A Study of Various Treatments in Serous or p53 Abnormal Endometrial Cancer

Study Overview
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Brief Summary
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This a phase II and III study whose purpose is to compare how long various treatment regimens can keep the cancer from worsening or coming back in people with serous or p53 abnormal endometrial cancer. The study is divided into three cohorts: Early stage cohort, advanced stage cohort, and exploratory cohort. Each cohort will have different arms to examine different treatment regimens to determine the best regimen for each cohort. The study will enroll participants into the early stage cohort at this time. The early stage cohort will compare the following treatments after standard of care surgery: Adjuvant chemotherapy with carboplatin and paclitaxel alone Adjuvant radiation therapy and chemotherapy with cisplatin, followed by chemotherapy with carboplatin and paclitaxel.

Detailed Description
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There is currently no standard or usual treatment for serous or p53 abnormal endometrial cancer after standard surgery. Additional treatment may sometimes be given after the main treatment in hopes of preventing the cancer from worsening or coming back (called adjuvant therapy). It is not fully know whether adjuvant therapy after surgery is useful in early stage endometrial cancer. It is also not known what the best adjuvant therapy after surgery is. The most commonly given adjuvant therapy is chemotherapy with carboplatin and paclitaxel. Sometimes, chemotherapy and radiation therapy may be given. There is not enough information available as to how useful adjuvant therapy is and what the most useful type of treatment is. This study will look at adjuvant chemotherapy alone compared with adjuvant radiation therapy and chemotherapy, after standard of care surgery, in patients with serous or p53 abnormal endometrial cancer.

Official Title
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Canadian Multi-arm Multi-stage Randomized Controlled Trial Assessing Front Line Treatment in Serous or p53 Mutant Endometrial Cancer

Conditions
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Endometrial Cancer, Serous Tumor, P53 Mutation

Intervention / Treatment
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* Drug: Cisplatin
* Radiation: External Beam Radiation
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Niraparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with pure serous endometrial carcinoma will be included. Other histotypes (endometrioid and clear cell) with abnormal/mutant-type p53 is acceptable. Local TP53 results must be available for Central review. Patients diagnosed with stage I, II tumors will be enrolled in the early stage cohort. Patients suitable for an optimal surgery. Eastern Cooperative Group (ECOG) performance status ≤ 2 (Karnofsky ≥60%). Life expectancy of greater than 3 months. Patients must have archival tissue available. If no tissue is available, tumor biopsy will be mandatory. Ability to understand and willing to sign a written informed consent document. Within 8 days of the proposed start of treatment, patients must have normal organ and marrow function. Women of child-bearing potential must agree to use effective contraceptive methods prior to study entry, during study participation, and for at least 30 days after the last administration of study medication. Exclusion Criteria: Patients who have previously received chemotherapy or hormonal treatment for endometrial cancer. Any other condition that would contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures. Mixed serous tumours or tumors with subclonal mutant-type p53 staining. Endometrial carcinosarcoma will also be excluded. Patients being treated with radiotherapy within 4 weeks, or palliative radiotherapy encompassing >20% of the bone marrow within 1 week of starting study treatment. Patients who are receiving any other investigational agents. Patients with known brain metastases are excluded from participation unless stable for greater than 1 month following definitive treatment. Patients with evidence of fistula will be excluded. History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in study. Uncontrolled inter-current illness that would limit compliance with study requirements. Pregnant women are excluded. Known HIV-positive patients on antiretroviral therapy or active Hepatitis B or C are ineligible. Patients with a history of other malignancy ≤ 3 years prior to registration, with exceptions.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Early Stage Cohort - Arm A<br>Carboplatin, intravenously, once every 3 weeks for 6 cycles Paclitaxel, intravenously, once every 3 weeks for 6 cycles | Drug: Carboplatin<br>* Chemotherapy drug given by vein.<br>Drug: Paclitaxel<br>* Chemotherapy drug given by vein.<br>|
| Experimental: Early Stage Cohort - Arm B1<br>External beam radiotherapy, 5 days per week, for 4-5 weeks Cisplatin intravenously, on the first and fourth week of radiotherapy. Brachytherapy will be given if needed Then Carboplatin, intravenously, once every 3 weeks for 4 cycles Paclitaxel, intravenously, once every 3 weeks for 4 cycles | Drug: Cisplatin<br>* Chemotherapy drug given by vein.<br>Radiation: External Beam Radiation<br>* Radiation therapy given outside the patient to a particular part of the body.<br>Drug: Carboplatin<br>* Chemotherapy drug given by vein.<br>Drug: Paclitaxel<br>* Chemotherapy drug given by vein.<br>|
| Experimental: Advanced Stage Cohort Arm C<br>Carboplatin, intravenously, once every 3 weeks for 6 cycles Paclitaxel, intravenously, once every 3 weeks for 6 cycles | Drug: Carboplatin<br>* Chemotherapy drug given by vein.<br>Drug: Paclitaxel<br>* Chemotherapy drug given by vein.<br>|
| Experimental: Advanced Stage Cohort Arm D1<br>Carboplatin, intravenously, once every 3 weeks for 6 cycles Paclitaxel, intravenously, once every 3 weeks for 6 cycles Then Niraparib daily continuous dosing for 28 day cycles | Drug: Carboplatin<br>* Chemotherapy drug given by vein.<br>Drug: Paclitaxel<br>* Chemotherapy drug given by vein.<br>Drug: Niraparib<br>* Oral drug<br>|
| No Intervention: Exploratory Cohort<br>Observation on Standard of care | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival Rate | Time from random assignment until disease recurrence or death | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Rate | Time from enrollment until death. | 5 years | 
| Number Adverse Events Experienced |  | 5 years |