Clinical trial NCT06982521: Phase 3 Study of RLY-2608 + Fulvestrant vs Capivasertib + Fulvestrant as Treatment for Locally Advanced or Metastatic PIK3CA-mutant HR+/HER2- Breast Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: PIK3CA Mutation
HER2- Negative Breast Cancer
Hormone Receptor Positive Tumor
Breast Cancer
Metastatic Breast Cancer
Advanced Breast Cancer
Lead sponsor: Relay Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2025-05-21
Enrollment: 540
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Progression-Free Survival (PFS) within the overall and kinase population by blinded independent central review (BICR)
timeFrame: 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 outcomes:
measure: Overall Survival (OS) within the overall and kinase populations
timeFrame: The time from randomization to the date of death by any cause, up to approximately 77 months
measure: PFS by Investigator within the overall and kinase populations
timeFrame: The time from date of randomization until radiographic progression per RECIST v1.1, or death due to any cause, up to approximately 77 months
measure: Objective Response Rate (ORR) within the overall and kinase populations
timeFrame: Up to approximately 77 months
measure: Duration of Response (DOR) within the overall and kinase populations
timeFrame: Up to approximately 77 months
measure: Clinical Benefit Rate (CBR) within the overall and kinase populations
timeFrame: Up to approximately 77 months
measure: Occurrence/frequency of Adverse Events (AEs) and its relationship to the study drugs (safety and tolerability) within the overall and kinase populations
timeFrame: Up to approximately 77 months
measure: Plasma concentrations of RLY-2608 (and its metabolites as appropriate)
timeFrame: Approximately every 2 weeks in Cycle 1 (4-week cycle) and during Cycles 2 and 3
measure: 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
timeFrame: Up to approximately 77 months
measure: 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
timeFrame: Up to approximately 77 months
measure: Health state utility data for economic evaluation by EQ-5D-5L health state utility index within the overall and kinase populations
timeFrame: Up to approximately 77 months
Other outcomes:
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