Patients (n ؍ 409) with severe skin and soft tissue infections (SSTIs) were randomized to receive clinafloxacin or piperacillin-tazobactam (plus optional vancomycin for methicillin-resistant cocci), administered intravenously, with the option to switch to oral medication. Most patients had cellulitis, wound infections, or diabetic foot infections. Staphylococcus aureus, Enterococcus faecalis, and Pseudomonas aeruginosa were the most common baseline pathogens. Fewer baseline pathogens were resistant to clinafloxacin (1.8%) than to piperacillin-tazobactam (6.2%) (P ؍ 0.001). The clinafloxacin and piperacillin-tazobactam groups did not differ significantly in clinical cure rates (68.8 and 65.2%, respectively) or microbiologic eradication rates (61.5 and 57.2%). Clinafloxacin yielded higher eradication rates for all three of the most common pathogenic species, although no differences were statistically significant. Within the power of this study, the overall frequency of adverse events was similar (P ؍ 0.577) in the two treatment groups. Drug-associated adverse events (P ؍ 0.050) and treatment discontinuations (P ؍ 0.052) were marginally more frequent in the clinafloxacin group, primarily due to phototoxicity in outpatients receiving clinafloxacin. Although most cases of phototoxicity were mild to moderate, four cases were reported as severe. In summary, clinafloxacin monotherapy was equivalent in effectiveness to therapy with piperacillin-tazobactam plus optional vancomycin in the treatment of hospitalized patients with severe SSTIs.Skin and soft tissue infections (SSTIs), such as spontaneous lymphangitis or cellulitis, and especially complicated infections, such as wound and surgical infections or diabetic foot ulcers, often require hospitalization and intravenous (i.v.) antibacterial treatment. These infections are caused by a mixture of aerobic and anaerobic organisms and are responsible for increased morbidity, prolonged hospital stay, and increased health care costs (3,13,19).Staphylococcus aureus and streptococci; gram-negative bacteria such as Pseudomonas aeruginosa, Enterobacteriaceae, and Enterococcus spp.; and anaerobes such as Bacteroides fragilis are frequently isolated (8,12,13,18,32 Frequently used antimicrobial agents have included expandedspectrum cephalosporins (e.g., cefoxitin, cefotetan, cefmetazole), imipenem-cilastatin, -lactam--lactamase inhibitor combinations (e.g., piperacillin-tazobactam, ticarcillin-clavulanate), and fluoroquinolones (13,14,15,18,20,35). However, emerging resistance, particularly among S. aureus, P. aeruginosa, and enterococci, is making the choice of treatment increasingly more difficult (23).Clinafloxacin is an extended-spectrum fluoroquinolone antibacterial that is bactericidal against S. aureus, including methicillin-resistant strains, and most strains of ciprofloxacinresistant S. aureus (7,33). Like other fluoroquinolones, clinafloxacin has activity against Pseudomonas spp. and the Enterobacteriaceae; the MICs of clinafloxacin at which 90% of isolates are ...
Transmembrane receptor tyrosine kinases have been shown to play an important role in the modulation of growth factor signaling and regulation of key cellular processes. The erbB receptor family is part of the receptor tyrosine kinase superfamily and consists of four members, erbB-1, erbB-2, erbB-3, and erbB-4. A majority of solid tumors express one or more members of this receptor family, and coexpression of multiple erbB receptors leads to an enhanced transforming potential and worsened prognosis. The erbB receptor family has been shown to play an important role in both the development of the normal breast and in the pathogenesis and progression of breast cancer. Receptor overexpression has also been shown to be a negative prognostic indicator and to correlate with both tumor invasiveness and a lack of responsiveness to standard treatment. Clinically, blockade of the erbB-2 receptor has recently been shown to provide benefit in a subset of chemotherapy-resistant breast cancer patients. CI-1033 is an orally available pan-erbB receptor tyrosine kinase inhibitor that, unlike the majority of receptor inhibitors, effectively blocks signal transduction through all four members of the erbB family. In addition, it blocks the highly tumorigenic, constitutively activated variant of erbB-1, EGFRvIII, and inhibits downstream signaling through both the Ras/MAP kinase, and PI-3 kinase/AKT pathways. CI-1033 is also unique in that it is an irreversible inhibitor, thereby providing prolonged suppression of erbB receptor-mediated signaling. Preclinical data have shown CI-1033 to be efficacious against a variety of human tumors in mouse xenograft models, including breast carcinomas. In a phase I study, CI-1033 has been shown to have an acceptable side effect profile at potentially therapeutic dose levels and demonstrates evidence of target biomarker modulation. Antitumor activity has also been observed in this study, including one partial clinical response and stable disease in over 30% of patients, including one patient with heavily pretreated breast cancer. By virtue of its pan-erbB receptor inhibition and potent interruption of downstream mitogenic signaling pathways, CI-1033 may have clinical activity for solid tumors that overexpress one erbB family member, coexpress multiple members of the erbB family, or express a constitutively activated, mutated form of these receptors. Given the important role of the erbB receptor family in the pathogenesis and progression of breast cancer, an irreversible pan-erbB inhibitor like CI-1033 could have an important role to play in the future treatment of breast cancer.
CI-1033 had modest activity in unselected NSCLC patients but did not meet its primary end point. Future studies should focus on identifying methods of patient selection.
Purpose: To determine the maximum tolerated dose of administrating CI-1033, an oral 4-anilinoquinazoline that irreversibly inhibits the tyrosine kinase domain of all erbB subfamilies, on an intermittent schedule, and assess the interaction of CI-1033 with food on the pharmacokinetic behavior.Experimental Design: Escalating doses of CI-1033 from a dose level of 300 mg/day for 7 days every other week were administered to patients with advanced solid malignancies. Plasma concentration-time data sets from all evaluable patients were used to develop a population pharmacokinetic model. Noncompartmental methods were used to independently assess the effect of a high-fat meal on CI-1033 absorption and bioavailability.Results: Twenty-four patients were treated with 69 twenty-eight day courses. The incidence of unacceptable toxicity, principally diarrhea and skin rash, was observed at the 300 mg/day dose level. At the 250 mg/day level, toxicity was manageable, and protracted administration was feasi- Conclusions: The recommended dose on this schedule is 250 mg/day. Its tolerability and the biological relevance of concentrations achieved at the maximal tolerated dose warrant consideration of disease-directed evaluations. This intermittent treatment schedule can be used without regard to meals.
Purpose:To determine the tolerability and pharmacokinetics of oral CI-1033, a pan-erbB tyrosine kinase inhibitor, administered over 14 consecutive days of a 21-day cycle. Design: Phase 1, multicenter trial involving patients with solid tumors that are refractory to standard therapy. CI-1033 was administered initially at 300 mg/day to a minimum cohort of three patients. Dose escalation proceeded at V40% increments. Patients were evaluated for toxicity, pharmacokinetic profile, and evidence of response. Results: Thirty-two patients entered the trial and were evaluable for safety assessment. Doselimiting toxicity (diarrhea, rash, and/or anorexia) occurred at the 560 mg dose level; the maximum tolerated dose was 450 mg. No patients achieved objective responses and six patients achieved stable disease. Plasma CI-1033 concentrations increased with increasing dose. CI-1033 was not eliminated in urine to any appreciable extent. Conclusions: CI-1033 is suitable for phase 2 testing at the 450 mg/day dose level when administered for 14 days in a 21-day cycle. The pharmacokinetic profile is consistent with biologically relevant plasma concentrations over the dosing interval.CI-1033, an orally available 4-anilinoquinazoline derivative, is a highly potent and selective pan-erbB tyrosine kinase inhibitor that irreversibly blocks intracellular signaling through all members of the erbB receptor family [erbB-1 (epidermal growth factor receptor, EGFR), erbB-2 (HER-2/neu), erbB-3, erbB-4, and the erbB-1 truncate, EGFR vIII; refs. (1 -3)]. The erbB family of tyrosine-specific protein kinases is involved in the regulation of many malignant cell functions, including proliferation, differentiation, survival, induction of angiogenesis, metastatic spread, and resistance to chemotherapy and radiotherapy (4,5). Over 90% of all solid tumors express at least one member of the erbB receptor family (6 -8) and erbB receptor/ligand overexpression correlates with poor prognosis and reduced survival in patients with a variety of cancers including breast cancer, melanoma, and head and neck cancer (3, 9 -15). In vitro work also shows that overexpression of two or more erbB family members has been correlated with a further worsening of prognosis (16 -20).Numerous anticancer therapeutic approaches to blocking signal transduction through erbB-mediated pathways have been attempted, including antibodies targeting the erbB extracellular domain, small molecule tyrosine kinase inhibitors specifically targeting one or more erbB family members, antisense oligonucleotides, ligand-linked toxins, and immunotoxin conjugates (21 -25). Trastuzumab (Herceptin), a monoclonal antibody that specifically targets the erbB-2 extracellular domain, was the first effective clinical translation of this approach and is approved for the treatment of erbB-2 overexpressing metastatic breast cancer-as second-line monotherapy and as first-line therapy when combined with paclitaxel (26 -31). More recently, an erbB-1-specific monoclonal antibody, cetuximab (Erbitux, IMC-C225...
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