e13585 Background: Everolimus (E) is an mTOR inhibitor with broad anti-tumour clinical activity. There is preclinical evidence of synergistic activity through the combination of E with fluvastatin (F) and zoledronic acid (ZA). F, an HMG CoA reductase inhibitor, and ZA, a bisphosphonate, have both been shown preclinically to inhibit isoprenylation (addition of hydrophobic molecules) of key signalling proteins with subsequent inhibition of the Ras pathway. We investigate their potential activity further in this open-label phase I trial. Methods: Patients (pts) with advanced solid tumours were treated with escalating doses of E, F and ZA to evaluate safety, clinical activity, pharmacokinetics (PK), pharmacodynamics (PD) and the recommended dose for further study. PK samples were obtained over 24 hrs on day 1 and 8 of cycle 1 and day 1 of cycle 2. Pre- and post-dose PBMCs were analysed for markers of MAPK and PI3K-AKT-mTOR pathways (pERK, pAKT and pS6). Results: Maximum doses of each drug in combination (DL 4) were feasible and no DLTs were observed. Of the 16 pts evaluable [median age=63yrs (range 47-81)], the median number of cycles was 3.8 (range 1-8), with 44% of pts receiving ≥ 4 cycles. Drug related toxicities were mainly G1/2, many within the expected toxicity profile of E, including fatigue (12 pts, 75%), myalgias (9 pts, 56%), anorexia (8 pts, 50%), infection (8pts, 50%), dyspnoea (7pts, 44%), diarrhoea (7 pts, 44%), nausea (7 pts, 44%), peripheral oedema (5 pts, 31%) and mucositis (4 pts, 25%). G3 adverse events were predominantly due to symptoms of disease progression. G1/2 anemia and thrombocytopaenia were the most common haematological toxicities, particularly in DL 3 and 4. 44% of pts achieved stable disease as best response (mean 4.5m [range 3-6m]); including 2 CRC pts (DL 4) and 2 CRPC pts (DL 3 and 4). PK and PD results will be presented in further detail. Conclusions: The combination of E/F/ZA is feasible without any added or overlapping toxicities in this phase 1 study. [Table: see text]
Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1–2 trial