A Phase I Dose Escalation Study of Steroid Sulfatase Inhibitor BN83495/STX64 in Postmenopausal Women with ER Positive Breast Cancer.
Authors: Coombes R. , Schmid P. , Isambert N. , Soulié P. , Cardoso F. , Besse-Hammer T. , Lesimple T. , Slosman D. , Kornowski A. , Fohanno V. , Fumoleau P. 
Published: December 2010

Background: BN83495/STX64 is an irreversible steroid sulfatase (STS) inhibitor blocking the hydrolysis of sulfated estrone E1S and dehydroepiandrosterone DHEAS to their unsulfated active forms and thereby preventing conversion to Estradiol (E2) and Androstenediol (adiol), respectively. A phase I dose escalation study was conducted in post-menopausal women (PW) with ER+ metastatic breast cancer (MBC). The aim of the study was to determine the optimal biological dose (OBD) defined as the dose at which STS inhibition in peripheral blood mononuclear cells (PBMCs) ≥ 95% after 7 (D7) and 28 (D28) days of repeated oral daily administration and which also showed a maximal reduction in plasma E2 and adiol levels at D28 with no drug-related Grade 3 (Gr 3) or higher toxicity. Pharmacokinetics (PK), safety, tolerability and anti-tumour activity of BN83495 were also assessed.Methods: Patients (pts) had received at least one line of hormone therapy (HT) and at most 2 lines of chemotherapy (CT) in the adjuvant and/or advanced disease setting. Three to six pts were recruited into each of 5 sequential dose cohorts (1, 5, 20, 40 and 80 mg). The steady-state PK of BN83495 were assessed in all pts. Serum concentrations of E2 and Adiol were determined pre-dose, on D7 and D28 by HPLC-MS/MS analysis. Objective antitumor response was assessed according to RECIST criteria (version 1.0).Results: 29 pts were evaluable for safety. All had received one prior HT for MBC (Aromatase Inhibitors (AI): 86.2% Tamoxifen: 13.8%) and 12 (41.4%) received 2 lines of HT for MBC. BN83495 was well tolerated at doses up to 40 mg. Gr 3 fatigue with positive rechallenge was observed after 3 months of treatment in one pt at 80 mg. The main toxicity was dry skin Gr≤2 (N=12) that was observed in some pts in all cohorts from 20 mg up and was treated with emollient creams. Other toxicities included Gr 1/2 fatigue (N=6), hot flushes (N=3) and nausea (N=2).27 pts were evaluable for efficacy and hormone and STS evaluation. 14 pts received ≥ 3 months treatment. There were 3 SD ≥ 6 months, one each at 13 months (#020, 40 mg), 8 months (#015, 20 mg) and 7 months (#027, 80 mg, hormone resistant pt). Biopsy-proven erythematous skin infiltration in one patient (#027) was no longer visible after 1 month of treatment. Nearly complete STS enzyme inhibition was observed at all doses. The OBD was determined to be 40 mg. At this dose, mean Adiol reduction was -54.0% (-74.0—34.0) and E2 was –27.4% (-47.6- -7.2).An additional cohort (6 pts) was enrolled at 40 mg and FDG PET-scan was performed. Decrease &gt;25% in hypermetabolic volume was noted in 2/5 lesions in 2 patients for whom data are available.Conclusion: BN83495 was well tolerated. Disease stabilizations ≥ 6 months were observed in this heavily pre-treated population including in one hormone resistant pt. The OBD was determined to be 40 mg. Complete FDG-PET scan data will be presented. Based on data obtained so far, BN83495 has shown activity. The study is ongoing.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4097.