Evaluation of Safety and Efficacy of GDC-4198 and Giredestrant Versus Abemaciclib and Giredestrant in ER-Positive, HER2-Negative Advanced Breast Cancer
- Trial ID
- 2025-521128-31-00
- Protocol
- GO46021
- Sponsor
- Genentech Inc.
Trial statistics
Objectives
The primary objectives of this study are to evaluate the safety of GDC-4198 administered as a monotherapy or in combination with giredestrant during the Phase Ib stage, and to compare the efficacy of two specific dose levels of GDC-4198 in combination with giredestrant against the efficacy of abemaciclib in combination with giredestrant during the Phase II stage in patients with estrogen receptor-positive, HER2-negative breast cancer who have progressed following CDK4/6 inhibitor therapy. Secondary objectives include:
- A preliminary assessment of the activity of GDC-4198 alone or in combination with giredestrant.
- Evaluation of the food-effect on the pharmacokinetics of GDC-4198 and its metabolites.
- Comparison of the safety profiles between the GDC-4198 and giredestrant combination and the abemaciclib and giredestrant combination.
- Characterization of the pharmacokinetics of GDC-4198 and its metabolites when administered in combination with giredestrant.
- Identification of a recommended dose of GDC-4198 for future clinical investigations.
Participants
This study involves 212 participants diagnosed with locally advanced or metastatic estrogen receptor-positive, HER2-negative breast cancer. The population consists of both male and female patients within specific age ranges. Eligible subjects must have histologically or cytologically confirmed adenocarcinoma of the breast and have experienced disease progression during or after treatment with a CDK4/6 inhibitor and endocrine therapy. Inclusion requires meeting established guidelines for tumor status and having evaluable disease according to RECIST v1.1. Participants must also possess an ECOG Performance Status of 0 or 1. The primary objectives are:
- To evaluate the safety of GDC-4198 alone and in combination with giredestrant
- To compare the efficacy of two dose levels of GDC-4198 in combination with giredestrant to the efficacy of abemaciclib in combination with giredestrant
Plans and Procedures
This Phase Ib/II, multicenter, open-label, randomized study evaluates the safety, pharmacokinetics, and activity of GDC-4198 administered alone or in combination with giredestrant compared to abemaciclib and giredestrant. The investigation is conducted in participants with locally advanced or metastatic estrogen receptor-positive, HER2-negative breast cancer who have experienced disease progression during or after treatment with a CDK4/6 inhibitor. In the Phase Ib stage, the primary objective is to assess safety and dose-limiting toxicities, while the Phase II stage compares the efficacy of two dose levels of GDC-4198 in combination with giredestrant against the comparator regimen. Primary endpoints include the incidence and severity of adverse events, changes in vital signs and clinical laboratory results, and progression-free survival. Secondary endpoints include overall response rate, clinical benefit rate, overall survival, and the relationship between dose and pharmacokinetics. The trial is estimated to conclude by August 31, 2028.
Treatment
The experimental treatment involves the administration of RGT-419B, which is provided in a hard capsule pharmaceutical form. This substance is administered via the oral route.
The experimental treatment also includes giredestrant, administered as a hard capsule. The oral route is utilized for this substance.
The comparator treatment consists of abemaciclib, which is administered via the oral route.
Efficacy
The efficacy of GDC-4198 in combination with giredestrant will be evaluated in participants with locally advanced or metastatic estrogen receptor-positive, HER2-negative breast cancer. The primary efficacy endpoint is progression-free survival. During the Phase Ib stage, efficacy is further assessed through the overall response rate and clinical benefit rate. In the Phase II stage, secondary efficacy assessments include the duration of response, overall survival, and specific survival rates at 6 and 12 months for both overall survival and progression-free survival.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically and/or cytologically confirmed adenocarcinoma of the breast that is locally advanced (not amenable to surgical or radiation therapy with curative intent) or metastatic
- Previously documented ER+ tumor according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP; Allison et al. 2020) or European Society of Medical Oncology (ESMO) guidelines or any national guidelines with criteria conforming to ASCO/CAP or ESMO guidelines
- Previously documented HER2– tumor according to ASCO/CAP (Wolff et al. 2023) or ESMO guidelines or any national guidelines with criteria conforming to ASCO/CAP or ESMO guidelines
- Disease progression during or after treatment with an approved CDK4/6 inhibitor (e.g., abemaciclib, palbociclib, ribociclib, etc.) and endocrine therapy (ET) in the locally advanced or metastatic setting
- Measurable or non-measurable evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
Exclusion Criteria
- Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term (including massive uncontrolled effusions [pleural, pericardial, peritoneal] or pulmonary lymphangitis) appropriate for treatment with cytotoxic chemotherapy at time of entry into the study, as per national or local treatment guidelines
- Have received more than one-line of therapy for locally advanced or metastatic disease
- Have received prior chemotherapy for metastatic breast cancer
- Treatment with anti-cancer therapies, including investigational therapies, within 28 days or 5 drug elimination half‑lives, whichever is shorter, prior to initiation of study drug
- Poor peripheral venous access
- Malabsorption condition (e.g., active inflammatory gastrointestinal (GI) disease, etc.) or other GI conditions/surgeries that the investigator assesses may significantly interfere with enteral absorption
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 20 Dec 2025 | 16 |
 Germany | Recruiting | 20 Dec 2025 | 17 |
 Italy | Recruiting | 20 Dec 2025 | 19 |
 Spain | Recruiting | 20 Dec 2025 | 21 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
RO7840734 | Test | CAPSULE, HARD | ORAL | — | — | PRD12210469 |
RO7840734 | Test | CAPSULE, HARD | ORAL | — | — | PRD12210468 |
ABEMACICLIB | Comparator | — | ORAL | — | — | SUB171907 |
RO7197597 | Test | CAPSULE, HARD | ORAL | — | — | PRD9491575 |
ABEMACICLIB | Comparator | — | ORAL | — | — | SUB171907 |
ABEMACICLIB | Comparator | — | ORAL | — | — | SUB171907 |