TOPOLOGY: A phase II study to evaluate the efficacy and toxicities of PLX038, in patients with locally advanced or metastatic triple-negative breast cancer.
Authors: Luc Cabel, Delphine Loirat, Jerome Martin Babau, Diana Bello, Jean-Yves Pierga, Florence Lerebours, Cyrine Ezzili, Frederique Berger, Francois Clement Bidard
Journal: Journal of Clinical Oncology (2024)

TPS1142 Background: Sacituzumab govitecan (SG) is an anti-TROP2 antibody-drug conjugate (ADC) with an SN-38 payload (topoisomerase I inhibitor) that was recently approved for use in advanced triple-negative breast cancer (TNBC). The rapid spontaneous linker hydrolysis in sacituzumab-govitecan releases a very large amount of SN-38 cargo systemically, which may in part contribute to efficacy and also in part be responsible for systemic side effects (1). PLX038 is a 40 kDa 4-arm PEG-SN38 conjugate with a half-life of 5 days. It has a controlled, slow-release rate which allows high SN-38 exposure over an extended period of time with a low C max , and very low levels of SN-38-glucuronide. The PLX038 nanomolecule also penetrates large pores of tumor vasculature, and accumulates and is retained in the tumor for long periods. The prolonged exposure of tumors to SN-38 may result in increased efficacy without resulting in severe gastrointestinal toxicity. We hypothesize that PLX038 may be effective in patients with advanced TNBC who have been previously treated with standard chemotherapy regimens. Methods: This is an open label, multi-centric phase II study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of PLX038 in locally advanced or metastatic TNBC previously treated with at least two prior cytotoxic chemotherapy regimens for locally advanced or metastatic breast cancer including an anthracycline, taxane and sacituzumab govitecan. Patients will be treated at a dose of 1730mg/m2 IV infusion on Day 1 of each cycle Q3W (every 21 days, 1 cycle = 1 injection) after at least a first cycle at 1300mg/m2. At the discretion of the treating physician, the PLX038 dose will be increased to 1730 mg/m2 for patients who tolerate at least 1 cycle. All included patients will receive PLX038 as single agent as long as study is ongoing or until progression of disease, unacceptable toxicity, patient withdrawal of consent, Investigator decision, lost to follow-up, death, patient non-compliance, or study termination by Sponsor. The primary endpoint is the best tumor response (defined as partial or complete response in the first 6 months of treatment) assessed by investigators per RECIST v1.1 criteria, with tumor assessments every 8 weeks (± 7 days). Secondary endpoints include i) efficacy criteria (time to response, duration of response, progression-free survival, overall survival), ii) toxicity criteria (AE/SAEs), iii) association between PLX038 efficacy and biomarkers (homologous recombination defect, replication stress-related biomarkers such as SFLN11 expression, RB1 loss), iv) PK/PD analysis. A Simon's two-stage optimum design will be used, and a maximum of N=44 patients will be included, 1. Santi et al., Biodrugs 2024. Clinical trial information: NCT06162351 .