Efficacy and Safety of Capivasertib Plus Docetaxel in Metastatic Castration-Resistant Prostate Cancer: A Phase III Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2023-504996-26-00
- Protocol
- D361EC00001
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the **superiority** of capivasertib combined with docetaxel compared to placebo combined with docetaxel in patients with **metastatic castration-resistant prostate cancer (mCRPC)**. This will be assessed by evaluating overall survival (OS) and radiographic progression-free survival (rPFS) in the overall population. The clinical relevance of this objective lies in potentially improving survival outcomes for patients with mCRPC, a condition characterized by limited treatment options and poor prognosis.
Secondary objectives include demonstrating the superiority of capivasertib + docetaxel over placebo + docetaxel by assessing: - OS in patients with mCRPC and PTEN-proficient tumors (IHC) - OS in patients with mCRPC and PTEN-deficient tumors (IHC) - Time to pain progression (TTPP) - Time to first symptomatic skeletal-related event (SSRE) in the overall population - Effectiveness by assessing rPFS in patients with mCRPC and PTEN-proficient tumors (IHC) - rPFS in patients with mCRPC and PTEN-deficient tumors (IHC) - Time to deterioration in urinary symptoms (TTDUS) - Time to deterioration in physical functioning (TTDPF) - Health-related quality of life (HrQoL) using the BPI-SF in the overall population - Evaluation of the pharmacokinetics (PK) of capivasertib in combination with docetaxel in the overall population.
Participants
The clinical trial involves a total of **951 participants** diagnosed with **Metastatic Castration Resistant Prostate Cancer (mCRPC)**. The study population is exclusively male, with an age range that includes adults and the elderly. Participants were selected based on specific criteria, including a histologically-confirmed diagnosis of prostate adenocarcinoma, the ability to swallow oral medication, and documented metastatic disease. All participants have previously been treated with a next-generation hormonal agent and have shown disease progression despite androgen deprivation therapy. The trial does not include a vulnerable population, and participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, with a minimum life expectancy of 12 weeks. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to remain abstinent or use contraceptive measures and refrain from donating sperm during the study period.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **capivasertib** in combination with **docetaxel** compared to placebo with docetaxel in patients with **metastatic castration-resistant prostate cancer (mCRPC)**. The primary objective is to demonstrate the superiority of the capivasertib and docetaxel combination in terms of overall survival and radiographic progression-free survival. The trial is expected to run from March 18, 2022, to December 21, 2026, with participants involved for the duration of the study unless early termination criteria are met.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically-confirmed prostate adenocarcinoma, evidence of metastatic disease, and previous treatment with a next-generation hormonal agent. Following randomization, participants will attend regular follow-up visits to monitor treatment effects and safety. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any adverse events.
The expected length of participant involvement is until the study's completion or until criteria for early termination are met, such as withdrawal of consent, adverse events, or disease progression. The trial's methodology ensures rigorous assessment of endpoints, including overall survival and radiographic progression-free survival, with secondary endpoints evaluating pain progression, symptomatic skeletal-related events, and changes in urinary symptoms and physical functioning. The study's design and procedures are structured to provide comprehensive data on the treatment's efficacy and safety in the target population.
Treatment
The clinical trial involves the administration of **Capivasertib**, a film-coated tablet, as an experimental medication. Capivasertib is chemically derived and produced by AstraZeneca AB. The active substance, capivasertib, is administered orally with a maximum daily dose of 400 mg. The treatment period for capivasertib extends up to 99999 days, ensuring long-term administration as required by the study protocol. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.
In addition to capivasertib, the trial includes a **placebo** designed to match the capivasertib film-coated tablet. The placebo is administered orally, following the same dosing schedule as the active medication, to maintain the double-blind nature of the study. The placebo serves as a control to evaluate the efficacy and safety of capivasertib in comparison to standard treatment.
**Docetaxel** is utilized as a standard-of-care therapy in this trial. It is provided in the form of a solution for infusion, with a concentration of 20 mg/ml or 80 mg/4 ml, depending on the specific product variant. Docetaxel is administered intravenously, with a maximum daily dose of 75 mg/m² and a total dose limit of 750 mg/m² over a treatment period of 30 days. The docetaxel products used in the trial are sourced from Bendalis GmbH, Hikma Farmacêutica (Portugal), S.A., and Accord Healthcare S.L.U., ensuring consistency in the chemical composition and administration across different study sites.
The trial is structured to assess the efficacy and safety of capivasertib in combination with docetaxel versus placebo with docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). The study's primary objectives include evaluating overall survival and radiographic progression-free survival in the patient population. Compliance with the treatment regimen is closely monitored to ensure the integrity of the trial data and outcomes.
Efficacy
The efficacy of the clinical trial will be assessed through the primary endpoints of **Overall Survival (OS)** and **Radiographic Progression-Free Survival (rPFS)**. Overall survival is defined as the time from randomization until the date of death due to any cause, encompassing all randomized patients regardless of therapy withdrawal or subsequent anticancer treatments. Radiographic progression-free survival will be evaluated using the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) for soft tissue and the Prostate Cancer Working Group 3 (PCWG3) criteria for bone, as assessed by the investigator.
Secondary endpoints include time to pain progression, time to start symptomatic skeletal-related events, time to deterioration in urinary symptoms, and time to deterioration in physical functioning. These will be measured using validated tools such as the Brief Pain Inventory-Short Form (BPI-SF) for pain progression and other patient-reported outcomes. Additionally, changes from baseline in BPI-SF worst pain score, pain severity, and interference domain scores will be monitored. Plasma concentration of capivasertib will also be derived from a population pharmacokinetic model to support efficacy assessments.
Inclusion and Exclusion 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 within4 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 correctedQT 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 bloodpressure < 90mmHg and/or diastolic bloodpressure < 50mmHg vi. Haemodynamic instability
- Clinically significant abnormalities of glucose metabolism as defined by any of the following i. Patients with diabetes mellitus (DM) type1 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 laboratory values as specified in the protocol
- 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), that makes it undesirable for the patient to participate in the study or that would jeopardise compliance with the protocol
- Known to have active hepatitis B or C infection; HIV with a detectable viral RNA or a CD4+ T-cell count < 350 cells/uL or a history of an AIDS defining opportunistic infection within the past 12 months
- 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, 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)
- 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 iv.Any other immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents (except ADT )within 3weeks of the first dose of study treatment v. Strong inhibitors or strong inducers of cytochrome P450 (CYP) 3A4 within2 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 the 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 18 Mar 2022 | 22 |
 Czechia | Not Recruiting | 18 Mar 2022 | 45 |
 France | Not Recruiting | 18 Mar 2022 | 120 |
 Greece | Not Recruiting | 18 Mar 2022 | 35 |
 Hungary | Not Recruiting | 18 Mar 2022 | 43 |
 The Netherlands | Not Recruiting | 18 Mar 2022 | — |
 Poland | Not Recruiting | 18 Mar 2022 | 32 |
 Spain | Not Recruiting | 18 Mar 2022 | 121 |
| Netherlands | — | — | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo to capivasertib | Placebo | N/A | — | — | — | N/A |
Capivasertib | Test | FILM-COATED TABLET | ORAL USE | 400 | 99999 | PRD10312011 |
Bendadocel 20 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | 75 | 30 | PRD2832945 |
Docetaxel Accord 80 mg/4 ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 75 | 30 | PRD378840 |
Capivasertib | Test | FILM-COATED TABLET | ORAL USE | 400 | 99999 | PRD10312009 |
Docetaxel Hikma 80 mg/4 ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | 75 | 30 | PRD4495642 |