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Refining Adjuvant Treatment IN Endometrial Cancer Based On Molecular Features (RAINBO)

Primary Purpose

Endometrial Cancer

Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Olaparib
Pelvic external beam radiotherapy
Chemotherapy
Durvalumab
Medroxyprogesterone Acetate
Megestrol Acetate
Vaginal brachytherapy
Observation
Sponsored by
Leiden University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Endometrial Cancer focused on measuring Endometrial Cancer, Molecular risk factors, Olaparib, Durvalumab, Progestagens, Chemoradiation, Radiotherapy, Observation, p53, MMRd, NSMP, POLE

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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 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
  • 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)
  • 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

Sites / Locations

  • The POLEmut-BLUE trial: Princess Margaret Cancer Centre, University of TorontoRecruiting
  • The POLEmut-BLUE trial: University of British ColumbiaRecruiting
  • The p53abn-RED trial: Institute Gustave Roussy
  • Amsterdam University Medical CenterRecruiting
  • Amphia ZiekenhuisRecruiting
  • Instituut VerbeetenRecruiting
  • Haags Medisch CentrumRecruiting
  • Catharina ZiekenhuisRecruiting
  • Medisch Spectrum TwenteRecruiting
  • Universitair Medisch Centrum GroningenRecruiting
  • The MMRd-GREEN trial: Leiden University Medical CenterRecruiting
  • Erasmus Medical CenterRecruiting
  • The NSMP-ORANGE trial: Barts Health NHS Trust
  • The NSMP-ORANGE trial: Manchester Academic Health Science Centre, St Mary's Hospita

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm Type

Experimental

Active Comparator

Experimental

Active Comparator

Experimental

Active Comparator

Other

Other

Arm Label

p53abn-RED trial: experimental

p53abn-RED trial: control

MMRd-GREEN trial: experimental

MMRd-GREEN trial: control

NSMP-ORANGE trial: experimental

NSMP-ORANGE trial: control

POLEmut-BLUE trial: main cohort

POLEmut-BLUE trial: exploratory cohort

Arm Description

Adjuvant radiotherapy and chemotherapy followed by olaparib (lynparza), 300 mg twice daily, for two years

Adjuvant radiotherapy and chemotherapy

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

Adjuvant pelvic external beam radiotherapy

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

Adjuvant radiotherapy and chemotherapy

No adjuvant therapy in women with: 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

No adjuvant therapy or vaginal brachytherapy or pelvic external beam radiotherapy in women with: stage IA (not confined to polyp), grade 3, pNx, with or without LVSI stage IB, grade 3, pNx, with or with LVSI. stage IB, grade 3, pN0, with substantial LVSI. stage II (microscopic), grade 1 or 2, pNx, with or without LVSI. stage II (microscopic), grade 1 or 2, pN0, with substantial LVSI. stage II (microscopic), grade 3, pNx/N0, with or without LVSI. stage II non-microscopic, any grade, pNx/N0, with or without LVSI. stage III, any grade, pNx/N0-2, with or without LVSI.

Outcomes

Primary Outcome Measures

p53abn-RED trial
Recurrence-free survival
MMRd-GREEN trial
Recurrence-free survival
NSMP-ORANGE trial
Recurrence-free survival
POLEmut-BLUE trial
Pelvic recurrence-free survival

Secondary Outcome Measures

Recurrence-free survival
All RAINBO trials
Pelvic recurrence-free survival
All RAINBO trials
Vaginal recurrence-free survival
All RAINBO trials
Endometrial cancer-specific survival
All RAINBO trials
Overall survival
All RAINBO trials
Treatment-related toxicity - according to CTCAE v5.0
All RAINBO trials
Health-related quality of life - Assessed using the EORTC QLQ-C30 questionnaire
All RAINBO trials
Health-related quality of life - Assessed using the EORTC QLQ-EN24 questionnaire
All RAINBO trials

Full Information

First Posted
February 1, 2022
Last Updated
July 11, 2023
Sponsor
Leiden University Medical Center
Collaborators
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, National Cancer Institute, France, Canadian Institutes of Health Research (CIHR)
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1. Study Identification

Unique Protocol Identification Number
NCT05255653
Brief Title
Refining Adjuvant Treatment IN Endometrial Cancer Based On Molecular Features
Acronym
RAINBO
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

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 11, 2021 (Actual)
Primary Completion Date
January 1, 2030 (Anticipated)
Study Completion Date
January 1, 2031 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Leiden University Medical Center
Collaborators
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, National Cancer Institute, France, Canadian Institutes of Health Research (CIHR)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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
Detailed Description
The p53abn-RED trial (NCT05255653-1) 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 (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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Endometrial Cancer
Keywords
Endometrial Cancer, Molecular risk factors, Olaparib, Durvalumab, Progestagens, Chemoradiation, Radiotherapy, Observation, p53, MMRd, NSMP, POLE

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
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 prospective clinical trial with two study arms.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
1615 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
p53abn-RED trial: experimental
Arm Type
Experimental
Arm Description
Adjuvant radiotherapy and chemotherapy followed by olaparib (lynparza), 300 mg twice daily, for two years
Arm Title
p53abn-RED trial: control
Arm Type
Active Comparator
Arm Description
Adjuvant radiotherapy and chemotherapy
Arm Title
MMRd-GREEN trial: experimental
Arm Type
Experimental
Arm Description
Adjuvant radiotherapy combined with and followed by durvalumab, 1500 mg intravenous once every 4 weeks for in total 1 year (13 cycles)
Arm Title
MMRd-GREEN trial: control
Arm Type
Active Comparator
Arm Description
Adjuvant pelvic external beam radiotherapy
Arm Title
NSMP-ORANGE trial: experimental
Arm Type
Experimental
Arm Description
Adjuvant radiotherapy followed by oral progestagens (medroxyprogesterone acetate or megestrol acetate) for two years
Arm Title
NSMP-ORANGE trial: control
Arm Type
Active Comparator
Arm Description
Adjuvant radiotherapy and chemotherapy
Arm Title
POLEmut-BLUE trial: main cohort
Arm Type
Other
Arm Description
No adjuvant therapy in women with: 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
Arm Title
POLEmut-BLUE trial: exploratory cohort
Arm Type
Other
Arm Description
No adjuvant therapy or vaginal brachytherapy or pelvic external beam radiotherapy in women with: stage IA (not confined to polyp), grade 3, pNx, with or without LVSI stage IB, grade 3, pNx, with or with LVSI. stage IB, grade 3, pN0, with substantial LVSI. stage II (microscopic), grade 1 or 2, pNx, with or without LVSI. stage II (microscopic), grade 1 or 2, pN0, with substantial LVSI. stage II (microscopic), grade 3, pNx/N0, with or without LVSI. stage II non-microscopic, any grade, pNx/N0, with or without LVSI. stage III, any grade, pNx/N0-2, with or without LVSI.
Intervention Type
Drug
Intervention Name(s)
Olaparib
Other Intervention Name(s)
Lynparza
Intervention Description
300 mg twice daily for two years
Intervention Type
Radiation
Intervention Name(s)
Pelvic external beam radiotherapy
Other Intervention Name(s)
EBRT
Intervention Description
45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week
Intervention Type
Drug
Intervention Name(s)
Chemotherapy
Other Intervention Name(s)
Cisplatin, Carboplatin, Paclitaxel
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Durvalumab
Other Intervention Name(s)
Imfinzi
Intervention Description
1500 mg intravenous once every 4 weeks for in total 1 year (13 cycles) starting within the first week of radiotherapy,
Intervention Type
Drug
Intervention Name(s)
Medroxyprogesterone Acetate
Other Intervention Name(s)
Progestogen
Intervention Description
Oral medroxyprogesterone acetate for two years
Intervention Type
Drug
Intervention Name(s)
Megestrol Acetate
Other Intervention Name(s)
Progestogen
Intervention Description
Oral medroxyprogesterone acetate for two years
Intervention Type
Radiation
Intervention Name(s)
Vaginal brachytherapy
Intervention Description
Vaginal brachytherapy is to be considered in patients with documented cervical stromal involvement and/or substantial LVSI. Brachytherapy is given with a vaginal cylinder or vaginal ovoids or ring applicator, according to the center's standard technique. When using a cylinder, the active length will ideally be 2-3 cm, with the reference isodose covering the proximal 2.5-3 cm of the vagina. High-dose-rate (HDR) and pulse-dose-rate (PDR) schedules are permitted, which deliver an EQD2 equivalent dose of 10-14 Gy at 5 mm from the vaginal mucosa (to obtain a cumulative EDQ2 of 60 Gy at 5 mm).
Intervention Type
Other
Intervention Name(s)
Observation
Intervention Description
No adjuvant therapy
Primary Outcome Measure Information:
Title
p53abn-RED trial
Description
Recurrence-free survival
Time Frame
3 years
Title
MMRd-GREEN trial
Description
Recurrence-free survival
Time Frame
3 years
Title
NSMP-ORANGE trial
Description
Recurrence-free survival
Time Frame
3 years
Title
POLEmut-BLUE trial
Description
Pelvic recurrence-free survival
Time Frame
3 years
Secondary Outcome Measure Information:
Title
Recurrence-free survival
Description
All RAINBO trials
Time Frame
5 years
Title
Pelvic recurrence-free survival
Description
All RAINBO trials
Time Frame
5 years
Title
Vaginal recurrence-free survival
Description
All RAINBO trials
Time Frame
3 years, 5 years
Title
Endometrial cancer-specific survival
Description
All RAINBO trials
Time Frame
3 years, 5 years
Title
Overall survival
Description
All RAINBO trials
Time Frame
3 years, 5 years
Title
Treatment-related toxicity - according to CTCAE v5.0
Description
All RAINBO trials
Time Frame
3 years, 5 years
Title
Health-related quality of life - Assessed using the EORTC QLQ-C30 questionnaire
Description
All RAINBO trials
Time Frame
3 years, 5 years
Title
Health-related quality of life - Assessed using the EORTC QLQ-EN24 questionnaire
Description
All RAINBO trials
Time Frame
3 years, 5 years

10. Eligibility

Sex
Female
Gender Based
Yes
Gender Eligibility Description
Female sex
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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 Stage III EC or stage IB/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 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, pNx, with or without LVSI stage IB, grade 3, pNx, with or with LVSI. stage IB, grade 3, pN0, with substantial LVSI. stage II (microscopic), grade 1 or 2, pNx, with or without LVSI. stage II (microscopic), grade 1 or 2, pN0, with substantial LVSI. stage II (microscopic), grade 3, pNx/N0, with or without LVSI. stage II non-microscopic, any grade, pNx/N0, with or without LVSI. stage III, any grade, pNx/N0-2, with or without LVSI. 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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Carien L Creutzberg, MD PhD
Phone
+31 71 52 65539
Email
c.l.creutzberg@lumc.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Nanda Horeweg, MD PhD
Phone
+31 71 52 65539
Email
n.horeweg@lumc.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alexandra Leary, Md PhD
Organizational Affiliation
Institute Gustave Roussy, Villejuif, France (p53abn-RED trial)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Judith R Kroep, MD PhD
Organizational Affiliation
Leiden University Medical Center, Leiden, The Netherlands (MMRd-GREEN trial)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Melanie E Powell, Md PhD
Organizational Affiliation
Barts Health NHS Trust, London, United Kingdom (NSMP-ORANGE trial)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Emma J Crosbie, Md PhD
Organizational Affiliation
St Mary's Hospital, Manchester, United Kingdom (NSMP-ORANGE trial)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Kathy Han, Md PhD
Organizational Affiliation
Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada (POLEmut-BLUE trial)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jessica N McAlpine, Md PhD
Organizational Affiliation
University of British Columbia,Vancouver, Canada (POLEmut-BLUE trial)
Official's Role
Principal Investigator
Facility Information:
Facility Name
The POLEmut-BLUE trial: Princess Margaret Cancer Centre, University of Toronto
City
Toronto
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kathy Han, MD PhD
Email
Kathy.Han@rmp.uhn.ca
Facility Name
The POLEmut-BLUE trial: University of British Columbia
City
Vancouver
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jessica N McAlpine, MD PhD
Email
Jessica.Mcalpine@vch.ca
Facility Name
The p53abn-RED trial: Institute Gustave Roussy
City
Villejuif
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alexandra Leary, MD PhD
Email
alexandra.LEARY@gustaveroussy.fr
Facility Name
Amsterdam University Medical Center
City
Amsterdam
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anneke M Westermann, Md PhD
Email
a.m.westermann@amc.uva.nl
Facility Name
Amphia Ziekenhuis
City
Breda
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joan Heijns, MD PhD
Email
jheijns@amphia.nl
Facility Name
Instituut Verbeeten
City
Breda
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Frederieke Koppe
Email
koppe.f@bvi.nl
Facility Name
Haags Medisch Centrum
City
Den Haag
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mandy Kiderlen, Md PhD
Email
m.kiderlen@haaglandenmc.nl
Facility Name
Catharina Ziekenhuis
City
Eindhoven
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Annemarie Thijs
Email
annemarie.thijs@catharinaziekenhuis.nl
Facility Name
Medisch Spectrum Twente
City
Enschede
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
A Wymenga, MD PhD
Email
a.wymenga@mst.nl
Facility Name
Universitair Medisch Centrum Groningen
City
Groningen
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ann KL Reyners, MD PhD
Email
a.k.l.reyners@umcg.nl
Facility Name
The MMRd-GREEN trial: Leiden University Medical Center
City
Leiden
ZIP/Postal Code
2333ZA
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Judith R Kroep, MD PhD
Phone
+31 71 526 5095
Email
j.r.kroep@lumc.nl
First Name & Middle Initial & Last Name & Degree
Merve Kaya, MD
Phone
+31 71 529 9661
Email
m.kaya@lumc.nl
Facility Name
Erasmus Medical Center
City
Rotterdam
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ingrid Boere, Md PhD
Email
i.boere@erasmusmc.nl
Facility Name
The NSMP-ORANGE trial: Barts Health NHS Trust
City
London
Country
United Kingdom
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Melanie E Powell, MD PhD
Email
melanie.powell10@nhs.net
Facility Name
The NSMP-ORANGE trial: Manchester Academic Health Science Centre, St Mary's Hospita
City
Manchester
Country
United Kingdom
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Emma J Crosbie, MD PhD
Email
Emma.Crosbie@manchester.ac.uk

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Following the planned translational work in the RAINBO programme and publications, the translational research (TR) committee will open up the sample collection to external researchers. Access will be granted following completion of a research proposal form and approval by the TR committee chaired by Dr. Tjalling Bosse. All external researchers will be expected to demonstrate funding for their project and ethics approval. Data will be made available as required through data sharing agreements. The following will be reviewed when considering applications for data sharing and sample access: data and sample use is in-keeping with patient consent, the proposed project has scientific value, with defined objectives and study plan, trial data are appropriate for the intended purpose, acknowledgement of the RAINBO Programme in all publications that arise from the data sharing, compliance with legal and regulatory requirements as applicable and patient confidentiality maintained at all times.
IPD Sharing Time Frame
The study protocols of the four trials will be made made available on the trial's websites by the time the trials open
IPD Sharing Access Criteria
Public
Citations:
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
Results Reference
background
PubMed Identifier
36600534
Citation
RAINBO Research Consortium. Refining adjuvant treatment in endometrial cancer based on molecular features: the RAINBO clinical trial program. Int J Gynecol Cancer. 2022 Dec 20;33(1):109-17. doi: 10.1136/ijgc-2022-004039. Online ahead of print.
Results Reference
background

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Refining Adjuvant Treatment IN Endometrial Cancer Based On Molecular Features

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