Randomized Phase Ib/III Study of Capivasertib with CDK4/6 Inhibitors and Fulvestrant in HR+/HER2- Advanced Breast Cancer
- Trial ID
- 2023-504997-39-00
- Protocol
- CAPItello-292
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the safety and tolerability of **capivasertib** in combination with CDK4/6 inhibitors (palbociclib, ribociclib, or abemaciclib) and fulvestrant in participants with hormone receptor-positive and human epidermal growth factor receptor 2-negative locally advanced, unresectable, or metastatic breast cancer. This assessment is crucial for determining the recommended Phase III dose and/or maximum tolerated dose of the combination therapy, which is essential for optimizing treatment regimens and improving patient outcomes.
Secondary objectives include:
- Phase Ib: Assessing the pharmacokinetics of palbociclib, ribociclib, or abemaciclib when administered alone and in combination with capivasertib and fulvestrant. Evaluating the pharmacokinetics of capivasertib in combination with CDK4/6 inhibitors and fulvestrant. Determining the effectiveness of capivasertib plus CDK4/6 inhibitors and fulvestrant by assessing objective response rate (ORR), clinical benefit rate (CBR), duration of response (DoR), and progression-free survival (PFS) in all participants.
- Phase III: Demonstrating the effectiveness of the capivasertib arm (capivasertib and fulvestrant with the investigator’s choice of CDK4/6 inhibitor) relative to the control arm (fulvestrant with the investigator’s choice of CDK4/6 inhibitor) by assessing overall survival (OS) and ORR in participants with HR+/HER2- locally advanced or metastatic breast cancer with gene alterations in PIK3CA, AKT1, or PTEN, as well as in confirmed non-altered and overall populations. Additional assessments include DoR, CBR, patient-reported physical functioning, global health status/quality of life (GHS/QoL), and overall side effect bother in the capivasertib arm relative to the control arm. The study also aims to evaluate the pharmacokinetics of capivasertib and assess the safety and tolerability of the capivasertib arm relative to the control arm in the overall population.
Participants
The clinical trial involves a total of **533 participants** diagnosed with **Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced, Unresectable or Metastatic 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 include middle-aged and older adults. Participants were selected based on histologically confirmed HR+/HER2- breast cancer, with eligibility for fulvestrant therapy and at least one CDK4/6 inhibitor, such as palbociclib, ribociclib, or abemaciclib. The trial population was chosen to ensure adequate organ and bone marrow function, and participants consented to provide a mandatory FFPE tumor sample. The study also considers lifestyle factors such as previous treatment with endocrine therapy and the presence of measurable lesions according to RECIST v1.1 criteria. Both genders are included, and the trial acknowledges the inclusion of a vulnerable population. The selection criteria ensure a comprehensive assessment of the safety and efficacy of the treatment regimen in a diverse cohort.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **capivasertib** in combination with CDK4/6 inhibitors and **fulvestrant** compared to CDK4/6 inhibitors and fulvestrant alone in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative locally advanced, unresectable, or metastatic breast cancer. This study is structured as a Phase Ib/III, open-label, randomized trial. The trial aims to assess the safety and tolerability of the combination therapy in Phase Ib and to demonstrate the superiority of the capivasertib arm in terms of progression-free survival (PFS) in Phase III. The estimated duration of the trial is from April 2023 to April 2028.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as histologically confirmed HR+/HER2- breast cancer and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor safety, tolerability, and efficacy outcomes. These visits will include assessments of adverse events, vital signs, and laboratory parameters. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement is approximately 20 months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will employ a rigorous methodology to ensure the reliability and validity of the results, with endpoints including safety, tolerability, and PFS assessed by blinded independent central review (BICR) according to RECIST v1.1 criteria.
Treatment
The clinical trial involves the administration of several experimental and comparator medications. **Capivasertib** is a film-coated tablet with a chemical origin, administered orally. The maximum daily dose is 640 mg, with a treatment period of up to 20 days. Capivasertib is the test drug in this study, and its role is to be evaluated in combination with other treatments.
**Palbociclib**, marketed as IBRANCE, is available in both film-coated tablets and hard capsules. The film-coated tablets are available in dosages of 75 mg, 100 mg, and 125 mg, while the hard capsules are available in 75 mg, 100 mg, and 125 mg. All forms are administered orally with a maximum daily dose of 125 mg for the highest dosage form. The treatment period is up to 20 days. Palbociclib serves as a comparator in the trial.
**Abemaciclib**, marketed as Verzenios, is provided as film-coated tablets in dosages of 50 mg, 100 mg, and 150 mg. The maximum daily dose for the 150 mg tablet is 300 mg, administered orally. The treatment period is up to 20 days. Abemaciclib is used as a comparator in the study.
**Ribociclib**, marketed as Kisqali, is a film-coated tablet with a dosage of 200 mg. It is administered orally with a maximum daily dose of 600 mg. The treatment period is up to 20 days. Ribociclib is also a comparator in the trial.
**Fulvestrant**, marketed as Faslodex, is a solution for injection with a dosage of 250 mg. It is administered as an injection with a maximum daily dose of 500 mg. The treatment period is up to 20 days. Fulvestrant is used as a comparator in the study.
All medications are of chemical origin and are administered according to the specified dosing schedules. Participant compliance is monitored throughout the trial to ensure adherence to the dosing regimen. The trial aims to assess the safety, tolerability, and efficacy of these medications in combination for the treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative locally advanced, unresectable, or metastatic breast cancer.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. In Phase III, the primary endpoint is **Progression-Free Survival (PFS)**, defined as the time from randomization until disease progression as per RECIST v1.1 criteria, assessed by Blinded Independent Central Review (BICR), or death due to any cause. This will be evaluated in the overall population, the altered population with gene alterations in PIK3CA, AKT1, and/or PTEN, and the confirmed non-altered population.
Secondary endpoints for Phase III include Overall Survival (OS) and Objective Response Rate (ORR) in both the overall and altered populations. Additional secondary endpoints for the overall population include PFS2, Duration of Response (DoR), Clinical Benefit Rate (CBR) at 24 weeks, Time to Deterioration (TTD) of physical functioning using the EORTC QLQ-C30, TTD of Global Health Status/Quality of Life (GHS/QoL), and Patient Global Impression of Treatment Tolerability (PGI-TT). Plasma concentrations of capivasertib will also be measured pre-dose and at various post-dose timepoints (C1h, C2h, and C4h).
In Phase Ib, safety and tolerability will be evaluated through Dose-Limiting Toxicities (DLTs), Adverse Events (AEs), Serious Adverse Events (SAEs), vital signs, clinical chemistry, hematology, glucose metabolism parameters, and ECG parameters. Pharmacokinetic (PK) parameters for palbociclib, ribociclib, abemaciclib, and capivasertib will be assessed, including maximum concentration (Cmax), area under the curve (AUC), and minimum concentration (Cmin) at specified cycles. Additional efficacy measures include ORR, CBR at 24 weeks, DoR, and PFS.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Key inclusion criteria for both phases: 1. Adult females (pre- and post-menopausal), and adult males. 2. Histologically confirmed HR+/ HER2- breast cancer determined from the most recent tumour sample (primary or metastatic) per the American Society of Clinical Oncology and College of American Pathologists guideline. To fulfil the requirement of HR+ disease, a breast cancer must express ER with or without co-expression of progesterone receptor. 3. Eligible for fulvestrant therapy and at least one of the following: palbociclib, ribociclib, or abemaciclib, as per local investigator assessment. Previous tolerance to specific CDK4/6 inhibitors and dose levels required. 4. Adequate organ and bone marrow functions. 5. Consent to provide a mandatory FFPE tumour sample.
- Key inclusion criteria only for phase III only: 1. Previous treatment with an ET (tamoxifen, AI, or oral SERD) as a single agent or in combination, with radiological evidence of breast cancer recurrence or progression while on, or within 12 months of, completing a (neo)adjuvant ET regimen. 2. Provision of mandatory blood samples at screening for central testing using an investigational ctDNA test to be stratified based on PIK3CA/AKT1/PTEN status. 3. Be eligible for fulvestrant and at least one out of palbociclib or ribociclib (depending on the available CDK4/6i options at time of enrolment), as per local investigator assessment. 4. Have radiologic evidence of recurrence or progression while on, or within 12 months of the end of (neo)adjuvant endocrine treatment (tamoxifen, AI, or oral SERD). 5. Have measurable lesion(s) according to Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1) or, in the absence of measurable disease, lytic or mixed bone lesions that can be assessed by computed tomography (CT) or magnetic resonance imaging (MRI).
Exclusion Criteria
- Key exclusion criteria for both phases: 1. 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. 2. Radiotherapy within 2 weeks prior to study treatment initiation. 3. Major surgery or significant traumatic injury within 4 weeks of the first dose of study treatment. 4. Persistent toxicities (CTCAE Grade >1) caused by previous anticancer therapy, excluding alopecia. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (eg, hearing loss or peripheral sensory neuropathy) after consultation with the AstraZeneca study physician. 5. Spinal cord compression, brain metastases or leptomeningeal metastases unless these lesions are definitively treated (eg. radiotherapy, surgery) and clinically stable off steroids for management of symptoms for at least 4 weeks prior to study treatment initiation. 6. Any of the following cardiac criteria at screening: (a). Mean resting corrected QT interval (QTcF): (i) Participants to be treated with palbociclib: QTcF ≥ 470 ms obtained from the average of 3 consecutive (triplicate) ECGs (ii) Participants to be treated with ribociclib: QTcF ≥ 450 ms obtained from the average of 3 consecutive (triplicate) ECGs (iii) Participants to be treated with abemaciclib (Phase Ib only): QTcF ≥ 470 ms obtained from the average of 3 consecutive (triplicate) ECGs (b). Any clinically important abnormalities in cardiac 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 QTc prolongation or risk of arrhythmic events (d). Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, unstable angina pectoris, congestive heart failure New York Heart Association (NYHA) grade ≥ 2 (e). Uncontrolled hypotension (f). uncontrolled hypertension (g). Cardiac ejection fraction outside institutional range of normal or < 50% (whichever is higher)
- uncontrolled or high grade or symptomatic arrhythmia and atrial fibrillation 8. Any of these clinically significant abnormalities of glucose metabolism at screening: (a). diabetes mellitus type I or type II requiring insulin treatment (b). Glycated haemoglobin (HbA1c) ≥ 8.0% (63.9 mmol/mol) 9. Previous allogeneic bone marrow transplant or solid organ transplant.
- Key exclusion criteria for the phase III only: 1. Any prior treatment with AKT, PI3K or mTOR inhibitors. 2. Prior treatment with CDK4/6 inhibitors in the metastatic setting (prior CDK4/6 inhibitors permitted in the adjuvant setting provided there was a CDK4/6i treatment free interval of at least 12 months). 3. More than 1 line of chemotherapy for metastatic disease 4. Any line of endocrine-based therapy for inoperable locally advanced or metastatic disease.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 10 May 2021 | 22 |
 Denmark | Not Recruiting | 10 May 2021 | 15 |
 France | Not Recruiting | 10 May 2021 | 38 |
 Germany | Not Recruiting | 10 May 2021 | 31 |
 Italy | Not Recruiting | 10 May 2021 | 22 |
 Poland | Not Recruiting | 10 May 2021 | 33 |
 Spain | Not Recruiting | 10 May 2021 | 38 |
 Sweden | Not Recruiting | 10 May 2021 | 15 |
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 | 800 | 20 | PRD10312011 |
Verzenios 150 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 300 | 20 | PRD6701108 |
Verzenios 50 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 100 | 20 | PRD6701098 |
IBRANCE 100 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 100 | 20 | PRD6503927 |
IBRANCE 75 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 75 | 20 | PRD6503929 |
IBRANCE 100 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 100 | 20 | PRD7907867 |
IBRANCE 125 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 125 | 20 | PRD6503996 |
Kisqali 200 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 600 | 20 | PRD5341538 |
IBRANCE 125 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 125 | 20 | PRD7907865 |
Verzenios 100 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 200 | 20 | PRD6701103 |