Background: Chemotherapy treatments that offer improved quality of life are needed. Tesetaxel (T) is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and Q3W dosing; no history of hypersensitivity reactions; and improved activity against chemotherapy-resistant tumors (Shionoya 2003; Chan 2006). 555 pts have been treated with T in clinical studies (492 monotherapy; 63 in combination with capecitabine (C)). In MBC, T had robust single-agent activity in 2 multicenter, Phase 2 studies. In TOB203, 38 pts with HER2-, HR+ MBC received single-agent T Q3W for MBC; the confirmed ORR per RECIST 1.1 in all 38 pts was 45% (95% CI: 29% - 62%); the median PFS was 5.7 mo (95% CI: 4.1 – 9.8 mo). In a Phase 1 study, the combination of T plus a reduced dose of C was associated with a tolerable AE profile with minimal overlapping toxicity. C is a preferred agent for pts with MBC. Combining the approved dose of C with currently available taxanes results in robust efficacy but significant toxicity, while preclinical and clinical studies suggest that reducing the dose of C in combination with a taxane may result in reduced toxicity without a reduction in efficacy. CONTESSA investigates T plus a reduced dose of C as an all-oral regimen in HER2-, HR+ MBC. Methods: CONTESSA is a 600-pt, multinational, multicenter, randomized (1:1), Phase 3 registration study comparing T (27 mg/m² on Day 1 of a 21-day cycle) plus a reduced dose of C (1,650 mg/m²/day on Days 1-14 of a 21-day cycle) to the approved dose of C alone (2,500 mg/m²/day on Days 1-14 of a 21-day cycle) in pts with HER2-, HR+ MBC previously treated with a taxane in the (neo)adjuvant setting. Where indicated, pts must have received endocrine therapy with or without a CDK 4/6 inhibitor. The primary endpoint is PFS assessed by an Independent Radiologic Review Committee (IRC). CONTESSA is 90% powered to detect a 42% improvement in PFS (HR = 0.71). Secondary endpoints are OS, ORR assessed by IRC, disease control rate assessed by IRC and patient reported outcomes. Enrollment was initiated in Dec 2017. Clinical trial information: NCT03326674