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

Simon J Crabb, Alison J Birtle, Karen Martin, Nichola Downs, Ian Ratcliffe, Tom Maishman, Mary Ellis, Gareth Griffiths, Stuart Thompson, Lidia Ksiazek, Vincent Khoo, Robert J Jones, Simon J Crabb, Alison J Birtle, Karen Martin, Nichola Downs, Ian Ratcliffe, Tom Maishman, Mary Ellis, Gareth Griffiths, Stuart Thompson, Lidia Ksiazek, Vincent Khoo, Robert J Jones

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.

Trial registration: ClinicalTrials.gov NCT02121639.

Keywords: AKT; AZD5363; Castration resistant prostate cancer; Docetaxel; Metastatic; Phase I.

Conflict of interest statement

SJC has undertaken consulting or advisory roles for Bayer, Sanofi, Astellas, Janssen, Pfizer and Roche and has received research funding from AstraZeneca, Astex Pharmaceuticals and Plexxikon. GG has undertaken consulting or advisory roles for Sirtex, GlaxoSmithKline and Pfizer. All other authors declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Schematic representation of the days of dosing (blue crossed boxes) for each of the indicated drugs at the following doses: docetaxel, 75 mg/m2 by one hour intravenous infusion on day 1; dexamethasone 8 mg orally, at 12, 3 and 1 h prior to each docetaxel infusion; AZD5363, dosed according to dose level cohort, BID, orally, taken 4 days on/3 days off, continuously from cycle 1 day 2; prednisolone, 5 mg BID orally days 1–21
Fig. 2
Fig. 2
Individual patient data for a plasma glucose, b insulin and (c) C-peptide levels at the indicated time points during cycle 1 of treatment. Samples on day 3, 9 and 16 of the cycle were taken prior to the morning AZD5363 dose
Fig. 3
Fig. 3
Percentage change from baseline of individual patient prostate specific antigen (PSA) level after 12 weeks of therapy

References

    1. Cancer Research UK. Cancer Stats: Cancer Statistics for the UK.
    1. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA, Investigators TAX. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502–1512. doi: 10.1056/NEJMoa040720.
    1. Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15):1513–1520. doi: 10.1056/NEJMoa041318.
    1. James ND, Spears MR, Clarke NW, Dearnaley DP, De Bono JS, Gale J, Hetherington J, Hoskin PJ, Jones RJ, Laing R, Lester JF, McLaren D, Parker CC, Parmar MK, Ritchie AW, Russell JM, Strebel RT, Thalmann GN, Mason MD, Sydes MR. Survival with newly diagnosed metastatic prostate cancer in the "docetaxel era": data from 917 patients in the control arm of the STAMPEDE trial (MRC PR08, CRUK/06/019) Eur Urol. 2015;67(6):1028–1038. doi: 10.1016/j.eururo.2014.09.032.
    1. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B, Investigators P. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424–433. doi: 10.1056/NEJMoa1405095.
    1. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE, Investigators C-A Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138–148. doi: 10.1056/NEJMoa1209096.
    1. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB, Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Flechon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI, Investigators C-A. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995–2005. doi: 10.1056/NEJMoa1014618.
    1. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO, Investigators T. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147–1154. doi: 10.1016/S0140-6736(10)61389-X.
    1. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF, Investigators IS. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–422. doi: 10.1056/NEJMoa1001294.
    1. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Flechon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS, Investigators A. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–1197. doi: 10.1056/NEJMoa1207506.
    1. Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737–746. doi: 10.1056/NEJMoa1503747.
    1. James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, Ritchie AW, Parker CC, Russell JM, Attard G, de Bono J, Cross W, Jones RJ, Thalmann G, Amos C, Matheson D, Millman R, Alzouebi M, Beesley S, Birtle AJ, Brock S, Cathomas R, Chakraborti P, Chowdhury S, Cook A, Elliott T, Gale J, Gibbs S, Graham JD, Hetherington J, Hughes R, Laing R, McKinna F, McLaren DB, O'Sullivan JM, Parikh O, Peedell C, Protheroe A, Robinson AJ, Srihari N, Srinivasan R, Staffurth J, Sundar S, Tolan S, Tsang D, Wagstaff J, Parmar MK, Investigators S. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2015 doi: 10.1016/S0140-6736(15)01037-5.
    1. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B, Antipin Y, Mitsiades N, Landers T, Dolgalev I, Major JE, Wilson M, Socci ND, Lash AE, Heguy A, Eastham JA, Scher HI, Reuter VE, Scardino PT, Sander C, Sawyers CL, Gerald WL. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18(1):11–22. doi: 10.1016/j.ccr.2010.05.026.
    1. Kosaka T, Miyajima A, Shirotake S, Suzuki E, Kikuchi E, Oya M. Long-term androgen ablation and docetaxel up-regulate phosphorylated Akt in castration resistant prostate cancer. J Urol. 2011;185(6):2376–2381. doi: 10.1016/j.juro.2011.02.016.
    1. Zhong B, Sallman DA, Gilvary DL, Pernazza D, Sahakian E, Fritz D, Cheng JQ, Trougakos I, Wei S, Djeu JY. Induction of clusterin by AKT--role in cytoprotection against docetaxel in prostate tumor cells. Mol Cancer Ther. 2010;9(6):1831–1841. doi: 10.1158/1535-7163.MCT-09-0880.
    1. Davies BR, Greenwood H, Dudley P, Crafter C, Yu DH, Zhang J, Li J, Gao B, Ji Q, Maynard J, Ricketts SA, Cross D, Cosulich S, Chresta CC, Page K, Yates J, Lane C, Watson R, Luke R, Ogilvie D, Pass M. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol Cancer Ther. 2012;11(4):873–887. doi: 10.1158/1535-7163.MCT-11-0824-T.
    1. Marques RB, Aghai A, de Ridder CM, Stuurman D, Hoeben S, Boer A, Ellston RP, Barry ST, Davies BR, Trapman J, van Weerden WM. High efficacy of combination therapy using PI3K/AKT inhibitors with androgen deprivation in prostate cancer preclinical models. Eur Urol. 2015;67(6):1177–1185. doi: 10.1016/j.eururo.2014.08.053.
    1. Tamura K, Hashimoto J, Tanabe Y, Kodaira M, Yonemori K, Seto T, Hirai F, Arita S, Toyokawa G, Chen L, Yamamoto H, Kawata T, Lindemann J, Esaki T. Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2016;77(4):787–795. doi: 10.1007/s00280-016-2987-9.
    1. Banerji U, Dean EJ, Perez-Fidalgo JA, Batist G, Bedard PL, You B, Westin SN, Kabos P, Davies B, Elvin P, Lawrence P, Yates JWT, Ambrose H, Rugman P, Foxley A, Salim S, Casson E, Lindemann JPO, Schellens JHM. A pharmacokinetically (PK) and pharmacodynamically (PD) driven phase I trial of the pan-AKT inhibitor AZD5363 with expansion cohorts in PIK3CA mutant breast and gynecological cancers. ASCO Meeting Abstracts. 2015;33(15_suppl):2500.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45(2):228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M, Prostate Cancer Clinical Trials Working G. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the prostate cancer clinical trials working group. J Clin Oncol. 2008;26(7):1148–1159. doi: 10.1200/JCO.2007.12.4487.
    1. . . Accessed 12 January 2017
    1. Turner NC, Oliveira M, Armstrong A, Sablin M-P, Perez-Fidalgo JA, Herebien S, Garcia-Murillas I, Johnson S, Foxley A, Mahmood A, Lindemann JP. Abstract CT331: “BEECH”, a phase I/II study of the AKT inhibitor AZD5363 combined with paclitaxel in patients with advanced or metastatic breast cancer: results from the dose-finding study, including quantitative assessment of circulating tumor DNA as a s. Cancer Res. 2015;75(15 Supplement):CT331–CT331. doi: 10.1158/1538-7445.am2015-ct331.

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