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

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    Author
    Crabb, SJ; Birtle, AJ; Martin, K; Downs, N; Ratcliffe, I; Maishman, T; Ellis, M; Griffiths, G; Thompson, S; Ksiazek, L; ...
    Date
    2017-10-01
    Source Title
    Investigational New Drugs
    Publisher
    SPRINGER
    University of Melbourne Author/s
    Khoo, Vincent
    Affiliation
    Medicine and Radiology
    Metadata
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    Document Type
    Journal Article
    Citations
    Crabb, S. J., Birtle, A. J., Martin, K., Downs, N., Ratcliffe, I., Maishman, T., Ellis, M., Griffiths, G., Thompson, S., Ksiazek, L., Khoo, V. & Jones, R. J. (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. https://doi.org/10.1007/s10637-017-0433-4.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257091
    DOI
    10.1007/s10637-017-0433-4
    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.

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