- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04705649
Tailored Adjuvant Therapy in POLE-mutated and p53-wildtype Early Stage Endometrial Cancer (TAPER)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Purpose:
This proposal will for the first time test the clinical utility of ProMisE in a pan-Canadian setting. Through molecular classification, Investigators are closer to providing consistent treatment to women with EC reducing disparities in care as might be observed according to geography/access to care, and/or racial differences. As the primary focus for this trial investigators will focus on identifying women investigators believe may be overtreated, working to avoid giving toxic therapies with consequential side effects of treatment as many women with EC may be cured by surgery alone. However, by performing molecular classification for all new ECs enrolled investigators will also be able to identify women who are at increased risk of recurrence or death from their disease based on molecular features and direct them to molecular-subtype-specific clinical trials. This will, investigators believe, reduce undertreatment (not identifying and treating women at high risk for recurrence) and will help select the best treatment according to an individuals tumor biology. In summary, the research proposed will assess the feasibility and impact of ProMisE-directed care within a rigorous clinical setting - fulfilling the last step in bringing molecular classification-driven care to women across the country with EC and ultimately improving outcomes for women with this disease.
Hypothesis:
There is a subgroup of early stage endometrial carcinomas that are at very low risk of pelvic recurrence and can be identified through molecular classification providing an opportunity to withhold or deescalate adjuvant therapy.
Objectives:
Primary Objective:
Determine if women with POLE-mutated or p53 wild type/NSMP early stage endometrial cancer who undergo surgery (hysterectomy, BSO, +/-LND)have a low risk (<5%) risk of pelvic (including vaginal) recurrence at 3 years with no or de-escalated adjuvant treatment.
Secondary Objectives:
- Determine recurrence-free survival.
- Determine overall survival.
- Determine sites of recurrence (vaginal, pelvic, distant).
- Determine health economic impact of molecular classification-tailored adjuvant therapy on the cost of treating endometrial cancer
- Determine the impact of molecular classification on patient Decisional Conflict Scale (DCS)
- Determine if variability in adjuvant treatment given to women with endometrial cancer is decreased by molecular classification-tailored adjuvant therapy as compared to current/historic standard of care.
Exploratory Objectives:
1. Are there additional molecular parameters that further stratify risk of recurrence within POLE or p53wt ECs.
Other mutations are also on the Contextual Genomics FindIt™ panel and will be recorded for testing of prognostic or predictive value but will not be used to stratify care nor direct therapy in real time. Similarly L1CAM IHC on whole sections of representative tumor will be performed and tested for associations with outcomes. Additional analysis might include further IHC, proteomic, epigenetic assessment, and immune markers.Investigators will have the opportunity to weigh multiple molecular and clinicopathological parameters captured in data collection post hoc to see if any of these improve prognostic ability when applied with ProMisE.
Research design:
This is A single arm prospective cohort study is the most efficient trial design to address the primary hypothesis. Study investigators have experience with similar successful trials in other disease sites (breast-DUCHESS, LUMINA). Some components of this molecular based tool are now widely reported on standard of care pathology reports (MMRd, p53) making the possibility of creating a cohort blinded to these molecular results and thus randomization of this cohort impractical. With implications of these molecular features impacting HCP referrals, pathology categorization, and treatment opportunities (e.g., immune blockade) it is not appropriate to withhold these molecular results from patients. Randomization and creation of true blinded cohorts are therefore no longer feasible. Despite increasing availability of some of these molecular features in most cancer centers, POLE mutation testing has not routinely been available, and as yet there are no algorithms to direct management based upon molecular status thus practice variability is large. A prospective trial will get all components of the molecular classifier into the hands of clinicians and patients. Investigators have evidence-based publications supporting treatment recommendations herein, although taken from retrospective series or preclinical work. Investigators have a randomized controlled trial in molecular classification-driven care (PORTEC4a) that although not mature enough to be published has revealed no concerns for higher rates of adverse events in the observation-only arms that would threaten continuation. As clinicians are already beginning to factor molecular features into their management recommendations it is imperative that investigators measure the impact of implementation of molecular based triage in a controlled setting. This will enable us to have preassigned 'stop' mechanisms in place if higher than anticipated recurrence rates are note and has the potential to change future algorithms for care.
NB: This trial will be conducted in compliance with the protocol, GCP and all applicable regulatory requirements.
Statistical design:
Primary Endpoint:
The primary aim of this study is to provide reliable estimates of the 3-year cumulative incidence of pelvic recurrence, and to confirm that this probability is sufficiently low e.g. de-escalation or no adjuvant therapy is safe in molecular classification selected early stage ECs.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
British Columbia
-
Vancouver, British Columbia, Canada, V5Z 2E6
- BC Cancer - Vancouver Centre
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Histologically confirmed endometrial carcinoma, with one of the following combinations of FIGO stage, grade, and LVI: Stage IA (not confined to polyp), grade 3 (with or without LVI), pN0 Stage IB, grade 1, 2 pNx/N0 with or without LVI Stage IB, grade 3 without LVI pN0 Stage II (microscopic), grade 1 or 2, pN0 and without substantial LVI Surgery consisting of hysterectomy (total abdominal, laparoscopic or robotic-assisted) and bilateral salpingo-oophorectomy. Lymph node dissection can be performed as per institutional standards (sentinel or full lymphadenectomy). Pelvic LN assessment is required for grade 3 or stage II cancers. Para-aortic lymphadenectomy is not mandated.
- Age ≥18 years
- Eastern Cooperative Group (ECOG) performance status 0, 1 or 2.
- Ability to understand and willing to sign a written informed consent document.
Exclusion Criteria:
- Prior chemotherapy for endometrial cancer or previous pelvic radiation.
- History of another invasive malignancy, except for non-melanoma skin cancers or tumors curatively treated with no evidence of disease for ≥ 5 years
- Inability to be registered and receive treatment within 12 weeks of hysterectomy .
- Abnormal p53 (p53abn) and/or mismatch repair deficiency (MMRd) on immunohistochemistry without pathogenic POLE mutation.
- MELF (microcystic, elongated and fragmented (MELF)) pattern of invasion is excluded within p53wt/NSMP tumors, not POLEmut
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Pelvic recurrence
Time Frame: every 6 months for the first 3 years
|
recurrent disease in the pelvis (including the vagina)
|
every 6 months for the first 3 years
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Recurrence free survival
Time Frame: every 6 months for the first 3 years
|
duration of time from registration to time of relapse or death, whichever occurs first
|
every 6 months for the first 3 years
|
Overall survival
Time Frame: every 6 months for the first 3 years
|
duration of time from registration to time of death from any cause.
|
every 6 months for the first 3 years
|
Sites of relapse
Time Frame: every 6 months for the first 3 years
|
local (vagina), regional (pelvic and/or paraaortic nodal), or distant.
|
every 6 months for the first 3 years
|
Patient Decisional Conflict Scale
Time Frame: through study completion, an average of 3 years
|
a validated tool reflecting patient decision making prior to and post intervention or new information
|
through study completion, an average of 3 years
|
Variation in treatment
Time Frame: through study completion, an average of 3 years
|
proportion of cases enrolled where adjuvant treatment administered deviated from recommendations
|
through study completion, an average of 3 years
|
Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- TAPER
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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