Clinical Trials /

Capivasertib+Abiraterone as Treatment for Patients With Metastatic Hormone-sensitive Prostate Cancer and PTEN Deficiency

NCT04493853

Description:

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.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Capivasertib+Abiraterone as Treatment for Patients With Metastatic Hormone-sensitive Prostate Cancer and PTEN Deficiency
  • 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

Clinical Trial IDs

  • ORG STUDY ID: D361BC00001
  • NCT ID: NCT04493853

Conditions

  • Hormone-Sensitive Prostate Cancer

Interventions

DrugSynonymsArms
CapivasertibCapivasertib + Abiraterone
Abiraterone AcetateZYTIGACapivasertib + Abiraterone

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Capivasertib + AbirateroneExperimentalParticipants receive capivasertib in combination with abiraterone (prednisone/prednisolone) on a background of ADT.
  • Capivasertib
  • Abiraterone Acetate
Placebo + AbirateronePlacebo ComparatorParticipants receive placebo in combination with abiraterone (prednisone/prednisolone) on a background of ADT.
  • Abiraterone Acetate

Eligibility 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
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Radiographic Progression-free Survival (rPFS)
Time Frame:Up to approximately 52 months
Safety Issue:
Description: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

Measure:Overall survival (OS)
Time Frame:Up to approximately 64 months
Safety Issue:
Description:Overall survival is the length of time from randomisation until the date of death due to any cause.
Measure:Time to Start of First Subsequent Therapy or Death (TFST)
Time Frame:Up to approximately 52 months
Safety Issue:
Description: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.
Measure:Symptomatic Skeletal Event-Free Survival (SSE-FS)
Time Frame:Up to approximately 64 months
Safety Issue:
Description: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.
Measure:Time to Pain Progression (TTPP)
Time Frame:Up to approximately 64 months
Safety Issue:
Description: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.
Measure:Time to PSA progression
Time Frame:Up to approximately 52 months
Safety Issue:
Description:The time from randomisation to PSA progression, as determined by PCWG3 criteria.
Measure:Time To Castration Resistance (TTCR)
Time Frame:Up to approximately 64 months
Safety Issue:
Description: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).
Measure:Fatigue intensity, severity and interference domains assessed by the Brief Fatigue Inventory (BFI)
Time Frame:Up to approximately 64 months
Safety Issue:
Description: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.
Measure:Overall Pain Severity and Pain Interference as assessed by BPI-SF questionnaire
Time Frame:Up to approximately 64 months
Safety Issue:
Description:BPI-SF: Change from baseline in pain severity and pain interference domain scores.
Measure:Disease-Related Symptoms and HRQoL using the Functional Assessment of Cancer Therapy - Prostate Cancer (FACT-P) questionnaire
Time Frame:Up to approximately 64 months
Safety Issue:
Description:FACT-P endpoints may include: Time to deterioration in FACT-P scores; Change from baseline in FACT-P scores.
Measure:Progression-Free Survival after next-line treatment (PFS2)
Time Frame:Up to approximately 64 months
Safety Issue:
Description: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.
Measure:Plasma concentration of capivasertib pre-dose
Time Frame:Cycle 1 Day 15, Cycle 2 Day 1, Cycle Day 15
Safety Issue:
Description:
Measure:Plasma concentration of capivasertib 1h post-dose
Time Frame:Cycle 1 Day 1
Safety Issue:
Description:
Measure:Plasma concentration of capivasertib 4h post-dose
Time Frame:Cycle 1 Day 1
Safety Issue:
Description:

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Prostate cancer
  • De Novo Metastatic Prostate cancer
  • PTEN
  • PTEN deficiency
  • Hormones
  • Hormone-Sensitive
  • Androgen Deprivation Therapy
  • Capivasertib
  • Abiraterone

Last Updated

July 27, 2020