ProCAID: a phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone chemotherapy for metastatic castration resistant prostate cancer

Crabb, S. J. et al. (2017) ProCAID: a phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone chemotherapy for metastatic castration resistant prostate cancer. Investigational New Drugs, 35(5), pp. 599-607. (doi: 10.1007/s10637-017-0433-4) (PMID:28144789) (PMCID:PMC5613074)

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Abstract

Background: 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.

Item Type:Articles
Additional Information:This work was supported by Cancer Research UK [C9317/A16029, CRUK/12/042], Cancer Research UK core funding to the Southampton Clinical Trials Unit and AstraZeneca.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jones, Professor Robert
Authors: Crabb, S. J., Birtle, A. J., Martin, K., Downs, N., Ratcliffe, I., Maishman, T., Ellis, M., Griffiths, G., Thompson, S., Ksiazek, L., Khoo, V., and Jones, R. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Investigational New Drugs
Publisher:Springer
ISSN:0167-6997
ISSN (Online):1573-0646
Published Online:01 February 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Investigational New Drugs 35(5):599-607
Publisher Policy:Reproduced under a Creative Commons License

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