Gregory A. Otterson

2602 Background: Triapine (T), an inhibitor of ribonucleotide reductase, enhances the activity of gemcitabine (G), and the synergism is most evident when the pre-exposure time to T is prolonged. In addition, fixed-dose rate G (FDR-G) seems to show improved clinical efficacy over standard dose G. Therefore, a phase I trial was initiated to assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), and therapeutic response of prolonged (24-hour) infusion of T, immediately followed by FDR-G. Methods: On any treatment day, T was given as a 24-hour infusion followed, in 0-2 hours, by FDR-G at 1000 mg/m² over 100 minutes. Initially, this combination was given on days 1 and 8 of a 21-day cycle, with starting dose of 120 mg for T (Arm A). Later, the study was amended after de-escalation to dose level - 2 on arm A, and the combination was given on days 1 and 15 of a 28-day cycle regimen with starting dose of T at 75 mg (Arm B). Steady state concentrations (C_SS) of T were measured for PK analysis. Results: The median number of prior systemic therapies was 3 (range 0-12). On Arm B, dose level 2 (90 mg triapine) was defined as the MTD, with DLTs including grade 4 thrombocytopenia, leukopenia, and neutropenia. Overall, the treatment was well tolerated with mild fatigue, nausea, and vomiting being the most common toxicities. Among 24 evaluable patients, 1 had a partial response and 12 (50%) had stable disease (SD) with a median time to progression of 3.5 months. At this point, 18 patient samples were evaluated for PK analysis (T doses ranging from 75 to 120 mg) and the mean C_SS was 492 ± 200 nM (range, 241-1,019 nM). PK profile is comparable with previously published data. Conclusions: In heavily pretreated patients with advanced solid tumors the combination of 24-hour infusion of T followed by FDR-G was generally well-tolerated. The MTD (recommended phase II dose, RP2D) was determined to be T 75 mg (24-hour infusion) immediately followed by G 1000 mg/m² (100-minute infusion), every 2 weeks of a 4-week cycle. There was evidence of interesting activity and we are currently in our 6-patient expansion phase at the MTD to further define preliminary activity and safety of the RP2D.

Background: Fenretinide is a semi-synthetic retinoid that has pro-apoptotic effects as a single agent and synergistically with chemotherapy in vitro. We performed this study to determine the toxicity of cisplatin, paclitaxel and fenretinide in patients with advanced cancer, the recommended phase II dose of these agents together, and the pharmacokinetics (PK) of fenretinide when administered with chemotherapy. Patients and methods: Fourteen patients (mean age 57.3) were assessable for pharmacokinetics, toxicity and response. Fenretinide was given orally in 2 divided daily doses for 7 days, starting 24 hours prior to cisplatin and paclitaxel. Cisplatin and paclitaxel were given in standard fashion. Cycles were repeated every 3 weeks. Cycle one fenretinide PK was obtained on days 2 and 8. Results: Dose limiting toxicity (Gr 3 diarrhea and Gr 4 neutropenia) was encountered in two patients during cycle one at 80/175/1800 mg/m² of cisplatin/paclitaxel/fenretinide (dose level 2), respectively. Seven patients received 2–8 cycles at the recommended level of 60/135/1800 (dose level 1). Severe cumulative toxicities included fatigue, nausea/vomiting, neuropathy, and dehydration. Two patients had a partial response and 4 patients had stable disease for up to 8 cycles. PK analysis demonstrated a reduction in fenretinide Cmax on day 8 compared to day 2, accompanying a decrease in AUC. Conclusions: Cisplatin/paclitaxel/fenretinide can be administered safely at 60/135/1800 mg/m² respectively on an every three-week schedule. This combination may have activity in a variety of tumors, however, the number of pills required complicates oral dosing of fenretinide, and limits the applicability of this regimen.

DNA methylation in the promoter of certain genes is associated with transcriptional silencing. Methylation affects gene expression directly by interfering with transcription factor binding and/or indirectly by recruiting histone deacetylases through methyl-DNA-binding proteins. In this study, we demonstrate that the human lung cancer cell line H719 lacks p53-dependent and -independent p21^Cip1 expression. p53 response to treatment with gamma irradiation or etoposide is lost due to a mutation at codon 242 of p53 (C→W). Treatment with depsipeptide, an inhibitor of histone deacetylase, was unable to induce p53-independent p21^Cip1 expression because the promoter of p21^Cip1 in these cells is hypermethylated. By analyzing luciferase activity of transfected p21^Cip1 promoter vectors, we demonstrate that depsipeptide functions on Sp1-binding sites to induce p21^Cip1 expression. We hypothesize that hypermethylation may interfere with Sp1/Sp3 binding. By using an electrophoretic mobility shift assay, we show that, although methylation within the consensus Sp1-binding site did not reduce Sp1/Sp3 binding, methylation outside of the consensus Sp1 element induced a significant decrease in Sp1/Sp3 binding. Depsipeptide induced p21^Cip1 expression was reconstituted when cells were pretreated with 5-aza-2′-deoxycytidine. Our data suggest, for the first time, that hypermethylation around the consensus Sp1-binding sites may directly reduce Sp1/Sp3 binding, therefore leading to a reduced p21^Cip1 expression in response to depsipeptide treatment.

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