Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCa), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases. In mice, midostaurin slows growth and delays lung metastasis of melanoma cell lines. We aimed to test midostaurin's safety, efficacy and biologic activity in a Phase IIA clinical trial in patients with metastatic melanoma. Seventeen patients with advanced metastatic melanoma received midostaurin 75 mg p.o. t.i.d., unless toxicity or disease progression supervened. Patient safety was assessed weekly, and tumour response was assessed clinically or by CT. Tumour biopsies and plasma samples obtained at entry and after 4 weeks were analysed for midostaurin concentration, PKC activity and multidrug resistance. No tumour responses were seen. Two (12%) patients had stable disease for 50 and 85 days, with minor response in one. The median overall survival was 43 days. Seven (41%) discontinued treatment with potential toxicity, including nausea, vomiting, diarrhoea and/or fatigue. One patient had 450% reduction in PKC activity. Tumour biopsies showed two PKC isoforms relatively insensitive to midostaurin, out of three patients tested. No modulation of multidrug resistance was demonstrated. At this dose schedule, midostaurin did not show clinical or biologic activity against metastatic melanoma. This negative trial reinforces the importance of correlating biologic and clinical responses in early clinical trials of targeted therapies.

Cancer patients prefer shorter bisphosphonate infusions-and at home, where practical. Regular Z 4 mg infusions appear to be safe in these patients, with routine monitoring of serum creatinine. Using Z rather than P could save busy cancer centres time and improve patient satisfaction.

INTRODUCTION: Proteasome inhibitors (PI) and histone deacetylase inhibitors (HDACi) have demonstrated synergistic pre-clinical activity in multiple myeloma (MM). The goals of this study were to evaluate this combination regimen’s clinical activity and adverse events, including thrombocytopenia (TCP) since both drug classes may cause transient TCP. We performed an open label, single-centre, single-arm, phase I/II, dose-escalation trial of bortezomib, dexamethasone and romidepsin (depsipeptide) in relapsed or refractory MM. This is the first clinical trial to combine these 3 agents. METHODS. All patients (pts) received bortezomib (1.3mg/m2 d1, 4, 8, 11) with dexamethasone (20mg d1, 2, 4, 5, 8, 9, 11, 12). Romidepsin commenced at 8 mg/m2 IV d1, 8, and 15 every 28 days with a planned accelerated intra-patient dose escalation to 10, 12 and 14 mg/m2 (n=10). After CR + 2 cycles or a maximum of 8 cycles, pts with SD or better commenced maintenance (Mx) therapy, romidepsin at the MTD on days 1 and 8 of a 28 day cycle until PD. An additional 15 pts were treated at the MTD in a phase II expansion. Response was assessed after every 2 cycles according to IMWG criteria (with minimal Response (MR) defined as ≥25% but <50% reduction in M protein). Toxicities were assessed using NCI-CTCAE version 3. RESULTS: In total, 25 pts have been enrolled of which 18 have completed more than 2 cycles and are evaluable for response. The median number of prior regimens was 2 (2–5). Most pts were treated previously with autologous stem cell transplantation (n=11) and neurotoxic regimens; VAD (n=10), thalidomide (n=12), bortezomib (n=6) and lenalidomide (n=4). The median number of treatment cycles delivered was 4 (1–8); Mx cycles 6 (3–15). 10 patients entered the Phase 1 study. No DLTs occurred at 8mg/m2 (n=1) or 10mg/m2 (n=6) of romidepsin. At 12mg/m2 (n=3), TCP (Grade 4, n=3), febrile neutropenia (n=1), peripheral neuropathy (PN) (n=1) and constipation (n=1) DLTs were observed. Of note, 2 pts with Grade 4 TCP had platelets 50–100×109/L before commencing therapy. The MTD for this regimen was determined as romidepsin (10mg/m2) with bortezomib (1.3mg/m2). Other drug-related toxicities observed included: Grade 3: fatigue (n=2), neutropaenia (n=1), sepsis (n=2), PN (n=1); Grade 2: PN (n=6), nausea (n=1). Five pts required bortezomib dose reductions because of PN (n=4). Two pts required a romidepsin dose reduction because of fatigue (n=1) and abnormal LFTs (n=1). The overall response rate (ORR) is 12/18 (67%) (4 CR/nCR, 4 VGPR, 4 PR) with an additional 5 (28%) patients achieving an MR. To date, 7 patients have entered the romi Mx phase. Pt numbers 1, 2, 6, 7, 9, 10 and 11 been on Mx for 15, 3, 12, 8, 7, 4, and 5 months respectively. Four pts have progressed after C1 (n=2), C4 (n=1) and C8+3Mx (n=1). Of note, 3 pts have entered this trial having progressed on a separate trial examining bortezomib maintenance therapy (study protocol PMCC 05/69). These 3 pts were receiving 2 weekly bortezomib and progressing. On the introduction of bortezomib/dexamethasone/romidepsin, the M band has fallen in all assessable pts [41 to 26 (C2); 16 to 11 (C2); 1 pt has not completed C1]. CONCLUSION. This combination of a bortezomib and dexamethasone with romidepsin is well tolerated, with similar TCP compared to single agent bortezomib and romidepsin and demonstrates substantial efficacy in a heavily pre-treated group of patients. The high response rate (OR 67% + 28% MR), impressive depth of response (44% CR + VGPR), durable responses and the observation of a drop in M band in pts progressing on bortezomib as their immediate prior therapy, all indicate that romidepsin has synergistic activity with bortezomib-dexamethasone.

INTRODUCTIONHelicobacter pylori is now thought to be the most important exogenous factor in the development of duodenal ulcer disease, and is present in over 95% of duodenal ulcer patients. 1, 2 Several studies have provided strong evidence that eradication of the infection reduces ulcer relapse rate, 3±5 so it has been suggested that an attempt to eradicate the infection should be made in all patients with duodenal ulcer disease. 6 Eradication therapy therefore offers a potential cure for the disease and provides the general practitioner with an alternative to long-term treatment with acid-lowering SUMMARY Background: Helicobacter pylori is the main acquired factor in the pathogenesis of duodenal ulcer disease. Methods: This multicentre study conducted in 32 general practice centres in the UK and Ireland was a double-blind, placebo-controlled, randomized, parallelgroup comparison of triple therapy (n 98: omeprazole 40 mg once daily and amoxycillin 1 g b.d. for 2 weeks, and metronidazole 400 mg t.d.s. for the ®rst week) and dual therapy (n 85: omeprazole 40 mg once daily and amoxycillin 1 g b.d. for 2 weeks, with placebo during the ®rst week) for the eradication of H. pylori in patients with symptomatic duodenal ulcer disease. Patients who were successfully treated entered a followup phase for 12 months to assess symptomatic relapse and use of health-care resources. Results: Eradication of H. pylori based on a second 13 C-urea breath test was successful in 95% (95% con®dence interval (CI) 90±100%) of patients receiving omeprazole triple therapy and 53% (95% CI 41±65%) of those receiving omeprazole dual

This study has shown that 10 mg omeprazole once daily is an effective and well-tolerated treatment strategy in general practice for the long-term management of symptoms of GORD in patients without erosive oesophagitis.