ABSTRACT
PURPOSE: Phase I dose-escalation study to determine the toxicity and maximum tolerated dose (MTD) of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, administered on a twice weekly schedule in patients with advanced cancer. EXPERIMENTAL DESIGN: 17-DMAG was administered as a 1- to 2-h infusion twice weekly in 4-week cycles. An accelerated titration design was followed until toxicity was observed, at which point standard dose-escalation proceeded. MTD was defined as the dose at which no more than one of the six patients experienced a dose-limiting toxicity (DLT). Pharmacokinetics were assessed, and Hsp70 mRNA, whose gene product is a chaperone previously shown to be upregulated following the inhibition of Hsp90, was measured in peripheral blood mononuclear cells (PBMCs). RESULTS: A total of 31 patients received 92 courses of treatment. The MTD was 21mg/m(2)/d; 20 patients were enrolled at this dose level. Nine patients had stable disease for a median of 4 (range 2-22) months. Both C(max) and AUC increased proportionally with dose. The most common toxicities were grade 1 or 2 fatigue, anorexia, nausea, blurred vision and musculoskeletal pain. DLTs were peripheral neuropathy and renal dysfunction. Expression of Hsp70 mRNA in PBMCs was highly variable. CONCLUSION: Twice-weekly i.v. infusion of 17-DMAG is well tolerated, and combination phase I studies are warranted.
Subject(s)
Antineoplastic Agents/administration & dosage , Benzoquinones/administration & dosage , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Lactams, Macrocyclic/administration & dosage , Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Benzoquinones/adverse effects , Benzoquinones/pharmacokinetics , Drug Administration Schedule , Female , HSP70 Heat-Shock Proteins/metabolism , Humans , Infusions, Intravenous , Lactams, Macrocyclic/adverse effects , Lactams, Macrocyclic/pharmacokinetics , Leukocytes, Mononuclear/metabolism , Male , Maximum Tolerated Dose , Middle Aged , Young AdultABSTRACT
Pancreatic cancer is a devastating disease often associated with other comorbid conditions that can complicate treatment and impact quality of life. Obstruction of the bile duct by pancreatic cancer can cause bile stasis and infection, a condition known as acute ascending cholangitis (AAC). Signs and symptoms include fever, pain, and increased serum bilirubin levels. Serious complications (e.g., sepsis, death) may be avoided with careful and timely patient assessment, prompt initiation of antibiotics, and drainage of the biliary system. AAC may present quickly, and patients can deteriorate rapidly. Nurses need to be aware of the clinical manifestations of AAC to ensure timely treatment of this sometimes fatal event.
