Abstract
SummaryBackground Docetaxel and prednisolone chemotherapy (DP) extends survival in metastatic castration resistant prostate cancer (mCRPC). However, emergent clinical resistance is almost inevitable. AKT pathway activation is highly prevalent in mCRPC contributing to disease progression and DP resistance. AZD5363 is a potent oral pan-AKT inhibitor with pre-clinical data indicating activity in mCRPC and synergy with docetaxel. Methods This phase I trial was to determine an AZD5363 recommended phase II dose (RP2D) for combination with DP. Eligibility criteria included chemotherapy naive mCRPC, PSA or radiographic disease progression and ECOG performance status 0 or 1. Treatment comprised DP (75 mg/m2, IV, day 1 and 5 mg BID, PO, day 1–21 respectively for ten cycles) and AZD5363 to disease progression for all patients. We utilised a 3 + 3 dose escalation design to determine a maximum tolerated dose according to defined dose limiting toxicity criteria assessed using CTCAE version 4.03. Planned AZD5363 dose levels were 320 mg (DL1), 400 mg (DL2) and 480 mg (DL3), BID, PO, 4 days on/3 days off, from day 2 of each cycle. Results 10 patients were treated. Dose limiting toxicities affected 2 patients (grade 3 rash ≥5 days; grade 3 diarrhoea) in DL2. The commonest grade 3 or 4, AZD5363 related, symptomatic adverse events were rash and diarrhoea. Hyperglycaemia affected all patients but was self-limiting. PSA reduction to <50% at 12 weeks occurred in 7 patients. Conclusions The RP2D for AZD5363 is 320 mg BID, 4 days on/3 days off, in combination with full dose DP for mCRPC.
Highlights
There are approximately 47,000 new cases and 11,000 deaths from prostate cancer in the UK per year [1]
All patients had disease progression based on PSA and/or radiographic criteria defined by the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) and the Prostate Cancer Working PSA prostate specific antigen (Group) 2 [20, 21]
One patient in dose level 1 was considered to be non-evaluable for dose limiting toxicity (DLT) assessment due to a compliance error, resulting from misunderstanding rather than treatment related adverse events (AE), in cycle 1 resulting in only 54.2% of the cumulative AZD5363 dose being taken
Summary
There are approximately 47,000 new cases and 11,000 deaths from prostate cancer in the UK per year [1]. Docetaxel and prednisolone chemotherapy (DP) extends survival and maintains quality of life in metastatic castration resistant prostate cancer (mCRPC) [2, 3]. Despite the advent of chemotherapy utilisation earlier in the treatment pathway for hormone sensitive disease, and the introduction of multiple other life extending therapeutic options, advanced prostate cancer remains incurable [4,5,6,7,8,9,10,11,12]. From the point of castrate resistance, median survival is in the range of 2–3 years [4,5,6].
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