This is a first-in-human, open-label, Phase 1 study evaluating BBI-940, an investigational kinesin oral molecular degrader, administered as monotherapy or in combination with fulvestrant in adults with advanced or metastatic breast cancer.

The study consists of two parts: Part 1 (dose escalation) and Part 2 (dose expansion).

Part 1 is a dose-escalation phase designed to evaluate the safety and tolerability of BBI-940 and to determine the recommended dose for expansion (RDE). Participants may have estrogen receptor-positive, HER2-negative (ER+/HER2-) breast cancer or triple-negative breast cancer of the luminal androgen receptor subtype (TNBC-LAR).

Part 2 is a dose-expansion phase designed to further evaluate BBI-940 at the selected RDE in defined participant populations.

Part 2A evaluates BBI-940 in combination with fulvestrant, including multiple dose cohorts to evaluate the safety of the combination regimen and to determine the combination RDE in participants with ER+/HER2- breast cancer without an ESR1 mutation.

Part 2B evaluates BBI-940 monotherapy at the RDE in participants with ER+/HER2- breast cancer with FGFR1 amplification.

Part 2C evaluates BBI-940 monotherapy at the RDE in participants with TNBC-LAR.

Across all parts of the study, treatment is administered in repeated 28-day cycles, and participants undergo protocol-specified safety assessments.

Key Inclusion Criteria

• Adults with locally advanced or metastatic breast cancer, including estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) disease or triple-negative breast cancer with luminal androgen receptor subtype (TNBC-LAR; androgen receptor expression ≥10% by immunohistochemistry), as applicable by study part.
• Prior treatment with standard therapies known to provide clinical benefit, appropriate for disease subtype and study part, including endocrine therapy with CDK4/6 inhibition for ER+/HER2- disease.
• Measurable disease per RECIST v1.1, except for participants enrolled in Part 1A.
• Molecular eligibility as applicable by study part, including absence of an ESR1 mutation (Part 2A) or presence of FGFR1 amplification (Part 2B), based on prior local testing.
• Availability of archival or newly obtained formalin-fixed, paraffin-embedded (FFPE) tumor tissue suitable for protocol-specified biomarker analyses.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate hematologic, hepatic, renal, and coagulation function per protocol-defined laboratory criteria.
• Estimated life expectancy of at least 12 weeks.
• Ability to swallow oral medication and provide written informed consent.

Key Exclusion Criteria

• Prior exposure to an inhibitor or degrader of Kinesin.
• Known hypersensitivity to study intervention(s) or excipients.
• Receipt of recent anticancer therapy within protocol-defined washout periods.
• Other active malignancy likely to interfere with study assessment.
• Baseline QTcF >470 msec or congenital long QT syndrome.
• Clinically significant pulmonary embolism within 6 weeks prior to first dose.
• Major surgery within 4 weeks or minor surgery within 2 weeks prior to first dose.
• Active infection requiring systemic therapy within 2 weeks prior to first dose.
• Pregnant or breastfeeding, or planning conception or gamete donation during the study or required post-treatment period.
• Prior solid organ transplant or allogeneic stem cell transplant with protocol-defined exceptions.
• Failure to recover to CTCAE Grade ≤1 (or baseline) from prior anticancer therapy, with protocol-specified exceptions.
• Any serious or uncontrolled medical, laboratory, or psychiatric condition that could compromise safety or study integrity.
• Other exclusion criteria as specified in the study protocol.