Durvalumab With or Without Olaparib as Maintenance Therapy After First-Line Treatment of Advanced and Recurrent Endometrial Cancer

Study Overview
=================
Brief Summary
-----------------
A study to assess the efficacy and safety of durvalumab in combination with platinum-based chemotherapy (paclitaxel + carboplatin) followed by maintenance durvalumab with or without olaparib for patients with newly diagnosed advanced or recurrent endometrial cancer.

Detailed Description
-----------------
This Phase III study will assess the efficacy and safety of durvalumab in combination with platinum-based chemotherapy (paclitaxel + carboplatin) followed by maintenance durvalumab with or without olaparib for patients with newly diagnosed advanced or recurrent endometrial cancer. Target patient population: Adult female patients with histologically confirmed diagnosis of epithelial endometrial carcinoma (excluding sarcomas): newly diagnosed Stage III, newly diagnosed Stage IV, or recurrent endometrial cancer

Official Title
-----------------
A Randomised, Multicentre, Double-blind, Placebo-controlled, Phase III Study of First-line Carboplatin and Paclitaxel in Combination With Durvalumab, Followed by Maintenance Durvalumab With or Without Olaparib in Patients With Newly Diagnosed Advanced or Recurrent Endometrial Cancer (DUO-E)

Conditions
-----------------
Endometrial Neoplasms

Intervention / Treatment
-----------------
* Drug: olaparib
* Biological: durvalumab
* Drug: durvalumab placebo
* Drug: olaparib placebo
* Drug: Carboplatin
* Drug: Paclitaxel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥18 years at the time of screening and female. Histologically confirmed diagnosis of epithelial endometrial carcinoma. All histologies, including carcinosarcomas, will be allowed. Sarcomas will not be allowed. Patient must have endometrial cancer in one of the following categories: Newly diagnosed Stage III disease (measurable disease per RECIST 1.1 following surgery or diagnostic biopsy), Newly diagnosed Stage IV disease (with or without disease following surgery or diagnostic biopsy) Recurrence of disease (measurable or non-measurable disease per RECIST 1.1) where the potential for cure by surgery alone or in combination is poor. Naïve to first line systemic anti-cancer treatment. For patients with recurrent disease only, prior systemic anti-cancer treatment is allowed only if it was administered in the adjuvant setting and there is at least 12 months from date of last dose of systemic anti-cancer treatment administered to date of subsequent relapse FPPE tumor sample must be available for MMR evaluation. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days of starting study treatment. Exclusion Criteria: History of leptomeningeal carcinomatosis. Brain metastases or spinal cord compression. Prior treatment with PARP inhibitors. Any prior exposure to immune-mediated therapy, including (but not limited to) other anti CTLA-4, anti-PD-1, anti-PD-L1, or anti-programmed-cell-death ligand 2 (anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 150 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: double-blind, placebo-controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (control)<br>Platinum-based chemotherapy and durvalumab placebo followed by maintenance durvalumab placebo and olaparib placebo (tablets). | Drug: durvalumab placebo<br>* Matching placebo for intravenous infusion<br>Drug: olaparib placebo<br>* Placebo tablets to match olaparib<br>Drug: Carboplatin<br>* Standard of care chemotherapy<br>Drug: Paclitaxel<br>* Standard of care chemotherapy<br>|
| Experimental: Arm B (durvalumab+placebo)<br>Platinum-based chemotherapy and durvalumab followed by maintenance durvalumab and olaparib placebo | Biological: durvalumab<br>* Durvalumab by intravenous infusion<br>Drug: olaparib placebo<br>* Placebo tablets to match olaparib<br>Drug: Carboplatin<br>* Standard of care chemotherapy<br>Drug: Paclitaxel<br>* Standard of care chemotherapy<br>|
| Experimental: Arm C (durvalumab+olaparib)<br>Platinum-based chemotherapy and durvalumab followed by maintenance durvalumab and olaparib. | Drug: olaparib<br>* Olaparib tablets<br>Biological: durvalumab<br>* Durvalumab by intravenous infusion<br>Drug: Carboplatin<br>* Standard of care chemotherapy<br>Drug: Paclitaxel<br>* Standard of care chemotherapy<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) for Arm B vs Arm A and Arm C vs Arm A | Defined as the time from randomisation until the date of objective disease progression (per RECIST 1.1 as assessed by investigator) or death (by any cause in the absence of progression) | Up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Second Progression (PFS2) | Defined as the time from randomisation to the earliest of progression event subsequent to first subsequent therapy (assessed by the investigator per local standard clinical practice and may involve any of the following: objective radiological imaging, symptomatic progression), or death due to any cause | Up to 6 years | 
| Overall Survival (OS) | Defined as the time from randomisation to death due to any cause | Up to 6 years | 
| Objective Response Rate (ORR) | Defined as the proportion of patients with measurable disease at baseline who have confirmed complete response (CR) or partial response (PR) as determined by the Investigator at local site. | Up to 4 years | 
| Duration of response (DoR) | Defined as time from the date of first documented response until date of documented progression or death in the absence of disease progression | Up to 4 years | 
| Time to first subsequent therapy (TFST) | Defined as the time from randomisation to the earlier of start date of the first subsequent anti-cancer therapy after discontinuation of randomised treatment or death due to any cause | Up to 6 years | 
| Time to second subsequent therapy (TSST) | Defined as the time from randomisation to the earlier of start date of the second subsequent anti-cancer therapy after discontinuation of first subsequent treatment or death due to any cause. | Up to 6 years | 
| Time to discontinuation or death (TDT) | Defined as the time from randomisation to the earlier of the date of study treatment discontinuation or death. | Up to 6 years | 
| The pharmacokinetics (PK) of durvalumab will be determined after steady state doses | Determination of durvalumab concentration in serum | Up to 4 years | 
| Safety and tolerability of drugs by assessment of AEs/SAEs | Graded according to the National Cancer Institute (NCI CTCAE) | Up to 6 years | 
| The immunogenicity of durvalumab as determined by concentration of Anti-drug antibodies (ADA) to durvalumab | Determination concentration of Anti-drug antibodies (ADA) to durvalumab in serum | Up to 4 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cancer of Endometrium, Cancer of the Endometrium, Carcinoma of Endometrium, Endometrial Cancer, Endometrial Carcinoma, Endometrium Cancer, Neoplasms, Endometrial