Health Condition 1: C61- Malignant neoplasm of prostate
Conditions
Interventions
Intervention1: Capivasertib plus Abiraterone with ADT: Route: Oral tablet
Frequency: Twice daily for 4 days each week with 3 days off the tablets each week. - 1:1 Assignment
Control Intervention1: Pla
Sponsors
AstraZeneca AB
AstraZeneca Pharma India Ltd
Eligibility
Inclusion criteria
Inclusion criteria: Age 1 Participant must be = 18 years of age, at the time of signing the informed consent. Type of Participant and Disease Characteristics 2 Histologically-confirmed de novo (ie, diagnosed within 3 months of randomisation) metastatic hormone-sensitive prostate adenocarcinoma. Note: adenocarcinoma must be the primary histological pattern and patients with small-cell tumours are not eligible. 3 Consent to provide a FFPE tissue block (preferred) or slides. Details on tissue requirements are specified in the Laboratory Manual. Cytologic or FNA samples are not acceptable. Tumour tissue from bone metastases is not acceptable. 4 A valid PTEN IHC result indicating PTEN deficiency (centralised testing). 5 Metastatic disease documented prior to randomisation by clear evidence of = 1 bone lesion (defined as 1 lesion with positive uptake on bone scan) and/or = 1 soft tissue lesion suitable for repeated assessment with CT and/or MRI. Patients with metastatic disease identified by PSMA PET only, will not be eligible. Local lymph node involvement is not considered metastatic disease. 6 Asymptomatic or mildly symptomatic form of prostate cancer based on the investigator’s clinical evaluation. 7 Candidate for abiraterone and steroid therapy. Previous treatment with abiraterone and/or a steroid for de novo disease is allowed up to a maximum of 3 months prior to randomisation (prior treatment with chemotherapy or other NHAs is not allowed) 8 Ongoing ADT with GnRH analogue (combination with first generation androgen receptor antagonists, eg, bicalutamide is allowed), or LHRH antagonist, or bilateral orchiectomy. Duration of ongoing ADT (regardless of method) is from 0 days to a maximum of 3 months prior to randomisation. 9 ECOG/WHO performance status 0 to 1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks. 10 Able and willing to swallow and retain oral medication. 11 Participants must complete the 7-day BPI-SF and BFI questionnaires and the analgesic diary during screening (only after PTEN deficiency is confirmed), prior to randomisation. Note: it is required to give participants at least 7 consecutive days to complete the assessments prior to randomisation. If a minimum of 4 assessments is not completed during the 7-day period, participants must be re-screened, a new 7 days of questionnaire/diary entries completed, and any screening tests which are consequently outside of the applicable 28 days prior to randomisation must also be repeated. Sex 12 Participants will be male Reproduction 13 Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm: i) Sterilisation (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). ii) Participants should use barrier contraception (ie, condoms) from the time of screening until 16 weeks after discontinuation of study drug. It is not known whether the pre-clinical 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 participants wish to father children, they should be advised to arrange for collection of sperm samples prior to the start of stud
Exclusion criteria
Exclusion criteria: Medical Conditions 1 Radiotherapy with a wide field of radiation (eg, more than one-third of the skeleton) within 4 weeks before the start of study treatment (capivasertib/placebo). 2 Major surgery (excluding placement of vascular access, transurethral resection of prostate, bilateral orchiectomy, or internal stents) within 4 weeks of the start of study treatment. 3 Brain metastases, or spinal cord compression (unless spinal cord compression is asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment). 4 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. 5 Any of the following cardiac criteria: i) Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 consecutive ECGs. ii) Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third-degree heart block). iii) 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 (within 5 half-lives of the first dose of study treatment). iv) Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or NYHA or Class II to IV heart failure or cardiac ejection fraction measurement of 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 Grade = 2. v) Uncontrolled hypotension – systolic blood pressure (SBP) vi) Cardiac ejection fraction outside institutional range of normal or vii) Uncontrolled hypertension (SBP = 160 mmHg or DBP = 95 mmHg). 6 Clinically significant abnormalities of glucose metabolism as defined by any of the following: i) Diabetes mellitus type I or diabetes mellitus type II requiring insulin treatment. ii) HbA1c = 8.0% (63.9 mmol/mol). 7 Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: i) Absolute neutrophil count ii) Platelet count iii) Haemoglobin 7 days prior to the determination of a haemoglobin = 9 g/dL (= 5.59 mmol/L)]. iv) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2.5x upper limit of normal (ULN) if no demonstrable liver metastases or > 5x ULN in the presence of liver metastases. Elevated alkaline phosphatase (ALP) is not exclusionary if due to the presence of bone metastases and liver function is otherwise considered adequate in the investigator’s judgement. v) Total bilirubin > 1.5x ULN (participants with confir
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To compare the effect of capivasertib PLUS abiraterone relative to placebo PLUS abiraterone by assessment of radiographic progression-free survival (rPFS) in patients with PTEN-deficient mHSPCTimepoint: Data Cut off 1 and IDMC (PFS will be assessed): Oct 2023 Data Cut off 2 and IDMC (PFS will be assessed):: Nov 2024 Data Cut off 3 and IDMC (12 month after Data cut off 2) : Nov 2025 | — |
Secondary
| Measure | Time frame |
|---|---|
| 10. To investigate the effect of capivasertib PLUS abiraterone vs placebo PLUS abiraterone on genetic alterations that may be detected in ctDNA. 11. To analyse biomarkers in tumour tissue and ctDNA for potential use in future diagnostic test development. 12. To compare the effect of capivasertib PLUS abiraterone vs placebo PLUS abiraterone on rPFS and OS in additional populations which may include but are not limited to PTEN loss of function alterations detected in ctDNA and or tumour tissue Timepoint: Progression free survival;13. To investigate predictive markers of response and acquired resistance to capivasertib PLUS abiraterone vs placebo PLUS abiraterone which may include but are not limited to additional biomarkers of AKT inhibitor sensitivity resistance and immunological biomarker 14. To investigate the effect of capivasertib PLUS abiraterone and placebo PLUS abiraterone on biomarkers that may be observed in paired pre and on treatment tumour tissue samples Timepoint: Progression free survival;15. To investigate the effect of capivasertib PLUS abiraterone relative to placebo PLUS abiraterone on circulating biomarkers detectable in peripheral blood 16. To conduct potential future exploratory research into factors that may influence the progression of cancer and or response efficacy tolerability safety or PK to capivasertib PLUS abiraterone or placebo PLUS abiraterone Timepoint: Progression free survival;17. To perform future exploratory research into genes genetic variation that may influence response ie distribution safety tolerability and efficacy to study drugs and or susceptibility to cancer Timepoint: Progression free survival;4. To compare the effect of capivasertib PLUS abiraterone relative to placebo PLUS abiraterone by assessment of time to first subsequent chemotherapy. 5. To evaluate patient-reported, treatment-related symptoms and tolerability directly from patients 6. To assess the health economic impact of capivasertib PLUS ab | — |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, China, Czech Republic, France, Germany, Hong Kong, Hungary, India, Israel, Japan, Mexico, Netherlands, Peru, Philippines, Poland, Republic of Korea, Russian Federation, Slovakia, South Africa, Spain, Taiwan, Thailand, Turkey, United Kingdom, United States of America, Viet Nam
Contacts
Public ContactMr Sandeep AV
AstraZeneca Pharma India Ltd
Outcome results
None listed