A Study of the New Investigational Drug GDC-4198, Either Alone or in Combination with the Investigational Drug Giredestrant, Compared with Abemaciclib and Giredestrant in Patients with Advanced, Hormone-Receptor-Positive, HER2-Negative Breast Cancer

Breast cancer (mammary carcinoma) is a malignant disease of the mammary gland tissue characterized by the uncontrolled proliferation of mammary gland cells. Treatment depends on numerous factors, such as the patient’s overall health, the stage of the disease, and the characteristics of the cancer cells—particularly the presence of detectable hormone receptors on the surface of the cancer cells (estrogen receptor- or progesterone receptor-positive) and the presence of the HER2 receptor (HER2-positive or HER2-negative). For hormone receptor-positive, HER2-negative breast cancer at an advanced or metastatic stage, anti-hormone therapy is routinely combined with a CDK4/6 inhibitor. CDK4/6 inhibitors stop cancer cells from dividing by inhibiting certain enzymes (CDK4 and CDK6) that are necessary for the cell cycle. One CDK4/6 inhibitor already approved for the treatment of hormone receptor-positive, HER2-negative breast cancer is, for example, abemaciclib. However, during the course of treatment, cancer cells can develop resistance to these drugs, causing the disease to progress despite therapy. One possible cause of this resistance is the increased activity of another enzyme (CDK2), which can bypass the blockade imposed by CDK4/6 inhibitors. The new study drug, GDC-4198, specifically inhibits both CDK4 and CDK2 and is therefore expected to be effective even in patients whose disease has continued to progress while on previous CDK4/6 inhibitor therapy. GDC-4198 is taken as a tablet. In addition, the study will use giredestrant, another investigational drug that, as an anti-hormonal agent, blocks and degrades the estrogen receptor on cancer cells, thereby inhibiting hormone-dependent tumor growth. Giredestrant is also taken as a tablet.

The goal of this Phase 1b/2 study is to investigate the safety and efficacy of the investigational drug GDC-4198, both alone and in combination with giredestrant, compared to abemaciclib and giredestrant. The study is divided into two phases: In Phase 1b, the safety and tolerability of GDC-4198 alone and in combination with giredestrant will first be evaluated to determine the appropriate dosage. In Phase 2, the efficacy of the combination of GDC-4198 and giredestrant will be compared with that of the combination of abemaciclib and giredestrant. The study is open-label, meaning that both the study physicians and the patients know which treatment is being administered. In Phase 2, patients will be randomly assigned to one of three study arms: Arm A with a higher dose of GDC-4198 plus giredestrant, Arm B with a lower dose of GDC-4198 plus giredestrant, or Arm C with the comparator treatment of abemaciclib plus giredestrant. Treatment is administered in 28-day cycles and continues until the disease progresses or unacceptable intolerance occurs. The primary endpoint in Phase 2 is time to disease progression (progression-free survival) for up to 36 months.

Eligible participants include women and men aged 18 years and older with hormone receptor-positive, HER2-negative breast cancer at the locally advanced or metastatic stage, whose disease has continued to progress during or after treatment with an approved CDK4/6 inhibitor and anti-hormone therapy. Patients must not have received more than one prior line of therapy for advanced or metastatic disease and must not have received prior chemotherapy for metastatic disease.