This is a Phase Ib, open-label, multi-centre study to determine the safety, tolerability and
pharmacokinetics (PK) of capivasertib when given in combination with novel agents
(enzalutamide or abiraterone) to inform the selection of capivasertib dose regimens for each
combination for further clinical evaluation when given to patients with metastatic castration
resistant prostate cancer (CRPC). The study design allows an exploration of different doses
with intensive safety monitoring to ensure the safety of the patients.
1. Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this
protocol prior to any mandatory study-specific procedures, sampling, and analyses.
2. Males aged 18 years and older at the time of signing the ICF.
3. Patients with documented evidence of metastatic CRPC who may benefit from treatment
with capivasertib or for whom no alternative approved therapy is available.
4. World Health Organization (WHO) performance status 0 to 2 with no deterioration over
the previous 2 weeks and minimum life expectancy of 12 weeks, as assessed at day 1.
5. Patients must be able to swallow and retain oral medication.
6. Agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures, and agreement to refrain from donating sperm.
- Sterilisation (with the appropriate post-vasectomy documentation of the absence
of sperm in the ejaculate).
- Patients should use barrier contraception (ie, condoms) from the time of
screening until 16 weeks after discontinuation of study treatment. It is not
known whether the preclinical changes seen in the male animal reproductive
organs, after treatment with capivasertib, will be fully reversible or will
permanently affect the ability to produce healthy sperm following treatment.
Therefore, if patients wish to father children they should be advised to arrange
for collection of sperm samples prior to the start of study treatment.
1. Previous enrolment in the present study.
2. Prior enzalutamide therapy in the last 8 weeks.
3. Treatment with any of the following:
- Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment.
- Any investigational agents or study drugs from a previous clinical study within
30 days of the first dose of study treatment.
- Any other chemotherapy, immunotherapy, immunosuppressant medication (other than
corticosteroids) or anti-cancer agents within 3 weeks of the first dose of study
treatment, except hormonal therapy with luteinising hormone-releasing hormone
(LHRH) analogues for medical castration in patients with prostate cancer, which
- Potent inhibitors or inducers or substrates of CYP3A4 within 2 weeks before the
first dose of study treatment (3 weeks for St. John's wort) or sensitive
substrates of CYP3A4, CYP2C9 and/or CYP2D6 with a narrow therapeutic window
within 1 week prior to the first dose of study treatment.
4. Major surgery (excluding placement of vascular access) within 4 weeks of the first
dose of study treatment.
5. Radiotherapy with a wide field of radiation within 4 weeks of the first dose of study
6. Clinically significant abnormalities of glucose metabolism as defined by any of the
- Diabetes mellitus Type I or Type II requiring insulin treatment.
- HbA1c ≥8.0% (63.9 mmol/mol).
7. Spinal cord compression or brain metastases unless asymptomatic, treated and stable
and not requiring steroids for at least 4 weeks prior to start of study treatment.
8. Past medical history of interstitial lung disease, drug-induced interstitial lung
disease, radiation pneumonitis which required steroid treatment, or any evidence of
clinically active interstitial lung disease.
9. As judged by the investigator, any evidence of severe or uncontrolled systemic
diseases, including uncontrolled hypertension, active bleeding diatheses, or active
infection including hepatitis B, hepatitis C, and human immunodeficiency virus.
Screening for chronic conditions is not required.
10. Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTc) >470 milliseconds obtained from 3
- Any clinically important abnormalities in rhythm, conduction, or morphology of a
resting ECG (eg, complete left bundle branch block, 3rd degree heart block).
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalaemia, potential for torsades de pointes,
congenital long QT syndrome, family history of long QT syndrome or unexplained
sudden death under 40 years-of-age, or any concomitant medication known to
prolong the QT interval.
- Clinically significant heart disease as evidenced by myocardial infarction or
arterial thrombotic events in the past 6 months, severe or unstable angina, or
New York Heart Association NYHA Class II to IV heart failure or cardiac ejection
fraction measurement of <50%.
- Experience of any of the following procedures or conditions in the preceding 6
months: coronary artery bypass graft, angioplasty, vascular stent, myocardial
infarction, angina pectoris, congestive heart failure NYHA ≥2.
- Uncontrolled hypotension defined as - systolic BP <90 mmHg and/or diastolic BP<50
- Uncontrolled hypertension defined as - systolic BP >160 mmHg and/or diastolic BP
- Cardiac ejection fraction outside institutional range of normal or <50%
(whichever is higher) as measured by echocardiogram (or multi gated acquisition
scan (MUGA), if an echocardiogram cannot be performed or is inconclusive).
11. With the exception of alopecia, any unresolved toxicities from prior therapy greater
than Common Terminology Criteria for Adverse Event (CTCAE) grade 1 at the time of
starting study treatment.
12. Absolute neutrophil count <1.5×10^9/L.
13. Platelets <100×10^9/L.
14. Haemoglobin <9 g/dL (<5.59 mmol/L). (Note: any blood transfusion must have been >14
days prior to the determination of a haemoglobin ≥9 g/dL [≥5.59 mmol/L]).
15. Aspartate aminotransferase (AST) >2.5 times the ULN if no demonstrable liver
metastases or >5 times ULN in the presence of liver metastases. Total bilirubin >1.5
times ULN (*patients with confirmed Gilbert's syndrome may be included in the study).
Elevated alkaline phosphatase (ALP) is not exclusionary if due to the presence of bone
metastasis and liver function is otherwise considered adequate in the investigator's
16. Creatinine >1.5 times ULN concurrent with creatinine clearance <50 mL/min (measured or
calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is
only required when creatinine is >1.5 times ULN.
17. Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal
diseases, inability to swallow the formulated product or previous significant bowel
resection that would preclude adequate absorption of capivasertib.
18. Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that, in the investigator's opinion, gives reasonable suspicion of
a disease or condition that contraindicates the use of an investigational drug, may
affect the interpretation of the results, render the patient at high risk from
treatment complications or interferes with obtaining informed consent.
19. History of hypersensitivity to active or inactive excipients of capivasertib or drugs
with a similar chemical structure or class to capivasertib.
20. Judgement by the investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions, and
21. Evidence of dementia, altered mental status or any psychiatric condition that would
prohibit understanding or rendering of informed consent.
22. Previous allogeneic bone marrow transplant or solid organ transplant.
23. Known immunodeficiency syndrome.
24. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).
25. Abiraterone-specific exclusion criteria: Any restriction or contraindication based on
the currently applicable approved abiraterone label that would prohibit the use of
26. Enzalutamide-specific exclusion criteria: Any restriction or contraindication based on
the currently applicable approved enzalutamide label that would prohibit the use of