International randomized phase 2 study on the addition of docetaxel to the combination of cisplatin and 5-fluorouracil in the induction treatment for nasopharyngeal carcinoma in children and adolescents.

PURPOSE: Nasopharyngeal carcinoma (NPC) is a rare but aggressive malignancy in children and adolescents. An international, randomized phase 2 trial was conducted to compare induction chemotherapy with docetaxel plus cisplatin and 5-fluorouracil (TPF) with cisplatin and 5-fluorouracil (PF) in NPC patients under the age of 21. METHODS: Patients with stage IIB-IV NPC were randomly assigned, in a 2:1 ratio, to receive TPF or PF 3-weekly for three cycles, followed by chemoradiotherapy. The primary endpoint was the complete response rate achieved with TPF or PF. Docetaxel pharmacokinetics was also evaluated. RESULTS: Seventy-five patients (median 16 years old) were randomized, with 50 assigned to the TPF group and 25 to the PF group. Overall response was assessed after induction treatment: one patient in the TPF group and none in the PF group had a complete response. Partial response was achieved in 76.0 and 80.0 % in the TPF and PF groups, respectively. The overall safety profile was consistent with findings in adults. The estimated 3-year overall survival rate was 78.0 % for the PF group and 85.7 % for the TPF group (median follow-up 3.3 years). Mean docetaxel area under the curve was 3.41 µg h/mL, compared with 3.51 µg h/mL seen in adult patients. CONCLUSION: This study demonstrated the feasibility of prospective randomized protocols, even for such rare tumors as pediatric NPC. Overall, there were no differences between the two treatment arms in terms of efficacy and toxicity. The pharmacokinetics of docetaxel in pediatric patients at 75 mg/m(2) was similar to those observed in adults.

United States-based practice patterns and resource utilization in advanced neuroendocrine tumor treatment.

AIM: To assess advanced neuroendocrine tumor (NET) treatment patterns and resource utilization by tumor progression stage and tumor site in the United States. METHODS: United States Physicians meeting eligibility criteria were provided with online data extraction forms to collect patient chart data on recent NET patients. Resource utilization and treatment pattern data were collected over a baseline period (after diagnosis and before tumor progression), as well as initial and secondary progression periods, with progression defined according to measureable radiographic evidence of tumor progression. Resource categories used in the analysis include: Treatments (e.g., surgery, chemotherapy, radiotherapy, targeted therapies), hospitalizations and physician visits, diagnostic tests (biomarkers, imaging, laboratory tests). Comparisons between categories of resource utilization and tumor progression status were examined using univariate (by tumor site) and multivariate analyses (across all tumor sites). RESULTS: Fifty-five physicians were included in the study and completed online data extraction forms using the charts of 110 patients. The physician sample showed a relatively even distribution for those affiliated with academic versus community hospitals (46% vs 55%). Forty (36.3%) patients were reported to have pancreatic NET (pNET), while 70 (63.6%) patients had gastrointestinal tract (GI)/Lung as the primary NET site. Univariate analysis showed the proportion of patients hospitalized increased from 32.7% during baseline to 42.1% in the progression stages. While surgeries were performed at similar proportions overall at baseline and progression, pNET patients, were more likely than GI/Lung NET patients to have undergone surgery during the baseline (33.3% vs 25.0%) and any progression periods (26.7% vs 23.4%). While peptide-receptor radionuclide and targeted therapy utilization was low across NET types and tumor stages, GI/Lung types exhibited greater utilization of these technologies compared to pNET. Chemotherapy utilization was also greater among GI/Lung types. Multivariate analysis results demonstrated that patients in first progression period were over 3 times more likely to receive chemotherapy when compared to baseline (odds ratio: 3.31; 95%CI: 1.46-7.48, P = 0.0041). Further, progression was associated with a greater likelihood of having a study physician visit [relative risk (RR): 1.54; 95%CI: 1.10-2.17, P = 0.0117], and an increased frequency of other physician visits (RR: 1.84; 95%CI: 1.10-3.10, P = 0.0211). CONCLUSION: Resource utilization in advanced NET in the United States is significant overall and data suggests progression has an impact on resource utilization regardless of NET tumor site.

Pharmacokinetics and in vitro and in vivo anti-tumor response of an interleukin-2-human serum albumin fusion protein in mice.

PURPOSE: Albuleukin fusion protein is a recombinant human interleukin-2 (rIL-2) genetically fused to recombinant human serum albumin (rHSA). The pharmacokinetics and pharmacologic activity of Albuleukin were examined in mice to determine whether the fusion protein had the immunomodulatory and anti-tumor properties of rIL-2 as well as a prolonged serum half-life due to the rHSA. METHODS: The effect of Albuleukin on lymphocyte proliferation, IL-2 receptor binding, and release of IFN-gamma from human NK cells were examined in vitro. For the pharmacokinetic analysis, Albuleukin and rIL-2 were administered intravenously (i.v.) and subcutaneously (s.c.) to BALB/c mice, both at a single dose of 500 microg/kg. The anti-tumor properties of Albuleukin were evaluated in a Renca tumor model in BALB/c mice and in a metastatic liver model of B16F10 melanoma in C57B1/6 mice. In the Renca tumor model, BALB/c mice were dosed intraperitoneally (i.p.) and s.c. with Albuleukin on days 12, 14, 16, 19, 21, and 23 and i.p. with rIL-2 daily for two periods of 5 days (days 10-14 and 17-21). In the B16 melanoma model, C57B1/6 mice were dosed s.c. with rIL-2 twice daily or Albuleukin every 48 h for 14 days. RESULTS: In vitro, Albuleukin induced the proliferation of primary human and mouse T cells and B cells and primary human NK cells, competed with rIL-2 for binding to the IL-2 receptors, and induced the production of IFN-gamma from primary human NK cells. The s.c. bioavailability of Albuleukin was about 45% relative to the i.v. dose. Plasma half-life was prolonged and ranged from 6 to 8 h with Albuleukin, compared to 19-57 min with rIL-2. Total clearance of Albuleukin was about 50-fold slower than that of rIL-2 after i.v. dosing. In vivo, Albuleukin suppressed the growth of Renca tumors and induced a dense infiltration of CD4+ and CD8+ T cells. Both Albuleukin and rIL-2 significantly reduced the tumor burden in mice with hepatic B16F10 metastases. Albuleukin significantly reduced the incidence of residual macroscopic hepatic tumors, resulting in improved survival relative to controls and rIL-2. CONCLUSION: Results from these studies suggest that the therapeutic efficacy of rIL-2 is improved in mice by prolonging its in vivo half-life through genetic fusion to albumin. Albuleukin, the fusion protein, had pronounced anti-tumor effects in Renca and hepatic melanoma tumor models without an increase in mortality. On the basis of its preclinical effects, Albuleukin was brought to the clinic to assess its therapeutic benefit in a variety of cancers.

An integrated functional genomics screening program reveals a role for BMP-9 in glucose homeostasis.

A coordinated functional genomics program was implemented to identify secreted polypeptides with therapeutic applications in the treatment of diabetes. Secreted factors were predicted from a diverse expressed-sequence tags (EST) database, representing >1,000 cDNA libraries, using a combination of bioinformatic algorithms. Subsequently, approximately 8,000 human proteins were screened in high-throughput cell-based assays designed to monitor key physiological transitions known to be centrally involved in the physiology of type 2 diabetes. Bone morphogenetic protein-9 (BMP-9) gave a positive response in two independent assays: reducing phosphoenolpyruvate carboxykinase (PEPCK) expression in hepatocytes and activating Akt kinase in differentiated myotubes. Purified recombinant BMP-9 potently inhibited hepatic glucose production and activated expression of key enzymes of lipid metabolism. In freely fed diabetic mice, a single subcutaneous injection of BMP-9 reduced glycemia to near-normal levels, with maximal reduction observed 30 hours after treatment. BMP-9 represents the first hepatic factor shown to regulate blood glucose concentration. Using a combination of bioinformatic and high-throughput functional analyses, we have identified a factor that may be exploited for the treatment of diabetes.

Albugranin, a recombinant human granulocyte colony stimulating factor (G-CSF) genetically fused to recombinant human albumin induces prolonged myelopoietic effects in mice and monkeys.

PURPOSE: Albugranin fusion protein is recombinant granulocyte colony stimulating factor (rG-CSF) genetically fused at its N-terminus to the C-terminus of recombinant serum human albumin and is expected to have a relatively long half-life compared with rG-CSF alone. In this study, the pharmacodynamics and pharmacokinetics of Albugranin were evaluated in BDF1 mice and cynomolgus monkeys. METHODS: Single doses of Albugranin (0.25-5 mg/kg) or Filgrastim (methionyl rG-CSF, 0.25, or 1.25 mg/kg) were administered subcutaneously (SC) to mice and multiple doses of Albugranin (25-100 microg/kg every 4 or 7 days) or Filgrastim (5 microg/kg daily) were administered SC for 14 days to monkeys for hematologic evaluation. For pharmacokinetics studies, mice were injected intravenously (IV) or SC with single doses of Albugranin (0.25-1.25 mg/kg) or Filgrastim (0.25 mg/ kg) and monkeys were injected SC with multiple doses of Albugranin (100-1,000 microg/kg once weekly for 5 weeks). Plasma levels of Albugranin and Filgrastim were measured by enzyme-linked immunosorbent assay. RESULTS: In mice, administration of Albugranin effectively increased the number of peripheral granulocytes and mobilized hematopoietic progenitor cells for up to 5 days. The magnitude and duration of this effect were dose-dependent. In contrast, administration of Filgrastim resulted in a small increase in both cell types on day 1 only. Albugranin administered to cynomolgus monkeys caused an increase in peripheral neutrophils, with a less prominent increase in peripheral monocytes. Albugranin-induced neutrophilia peaked 24 h following each dose administration. Administration of Filgrastim daily in monkeys resulted in moderate increases in neutrophils that were maximal on days 8-12 during the course of treatment. Compared with Filgrastim, Albugranin had a longer terminal half-life (t(1/2,term)) and mean residence time (MRT), and slower clearance (CL/F) in mice. The t(1/2,term), MRT, and CL/F of Albugranin following SC administration to BDF1 mice were 5.6-5.7 h, 16.7-20.7 h, and 6.37-12.2 mL/h/kg, respectively, compared with 2.54 h, 4.9 h, and 164 mL/h/kg, respectively for Filgrastim. In cynomolgus monkeys, the corresponding values of t(1/2,term), MRT, and CL/F for Albugranin were 7.73-133 h, 19.4-27.3 h, and 7.90-27.5 mL/h/kg, respectively, for doses of 100-1000 microg/kg. An exposure-response relationship that could be empirically described with a simple Emax model with baseline was found between day 15 absolute neutrophil count and area under the curve following the first dose in cynomolgus monkeys. CONCLUSION: The sustained activity of Albugranin in mice and monkeys demonstrated in these studies suggests that this agent could be given less frequently than Filgrastim to achieve similar therapeutic effects in patients.