GCS-100, a galectin-3 antagonist, in refractory solid tumors: A phase I study

Abstract

13023 Background: Galectin-3 is a galactoside-binding protein implicated in inhibition of apoptosis, and promotion of angiogenesis, metastasis, cellular proliferation by a direct association with oncogenic K-ras. Modified citrus pectin (MCP) is a complex carbohydrate derived from citrus fruit and is rich in galactoside residues. GCS-100 is an MCP capable of binding to and antagonizing galectin-3, resulting in anti-tumor activity in vitro and in vivo. Methods: GCS-100 was administered to patients with refractory solid tumors in a Phase I dose-escalating study using standard eligibility criteria. Objectives were to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK) and efficacy. Study drug was delivered by IV infusion over 1–2 hours for 5 consecutive days of a 21 day cycle. Results: 24 patients (17 F, 7 M, age 45–80 yo) were enrolled at 6 dose levels between 30–200 mg/m2. DLT and MTD for this dosing regimen were established at 200 mg/m2 and 160 mg/m2, respectively. DLT was a Grade 3 erythematous, maculopapular rash, resolving with systemic steroid treatment. There were no associated systemic findings, and the rash did not preclude further GCS-100 therapy. Skin biopsy revealed a vasculitis similar to findings seen in dog models. 9 other patients experienced Grade 1–2 rashes that did not require systemic treatment. The majority of adverse events (AEs) were Grade 1 or 2; the most common being nausea, vomiting, diarrhea, fatigue, fever and hyperglycemia. AEs thought to be related to treatment were rash, nausea and fatigue. Linear PKs were observed with a terminal half-life (t1/2) between 30–40 h and an effective t1/2 of 36 h. Peak GCS-100 concentrations reached 424 μg/mL at MTD. The median number of cycles was 4 (range 1–17). Best overall response per RECIST was stable disease observed in 16 patients with 6 of these patients on study for ≥ 6 months. Conclusion: Overall tolerability of GCS-100 was excellent with serum concentrations at MTD reaching levels associated with preclinical activity. Sustained periods of stable disease were achieved in patients with previously treated advanced solid tumors warranting Phase II studies. [Table: see text]