Overview
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
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.
Eligibility
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)