RecruitingInterventionalPhase 3

A Phase 3 Open-Label Randomized Study Assessing the Efficacy and Safety of RLY-2608 + Fulvestrant Versus Capivasertib + Fulvestrant as Treatment for PIK3CA-mutant Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) Locally Advanced or Metastatic Breast Cancer Following Recurrence or Progression On or After Treatment With a CDK4/6 Inhibitor

NCT ID: NCT06982521Sponsor: Relay Therapeutics, Inc.Last updated: 2026-06-11

Summary

This is a global, multicenter, open-label, randomized Phase 3 study comparing the efficacy and safety of RLY-2608 + fulvestrant to capivasertib + fulvestrant for the treatment of patients with HR+/HER2- ABC with PIK3CA mutation following recurrence or progression on or after treatment with a CDK4/6 inhibitor.

Arms & interventions

DrugRLY-2608
400 mg orally BID administered daily on a 28-day treatment cycle
DrugCapivasertib
400mg orally BID administered on an intermittent weekly dosing schedule. Patients will dose on Days 1 through 4 each week of a 28-day treatment cycle
DrugFulvestrant
500 mg intramuscularly administered on Cycle 1 Day 1, Day 15, and Day 1 of each subsequent cycle (28-day treatment cycle)

Outcome measures

Primary

Progression-Free Survival (PFS) within the overall and kinase population by blinded independent central review (BICR)
Time frame: The time from date of randomization until radiographic progression per RECIST v1.1, or death due to any cause, up to approximately 77 months

Secondary

Overall Survival (OS) within the overall and kinase populations
Time frame: The time from randomization to the date of death by any cause, up to approximately 77 months
PFS by Investigator within the overall and kinase populations
Time frame: The time from date of randomization until radiographic progression per RECIST v1.1, or death due to any cause, up to approximately 77 months
Objective Response Rate (ORR) within the overall and kinase populations
Time frame: Up to approximately 77 months
Duration of Response (DOR) within the overall and kinase populations
Time frame: Up to approximately 77 months
Clinical Benefit Rate (CBR) within the overall and kinase populations
Time frame: Up to approximately 77 months
Occurrence/frequency of Adverse Events (AEs) and its relationship to the study drugs (safety and tolerability) within the overall and kinase populations
Time frame: Up to approximately 77 months
Plasma concentrations of RLY-2608 (and its metabolites as appropriate)
Time frame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and during Cycles 2 and 3
European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30) scale/item scores including change from baseline and time to deterioration within overall and kinase populations
Time frame: Up to approximately 77 months
EORTC Quality of Life Questionnaire Breast Cancer-Specific Module (EORTC QLQ-BR23) scale/item scores including change from baseline and time to deterioration within the overall and kinase populations
Time frame: Up to approximately 77 months
Health state utility data for economic evaluation by EQ-5D-5L health state utility index within the overall and kinase populations
Time frame: Up to approximately 77 months

Eligibility criteria

Sex: AllAge: 18 Years and olderHealthy volunteers: No

Inclusion Criteria: * Patient has ECOG performance status of 0-1 * One or more known primary oncogenic PIK3CA mutation(s) * 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. * 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 * Measurable disease per RECIST v1.1 or evaluable bone-only disease. * 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: 1. CDK4/6 inhibitor + ET in the ABC setting 2. 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 3. 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: * Prior treatment with any of the following: 1. CDK2 or selective CDK4 inhibitors or any investigational therapies targeting cyclin dependent kinases 2. PIK3, AKT, or mTOR inhibitors or any agent whose mechanism of action is the inhibit the PIK3/AKT/mTOR pathway 3. Immunotherapy 4. Antibody drug conjugates * Type 1 diabetes, or Type 2 diabetes requiring antihyperglycemic medication, or fasting plasma glucose ≥ 140 mg/dL, or glycosylated hemoglobin (HbA1c) ≥7.0% (≥ 53 mmol/mol). * Clinically significant, uncontrolled cardiovascular disease * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events * Known active uncontrolled or symptomatic CNS metastases associated with progressive neurological symptoms or requiring ongoing corticosteroids or anticonvulsants for symptomatic control * 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 * History of hypersensitivity to fulvestrant or drugs in a similar class as fulvestrant, RLY-2608, or capivasertib, including their excipients * Known activating AKT mutations, loss-of-function PTEN mutations, or loss of PTEN expression resulting in oncogenic pathway activation downstream of PI3K

Study locations (51)

Banner MD Anderson Cancer Center

Gilbert, Arizona, 85234

Recruiting

Beverly Hills Cancer Center

Beverly Hills, California, 90211

Recruiting

City of Hope National Medical Center

Duarte, California, 91010

Recruiting

Cedars-Sinai Medical Center

Los Angeles, California, 90048

Recruiting

Stanford Women's Cancer Center

Palo Alto, California, 94304

Recruiting

University of California, Davis Comprehensive Cancer Center

Sacramento, California, 95817

Recruiting

University of California San Diego Moores Cancer Center

San Diego, California, 92037

Recruiting

University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center

San Francisco, California, 94158

Recruiting

Kaiser Permanente Medical Center

Vallejo, California, 94589

Recruiting

Rocky Mountain Cancer Centers, LLP

Longmont, Colorado, 80504

Recruiting

Yale-New Haven Hospital-Yale Cancer Center

New Haven, Connecticut, 06510

Recruiting

Medical Oncology Hematology Consultants, P.A.

Newark, Delaware, 19713

Recruiting

Georgetown University Medical Center

Washington D.C., District of Columbia, 20007

Recruiting

AdventHealth

Altamonte Springs, Florida, 32701

Recruiting

Florida Cancer Specialists-South

Fort Myers, Florida, 33901

Recruiting

Cancer Care Centers of Brevard, Inc

Palm Bay, Florida, 32909

Recruiting

Rush University Medical Center

Chicago, Illinois, 60607

Recruiting

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Chicago, Illinois, 60611

Recruiting

Community Health Network, Inc

Indianapolis, Indiana, 46250

Recruiting

University of Kansas Cancer Center

Westwood, Kansas, 66205

Recruiting

Cancer Center of Kansas

Wichita, Kansas, 67214

Recruiting

Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins

Baltimore, Maryland, 21287

Recruiting

Tufts Medical Center

Boston, Massachusetts, 02111

Recruiting

Dana Farber Cancer Institute

Boston, Massachusetts, 02215

Recruiting

University of Michigan

Ann Arbor, Michigan, 48109

Recruiting

Profound Research LLC

Royal Oak, Michigan, 48073

Recruiting

Minnesota Oncology Hematology, P.A.

Minneapolis, Minnesota, 55404

Recruiting

University of Mississippi Medical Center

Jackson, Mississippi, 39213

Recruiting

Washington University School of Medicine- Siteman Cancer Center

St Louis, Missouri, 63108

Recruiting

Nebraska Cancer Specialists

Omaha, Nebraska, 68130

Recruiting

Renown Health Medical Oncology

Reno, Nevada, 89502

Recruiting

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601

Recruiting

Rutgers Cancer Institute

New Brunswick, New Jersey, 08901

Recruiting

Laura and Isaac Perlmutter Cancer Center at NYU Langone Health

New York, New York, 10016

Recruiting

Icahn School of Medicine at Mount Sinai

New York, New York, 10029

Recruiting

Columbia University Irving Medical Center

New York, New York, 10032

Recruiting

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065

Recruiting

Oregon Health & Science University, Knight Cancer Institute

Portland, Oregon, 97210

Recruiting

Avera Cancer Institute

Sioux Falls, South Dakota, 57105

Recruiting

Tennessee Cancer Specialists

Knoxville, Tennessee, 37909

Recruiting

Tennessee Oncology, PLLC

Nashville, Tennessee, 37203

Recruiting

Texas Oncology Central/South

Austin, Texas, 78731

Recruiting

Texas Oncology DFW

Dallas, Texas, 75246

Recruiting

University of Texas Southwestern Medical Center

Dallas, Texas, 75390

Recruiting

Houston Methodist Hospital Cancer Center

Houston, Texas, 77030

Recruiting

The University of Texas M.D. Anderson Cancer Center

Houston, Texas, 77030

Recruiting

Baylor Scott and White Medical Center

Temple, Texas, 76508

Recruiting

Huntsman Cancer Institute, University of Utah

Salt Lake City, Utah, 84112

Recruiting

Virginia Cancer Specialists, PC

Fairfax, Virginia, 22031

Recruiting

Virginia Oncology Associates

Norfolk, Virginia, 23502

Recruiting

University of Wisconsin Carbone Cancer Center- University Hospital

Madison, Wisconsin, 53792

Recruiting