Capivasertib+Fulvestrant vs Placebo+Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic HR+/HER2- Breast Cancer

Locally Advanced (Inoperable) or Metastatic Breast Cancer Clinical Trial

— CAPItello-291  

Official title:

A Phase III Double-blind Randomised Study Assessing the Efficacy and Safety of Capivasertib + Fulvestrant Versus Placebo + Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) Breast Cancer Following Recurrence or Progression On or After Treatment With an Aromatase Inhibitor

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04305496
• Other study ID #: D3615C00001
• Secondary ID: 2019-003629-78
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: April 16, 2020
• Est. completion date: June 7, 2024

Study information

• Verified date: May 2023
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Phase III, double-blind, randomised study assessing the efficacy of capivasertib + fulvestrant vs placebo + fulvestrant for the treatment of patients with locally advanced (inoperable) or metastatic HR+/HER2- breast cancer following recurrence or progression on or after AI therapy.

Description:

Phase III, double-blind, randomised study assessing the efficacy of capivasertib + fulvestrant vs placebo + fulvestrant for the treatment of 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 on or after aromatase inhibitor (AI) therapy.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 818
• Est. completion date: June 7, 2024
• Est. primary completion date: August 15, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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:

1. 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

2. 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

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:

1. AKT, PI3K and mTOR inhibitors

2. Fulvestrant, and other SERDs

3. Any other chemotherapy, immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents within 3 weeks prior to study treatment initiation.

4. 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 CYP3A4 inhibition 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:

1. Mean resting QT interval corrected by Fridericia's formula (QTcF) >470 msec obtained from 3 consecutive ECGs

2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third degree heart block)

3. 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

4. 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

5. Uncontrolled hypotension - systolic blood pressure <90 mmHg and/or diastolic blood pressure <50 mmHg

6. 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:

1. Patients with diabetes mellitus type 1 or diabetes mellitus type 2 requiring insulin treatment

2. 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

Related Conditions & MeSH terms

• Breast Neoplasms
• Locally Advanced (Inoperable) or Metastatic Breast Cancer

Intervention

Drug:
• Fulvestrant
Patients will be administered 500 mg (2 injections) on Day 1 of Weeks 1 and 3 of Cycle 1, and then on Day 1, Week 1 of each cycle thereafter
• Capivasertib
400 mg BD (2 tablets of 200 mg taken twice a day = total daily dose 800 mg) given on an intermittent weekly dosing schedule. Patients will be dosed on Days 1 to 4 in each week of a 28-day treatment cycle
• Placebo
Placebo to match 400 mg BD (2 tablets of placebo to match 200 mg taken twice daily = placebo to match total daily dose of 800 mg) given on an intermittent weekly dosing schedule. Patients will be dosed on Days 1 to 4 in each week of a 28-day treatment cycle

Locations

Country	Name	City	State
Argentina	Research Site	Berazategui
Argentina	Research Site	Ciudad Autonoma De Buenos Aire
Argentina	Research Site	La Rioja
Argentina	Research Site	Rosario
Argentina	Research Site	Viedma
Australia	Research Site	Adelaide
Australia	Research Site	Ballarat
Australia	Research Site	Birtinya
Australia	Research Site	Box Hill
Australia	Research Site	Concord
Australia	Research Site	Kurralta Park
Australia	Research Site	North Sydney
Australia	Research Site	Orange
Australia	Research Site	Ringwood East
Australia	Research Site	South Brisbane
Australia	Research Site	Waratah
Australia	Research Site	Wendouree
Belgium	Research Site	Brussels
Belgium	Research Site	Bruxelles
Belgium	Research Site	Charleroi
Belgium	Research Site	Edegem
Belgium	Research Site	Namur
Belgium	Research Site	Wilrijk
Canada	Research Site	Kingston	Ontario
Canada	Research Site	North York	Ontario
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Winnipeg	Manitoba
China	Research Site	Baoding
China	Research Site	Beijing
China	Research Site	Beijing
China	Research Site	Changchun
China	Research Site	Chongqing
China	Research Site	Chongqing
China	Research Site	Dalian
China	Research Site	Foshan
China	Research Site	Gongshu District
China	Research Site	Guangzhou
China	Research Site	Guangzhou
China	Research Site	Hangzhou
China	Research Site	Hangzhou
China	Research Site	Harbin
China	Research Site	Hefei
China	Research Site	Hefei
China	Research Site	Jinan
China	Research Site	Linyi
China	Research Site	Nanchang
China	Research Site	Nantong
China	Research Site	Neijiang
China	Research Site	Shanghai
China	Research Site	Shanghai
China	Research Site	Shantou
China	Research Site	Shenyang
China	Research Site	Shenyang
China	Research Site	Wuhan
China	Research Site	Wuhan
China	Research Site	Wuhan
China	Research Site	Zhengzhou City
France	Research Site	Besancon
France	Research Site	Brest
France	Research Site	Metz Cedex 03
France	Research Site	Pierre Benite CEDEX
France	Research Site	Plerin SUR MER
France	Research Site	Pringy
France	Research Site	Rouen
France	Research Site	STRASBOURG Cedex
France	Research Site	Toulouse cedex 9
Germany	Research Site	Dresden
Germany	Research Site	Erlangen
Germany	Research Site	Essen
Germany	Research Site	Frankfurt
Germany	Research Site	Gelsenkirchen
Germany	Research Site	Hamburg
Germany	Research Site	Hamburg
Germany	Research Site	Hamburg
Germany	Research Site	Hannover
Germany	Research Site	Heidelberg
Germany	Research Site	Kiel
Germany	Research Site	Mannheim
Germany	Research Site	Minden
Germany	Research Site	Muenchen
Germany	Research Site	München
Germany	Research Site	Münster
Germany	Research Site	Paderborn
Germany	Research Site	Potsdam
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Debrecen
Hungary	Research Site	Kecskemét
Hungary	Research Site	Szekszárd
Hungary	Research Site	Szolnok
Israel	Research Site	Afula
Israel	Research Site	Beer Sheva
Israel	Research Site	Haifa
Israel	Research Site	Jerusalem
Israel	Research Site	Jerusalem
Israel	Research Site	Kfar-Saba
Israel	Research Site	Petah Tikva
Israel	Research Site	Ramat Gan
Italy	Research Site	Bergamo
Italy	Research Site	Candiolo
Italy	Research Site	Catanzaro
Italy	Research Site	Livorno
Italy	Research Site	Macerata
Italy	Research Site	Meldola
Italy	Research Site	Milano
Italy	Research Site	Modena
Italy	Research Site	Napoli
Italy	Research Site	Prato
Italy	Research Site	Roma
Japan	Research Site	Chiba-shi
Japan	Research Site	Fukuoka-shi
Japan	Research Site	Fukushima-shi
Japan	Research Site	Hidaka-shi
Japan	Research Site	Hiroshima-shi
Japan	Research Site	Kagoshima-shi
Japan	Research Site	Kitaadachi-gun
Japan	Research Site	Koto-ku
Japan	Research Site	Kumamoto-shi
Japan	Research Site	Kyoto-shi
Japan	Research Site	Matsuyama-shi
Japan	Research Site	Nagoya-shi
Japan	Research Site	Nagoya-shi
Japan	Research Site	Osaka-shi
Japan	Research Site	Osaka-shi
Japan	Research Site	Ota-shi
Japan	Research Site	Sapporo-shi
Japan	Research Site	Sapporo-shi
Japan	Research Site	Shinagawa-ku
Japan	Research Site	Tsu-shi
Japan	Research Site	Yokohama-shi
Korea, Republic of	Research Site	Busan
Korea, Republic of	Research Site	Daegu
Korea, Republic of	Research Site	Goyang-si
Korea, Republic of	Research Site	Incheon
Korea, Republic of	Research Site	Seongnam-si
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Suwon-si
Korea, Republic of	Research Site	Suwon-si
Peru	Research Site	Arequipa
Peru	Research Site	Lima
Poland	Research Site	Bydgoszcz
Poland	Research Site	Krakow
Poland	Research Site	Olsztyn
Poland	Research Site	Warszawa
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	Samara
Russian Federation	Research Site	Sochi
Spain	Research Site	A Coruña
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Córdoba
Spain	Research Site	Hosp de Llobregat(Barcelona)
Spain	Research Site	Jaén
Spain	Research Site	La Laguna (Tenerife)
Spain	Research Site	Lérida
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Majadahonda
Spain	Research Site	Malaga
Spain	Research Site	Pamplona
Spain	Research Site	Reus,Tarragona
Spain	Research Site	Santiago de Compostela
Spain	Research Site	Sevilla
Spain	Research Site	Valencia
Spain	Research Site	Valencia
Taiwan	Research Site	Kaohsiung City
Taiwan	Research Site	Taichung
Taiwan	Research Site	Tainan
Taiwan	Research Site	Tainan City
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taoyuan
United Kingdom	Research Site	Aberdeen
United Kingdom	Research Site	Bournemouth
United Kingdom	Research Site	Bristol
United Kingdom	Research Site	Cardiff
United Kingdom	Research Site	Cheltenham
United Kingdom	Research Site	London
United Kingdom	Research Site	London
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Sutton
United States	Research Site	Baltimore	Maryland
United States	Research Site	Boston	Massachusetts
United States	Research Site	Chattanooga	Tennessee
United States	Research Site	Dallas	Texas
United States	Research Site	Farmington	New Mexico
United States	Research Site	Fort Myers	Florida
United States	Research Site	Gilbert	Arizona
United States	Research Site	Greensboro	North Carolina
United States	Research Site	Jacksonville	Florida
United States	Research Site	Kansas City	Missouri
United States	Research Site	Lake Success	New York
United States	Research Site	Midlothian	Virginia
United States	Research Site	Nashville	Tennessee
United States	Research Site	New York	New York
United States	Research Site	Orange	California
United States	Research Site	Paramus	New Jersey
United States	Research Site	Puyallup	Washington
United States	Research Site	Rochester	Minnesota
United States	Research Site	Saint Louis	Missouri
United States	Research Site	San Francisco	California
United States	Research Site	Westwood	Kansas
United States	Research Site	Whittier	California

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Canada,  China,  France,  Germany,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Peru,  Poland,  Russian Federation,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-Free Survival (PFS) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup	Progression-Free Survival by investigator assessment (in accordance with RECIST 1.1)	The time from date of randomisation to the date of progression or death due to any cause, whichever occurs earlier, up to approximately 51 months
Secondary	Overall Survival (OS) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup.	Overall Survival (OS) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup	The time from date of randomisation to the date of death due to any cause up to 51 months
Secondary	Investigator assessment of PFS2 in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup.	PFS2 - time from randomisation to second progression by investigator assessment	The time from the date of randomisation to the date of progression subsequent to the first subsequent therapy, or death due to any cause, whichever occurs earlier, up to approximately 51 months
Secondary	Response Rate (ORR) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup.	percentage of patients with at least one investigator-assessed visit response of complete or partial response (as assessed by the investigator, using RECIST 1.1)	Up to Approximately 51 months
Secondary	Duration of Response (DoR) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup.	time from the date of first documented response until date of documented progression (as assessed by the investigator, using RECIST 1.1) or death in the absence of disease progression	Up to Approximately 51 months
Secondary	Clinical Benefit Rate (CBR) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup.	number of patients with complete or partial response or with stable disease maintained =24 weeks after randomisation (as assessed by the investigator, using RECIST 1.1)	Up to Approximately 51 months
Secondary	ocurrence/frequency of AEs and its relationship to study drugs (safety and tolerability) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup	AEs graded according to the National Cancer Institute (NCI CTCAE)	Up to Approximately 51 months
Secondary	plasma concentration of capivasertib	plasma concentration of capivasertib pre-dose and post-dose (C1h and C4h) in the overall population	Minimum plasma concentration (Cmin), plasma concentration 1 hour post-dose (C1h) and 4 hours post-dose (C4h) during cycles 1 and 2 (each cycle is 28 days)
Secondary	EORTC QLQ BR23(European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer specific module) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup where applicable	The self-administered instrument includes 23-items and yields 5 multi-item scores (body image, sexual functioning, arm symptoms, breast symptoms, and systemic therapy side effects). Items are scored on a 4-point verbal rating scale: "Not at All," "A Little," "Quite a Bit," and "Very Much". Scores are transformed to a 0 to 100 scale, where higher scores indicate better unctioning, better HRQoL, or greater level of symptom	Up to Approximately 51 months
Secondary	The EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items) in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup where applicable	5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea/vomiting), and global health status/QoL scale, along with 5 individual item symptom scores (appetite loss, dyspnoea, insomnia, constipation, and diarrhoea. The EORTC QLQ-C30 will be scored according to the EORTC QLQ-C30 Scoring Manual (Fayers et al. 2001). Higher scores on the global measure of health status and functional scales indicate better health status/function, but higher scores on symptom scales/scores represent greater symptom severity	Up to Approximately 51 months
Secondary	Time to definitive deterioration of the ECOG (Eastern Cooperative Oncology Group) performance status in the overall population and in the PIK3CA/AKT1/PTEN-altered subgroup where applicable	Time from randomisation to the earlier of the date of the first definitive deterioration or death due to any cause. Deterioration is defined as a 1-point decrease in ECOG score from baseline, and the deterioration is considered definitive if no improvements in the ECOG performance status are observed at a subsequent time of measurement during the treatment period, or at no further assessments following the time point where the deterioration is observed	Up to approximately 51 months