| Eligibility |
Inclusion Criteria:
1. Written informed consent obtained prior to any study-related procedures.
2. Age = 18 years and male.
3. ECOG performance status = 2.
4. Histologically/cytologically confirmed adenocarcinoma of the prostate, and without
neuroendocrine differentiation or small cell histology.
5. Documented metastatic disease with at least 1 bone metastasis on bone scan and
confirmed, if necessary, by CT scan or MRI, if results of the bone scans are
ambiguous. Patients with or without visceral involvement / lymph nodes (documented by
RECIST 1.1) are allowed.
6. Patients must have documented Progressive disease (PD) either by radiographic or PSA
criteria as defined in a) and b) below:
1. For the Radiographic PD assessment, 2 sets of scans using the same imaging
modality (ie CT/MRI or bone scan) and taken at separate time points are required
to document radiographic disease progression during or following the patient's
most recent anti-neoplastic therapy, (note: the 1st bone scan can be from before
most recent therapy but the 2nd scan must show disease progression during or
after the most recent therapy).
For patients with bone disease, progression will be assessed following
recommendations by the Prostate Cancer Working Group (PCWG3) (Appendix I):
appearance of 2 or more new lesions on bone scan, confirmed, if necessary, by
other imaging modalities (such as CT scan or MRI), if results of the bone scans
are ambiguous).
For patients with soft tissue lesions progression will be assessed using RECIST
1.1 criteria, (see Appendix C). Patients may have measurable or non-measurable
disease according to RECIST criteria version 1.1 (see Appendix C)
2. PSA progression as per PCWG3 (Appendix I) is defined as an increase in PSA, as
determined by 2 separate measurements taken at least 1 week apart and confirmed
by a third. If the third measurement is not greater than the second measurement,
then a fourth measurement must be taken and must be greater than the second
measurement for the patient to be eligible for the study. Furthermore, the
confirmatory PSA measurement (i.e. the third or, if applicable, fourth PSA
measurement) must be defined. If a patient has received prior anti-androgen
therapy (e.g. bicalutamide), PSA progression must be evident and documented after
discontinuation of anti-androgen therapy, (note: The 1st PSA reading taken to
document disease progression when the patient presents can be while the patient
is on Casodex or other ADT).
7. Prior surgical castration or concurrent use of an agent for medical castration (e.g.
GnRH analogue) with testosterone at screening less than 1.73 nmol /l (50ng/dL).
8. Screening PSA = 2 ng/mL.
9. Patients must agree to:
- abstain from intercourse or
- if the patient engages in sexual intercourse with a woman of childbearing
potential, a condom and a highly effective birth control must be used (i.e.
hormonal contraception associated with inhibition of ovulation, intrauterine
device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal
occlusion or a vasectomy that has received medical assessment of the surgical
success) during treatment and for 5 months after treatment.
10. Stable medical condition, including the absence of acute exacerbations of chronic
illnesses, serious infections, or major surgery within 28 days prior to registration.
11. Life expectancy of 12 months or more based on general health and prostate cancer
disease status as judged by the investigator.
12. Able to swallow study drug as whole tablet.
13. Adequate haematological, hepatic, and renal function.
- Haemoglobin = 10g/dL.
- Neutrophils (ANC/AGC) = 1500/mm³ (1.5 x 109/L).
- Platelets = (100 x 109/L).
- Total bilirubin = 1.5mg/dL (25.65 µmol/L) with the exception of Gilberts
syndrome.
- Both Alanine aminotransferase (ALT (SGPT)) and Aspartate aminotransferase (AST
(SGOT) = 3 x ULN with or without liver Metastasis.
- Calculated creatinine clearance (CrCl) = 30mL/min according to the Cockcroft and
Gault formula (Appendix D).
- Serum corrected Calcium within normal range and > 2 mmol/L
14. Continuous daily use of oral prednisone, oral dexamethasone, or other systemic
corticosteroids is allowed prior to study entry but must be discontinued a minimum of
2 weeks prior to start of study treatment.
Exclusion Criteria:
1. Patients should not be receiving any other investigational agents for the treatment of
prostate cancer or other diseases (within 30 days prior to registration).
2. Patients with GI tract disease resulting in an inability to take oral medication,
malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures
affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease,
ulcerative colitis).
3. Have current active hepatic or biliary disease (with exception of patients with
Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per
investigator assessment).
4. Prior therapy with orteronel, ketoconazole, aminoglutethimide, abiraterone or
enzalutamide, denosumab or radium 223.
5. All anti-androgen therapy (including bicalutamide) is excluded within 6 weeks prior to
first dose of study drug. Any other therapies for prostate cancer, other than GnRH
analogue therapy, such as progesterone, medroxyprogesterone, progestins (megesterol),
or 5-alpha reductase inhibitors (eg, finasteride or dutasteride), must be discontinued
2 weeks before the first dose of study drug. No prior bisphosphonates/Rank ligand
inhibitors are allowed except when administered for bone density preservation in
association with androgen deprivation therapy.
6. Prior chemotherapy for prostate cancer, with the exception of:
- neoadjuvant/ adjuvant therapy as part of initial primary treatment for local
disease that was completed 2 or more years prior to screening.
- Patients who received prior docetaxol for castrate sensitive metastatic prostate
cancer commencing with 120 days of ADT initation where total dose received did
not exceed 450mg/m2
7. Diagnosis of or treatment for another systemic malignancy within 2 years before the
first dose of study drug, or previously diagnosed with another malignancy and have any
evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in
situ of any type are not excluded if they have undergone complete resection.
8. History of myocardial infarction, unstable symptomatic ischemic heart disease/
unstable angina, uncontrolled on-going arrhythmias of Grade >2 (National Cancer
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5),
pulmonary embolism, or any other cardiac condition (e.g. pericardial effusion
restrictive cardiomyopathy) within 6 months prior to first dose of study drug.
Patients with long QT, QTcF >470ms or uncontrolled hypertension are excluded.
9. New York Heart Association Class III or IV heart failure (see Appendix F).
10. History of seizure, underlying brain injury with loss of consciousness, stroke,
transient ischaemic attack (TIA), cerebral vascular accident, primary brain tumours or
brain metastases, brain arteriovenous malformation, alcoholism, or the use of
concomitant medications that may lower the seizure threshold.
11. Known human immunodeficiency virus (HIV) infection, active chronic hepatitis B or C,
life-threatening illness unrelated to cancer, or any ongoing serious medical or
psychiatric illness that could, in the investigator's opinion, potentially interfere
with participation in this study. Patients will be tested for hepatitis B or C or HIV
infection during screening if they are considered by the investigator to be at higher
risk for these infections and have not been previously tested, or if testing is
required by the independent ethics committee or institutional review board.
12. Prohibited medications, including drugs that are known to lower the seizure threshold
or prolong QT interval are not permitted see section 7.4.2.
13. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or
jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned
invasive dental procedure are excluded as confirmed by dental examination.
14. Patients with rare hereditary problems of fructose intolerance.
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