A Study to compare RLY-2608 + Fulvestrant with Capivasertib + Fulvestrant in people with PIK3CA-mutated, hormone-receptor positive, HER2-negative advanced or metastatic breast cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Relay Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

8 Dec 2025 → ongoing

Decision date (initial)

2025-11-17

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2025-523083-21-00

ClinicalTrials.gov

NCT06982521

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To compare the efficacy of RLY-2608 + fulvestrant relative to capivasertib + fulvestrant by assessment of PFS within the overall and kinase populations by BICR.

Secondary objectives 9

1. To compare the efficacy of RLY-2608 + fulvestrant relative to capivasertib + fulvestrant by assessment of OS within the overall and kinase populations.
2. To compare the efficacy of RLY-2608 + fulvestrant relative to capivasertib + fulvestrant by assessment of PFS by the Investigator within the overall and kinase populations.
3. To compare the efficacy of RLY-2608 + fulvestrant relative to capivasertib + fulvestrant by assessment of ORR by BICR and by the Investigator within the overall and kinase populations.
4. To compare the efficacy of RLY-2608 + fulvestrant relative to capivasertib + fulvestrant by assessment of DOR by BICR and by the Investigator within the overall and kinase populations.
5. To compare the efficacy of RLY-2608 + fulvestrant relative to capivasertib + fulvestrant by assessment of CBR by BICR and by the Investigator within the overall and kinase populations.
6. To assess safety and tolerability of RLY-2608 + fulvestrant relative to capivasertib + fulvestrant within the overall and kinase populations.
7. To evaluate the PK of RLY-2608 (and its metabolites as appropriate) within the overall and kinase populations.
8. To assess the impact of RLY-2608 + fulvestrant relative to capivasertib + fulvestrant on participants’ disease-related symptoms, function, and HRQoL within the overall and kinase populations.
9. To assess the impact of treatment and disease state on health state utility within the overall and kinase populations.

Conditions and MedDRA coding

PIK3CA-mutant Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) Locally Advanced or Metastatic Breast Cancer

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Patient has ECOG performance status of 0-1
2. Adult females, pre- and/or post-menopausal, and adult males. Pre-menopausal (and peri-menopausal) women can be enrolled if amenable to treatment with a gonadotropin-releasing hormone (GnRH) agonist. Patients are to have commenced treatment with a GnRH agonist at least 4 weeks prior to randomization and must be willing to continue on it for the duration of the study.
3. Histologically or cytologically confirmed diagnosis of HR+/HER2- locally advanced or metastatic breast cancer (ABC) with radiological or objective evidence of recurrence or progression; locally advanced disease must not be amenable to resection with curative intent
4. Measurable disease per RECIST v1.1 or evaluable bone-only disease.
5. One or more known primary oncogenic PIK3CA mutation(s)
6. Must have radiological evidence of progression on or after previous treatment for HR+/HER2- ABC with: 1. At least 1 and no more than 2 lines of endocrine therapy (ET) in the (neo)adjuvant setting with recurrence on or within 12 months of completion or in the ABC setting 2. 1 prior line of CDK4/6 inhibitor therapy in one of the following settings: CDK4/6 inhibitor + ET in the ABC setting CDK4/6 inhibitor therapy in the adjuvant setting if progression occurred during or within 12 months of completion of adjuvant CDK4/6 inhibitor with ET Patients who progressed during or within 12 months of completion of adjuvant CDK4/6 inhibitor and after receiving CDK4/6 inhibitor therapy in the advanced setting are considered to have had >1 prior line of CDK4/6 inhibitor and are not eligible

Exclusion criteria 8

1. History of hypersensitivity to fulvestrant or drugs in a similar class as fulvestrant, RLY-2608, or capivasertib, including their excipients
2. Prior treatment with any of the following: CDK2 or selective CDK4 inhibitors or any investigational therapies targeting cyclin dependent kinases PIK3, AKT, or mTOR inhibitors or any agent whose mechanism of action is the inhibit the PIK3/AKT/mTOR pathway Immunotherapy Antibody drug conjugates
3. Known activating AKT mutations, loss-of-function PTEN mutations, or loss of PTEN expression resulting in oncogenic pathway activation downstream of PI3K
4. Type 1 diabetes, or Type 2 diabetes requiring antihyperglycemic medication, or fasting plasma glucose ≥ 140 mg/dL (7.8 mmol/L), or glycosylated hemoglobin (HbA1c) ≥7.0% (≥ 53 mmol/mol).
5. Known active uncontrolled or symptomatic CNS metastases associated with progressive neurological symptoms or requiring ongoing corticosteroids or anticonvulsants for symptomatic control
6. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
7. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
8. Clinically significant, uncontrolled cardiovascular disease

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PFS is defined as the time from randomization until radiographic progression per RECIST v1.1, or death due to any cause.

Secondary endpoints 9

1. OS is defined as the time from randomization to the date of death by any cause.
2. PFS is defined as the time from randomization until radiographic progression per RECIST v1.1, or death due to any cause.
3. ORR is defined as the percentage of participants with CR or PR per RECIST v1.1.
4. DOR is defined as the time from the date of first documented response per RECIST v1.1 until date of documented progression or death in the absence of disease progression.
5. CBR is defined as the percentage of participants who achieved CR or PR at any time or SD maintained for ≥24 weeks per RECIST v1.1 (without subsequent therapy) after randomization.
6. • Frequency, severity, timing, and relationship to RLY-2608/fulvestrant or capivasertib/fulvestrant of any AEs, SAEs, changes in vital signs, ECGs, and safety laboratory tests. All AEs and SAEs will be collected and graded according to the NCI CTCAE, Version 5.0. • Dose intensity. • Dose modification.
7. Plasma concentrations of RLY-2608 (and its metabolites as appropriate).
8. Evaluation of EORTC QLQ-C30, EORTC QLQ-BR23 scale/item scores including change from baseline and time to deterioration.
9. Health state utility data for economic evaluation will be derived by using the EQ-5D-5L health state utility index.

Investigational products

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

Test 4

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Relay Therapeutics Inc.

Sponsor organisation

Relay Therapeutics Inc.

Address

60 Hampshire Street

City

Cambridge

Postcode

02139-1548

Country

United States

Scientific contact point

Organisation

Relay Therapeutics Inc.

Contact name

Medical team

Public contact point

Organisation

Relay Therapeutics Inc.

Contact name

Clinical Operations

Third parties 18

Locations

14 EU/EEA countries · 131 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 272 files

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

Application history

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