Phase III Study of Capivasertib + Fulvestrant vs Placebo + Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic HR+/HER2− Breast Cancer (CAPItello-291)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 May 2020 → ongoing

Decision date (initial)

2024-02-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2023-505042-25-00

EudraCT number

2019-003629-78

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Efficacy, Safety, Pharmacogenomic, Pharmacokinetic

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 objectives 9

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

Conditions and MedDRA coding

Locally advanced (inoperable) or metastatic HR+/HER2 breast cancer

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared. AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment https://vivli.org/. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 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.
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 coexpression 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.

Exclusion criteria 11

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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 9

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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

Information Center

Third parties 12

Locations

7 EU/EEA countries · 72 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 55 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications