Enzalutamide (MDV3100) in combination with AZD5363 in patients with metastatic castration-resistant prostate cancer

ISRCTN	ISRCTN17168679
DOI	https://doi.org/10.1186/ISRCTN17168679
EudraCT/CTIS number	2013-004091-34
ClinicalTrials.gov number	NCT02525068
Secondary identifying numbers	16580

Submission date: 08/05/2014
Registration date: 08/05/2014
Last edited: 20/06/2022

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

http://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-azd5363-and-enzalutamide-for-advanced-prostate-cancer

Contact information

Ms Claire Paulding
Scientific

Institute of Cancer Research
Surrey Clinical Trials & Statistics Unit (ICR-CTSU)
Section of Clinical Trials
Brookes Lawley Building
15 Cotswold Road
Sutton
SM2 5NG
United Kingdom

Email	RE-AKT-icrctsu@icr.ac.uk

Study information

Study design	Randomised; Interventional; Design type: Treatment
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Scientific title	A randomised Phase II study of enzalutamide (MDV3100) in combination with AZD5363 in patients with metastatic castration-resistant prostate cancer
Study acronym	RE-AKT
Study objectives	The primary aim is to determine the anti-tumour activity of enzalutamide (potent AR targeting drug) in combination with AZD5363 (AKT inhibitor) compared to enzaluatmide alone in patients with castration-resistant prostate cancer.
Ethics approval(s)	NRES Committee London-Surrey Borders, 19/03/2014, ref. 14/LO/0259
Health condition(s) or problem(s) studied	Topic: Cancer; Subtopic: Prostate Cancer; Disease: Prostate
Intervention	AZD5363: Phase I safety run-in: Enzalutamide and AZD5363 will be given in a combination of once daily enzalutamide (MDV3100) with twice daily AZD5363 administered four days on and three days off Randomised Phase II: AZD5363 + enzalutamide versus placebo + enzalutamide Single-stage phase II expansion: AZD5363 + enzalutamide in patients who have previously progressed on enzalutamide alone; Enzalutamide, Phase I safety run-in: Enzalutamide and AZD5363 will be given in a combination of once daily enzalutamide (MDV3100) with twice daily AZD5363 administered four days on and three days off Randomised Phase II: AZD5363 + enzalutamide versus placebo + enzalutamide Single stage phase II expansion: AZD5363 + enzalutamide in patients who have previously progressed on enzalutamide alone
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	Enzalutamide (MDV3100), AZD5363
Primary outcome measure	Phase I - safety run in 1. Type, frequency, severity, seriousness and relatedness of adverse events - assessed at C0D1, C1D1, C1D4, C1D11, C2D1, C2D11, C3D1, C4D1 and D1 each subsequent cycle (28-day cycle), treatment discontinuation and safety follow-up visit (30 days after last dose) 2. Laboratory abnormalities. - Screening (C0D1-28 days), C0D1, C1D1, C1D11, C2D1, C2D11, C3D1, C4D1 and D1 each subsequent cycle (28-day cycle), treatment discontinuation and safety follow-up visit (30 days after last dose) Randomised Phase II 1. Best overall tumour response by RECIST (v1.1) and PCWG2 criteria - RECIST: Screening (C0D1- 28 days), C1D4 or C1D11), treatment discontinuation. PCWGC2: Screening, C1D1, C2D1, 12 weekly, safety follow-up visit Single-stage phase II - expansion cohort 2. Best overall tumour response by RECIST (v1.1) and PCWG2 criteria. - RECIST: Screening (C0D1- 28 days), C1D4 or C1D11), treatment discontinuation. PCWGC2: Screening, C1D1, C2D1, 12 weekly, safety follow-up visit
Secondary outcome measures	Phase I - safety run-in 1. PK assay analyses - C0D1, C0D2, C0D3, C2D1, C2D2, C2D3, C2D4, C2D11 2. Antitumour activity of the combination - every 12 weeks Randomised Phase II and single-stage phase II - expansion cohort 1. Overall survival and radiographic progression-free survival - OS: patients will be followed up 3 monthly for 12 months and then 6 monthly from 12 months. Radiographic PFS: RECIST and bone scan every 12 weeks 2. Maximum PSA decline and circulating tumour cell (CTC) fall - Screening, C1D1, C4D1 and D1 each subsequent cycle (28-day cycle), safety follow-up visit 3. Pain palliation (using BPI-SF) (randomised phase II only) - Screening, C1D1, C2D1, C3D1, C4D1 and D1 each subsequent cycle (28-day cycle), safety follow-up visit 4. Safety - adverse events measured every visit 5. PK assay analyses - C1D1, C2D1, C2D4, C2D11
Overall study start date	01/12/2014
Completion date	30/09/2019

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Male
Target number of participants	Planned Sample Size: 136; UK Sample Size: 136
Key inclusion criteria	1. Written informed consent 2. Histological diagnosis of adenocarcinoma of the prostate and with archival tumour tissue 3. Metastatic castration-resistant prostate cancer (mCRPC) 4. Progressed after one or two lines of taxane-based chemotherapy 5. Progressed after at least 12 weeks of abiraterone 6. Age 18 years or above. 7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 02 8. PSA greater than or equal to 10 ng/ml 9. Documented willingness to use an effective means of contraception while participating in the study and for 12 months post last dose of treatment 10. Documented ongoing castrate serum testosterone <50 ng/dL (<2.0 nM) 11. Received prior castration by orchiectomy and/or ongoing luteinizing hormone releasing hormone (LHRH) agonist treatment 12. Progression of disease by PSA utilizing PCWG2 criteria and at least another of the following criteria: 12.1. Dsease progression as defined by at least two new lesions on bone scan 12.2.Soft tissue disease progression defined by modified RECIST 1.1 12.3.Clinical progression (worsening pain and the need for palliative radiotherapy) PHASE I SAFETY RUN IN and EXPANSION COHORT inclusion criteria: 13. Willing to have a biopsy to obtain tumour tissue for biomarker analyses prior to and after treatment SINGLE STAGE PHASE II EXPANSION COHORT ONLY inclusion criteria: 14. Prior exposure to enzalutamide of at least 12 weeks is required with documented disease progression 15. Archival tumour tissue available for the analysis of PTEN loss by the central laboratory
Key exclusion criteria	1. Prior treatment with enzalutamide (not applicable for the phase I safety run in or for the single stage phase II expansion cohort) 2. Prior treatment with PI3K, AKT, TOR kinase or mTOR inhibitors 3. Surgery, chemotherapy, or other anticancer therapy within 4 weeks prior to trial entry/randomisation into the study (6 weeks for bicalutamide). Any other therapies for prostate cancer, other than GnRH analogue therapy, such as progesterone, medroxyprogesterone, progestins (megesterol), or 5-alpha reductase inhibitors (e.g., finasteride or dutasteride), must be discontinued at least 2 weeks before the first dose of study drug 4. Participation in another clinical trial and any concurrent treatment with any investigational drug within 4 weeks prior to trial entry/randomisation. 5. Prior limited field radiotherapy within 2 weeks or wide field radiotherapy within 4 weeks of trial entry/randomisation 6. History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumours, brain metastases, or alcoholism 7. History of loss of consciousness or transient ischemic attack within the previous 12 months of trial entry/randomisation 8. Known brain or leptomeningeal involvement 9. Use of potent inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19 within 2 weeks before trial entry/randomisation (3 weeks for St John's Wort) must be avoided 10. Clinically significant abnormalities of glucose metabolism as defined by any of the following: 10.1. Diagnosis of diabetes mellitus type I or II 10.2. Glycosylated haemoglobin (HbA1C) =8.0% at screening 10.3. Fasting plasma glucose =8.9mmol/L at screening 11. Inadequate organ and bone marrow function as evidenced by: 11.1. Haemoglobin <8.5 g/dL 11.2. Absolute neutrophil count <1.0 x 10^9/L 11.3. Platelet count < 75 x 10^9/L 11.4. Albumin =25 g/dL. 11.5. AST/SGOT and/or ALT/SGPT = 2.5 x ULN (=5 x ULN if liver metastases) 11.6. Total bilirubin = 1.5 x ULN (except for patient with Gilbert's disease) 11.7. Serum creatinine > 1.5 x ULN 12. Inability or unwillingness to swallow oral medication 13. Malabsorption syndrome or other condition that would interfere with enteral absorption 14. Any of the following cardiac criteria: 14.1. Mean resting corrected QT interval (QTcF) >470 msec obtained triplicate ECGs 14.2. Clinically important abnormalities (rhythm/conduction/morphology) resting ECG 14.3. Factors that increase risk of QTc prolongation or risk of arrhythmic events 14.4. Experience of any of the following in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure NYHA = Grade 2 14.5. Uncontrolled hypotension 15. Clinically significant history of liver disease consistent with ChildPugh Class B or C, including viral or other hepatitis, current alcohol abuse, or cirrhosis 16. Any other finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patients at high risk from treatment complications 17. Need for chronic corticosteroid therapy of >10 mg of prednisolone or >0.5 mg of dexamethasone per day or an equivalent dose of other anti-inflammatory corticosteroid 18. Malignancies other than prostate cancer within 5 years prior to trial entry/randomisation, except for adequately treated basal or squamous cell skin cancer 19. Unresolved clinically significant toxicity from prior therapy except for alopecia and Grade 1 peripheral neuropathy 20. Inability to comply with study and follow-up procedures
Date of first enrolment	17/12/2014
Date of final enrolment	30/09/2019

Locations

Countries of recruitment

England
United Kingdom

Study participating centre

Institute of Cancer Research

Sutton
SM2 5NG
United Kingdom

Sponsor information

Royal Marsden NHS Foundation Trust
Hospital/treatment centre

Downs Road
Sutton
SM2 5PT
England
United Kingdom

Website	http://www.royalmarsden.nhs.uk/pages/home.aspx
"ROR"	https://ror.org/0008wzh48

The Institute of Cancer Research (UK)
Research organisation

15 Cotswold Road
Belmont
Sutton
SM2 5NG
United Kingdom

Funders

Funder type

Industry

Astellas Pharma Europe
Private sector organisation / International organizations

Alternative name(s): Astellas Pharma Europe Ltd
Location: United Kingdom

AstraZeneca
Government organisation / For-profit companies (industry)

Alternative name(s): AstraZeneca PLC, Pearl Therapeutics
Location: United Kingdom

Cancer Research UK (UK)
Private sector organisation / Other non-profit organizations

Alternative name(s): CR_UK, Cancer Research UK - London, CRUK
Location: United Kingdom

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan	Not provided at time of registration

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article		01/05/2020	20/06/2022	Yes	No
HRA research summary			28/06/2023	No	No

Editorial Notes

20/06/2022: Publication reference added.
05/08/2019: ClinicalTrials.gov number added, recruitment end date changed from 17/06/2017 to 30/09/2019.
03/10/2014: The following changes were made to the trial record:
1. The overall trial start date was changed from 01/06/2014 to 01/12/2014.
2. The overall trial end date was changed from 01/06/2014 to 01/01/2017.