Clinical trial NCT05348577: Study of Capivasertib + Docetaxel vs Placebo + Docetaxel as Treatment for Metastatic Castration Resistant Prostate Cancer (mCRPC)
Official title: A Phase III Double-Blind, Randomised, Placebo-Controlled Study Assessing the Efficacy and Safety of Capivasertib + Docetaxel Versus Placebo + Docetaxel as Treatment for Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Prostate Cancer
Keywords: prostate cancer,
metastatic
castration resistant
capivasertib,
AKT inhibitor,
docetaxel
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2022-04-27
Enrollment: 1035
Sex: MALE
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Approximately 1350 participants will be enrolled and screened to achieve a total of approximately 1000 assigned in a 1:1 ratio to one of the two parallel groups to receive either capivasertib or placebo, in combination with docetaxel on a background of ADT for the duration of the study.
Primary purpose: TREATMENT

Brief summary: This study will assess the efficacy and safety of capivasertib plus docetaxel versus placebo plus docetaxel in participants with metastatic castration resistant prostate cancer (mCRPC), all participants will receive the docetaxel with steroid therapy and receive androgen deprivation therapy. The intention of the study is to demonstrate that the combination of capivasertib plus docetaxel is superior to placebo plus docetaxel with respect to the overall survival and/or the radiographic progression free survival of study participants.


Eligibility criteria: Inclusion Criteria:

* Histologically-confirmed prostate adenocarcinoma without predominant neuroendocrine or small cell cancers
* 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 (measurable or non-measurable)
* Patient must have been previously treated with a next generation hormonal agent (NHA), ie, abiraterone, enzalutamide, apalutamide or darolutamide, for prostate cancer for at least 3 months and shown evidence of disease progression (radiological or via PSA assessment) while receiving the NHA
* Evidence of mCRPC with progression of disease despite androgen deprivation therapy (ADT)
* Serum testosterone level ≤ 50 ng/dL
* Candidate for docetaxel and steroid therapy
* Ongoing ADT with LHRH agonist, LHRH antagonist, or bilateral orchiectomy
* Eastern Cooperative Oncology Group (ECOG)/World Health Organisation (WHO) performance status 0 to 1 and anticipated minimum life expectancy of 12 weeks
* Confirmation that archival formalin-fixed paraffin-embedded (FFPE) tumour tissue sample which meets the minimum pathology and sample requirements is available to send to the central laboratory
* Able and willing to swallow and retain oral medication
* 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 start of study treatment
* Major surgery (excl. placement of vascular access, transurethral resection of prostate, bilateral orchiectomy, internal stents) within 4 weeks of start of study treatment
* Brain metastases,or spinal cord compression (unless spinal cord compression is asymptomatic and stable and not requiring steroids for at least 4 weeks prior to start of study treatment)
* Any of the following cardiac criteria:

  i. Mean resting corrected QT interval (QTc) \>470 msec from 3 consecutive ECGs ii. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG 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. Experience of any of the following procedures or conditions in the preceding 3 months: coronary artery bypass graft, vascular stent, myocardial infarction, unstable angina pectoris, congestive heart failure NYHA Grade ≥2 v. Symptomatic hypotension - systolic blood pressure \<90 mmHg and/or diastolic blood pressure \<50 mmHg vi. haemodinamic instability
* Clinically significant abnormalities of glucose metabolism as defined by any of the following:

  i. Patients with diabetes mellitus (DM) type 1 or DM 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 10\^9/L ii. Platelet count \< 100x 10\^9/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 per the Cockcroft and Gault formula without the need for chronic dialysis;
* As judged by the investigator, any evidence of diseases (including severe or uncontrolled systemic diseases, uncontrolled hypertension, history of interstitial pneumonia / pneumonitis or interstitial lung disease, renal transplant and active bleeding diseases), which, in the investigator's opinion, makes it undesirable for the patient to participate in the study or that would jeopardise compliance with the protocol.
* 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, 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
* History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥2 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer and curatively treated in situ disease.
* Persistent toxicities (CTCAE Grade ≥2) caused by previous anticancer therapy, excluding alopecia. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included (eg, hearing loss)
* Known to have active hepatitis infection.
* Known to have human immunodeficiency virus (HIV) with a detectable viral RNA load or a CD4+ T-cell count \< 350 cells/uL or a history of an acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the past 12 months, or receiving anti-HIV medications for less than 4 weeks.
* Known to have active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
* Treatment with any of the following:

  i. Prior chemotherapy for CRPC. Chemotherapy for metastatic or localized HSPC (including docetaxel) is allowed provided that chemotherapy was completed ≥ 6months before randomisation and progression of the prostate cancer occurred ≥ 6months after the completion of therapy.

ii. Prior exposure to AKT inhibitors or PI3K inhibitors iii. 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 iv. Any other immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents (except ADT) within 3 weeks of the first dose of study treatment v. Strong inhibitors or strong inducers of cytochrome P450 (CYP)3A4 within 2 weeks prior to the first dose of study treatment (3 weeks for St John's wort), vi.Use of any live vaccine administration 30 days prior to the initiation of study treatment, during, and for at least 90 days after the last dose of the study treatment

* Drugs known to significantly prolong the QT interval and associated with Torsade de Pointes within 5 half-lives of the first dose of study treatment
* History of hypersensitivity to active or inactive excipients of capivasertib, docetaxel, 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 docetaxel

Primary outcomes:
measure: Overall Survival (OS) in the overall population
timeFrame: up to approximately 46 months
measure: Radiographic Progression-free Survival (rPFS) in the overall population
timeFrame: up to approximately 37 months
Secondary outcomes:
measure: Overall Survival (OS) in patients with mCRPC and PTEN-proficient tumours (IHC)
timeFrame: up to approximately 46 months
measure: Overall Survival (OS) in patients with mCRPC and PTEN-deficient tumours (IHC).
timeFrame: up to approximately 46 months
measure: Radiographic Progression-free Survival (rPFS) in patients with mCRPC and PTEN-proficient tumours (IHC)
timeFrame: up to approximately 37 months
measure: Radiographic Progression-free Survival (rPFS) in patients with mCRPC and PTEN-deficient tumours (IHC)
timeFrame: up to approximately 37 months
measure: Time to pain progression (TTPP) in the overall population
timeFrame: up to approximately 37 months
measure: Time to first Symptomatic Skeletal-Related Event (SSRE) in the overall population
timeFrame: up to approximately 46 months
measure: Time to deterioration in urinary symptoms (TTDUS) in the overall population
timeFrame: up to approximately 37 months
measure: Time to deterioration in Physical Functioning (TTDPF) in the overall population
timeFrame: up to approximately 37 months
measure: Overall Pain Severity and Pain Interference as assessed by BPI-SF questionnaire in the overall population
timeFrame: up to approximately 37 months
measure: Plasma concentration of capivasertib derived from a population PK model in the overall population
timeFrame: pre dose (up to 90 minutes prior) and post dose (1 hour, 2 hours and 4 hours post dose)
Other outcomes:
measure: The number of participants with adverse events in the overall population
timeFrame: Up to approximately 46 months
measure: Systolic and diastolic blood pressure
timeFrame: Up to approximately 46 months
measure: Pulse rate (heart rate)
timeFrame: Up to approximately 46 months
measure: Body Temperature
timeFrame: Up to approximately 46 months
measure: Weight
timeFrame: Up to approximately 46 months
Locations:
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city: Nagano-Shi
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city: Nagoya-shi
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city: Nakano-Ku
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city: Osakasayama-shi
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city: Sapporo-shi
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city: Tsu-shi
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country: Japan
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city: Yokohama-shi
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country: Korea, Republic of
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city: Busan
country: Korea, Republic of
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city: Goyang-si
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Aguascalientes
country: Mexico
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city: Ciudad de México
country: Mexico
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city: Culiacan
country: Mexico
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city: Guadalajara
country: Mexico
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city: Guadalajara
country: Mexico
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city: Mexico
country: Mexico
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city: Oaxaca
country: Mexico
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city: Zapopan
country: Mexico
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city: Den Haag
country: Netherlands
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city: Hoofddorp
country: Netherlands
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city: Nowa Sol
country: Poland
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city: Opole
country: Poland
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city: Wieliszew
country: Poland
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city: Barcelona
country: Spain
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city: Barcelona
country: Spain
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city: Barcelona
country: Spain
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city: Barcelona
country: Spain
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city: Cordoba
country: Spain
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city: Lugo
country: Spain
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city: Madrid
country: Spain
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city: Madrid
country: Spain
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city: Malaga
country: Spain
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city: Sabadell
country: Spain
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city: Sevilla
country: Spain
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city: Kaohsiung
country: Taiwan
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city: Taichung
country: Taiwan
facility: Research Site
city: Tainan
country: Taiwan
facility: Research Site
city: Tainan
country: Taiwan
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city: Taipei
country: Taiwan
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city: Taipei
country: Taiwan
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city: Adana
country: Turkey
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city: Edirne
country: Turkey
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city: Izmir
country: Turkey
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city: Sahinbey
country: Turkey
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city: Yüreğir
country: Turkey
facility: Research Site
city: Edinburgh
country: United Kingdom
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city: Glasgow
country: United Kingdom
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city: Guildford
country: United Kingdom
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city: Hackensack
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Southampton
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
References: