Metastatic castration resistant prostate cancer
Conditions
Interventions
Trade Name: Xtandi
Product Name: Xtandi
Pharmaceutical Form: Capsule, soft
INN or Proposed INN: Enzalutamide
CAS Number: 915087-33-1
Current Sponsor code: MDV3100
Other descriptive name: Xtandi
Concen
Sponsors
The Institute of Cancer Research
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: 1.Written informed consent and be capable of cooperating with treatment. 2.Age = 18 years 3.Histologically confirmed adenocarcinoma of the prostate and with tumour tissue accessible for research analysis for this trial. Patients who have no histological diagnosis must be willing to undergo a biopsy to prove prostate adenocarcinoma. 4.Metastatic castration resistant prostate cancer. 5.Documented prostate cancer progression as assessed by the investigator with RECIST (v1.1) and PCWG2 criteria. 6.PSA = 10ng/ml. 7.Received prior castration by orchiectomy and/or ongoing luteinizing hormone releasing hormone agonist treatment. 8.Ongoing androgen deprivation with serum testosterone =65 years) F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: 1.Surgery, chemotherapy or other anti-cancer therapy within 4 weeks prior to trial entry/randomization into the study (with the exception of enzalutamide, apalutamide or darolutamide).Any other therapy for prostate cancer, other than gonadotropin releasing hormone analogue therapy, such as progesterone, medroxyprogesterone, progestins or 5-alpha reductase inhibitors, must be discontinued at least 2 weeks before the first dose of the study drug. 2.Participation in another interventional clinical trial of an IMP within 4 weeks prior to trial entry. Participation in trials of licenced medications is allowed provided the medication is not a prohibited concomitant medication. 3.Prior limited field radiotherapy within 2 weeks and wide field radiotherapy within 4 weeks prior to trial entry. 4.Clinical and/or biochemical evidence of hyperaldosteronism or hypopituitarism. 5.History of seizures or other predisposing factors including, but not limited to, underlying brain injury, stroke, primary brain tumours, brain metastases and leptomeningeal disease, or alcoholism. 6.Use of potent inhibitors/inducers of CYP3A4, CYP2C9 and CYP2C19 should be avoided during the trial and 4 weeks prior to trial entry. Co-administration of drugs that are known potent or moderate CYP3A4 inhibitors, potent or moderate CYP3A4 inducers (with the exception of enzalutamide), P-gp substrates with narrow therapeutic index, sensitive CYP2B6 substrates, warfarin or any other coumarin derivative, BCRP-substrates that reduce blood neutrophils, Seville orange or grapefruit products. Use of herbal medications during the trial and 4 weeks afterwards. 7.Malabsorption syndrome or other condition that would interfere with enteral absorption. 8.Any of the following cardiac criteria: • QT interval > 470 msec. • Clinically important abnormalities including rhythm, conduction or ECG changes (left bundle branch block, third degree heart block). • Factors predisposing to QT prolongation including heart failure, hypokalemia, congenital long QT syndrome, family history of prolonged QT syndrome, unexplained sudden death (under 40) and concomitant medications known to prolong QT interval. •Coronary artery bypass, angioplasty, vascular stent, myocardial infarction, angina or congestive heart failure (NYHA = grade 2) in the last 6 months (see appendix 4 for NYHA scale). •Uncontrolled hypotension (systolic blood pressure < 90mmHg and or diastolic blood pressure < 50 mmHg). •Uncontrolled hypertension on optimal medical management 9.Clinically significant history of liver disease (Chlid-Pugh B or C, viral or other hepatitis, current alcohol abuse or cirrhosis). 10.Any other finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect interpretation of the results or renders the patients at high risk from treatment complications e.g patients with a hypersensitivity to the active substance or any of the excipients. 11.Malignancy other than prostate cancer within 5 years of trial entry with the exception of adequately treated basal cell carcinoma. 12.Unresolved significant toxicity from prior therapy (except alopecia and grade 1 peripheral neuropathy). 13.Inability to comply with study and follow-up procedures. 14.Patients with predominantly small cell or neuroendocrine differentiated prostate cancer are not eligible. 15.Immunocompromised patients. 16.Active or uncontrolled autoimmune disease requiring corticosteroid thera
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I study The main aim of the Phase I study is to establish a maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the combination of AZD5069 and enzalutamide in patients with metastatic castration resistant prostate cancer. To then determine the maximum tolerated dose of the best combination to take forward to the Phase II study. To also assess the safety and toxicity profile of the combination of AZD5069 and enzalutamide. Phase II study The main aim of the Phase II study is to establish how effective AZD5069 in combination with enzalutamide is at reducing prostate cancer. ;Secondary Objective: Phase I study: - To characterize the pharmacokinetic profile of AZD5069 in combination with enzalutamide - To characterize the pharmacodynamic behaviour of AZD5069 in combination with enzalutamide - To establish how effective AZD5069 in combination with enzalutamide is at reducing prostate cancer Phase II study: - To determine the maximum PSA (prostate specific antigens) decline during the study for patients on AZD5069 and enzalutamide - To estimate overall survival (OS) in these patients. - To estimate the radiologic progression free survival (rPFS) on the combination of AZD5069 and enzalutamide in these patients. - To assess the effects of AZD5069 and enzalutamide on the number of circulating tumour cells. - To further evaluate the safety and tolerability of the combination in patients who progress on enzalutamide. - To further characterise the PD profile of AZD5069 and enzalutamide when administered in combination. ;Primary end point(s): - In the Phase I study the primary objective is to identify the safety and tolerability of enzalutamide and AZD5069 when given in combination continuously. This will be determined by identifying the dose-limiting toxicities (DLTs), estimate the maximum tolerated dose (MTD) and identify the recommended phase II dose (RP2D) of AZD5069 administered in combination with enzalutamide at 160mg OD. - In t | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): PhaseI - To characterise the PK and PD of enzalutamide and AZD5069 when administered in combination and assess drug interaction. -To estimate the antitumour activity of AZD5069 in combination with enzalutamide as measured by response rate. - To estimate the antitumour activity of AZD5069 in combination with enzalutamide as measured by response rate. Phase II -To establish the maximum PSA decline at any point on trial and at 12 weeks for patients on AZD5069 and enzalutamide. -To estimate overall survival (OS) in these patients. -To estimate the radiologic progression free survival (rPFS) on the combination of AZD5069 and enzalutamide in these patients. -To assess the effects of AZD5069 and enzalutamide on the number of circulating tumour cells (CTCs). -To further evaluate the safety and tolerability of the combination in patients who progress on enzalutamide. -To further characterise the PD profile of AZD5069 and enzalutamide when administered in combination. ;Timepoint(s) of evaluation of this end point: Phase I and II -Safety and tolerability of combination treatment will be assessed by the Safety Review Committee and PK/PD data will be reviewed as part of that. -Response assessment will be carried out for patients that have received at least 1 cycle of treatment and have a baseline disease assessment. A status of complete response (CR) or partial response (PR) will be confirmed by repeat measuraments performed no less than four weeks after the response criteria are met. -Maximal PSA decline at any time during the trial and PSA decline after 12 weeks (as per PCWG2 criteria) of combination treatment. -Overall survival will be measured from the date of combination treatment to the date of death (whatever cause). - CTC fall will be defined as >30% after 12 weeks of combination treatme | — |
Countries
Switzerland, United Kingdom
Contacts
Public ContactAlison Turner
The Institute of Cancer Research, Drug Development Unit
Outcome results
None listed