Abstract OT1-4-01: Multicenter phase II trial of the novel compound PM01183 (P) in BRCA1/2-associated or unselected metastatic breast cancer (MBC)
Authors: Isakoff SJ , Cruz C , Garber J , LLuch A , Perez Fidalgo JA , Tung N , Fernandez C , Kahatt C , Szyldergemajn S , Soto Matos-Pita A , Baselga J , Balmaña J 
Published: August 2014

Abstract
Background: MBC is a clinically heterogeneous disease that cannot be cured with currently available treatment options. Selective approaches are needed to identify patient subgroups with different tumor sensitivities who will benefit the most from available therapies for MBC. PM01183 (P), also known as lurbinectedin, is a new anticancer drug that binds to the DNA minor groove inducing both double-strand breaks and transcription blocking. It has significant in vitro and in vivo activity against several tumor models, particularly breast cancer. P is more active against homologous recombination (HR)-deficient cell lines; hence, MBC patients (pts) with deleterious germline BRCA mutations might be more sensitive to P than sporadic tumors.
Methods: A multicenter, open-label, phase II study of P (7.0 mg fixed dose) as 1-hour intravenous infusion every 3 weeks in pts with MBC with or without known BRCA1/2 mutation at study entry. To be enrolled, pts must be women 18-75 years old with confirmed MBC pretreated with 1-3 chemotherapy regimens for MBC (including at least one prior trastuzumab-containing regimen for HER-2 overexpressing pts), measurable disease as per RECIST v1.1, performance status (PS) of 0-1 and adequate major organ function. Pts are excluded if pretreated with P, trabectedin, or radiotherapy (RT) on &gt;35% of bone marrow; if they have prior/concurrent malignant disease not in complete remission for &gt;5 years, clinically unstable central nervous system involvement, and other diseases/situations that might increase patient's risk; if they are pregnant or lactating women; or if they require RT.
Aims: The primary aim is to determine the antitumor activity of P, in terms of overall response rate (ORR), in two cohorts of MBC pts: BRCA+ (with known BRCA1/2 mutation), and unselected (with BRCA1/2 wild type or unknown mutation status). Secondary aims are to determine duration of response, clinical benefit (response or stable disease &gt; 3 months), PFS and one-year overall survival; to evaluate whether presence of BRCA1/2 mutation predicts response to P in MBC; to explore the activity of P in specific MBC subpopulations, safety, pharmacokinetics (PK), PK/pharmacodynamic correlations, and pharmacogenomics.
Planned enrollment is 117 evaluable pts: 53 in the BRCA+ cohort and 64 in the unselected cohort. P will be considered effective if confirmed objective response is achieved in ≥ 17 BRCA+ pts and ≥ 12 unselected patients. An ORR-based futility analysis will be conducted when 20 and 30 evaluable pts have been recruited in each cohort, respectively. If &lt;4 BRCA+ pts or &lt;3 unselected pts achieve response, recruitment into that cohort will be terminated. To date, 36 patients have been enrolled at 5 centers in 2 countries: 7 in the BRCA+ cohort and 29 in the unselected cohort. Additional sites are being recruited to participate.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-4-01.