A Randomised, Multi-centre Phase II Trial of Weekly Paclitaxel and Vistusertib in Platinum-Resistant Ovarian High-Grade Serous Carcinoma: OCTOPUS Arm 1

Background Preclinical studies support targeting PI3K/AKT/mTOR signalling in platinum-resistant ovarian cancer (PROC). A phase I study of the dual mTORC1/mTORC2 inhibitor vistusertib with weekly paclitaxel (wP) showed activity. We report the results of Arm 1 of OCTOPUS, the first randomised trial of weekly paclitaxel and dual mTORC1/2 inhibition in ovarian cancer. Methods Patients with platinum-resistant or refractory high grade serous carcinoma were randomised (1:1) to wP (80mg/m2 D1,8,15 of 28 day cycle) plus oral vistusertib (50mg BD) or placebo (P). The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate (RR) and overall survival (OS). Results 140 patients (median age 63, range: 36-86; 18% platinum-refractory; 54% ≥3 prior therapies) were randomised. There was no difference in PFS (median 4.5 vs 4.1m (HR 0.84; 80% CI (0.67, 1.07); 1-sided p=0.18), OS (median 9.7 vs 11.1m (HR 1.21; 80% CI (0.91, 1.60); 1-sided p=0.80) or RR (odds ratio 0.86; 80% CI (0.55, 1.36); 1-sided p=0.66). Grade 3/4 adverse events were 41.2% (wP+V) vs 36.7% (wP+P). Low tumour PTEN expression was associated with longer PFS in the wP+V arm (9.4 vs 4.1m p=0.003) but not in the wP arm (4.8 vs 4.2m p=0.60). Tumour genome-wide copy number (CN) analysis suggested that high CN signature 4 was associated with worse outcome in the wP+P arm (2.3 vs 4.6m p=0.018) but not the wP+V arm (5.4 vs 3.3m). Conclusions Vistusertib did not improve clinical activity of wP in PROC. However, low tumour cell PTEN expression may be a predictive biomarker for vistusertib activity. Translational Relevance Preclinical studies suggest that activation of the PI3K/AKT/mTOR signalling pathway contributes to platinum-resistance in ovarian high grade serous carcinoma (HGSC). Based on activity in a phase I study, we evaluated the clinical efficacy of the dual mTORC1/mTORC2 inhibitor vistusertib in combination with weekly paclitaxel in the OCTOPUS study - a multi-centre, randomised, placebo-controlled, phase II trial in platinum-resistant ovarian (HGSC). In the first randomised trial of weekly paclitaxel and dual mTORC1/2 inhibition in ovarian cancer, vistusertib did not improve clinical activity of weekly paclitaxel. However, translational analyses indicated that low tumour cell PTEN expression may be a predictive biomarker for vistusertib activity. We also showed genome-wide copy number (CN) analysis, in particular high exposure to CN signature 4, may also allow identification of patients with greater chance of benefit from dual mTORC inhibition. Potential predictive biomarkers identified in our study should be evaluated in ongoing/future studies. ### Competing Interest Statement S Banerjee Research Grants: Astrazeneca, GlaxoSmithKline; Advisory Boards: Amgen, Astrazeneca, Genmabs, GlaxoSmithKline Immunogen, Merck Sharpe Dohme, Merck Sereno, Mersana, Oncxerna, Seagen, Shattuck Labs; Honoraria for lectures: Amgen, Astrazeneca, Clovis, GlaxoSmithKine, Immunogen, Merck Sharpe Dohme, Mersana, Pfizer, Roche, Takeda. Clinical Advisory Board (uncompensated) Epsilogen G Giannone Payment for educational events from Mylan, outside the submitted manuscript. A Clamp Research grant AstraZeneca, Advisory Board- GSK, MSD, Honoraria- Clovis Oncology, AstraZeneca R Glasspool Rosalind Glasspool is Principal Investigator for trials sponsored by AstraZeneca, Clovis, GlaxoSmithKline/Tesaro, Immunogen, AbbVie, Pfizer, Lilly, and Novartis, and reports research funding from Clovis, Boehringer Ingelheim, and Lilly/Ignyta; institution research funding from GlaxoSmithKline/Tesaro; personal speaker and/or consultancy fees from AstraZeneca, MSD, Clovis, Tesaro, GlaxoSmithKline, Immunogen, and Sotio; and institutional consultancy fees from Novartis R Kristeleit Grants: Clovis, MSD Advisory Boards/Consulting: GSK, Eisai, Astra Zeneca, Clovis, MSD, Basilea, Shattuck Labs, Zydus Cadila, iTEOS, InCyte, Regeneron. IA McNeish COI Advisory boards and speaker fees for AZ, Clovis Oncology, GSK/Tesaro, Roche, OncoC4, Epsila Bio, Theolytics and Duke St Bio, all outside the scope of OCTOPUS. Institutional grant income from AZ also outside the scope of OCTOPUS. ### Clinical Trial ISRCTN16426935 ### Funding Statement Funding was provided from AstraZeneca via the NIHR Alliance and Endorsed by Cancer Research UK (CRUKE/14/053); Funding for translational research was provided by AstraZeneca, the Lady Garden Foundation and NIHR Imperial Biomedical Research Centre. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was conducted in accordance with the Research Governance Framework for Health and Community Care (Second edition; 2006) and the Medicines for Human Use (Clinical Trials) Regulations, 2004 SI 2004:1031 (as amended) and World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects 1964 (as amended) and was co-sponsored by University of Glasgow and NHS Greater Glasgow and Clyde. Ethical approval was obtained from London, Brighton and Sussex Research Ethics Committee (reference 15/LO/1302) and all patients provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors