Phase 3 Study of RLY-2608 + Fulvestrant vs Capivasertib + Fulvestrant as Treatment for Locally Advanced or Metastatic PIK3CA-mutant HR+/HER2- Breast Cancer (ReDiscover-2)

Relay Therapeutics

Status and phase: Begins enrollment this month; Phase 3

Conditions: Breast Cancer; PIK3CA Mutation; Hormone Receptor Positive Tumor; Metastatic Breast Cancer; Advanced Breast Cancer; HER2- Negative Breast Cancer

Treatments: Drug: Capivasertib; Drug: RLY-2608; Drug: Fulvestrant

Study type: Interventional

Funder types: Industry

Identifiers

NCT06982521

RLY-2608-102

Details and patient eligibility

About

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.

Enrollment: 540 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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540 participants in 2 patient groups

RLY-2608 + fulvestrant

Experimental group

Description:

RLY-2608 + fulvestrant combination for participants with HR+/HER2- advanced breast cancer

Treatment:

Drug: Fulvestrant

Drug: RLY-2608

capivasertib + fulvestrant

Active Comparator group

Description:

capivasertib + fulvestrant combination for participants with HR+/HER2- advanced breast cancer

Treatment:

Drug: Fulvestrant

Drug: Capivasertib