A pilot trial of oral topotecan (TPT) in patients with refractory advanced solid neoplasms expressing HIF-1α.

Abstract

e13518 Background: HIF-1α is a transcription factor that mediates tumor angiogenesis and survival. Previous studies have demonstrated that daily administration of topotecan (TPT) - a topoisomerase-1 inhibitor - inhibits HIF-1α expression, angiogenesis, and tumor growth in human xenograft models. The primary aim of this study is to investigate whether TPT inhibits HIF-1α expression in human cancers. Methods: TPT was administered orally at 1.6 mg/m2 daily × 5 for 2 weeks, of a 28-day cycle, to patients with advanced solid tumors expressing HIF-1α in at least 10% of tumor cells. Tumor biopsies were obtained before and after 2 cycles of TPT. The primary endpoint was modulation of HIF-1α expression by IHC. mRNA expression of HIF-1α target genes was assessed by real-time PCR. Radiologic correlative studies (comprising 18FDG-PET, to assess tumor metabolism, and DCE-MRI, to assess blood flow and permeability) were obtained at baseline, after 2 weeks of therapy and post cycle 2. The statistical significance of the difference in HIF-1α values was determined by a Wilcoxon signed rank test. Results: 15 patients, median age 54 (range 25-70), were treated, with n=7 undergoing paired tumor biopsies and being evaluable for the primary endpoint. Disease types: melanoma, colon (n=3), ovarian (n=2), sarcoma (n=2), lung, bladder, adrenocortical (n=2), anal, pancreatic, head and neck. Three patients received TPT 1.6 mg/m2before protocol amended to 1.2 mg/m2because of dose-limiting G3 neutropenia and G4 thrombocytopenia. The median number of cycles received was 2. Only 5 patients proceeded beyond 2 cycles (maximum 6). The median reduction in HIF-1α by IHC was -7.5% (range -50.0 to +5.0%; p=0.16). 6 of 7 patients exhibited declines in K trans on DCE-MRI (p=0.13) and 5 of 7 exhibited Kep changes (p=0.45). One patient obtained a PR and 2 patients had SD. Conclusions: This is the first study evaluating HIF-1α modulation in tumor tissue as a primary clinical trial endpoint in cancer patients. Whilst trends in both HIF-1α modulation and radiologic correlates (kTrans alteration on DC-MRI) were seen, these were not statistically significant due to low patient numbers. No significant financial relationships to disclose.