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Tri Association in Patient With Advanced Epithelial Ovarian Cancer in Relapse

2019-07-17 10:05:16 | BioPortfolio

Summary

Assessing the safety and efficacy of the bevacizumab (FKB238), Olaparib and Durvalumab (MEDI 4736) combination in patient with high grade serous or high grade endometrioid or other high grade epithelial non mucinous ovarian tumor, with at least one previous line of platinum-taxane chemotherapy, and present with platinum resistant disease (PRR) or platinum-sensitive relapse (PSR), whatever the line of chemotherapy given at relapse.

Description

Bevacizumab and olaparib have already been tested on 12 patients in a phase I trial at their usual doses (10 mg/kg q2w and 400 mg bid - 50 mg capsules -, respectively), and no DLTs were observed. The addition of an anti-VEGF small molecule, cediranib, to olaparib doubled the median PFS in a randomized phase II trial in patients with platinum sensitive relapse, with a manageable safety profile.

A recently reported phase I trial established the RDP2D of Durvalumab and Olaparib - 150 mg tablets -, when given in combination, at 1500 mg every 4 weeks, and 300 mg bid, respectively. In addition, the ENGOT/GINECO PAOLA phase III trial is currently evaluating the combination of Olaparib and Bevacizumab as first-line maintenance after platinum-paclitaxel combination, in patients with advanced high-grade serous ovarian carcinoma. Under the hypothesis of a survival benefit in favor of this combination, it would also be of interest to assess the value of adding Durvalumab in order to improve the efficacy of the overall combination.

There are no trials to date assessing anti-VEGF in combination with anti-PARP and anti-PD-L1 therapy.

Beside additive efficacy, a synergistic effect could be expected :

- Between bevacizumab and durvalumab, through normalization of blood vessel and potentiation of immunologic infiltration.

- Between olaparib and durvalumab, through cytotoxicity-mediated release of antigens and impairment of mutation repair mechanisms, thereby increasing neoantigen loads.

- Between olaparib and bevacizumab, through tumor environment modulation and signaling of DNA damage inhibition, which has already been tested with the anti-VEGF cediranib.

For those reasons the sponsor propose a phase II trial of Olaparib, Bevacizumab and Durvalumab combination, in patients with relapsing AO high grade carcinoma :

- In platinum sensitive relapse (PSR), whatever the line, in patients not amenable to frontline surgery of the relapse and previously-treated by a platinum-containing chemotherapy in first line and

- Either didn't receive any of the tested drugs,

- Or previously received either bevacizumab or olaparib BUT NOT the combination of both drugs.

- In platinum-resistant relapse (PRR), in previously untreated patients for their relapse, or in patients who received a maximum of 1 chemotherapy regimen in this setting and either

- Either didn't receive any of the tested drugs,

- Or previously received either bevacizumab or olaparib BUT NOT the combination of both drugs.

The trial will also propose translational research, including :

- Assessment of germline and somatic BRCA mutations and determination of HRD phenotype and mutational load by NGS

- Quantification of mutagenesis in simultaneous treatment on ctDNA

- Characterization of immune response in the tumor by Nanostring immuno-oncology panel on tumors

Study Design

Conditions

Epithelial Ovarian Cancer

Intervention

Bevacizumab (FKB238), Olaparib and Durvalumab (MEDI 4736) combination

Location

Centre Hospitalier Lyon Sud
Lyon
France
69495

Status

Recruiting

Source

ARCAGY/ GINECO GROUP

Results (where available)

View Results

Links

Published on BioPortfolio: 2019-07-17T10:05:16-0400

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

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A Phase II, Randomized, Multi-Center, Double-Blind, Comparative Global Study to Determine the Efficacy and Safety of Durvalumab in Combination With Olaparib for First-Line Treatment in Cis...

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Study of Olaparib and Durvalumab in IDH-Mutated Solid Tumors

This is a phase 2 study of the combination of drugs olaparib and durvalumab for the treatment of isocitrate dehydrogenase or (IDH) mutated solid tumors. The purpose of this study is to ass...

PubMed Articles [2728 Associated PubMed Articles listed on BioPortfolio]

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Despite high tumor mutation burden, immune checkpoint blockade has limited efficacy in small cell lung cancer (SCLC). We hypothesized that poly (ADP-ribose) polymerase (PARP) inhibition could render S...

Gamma Knife Stereotactic Radiosurgery in Combination with Bevacizumab for Recurrent Glioblastoma.

Prior retrospective and prospective studies suggest improved survival with the use of stereotactic radiosurgery (SRS) and bevacizumab in the treatment of limited-volume glioblastoma (GBM) recurrences.

Overexpressed ABCB1 Induces Olaparib-Taxane Cross-Resistance in Advanced Prostate Cancer.

Castration-resistant prostate cancer remains as an incurable disease. Exploiting DNA damage repair defects via inhibition of poly (ADP-ribose) polymerase (PARP) is becoming an attractive therapeutic o...

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Medical and Biotech [MESH] Definitions

An anti-VEGF recombinant monoclonal antibody consisting of humanized murine antibody. It inhibits VEGF receptors and prevents the proliferation of blood vessels.

An immature epithelial tumor of the JAW originating from the epithelial rests of Malassez or from other epithelial remnants of the ENAMEL from the developmental period. It is a slowly growing tumor, usually benign, but displays a marked propensity for invasive growth.

A cell adhesion molecule that is expressed on the membranes of nearly all EPITHELIAL CELLS, especially at the junctions between intestinal epithelial cells and intraepithelial LYMPHOCYTES. It also is expressed on the surface of ADENOCARCINOMA and epithelial tumor cells. It may function in the MUCOSA through homophilic interactions to provide a barrier against infection. It also regulates the proliferation and differentiation of EMBRYONIC STEM CELLS.

Neoplasms composed of glandular tissue, an aggregation of epithelial cells that elaborate secretions, and of any type of epithelium itself. The concept does not refer to neoplasms located in the various glands or in epithelial tissue.

Compounds that either stimulate the opening or prevent closure of EPITHELIAL SODIUM ION CHANNELS.

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