Plain English Summary
Trial website
Contact information
Type
Scientific
Primary contact
Ms Claire Paulding
ORCID ID
Contact details
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
-
RE-AKT-icrctsu@icr.ac.uk
Additional identifiers
EudraCT number
2013-004091-34
ClinicalTrials.gov number
NCT02525068
Protocol/serial number
16580
Study information
Scientific title
A randomised Phase II study of enzalutamide (MDV3100) in combination with AZD5363 in patients with metastatic castration-resistant prostate cancer
Acronym
RE-AKT
Study hypothesis
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
NRES Committee London-Surrey Borders, 19/03/2014, ref. 14/LO/0259
Study design
Randomised; Interventional; Design type: Treatment
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Condition
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
Phase
Phase II
Drug names
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 trial start date
01/12/2014
Overall trial end date
30/09/2019
Reason abandoned (if study stopped)
Eligibility
Participant 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
Participant type
Patient
Age group
Adult
Gender
Male
Target number of participants
Planned Sample Size: 136; UK Sample Size: 136
Participant 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
Recruitment start date
17/12/2014
Recruitment end date
30/09/2019
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Institute of Cancer Research
Sutton
SM2 5NG
United Kingdom
Sponsor information
Organisation
Royal Marsden NHS Foundation Trust (UK)
Sponsor details
Downs Road
Sutton
SM2 5PT
United Kingdom
Sponsor type
Hospital/treatment centre
Website
Organisation
The Institute of Cancer Research (UK)
Sponsor details
15 Cotswold Road
Belmont
Sutton
SM2 5NG
United Kingdom
Sponsor type
Research organisation
Website
Organisation
Royal Marsden NHS Foundation Trust
Sponsor details
Sponsor type
Not defined
Website
Funders
Funder type
Industry
Funder name
Astellas Pharma Europe
Alternative name(s)
Astellas Pharma Europe Ltd
Funding Body Type
private sector organisation
Funding Body Subtype
International organizations
Location
United Kingdom
Funder name
AstraZeneca
Alternative name(s)
AstraZeneca PLC
Funding Body Type
private sector organisation
Funding Body Subtype
For-profit companies (industry)
Location
United Kingdom
Funder name
Cancer Research UK (UK)
Alternative name(s)
CRUK
Funding Body Type
private sector organisation
Funding Body Subtype
Other non-profit organizations
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list