Locally advanced (inoperable) or metastatic HR+/HER2 breast cancer MedDRA version: 20.0 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification code 10057654 Term: Breast cancer female System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: LLT Classification code 1
Conditions
Sponsors
AstraZeneca AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Adult females, pre- and/or post-menopausal, and adult males. Pre-menopausal (and peri-menopausal) women can be enrolled if amenable to treatment with an LHRH agonist. Patients are to have commenced concomitant treatment with LHRH agonist prior to or on Cycle 1, Day 1 and must be willing to continue on it for the duration of the study 2. Histologically confirmed HR+/HER2- breast cancer determined from the most recent tumour sample (primary or metastatic), as per the American Society of Clinical Oncology and College of American Pathologists guideline recommendations. To fulfil the requirement of HR+ disease, a breast cancer must express ER with or without co-expression of progesterone receptor. 3.Metastatic or locally advanced disease with radiological or objective evidence of recurrence or progression (the cancer should have shown progression during or after most recent therapy); locally advanced disease must not be amenable to resection with curative intent (patients who are considered suitable for surgical or ablative techniques following potential down-staging with study treatment are not eligible) 4. ECOG/WHO PS: 0-1 5. Patients are to have received treatment with an AI (aromatase inhibitor) containing regimen (single agent or in combination) and have: a) Radiological evidence of breast cancer recurrence or progression while on, or within 12 months of the end of (neo)adjuvant treatment with an AI, OR b) Radiological evidence of progression while on prior AI administered as a treatment line for locally advanced or metastatic breast cancer (this does not need to be the most recent therapy) 6. Patients must have measurable disease according to RECIST 1.1 and/or at least 1 lytic or mixed (lytic + sclerotic) bone lesion that can be assessed by CT or MRI; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible 7. FFPE tumour sample from primary/recurrent cancer for central testing Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 500 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 200
Exclusion criteria
Exclusion criteria: 1.Symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator’s best judgement 2. More than 2 lines of endocrine therapy for inoperable locally advanced or metastatic disease 3. More than 1 line of chemotherapy for inoperable locally advanced or metastatic disease. Adjuvant and neoadjuvant chemotherapy are not classed as lines of chemotherapy for advanced breast cancer 4. Prior treatment with any of the following: a) AKT, PI3K and mTOR inhibitors b) Fulvestrant, and other SERDs c) Any other chemotherapy, immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents within 3 weeks prior to study treatment initiation. d) Potent inhibitors or inducers of CYP3A4 within 2 weeks prior to the first dose of study treatment (3 weeks for St John’s wort) or drugs that are sensitive to CYP3A within 1 week prior to study treatment initiation. 5.Radiotherapy with a wide field of radiation up to 4 weeks before study treatment initiation (capivasertib/placebo) and/or radiotherapy with a limited field of radiation for palliation up to 2 weeks before study treatment initiation (capivasertib/placebo) 6.With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment 7. Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids up to 4 weeks before study treatment initiation 8. Any of the following cardiac criteria: a) Mean resting QT interval corrected by Fridericia's formula (QTcF) >470 msec obtained from 3 consecutive ECGs b) Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third degree heart block) c) Any factors that increase the risk of corrected QT interval (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 d) 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 New York Heart Association (NYHA) grade =2 e) Uncontrolled hypotension – systolic blood pressure <90 mmHg and/or diastolic blood pressure <50 mmHg f) 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) 9. Clinically significant abnormalities of glucose metabolism as defined by any of the following: a) Patients with diabetes mellitus type 1 or diabetes mellitus type 2 requiring insulin treatment b) HbA1c =8.0% (63.9 mmol/mol) 10. Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of fulvestrant or LHRH agonist (if applicable) 11. Currently pregnant (confirmed with positive pregnancy test) or breast-feeding
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To compare the effect of capivasertib + fulvestrant relative to placebo + fulvestrant by assessment of PFS in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup.;Secondary Objective: 1) To compare the effect of capivasertib + fulvestrant relative to placebo + fulvestrant by assessment of OS in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup 2) PFS2 3) ORR 4) DoR 5) CBR 6) To assess the safety and tolerability of capivasertib + fulvestrant as compared to placebo + fulvestrant in the overall population and in the PIK3CA/AKT/PTEN-altered subgroup. 7) To evaluate the PK of capivasertib when given in combination with fulvestrant. 8) To assess the impact of capivasertib + fulvestrant vs placebo + fulvestrant on patients' disease-related symptoms, function and HRQoL in the overall population and in the PIK3CA/AKT/PTEN-altered subgroup where applicable. 9) To compare the effect of capivasertib + fulvestrant relative to placebo + fulvestrant by assessment of time to definitive deterioration of ECOG performance status from baseline in the overall population and in the PIK3CA/AKT/PTEN-altered subgroup.;Primary end point(s): Progression-free survival (PFS) is defined as the time from randomisation until progression per RECIST v1.1, as assessed by the investigator at the local site, or death due to any cause.;Timepoint(s) of evaluation of this end point: From randomisation until progression per RECIST v1.1 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1) OS, overall survival 2) PFS2, time from randomisation to second progression or death. 3) ORR, objective response rate 4) DoR, duration of response 5) CBR, clinical benefit rate 6) Safety and tolerability evaluated as AEs/SAEs, vital signs, clinical chemistry/haematology/glucose metabolism parameters, and ECG parameters 7) Plasma concentration of capivasertib 8) EORTC QLQ-C30, EORTC Quality of Life Questionnaire-Core 30 items and EORTC QLQ-BR23, EORTC Quality of Life Questionnaire breast cancer specific module, scale/item scores 9) Deterioration of ECOG, Eastern Cooperative Oncology Group, performance status;Timepoint(s) of evaluation of this end point: 1) from randomisation until the date of death 2) from randomisation until second progression on next line treatment or death 3) percentage of patients with at least one CR or PR 4) from the date of first documented response until RECIST progression or death 5) percentage of patients who have a CR, PR or SD 24 weeks after randomisation 6) AE/SAE and maximum CTCAE grade shift from baseline 7) Ctrough, C1h and C4h. AUC 0-12h, Cmax and tmax in Japanese patients with rich PK sampling. 8) change from baseline and time to deterioration 9) from randomisation to the first deterioration or death | — |
Countries
Argentina, Australia, Belgium, China, France, Germany, Hungary, Israel, Italy, Japan, Korea, Republic of, Peru, Poland, Russian Federation, Spain, Taiwan, United Kingdom
Contacts
Public ContactInformation Center
AstraZeneca
Outcome results
None listed