Studio di Fase I/II con l’antagonista di- CXCR2 AZD 5069 somministrato in combinazione con enzalutamide in pazienti con carcinoma prostatico metastatico resistente alla terapia ormonale

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
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-

Product Name: AZD5069
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: AZD5069
CAS Number: 878385-84-3
Current Sponsor code: D5660C00004
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
INN or Proposed INN: AZD5069
CAS Number: 878385-84-3
Current Sponsor code: D5660C00004
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-

Trade Name: Xtandi
Product Name: Xtandi
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Enzalutamide
CAS Number: 915087-33-1
Current Sponsor code: MDV3100
Other descriptive name: Xtandi
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-

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 < 50 ng/dL (<2.0 nM).
9.Willing to have pre- and post-treatment biopsies to obtain proof of mechanism from translational studies. Archival tissue must be available for research analysis
10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
11. Documented willingness to use an effective means of contraception while participating in the study and for 6 months post last treatment dose.
12. Able to swallow the study drug.
13. All efforts should be made to discontinue steroid usage but up-to 5mg BD prednisolone (or equivalent) will be allowed.
14. Haematological and biochemical indices within the required ranges. These measurements must be performed within one week (Day -7 to Day 1) before the patient goes in the trial.
15. Phase I safety run in cohort ONLY: Patients that have progressed after either enzalutamide, apalutamide, darolutamide or abiraterone treatment (having received a minimum of 12 weeks of one of these treatments).
16. Phase II enzalutamide resistance run in cohort ONLY: Patients with histologically confirmed adenocarcinoma of the prostate that have progressed after either enzalutamide, apalutamide or darolutamide (having received a minimum of 12 weeks of one of these treatments) more than 6 months prior to entry (day of starting IMP). Prior treatment with abiraterone is not an exclusion criteria.
17. Phase II reversal of enzalutamide resistance cohort ONLY: Patients with histologically confirmed adenocarcinoma of the prostate that have progressed after either enzalutamide, apalutamide or darolutamide treatment (having received a minimum of 12 weeks of one of these treatments) within 6 months prior to entry (day of starting IMP). Prior treatment with abiraterone is not an exclusion criteria.

Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years)
F.1.2.1 Number of subjects for this age range 0
F.1.3 Elderly (>=65 years)
F.1.3.1 Number of subjects for this age range 0

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