Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study.

BACKGROUND: This phase I/II study in patients with metastatic castration-resistant prostate cancer (mCRPC) explored ipilimumab as monotherapy and in combination with radiotherapy, based on the preclinical evidence of synergistic antitumor activity between anti-CTLA-4 antibody and radiotherapy. PATIENTS AND METHODS: In dose escalation, 33 patients (≥6/cohort) received ipilimumab every 3 weeks × 4 doses at 3, 5, or 10 mg/kg or at 3 or 10 mg/kg + radiotherapy (8 Gy/lesion). The 10-mg/kg cohorts were expanded to 50 patients (ipilimumab monotherapy, 16; ipilimumab + radiotherapy, 34). Evaluations included adverse events (AEs), prostate-specific antigen (PSA) decline, and tumor response. RESULTS: Common immune-related AEs (irAEs) among the 50 patients receiving 10 mg/kg ± radiotherapy were diarrhea (54%), colitis (22%), rash (32%), and pruritus (20%); grade 3/4 irAEs included colitis (16%) and hepatitis (10%). One treatment-related death (5 mg/kg group) occurred. Among patients receiving 10 mg/kg ± radiotherapy, eight had PSA declines of ≥50% (duration: 3-13+ months), one had complete response (duration: 11.3+ months), and six had stable disease (duration: 2.8-6.1 months). CONCLUSIONS: In mCRPC patients, ipilimumab 10 mg/kg ± radiotherapy suggested clinical antitumor activity with disease control and manageable AEs. Two phase III trials in mCRPC patients evaluating ipilimumab 10 mg/kg ± radiotherapy are ongoing. ClinicalTrials.gov identifier: NCT00323882.

Review of the safety of diclofenac/misoprostol.

The safety of a fixed combination of diclofenac 50mg/misoprostol 200 micrograms has been evaluated in clinical trials involving almost 2000 patients. Short term trials have been conducted in patients with osteoarthritis (n = 1032) and rheumatoid arthritis (n = 685) over 1 or 3 months. Patients randomly received either diclofenac alone or diclofenac/misoprostol. In both groups, the most frequently reported adverse events were gastrointestinal in nature, with abdominal pain reported most frequently (in 22.6% of patients receiving diclofenac/misoprostol and 19.8% of patients receiving diclofenac), followed by diarrhoea (19.5 vs 11.3%), nausea (11.0 vs 6.5%) and dyspepsia (10.6 vs 7.8%). The most frequent nongastrointestinal adverse event was headache, which occurred in 7.9% of diclofenac/misoprostol recipients and 9.3% of diclofenac recipients. Although diclofenac/misoprostol was associated with a slightly higher prevalence of adverse events than diclofenac in these studies, the majority were of mild or moderate severity, and the treatment groups were similar as regards the number of patient withdrawals resulting from adverse events. An interim analysis of the results of an ongoing trial of longer term administration of diclofenac/misoprostol (for up to 24 months) has been conducted. In this uncontrolled study, patients with rheumatoid arthritis, osteoarthritis or ankylosing spondylitis received diclofenac/misoprostol for up to 24 months; to date 1003 patients have been enrolled and treatment has been continued for 6, 12, 18 and 24 months in 640, 327, 108 and 13 patients, respectively. As in the short term trials, the adverse events reported most commonly in this study have been predominantly gastrointestinal.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of combination therapy with dutasteride plus tamsulosin on clinical outcomes in men with symptomatic BPH: 4-year post hoc analysis of European men in the CombAT study.

CombAT (Combination of Avodart and Tamsulosin) was a randomised, double-blind study in men (n=4844) aged ≥ 50 years with a clinical diagnosis of BPH. Patients were randomised to daily tamsulosin 0.4 mg, dutasteride 0.5 mg or both for 4 years. The primary endpoint was time to acute urinary retention (AUR) or BPH-related surgery. Secondary endpoints included BPH clinical progression, symptoms and maximum urinary flow rate. A post hoc analysis of data from the European subgroup was conducted. A total of 2925 men were randomised to treatment in Europe as part of CombAT (tamsulosin, n=972; dutasteride, n=970; combination, n=983). Combination therapy significantly reduced the relative risk of AUR or BPH-related surgery compared with either monotherapy at 4 years, and also significantly reduced the risk of BPH clinical progression. Combination therapy also provided significantly greater symptom improvement than either monotherapy at 4 years. Safety and tolerability of dutasteride plus tamsulosin was consistent with previous experience of this combination and with the monotherapies. These data provide further evidence to support the use of long-term combination therapy (dutasteride plus tamsulosin) in men with moderate-to-severe lower urinary tract symptoms because of BPH and prostatic enlargement. The results in the European subgroup are generally consistent with those in the overall study population.

Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Pediatric AIDS Clinical Trials Group Protocol 250 Team.

The safety, toxicity, and pharmacokinetics of intrapartum and early newborn nevirapine were evaluated in 17 human immunodeficiency virus type 1-infected women in labor and their newborns. No adverse effects of nevirapine were noted in any study mothers or infants. Following maternal dosing with 200 mg during labor, concentrations exceeding 100 ng/mL (10 times the in vitro IC50) were achieved in the newborns. Nevirapine elimination was prolonged in both mothers and infants, with median half-lives ranging from 36.8 to 65.7 h. Administration of 200 mg orally to the mothers in labor and of a single 2-mg/kg oral dose to the infants at 48-72 h after birth maintained serum concentrations in the infants > 100 ng/mL through 7 days of life.