| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Hormone-Sensitive 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 | 27.0 |
| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the effect of capivasertib+abiraterone relative to placebo+abiraterone assessment by the investigator of radiographic progression-free survival (rPFS) in patients with PTEN-deficient mHSPC |
|
| E.2.2 | Secondary objectives of the trial |
1.To compare the effect of capivasertib+abiraterone relative to placebo+abiraterone by assessment of overall survival
2.To compare the effect of capivasertib+abiraterone relative to placebo+abiraterone by assessment of time to start of first subsequent therapy or death (TFST)
3.To compare the effect of capivasertib+abiraterone relative to placebo+abiraterone by assessment of time to start symptomatic skeletal event-free survival (SSE-FS)
4.To compare the effect of capivasertib+abiraterone relative to placebo+abiraterone by assessment of time to pain progression (TTPP)
5.To compare the effect of capivasertib+abiraterone relative to placebo+abiraterone by assessment of time to PSA progression
6.To compare the effect of capivasertib+abiraterone relative to placebo+abiraterone by assessment of progression-free survival after next-line treatment (PFS2)
7.To evaluate the PK of capivasertib in combination with abiraterone |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
- 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 |
|
| E.4 | Principal exclusion criteria |
-Radiotherapy with a wide field of radiation within 4weeks(wks) before start of study treatment (capivasertib/placebo)
-Major surgery (excl.placement of vascular access,transurethral resection of prostate,bilateral orchiectomy,internal stents) within 4wks 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 least 4wks 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 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 40years 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 6months:coronary artery bypass graft,angioplasty,vascular stent,myocardial infarction,angina pectoris,congestive heart failure NYHA Grade≥2
vi.Uncontrolled hypotension-systolic blood pressure <90mmHg and/or diastolic blood pressure <50mmHg
vii.Cardiac ejection fraction outside institutional range of normal or <50% (whichever is higher) as measured by echocardiogram (or multiple-gated acquisition scan if an echocardiogram cannot be performed or is inconclusive)
viii.Uncontrolled hypertension (SBP ≥160mmHg or DBP ≥95mmHg).
-Clinically significant abnormalities of glucose metabolism as defined by any of the following:
i.Patients with diabetes mellitus (MS) type 1 or MS type 2 requiring insulin treatment
ii.HbA1c ≥8.0% (63.9mmol/mol)
-Inadequate bone marrow reserve or organ function
-As judged by the investigator,any evidence of severe or uncontrolled systemic diseases,including active bleeding diatheses,or known active infection including hepatitis B and 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 3years.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 6wks of the start of study treatment
ii.Any investigational agents or study drugs from a previous clinical study within 30days or 5half-lives (whichever is longer) of the start of study treatment
iii.Any other chemotherapy,immunotherapy,immunosuppressant medication (other than corticosteroids) or anticancer agents within 3wks 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 2wks before the start of study treatment (3wks for St John’s wort), or sensitive substrates of CYP3A4,CYP2C9 and/or CYP2D6 with a narrow therapeutic window within 1wk before the start of study treatment
-Drugs known to prolong the QT interval within 5half-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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1.Radiographic Progression-free Survival (rPFS) in patients with PTEN-deficient 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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1.The time from randomisation to: 1) radiographic progression, as assessed by
the investigator per RECIST version 1.1 (soft tissue) and/or PCWG3 criteria (bone), or 2) death due to any cause |
|
| E.5.2 | Secondary end point(s) |
1.To compare the effect of capivasertib+abiraterone relative to placebo+abiraterone by assessment of overall survival
2.To compare the effect of capivasertib+abiraterone relative to placebo+abiraterone by assessment of time to start of first subsequent therapy or death (TFST)
3.To compare the effect of capivasertib+abiraterone relative to placebo+abiraterone by assessment of time to start symptomatic skeletal event-free survival (SSE-FS)
4.To compare the effect of capivasertib+abiraterone relative to placebo+abiraterone by assessment of time to pain progression (TTPP)
5.To evaluate the PK of capivasertib in combination with abiraterone
6.To evaluate safety and tolerability assessment of capivasertib+abiraterone as compared to placebo+abiraterone in patients with PTEN-deficient mHSPC |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Time from randomisation until the date of death due to any cause
2.Time from randomisation to the earlier of:the start date of the first subsequent anticancer therapy,or death due to any cause
3.The time from randomisation until: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; Death due to any cause
4.Time from randomisation to clinically meaningful pain progression (2-points) increase from baseline BPI-SF and/or initiation of/increase in the analgesic use
5.Pre-dose and post-dose(1h and 4h)
6.The overall duration of the study |
|
| 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 | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 103 |
| 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 |
| Argentina |
| Chile |
| Peru |
| Philippines |
| Hong Kong |
| Taiwan |
| Australia |
| Brazil |
| Canada |
| China |
| India |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| South Africa |
| Thailand |
| United Kingdom |
| United States |
| Viet Nam |
| Austria |
| Belgium |
| Bulgaria |
| Czechia |
| France |
| Germany |
| Hungary |
| Netherlands |
| Poland |
| Slovakia |
| Spain |
| Türkiye |
|
| 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
undergoing the study. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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