The University of Southampton
University of Southampton Institutional Repository

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

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

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/m(2), 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.

Journal Article
0167-6997
1-9
Crabb, Simon J.
bcd1b566-7677-4f81-8429-3ab0e85f8373
Birtle, Alison J.
5016770c-8e37-4c38-9215-3f745f24c6fe
Martin, Karen
0de5a0ff-bb29-4cbd-890d-169cc0d7c032
Downs, Nichola
f22ed202-1f46-4554-90b4-f40d3bf23393
Ratcliffe, Ian
0688ee1f-37ac-42ee-8238-fc3e9ea5bb68
Maishman, Thomas
cf4259a4-0eef-4975-9c9d-a2c3d594f989
Ellis, Mary
f9c39516-e078-4d80-807b-9ab91890df41
Griffiths, Gareth
7fd300c0-d279-4ff6-842d-aa1f2b9b864d
Thompson, Stuart
9816f791-32c7-4a81-9d85-b038f2a325a7
Ksiazek, Lidia
f9aa9484-8c10-4b43-985a-7bf909521f41
Khoo, Vincent
d650b6bc-1490-439c-9ee1-e1e657b81d24
Jones, Robert J
bd215beb-7527-4479-be9a-b7df94aae7c4
Crabb, Simon J.
bcd1b566-7677-4f81-8429-3ab0e85f8373
Birtle, Alison J.
5016770c-8e37-4c38-9215-3f745f24c6fe
Martin, Karen
0de5a0ff-bb29-4cbd-890d-169cc0d7c032
Downs, Nichola
f22ed202-1f46-4554-90b4-f40d3bf23393
Ratcliffe, Ian
0688ee1f-37ac-42ee-8238-fc3e9ea5bb68
Maishman, Thomas
cf4259a4-0eef-4975-9c9d-a2c3d594f989
Ellis, Mary
f9c39516-e078-4d80-807b-9ab91890df41
Griffiths, Gareth
7fd300c0-d279-4ff6-842d-aa1f2b9b864d
Thompson, Stuart
9816f791-32c7-4a81-9d85-b038f2a325a7
Ksiazek, Lidia
f9aa9484-8c10-4b43-985a-7bf909521f41
Khoo, Vincent
d650b6bc-1490-439c-9ee1-e1e657b81d24
Jones, Robert J
bd215beb-7527-4479-be9a-b7df94aae7c4

Crabb, Simon J., Birtle, Alison J., Martin, Karen, Downs, Nichola, Ratcliffe, Ian, Maishman, Thomas, Ellis, Mary, Griffiths, Gareth, Thompson, Stuart, Ksiazek, Lidia, Khoo, Vincent and Jones, Robert 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, pp. 1-9. (doi:10.1007/s10637-017-0433-4).

Record type: Article

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/m(2), 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.

Text art%3A10.1007%2Fs10637-017-0433-4 - Version of Record
Available under License Creative Commons Attribution.
Download (790kB)

More information

Accepted/In Press date: 16 January 2017
e-pub ahead of print date: 1 February 2017
Published date: 1 February 2017
Keywords: Journal Article
Organisations: Cancer Sciences, Clinical Trials Unit

Identifiers

Local EPrints ID: 407483
URI: http://eprints.soton.ac.uk/id/eprint/407483
ISSN: 0167-6997
PURE UUID: fd9e9e5a-e595-46c2-9bac-cded39f56d66
ORCID for Gareth Griffiths: ORCID iD orcid.org/0000-0002-9579-8021

Catalogue record

Date deposited: 12 Apr 2017 01:07
Last modified: 23 Oct 2017 16:33

Export record

Altmetrics

Contributors

Author: Simon J. Crabb
Author: Alison J. Birtle
Author: Karen Martin
Author: Nichola Downs
Author: Ian Ratcliffe
Author: Thomas Maishman
Author: Mary Ellis
Author: Stuart Thompson
Author: Lidia Ksiazek
Author: Vincent Khoo
Author: Robert J Jones

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×