| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castration Resistant Prostate Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060862 |
| E.1.2 | Term | Prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036909 |
| E.1.2 | Term | Prostate cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 26.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062904 |
| E.1.2 | Term | Hormone-refractory prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate superiority of capivasertib + docetaxel relative to placebo + docetaxel by assessment of overall survival (OS) in patients with mCRPC in the overall population. |
|
| E.2.2 | Secondary objectives of the trial |
To demonstrate superiority of capivasertib + docetaxel relative to placebo+docetaxel by assessment of:
- OS in patients with mCRPC and PTEN- proficient tumours (IHC)
-OS in patients with mCRPC and PTEN-deficient tumours (IHC)
-radiographic progression free survival (rPFS)
-time to pain progression (TTPP)
- time to first Symptomatic Skeletal-Related Event (SSRE) in the overall population
To demonstrate effectiveness of capivasertib + docetaxel relative to placebo+docetaxel by
assessment of:
- rPFS in patients with mCRPC and PTEN-proficient tumours (IHC)
- rPFS in patients with mCRPC and PTEN-deficient tumours (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
To evaluate the PK of capivasertib in combination with docetaxel in the overall population. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 |
|
| E.4 | Principal 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)within4 weeks of 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 least4 weeks prior to start of study treatment)
-Any of the following cardiac criteria
i.Mean resting correctedQT interval(QTc)>470msec from3consecutiveECGs
ii.Any clinically important abnormalities in rhythm,conduction or morphology of restingECG
iii.Any factors that increase the risk ofQTc prolongation or risk of arrhythmic events such as heart failure,hypokalaemia, potential for torsades de pointes, congenital longQTsyndrome,family history of longQT syndrome or unexplained sudden death under40years of age,orany concomitant medication known to prolong theQTinterval
iv.Experience of any of the following procedures or conditions in the preceding3months: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 DMtype2requiring insulin treatment
ii.HbA1c≥8.0%(63.9mmol/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 BorCinfection;HIVwith a detectable viral RNA or a CD4+ T-cell count<350cells/uL or a historyof an AIDS-defining opportunistic infection within the past12months
- 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 organtransplant
- History of another primary malignancy except for malignancy treated with curative intent with no known active disease≥2years 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 forCRPC. 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 AKTinhibitors or PI3Kinhibitors
iii.Any investigational agents or study drugs from a previous clinical study within30 days or5 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 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 30days prior to the initiation of the study treatment, during,and for at least 90days after the last dose of studytreatment
- Drugs known to significantly prolong the QTinterval and associated with Torsade de Pointes within5 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 chemicalstructure or class
-Any restriction or contraindication based on the local prescribing information that would prohibit the use of docetaxel |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall survival is defined as time from randomisation until the date of death due to any cause.
The comparison will include all randomised patients as randomised, regardless of whether the patient withdraws from therapy or receives another anti-cancer therapy. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time from randomisation until the date of death due to any cause |
|
| E.5.2 | Secondary end point(s) |
1. OS is defined as time from randomisation until the date of death due to any cause.
2.Radiographic Progression-free Survival (rPFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1(RECIST 1.1) for soft tissue and/or Prostate Cancer Working Group 3(PCWG3) for bone as Assessed by the Investigator
3. Time to pain progression (TTPP) based 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 opioid analgesic use
4. Time to start Symptomatic Skeletal-Related Event (SSRE)
5. Time to deterioration in urinary symptoms (TTDUS), change from baseline that reaches a clinically meaningful deterioration threshold.
6. Time to deterioration in Physical Functioning (TTDPF), change from baseline that reaches a clinically meaningful deterioration threshold.
7. Change from baseline in BPI-SF worst pain score, pain severity and interference domain scores.
8. Plasma concentration of capivasertib derived from a population PK model |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Time from randomization to:
1. OS: until the date of death due to any cause
2.radiographic progression per RECIST version 1.1 (soft tissue) and/or PCWG3 (bone) criteria, or death due to any cause
3.clinically meaningful pain progression increase from baseline BPI-SF and/or initiation of/increase in opioid analgesic use
4.use of radiation therapy to prevent or relieve skeletal symptoms; Occurrence of new symptomatic pathological bone fractures; Occurrence of spinal cord compression; Orthopaedic surgical intervention for bone metastasis
5.date of deterioration in EORTC, QLQ-PR25 (US) subscale scores
6.date of deterioration in EORTC, QLQ-C30 PF subscale scores
7.From baseline to post-baseline
8.Plasma concentration of capivasertib pre‑and post‑dose (1h, 2h, 4h) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Chile |
| Taiwan |
| Australia |
| Brazil |
| Canada |
| China |
| India |
| Japan |
| Korea, Republic of |
| Mexico |
| United Kingdom |
| United States |
| Belgium |
| Czechia |
| France |
| Greece |
| Hungary |
| Netherlands |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the study is defined as the date of last expected visit/contact of the last participant
for any protocol related activity |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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