The purpose of this study is to find out the side effects and safety of a combination of the
CXCR2 antagonist, AZD5069 in combination with the androgen receptor antagonist, enzalutamide
in patients with metastatic castration resistant prostate cancer and to determine the most
appropriate dose of this combination. In the Phase I part of this study groups of 3 to 6
patients will be treated with increasing doses of AZD5069 in combination with a fixed dose of
enzalutamide (160mg once daily). Once Phase I has been completed the combination with the
optimum safety and pharmacokinetic/pharmacodynamic profile will be taken forward to the Phase
II part of the study. The Phase II part of the study will evaluate the optimized
dose/schedule identified in Phase I of the study in patients with metastatic castration
resistant prostate cancer.
In the Phase I part of the study, the AZD5069 is started first and will be taken twice daily
as an oral tablet at Cycle 1, Day -14 for 14 days. Two weeks later on Cycle 1 Day 1, patients
will start taking 160mg enzalutamide once a day in addition to the AZD5069. The starting dose
of AZD5069 will be 40mg taken orally twice daily with single dose escalations to 80mg, 120mg
and 160mg taken orally twice daily to determine the MTD to take forward to a Phase II
reversal of resistance cohort. The Phase II reversal of enzalutamide resistance study will
explore whether the addition of AZD5069 to enzalutamide reverses resistance to enzalutamide
alone. In the phase II reversal of enzalutamide resistance study patients will start taking
the AZD5069 at the dose established in the Phase I safety run in part of the study in
combination with 160mg of enzalutamide once a day and at the same time from Cycle 1 Day 1
onwards. Potential patients who previously progressed on enzalutamide (having received at
least 12 weeks treatment) within 6 months of trial entry (first dose of IMP) will enter the
Phase II reversal of enzalutamide resistance study immediately. However, those patients who
progressed on enzalutamide (having received at least 12 weeks treatment) greater than 6
months before trial entry will first enter the Phase II enzalutamide resistance cohort to
confirm resistance. Study patients will receive 160mg enzalutamide once a day until disease
progression. Once enzalutamide resistance is confirmed in these patients, they will be
eligible to enter the Phase II reversal of enzalutamide resistance cohort.
Approximately 26 to 49 patients will be entered into this trial, approximately 12 to 24
patients in the phase I safety run in cohort depending on number of patients required to
determine RP2D and schedule and between 14 and 25 patients in the phase II reversal of
enzalutamide resistance cohort (the investigators predict around 50% of these patients will
enter the phase II enzalutamide resistance run in cohort first).
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 (section 3.6) with at least one of the following criteria:
1. Progression of soft tissue/visceral disease by RECIST (v1.1) and/or,
2. Progression of bone disease by PCWG2 bone scan criteria and/or,
3. Progression of PSA by PCWG2 PSA criteria and/or,
4. Clinical progression with worsening pain and need for palliative radiotherapy for
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 as defined in section 9.6.
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 ranges shown below. These
measurements must be performed within one week (Day -7 to Day 1) before the patient
goes in the trial.
Laboratory Test Value required Haemoglobin (Hb) ≥ 9.0 g/dL Absolute neutrophil count ≥
1.5 x 109/L Platelet count ≥ 100 x 109/L WBC ≥ 3.0 x 109/L Calculated creatinine
clearance ≥ 50 mL/min (uncorrected value) Serum bilirubin
≤ 1.5 x upper limit of normal (ULN) unless documented Gilbert's disease. Alanine
aminotransferase (ALT) and aspartate aminotransferase (AST)
≤ 2.5 x (ULN) unless raised due to known metastatic liver disease in which case ≤ 5 x
ULN is permissible
15. Phase I safety run in cohort ONLY Patients that have progressed after at least 1 line
of taxane based chemotherapy and either enzalutamide or abiraterone treatment (having
received a minimum of 12 weeks enzalutamide or abiraterone).
16. 188.8.131.52.1.1 Phase II enzalutamide resistance run in cohort ONLY Patients with
histologically confirmed adenocarcinoma of the prostate that have progressed after at
least 1 line of taxane based therapy and progressed on enzalutamide treatment (having
received a minimum of 12 weeks enzalutamide) 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 at least 1 line of
taxane based therapy and progressed on enzalutamide treatment (having received a
minimum of 12 weeks enzalutamide) within 6 months prior to entry (day of starting
IMP). Prior treatment with abiraterone is not an exclusion criteria.
- 1. Surgery, chemotherapy or other anti-cancer therapy within 4 weeks prior to trial
entry/randomization into the study. 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 clinical trial and any concurrent treatment with any
investigational drug within 4 weeks prior to trial entry.
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. Malabsorbtion
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
- 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
13. Inability to comply with study and follow-up procedures. 14. Patients with
predominantly small cell or neuroendocrine differentiated prostate cancer are not
15. Immunocompromised patients. 16. Active or uncontrolled autoimmune disease
requiring corticosteroid therapy.
17. History of thromboembolic disease within 12 months of commencement of trial.
18. At high-risk because of non-malignant systemic disease including active infection
and any serious concurrent illness.
19. Any known intolerance to enzalutamide, AZD5069 or to any constituents