RAINBO: Refining Adjuvant Treatment IN Endometrial Cancer Based On Molecular Features

Sponsor
Leiden University Medical Center (Other)
Overall Status
Recruiting
CT.gov ID
NCT05255653
Collaborator
Institute Gustave Roussy (sponsor p53abn-RED trial) (Other), Leiden University Medical center (sponsor MMRd-GREEN trial) (Other), University College London (sponsor NSMP-ORANGE trial) (Other), Canadian Clinical Trials Group (sponsor POLEmut-BLUE trial) (Other), Dutch Gynaecological Oncology Group (Other), Comprehensive Cancer Centre The Netherlands (Other), Cancer Research UK & UCL Cancer Trials Centre (Other), Dutch Cancer Society (Other), AstraZeneca (Industry)
1,611
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7
102.7
268.5
2.6

Study Details

Study Description

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

Condition or Disease Intervention/Treatment Phase
Phase 2/Phase 3

Detailed Description

The p53abn-RED trial is an international, multicenter, phase III randomised trial wherein adjuvant chemoradiation followed by olaparib for two years is compared to adjuvant chemoradiation.

The MMRd-GREEN trial 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.

The NSMP-ORANGE trial 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 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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
1611 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Umbrella 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 single arm clinical trial.Umbrella 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 single arm clinical trial.
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Jun 10, 2022
Anticipated Primary Completion Date :
Jan 1, 2030
Anticipated Study Completion Date :
Jan 1, 2031

Arms and Interventions

Arm Intervention/Treatment
Experimental: p53abn-RED trial: experimental

Adjuvant chemoradiation followed by olaparib (lynparza), 300 mg twice daily, for two years

Drug: Olaparib
300 mg twice daily for two years
Other Names:
  • Lynparza
  • Radiation: Pelvic external beam radiotherapy
    45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week
    Other Names:
  • EBRT
  • Drug: Chemotherapy
    Preferably concurrent and adjuvant according to the PORTEC-3 schedule: two cycles of intravenous cisplatin 50mg/m² in the first and fourth week of the pelvic external beam radiotherapy followed by four cycles of intravenous carboplatin AUC 5 and paclitaxel 175 mg/m² at 21-day intervals.
    Other Names:
  • Cisplatin
  • Carboplatin
  • Paclitaxel
  • Active Comparator: p53abn-RED trial: control

    Adjuvant chemoradiation

    Radiation: Pelvic external beam radiotherapy
    45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week
    Other Names:
  • EBRT
  • Drug: Chemotherapy
    Preferably concurrent and adjuvant according to the PORTEC-3 schedule: two cycles of intravenous cisplatin 50mg/m² in the first and fourth week of the pelvic external beam radiotherapy followed by four cycles of intravenous carboplatin AUC 5 and paclitaxel 175 mg/m² at 21-day intervals.
    Other Names:
  • Cisplatin
  • Carboplatin
  • Paclitaxel
  • Experimental: MMRd-GREEN trial: experimental

    Adjuvant pelvic external beam radiotherapy combined with and followed by durvalumab, 1500 mg intravenous once every 4 weeks for in total 1 year (13 cycles)

    Radiation: Pelvic external beam radiotherapy
    45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week
    Other Names:
  • EBRT
  • Drug: Durvalumab
    1500 mg intravenous once every 4 weeks for in total 1 year (13 cycles) starting within the first week of radiotherapy,
    Other Names:
  • Imfinzi
  • Active Comparator: MMRd-GREEN trial: control

    Adjuvant pelvic external beam radiotherapy

    Radiation: Pelvic external beam radiotherapy
    45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week
    Other Names:
  • EBRT
  • Experimental: NSMP-ORANGE trial: experimental

    Adjuvant pelvic external beam radiotherapy followed by oral progestagens (medroxyprogesterone acetate or megestrol acetate) for two years

    Radiation: Pelvic external beam radiotherapy
    45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week
    Other Names:
  • EBRT
  • Drug: Medroxyprogesterone Acetate
    Oral medroxyprogesterone acetate for two years
    Other Names:
  • Progestogen
  • Drug: Megestrol Acetate
    Oral medroxyprogesterone acetate for two years
    Other Names:
  • Progestogen
  • Active Comparator: NSMP-ORANGE trial: control

    Adjuvant chemoradiation

    Radiation: Pelvic external beam radiotherapy
    45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week
    Other Names:
  • EBRT
  • Drug: Chemotherapy
    Preferably concurrent and adjuvant according to the PORTEC-3 schedule: two cycles of intravenous cisplatin 50mg/m² in the first and fourth week of the pelvic external beam radiotherapy followed by four cycles of intravenous carboplatin AUC 5 and paclitaxel 175 mg/m² at 21-day intervals.
    Other Names:
  • Cisplatin
  • Carboplatin
  • Paclitaxel
  • Experimental: POLEmut-BLUE

    no adjuvant therapy for stage I-II disease and no adjuvant therapy or pelvic external beam radiotherapy only for stage III disease

    Radiation: Pelvic external beam radiotherapy
    45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week
    Other Names:
  • EBRT
  • Other: Observation
    No adjuvant treatment
    Other Names:
  • Watchful waiting
  • No adjuvant treatment
  • Outcome Measures

    Primary Outcome Measures

    1. p53abn-RED trial [3 years]

      Recurrence-free survival

    2. MMRd-GREEN trial [3 years]

      Recurrence-free survival

    3. NSMP-ORANGE trial [3 years]

      Recurrence-free survival

    4. POLEmut-BLUE trial [3 years]

      Pelvic recurrence-free survival

    Secondary Outcome Measures

    1. Recurrence-free survival [5 years]

      All RAINBO trials

    2. Pelvic recurrence-free survival [5 years]

      All RAINBO trials

    3. Vaginal recurrence-free survival [3 years, 5 years]

      All RAINBO trials

    4. Endometrial cancer-specific survival [3 years, 5 years]

      All RAINBO trials

    5. Overall survival [3 years, 5 years]

      All RAINBO trials

    6. Treatment-related toxicity - according to CTCAE v5.0 [3 years, 5 years]

      All RAINBO trials

    7. Health-related quality of life - Assessed using the EORTC QLQ-C30 questionnaire [3 years, 5 years]

      All RAINBO trials

    8. Health-related quality of life - Assessed using the EORTC QLQ-EN24 questionnaire [3 years, 5 years]

      All RAINBO trials

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No

    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 II EC with substantial LVSI or stage 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 Stage III EC or stage II EC with substantial lympovascular space invasion (LVSI)

    • 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

    • PR 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)

    • Histologically confirmed stage I-III EC

    • Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment 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.

    • Patients must be accessible for treatment and follow up. Patients enrolled on this trial must be treated and followed at the participating centre. 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.

    Exclusion criteria:
    • Inability to be registered on study within 10 weeks of hysterectomy procedure

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 The POLEmut-BLUE trial: Princess Margaret Cancer Centre, University of Toronto Toronto Canada
    2 The POLEmut-BLUE trial: University of British Columbia Vancouver Canada
    3 The p53abn-RED trial: Institute Gustave Roussy Villejuif France
    4 The MMRd-GREEN trial: Leiden University Medical Center Leiden Netherlands 2333ZA
    5 The NSMP-ORANGE trial: Barts Health NHS Trust London United Kingdom
    6 The NSMP-ORANGE trial: Manchester Academic Health Science Centre, St Mary's Hospita Manchester United Kingdom

    Sponsors and Collaborators

    • Leiden University Medical Center
    • Institute Gustave Roussy (sponsor p53abn-RED trial)
    • Leiden University Medical center (sponsor MMRd-GREEN trial)
    • University College London (sponsor NSMP-ORANGE trial)
    • Canadian Clinical Trials Group (sponsor POLEmut-BLUE trial)
    • Dutch Gynaecological Oncology Group
    • Comprehensive Cancer Centre The Netherlands
    • Cancer Research UK & UCL Cancer Trials Centre
    • Dutch Cancer Society
    • AstraZeneca

    Investigators

    • Principal Investigator: Alexandra Leary, Md PhD, Institute Gustave Roussy, Villejuif, France (p53abn-RED trial)
    • Principal Investigator: Judith R Kroep, MD PhD, Leiden University Medical Center, Leiden, The Netherlands (MMRd-GREEN trial)
    • Principal Investigator: Melanie E Powell, Md PhD, Barts Health NHS Trust, London, United Kingdom (NSMP-ORANGE trial)
    • Principal Investigator: Emma J Crosbie, Md PhD, St Mary's Hospital, Manchester, United Kingdom (NSMP-ORANGE trial)
    • Principal Investigator: Kathy Han, Md PhD, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada (POLEmut-BLUE trial)
    • Principal Investigator: Jessica N McAlpine, Md PhD, University of British Columbia,Vancouver, Canada (POLEmut-BLUE trial)

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Carien Creutzberg, prof, Leiden University Medical Center
    ClinicalTrials.gov Identifier:
    NCT05255653
    Other Study ID Numbers:
    • RAINBO
    • ENGOT-en14-1,2,3,4
    First Posted:
    Feb 24, 2022
    Last Update Posted:
    Jul 14, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Carien Creutzberg, prof, Leiden University Medical Center
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jul 14, 2022