Capivasertib+Abiraterone as Treatment for Patients With Metastatic Hormone-sensitive Prostate Cancer and PTEN Deficiency (CAPItello-281)
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|ClinicalTrials.gov Identifier: NCT04493853|
Recruitment Status : Recruiting
First Posted : July 30, 2020
Last Update Posted : May 30, 2023
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|Condition or disease||Intervention/treatment||Phase|
|Hormone-Sensitive Prostate Cancer||Drug: Capivasertib Other: Placebo Drug: Abiraterone Acetate||Phase 3|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||1000 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||Approximately 1000 participants are assigned to one of the two parallel groups (1:1 ratio) to receive either capivasertib or placebo, in combination with abiraterone on a background of ADT for the duration of the study.|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||A Phase III Double-Blind, Randomised, Placebo-Controlled Study Assessing the Efficacy and Safety of Capivasertib+Abiraterone Versus Placebo+Abiraterone as Treatment for Patients With DeNovo Metastatic Hormone-Sensitive Prostate Cancer Characterised by PTEN Deficiency.|
|Actual Study Start Date :||July 13, 2020|
|Estimated Primary Completion Date :||February 17, 2025|
|Estimated Study Completion Date :||March 10, 2026|
Experimental: Capivasertib + Abiraterone
Participants receive capivasertib in combination with abiraterone (prednisone/prednisolone) on a background of ADT.
400 mg (2 tablets) BD given on an intermittent weekly dosing schedule. Patients will be dosed on Days 1 to 4 in each week of a 28-day treatment cycle. Number of Cycles: until disease progression or unacceptable toxicity develops.
Drug: Abiraterone Acetate
Administered orally as tablets at a dosage of 1000 mg daily. Administered continuously until criteria for discontinuation are met.
Other Name: ZYTIGA
Placebo Comparator: Placebo + Abiraterone
Participants receive placebo in combination with abiraterone (prednisone/prednisolone) on a background of ADT.
matched to capivasertib appearance (2 tablets) BD given on an intermittent weekly dosing schedule. Patients will be dosed on Days 1 to 4 in each week of a 28-day treatment cycle. Number of Cycles: until disease progression or unacceptable toxicity develops.
Drug: Abiraterone Acetate
Administered orally as tablets at a dosage of 1000 mg daily. Administered continuously until criteria for discontinuation are met.
Other Name: ZYTIGA
- Radiographic Progression-free Survival (rPFS) [ Time Frame: Up to approximately 52 months ]rPFS is defined as the time from randomisation to radiographic progression, as assessed by the investigator per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST) for soft tissue and/or Prostate Cancer Working Group 3 (PCWG3) for bone, or death due to any cause for each study arm.
- Overall survival (OS) [ Time Frame: Up to approximately 64 months ]Overall survival is the length of time from randomisation until the date of death due to any cause.
- Time to Start of First Subsequent Therapy or Death (TFST) [ Time Frame: Up to approximately 52 months ]TFST is defined as time from randomisation to the earlier of: the start date of the first subsequent anticancer therapy after discontinuation of randomised treatment (capivasertib/placebo), or death due to any cause.
- Symptomatic Skeletal Event-Free Survival (SSE-FS) [ Time Frame: Up to approximately 64 months ]SSE-FS is defined as time from randomisation until any of the following: use of radiation therapy to prevent or relieve skeletal symptoms; Occurrence of new symptomatic pathological bone fractures (vertebral or non-vertebral); Occurrence of spinal cord compression; Orthopaedic surgical intervention for bone metastasis; Death due to any cause.
- Time to Pain Progression (TTPP) [ Time Frame: Up to approximately 64 months ]TTPP is defined as the time from randomisation to clinically meaningful pain progression base on a 2-point increase from baseline in the Brief Pain Inventory-Short Form (BPI-SF) Item 3 ("worst pain in 24 hours") score and/or initiation of/increase in opiate analgesic use.
- Time to PSA progression [ Time Frame: Up to approximately 52 months ]The time from randomisation to PSA progression, as determined by PCWG3 criteria.
- Time To Castration Resistance (TTCR) [ Time Frame: Up to approximately 64 months ]TTCR is defined as the time from randomisation to the first castration-resistant event (radiographic disease progression, PSA progression, or SSE), whichever occurs first, with castrate levels of testosterone (below 50 ng/dL).
- Fatigue intensity, severity and interference domains assessed by the Brief Fatigue Inventory (BFI) [ Time Frame: Up to approximately 64 months ]BFI endpoints may include: Time to deterioration in fatigue intensity; Time to deterioration in fatigue interference; Change from baseline in fatigue severity and fatigue interference domain scores.
- Overall Pain Severity and Pain Interference as assessed by BPI-SF questionnaire [ Time Frame: Up to approximately 64 months ]BPI-SF: Change from baseline in pain severity and pain interference domain scores.
- Disease-Related Symptoms and HRQoL using the Functional Assessment of Cancer Therapy - Prostate Cancer (FACT-P) questionnaire [ Time Frame: Up to approximately 64 months ]FACT-P endpoints may include: Time to deterioration in FACT-P scores; Change from baseline in FACT-P scores.
- Progression-Free Survival after next-line treatment (PFS2) [ Time Frame: Up to approximately 64 months ]PFS2 is defined as time from randomisation until progression on next-line treatment, as clinical progression, PSA progression, or radiographic progression determined by RECIST version 1.1 (soft tissue) and/or PCWG3 criteria (bone), as assessed by the investigator, or death due to any cause.
- Plasma concentration of capivasertib pre-dose [ Time Frame: Cycle 1 Day 15, Cycle 2 Day 1, Cycle Day 15 ]
- Plasma concentration of capivasertib 1h post-dose [ Time Frame: Cycle 1 Day 1 ]
- Plasma concentration of capivasertib 4h post-dose [ Time Frame: Cycle 1 Day 1 ]
- Incidence and Severity of Adverse Events (AEs) [ Time Frame: Up to approximately 64 months ]Percentage of participants with an adverse event (AE), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0, including analysis of pre-specified AEs.
- Systolic and diastolic blood pressure [ Time Frame: Up to approximately 64 months ]millimetre or mercury (mmHg)
- Pulse rate (heart rate) [ Time Frame: Up to approximately 64 months ]Beats per minute (BPM)
- Body Temperature [ Time Frame: Up to approximately 64 months ]Celsius (°C)
- Weight [ Time Frame: Up to approximately 64 months ]Kilograms (kg)
- Changes in Targeted Laboratory Results [ Time Frame: Up to approximately 64 months ]Change from baseline in selected laboratory test results
- QT interval (QTc) by electrical activity [ Time Frame: Up to approximately 64 months ]Milliseconds (msec)
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||18 Years to 130 Years (Adult, Older Adult)|
|Sexes Eligible for Study:||Male|
|Accepts Healthy Volunteers:||No|
- Asymptomatic or mildly symptomatic, histologically-confirmed de novo hormone-sensitive prostate adenocarcinoma without small-cell tumours diagnosed within 180 days of randomisation
- Provide a FFPE tissue block (preferred) or slides. Tissue from bone metastases is not acceptable
- A valid PTEN IHC result indicating PTEN deficiency (centralized testing)
- Metastatic disease documented prior to randomisation by clear evidence of ≥ 1 bone lesion and/or ≥ 1 soft tissue lesion accurately assessed at baseline and suitable for repeated assessment with CT and/or MRI. PSMA PET identification only will not be eligible
- Candidate for abiraterone and steroid therapy
- Ongoing ADT with GnRH analogue, or LHRH agonists or antagonist, or bilateral orchiectomy (regardless of method) is from 0 days to a max. of 93 days prior to randomisation
- Eastern Cooperative Oncology Group (ECOG)/WHO performance status 0 to 1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks
- Able and willing to swallow and retain oral medication
- 7-day Brief Pain Inventory-Short Form (BPI-SF) and Brief Fatigue Inventory(BFI) questionnaires and the analgesic diary during screening completed
- Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm
- Prior radical prostatectomy or definitive radiotherapy with therapeutic intent for prostate cancer. Palliative radiotherapy is allowed providing any wide field radiation therapy is completed more than 4 weeks before randomisation
- 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
- 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)
- 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
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 significantly prolong the QT interval 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 < 50% v. 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 vi. Symptomatic hypotension - systolic blood pressure (SBP) <90 mmHg and/or diastolic blood pressure (DBP) <50 mmHg vii. Cardiac ejection fraction below the institutional range of normal or <50% (whichever is higher) as measured by echocardiogram (or multiple-gated acquisition [MUGA] scan if an echocardiogram cannot be performed or is inconclusive) viii. Uncontrolled hypertension (SBP ≥ 160 mmHg or DBP ≥ 95 mmHg).
Clinically significant abnormalities of glucose metabolism as defined by any of the following:
i. Patients with diabetes mellitus type 1 or diabetes mellitus type 2 requiring insulin treatment ii. HbA1c ≥8.0% (63.9 mmol/mol)
Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
i. Absolute neutrophil count < 1.5x 109/L ii. Platelet count < 100x 109/L iii. 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 confirmed Gilbert's syndrome may be included in the study with a higher value) vi. Creatinine clearance < 50 mL/min (measured or calculated by Cockcroft and Gault equation)
- As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, or known active infection including hepatitis B, hepatitis C, and HIV
- unevaluable for both bone and soft tissue progression as defined by meeting both of the following criteria: i. a "superscan" of bone scan, and ii. no soft tissue lesion that can be assessed by RECIST criteria
- Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection, or other condition that would preclude adequate absorption of capivasertib
- 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 contra-indicates 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
- Evidence of dementia, altered mental status, or any psychiatric condition that would prohibit understanding or rendering of informed consent
- Previous allogeneic bone marrow transplant or solid organ transplant
- Known additional malignancy that has had progression or has required active treatment in the last 3 years. Exceptions include basal cell carcinoma of the skin, and squamous cell carcinoma of the skin that has undergone potentially curative therapy
Treatment with any of the following:
i. Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment ii. Any investigational agents or study drugs from a previous clinical study within 30 days or 5 half-lives (whichever is longer) of the first dose of study treatment iii. Any other chemotherapy, immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents within 3 weeks of the first dose of study treatment. A longer washout may be required for drugs with a long half-life (eg, biologics) iv. Potent inhibitors or inducers of CYP3A4 within 2 weeks before the start of study treatment (3 weeks for St John's wort), or sensitive substrates of CYP3A4 with a narrow therapeutic window within 1 week before the start of study treatment
- Drugs known to significantly prolong the QT interval within 5 half-lives of the first dose of study treatment
- History of hypersensitivity to active or inactive excipients of capivasertib, abiraterone, or drugs with a similar chemical structure or class
- Any restriction or contraindication based on the local prescribing information that would prohibit the use of abiraterone
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04493853
|Contact: AstraZeneca Clinical Study Information Centerfirstname.lastname@example.org|
|Other Study ID Numbers:||
2020-000346-33 ( EudraCT Number )
|First Posted:||July 30, 2020 Key Record Dates|
|Last Update Posted:||May 30, 2023|
|Last Verified:||May 2023|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:
Statistical Analysis Plan (SAP)
|Time Frame:||AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.|
|Access Criteria:||When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
De Novo Metastatic Prostate cancer
Androgen Deprivation Therapy
Genital Neoplasms, Male
Neoplasms by Site
Genital Diseases, Male
Male Urogenital Diseases
Immune System Diseases
Steroid Synthesis Inhibitors
Molecular Mechanisms of Pharmacological Action
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 Enzyme Inhibitors