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A phase I/II trial evaluating the safety and efficacy of eribulin in combination with copanlisib in patients with metastatic triple-negative breast cancer (TNBC).

TPS1128 Background: Metastatic (met) TNBC remains a clinical challenge with limited treatment options and inevitable chemoresistance. Aberrant PI3K pathway signaling is frequently observed in TNBC. Increasing evidence shows PI3K pathway activation maintains the stemness and chemoresistance of BC stem cells (CSCs), and PI3K inhibition sensitizes CSCs to chemotherapy (chemo). Eribulin (E), a non-taxane microtubule dynamics inhibitor, showed survival benefit in met HER2 negative BC. Preclinically, E impacts tumor vascular remodeling, inhibits epithelial-to-mesenchymal transition and metastasis – key mechanisms implicated in PI3K inhibition resistance. Copanlisib (C), a potent pan-class I PI3K inhibitor ( i), improved anti-tumor effect in E-sensitive and resistant TNBC patient-derived xenograft models, irrespective of PIK3CA/PTEN mutation (mut) status, when combined with E. This phase I/II study is aimed to determine the safety and efficacy of E+C in pts with met TNBC. Methods: This trial includes a phase I portion with the primary objective to determine the dose limiting toxicity (DLT) and recommended phase 2 dose (RP2D) of E+C, followed by a phase II randomized portion of E+C (at RP2D) versus ( vs) E with the primary objective of progression-free survival (PFS). Key secondary objectives include objective response rate (ORR) and clinical benefit rate (CBR) [phase I]; and ORR and CBR, by arm and by PIK3CA/PTEN mut status and assessment of treatment induced target engagement [phase II]. Key exploratory objectives include analysis of genomic, proteomic and metabolomic changes as potential response biomarkers in tumor tissue and blood. Key eligibility criteria include pts with: met TNBC who progressed on ≤5 chemo lines, including anthracycline/taxane (unless contraindicated), ECOG 0-1, adequate organ function and known archival tumor PIK3CA/PTEN mut status. Key exclusions: prior E or PI3K/mTOR/AKT i, grade ≥2 neuropathy, tumor AKT mut, congenital QT prolongation, and uncontrolled diabetes or hypertension. Phase I portion will follow a 3+3 design for E+C dose escalation to enroll 18 max pts, starting at E 1.1 mg/m2 IV and C 45 mg IV on days (D) 1/8 of 21-D cycle (C) (to E 1.4 mg/m2 and C 60 mg max). RP2D will be defined as the highest dose level at which at most 1 of 6 pts experience DLT during C1. 88 pts will be randomized (1:1) in the phase II portion to E+C vs E (1.4 mg/m2 D 1/8), stratified by PTEN/PIK3CA mut status. Response assessment by Response Evaluation Criteria in solid tumors (RECIST) v1.1 will occur every 9 weeks (+/-7 D). Tumor biopsy is required at baseline and C2D1-2, and optional at progression. A sample size of 88 achieves 80% power to detect PFS difference of median PFS 6.95 vs 4 months (corresponding to a hazard ratio of 0.5755) between the 2 arms, based on 1-sided two-sample log rank test at 0.1 α level. The phase I study is actively enrolling pts. Clinical trial information: NCT04345913.