Background: Standard care for locally advanced squamous cell carcinoma of the head and neck (HNSCC) is cisplatin-based chemoradiotherapy (C-CRT). Use of intensity modulated radiotherapy (IMRT) reduces toxicity to normal tissue but despite aggressive primary management many patients with high risk disease develop recurrence. The PARP-1 inhibitor olaparib inhibits DNA damage repair and may potentiate the anti-tumour activity of C-CRT. Preclinical data demonstrate potent radio-sensitisation but the optimal dosing schedule to enhance anti-tumour activity, whilst allowing normal tissue recovery, has not been investigated clinically. ORCA-2 aims to determine the recommended dose and duration of olaparib to give in combination with weekly cisplatin and IMRT. Methods: This is a phase I trial in which olaparib will be escalated by increasing both the dose (50, 100, 150 & 200 mg bd) and duration (3, 4 & 5 days). Olaparib tablets will be taken orally twice daily (bd) on a weekly dosing schedule (initially 50 mg bd for 3 sequential days), cisplatin 35 mg/m²weekly and IMRT 70 Gy in 35 fractions. Primary endpoint is occurrence of dose limiting toxicities over 13 weeks (7 weeks C-CRT and 6 weeks follow up). A novel dual escalation design called Product of Independent Beta Probabilities Escalation (PIPE) is being used. Escalation decisions are based on a pre-specified maximum allowable target toxicity level of 33%, predicted prior probabilities of toxicity in each dose-duration combination and cumulative toxicity data from a minimum of 2 patients in each cohort. This design allows flexibility and adaptability to provide better estimates of the recommended dose-duration combinations for further investigation than a standard 3+3 escalation. Eligible patients have newly diagnosed, histologically confirmed, high risk, locally advanced HNSCC and WHO performance status 0-1. Blood and fresh tissue will be collected for exploratory biological studies including evaluation of pharmacodynamic markers of PARP inhibition. The trial opened on 28 September 2015 and recruitment is ongoing. Clinical trial information: NCT02308072