5130 - OCTOPUS - A Randomised, Multi-centre Phase II Umbrella Trial of Weekly Paclitaxel+/- Novel Agents in Platinum-Resistant Ovarian Cancer: vistusertib

Background

OCTOPUS, an NCRI investigator-initiated umbrella phase II trial, tests the addition of targeted agents to weekly paclitaxel (wP) in recurrent platinum-resistant/refractory ovarian cancer. The first agent tested is the dual mTORC1/mTORC2 inhibitor vistusertib (V). Preclinical studies support targeting PI3K/AKT/mTOR signalling. The combination of V and wP showed activity in ovarian high grade serous carcinoma (HGSC) in phase I. This is the first randomised trial of wP and dual mTORC1/2 inhibition in ovarian cancer.

Methods

In this double-blind trial, patients with platinum-resistant/refractory HGSC were randomised 1:1 to wP (80mg/m2 D1, D8, D15 of 28 day cycle) + oral V (50mg BD) or placebo (P) (D1-3, D8-10, D15-17). The primary endpoint is progression-free survival (PFS) (RECIST v1.1/GCIG CA125 criteria) and response is a key secondary end-point. A mandatory pre-treatment biopsy (if technically feasible), archival tumour tissue and serial blood samples were collected. The study uses a 3-outcome approach: significance at 10% (1-sided) for PFS indicates activity, significance at 20% also requires evidence of an improvement in response. The study has 90% power to detect a hazard ratio (HR) of 0.67.

Results

140 patients were randomised; median age 63 (range: 36-86); 18% platinum-refractory; 54% had ≥3 prior therapy; 7% had prior taxane in previous 6 months (m); 66% had an image-guided biopsy at study entry. Median PFS was 4.5 vs 4.2m (HR 0.84; 80% CI 0.67 to 1.07; 1-sided p = 0.18); median OS was 9.7 vs 11.1m (HR 1.21, 80% CI 0.91 to 1.60; p = 0.80); RR (RECIST/GCIG CA125: CR+PR) was 53% vs 56% for wP+V vs wP+P respectively. Grade 3/4 adverse events were 24 vs 25%. There was significantly more gastro-oesophageal reflux (grd 1/2 10 v 0%), rash (grd 2/3 9 v 0%) and lymphopenia (grd 2/3/4 47 v 31%) on wP+V. Ongoing translational research exploring the influence of PI3K/mTOR signalling on platinum resistance and response to wP will be presented.

Conclusions

There was modest evidence of improvement in PFS with the addition of V, but this was not supported by response or OS. Translational research and subgroup analyses are ongoing.

Clinical trial identification

ISRCTN16426935.

Editorial acknowledgement

Legal entity responsible for the study

NHS Greater Glasgow and Clyde/University of Glasgow.

Funding

AstraZeneca.

Disclosure

S. Banerjee: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self): Roche; Honoraria (self): Merck; Travel / Accommodation / Expenses: Nucana; Honoraria (self): Immunogen; Honoraria (self), Advisory / Consultancy: Seattle Genetics; Honoraria (self), Advisory / Consultancy: Gamamabs. A.R. Clamp: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Clovis. J. krell: Honoraria (self), Advisory / Consultancy: AstraZeneca; Research grant / Funding (institution): Takeda. R.M. Glasspool: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy: Immunogen; Honoraria (self), Advisory / Consultancy: Sotio; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Lilly/Ignyta; Travel / Accommodation / Expenses: Roche. C. Orbegoso: Full / Part-time employment: AstraZeneca. C. Gourley: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Tesaro; Honoraria (self), Advisory / Consultancy: Foundation One; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Nucana; Honoraria (self), Advisory / Consultancy: Chugai; Research grant / Funding (institution): Aprea; Research grant / Funding (institution): Novartis. U. Banerji: Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Karas Therapeutics; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Astex; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Phoenix ACT; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): ONX; Research grant / Funding (institution): BTG; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Verastem. C. Shepherd: Full / Part-time employment: AstraZeneca. W. Brugger: Full / Part-time employment: AstraZeneca. I.A. McNeish: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Clovis; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Takeda. All other authors have declared no conflicts of interest.