Topic: Cancer
Conditions
Interventions
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
Rando
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
Sponsors
Royal Marsden NHS Foundation Trust
The Institute of Cancer Research (UK)
Eligibility
Sex/Gender
Male
Age
18 Years to 110 Years
Inclusion criteria
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
Exclusion criteria
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 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. Un
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 | — |
Countries
England, United Kingdom
Outcome results
None listed