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)

The primary objective of this study is to demonstrate the efficacy of **durvalumab** in combination with platinum-based chemotherapy (paclitaxel and carboplatin), followed by maintenance durvalumab (Arm B) or durvalumab with **olaparib** (Arm C), compared to platinum-based chemotherapy alone (Arm A) in patients with newly diagnosed advanced or recurrent **endometrial cancer**. This is assessed by progression-free survival (PFS), which is clinically relevant as it measures the length of time during and after treatment that a patient lives with the disease without it worsening.

Secondary objectives include:

• Determining the efficacy of durvalumab in combination with platinum-based chemotherapy followed by maintenance durvalumab or durvalumab with olaparib compared to platinum-based chemotherapy alone, assessed by PFS2, overall survival (OS), objective response rate (ORR), duration of response (DoR), time to first subsequent therapy (TFST), time to second subsequent therapy (TSST), and time to treatment discontinuation (TDT).
• Characterizing the pharmacokinetics (PK) and immunogenicity of durvalumab and durvalumab in combination with olaparib.
• Evaluating the safety and tolerability of durvalumab in combination with platinum-based chemotherapy followed by maintenance durvalumab or durvalumab with olaparib compared to platinum-based chemotherapy alone.
• Determining the effects on symptoms, functioning, and overall health-related quality of life (HRQoL) of durvalumab in combination with platinum-based chemotherapy followed by maintenance durvalumab or durvalumab with olaparib compared to platinum-based chemotherapy alone.

The clinical trial involves a total of **693 participants** diagnosed with **endometrial cancer**. The study population is exclusively female, with an age range of 18 years and older. Participants were selected based on a histologically confirmed diagnosis of epithelial endometrial carcinoma, including all histologies such as carcinosarcomas, but excluding sarcomas. The trial includes patients with newly diagnosed Stage III or IV disease, as well as those with recurrent disease where surgical cure is unlikely. All participants are required to be naïve to first-line systemic anti-cancer treatment, except for those with recurrent disease who may have received prior treatment in the adjuvant setting, provided there is a minimum 12-month interval since the last chemotherapy dose. An **ECOG performance status** of 0 or 1 is mandatory within 7 days of starting the study treatment. The trial does not include male subjects and considers vulnerable populations. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** Phase III study to evaluate the efficacy of **durvalumab** in combination with platinum-based chemotherapy, followed by maintenance durvalumab with or without **olaparib** in patients with newly diagnosed advanced or recurrent **endometrial cancer**. The trial aims to assess progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival (OS), objective response rate (ORR), and duration of response (DoR), among others. The trial is expected to run from March 2020 to August 2026, with recruitment having commenced in March 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological diagnosis, and performance status. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, including assessments of adverse events, vital signs, and laboratory parameters. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to 360 days, depending on individual response and treatment tolerability.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial's design ensures rigorous monitoring and data collection to evaluate the safety and efficacy of the investigational treatments, contributing valuable insights into the management of advanced or recurrent endometrial cancer.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Myfenax 250 mg hard capsules** contain the active substance **mycophenolate mofetil**. These capsules are administered orally, with a maximum daily dose of 2 grams and a total maximum dose of 28 grams over a treatment period of 14 days. The original commercial packaging will be over-labelled and placed in a carton with local language translated text in accordance with regulatory guidelines.

**Lynparza 100 mg and 150 mg film-coated tablets** contain the active substance **olaparib**. These tablets are administered orally, with a maximum daily dose of 600 mg and a total maximum dose of 1514 grams over a treatment period of 360 days. Olaparib is a potent inhibitor of human poly (ADP-ribose) polymerase enzymes (PARP-1, PARP-2, PARP-3). The tablets are identical to the investigational medicinal product (IMP) except for the commercial deboss/marking and packaging differences to facilitate blinding in placebo-controlled studies.

**IMFINZI 50 mg/mL concentrate for solution for infusion** contains the active substance **durvalumab**. This solution is administered intravenously, with a maximum daily dose of 1500 mg and a total maximum dose of 142 grams over a treatment period of 360 days. The product is provided in its original commercial packaging without modifications.

**Flixabi 100 mg powder for concentrate for solution for infusion** contains the active substance **infliximab**. This solution is administered intravenously, with a maximum daily dose of 5 mg/kg and a total maximum dose of 210 mg/kg over a treatment period of 6 days. The original commercial packaging will be over-labelled and placed in a carton with local language translated text in accordance with regulatory guidelines.

Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of these treatments in patients with newly diagnosed advanced or recurrent endometrial cancer, with a focus on progression-free survival as the primary endpoint.

The efficacy of the clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)**, as defined by the time from randomization until the date of objective disease progression or death from any cause in the absence of progression. This will be evaluated per RECIST 1.1 criteria as assessed by the investigator. Secondary endpoints include second progression-free survival (PFS2), overall survival (OS), objective response rate (ORR), duration of response (DoR), time to first subsequent therapy or death (TFST), time to second subsequent therapy or death (TSST), and time to study treatment discontinuation or death (TDT). Additionally, serum concentrations of durvalumab and anti-drug antibodies (ADA) to durvalumab will be measured.

Data collection will involve objective radiological imaging and symptomatic progression assessments, conducted according to local standard clinical practice. The trial will also monitor safety and tolerability through adverse events (AEs), serious adverse events (SAEs), physical examinations, vital signs, clinical laboratory parameters, and electrocardiograms (ECGs). The trial is designed to compare the efficacy of durvalumab in combination with platinum-based chemotherapy followed by maintenance durvalumab or durvalumab with olaparib against platinum-based chemotherapy alone in patients with newly diagnosed advanced or recurrent endometrial cancer.