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2571 Background: In ovarian cells isolated from ascites, p-S6K levels were found to correlate with resistance to chemotherapy. We hypothesised that inhibiting p-S6K signalling with dual m-TORC1/2 inhibitor vistusertib (V) in addition to paclitaxel (P) would improve outcomes of patients with high-grade serous ovarian cancer (HGSOC). Methods: In the dose escalation part, weekly P 80mg/m2IV (6/7 weeks) was evaluated in combination with two schedules of V; Schedule A: V (25, 50 or 75mg) BID PO on day(D) 1-3/week and Schedule B: V (75 or 100mg) BID PO D1-2/week. This was followed by an expansion cohort in 25 HGSOC patients. Results: Dose limiting toxicities in Schedule A were fatigue and mucositis and in Schedule B were diarrhoea, rash and fatigue. The AUC, Cmax and half-life of V in the 50mg-cohort were 2821ng.hr/ml, 926ng/ml and 3hrs, comparable to single agent studies. PD analysis (from six 50mg-cohort patients) in platelet-rich plasma showed increased phosphorylation of Ser473 AKT following P induction (1.4 fold, p = 0.1378). Following addition of V to P, phosphorylation levels 4hrs post-treatment with V fell significantly to 53% of pre-dose levels (p = 0.0495). This was 61% lower than the corresponding time point following P alone. Based on toxicity, pharmacokinetic and PD evaluation, recommended phase 2 dose was established as P 80mg/m2 D1 and V 50mg BID D1-3 for 6/7 weeks. In the HGSOC expansion, 96% of patients had relapsed within 12 months of last platinum therapy and 100% had received previous paclitaxel, with a median of 3 previous lines of treatments. RECIST and GCIG CA125 response rates were 13/25 (52%) and 15/25 (60%) respectively, with median progression free survival of 5.5 months. MC was performed on archival tumor tissue of 24/25 HGSOC expansion cohort patients, with the most common mutations occurring in p53 (100%), BRCA (17%), and MUC16 (17%). ATM mutations occurred in 17% (n = 4), 3 of whom had a response. Conclusions: We report a highly active combination of paclitaxel with an intermittent schedule of vistusertib in patients with HGSOC. This combination is now being evaluated in a randomised controlled trial for this indication. Clinical trial information: NCT02193633.

2583 Background: The clinical utility of agents that target EGFR and VEGFR signaling in Non-Small Cell Lung Cancer (NSCLC) is limited by resistance due to emergent alternative growth stimulatory pa...

1011 Background: Paclitaxel (PTX), plus gemcitabine (GEM) showed survival advantage over paclitaxel in advanced breast cancer (ABC) patients who relapsed after adjuvant anthracycline. This was asso...

7081 Background: Cisplatin is one of the most active drugs available in MPM while bortezomib has shown some activity in single agent phase II studies against MPM. This was a prospective phase II study of cisplatin and bortezomib (CB) in the first line treatment of MPM. Methods: Patients with histological proven MPM, with performance status (PS) 0/1, were eligible. The doses were cisplatin 75mg/m2 /3 wks and bortezomib 1.3mg/m2 day 1, 4, 8, 11 every 3 wks. The primary end-point was progression free survival rate at 18 wks (PFSR=18). The 2-stage Simon design (a=0.1; b = 0.05, P0=0.50 and P1=0.675) was used. In the first step of the study 37 eligible patients were planned. If more than 19 patients were alive and free of progression at 18 wks the total sample size was increased to 76 eligible patients. Results: Between 2007 and 2010 82 patients were entered. The median follow-up time is 32.3 months The median age was 55 years (range: 22-77yrs), male/female: 55/27 , PS 0/1: 9/73, Stage T1: 10%; T2: 42%, T3: 25%; T4: 23% and N0: 57%; N1: 4%; N2: 33%; N3: 6%. The median number of cycles received was 4 and 38% received 6 cycles. Cisplatin/ bortezomib dose intensity was 98/ 80%. Toxicity (grade 3/4): neutropenia 10%, thrombocytopenia 11%, anaemia 1%. Grade 3-4 hyponatraemia/ hypokalaemia occurred in 46/ and 17%. Grade 2 tinnitus, grade 3 fatigue occurred in 16%, and 12%, of patients. Motor/sensory/other neurotoxicity was grade 1: 6/28/7%, grade 2: 2/26/2% and grade 3: 1/7/2% respectively. There were 2 toxic deaths at 32 and 74 days due to acute pneumonitis and cardiac arrest. The PFRS-18 (including symptomatic progression) was 53% (80% confidence intervals, CI, 42-64%). The overall survival was 13.5 months (95% CI 10.5-15) with 56% (95% CI 44-66%) alive at 1 year. The PFS was 5.1 months (95% CI 3.3-6.5). Conclusions: On the basis of the PFRS-18, the null hypothesis could not be rejected, although CB gave predictable toxicity and was as active as other reported regimens in MPM.