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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 1,615
- 试验地点
- 16
- 主要终点
- p53abn-RED trial
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Participants of the four RAINBO trials should be eligible according to the inclusion and
排除标准
- •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). \<\\> AND ALT (SGPT) and/or AST (SGOT) ≤2.5 x ULN
- •Exclusion criteria:
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研究组 & 干预措施
p53abn-RED trial: experimental
Adjuvant radiotherapy and chemotherapy followed by olaparib (lynparza), 300 mg twice daily, for one year
干预措施: Olaparib (Drug)
p53abn-RED trial: experimental
Adjuvant radiotherapy and chemotherapy followed by olaparib (lynparza), 300 mg twice daily, for one year
干预措施: Pelvic external beam radiotherapy (Radiation)
p53abn-RED trial: control
Adjuvant radiotherapy and chemotherapy
干预措施: Chemotherapy (Drug)
p53abn-RED trial: experimental
Adjuvant radiotherapy and chemotherapy followed by olaparib (lynparza), 300 mg twice daily, for one year
干预措施: Chemotherapy (Drug)
MMRd-GREEN trial: experimental
Adjuvant radiotherapy combined with and followed by durvalumab, 1500 mg intravenous once every 4 weeks for in total 1 year (13 cycles)
干预措施: Pelvic external beam radiotherapy (Radiation)
p53abn-RED trial: experimental
Adjuvant radiotherapy and chemotherapy followed by olaparib (lynparza), 300 mg twice daily, for one year
干预措施: Vaginal brachytherapy (Radiation)
p53abn-RED trial: control
Adjuvant radiotherapy and chemotherapy
干预措施: Pelvic external beam radiotherapy (Radiation)
p53abn-RED trial: control
Adjuvant radiotherapy and chemotherapy
干预措施: Vaginal brachytherapy (Radiation)
MMRd-GREEN trial: experimental
Adjuvant radiotherapy combined with and followed by durvalumab, 1500 mg intravenous once every 4 weeks for in total 1 year (13 cycles)
干预措施: Vaginal brachytherapy (Radiation)
MMRd-GREEN trial: control
Adjuvant pelvic external beam radiotherapy +/- chemotherapy
干预措施: Pelvic external beam radiotherapy (Radiation)
MMRd-GREEN trial: control
Adjuvant pelvic external beam radiotherapy +/- chemotherapy
干预措施: Chemotherapy (Drug)
MMRd-GREEN trial: control
Adjuvant pelvic external beam radiotherapy +/- chemotherapy
干预措施: Vaginal brachytherapy (Radiation)
NSMP-ORANGE trial: experimental
Adjuvant radiotherapy followed by oral progestagens (medroxyprogesterone acetate or megestrol acetate) for two years
干预措施: Pelvic external beam radiotherapy (Radiation)
NSMP-ORANGE trial: experimental
Adjuvant radiotherapy followed by oral progestagens (medroxyprogesterone acetate or megestrol acetate) for two years
干预措施: Vaginal brachytherapy (Radiation)
NSMP-ORANGE trial: control
Adjuvant radiotherapy and chemotherapy
干预措施: Pelvic external beam radiotherapy (Radiation)
NSMP-ORANGE trial: control
Adjuvant radiotherapy and chemotherapy
干预措施: Chemotherapy (Drug)
NSMP-ORANGE trial: control
Adjuvant radiotherapy and chemotherapy
干预措施: Vaginal brachytherapy (Radiation)
POLEmut-BLUE trial: main cohort
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
干预措施: Observation (Other)
POLEmut-BLUE trial: exploratory cohort
No adjuvant therapy or vaginal brachytherapy or pelvic external beam radiotherapy in women with:
- stage IA grade 3 - stage III not included in main cohort of the POLEmut-BLUE trial
- Multiple molecular classifiers Stage IA (not confined to polyp), grade 3 - Stage III
干预措施: Pelvic external beam radiotherapy (Radiation)
POLEmut-BLUE trial: exploratory cohort
No adjuvant therapy or vaginal brachytherapy or pelvic external beam radiotherapy in women with:
- stage IA grade 3 - stage III not included in main cohort of the POLEmut-BLUE trial
- Multiple molecular classifiers Stage IA (not confined to polyp), grade 3 - Stage III
干预措施: Vaginal brachytherapy (Radiation)
POLEmut-BLUE trial: exploratory cohort
No adjuvant therapy or vaginal brachytherapy or pelvic external beam radiotherapy in women with:
- stage IA grade 3 - stage III not included in main cohort of the POLEmut-BLUE trial
- Multiple molecular classifiers Stage IA (not confined to polyp), grade 3 - Stage III
干预措施: Observation (Other)
MMRd-GREEN trial: experimental
Adjuvant radiotherapy combined with and followed by durvalumab, 1500 mg intravenous once every 4 weeks for in total 1 year (13 cycles)
干预措施: Durvalumab (Drug)
NSMP-ORANGE trial: experimental
Adjuvant radiotherapy followed by oral progestagens (medroxyprogesterone acetate or megestrol acetate) for two years
干预措施: Medroxyprogesterone Acetate (Drug)
NSMP-ORANGE trial: experimental
Adjuvant radiotherapy followed by oral progestagens (medroxyprogesterone acetate or megestrol acetate) for two years
干预措施: Megestrol Acetate (Drug)
结局指标
主要结局
p53abn-RED trial
时间窗: 3 years
Recurrence-free survival
MMRd-GREEN trial
时间窗: 3 years
Recurrence-free survival
NSMP-ORANGE trial
时间窗: 3 years
Recurrence-free survival
POLEmut-BLUE trial
时间窗: 3 years
Pelvic recurrence-free survival
次要结局
- Endometrial cancer-specific survival(3 years, 5 years)
- Overall survival(3 years, 5 years)
- Treatment-related toxicity - according to CTCAE v5.0(3 years, 5 years)
- Recurrence-free survival(5 years)
- Pelvic recurrence-free survival(5 years)
- Vaginal recurrence-free survival(3 years, 5 years)
- Health-related quality of life - Assessed using the EORTC QLQ-C30 questionnaire(3 years, 5 years)
- Health-related quality of life - Assessed using the EORTC QLQ-EN24 questionnaire(3 years, 5 years)
研究者
Carien Creutzberg
prof
Leiden University Medical Center