. OS (median, 3yr, 5yr)
3. Vaginal RFS, pelvic RFS, distant metastasis free-survival (median, 3-year, 5-year)
4. Disease-specific survival (median, 3-year, 5-year)
5. HRQoL
6. Safety & tolerability (NCI-CTC grade 3-5)
7. Exploratory translational research (TR), including PD-L1 testing using SP263 assay and TIP algorithm (>1% and 5%) on biopsy or resections of EC samples

Conditions and MedDRA coding

Patients with a histological diagnosis of mismatch- repair deficient high risk endometrial cancer (MMRd HREC; no POLEmut; all histology including carcinosarcoma), Stage IB/II with LVSI or stage IIIA-C. Patients are treated with curative intent, after surgery (hysterectomy and bilateralsalpingo-oophorectomy, with or without lymphadenectomy or sentinel node biopsy), without signs of residual disease or distant metastases.

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. 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.
2. Full molecular classification performed following the diagnostic algorithm described in WHO 2020 (5th Edition, IARC, Lyon, 2020, adapted from Vermij et al. 2020)
3. TLH-BSO or TAH-BSO with or without lymphadenectomy or sentinel node biopsy, without macroscopic residual disease after surgery
4. No distant metastases as determined by pre-surgical or post-surgical imaging (CT/MRI scan of chest, abdomen and pelvis or PET-CT scan)
5. Age ≥ 18 years
6. Expected start of adjuvant treatment (if applicable) within 10 weeks after surgery
7. Patients must be accessible for treatment and follow-up
8. 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.
9. Written informed consent
10. WHO Performance score 0-1
11. 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)
12. 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)
13. No prior pelvic radiotherapy
14. Body weight > 30 kg
15. 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

Exclusion criteria 13

1. History of another primary malignancy, except for non-melanoma skin cancer, in the past 5 years
2. Prior pelvic irradiation
3. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP
4. History of allogenic organ transplantation
5. 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
6. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab
7. 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
8. 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)
9. History of active primary immunodeficiency
10. 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
11. 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
12. Known allergy for durvalumab.
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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 3 year recurrence free survival (RFS) in patients with MMRd EC. 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 7

1. Investigator assessed 5 yr RFS
2. OS (median, 3yr, 5yr)
3. Vaginal RFS, pelvic RFS, distant metastasis free-survival (median, 3-year, 5-year)
4. Disease-specific survival (median, 3-year, 5-year)
5. HRQoL (EORTC QLQC30 and EORTC QLQEN24)
6. Safety & tolerability, grade 3-5 according to NCI-CTC version 5.0.
7. Exploratory TR, including PD-L1 testing using SP263 assay and TIP algorithm (>1% and 5%) on biopsy or resections of ECsamples

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Leiden University Medical Center

Sponsor organisation

Leiden University Medical Center

Address

P. O. Box 9600

City

Leiden

Postcode

2300 RC

Country

Netherlands

Scientific contact point

Organisation

Leiden University Medical Center

Contact name

Judith Kroep

Public contact point

Organisation

Leiden University Medical Center

Contact name

Judith Kroep

Third parties 1

Locations

6 EU/EEA countries · 57 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 30 files

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

Application history

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