Durvalumab Treatment in Combination With Chemotherapy and Bevacizumab, Followed by Maintenance Durvalumab, Bevacizumab and Olaparib Treatment in Advanced Ovarian Cancer Patients

Study Overview
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Brief Summary
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This is a Phase III randomised, double-blind, multi-centre study to evaluate the efficacy and safety of durvalumab in combination with standard of care platinum based chemotherapy and bevacizumab followed by maintenance durvalumab and bevacizumab or durvalumab, bevacizumab and olaparib in patients with newly diagnosed advanced ovarian cancer.

Detailed Description
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Eligible patients will be those patients with newly diagnosed, histologically confirmed advanced (Fédération Internationale de Gynécologie et d'Obstétrique [FIGO] Stage III-IV) ovarian, primary peritoneal cancer and/or fallopian-tube cancer. All patients should be candidates for cytoreductive surgery which could be conducted as immediate upfront primary surgery following diagnosis or can be conducted after initiation of platinum based neoadjuvant chemotherapy. All patients should be eligible to start first line platinum based chemotherapy in combination with bevacizumab. The study aims to evaluate the efficacy and safety of standard of care (SoC) platinum-based chemotherapy and bevacizumab followed by maintenance bevacizumab either as monotherapy, or in combination with durvalumab, or in combination with durvalumab and olaparib. Therefore, this study aims to see which combination allows patients to live longer without the cancer coming back or getting worse. The study is also looking to see which combination makes patients live longer and how the treatment and the cancer affects their quality of life.

Official Title
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A Phase III Randomised, Double-Blind, Placebo-Controlled, Multicentre Study of Durvalumab in Combination With Chemotherapy and Bevacizumab, Followed by Maintenance Durvalumab, Bevacizumab and Olaparib in Newly Diagnosed Advanced Ovarian Cancer Patients (DUO-O).

Conditions
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Advanced Ovarian Cancer

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Durvalumab
* Drug: Olaparib
* Drug: Placebo olaparib
* Drug: Durvalumab placebo
* Drug: Carboplatin+Paclitaxel


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Female patients with newly diagnosed, histologically confirmed, advanced (Stage III-IV) high grade epithelial ovarian cancer including high grade serious, high grade endometriod, clear cell ovarian cancer or carcinosarcoma, primary peritoneal cancer and / or fallopian-tube cancer Patients must be aged ≥18 years of age. For patients enrolled in Japan that are aged <20 year All patients should be candidates for cytoreductive surgery either: upfront primary surgery OR plan to undergo chemotherapy with interval debulking surgery Evidence of presence or absence of BRCA1/2 mutation in tumour tissue Mandatory provision of tumour sample for centralised tBRCA testing ECOG performance status 0-1 Patients must have preserved organ and bone marrow function Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test Key Exclusion Criteria: Non-epithelial ovarian cancer, borderline tumors, low grade epithelial tumors or mucinous histology Prior systemic anti-cancer therapy for ovarian cancer Inability to determine the presence or absence of a deleterious or suspected deleterious BRCA mutation Prior treatment with PARP inhibitor or immune mediated therapy Planned intraperitoneal cytotoxic chemotherapy Active or prior documented autoimmune or inflammatory disorders Patients considered a poor medical risk due to a serious, uncontrolled intercurrent illness Clinically significant cardiovascular disease Patients with known brain metastases History of another primary malignancy except for: Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study treatment and of low potential risk for recurrence (patients who have received prior adjuvant chemotherapy for early stage breast cancer may be eligible, provided that it was completed ≥3 years prior to registration, and that the patient remains free of recurrent or metastatic disease) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated carcinoma in situ without evidence of disease Endometrial cancer FIGO Stage IA, Grade 1 or Grade 2 Persistent toxicities CTCAE Grade >2 caused by previous cancer therapy Patients with a known hypersensitivity to olaparib, durvalumab or any of the excipients of these products and to the combination/comparator agents Breast feeding women

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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
Interventional Model Description: The study consists of 2 independent cohorts: 3 double-blind treatment arms cohort for patients with no tBRCA mutation, and a single open label arm cohort for patients with tBRCA mutation
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1<br>Platinum-based chemotherapy in combination with bevacizumab and durvalumab placebo (saline IV infusion) followed by maintenance bevacizumab, durvalumab placebo (saline IV infusion) and olaparib placebo (tablets). | Drug: Bevacizumab<br>* Bevacizumab by intravenous infusion. In tBRCAm cohort bevacizumab is optional according to local practice.<br>Drug: Placebo olaparib<br>* Placebo tablets to match olaparib<br>Drug: Durvalumab placebo<br>* Matching placebo for intravenous infusion<br>Drug: Carboplatin+Paclitaxel<br>* Standard of care chemotherapy<br>|
| Experimental: Arm 2<br>Platinum-based chemotherapy in combination with bevacizumab and durvalumab followed by maintenance bevacizumab, durvalumab and olaparib placebo. | Drug: Bevacizumab<br>* Bevacizumab by intravenous infusion. In tBRCAm cohort bevacizumab is optional according to local practice.<br>Drug: Durvalumab<br>* Durvalumab by intravenous infusion<br>Drug: Placebo olaparib<br>* Placebo tablets to match olaparib<br>Drug: Carboplatin+Paclitaxel<br>* Standard of care chemotherapy<br>|
| Experimental: Arm 3<br>Platinum-based chemotherapy in combination with bevacizumab and durvalumab followed by maintenance bevacizumab, durvalumab and olaparib. | Drug: Bevacizumab<br>* Bevacizumab by intravenous infusion. In tBRCAm cohort bevacizumab is optional according to local practice.<br>Drug: Durvalumab<br>* Durvalumab by intravenous infusion<br>Drug: Olaparib<br>* Olaparib tablets<br>Drug: Carboplatin+Paclitaxel<br>* Standard of care chemotherapy<br>|
| Experimental: tBRCAm cohort<br>Platinum-based chemotherapy in combination with bevacizumab and durvalumab followed by maintenance bevacizumab, durvalumab and olaparib. Bevacizumab is optional according to local practice. | Drug: Bevacizumab<br>* Bevacizumab by intravenous infusion. In tBRCAm cohort bevacizumab is optional according to local practice.<br>Drug: Durvalumab<br>* Durvalumab by intravenous infusion<br>Drug: Olaparib<br>* Olaparib tablets<br>Drug: Carboplatin+Paclitaxel<br>* Standard of care chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) - in non-tBRCA HRD positive patients | Defined as time from randomisation to first progression by investigator assessment using modified RECIST 1.1 or death (by any cause in the absence of progression) | Approximately 4 years | 
| Progression Free Survival (PFS) - in all non-tBRCA patients | Defined as time from randomisation to first progression by investigator assessment using modified RECIST 1.1 or death (by any cause in the absence of progression) | Approximately 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) - in non-tBRCAm patients | Defined as time from randomisation to first progression by investigator assessment using modified RECIST 1.1 or death (by any cause in the absence of progression) | Approximately 4 years | 
| Overall Survival (OS) - in non-tBRCA HRD positive patients and in all non-tBRCA patients | Defined as the time from randomisation to death due to any cause | Approximately 7 years | 
| Second Progression (PFS2) - in non-tBRCAm patients | Defined as time from randomisation to second progression by investigator assessment of radiological progression, symptomatic progression or death (by any cause in the absence of progression) | Approximately 7 years | 
| Health-related quality of life - in non-tBRCAm patients | Change from baseline in the physical functioning subscale of the EORTC-QLQ-C30 | Approximately 4 years | 
| Pathological Complete Response (pCR) - in non-tBRCAm patients | Defined as the proportion of patients with pCR in patients undergoing IDS | Approximately 4 years | 
| The pharmacokinetics (PK) and immunogenicity of durvalumab and olaparib as determined by peak concentration - in non-tBRCAm patients | Determination of durvalumab concentration in serum and olaparib concentration in plasma in a subset of patients | Approximately 4 years | 
| Objective Response Rate (ORR) - in non-tBRCAm patients | Defined as the number (%) of patients with at least one investigator-assessed visit response of CR or PR as per RECIST 1.1 | Approximately 4 years | 
| Duration of response (DoR) - in non-tBRCAm patients | Defined as the time form the date of first documented response (CR/PR) until the first progression or death in the absence of disease progression | Approximately 4 years | 
| Time to first subsequent therapy (TFST) - in non-tBRCAm patients | Time elapsed from randomisation to first subsequent therapy or death | Approximately 7 years | 
| Time to second subsequent therapy (TSST) - in non-tBRCAm patients | Time elapsed from randomisation to second subsequent therapy or death | Approximately 7 years | 
| Time to discontinuation or death (TDT) - in non-tBRCAm patients | Time elapsed from randomisation to study treatment discontinuation or death | Approximately 4 years | 
| PFS - in tBRCAm patients | To assess the potential additional clinical benefit of durvalumab added to SoC and olaparib in the first line treatment of tBRCAm patients | Approximately 4 years | 
| PFS2 - in tBRCAm patients | To assess the potential additional clinical benefit of durvalumab added to SoC and olaparib in the first line treatment of tBRCAm patients | Approximately 7 years | 
| ORR - in tBRCAm patients | To assess the potential additional clinical benefit of durvalumab added to SoC and olaparib in the first line treatment of tBRCAm patients | Approximately 4 years | 
| ORR pre-surgery in IDS group - in tBRCAm patients | To assess the potential additional clinical benefit of durvalumab added to SoC and olaparib in the first line treatment of tBRCAm patients | Approximately 4 years | 
| Duration of response (DoR) - in tBRCAm patients | To assess the potential additional clinical benefit of durvalumab added to SoC and olaparib in the first line treatment of tBRCAm patients | Approximately 4 years | 
| Time to first subsequent therapy (TFST) - in tBRCAm patients | To assess the potential additional clinical benefit of durvalumab added to SoC and olaparib in the first line treatment of tBRCAm patients | Approximately 7 years | 
| Time to second subsequent therapy (TSST) - in tBRCAm patients | To assess the potential additional clinical benefit of durvalumab added to SoC and olaparib in the first line treatment of tBRCAm patients | Approximately 7 years | 
| Time to discontinuation or death (TDT) - in tBRCAm patients | To assess the potential additional clinical benefit of durvalumab added to SoC and olaparib in the first line treatment of tBRCAm patients | Approximately 4 years | 
| Health-related quality of life - in tBRCAm patients | Change from baseline in the physical functioning subscale of the EORTC-QLQ-C30 | Approximately 4 years | 
| Proportion of patients with pCR in patients undergoing IDS - in tBRCAm patients | To assess the potential additional clinical benefit of durvalumab added to SoC and olaparib in the first line treatment of tBRCAm patients | Approximately 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Ovarian Cancer, Ovarian neoplasms