Inclusion Criteria:
1. Patients, males ≥18 years of age, must be able to provide written informed consent.
2. Patients must have documented histological or cytological evidence of adenocarcinoma
of the prostate (excluding neuroendocrine differentiation or small cell histology).
3. Patients must have radiographic evidence of metastatic disease based on RECIST 1.1
within the 28 days before enrollment.
4. Patients are able to provide tumor biopsy samples for PTEN and PIK3CA/AKT status.
Phase I: The PTEN status test is optional and the result could be either positive,
negative, invalid or failed. Phase II: The PTEN status test is mandatary. Patients
that have a documentation of "PTEN LOSS" and/or PTEN/PI3KCA/AKT alteration from a
previous test (e.g. next generation sequencing NGS, or IHC), they are allowed to be
enrolled in this study. Patients who have PTEN status test reported other than "PTEN
LOSS" or never completed any PTEN test before, they could either give the archival
tumor samples collected within 12 months before study enrollment or do a fresh core
tumor biopsy. Alternatively, patients with confirmed PTEN LOSS and/or PIK3CA/AKT/PTEN
alteration by NGS of ctDNA testing of peripheral blood could also be permitted for
enrollment after getting the permission from the sponsor. The PTEN IHC results should
be either performed or confirmed, if there is a previous PTEN IHC result, by central
laboratory testing. (Please consult sponsor for participants with an "invalid" or
"failed" PTEN/PIK3CA/AKT alteration results
5. Patients must have progressive disease based on the PCWG3 criteria:
- Patients who progressed based solely on total PSA rising, should have had a
sequence of rising values on 3 consecutive occasions of at least 1-week intervals
(if the third measurement is not greater than the second measurement, a fourth
measurement at least a week apart must be taken and must be greater than the
second measurement) and should have 2.0 ng/mL minimum level for entry.
- Patients who have documented disease progression per RECIST 1.1 are eligible
independent of PSA.
- Patients with bone only progression according to PCWG3 (ie, bone scan showing
appearance of ≥2 new lesions).
Note: Patients must have had a prior PSA response, followed by documented PSA
progression on prior hormone treatment.
6. Patients must have castration levels of testosterone (<50 ng/dL or 1.7 nmol/L). Note:
Patients must have undergone androgen deprivation therapy (ADT), such as orchiectomy,
or have been on Luteinizing Hormone Releasing Hormone (LHRH) agonists or antagonists,
for at least 3 months prior to study enrollment. Patients on LHRH agonists/antagonists
must remain on these agents for the duration of the study.
7. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
≤1.
8. Patients must have adequate hematopoietic function by local laboratory within the 28
days before enrollment, as evidenced by:
- Absolute neutrophil count ≥1,500/μL
- Platelet count ≥75,000/μL
- Hemoglobin ≥9 g/dL
9. Total serum bilirubin ≤1.5 × Upper Limit of Normal (ULN) within the 28 days before
enrollment (in patients with known Gilbert's syndrome, total bilirubin ≤3 × ULN with
direct bilirubin ≤1.5 × ULN).
10. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN except
for patients with tumor involvement of the liver who must have AST and ALT ≤5 × ULN
within the 28 days before enrollment.
11. Patients must have adequate renal function as evidenced by a serum creatinine of ≤1.5
× the ULN for the reference laboratory or creatinine clearance ≥50 mL/min within the
28 days before enrollment (calculated from Cockcroft-Gault formula or 24-hour urine
collection).
12. Serum potassium ≥3.5 mmol/L and < ULN within the 28 days before enrollment.
13. Fasting glucose ≤120 mg/dL or ≤6.7 mmol/L; glycosylated hemoglobin ≤8% within the 28
days before enrollment.
14. Phase I: Patients who have mCRPC progressed or are intolerant after receiving at least
1 prior treatments of any anti-androgen (such as abiraterone, enzalutamide,
apalutamide, or any other AR antagonists that are approved later), and/or
chemotherapy. Patients must have at least 3 weeks of treatment of any antiandrogen
and/or completed at least 4 Cycles of docetaxel or cabazitaxel treatment before their
screening visit.
Phase II: Patients who have mCRPC progressed or are intolerant after receiving 1-3
prior standard treatments for mCSPC, or nmCRPC, or mCRPC, including at least one
second-generation antiandrogen treatment (i.e., abiraterone, enzalutamide,
apalutamide, or darolutamide), and no more than one chemotherapy. Patients must have
at least 3 weeks of treatment of any antiandrogen and/or completed at least 3 Cycles
of docetaxel or cabazitaxel treatment and/or at least 3 injections of R223 and/or at
least 2 injections of sipuleucel-T to be counted as one prior therapy. Patient's
current diagnosis at screening must be mCRPC and can be treated with docetaxel in Arm
2.
15. Concomitant use of bisphosphonates and other bone supportive agents is allowed if the
dose and renal function have been stable for at least 12 weeks before enrollment and
no related ≥Grade 2 side effects are present for at least 4 weeks prior to study drug
treatment. The minimum washout period is 4 weeks for prostate cancer therapy
(cytotoxic, biologics, antiandrogens, R223, etc.) before enrollment, starting from the
day the therapies were stopped.
16. Patients with a female partner of childbearing potential must agree to use condoms
plus an additional contraceptive method to avoid conception until the end of relevant
systemic exposure plus 90 days following the Clinical Trial Facilitation Group
contraception guideline from September 2014.
17. Patient should be able to swallow and retain oral medication and should not have any
known gastrointestinal diseases that may interfere with drug absorption.
18. Life expectancy of at least 6 months.
Exclusion Criteria:
- 1. Major surgery within 28 days before study treatment and/or have not recovered fully
from the adverse effects of any major surgical procedures before study treatment.
2. Patients that received other second-line Androgen Deprivation Therapy (ADT)
(including but not limited to ketoconazole and amino glutethimide) within 6 weeks
before enrollment.
3. Patients who have completed sipuleucel-T (Provenge®) treatment within 3 months of
enrollment.
4. Patients who have received antiandrogens such as flutamide (EULEXIN®), bicalutamide
(CASODEX®), or nilutamide (NILANDRON®) for >3 months must be off treatment for 6 weeks
prior to enrollment and should demonstrate a continued rise in PSA after withdrawal.
5. Patients on 5-alpha reductase inhibitors such as finasteride (PROSCAR®, PROPECIA®),
or dutasteride (AVODART®) must stop medication at least 3 months prior to enrollment.
6. Patients who have received Radium Ra 223 dichloride (XOFIGO®) or Samarium Sm 153
lexidronam (QUADRAMET®) must be off therapy for at least 3 months prior to enrollment.
7. Patients that are currently receiving increasing or chronic treatment (>5 days)
with corticosteroids or another immunosuppressive agent, other than daily use of up to
10 mg prednisone (or equivalent) or low-dose steroid for the control of nausea and
vomiting, topical steroid, or inhaled steroid use.
8. Patients who require potassium-wasting diuretics. 9. Patients who have received any
investigational agent beyond those indicated for the treatment of prostate cancer
within 5 half-lives of the agent; if the half-life of the agent is not known, the
patients must be off investigational therapy for 4 weeks prior to enrollment.
10. Patients who have received palliative and other radiotherapy within 4 weeks of
study enrollment.
11. Patients with symptomatic or known central nervous system metastases from prostate
cancer or who are at high risk for spinal cord compression, per investigator's
judgment.
12. Patients with a history of hypothalamus, pituitary or adrenal insufficiency.
13. Patients with diabetes mellitus that require insulin at study enrollment. 14.
History of another primary malignancy that is currently clinically significant or
currently requires active intervention.
15. Inadequately controlled hypertension (eg, systolic blood pressure ≥160 mmHg or
diastolic blood pressure ≥95 mmHg) or hypotension (eg, systolic blood pressure ≤80
mmHg or diastolic blood pressure ≤50 mmHg) after up to 3 measurements with at least 5
minutes apart during 28 days before study enrollment.
16. Patients with active cardiac disease or a history of cardiac dysfunction including
any of the following:
- Severe or unstable angina pectoris or acute coronary syndrome or stroke within 6
months prior to study enrollment.
- Symptomatic pericarditis.
- Documented myocardial infarction or arterial thrombotic events within 6 months prior
to study enrollment.
- History of documented congestive heart failure (New York Health Association functional
classification III to IV).
- Documented history of cardiomyopathy.
- Known left ventricular ejection fraction <50% as determined by multiple gated
acquisition scan or echocardiogram within 28 days prior to enrollment.
- History of clinically significant cardiac arrhythmias, as determined by the
investigator.
17. Patients with a Fridericia-corrected QT (QTcF) interval of >450 msec on the
screening electrocardiogram (ECG) (using the QTcF formula), has a short/long QT
syndrome, or history of QT prolongation/Torsades de Pointes.
18. Patients with a history of an active infection (viral, bacterial, or fungal)
requiring systemic therapy within 10 days before enrollment, including but not limited
to tuberculosis.
19. Patients who have active human immunodeficiency virus (HIV), hepatitis B, or
hepatitis C infections.
20. Patients that are currently receiving treatment with drugs known to be moderate or
strong inhibitors or inducers of isoenzyme CYP1A (including but not limited:
α-Naphthoflavone, Furafylline, Omeprazole, Lansoprazole) and isoenzyme CYP3A
(including but not limited: Itraconazole, Ketoconazole, Azamulin, Troleandomycin,
Verapamil, Rifampicin). The patients must have discontinued moderate or strong
inducers for at least 2 weeks prior to study enrollment and must have discontinued
moderate or strong inhibitors for at least 1 week before study enrollment.
Spironolactone, Strong bile salt export pump (BSEP) inhibitors, grapefruit juice,
herbal medicines such as St. John's wort, Kava, ephedra, gingko biloba,
dehydroepiandrosterone, yohimbe, saw palmetto and ginseng should be discontinued.
21. Sexually active males not willing to use a condom during the whole course of the
study and for 16 weeks after stopping treatment. Male patients must not father a child
in this period. A condom is required to be used also by vasectomized men as well as
during intercourse with a male partner in order to prevent delivery of the drug via
seminal fluid.
22. Patients with any other medical, psychiatric, or social condition, including
substance abuse, which in the opinion of the investigator, would preclude
participation in the study.
23. Patients with a history of upper gastrointestinal bleeding or peptic disease in
the previous 6 months.
24. Patients have previously received AKT or PI3 kinase pathway or mTOR inhibitors.
25. Any condition that in the assessment of the investigator renders the patient not
suitable for participation in this clinical study protocol
