Carcinoma, Squamous Cell
Conditions
Keywords
Radiotherapy, Biomarkers, pharmacological, Pharmacokinetics, Genetic Markers, Cisplatin, Poly(ADP-ribose) Polymerases, AZD 2281, Radiotherapy, Intensity-Modulated, Head and Neck, Chemoradiotherapy, SCC
Brief summary
The aim of this study is to find the safe dose and best dosing schedule of olaparib to give in combination with cisplatin based chemoradiotherapy (CRT) in patients with locally advanced head and neck cancer. The dose decided on in this part of the study will become the recommended dose for the randomised Phase II trial.
Detailed description
This is a dose escalating Phase I/II trial evaluating the safety and tolerability of the addition of olaparib to CRT in high risk locally advanced human papillomavirus (HPV) negative Squamous Cell Carcinoma of the Head and Neck (HNSCC). A fixed dose of weekly cisplatin and intensity-modulated radiation therapy (IMRT) will be used, with doses of olaparib escalating for consecutive days and both dose level and duration will be increased through each cohort. This Phase I trial will assess how olaparib, a poly ADP ribose polymerase (PARP) inhibitor is tolerated when added to standard chemoradiotherapy treatment. Patients will be recruited from sites in the UK only. A placebo controlled, randomised Phase II trial will follow once the recommended dose and schedule of olaparib has been established.
Interventions
DRUGolaparib
Given twice daily. Exposure will escalate by daily dose and duration.
DRUGcisplatin
Dose will be 35mg/m2 i.v. once weekly.
RADIATIONIntensity Modulated Radiotherapy
Total dose will be 70Gy in 35 fractions over 7 weeks.
Sponsors
AstraZeneca
University College, London
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed high risk, locally advanced HNSCC patients (TNM staging: T-any N2/3 M0, bulky T3 or T4 N-any M0) who would normally be offered cisplatin-based radical chemoradiotherapy * Estimated life expectancy of at least 12 weeks * WHO performance status of 0 or 1 * Aged ≥18 years of age * Adequate major organ function * Willing to use contraception for the duration of the trial treatment and for six months after completion of treatment * Able to give informed consent * Willing and able to comply with the protocol for the duration of the study
Exclusion criteria
* Head & neck cancers of the following types: * Nasopharyngeal and paranasal sinus tumours, * Oral squamous cell carcinomas (tumours of the oral cavity), * Human Papilloma Virus positive oropharyngeal tumours (tonsillar and tongue base tumours) * Confirmed distant metastatic disease * Previous chemotherapy or radiotherapy for the treatment of HNSCC tumour * Previous therapy with a PARP inhibitor * Pre-existing gastrointestinal disorders that may interfere with the delivery or absorption of olaparib * Grade 3 or 4 peripheral neuropathy * Significant hearing difficulties or tinnitus (deaf patients can be included) * The current use of drugs which are known to inhibit or induce CYP3A4
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Frequency of dose limiting toxicities | 6 weeks post completion of treatment |
Secondary
| Measure | Time frame |
|---|---|
| Complete response rate | 12 weeks post completion of treatment |
| Time to loco-regional progression | 2 years post completion of treatment |
Outcome results
None listed