Novel intrapatient dose escalation phase I trial of two schedules of the combination of the PARP inhibitor olaparib and AKT inhibitor AZD5363 in BRCA1/2 and non-BRCA1/2 mutation patients with advanced cancers
1The Institute of Cancer Research, London, UK,2Royal Marsden Hospital, London, UK
In vivo synergy between PARP and phosphatidylinositol 3-kinase pathway inhibition was seen in BRCA1-related and sporadic cancers, providing rationale for this study. A novel intrapatient dose escalation trial design was used to optimise drug exposures and accelerate drug development (Yap et al, JCO 2013).
Two-stage investigator-initiated ECMC Combinations Alliance phase I trial: a) Intrapatient dose escalation; b) Recommended Phase II combination dose (RP2CD) expansion. Advanced cancer patients received escalating doses of AZD5363 BD in 2 parallel arms (4-days-on 3-days-off [4/7 arm]; 2-days-on, 5-days-off [2/7 arm]) with olaparib at 300mg BD 3-weekly. Pharmacokinetics and pharmacodynamics were assessed. Next generation sequencing of tumour and plasma DNA was undertaken in all patients.
The first patients first treatment was achieved <6 months after CR-UK NAC approval. Dose escalation was completed in 7.5 months in 20 patients in 1 centre. 30 advanced cancer patients (15 with BRCA1/2 mutations) were enrolled. Common G1-2 toxicities were gastrointestinal symptoms, fatigue and anaemia. A DLT of G3 rash was seen at 480mg BD 4/7 AZD5363 + 300mg BD olaparib. Non-DLT G3 anaemia (n=2), diarrhoea (n=2), fatigue (n=1) and vomiting (n=1) were seen in 4/7 arm (n=10), while G3 hyperglycemia, transaminitis, anaemia, diarrhoea (all n=1), rash (n=2) and fatigue (n=3) in 2/7 arm (n=20). No obvious PK drug-drug interactions were observed. pSer9 GSK3? decreased on therapy in platelet-rich plasma at all dose levels. Multiple responses were seen in BRCA1/2 and non-BRCA1/2 mutation tumours, including 4 confirmed RECIST partial responses. A BRCA1 mutation prostate cancer patient has MRI and PSA responses for 11m+. A peritoneal mesothelioma patient (prior PI3K/mTOR inhibitor) has RECIST stable disease for 12m+ with CA125 response.
This novel trial design led to rapid completion of dose escalation. RP2CD expansion is ongoing in: a) germline BRCA1/2 mut cancers; b) sporadic cancers with relevant somatic mutations.