RESUMEN
BACKGROUND: Atu027 is a liposomally formulated short interfering RNA with anti-metastatic activity, which silences the expression of protein kinase N3 (PKN3) in the vascular endothelium. This trial was designed to assess the safety, pharmacokinetics and efficacy of Atu027 in combination with gemcitabine in advanced pancreatic carcinoma (APC). METHODS: In total, 23 patients (pts) with inoperable APC were randomly assigned to gemcitabine combined with two different Atu027 schedules (0.235 mg/kg once weekly vs. 0.235 mg/kg twice weekly). ClinicalTrials.gov Identifier: NCT01808638. RESULTS: The treatment was well-tolerated. There were Grade 3 adverse events (AEs) in 9/11 pts (arm 1) and 11/12 pts (arm 2), while Grade 4 AEs were reported for two pts in each arm. The AEs were mainly laboratory abnormalities without clinical significance. The median progression-free survival reached statistical significance in patients who had metastatic disease (1.6 vs. 2.9 months, p = 0.025). Disease control during treatment was achieved in 4/11 pts (arm 1) and in 7/12 pts (arm 2). Pts in arm 1 experienced stable global health status while pts in arm 2 reported improvement. CONCLUSIONS: Combining Atu027 with gemcitabine is safe and well tolerated. In pts with metastatic APC, twice-weekly Atu027 is associated with significantly improved outcomes. Our clinical results support the significant involvement of the vascular endothelium in the spread of cancer, and thus the further investigation of its target role.
RESUMEN
BACKGROUND: Studies have demonstrated that body surface area-based dosing of chemotherapy drugs leads to significant individual exposure variability, with a substantial risk of under- or overdosing. The present study was initiated to validate the use of therapeutic drug management (TDM) to personalize 5-fluorouracil (5-FU) dosing in patients with metastatic colorectal cancer treated in routine clinical practice. PATIENTS AND METHODS: A total of 75 patients with metastatic colorectal cancer from 8 German medical centers received ≤ 6 administrations of infusional 5-FU according to the AIO (folinate, 5-FU; n = 16), FOLFOX6 (leucovorin calcium [folinic acid], 5-FU, and oxaliplatin; n = 26), or FUFOX (oxaliplatin plus 5-FU/folinic acid; n = 33) regimen. Initial infusional 5-FU dosing for all patients was determined by the BSA. Individual 5-FU exposure (area under the curve [AUC]) was measured using an immunoassay of a blood sample taken during each infusion. To achieve a target AUC of 20 to 30 mg × h/L, subsequent infusional 5-FU doses were adjusted according to the previous cycle's 5-FU AUC. The primary objective was to confirm that TDM of infusional 5-FU resulted in an increased proportion of patients in the target AUC range at the fourth versus the first administration. The secondary objective was to determine whether 5-FU TDM reduced the treatment-related toxicities compared with the historical data. RESULTS: The average 5-FU AUC at the first administration was 18 ± 6 mg × h/L, with 64%, 33%, and 3% of the patients below, within, or above the target AUC range, respectively. By the fourth administration, the average 5-FU AUC was 25 ± 7 mg × h/L (P < .001), with 54% of patients within the target 5-FU AUC range (P = .0294). The incidence of 5-FU-related grade 3 and 4 diarrhea (4.6%), nausea (3.4%), fatigue (0.0%), and mucositis (0.2%) was reduced compared with the historical data, despite 55% of the patients receiving increased doses. CONCLUSION: Personalization of 5-FU dosing using TDM in routine clinical practice resulted in significantly improved 5-FU exposure and suggested a lower incidence of 5-FU-related toxicities.
