Clinical trial NCT05255653: Refining Adjuvant Treatment in Endometrial Cancer Based on Molecular Features
Official title: Refining Adjuvant Treatment in Endometrial Cancer Based on Molecular Features: the P53abn-RED Trial, the MMRd-GREEN Trial, the NSMP-ORANGE Trial and the POLEmut-BLUE Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Endometrial Cancer
Keywords: Endometrial Cancer
Molecular risk factors
Olaparib
Durvalumab
Progestagens
Chemoradiation
Radiotherapy
Observation
p53
MMRd
NSMP
POLE
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: Institute Gustave Roussy (sponsor p53abn-RED trial)
name: Leiden University Medical center (sponsor MMRd-GREEN trial)
name: University College London (sponsor NSMP-ORANGE trial)
name: Canadian Clinical Trials Group (sponsor POLEmut-BLUE trial)
name: Dutch Gynaecological Oncology Group
name: Comprehensive Cancer Centre The Netherlands
name: Cancer Research UK & UCL Cancer Trials Centre
name: Dutch Cancer Society
name: AstraZeneca
name: National Cancer Institute, France
name: Canadian Institutes of Health Research (CIHR)
First posted: 2022-02-24
Enrollment: 1615
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Platform trial wherein eligible patients are assigned to one of four parallel running clinical trials. Three of four trials are randomised controlled trials and one is a prospective clinical trial with two study arms.
Primary purpose: TREATMENT

Brief summary: The RAINBO umbrella program consists of four clinical trials investigating new adjuvant therapies in endometrial cancer patients. Eligible patients will be assigned to one of the four RAINBO trials based on the molecular profile of their cancer:

* p53 abnormal endometrial cancer patients to the p53abn-RED trial
* mismatch repair deficient endometrial cancer patients to the MMRd-GREEN trial
* no specific molecular profile endometrial cancer patients to NSMP-ORANGE trial
* POLE mutant endometrial cancer patients to the POLEmut-BLUE trial

Detailed description: The p53abn-RED trial (NCT05255653-1) is an international, multicenter, phase III randomised trial wherein adjuvant chemoradiation followed by olaparib for one year is compared to adjuvant chemoradiation.

The MMRd-GREEN trial (NCT05255653-2) is an international, multicenter, phase III randomised trial wherein adjuvant pelvic external beam radiotherapy combined with and followed by durvalumab for one year is compared to adjuvant pelvic external beam radiotherapy with or without chemotherapy.

The NSMP-ORANGE trial (NCT05255653-3) is an international, multicenter, phase III randomised trial wherein adjuvant pelvic external beam radiotherapy followed by progestogens for two years is compared to adjuvant chemoradiation.

The POLEmut-BLUE trial (NCT05255653-4) is an international, multicenter, single arm, phase II trial wherein safety of de-escalation of adjuvant therapy is investigated: no adjuvant therapy for stage I-II disease and no adjuvant therapy or pelvic external beam radiotherapy only for stage III disease.

The overarching RAINBO research project will combine the data and tumor material of the four RAINBO clinical trials to perform translational research and compare molecular profile-based adjuvant therapy to standard adjuvant therapy in terms of effectiveness, toxicity, quality of life and cost utility.

Eligibility criteria: Participants of the four RAINBO trials should be eligible according to the inclusion and exclusion criteria of both the overarching RAINBO trials program and the clinical trial that they are assigned to based on the molecular profile.

Inclusion Criteria of the overarching RAINBO program:

* Histologically confirmed diagnosis of endometrial cancer (EC) of the following histotypes: 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)
* Hysterectomy and bilateral salpingo-oophorectomy 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 scan of chest, abdomen and pelvis or whole-body PET-CT scan)
* WHO performance status 0, 1 or 2
* 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.

Exclusion Criteria overarching RAINBO program:

* History of another primary malignancy, except for non-melanoma skin cancer, in the past 5 years
* Prior pelvic radiation

The p53abn-RED trial

Inclusion criteria:

* p53 abnormal EC
* Histologically confirmed stage I (with invasion) II or III EC
* WHO Performance score 0-1
* 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). 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, AND ALT (SGPT) and/or AST (SGOT) ≤2.5 x ULN

Exclusion criteria:

* Pathogenic POLE mutation(s)
* Mismatch repair deficiency
* Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of the 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 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.
* 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.

The MMRd-GREEN trial

Inclusion criteria:

* Mismatch repair deficient EC
* Histologically confirmed (FIGO 2009) stage IB/II EC with myometrial or cervical stroma involvement and lympovascular space invasion (LVSI) OR Stage III EC OR Stage IVA with limited pelvic peritoneal involvement
* WHO Performance score 0-1
* 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). \<\<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.\>\> AND ALT (SGPT) and/or AST (SGOT) ≤2.5 x ULN

Exclusion criteria:

* Pathogenic POLE mutation(s)
* Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of investigational medicinal product (IMP)
* 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 PD(L)1 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 IMP.
* 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 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.
* 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.

The NSMP-ORANGE trial

Inclusion criteria:

* NSMP EC
* Histologically confirmed stage II EC with substantial LVSI or stage III EC
* ER positive EC
* WHO performance status 0-1

Exclusion criteria:

* Pathogenic POLE mutation(s)
* Mismatch repair deficiency
* p53 abnormality

The POLEmut-BLUE trial

Inclusion criteria:

* Pathogenic POLE mutation(s)
* For the main cohort, patients must have one of the following combinations of FIGO stage, grade, and LVSI:

  * stage IA (not confined to polyp), grade 3, pN0, with or without LVSI
  * stage IB, grade 1 or 2, pNx/N0, with or without LVSI
  * stage IB, grade 3, pN0, without substantial LVSI
  * stage II (microscopic), grade 1 or 2, pN0, without substantial LVSI
* For the exploratory cohort, patients must have one of the following combinations of FIGO stage, grade, and LVSI:

  * stage IA (not confined to polyp), grade 3 - Stage III not included in main cohort
  * Multiple molecular classifiers stage IA (not confined to polyp), grade 3 - Stage III
* Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrolment in the trial to document their willingness to participate. A similar process must be followed for sites outside of Canada as per their respective cooperative group's procedures.
* Patient is able (i.e., sufficiently fluent) and willing to complete the QOL and/or health utility questionnaires in either English, French or a validated language. The baseline assessment must be completed within the required timelines, prior to enrolment. Inability (lack of comprehension in English or French, or other equivalent reason such as cognitive issues or lack of competency) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible.
* Patients must be accessible for treatment and follow up. Patients enrolled on this trial must be treated and followed at the participating center. Investigators must assure themselves the patients enrolled on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.
* Patients must agree to return to their primary care facility for any adverse events which may occur through the course of the trial.
* In accordance with CCTG policy, protocol treatment is to begin within 10 weeks of hysterectomy/bilateral salpingo-oophorectomy.

Exclusion criteria:

* Prior chemotherapy for EC
* Isolated tumor cells identified in lymph node(s) for main study cohort (patient can be included in exploratory cohort)

Primary outcomes:
measure: p53abn-RED trial
timeFrame: 3 years
measure: MMRd-GREEN trial
timeFrame: 3 years
measure: NSMP-ORANGE trial
timeFrame: 3 years
measure: POLEmut-BLUE trial
timeFrame: 3 years
Secondary outcomes:
measure: Recurrence-free survival
timeFrame: 5 years
measure: Pelvic recurrence-free survival
timeFrame: 5 years
measure: Vaginal recurrence-free survival
timeFrame: 3 years, 5 years
measure: Endometrial cancer-specific survival
timeFrame: 3 years, 5 years
measure: Overall survival
timeFrame: 3 years, 5 years
measure: Treatment-related toxicity - according to CTCAE v5.0
timeFrame: 3 years, 5 years
measure: Health-related quality of life - Assessed using the EORTC QLQ-C30 questionnaire
timeFrame: 3 years, 5 years
measure: Health-related quality of life - Assessed using the EORTC QLQ-EN24 questionnaire
timeFrame: 3 years, 5 years
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: The POLEmut-BLUE trial: Princess Margaret Cancer Centre, University of Toronto
city: Vancouver
country: Canada
facility: The POLEmut-BLUE trial: University of British Columbia
city: Villejuif
country: France
facility: The p53abn-RED trial: Institute Gustave Roussy
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Center
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Breda
country: Netherlands
facility: Instituut Verbeeten
city: Den Haag
country: Netherlands
facility: Haags Medisch Centrum
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Leiden
country: Netherlands
facility: The MMRd-GREEN trial: Leiden University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: London
country: United Kingdom
facility: The NSMP-ORANGE trial: Barts Health NHS Trust
city: Manchester
country: United Kingdom
facility: The NSMP-ORANGE trial: Manchester Academic Health Science Centre, St Mary's Hospita
Study officials:
affiliation: Institute Gustave Roussy, Villejuif, France (p53abn-RED trial)
name: Alexandra Leary, Md PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center, Leiden, The Netherlands (MMRd-GREEN trial)
name: Judith R Kroep, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Barts Health NHS Trust, London, United Kingdom (NSMP-ORANGE trial)
name: Melanie E Powell, Md PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: St Mary's Hospital, Manchester, United Kingdom (NSMP-ORANGE trial)
name: Emma J Crosbie, Md PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada (POLEmut-BLUE trial)
name: Kathy Han, Md PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of British Columbia,Vancouver, Canada (POLEmut-BLUE trial)
name: Jessica N McAlpine, Md PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: IMPLEMENTATION OF COLLABORATIVE TRANSLATIONAL RESEARCH (TRANSPORTEC) FINDINGS IN AN INTERNATIONAL ENDOMETRIAL CANCER CLINICAL TRIALS PROGRAM (RAINBO). T Bosse, M Powell, E Crosbie, A Leary, J Kroep, K Han, J Mcalpine, N Horeweg, S De Boer, M De Bruyn, R Nout, V Smit, HW Nijman, N Singh, H Mackay, R Edmondson, L Mileshkin, D Church, H Kitchener, CL Creutzberg. Int J Gynecol Cancer 2021;31(Suppl 3):A1-A395. DOI: 10.1136/ijgc-2021-ESGO.171
citation: RAINBO Research Consortium. Refining adjuvant treatment in endometrial cancer based on molecular features: the RAINBO clinical trial program. Int J Gynecol Cancer. 2023 Jan 3;33(1):109-117. doi: 10.1136/ijgc-2022-004039.