A phase 1 study of nevanimibe HCl, a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, in adrenocortical carcinoma.

Background Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with very limited treatment options. Nevanimibe HCl (formerly ATR-101), a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, has been shown in nonclinical studies to decrease adrenal steroidogenesis at lower doses and to cause apoptosis of adrenocortical cells at higher doses. Methods This phase 1, multicenter, open-label study assessed the safety and pharmacokinetics (PK) of nevanimibe in adults with metastatic ACC (NCT01898715). A "3 + 3" dose-escalation design was used. Adverse events (AEs), PK, and tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were evaluated every 2 months. Results 63 patients with metastatic ACC, all of whom had previously failed systemic chemotherapy and only 2 of whom were mitotane-naïve, were dosed with oral nevanimibe at doses ranging from 1.6 mg/kg/day to 158.5 mg/kg/day. Subjects who did not experience tumor progression or a dose-limiting toxicity (DLT) could continue to receive additional cycles. No patients experienced a complete or partial response; however, 13 of the 48 (27%) patients who underwent imaging at 2 months had stable disease (SD), and 4 of these had SD > 4 months. In addition, drug-related adrenal insufficiency, considered a pharmacologic effect of nevanimibe, was observed in two patients. The most common treatment-emergent AEs were gastrointestinal disorders (76%), including diarrhea (44%) and vomiting (35%). A maximum tolerated dose (MTD) could not be defined, as very few dose-limiting toxicities (DLTs) occurred. Because the large number of tablets required at the highest dose (i.e., ~24 tablets/day) resulted in low-grade gastrointestinal adverse effects, a maximum feasible dose of 128.2 mg/kg/day was established as a dose that could be taken on a long-term basis. Conclusions This study demonstrated the safety of nevanimibe at doses of up to ~6000 mg BID. As the total number of tablets required to achieve an MTD exceeded practical administration limits, a maximum feasible dose was defined. Given that the expected exposure levels necessary for an apoptotic effect could not be achieved, the current formulation of nevanimibe had limited efficacy in patients with advanced ACC.

Complicated skin and skin-structure infections and catheter-related bloodstream infections: noninferiority of linezolid in a phase 3 study.

BACKGROUND: Catheter-related bloodstream infection (CRBSI) causes substantial morbidity and mortality, but few randomized, controlled studies have been conducted to guide therapeutic interventions. METHODS: To determine whether linezolid would be noninferior to vancomycin in patients with CRBSI, we conducted an open-label, multicenter, comparative study. Patients with suspected CRBSI were randomized to receive linezolid or vancomycin (control group). The primary end point was microbiologic outcome at test of cure 1-2 weeks after treatment, as assessed by step-down procedure. The first analysis population was complicated skin and skin structure infection (cSSSI) in patients with suspected CRBSI; patients with CRBSI were analyzed if noninferiority criteria (lower bound of the 95% confidence interval [CI] not outside -15%) were met. RESULTS: Noninferiority criteria were met for cSSSI (microbiologic success rate for linezolid recipients, 89.6% [146 for 163 patients]; for the control group, 89.9% [134 of 149]; 95% CI, -7.1 to 6.4) and CRBSI (for linezolid recipients, 86.3% [82 of 95]; for the control group, 90.5% [67 of 74]; 95% CI, -13.8 to 5.4). The frequency and severity of adverse events were similar between groups. Mortality rates were 10.4% for linezolid recipients (28 of 269 patients) and 10.1% for control subjects (26 of 257) in the modified intent-to-treat population (i.e., all patients with gram-positive baseline culture) through test of cure, and they were 21.5% for linezolid recipients (78 of 363) and 16.0% for the control group (58 of 363; 95% CI, -0.2 to 11.2) for all treated patients through poststudy treatment day 84. CONCLUSIONS: Linezolid demonstrated microbiologic success rates noninferior to those for vancomycin in patients with cSSSIs and CRBSIs caused by gram-positive organisms. Patients with catheter-related infections must be carefully investigated for the heterogeneous underlying causes of high morbidity and mortality, particularly for infections with gram-negative organisms.

Combined retrospective analysis of seven phase II and III trials of the efficacy of linezolid in the treatment of pneumonia caused by multidrug-resistant Streptococcus pneumoniae.

BACKGROUND: Antimicrobial resistance among Streptococcus pneumoniae is of concern. Up to 30% of pneumococcal isolates worldwide are multidrug resistant. OBJECTIVE: The objective of this analysis was to assess the effectiveness of linezolid for the treatment of pneumonia caused by S pneumoniae, including multidrug-resistant S pneumoniae (MDRSP). METHODS: Data from 7 Phase II and III clinical trials that assessed the efficacy of linezolid in community- or hospital-acquired pneumonia were pooled. Adults and children (aged ≤12 years) received linezolid 600 mg and 10 mg/kg, respectively, IV or PO q12h for 7 to 14 days, with the exception of patients with documented bacteremia who could be treated for up to 28 days. Patients with a confirmed baseline isolate of S pneumoniae, including MDRSP, were assessed for clinical and microbiological outcomes. MDRSP was defined as an isolated strain of S pneumoniae that was resistant to ≥3 classes of antibiotics. Clinical cure was defined as the resolution of clinical signs and symptoms of pneumonia compared with baseline, with either improvement or absence of progression of abnormalities on chest radiography. Microbiological eradication was defined as documented or presumed eradication at the test-of-cure (TOC) visit. Results from patients with indeterminate or missing outcomes at TOC were not included in the analyses. RESULTS: Of the patients with no bacteremia and treated with linezolid, 19 adults had MDRSP and 165 had non-MDRSP, and 3 children had MDRSP and 7 had non-MDRSP. Clinical cure and microbiological eradication rates were not significantly different between those infected with an MDRSP or non-MDRSP pathogen, respectively, in adults (16/19 [84%] and 150/164 [91%]) and children (3/3 [100%] and 7/7 [100%]). CONCLUSION: Linezolid was efficacious for the treatment of pneumonia caused by S pneumoniae, including multidrug-resistant strains.