| Eligibility |
Inclusion Criteria:
The following will be required prior to REGISTRATION:
- Patients must have histologically confirmed adenocarcinoma of the prostate without
pathologic or clinical evidence (e.g. PSA < 2.0 µg/L with liver metastases) of small
cell neuroendocrine differentiation.
- Patients must consent prior to blood collection for screening correlative testing by a
central reference laboratory. The screening blood sample cannot be sent for analysis
prior to screening registration.
- All patients must have consented to the release of a tumour block from their primary
or metastatic tumour. The centre/pathologist must have agreed to the submission of the
specimen(s). Contact CCTG if no archival tissue is available.
- Patients must have evidence of castrate resistance with either biochemical or
radiological disease progression in the setting of surgical or medical castration:
PSA Progression:
- Minimum of two rising PSA values from a baseline measurement with an interval of = 1
week between each measurement
- PSA must be = 2.0 µg/L (ng/mL)
Objective progression:
- RECIST 1.1, or
- PCWG3 Criteria for bone progression
Surgical/Medical Castration:
- Prior bilateral orchiectomy, or
- LHRH agonist/antagonist and testosterone < 50 ng/dL or < 1.7 nmol/L. LHRH
agonist/antagonist therapy must be maintained for the duration of study therapy and if
previously discontinued, must be restarted and castrate level of testosterone present.
- Patients must be =18 years of age.
- ECOG performance status 0 or 1 (Appendix I) and have a life expectancy of = 6 months.
- Patients must have radiologically documented disease (measurable or non-measurable as
defined by RECIST 1.1. Patients with elevated PSA only are not eligible.
- Neutrophils = 1.5 x 10^9/L
- Platelets = 100 x 10^9/L
- Hemoglobin = 90 g/L; contact CCTG if hemoglobin is between 80-89 g/L, patient is not
decompensated, is asymptomatic and transfusion is not indicated.
- Serum potassium within normal limits
- Bilirubin = 1.5 ULN; if confirmed Gilbert's then bilirubin = 3.0 x ULN
- ALT = 2.5 x ULN; if patient has liver metastases = 5.0 x ULN
- Serum creatinine = 1.5 x ULN or Creatinine clearance = 45 mL/min; measured directly by
24-hour urine sampling OR as calculated by Cockcroft and Gault equation: Males: GFR =
1.23 x (140-age) x weight in kg/serum creatinine in µmol/L
- Patient consent for screening and subsequent enrollment (as applicable) must be
appropriately obtained in accordance with applicable local and regulatory
requirements. Each patient must sign a consent form prior to screening and subsequent
enrollment (as applicable) in the trial to document their willingness to participate.
Additional Criteria to be met prior to SUB-STUDY ENROLLMENT:
- Patients must have recovered from any treatment-related toxicities prior to enrollment
(unless = grade 1, irreversible, or considered by investigator as not clinically
significant).
- Prior major surgery is permitted provided that a minimum of 14 days have elapsed
between any major surgery and enrollment (7 days for minor surgery e.g. port
insertion), and that wound healing has occurred.
- Prior external beam radiation or radium-223 is permitted provided a minimum of 28 days
(4 weeks) have elapsed between the last dose and enrollment. Consult CCTG if patients
have received other therapeutic radioisotopes. Exceptions may be made for low-dose
non-myelosuppressive radiotherapy after consultation with CCTG. Concurrent radiation
is not permitted. If radiation is required for example for pain control, it must be
completed prior to enrollment. Prior strontium-89 at any time is not permitted.
- Previous Hormone Therapy: Patients must have received prior hormonal treatment with at
least one of: abiraterone acetate, enzalutamide, apalutamide (ARN-509), darolutamide
(ODM-201), TAK-700 and TOK-001 or other next-generation AR-pathway inhibitor (if agent
is not listed, must be discussed and approved with CCTG prior to registration).
Consult substudies for additional criteria
- Prior cytotoxic therapy: Patients may have received cytotoxic therapy in the castrate
sensitive setting as well as up to 1 regimen of cytotoxic therapy in the CRPC setting
- Patients must have an adequate washout prior to enrollment as follows:
- Longest of one of the following:
- Standard cycle length of standard therapies;
- Two weeks;
- The longer of 30 days or 5 half-lives for investigational agents;
- Patients must have discontinued anti-androgens for at least 4 weeks prior to substudy
entry/enrollment (at least 6 weeks for bicalutamide).
- LHRH agonist therapy must continue unless surgically castrated. Note: after
discussion, CCTG selected patients may be screened prior to adequate washout.
- Patient must have progressed (biochemically or radiologically, as defined in 4.1.4)
during or after their last systemic therapy
- Patients must be accessible for treatment and follow up. Patients registered enrolled
on this trial must be treated and followed at the participating centre. This implies
there must be reasonable geographical limits (for example: 1 ½ hour's driving
distance) placed on patients being considered for this trial.
- Investigators must assure themselves the patients enrolled on this trial will be
available for complete documentation of the treatment, adverse events, response
assessment and follow-up.
- Patients must agree to return to their primary care facility for any adverse events,
which may occur through the course of the trial.
- In accordance with CCTG policy, protocol treatment is to begin within 2 working days
of patient enrollment.
- Men of childbearing potential must have agreed to use a highly effective contraceptive
method during study drug treatment for 6 months after stopping treatment and should
not father a child or donate sperm during this period.
- In addition to routine contraceptive methods, "effective contraception" also includes
heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect
of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or
bilateral tubal ligation, or vasectomy / vasectomized partner. However, if at any
point a previously celibate patient chooses to become heterosexually active during the
time period for use of contraceptive measures outlined in the protocol, he is
responsible for beginning contraceptive measures.
Exclusion Criteria:
- Patients with a history of other malignancies, except: adequately treated non-melanoma
skin cancer, or other solid tumours curatively treated with no evidence of disease for
= 2 years.
- Patients with central nervous system (CNS) involvement unless at least 4 weeks from
prior therapy completion (including radiation and/or surgery) AND clinically stable
and not receiving steroids and/or enzyme-inducing anti-epileptic medications for brain
metastases. Patients with epilepsy not due to CNS metastases are eligible as long as
no contraindication or concern with drug interactions.
- Patients with serious illnesses or medical conditions which could cause unacceptable
safety risks or would not permit the patient to be managed according to the protocol.
This includes but is not limited to:
- active infection requiring systemic therapy;
- active or known human immunodeficiency virus (HIV) with detectable viral load;
- uncontrolled or recent clinically significant cardiac disease, including:
- angina pectoris, symptomatic pericarditis, coronary artery bypass grafting,
coronary angioplasty, or stenting, or myocardial infarction in the previous
12 months;
- history of documented congestive heart failure (New York Heart Association
functional classification III-IV) or cardiomyopathy;
- history of any cardiac arrhythmias, e.g. ventricular, supraventricular,
nodal arrhythmias, or conduction abnormality in the previous 12 months;
- patients with uncontrolled hypertension.
- Patients with significant liver diseases including viral/other hepatitis, current
alcohol abuse or cirrhosis.
- Patients who are unable to swallow oral medication and/or have impairment of
gastrointestinal (GI) function or GI disease that may significantly alter the
absorption of the study drugs (e.g. Crohn's disease, ulcerative diseases, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome, active bowel inflammation (e.g.
diverticulitis) or small bowel resection), unless agreed with CCTG (exceptions may be
given if parenteral substudy is available/appropriate.
- Patients who require continued or concurrent treatment with:
- Systemic corticosteroids at a dose equivalent to prednisone > 10 mg daily.
Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways
diseases), eye drops or local injections (e.g. intra-articular) are allowed.
- Bisphosphonates / denosumab for reasons other than hypercalcemia, osteoporosis or
prevention of skeletal-related events.
- Other anti-cancer or investigational agents (except LHRH)
- History of hypersensitivity to any of the study drugs or any excipient.
- Patients with a history of non-compliance to medical regimens.
- Patients who have received growth factors within 28 days prior to initiation of dosing
of study drug or who are likely to require treatment with growth factors throughout
the duration of the trial.
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