Abstract 866P
Background
Cisplatin-based chemoradiotherapy (C-CRT) is a standard of care for LA HNSCC, but recurrence is common. Olaparib (PARP-1 inhibitor) inhibits DNA damage and may potentiate anti-tumour activity of C-CRT.
Methods
Patients with treatment-naïve high risk LA HNSCC (Tany N2/3 M0, bulky T3 or T4 Nany M0 patients, who would normally be offered C-CRT), WHO PS 0-1 were eligible. A novel Product of Independent Beta Probabilities Escalation design was used. Escalation decisions were based on a pre-specified target toxicity level of 33%, prior probabilities of toxicity per dose-duration combination and cumulative toxicity data from at least 2 patients per cohort. Olaparib was escalated by dose (50 & 100 mg bd) and duration (3 & 4 days per week). A radiotherapy QA programme was conducted by the National RTTQA Group to monitor protocol compliance. Primary endpoint was occurrence of dose limiting toxicity (DLT) over 13 weeks (7 weeks C-CRT, 6 weeks follow up). Secondary endpoints were best overall response (BOR) using RECIST, time to progression (TTP), progression free survival (PFS) and overall survival (OS).
Results
16 patients were enrolled from 3 UK hospitals between February 2016 and December 2019; 15 (median age 57 years, range 53-59) were treated, with 14 eligible for DLT assessment. No DLTs were observed in 50 mg bd 3 days cohort (n=2). DLTs were observed in all patients at 50 mg bd 4 days (n=2) & 100 mg bd 3 days (n=2) cohorts. Expansion of 50 mg bd 3 days cohort (n=8) saw 4 DLTs, including 1 patient who died on treatment. Posterior mean probability of DLT at 50 mg bd 3 days was 0.40 (90% credible interval 0.17-0.65). For BOR (n=12), 5 (42%) had complete response, 5 (42%) had partial response, 1 (8%) had stable disease and 1 had progressive disease. Three patients are currently unevaluable due to lack of follow-up data. Median TTP and PFS were not evaluable (NE; 95% confidence interval (CI) 21.6-NE months). Three patients died during follow up; 24-month OS was 75% (95% CI 40-91).
Conclusions
Data suggest promising anti-tumour activity, but due to excess acute toxicity seen this combination will not be proposed for future investigative studies.
Clinical trial identification
NCT02308072.
Editorial acknowledgement
Legal entity responsible for the study
University College London.
Funding
Cancer Research UK AstraZeneca.
Disclosure
M. Forster: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Pharmamar; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Nanobiotix; Financial Interests, Personal, Advisory Role: Guardant Health; Financial Interests, Personal, Advisory Role: Oxford VacMadix; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Institutional, Principal Investigator: Merck Sharp & Dohme; Financial Interests, Personal, Other, Travel/Accommodation expenses: AstraZeneca; Financial Interests, Personal, Other, Travel/Accommodation expenses: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel/Accommodation expenses: Merck; Financial Interests, Personal, Other, Travel/Accommodation expenses: Merck Sharp & Dohme; Financial Interests, Personal, Other, Travel/Accommodation expenses: Roche; Financial Interests, Personal, Other, Travel/Accommodation expenses: Guardant Health; Financial Interests, Personal, Other, Travel/Accommodation expenses: Celgene. T. Guerrero Urbano: Financial Interests, Personal and Institutional, Advisory Role: Therapanacea. G. Wheeler: Financial Interests, Personal, Other, Honorarium for organising Junior Investigator Workshop: AstraZeneca. All other authors have declared no conflicts of interest.