MAdCaP: MDM2 inhibition and Abiraterone in Carcinoma of the Prostate

ISRCTN	ISRCTN38949950
DOI	https://doi.org/10.1186/ISRCTN38949950
EudraCT/CTIS number	2013-002014-13
Secondary identifying numbers	Sponsor reference number: GN12ON129

Submission date: 07/10/2013
Registration date: 07/11/2013
Last edited: 20/05/2022

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-of-idasanutlin-with-abiraterone-or-enzalutamide-for-men-with-prostate-cancer-who-havent-had

Contact information

Mr Rob Jones
Scientific

Consultant Medical Oncologist
Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

Phone	+44 (0)141 301 7194
Email	lynn.mcmahon@glasgow.ac.uk

Ms Lorna Sweeting
Public

Cancer Research UK Clinical Trials Unit
(Partner in CaCTUS - Cancer Clinical Trials Unit Scotland)
Level 0
Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

Study information

Study design	Open-label dose escalation study followed by a randomised placebo-controlled double blind multi-centre phase II study
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details to request a patient information sheet
Scientific title	A phase I/randomised phase II trial of abiraterone acetate with or without RO5503781 in patients with metastatic castration resistant prostate cancer (mCRCP) who have not previously received docetaxel
Study acronym	MAdCaP
Study objectives	To establish if the addition of RO5503781 to abiraterone improves radiological progression-free survival (PFS) in patients with mCRPC.
Ethics approval(s)	West of Scotland Research Ethics Service, 10/03/2014, REC ref: 14/WS/0001
Health condition(s) or problem(s) studied	Prostate cancer
Intervention	Phase I After a single dose pharmacokinetic (PK) study on day 7 of cycle 1 patients will commence combination treatment on day 1 of cycle 1 and will continue on treatment until confirmed disease progression, intolerable toxicity or withdrawal. Prednisolone will continue until the final dose of abiraterone. Prednisolone may be continued or tapered off and stopped after this, off study, at the investigators discretion. Phase II Patients will be randomized in a 1:1 ratio to either the control arm (Arm A) or experimental arm (Arm B). The study will be double-blinded. Control Arm A: 1. Abiraterone (1000mg PO daily, days 1 - 28) 2. Prednisolone (5mg PO twice daily, days 1- 28) 3. Placebo (PO twice daily, days 1 5). A cycle length is 28 days. Upon confirmed radiological progression, patients will be permitted to continue abiraterone and add in open label RO5503781 (days 1 5) until further progression (defined by PSA). Experimental Arm B: 1. Abiraterone (1000mg PO daily, days 1 - 28) 2. Prednisolone (5mg PO twice daily, days 1- 28) 3. RO5503781 (PO twice daily, days 1 5). A cycle length is 28 days. Patients will commence treatment on day 1 and will continue on treatment until confirmed disease progression, intolerable toxicity or withdrawal. Prednisolone will continue until the final dose of abiraterone. Prednisolone may be continued or tapered off and stopped after this, off study, at the investigator's discretion.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase I/II
Drug / device / biological / vaccine name(s)	Abiraterone acetate, RO5503781
Primary outcome measure	Radiological progression free survival [as per Prostate Cancer Working Group (2) (PCWG2)] Patients will have CT and bone scans at baseline then every 8 weeks for the first 24 weeks, thereafter every 12 weeks until progression is confirmed. Progression-free survival will be measured from the date of randomisation to the date of progression or date of death (any cause) for those who do not progress.
Secondary outcome measures	1. Prostate-specific antigen (PSA) response rate will be the proportion of patients achieving >50% drop in PSA for greater than 4 weeks. Patients will have PSA measured every 4 weeks. 2. Radiological response rate will be as per RECIST 1.1 for those patients with measurable disease at baseline. 3. For patients crossing over from placebo, PSA response rate will be the proportion of patients achieving >50% reduction in PSA from the point of cross over for > 4weeks 4. Biochemical and radiological PFS will be defined as the time from randomisation until the either PSA progression or radiological progression, (both as defined in PCWG2) or death (any cause) for patients who do not progress. 5. Pharmacokinetics (PK) of RO5503781 with and without abiraterone (phase I only) 6. Pharmacokinetics of abiraterone with and without RO5503781 (phase I only) 7. Pharmacokinetics of abiraterone in combination with RO5503781 Pharmacokinetics samples will be taken in the dose escalation phase of the study to explore the PK of both drugs alone and in combination.
Overall study start date	28/02/2014
Completion date	28/02/2020

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Male
Target number of participants	132 in total (phase I: 3 -18 and phase II: 114)
Key inclusion criteria	1. Histologically proven adenocarcinoma of the prostate with documented metastases (where the metastatic lesions are confined to 1 or 2 lesions on a bone scan. These must be confirmed by a second modality (e.g. CT, MRI or biopsy). 2. Availability of archival tumour samples. Where patients are willing to undergo a biopsy as part of the study, these specimens may be used as an alternative where no archival specimen is available. 3. Proven disease progression since last change in therapy defined by at least one of the following: 3.1. Prostate-specific antigen (PSA) progression. This must be based on a series of at least three successively increasing readings each taken at least 7 days apart. The 3rd reading must be >= 2ng/ml. In the event where an intermediate reading is lower than a previous reading, then the patient will still be eligible (i.e. the three readings do not need to be consecutive). The first of the three readings must have been obtained after commencing the previous systemic therapy, or, in the case of androgen receptor antagonists, after discontinuing. 3.2. Radiographic progression since commencing last systemic anti-cancer therapy as defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 (Eisenhauer et al. 2009 Eur J Cancer. 4 5:2 2 8) for non-bone disease or the appearance of two or more new lesions on a bone scan. 4. Castrate levels of serum testosterone (<1.7nmol/l) 5. On-going castration therapy 6. Male aged 18 or over 7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) = 0 or 1 8. Haemoglobin (Hb)>= 10g/dL; platelets >= 150 x 109/L; neutrophils >=1.5 x109/L 9. Bilirubin < 1.5 x ULN; alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < 2.5 x ULN 10. Serum potassium ≥ LLN; Alb ≥ 30 g/L 11. Serum creatinine < 1.5 x ULN or a calculated creatinine clearance ≥ 60 mL/min 12. Able to swallow study drugs 13. Life expectancy of more than 3 months 14. Provision of written informed consent
Key exclusion criteria	1. Prior cytotoxic chemotherapy for castration resistant prostate cancer (patients may have received previous or ongoing bisphosphonates, eg. zoledronate, or denosumab) 2. Prior ketoconazole, abiraterone, MDV3100 (enzalutamide), TAK-700 (orteronel) or other novel anti-hormonal therapies 3. Uncontrolled hypertension ( BP≥ 160 / 95 mmHg) 4. Significant heart disease as evident by myocardial infarction (MI) or arterial thrombotic events in past 6 months, severe unstable angina, or New York Heart Association class (NYHA) III or IV heart failure or class II to IV heart failure or cardic ejection fraction measurement of <50%. 5. Other anticancer therapy [apart from Luteinizing-hormone-releasing hormone (LHRH) agonist / antagonist] within 4 weeks (6 weeks for bicalutamide). This includes radiotherapy and therapeutic radionucleotides. Where patients are receiving bisphosphonates or denosumab they must have been on a stable dose for at least 6 weeks prior to starting study drug. 6. The requirement for strong opiates to control cancer related pain in the two weeks before study entry (codeine and tramadol are permitted) 7. Patient with a partner of child-bearing potential who is not using a highly effective method of contraception, who is unwilling to use condoms during the study and for 30 days after the last dose of study drug 8. Patients with known coagulopathy, platelet disorder or history of non-drug induced thrombocytopenia 9. Patients receiving oral or parenteral anti-coagulants/anti-platelet agents (chronic daily treatment with aspirin with doses >325 mg po daily, clopidogrel, low molecular weight heparin, or dagibatran, etc.) prior to the start of study therapy are excluded. Patients may receive anticoagulant flushes for maintenance of indwelling catheters. 10. Patients with known bone marrow disorders which may interfere with bone marrow recovery (due to tumor involvement, fibrosis) (e.g. Concomitant myelodysplastic syndrome) 11. Patients who refuse blood products
Date of first enrolment	28/02/2014
Date of final enrolment	03/07/2017

Locations

Countries of recruitment

Scotland
United Kingdom

Study participating centre

Beatson West of Scotland Cancer Centre

Glasgow
G12 0YN
United Kingdom

Sponsor information

NHS Greater Glasgow and Clyde (UK)
Hospital/treatment centre

c/o Dr Nathaniel Brittain
Academic Research Co-ordinator
Research and Development Central Office
The Tennent Institute, 1st Floor
Western Infirmary General
38 Church Street
Glasgow
G11 6NT
Scotland
United Kingdom

Phone	+44 (0)141 211 8544
Email	nathaniel.brittain@ggc.scot.nhs.uk
Website	http://www.nhsggc.org.uk/r&d
"ROR"	https://ror.org/05kdz4d87

Funders

Funder type

Industry

Roche (UK)
Government organisation / For-profit companies (industry)

Alternative name(s): F. Hoffmann-La Roche Ltd, F. Hoffmann-La Roche & Co, F. Hoffmann-La Roche AG, Roche Holding AG, Roche Holding Ltd, Roche Holding, Roche Holding A.G., Roche Holding, Limited, F. Hoffmann-La Roche & Co.
Location: Switzerland

Cancer Research UK (CTAAC) (UK); CRUK Grant award No: A15846
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?
Basic results		25/12/2020	20/05/2022	No	No
HRA research summary			28/06/2023	No	No

Editorial Notes

20/05/2022: EU Clinical Trials Register results added.
14/02/2019: The overall end date was changed from 28/02/2018 to 28/02/2020.
10/04/2018: The recruitment end date was changed from 28/02/2018 to 03/07/2017.