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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 : November 12, 2020
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
This study will assess the efficacy and safety of capivasertib plus abiraterone (+prednisone/prednisolone) plus androgen deprivation therapy (ADT) versus placebo plus abiraterone (+prednisone/prednisolone) plus ADT in participants with mHSPC whose tumours are characterised by PTEN deficiency. The intention of the study is to demonstrate that in participants with mHSPC, the combination of capivasertib plus abiraterone (+prednisone/prednisolone) plus ADT is superior to placebo plus abiraterone (+prednisone/prednisolone) plus ADT in participants with mHSPC characterised by PTEN deficiency with respect to radiographic progression-free survival (rPFS) per 1) Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for soft tissue and/or Prostate Cancer Working Group (PCWG3) for bone as assessed by the investigator 2) death due to any cause.

Condition or disease Intervention/treatment Phase
Hormone-Sensitive Prostate Cancer Drug: Capivasertib Other: Placebo Drug: Abiraterone Acetate Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1000 participants
Allocation: Randomized
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)
Primary Purpose: Treatment
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 : November 11, 2024
Estimated Study Completion Date : November 11, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Capivasertib + Abiraterone
Participants receive capivasertib in combination with abiraterone (prednisone/prednisolone) on a background of ADT.
Drug: Capivasertib
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.
Other: Placebo
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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. Time to PSA progression [ Time Frame: Up to approximately 52 months ]
    The time from randomisation to PSA progression, as determined by PCWG3 criteria.

  6. 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).

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. Plasma concentration of capivasertib pre-dose [ Time Frame: Cycle 1 Day 15, Cycle 2 Day 1, Cycle Day 15 ]
  12. Plasma concentration of capivasertib 1h post-dose [ Time Frame: Cycle 1 Day 1 ]
  13. Plasma concentration of capivasertib 4h post-dose [ Time Frame: Cycle 1 Day 1 ]

Other Outcome Measures:
  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.

  2. Systolic and diastolic blood pressure [ Time Frame: Up to approximately 64 months ]
    millimetre or mercury (mmHg)

  3. Pulse rate (heart rate) [ Time Frame: Up to approximately 64 months ]
    Beats per minute (BPM)

  4. Body Temperature [ Time Frame: Up to approximately 64 months ]
    Celsius (°C)

  5. Weight [ Time Frame: Up to approximately 64 months ]
    Kilograms (kg)

  6. Changes in Targeted Laboratory Results [ Time Frame: Up to approximately 64 months ]
    Change from baseline in selected laboratory test results

  7. QT interval (QTc) by electrical activity [ Time Frame: Up to approximately 64 months ]
    Milliseconds (msec)



Information from the National Library of Medicine

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.


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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Asymptomatic or mildly symptomatic, histologically-confirmed de novo metastatic hormone-sensitive prostate adenocarcinoma without small-cell tumours
  • 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 3 months 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

Exclusion Criteria:

  • Radiotherapy with a wide field of radiation within 4 weeks before the start of study treatment (capivasertib/placebo)
  • 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 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. Uncontrolled hypotension - systolic blood pressure (SBP) <90 mmHg and/or diastolic blood pressure (DBP) <50 mmHg vii. Cardiac ejection fraction outside 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 > 1.5x 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 > 1.5x ULN

  • 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, CYP2C9 and/or CYP2D6 with a narrow therapeutic window within 1 week before the start of study treatment

  • Drugs known to 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

Information from the National Library of Medicine

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


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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Sponsors and Collaborators
AstraZeneca
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04493853    
Other Study ID Numbers: D361BC00001
First Posted: July 30, 2020    Key Record Dates
Last Update Posted: November 12, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

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:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Supporting Materials: Study Protocol
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
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Prostate cancer
De Novo Metastatic Prostate cancer
PTEN
PTEN deficiency
Hormones
Hormone-Sensitive
Androgen Deprivation Therapy
Capivasertib
Abiraterone
Additional relevant MeSH terms:
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Prostatic Neoplasms
Hypersensitivity
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Prostatic Diseases
Immune System Diseases
Abiraterone Acetate
Antineoplastic Agents
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 Enzyme Inhibitors