Phase III Randomized, Double-Blind Study of Capivasertib and Fulvestrant Versus Placebo and Fulvestrant in HR+/HER2- Advanced or Metastatic Breast Cancer
- Trial ID
- 2023-505042-25-00
- Protocol
- D3615C00001
- Sponsor
- AstraZeneca AB
Trial statistics
Objectives
The primary objective of this study is to compare the effect of **capivasertib** combined with **fulvestrant** versus placebo combined with fulvestrant by assessing progression-free survival (PFS) in patients with locally advanced (inoperable) or metastatic hormone receptor-positive, human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer. This objective is clinically relevant as it aims to determine the efficacy of the treatment in delaying disease progression, which is crucial for improving patient outcomes in this population.
Secondary objectives include:
- Comparing the effect of capivasertib + fulvestrant relative to placebo + fulvestrant by assessment of overall survival (OS) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup.
- Evaluating progression-free survival 2 (PFS2).
- Assessing the objective response rate (ORR).
- Determining the duration of response (DoR).
- Evaluating the clinical benefit rate (CBR).
- Assessing the safety and tolerability of capivasertib + fulvestrant compared to placebo + fulvestrant in the overall population and in the PIK3CA/AKT/PTEN-altered subgroup.
- Evaluating the pharmacokinetics (PK) of capivasertib when given in combination with fulvestrant.
- Assessing the impact of capivasertib + fulvestrant versus placebo + fulvestrant on patients' disease-related symptoms, function, and health-related quality of life (HRQoL) in the overall population and in the PIK3CA/AKT/PTEN-altered subgroup where applicable.
- Comparing 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.
Participants
The clinical trial involves a total of **334 participants** diagnosed with **locally advanced (inoperable) or metastatic HR+/HER2- breast cancer**. The study population includes both adult females, pre- and post-menopausal, and adult males, with an age range corresponding to categories 3 and 4, which typically includes middle-aged to older adults. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of HR+/HER2- breast cancer and evidence of disease progression. The trial population is characterized by a general health status of ECOG/WHO performance status 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Lifestyle considerations such as diet and physical activity are not specified, but participants must have commenced treatment with an LHRH agonist if premenopausal. The trial includes a vulnerable population, ensuring careful monitoring and ethical considerations throughout the study. Participants must have previously received treatment with an aromatase inhibitor and have measurable disease according to RECIST 1.1 criteria.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of **Capivasertib** in combination with **Fulvestrant** compared to a placebo combined with Fulvestrant. The trial targets patients with locally advanced (inoperable) or metastatic hormone receptor-positive, human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer, following recurrence or progression after treatment with an aromatase inhibitor. The primary objective is to assess progression-free survival (PFS) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup. Secondary endpoints include overall survival (OS), time to second progression (PFS2), objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), and safety and tolerability assessments.
The trial is expected to run from March 2020 to June 2025. Participants will be involved in the study for the duration of their treatment period, which is determined by the progression of their disease or the occurrence of unacceptable toxicity. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to have histologically confirmed HR+/HER2- breast cancer, measurable disease according to RECIST 1.1, and prior treatment with an aromatase inhibitor. Exclusion criteria are not specified in the provided data.
Participants may be withdrawn from the study early if they experience disease progression, unacceptable adverse events, or if they choose to withdraw consent. The trial involves the administration of Capivasertib as a film-coated tablet for oral use, with a maximum daily dose of 800 mg, and Fulvestrant as a solution for injection, with a maximum daily dose of 500 mg. The placebo is administered in a similar manner to Capivasertib. The study is not categorized as a low-intervention trial and is classified as a Phase III trial, indicating a focus on efficacy and safety in a larger patient population.
Treatment
The clinical trial involves the administration of **Fulvestrant**, marketed as Faslodex 250 mg solution for injection. This medication is provided in the form of a solution for injection and is administered via the **intramuscular** route. The maximum daily dose is 500 mg, and the treatment period is not specified with a defined endpoint, allowing for continuous administration as required by the study protocol. Fulvestrant is a chemical substance, specifically an estrogen receptor antagonist, and is utilized in this trial to treat patients with locally advanced or metastatic hormone receptor-positive, HER2-negative breast cancer.
**Capivasertib** is another experimental medication used in this study. It is provided as a film-coated tablet and is administered orally. The maximum daily dose for Capivasertib is 800 mg, with a similar undefined maximum treatment period as Fulvestrant. Capivasertib is a chemical substance, classified as an AKT inhibitor, and is being evaluated for its efficacy in combination with Fulvestrant in the specified patient population. The study also includes a comparator group receiving a placebo to Capivasertib, which is used to assess the efficacy of the active treatment regimen.
The placebo used in this trial is designed to match the Capivasertib film-coated tablet in appearance but does not contain any active pharmaceutical ingredient. The placebo is administered orally, following the same schedule as the active Capivasertib treatment, to maintain blinding and ensure the integrity of the study results. Compliance with the dosing schedule for both Capivasertib and the placebo is monitored throughout the trial to ensure adherence to the protocol and to accurately assess the treatment outcomes.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **Progression-Free Survival (PFS)**. PFS is defined as the time from randomization until disease progression, as determined by RECIST v1.1 criteria, or death from any cause. This assessment will be conducted by the investigator at the local site. Secondary endpoints include overall survival (OS), time from randomization to second progression or death (PFS2), objective response rate (ORR), duration of response (DoR), and clinical benefit rate (CBR). Additionally, safety and tolerability will be evaluated through adverse events (AEs), serious adverse events (SAEs), vital signs, clinical chemistry, hematology, glucose metabolism parameters, and ECG parameters. Plasma concentration of capivasertib will also be measured.
Patient-reported outcomes will be assessed using the EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires, which evaluate quality of life and breast cancer-specific symptoms, respectively. The deterioration of the Eastern Cooperative Oncology Group (ECOG) performance status will also be monitored. These efficacy parameters will be collected and analyzed at various time points throughout the study to provide a comprehensive evaluation of the treatment's impact on patients with locally advanced or metastatic hormone receptor-positive, HER2-negative breast cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adult females, pre- and/or post-menopausal, and adult males. Premenopausal (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.
- 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 coexpression of progesterone receptor.
- 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).
- ECOG/WHO PS: 0-1
- 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).
- 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.
- FFPE tumour sample from primary/recurrent cancer for central testing.
Exclusion Criteria
- Symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's best judgement.
- More than 2 lines of endocrine therapy for inoperable locally advanced or metastatic disease.
- 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.
- 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.
- 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).
- With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE \ grade 1 at the time of starting study treatment.
- Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids up to 4 weeks before study treatment initiation.
- 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).
- 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).
- Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of fulvestrant or LHRH agonist (if applicable).
- Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 13 Mar 2020 | 34 |
 France | Not Recruiting | 13 Mar 2020 | 36 |
 Germany | Not Recruiting | 13 Mar 2020 | 72 |
 Hungary | Not Recruiting | 13 Mar 2020 | 42 |
 Italy | Not Recruiting | 13 Mar 2020 | 64 |
 Poland | Not Recruiting | 13 Mar 2020 | 22 |
 Spain | Not Recruiting | 13 Mar 2020 | 96 |
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 |
|---|---|---|---|---|---|---|
Capivasertib | Test | FILM-COATED TABLET | ORAL USE | 640 | 99999 | PRD10312009 |
Faslodex 250 mg solution for injection. | Test | SOLUTION FOR INJECTION | INTRAMUSCULAR USE | 500 | 99999 | PRD3545745 |
Placebo to Capivasertib | Placebo | N/A | — | — | — | N/A |
Capivasertib | Test | FILM-COATED TABLET | ORAL USE | 800 | 99999 | PRD10312011 |