A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours

The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel. Patients with advanced solid tumours were treated with ispinesib (6–12 mg m−2) and docetaxel (50–75 mg m−2). Docetaxel was administered over 1 h followed by a 1-h infusion of ispinesib on day 1 of a 21-day schedule. At least three patients were treated at each dose level. Blood samples were collected during cycle 1 for PK analysis. Clinical response assessments were performed every two cycles using RECIST guidelines. Twenty-four patients were treated at four dose levels. Prolonged neutropaenia and febrile neutropaenia were dose limiting in six and two patients, respectively. The MTD was ispinesib 10 mg m−2 with docetaxel 60 mg m−2. Pharmacokinetic assessment demonstrated concentrations of ispinesib and docetaxel, consistent with published data from single agent studies of the drugs. Seven patients (six hormone refractory prostate cancer (HRPC), one renal cancer) had a best response of stable disease (⩾18 weeks). One patient with HRPC had a confirmed >50% prostatic-specific antigen decrease. The MTD for ispinesib and docetaxel was defined and the combination demonstrated an acceptable toxicity profile. Preliminary PK data suggest no interaction between ispinesib and docetaxel

Randomized trial of the combination of lomeguatrib and temozolomide compared with temozolomide alone in chemotherapy naive patients with metastatic cutaneous melanoma

PURPOSE: To evaluate tumor response, pharmacodynamic effects, and safety of a combination of lomeguatrib (LM), an O6-methylguanine DNA-methyltransferase (MGMT) inactivator, and temozolomide (TMZ), TMZ alone, and LM/TMZ after disease progression on TMZ alone in patients with advanced melanoma. PATIENTS AND METHODS: Patients with unresectable stage III or IV cutaneous melanoma who had no prior systemic chemotherapy were randomly assigned to receive either 40 to 80 mg LM and 125 mg/m2 TMZ or 200 mg/m2 TMZ on days 1 through 5 of each 28-day treatment cycle. Drugs were administered orally for up to six cycles of treatment. Patients on TMZ alone were offered LM/TMZ at progression, if fit enough to receive treatment. RESULTS: One hundred four patients were enrolled, with 52 in each trial arm. Twenty-seven TMZ-treated patients received LM/TMZ after progression on TMZ. Unexpectedly, analysis of tumor biopsies showed rapid recovery of MGMT after LM/TMZ with 40 mg/d LM. Therefore, doses of LM were escalated to 60 then 80 mg/d. Tumor response rates were 13.5% with LM/TMZ and 17.3% with TMZ alone. No patient responded to LM/TMZ having progressed through TMZ. Median time to disease progression was 65.5 days for LM/TMZ and 68 days for TMZ. All treatments were well tolerated, although hematologic and gastrointestinal adverse events were common. A higher incidence of hematological adverse events was observed in the LM/TMZ combination arm. CONCLUSION: The efficacy of LM and TMZ in the current dosing schedule is similar to that of TMZ alone. To maintain MGMT depletion in tumor dosing of LM needs to be continued beyond that of TMZ

Inflammation drives thrombosis after Salmonella infection via CLEC-2 on platelets

Thrombosis is a common, life-threatening consequence of systemic infection; however, the underlying mechanisms that drive the formation of infection-associated thrombi are poorly understood. Here, using a mouse model of systemic Salmonella Typhimurium infection, we determined that inflammation in tissues triggers thrombosis within vessels via ligation of C-type lectin-like receptor-2 (CLEC-2) on platelets by podoplanin exposed to the vasculature following breaching of the vessel wall. During infection, mice developed thrombi that persisted for weeks within the liver. Bacteria triggered but did not maintain this process, as thrombosis peaked at times when bacteremia was absent and bacteria in tissues were reduced by more than 90% from their peak levels. Thrombus development was triggered by an innate, TLR4-dependent inflammatory cascade that was independent of classical glycoprotein VI-mediated (GPVI-mediated) platelet activation. After infection, IFN-ã release enhanced the number of podoplanin-expressing monocytes and Kupffer cells in the hepatic parenchyma and perivascular sites and absence of TLR4, IFN-ã, or depletion of monocytic-lineage cells or CLEC-2 on platelets markedly inhibited the process. Together, our data indicate that infection-driven thrombosis follows local inflammation and upregulation of podoplanin and platelet activation. The identification of this pathway offers potential therapeutic opportunities to control the devastating consequences of infection-driven thrombosis without increasing the risk of bleeding

Triple therapy with clarithromycin, omeprazole, and amoxicillin for eradication of Helicobacter pylori in duodenal ulcer patients in Asia and Africa

Background: Studies assessing the efficacy of triple therapy containing clarithromycin and amoxicillin for the eradication of Helicobacter pylori infection and healing of duodenal ulcers in Asian and African countries are limited. Aim: To determine the efficacy and safety of 1-week triple therapy with omeprazole, amoxicillin and clarithromycin for eradicating H. pylori infection in patients with active duodenal ulcer living in Asian and African regions. Methods: This was an open-label, multicentre study in 11 centres in Asia and Africa. Patients with endoscopy-proven duodenal ulcer and who were H. pylori-positive were treated with clarithromycin 500 mg, omeprazole 20 mg, and amoxicillin 1000 mg, all given twice daily for 7 days. Upper endoscopy was repeated at week 6 to check for ulcer healing and H. pylori status. Results: A total of 117 patients were recruited. H. pylori eradication rates were 85% by per protocol analysis and 80% by intention-to-treat analysis. Ulcer healing was found in 94% of subjects (per protocol analysis). Clinical success, measured by change of pre-treatment ulcer symptoms, was strongly supported by complete resolution or improvement in 100% of the evaluable patients (per protocol analysis). Since treatment-related adverse events, when present, were largely mild or moderate, the triple therapy regimen was considered safe. Conclusion: Seven-day triple therapy with omeprazole, amoxicillin, and clarithromycin was efficacious for treating Asian and African patients with duodenal ulcer disease associated with H. pylori infection, and the treatment regimen was well-tolerated.Articl