Metastatic Castration- Resistant Prostate Cancer MedDRA version: 16.1 Level: PT Classification code 10062904 Term: Hormone-refractory prostate cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Xtandi
Product Name: Enzalutamide
Product Code: N/A
Pharmaceutical Form: Capsule, soft
INN or Proposed INN: Enzalutamide
CAS Number: 915087-33-1
Current Sponsor code: N/A
Other descriptive
Sponsors
The Royal Marsden NHS Foundation Trust
The Institute of Cancer Reseacrh
Eligibility
Sex/Gender
Male
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 1 or 2 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) 0-2. 8)PSA greater than or equal to 10ng/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 =65 years) yes F.1.3.1 Number of subjects for this age range 90
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 anti-cancer 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: a.Diagnosis of diabetes mellitus type I or II b.Glycosylated haemoglobin (HbA1C) =8.0% at screening c.Fasting Plasma Glucose =8.9mmol/L at screening. 11)Inadequate organ and bone marrow function as evidenced by: a.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; a.Mean resting corrected QT interval (QTcF) >470msec obtained triplicate ECGs b.Clinically important abnormalities(rhythm/conduction/morphology)resting ECG c.Factors that increase risk of QTc prolongation or risk of arrhythmic events d.Experience of any of the following in the preceding six months: - coronary artery bypass graft - angioplasty - vascular stent - myocardial infarction - angina pectoris - congestive heart failure NYHA = Grade2 e.Uncontrolled hypotension 15)Clinically significant history of liver disease consistent with Child-Pugh 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 >0.5mg 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 ent
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): PHASE I - SAFETY RUN IN: - Type according to MedDRA (Medical Dictionary for Regulatory Activities), frequency and severity according to NCICTCAE V4, seriousness, and relatedness of study treatment-emergent adverse events will be assessed. - Laboratory abnormalities will be assessed according to the NCI CTCAE v.4. RANDOMISED PHASE II: - The primary endpoint of best overall tumour response will be defined on the basis of the following outcomes; if any of these occur without contrary evidence from any other of the other criteria patients will be considered to have responded: - PSA decline of = 50% (according to the PCWG2) - Confirmed objective response (complete &/or partial response) by RECIST v1.1 - ONLY for patients with detectable CTC of =5/7.5ml blood at baseline, conversion of CTC to <5/7.5ml blood nadir. Failure of treatment will be defined as progression by RECIST (v1.1) and/or progression by bone scan. The PCWG2 and RECIST (v1.1) criteria will be used to determine PSA response and soft tissue response respectively. SINGLE STAGE PHASE II EXPANSION COHORT: Best overall response after the addition of AZD5363 in patients who progress after 12 weeks of enzalutamide alone will be defined on the basis of the following outcomes. If any of these occur without contrary evidence from any other of the other criteria patients will be considered to have responded: - PSA decline of = 50% after at least 12 weeks (according to the PCWG2 criteria) - - Confirmed objective response (complete and/or partial response) by RECIST v1.1 - ONLY for patients with detectable circulating tumour cell count (CTC) of =5/7.5ml blood at baseline, conversion of CTC to <5/7.5ml blood nadir. Failure of treatment will be defined as progression by RECIST and/or progression by bone scan. PSA response and PSA progression (for the addition of AZD5363 on the single stage expansion cohort) will be defined according to the consensus guidelines of | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase I – safety run in: ? Pharmacokinetic assay analyses. ? Antitumour activity of the combination. ? Pharmacodynamic assay analyses (tertiary/ exploratory endpoint) Randomised Phase II: ? Radiographic progression-free survival (rPFS- according to PCWG2 criteria & RECIST v1.1) measured from date of randomisation until: • Bone scan progression- a patient is considered to have progressed by bone scan if: i.The first bone scan with =2 new lesions compared to baseline is observed at 12 weeks from randomization and is confirmed by a second bone scan taken =6 weeks later showing =2 additional new lesions (a total of =4 new lesions compared to baseline). ii. A bone scan obtained later than the 12 week assessment shows =2 new lesions. • Progression of soft tissue lesions measured by CT or MRI • Death from any cause If a patient is withdrawn for any reason prior to radiological progression then the patient should be assessed until radiological progression has occurred. If however they have started another treatment then they will be censored at the start of the new treatment. ? Overall survival measured from the date of randomisation to the date of death (whatever the cause). Survival time of living patients will be censored on the last date a patient is known to be alive or lost to follow up. ? Number of skeletal-related events defined as either the use of external beam radiotherapy to relieve skeletal symptoms or the occurrence of new symptomatic bone fractures (vertebral or non-vertebral) or the occurrence of spinal cord compression or a tumour related orthopaedic surgical intervention. ? Maximum PSA decline at any time during the trial and PSA decline at 12 weeks (as per PCWG2 criteria) presented as a waterfall plot. ? Circulating Tumour Cell (CTC) fall by >30%: This will be expressed as the proportion of patients that have demonstrated a CTC fall of >30%. Also the maximum CTC decline at any time during the | — |
Countries
United Kingdom
Contacts
Public ContactAlexa Gillman
The Institute of Cancer Research
Outcome results
None listed