Phase I Study of Olaparib Combined With Cisplatin-based Chemoradiotherapy to Treat Locally Advanced Head and Neck Cancer

The phase I trial aims to determine the recommended phase II dose (RP2D) and schedule of olaparib in combination with standard cisplatin-based chemoradiotherapy, in patients with high-risk locally advanced squamous cell carcinoma of the head and neck (HNSCC), by assessing the safety and tolerability of the treatment combination.

ORCA-2 is a phase I trial in patients with locally advanced, with or without metastatic nodal disease.

Patients will receive olaparib (a PARP inhibitor) in combination with standard cisplatin-based chemotherapy and intensity modulated radiotherapy (IMRT).

Olaparib, cisplatin and radiotherapy will be given in combination every week for a maximum of 7 weeks. Prior to starting combination treatment, olaparib will be started 7 days before the first week of combination treatment. Olaparib will be given twice daily on days 1-3 of each week of treatment (either alone during week 0 or in combination with chemotherapy and radiotherapy during weeks 1-7). Cisplatin will be started on day 1 of each week, and given once a week during radiotherapy treatment for a total of 7 weeks. Radiotherapy will be delivered on days 1-5 of each week using IMRT, for a total of 7 weeks.

The phase I trial aims to determine the recommended phase II dose of olaparib (50mg, 100mg, 150mg or 200mg bd) - the dose of olaparib patients receive will depend on the dose under investigation at the time of patient registration.

Dose escalation will be guided by the two-dimensional dose escalation design called Product of Independent Beta Probabilities escalation (PIPE). It will recommend the choice of dose/duration combination cohort of olaparib for subsequent patients by estimating the contour that divides dose/duration combination cohorts to be those above the target toxicity rate (equal to 33%) and those below. The recommended phase II cohort(s) are those that have been experimented on during the trial and are also closest to (but not above) the estimated contour calculated using all trial data.

Eligibility Criteria:
Inclusion Criteria:

1. Histologically confirmed high-risk locally advanced HNSCC, patients who would normally be offered cisplatin-based radical chemoradiotherapy
2. Estimated life expectancy of at least 16 weeks
3. WHO performance status 0 or 1
4. Aged ≥18 years
5. Adequate bone marrow function: absolute neutrophils grade 0 or 1, platelets grade 0 or 1, haemoglobin grade 0 or 1
6. Adequate renal function: Creatinine grade 0 or 1, Calculated GFR ≥60 mL/min (if calculated value is \<60 mL/min then an isotope GFR assessment should be performed or an estimation from 24h urine collection)
7. Adequate liver function: Serum bilirubin grade 0 or 1, AST or ALT grade 0 or 1
8. Patients must be able to swallow olaparib tablets
9. Willing to use contraception for the duration of the trial treatment and for six months after completion of treatment
10. Able to give informed consent
11. Patients willing and able to comply with the protocol for the duration of the study

Exclusion Criteria:

1. Head \& neck cancers of the following types: Nasopharyngeal and paranasal sinus tumours, Oral squamous cell carcinomas (tumours of the oral cavity), Low risk Human Papilloma Virus positive oropharyngeal tumours (tonsillar and tongue base tumours)
2. Confirmed distant metastatic disease
3. Previous chemotherapy or radiotherapy for the treatment of HNSCC tumour
4. Previous therapy with a PARP inhibitor
5. Chemotherapy, immunotherapy or radiotherapy within 28 days prior to registration
6. Prior history of malignancy, except for basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, breast or prostate. Patient must have been free of malignancy for a period of 3 years prior to first dose of trial drug
7. Women who are pregnant or lactating
8. Pre-existing gastrointestinal disorders that may interfere with the delivery or absorption of olaparib
9. Grade 3 or 4 peripheral neuropathy - If considered significant by the treating clinician a lower grade neuropathy may be considered as exclusion criterion
10. Significant hearing difficulties or tinnitus (deaf patients can be included) - Whilst not excluded, patients with mildly impaired hearing or tinnitus must be made aware of potential ototoxicity and may choose not to be included. If included, it is recommended that audiograms be carried out at baseline.
11. Any serious and/or unstable pre-existing medical, psychiatric or other condition that, in the treating clinician's judgment, could interfere with patient safety or obtaining informed consent
12. Known hepatitis B or C infection (testing for Hepatitis and HIV for the trial is not mandatory)
13. Immunocompromised patients (e.g. known HIV positive status)
14. Active uncontrolled infection
15. The current use of drugs which are known to inhibit or induce CYP3A4
16. Resting ECG with QTc \> 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
17. Patients with myelodysplastic syndrome/acute myeloid leukaemia.
18. Patients with a known hypersensitivity to olaparib or any of the excipients of the product.