Continuous Oral Treatment Research Articles

Prediction of SSRI treatment response in major depression based on serotonin transporter interplay between median raphe nucleus and projection areas

Recent mathematical models suggest restored serotonergic burst-firing to underlie the antidepressant effect of selective serotonin reuptake inhibitors (SSRI), resulting from down-regulated serotonin transporters (SERT) in terminal regions. This mechanism possibly depends on the interregional balance between SERTs in the raphe nuclei and in terminal regions before treatment. To evaluate these hypotheses on a systems level in humans in vivo, we investigated SERT availability and occupancy longitudinally in patients with major depressive disorder using positron emission tomography (PET) and the radioligand [11C]DASB. Measurements were performed before and after a single oral dose, as well as after three weeks (mean 24.73±3.3 days) of continuous oral treatment with either escitalopram (10 mg/day) or citalopram (20 mg/day). Data were analyzed using voxel-wise linear regression and ANOVA to evaluate SERT binding, occupancy and binding ratios (SERT binding of the entire brain compared to SERT binding in the dorsal and median raphe nuclei) in relation to treatment outcome. Regression analysis revealed that treatment response was predicted by pre-treatment SERT binding ratios, i.e., SERT binding in key regions of depression including bilateral habenula, amygdala-hippocampus complex and subgenual cingulate cortex in relation to SERT binding in the median but not dorsal raphe nucleus (p<0.05 FDR-corrected). Similar results were observed in the direct comparison of responders and non-responders. Our data provide a first proof-of-concept for recent modeling studies and further underlie the importance of the habenula and subgenual cingulate cortex in the etiology of and recovery from major depression. These findings may indicate a promising molecular predictor of treatment response and stimulate new treatment approaches based on regional differences in SERT binding.

Abstract 2795: Safety profile and therapeutic potential in breast cancer of STX140, an original tubulin binding agent

Abstract STX-140 is an anti-tubulin binding agent which has demonstrated a good anti-tumor efficacy profile. Although the binding site on tubulin differs from other classical tubulin binders, one could anticipate the same type of safety issues with such an agent, namely neurotoxicity. In order to differentiate this compound, we evaluated its efficacy in a transgenic model of mammary cancer, its neurotoxicity potential, and its therapeutic index in a breast cancer model. STX140 efficacy was evaluated in C3(1) Tag transgenic mice which develop mammary carcinomas. In those transgenic animals, the disease progresses in a similar fashion to human breast cancer, with the development of tumors which show the same histological characteristics as the human pathology. In these mice, STX140 was able to significantly increase the survival of the animals and to suppress the emergence of metastases, whereas paclitaxel was completely inactive on both parameters. Neurotoxicity potential was assessed in a thermal hyperalgesia model in comparison with paclitaxel. Continuous oral treatment of mice with STX-140 did not induce an increase sensibility to heat as measured by the latency of paw withdrawal after a heat stimulus. However, paclitaxel increased this heat sensitivity starting after the second i.v. administration, underlying the neurotoxicity of this compound, which is observed in the clinic. Finally, in MDA-MB-231 breast cancer xenografts, two different schedules of oral administration were evaluated in order to determine the therapeutic index and PK parameters were measured in parallel to the anti-tumor efficacy. Continuous (QD) and intermittent (Monday, Wednesday, Friday; MWF) treatments were evaluated and a large panel of doses were tested. The therapeutic index was determined as the ratio of the exposure observed between the first toxic dose and first active dose. The TI for the QD schedule was 2.1 and was 1.7 for the MWF schedule, showing the potential good safety index of this compound. Taking into account the previous data reported elsewhere and new data presented here, which underline the great efficacy and safety profile of STX140, this compound is considered for further preclinical and clinical development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2795. doi:1538-7445.AM2012-2795

Efficacy Test of Polycan, a Beta-Glucan Originated from Aureobasidium pullulans SM-2001, on Anterior Cruciate Ligament Transection and Partial Medial Meniscectomy-Induced-Osteoarthritis Rats

The object of this study was to assess the efficacy of Polycan from Aureobasidium pullulans SM-2001, which is composed mostly of beta-1,3-1,6-glucan, on osteoarthritis (OA)-induced by anterior cruciate ligament transection and partial medial meniscectomy (ACLT&PMM). Three different dosages of Polycan (85, 42.5, and 21.25 mg/kg) were orally administered once a day for 84 days to male rats a week after ACLT&PMM surgery. Changes in the circumference and maximum extension angle of each knee, and in cartilage histopathology were assessed using Mankin scores 12 weeks after Polycan administration. In addition, cartilage proliferation was evaluated using bromodeoxyuridine (BrdU). As the result of ACLT&PMM, classic OA was induced with increases in maximum extension angles, edematous knees changes, and capsule thickness, as well as decreases in chondrocyte proliferation, cartilages degenerative changes, and loss of articular cartilage. However, these changes (except for capsule thickness) were markedly inhibited in all Polycan- and diclofenac sodium-treated groups compared with OA control. Although diclofenac sodium did not influence BrdU uptake, BrdU-immunoreactive cells were increased with all dosages of Polycan, which means that Polycan treatment induced proliferation of chondrocytes in the surface articular cartilage of the tibia and femur. The results obtained in this study suggest that 84 days of continuous oral treatment of three different dosages of Polycan led to lesser degrees of articular stiffness and histological cartilage damage compared with OA controls 91 days after OA inducement, suggesting that the optimal Polycan dosage to treat OA is 42.5 mg/kg based on the present study.

Comparison of metabolic changes in patients with schizophrenia during randomized treatment with intramuscular olanzapine long‐acting injection versus oral olanzapine

Metabolic changes were examined in patients with schizophrenia during treatment with either oral olanzapine or olanzapine long-acting injection (LAI). Data were collected from patients who had been stabilized on oral olanzapine (10, 15, or 20 mg/day) for ≥4 weeks and then randomized to either continued olanzapine oral treatment (n = 322) or LAI (n = 599; 150 mg/2 weeks, 405 mg/4 weeks, or 300 mg/2 weeks) for up to 24 weeks. Mean and categorical changes in metabolic parameters were analyzed. Mean changes in weight, glucose, and most lipids were generally not significantly different between treatment groups. Weight changes over time followed similar patterns and were not significantly different at endpoint between the two treatment-formulation groups. Low-density lipoprotein cholesterol decreased significantly less among olanzapine LAI-treated patients. Percentages of patients with potentially clinically significant changes in blood glucose and lipid concentrations were similar for the two treatments. Percentages of patients experiencing adverse events related to weight, diabetes, or dyslipidemia were also not significantly different between treatments. Metabolic changes in patients with schizophrenia appeared generally similar during treatment with oral olanzapine or olanzapine LAI.

L-carnitine ameliorates cancer cachexia in mice by regulating the expression and activity of carnitine palmityl transferase

Cancer cachexia is characterized by progressive weight loss with the depletion of adipose tissue and skeletal muscle. Impaired fatty acid oxidation mainly resulting from the decrease of carnitine palmitoyltransferase I and II activities in the liver is an important factor that contributes to cancer cachexia . Although recent studies suggest a potential application of L-carnitine in treatment of cancer cachexia, the underlying mechanisms are unknown. In the present study, we aim to assess the effects of L-carnitine on the activity and expression of CPT I and II in the liver of cachectic cancer mice. Our results show that the inoculation of colon-26 adenocarcinoma cells into mice led to cancer cachexia characterized by notable decreases in food intake, gastrocnemius muscle and epididymus fat weight. In addition, the mRNA level and activity of liver carnitine palmitoyltransferase (CPT) I and II, and serum levels of free carnitine and acetylcarnitine were markedly decreased in cachectic mice, accompanied by marked increases in serum levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). A continuous oral treatment with L-carnitine at 18 mg/kg per day increased dietary uptake, gastrocnemius muscle weight and epididymus fat weight, increased blood glucose and serum albumin levels, and decreased total cholesterol level in cancer cachectic mice, but did not affect tumor growth. These effects of L-carnitine on cancer cachexia mice were accompanied by the upregulation of mRNA level of CPT I and II and increased enzyme activity of CPT I in the liver, as well as the downregulation of serum TNF-α and IL-6 levels. Moreover, free carnitine levels were negatively correlated with serum TNF-α or IL-6 level. These results indicate that L-carnitine ameliorates cancer cachexia by regulating serum TNF-α and IL-6 levels and modulating the expression and activity of CPT in the liver.

Phase IB study of sorafenib in combination with gemcitabine and cisplatin in patients with refractory solid tumors

Sorafenib (BAY 43-9006), a multikinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. This study investigated the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with gemcitabine and cisplatin. Patients with advanced solid tumors were treated with 75mg/m(2) cisplatin on day 1 and 1,250mg/m(2) gemcitabine on days 1 and 8 of each 21-day cycle. On day 5 of cycle 1, sorafenib 400mg twice daily was started and continued throughout the complete treatment cycles without interruption. Nineteen patients were valid for safety analysis. The most frequent toxicities related to the cytotoxic agents were hematological disorders. Sorafenib-related toxicities were skin-related, gastrointestinal, and constitutional symptoms. No clinically relevant pharmacokinetic drug-drug interaction between sorafenib, cisplatin, and gemcitabine was detected. AUC(0-72) and C (max) of total and unbound platinum were only marginally changed by concomitant sorafenib. Concomitant sorafenib increased mean AUC and C (max) of gemcitabine by 12 and 21%. Sorafenib as continuous oral treatment in combination with gemcitabine and cisplatin demonstrated an acceptable safety profile. No clinically relevant pharmacokinetic interaction was detected. Preliminary antitumor activity, pharmacokinetic, and safety data support the recommendation of 400mg sorafenib twice daily in combination with cisplatin and gemcitabine to be further evaluated in clinical studies.

Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib

AbstractSeveral cancer treatments are shifting from traditional, time-limited, nonspecific cytotoxic chemotherapy cycles to continuous oral treatment with specific protein-targeted therapies. In this line, imatinib mesylate, a selective tyrosine kinases inhibitor (TKI), has excellent efficacy in the treatment of chronic myeloid leukemia. It has opened the way to the development of additional TKIs against chronic myeloid leukemia, including nilotinib and dasatinib. TKIs are prescribed for prolonged periods, often in patients with comorbidities. Therefore, they are regularly co-administered along with treatments at risk of drug-drug interactions. This aspect has been partially addressed so far, calling for a comprehensive review of the published data. We review here the available evidence and pharmacologic mechanisms of interactions between imatinib, dasatinib, and nilotinib and widely prescribed co-medications, including known inhibitors or inducers of cytochromes P450 or drug transporters. Information is mostly available for imatinib mesylate, well introduced in clinical practice. Several pharmacokinetic aspects yet remain insufficiently investigated for these drugs. Regular updates will be mandatory and so is the prospective reporting of unexpected clinical observations.

A double-blind, randomized, prospective, phase II trial of capecitabine (Cap) plus enzastaurin (Enz) versus cap plus placebo in patients (pts) with advanced breast cancer (BrCa) and prior anthracycline and taxane treatment.

1054 Background: This international trial studied the efficacy and safety of Cap plus Enz in treating advanced BrCa. Methods: Eligible pts (advanced BrCa, prior anthracycline and taxanes, ≤2 prior chemotherapy regimens and performance status ≤2) were randomized to 1250 mg/m2 Cap (days 1 to 14) and a loading dose of 1125 mg Enz on day 1 of Cycle 1 preceding daily 500 mg Enz (Cap-E) or daily placebo (Cap-P) as continuous oral 21-day cycle treatment. Pts discontinued due to progression, death, or adverse event (AE). Response was assessed before alternate cycles. The primary endpoint, progression-free survival (PFS), was compared between arms using log-rank test. Planned enrollment of 60 pts/study arm provided 80% power to detect a 40% PFS improvement with Cap-E over Cap-P (1-sided type-I error=0.20). Results: Prespecified efficacy and safety conditions were not met in a planned interim analysis and the study was terminated. All data from study enrollment to termination were analyzed. 85 pts were randomized (Cap-E, n=42; Cap-P, n=43; median age, 54.2 years) and received ≥1 study drug dose. There were no statistically significant differences between Cap-E and Cap-P, respectively, in PFS (median [95% CI]=2.8 months [2.1, 4.6] versus 4.3 months [2.9, 6.2]; log-rank p=0.237), overall survival (median [95% CI]=9.9 months [7.0, 16.6] versus 14.9 months [9.9, 19.3); log-rank p=0.181), best overall response (11.9% versus 11.6%; Fisher's Exact p=1.00) or duration of response (median [95% CI]=4.3 months [2.2, 4.3] versus 3.5 months [2.8, N/A]; log-rank p=0.812). More Cap-E than Cap-P pts, respectively, experienced ≥1 drug-related (d-r) Grade 3/4 toxicity (42.9% versus 32.6%), d-r serious AE (16.7% versus 14.0%) and d-r hospitalization (14.3% versus 9.3%). Fewer Cap-E (9.5%) than Cap-P pts (11.6%) discontinued due to d-r AEs. There were 4 study d-r deaths (Cap-E, n=2; Cap-P, n=2) on therapy or within 30 days of study treatment discontinuation. Conclusions: When compared with Cap-P, Cap-E did not improve survival outcomes and increased d-r toxicity. These data do not support use of Cap-E in this patient population. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Lilly Lilly Lilly, Roche Lilly

Review on Pulse Therapy: A Novel Approach in the Treatment of Pemphigus Vulgaris

Objective: Pemphigus vulgaris, a fatal autoimmune mucocutaneous disorder commonly seen involving the oral cavity, has since a long time remained a topic of concern regarding its treatment modalities. Pulse therapy, introduced in 1984, employs high-dose corticosteroids along with certain immunosuppressive agents and has gained wide popularity since the last three decades due to its advantage of minimizing the adverse effects of conventional corticosteroid therapy. This article provides a detailed review about various studies conducted utilizing different regimens in pulse therapy and the outcome of these studies. Materials and methods: Information from various studies conducted over the last three decades was collected and a thorough analysis of the results of these studies has been provided in this article. Results: Extensive review of the existing data revealed that pulse therapy minimizes the adverse effects of long-term corticosteroid therapy, controls the disease process faster and has quicker and long-lasting remission rates. Conclusion: Pulse therapy appears to be successful in the treatment of pemphigus vulgaris. Various studies have proven the efficacy of pulse therapy along with reduced side effects of conventional corticosteroid therapy. However, long-term follow-up is necessary to compare the incidence of malignancy in patients receiving pulse doses of immunosuppressive agents with that in patients receiving continuous oral treatment.

Clinical Results in Patients with Primary and Secondary Myelofibrosis Treated with Monthly Cycles of Oral Melphalan.

Abstract 4985Prolonged continuous oral Melphalan treatment was successfully employed in patients with Idiopathic Myelofibrosis (IM); however, a high incidence of evolution into blastic phase (BP) was observed. In order to reduce the incidence of BP and other side effects, a different Melphalan schedule with intermittent monthly cycles was tested at our Institution. From 1/2003 to 2/2009, 24 patients (16 males and 8 females, median age 66.2 years, range 41.7 – 76.2) were enrolled into the study; 19/24 had primary IM while in 5 there was a previous history of Polycythemia Vera/Essential Thrombocythemia. Six patients (25%) had been pretreated with Hydroxyurea. A symptomatic splenomegaly was present in all patients, with median spleen enlargement below costal margin of 12 cm (range 7 – 22). Median WBC level was 11.6 × 109/l (range 3.6 – 63.6), with 11/24 patients having WBC > 12.0 × 109/l; in addition, 3 patients had PLT level > 500 × 109/l, 11 patients Hb level < 10 g/dl and 3 patients had transfusional requirement. Melphalan was administered orally at the dose of 8 mg/day for 5 consecutive days every month. Twelve patients (50%) had a reduction of spleen enlargement > 75%, 2 patients > 50% and 1 patient > 25%, with a global response rate of 15/24 patients (62.5%): the remaining 9 patients had no variation in spleen volume. Elevated WBC values reduced to normal in all but one patient, elevated PLT values reduced to normal in 2 out of 3 patients, transfusional requirement disappeared in 1 out of 3 patients. Median number of cycles to best response was 10 (range 2 – 30). As concerns hematological toxicity, 4 patients had Hb decrease < 8 g/dl, with 3/4 requiring transient transfusional support, and 1 patient had PLT decrease to < 50 × 109/l. One patient resistant to treatment died from broncopneumonia and 1 patient with normal PLT values died from cerebral hemorrhage; two patients had a grade 3 – 4 gastro-intestinal hemorrhage. Interestingly, only 2/24 patients (8.3%) had a BP evolution after 8 and 16 months from start of Melphalan, respectively. After a median number of treatment cycles of 18 (range 2 – 68), 12 patients are still in therapy and 12 discontinued Melphalan due to toxicity (4), resistance (3), relapse (3) or evolution to BP (2). In conclusion, the intermittent cyclic schedule of oral Melphalan seems capable to maintain a good response rate with reduction of symptomatic spleen enlargement in more than 50% of patients without excessive toxicity and with a lower rate of BP evolution, as compared to continuous Melphalan administration. DisclosuresNo relevant conflicts of interest to declare.

1243 Phase I dose-escalation study of continuous oral treatment with the angiokinase inhibitor BIBF 1120 in patients with advanced solid tumors

1243 Phase I dose-escalation study of continuous oral treatment with the angiokinase inhibitor BIBF 1120 in patients with advanced solid tumors

Evaluation of desloratadine on conjunctival allergen challenge‐induced ocular symptoms

Allergic conjunctivitis (AC) is frequently associated with allergic rhinitis (AR) and affects up to 91% of patients with AR. Desloratadine, an orally administered, non-sedating second-generation antihistamine, has proven efficacy and safety in the control of nasal and non-nasal--including ocular--symptoms of AR. This randomized-controlled trial is the first to evaluate the effects of continuous oral desloratadine treatment on ocular symptoms after conjunctival allergen challenge. To evaluate the impact of administering oral desloratadine 5 mg daily for 7 days on ocular symptoms in conjunctival allergen-challenged subjects. In this crossover study, adults with a history of seasonal AC and a minimal threshold response to allergen challenge were randomized to receive desloratadine 5 mg daily (n=20) or placebo (n=21) for 7 days after which they underwent a second ocular allergen challenge. After a 2-week washout period, subjects crossed over to the other treatment. The primary efficacy parameter was the intra-subject difference from baseline at end-point in the post-challenge mean composite ocular redness score (the sum of redness scores in ciliary, conjunctival, or episcleral vessel beds). Secondary efficacy parameters included the intra-subject and inter-subject differences in individual symptom scores for ciliary, conjunctival, or episcleral redness; pruritus; chemosis; eyelid swelling; and tearing. The mean composite ocular redness score was reduced at 10, 15, and 20 min post-challenge with desloratadine treatment compared with placebo, though these differences were not statistically significant (P=NS). Desloratadine was significantly more effective than placebo in preventing post-challenge ocular pruritus (P<0.001). Significant improvements post-challenge were also seen in ciliary and episcleral redness, chemosis, eyelid swelling, and tearing (P<0.05 vs. placebo for all comparisons). Desloratadine was well tolerated. Treatment with desloratadine 5 mg daily for 7 days reduced allergic ocular symptoms following allergen challenge.

Long-term treatment results and the immunoglobulin G subclass distribution patterns of proteinase-3-antineutrophil cytoplasm antibody (ANCA) and myeloperoxidase-ANCA in ANCA-associated vasculitis

Small vessel vasculitis associated with antibodies to neutrophil cytoplasm antigens has been denominated antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). Ninety-eight patients with various forms of AAV with renal involvement were studied retrospectively with regard to treatment, side-effects and outcome. The immunoglobulin G (IgG) subclass distribution patterns in serum were determined in 51 patients with nephelometry and those of anti-proteinase-3 (PR3) and anti-myeloperoxidase (MPO) in 44 patients by enzyme-linked immunosorbent assay. Fifty-nine patients with a mean age of 63 years were given treatment with intermittent intravenous regimens of cyclophosphamide and continuous corticosteroids, whereas 39 patients with a mean age of 58 years were given continuous oral treatment. Malignancy, mainly due to skin tumours, was more common in AAV than in the general population. The total IgG subclass distribution pattern was asymmetric. The response to PR3 was of IgG(1), IgG(3) and IgG(4) isotypes, while IgG(1) and IgG(3) predominated in the response to MPO. The aberrant IgG subclass distribution pattern detected in the autoantibodies may be of importance in the pathogenesis of AAV.

Case of Budd–Chiari syndrome 3 months after vaginal delivery

Budd-Chiari syndrome is a rather unusual clinical situation caused by occlusion of the hepatic vein of inferior vena cava, the classical triad of which are abdominal pain, ascites and hepatomegaly. A 29-year-old gravida 3 para 1 woman delivered an immature male baby weighing 2172 g with an Apgar score of 9 points at 35 weeks and 3 days of gestation. She was transferred to the National Hospital Organization Osaka National Hospital 112 days after delivery due to the sudden development of massive ascites. Magnetic resonance angiography and enhanced computed tomography detected the occlusion by thrombosis of both the middle and left hepatic veins, so she was diagnosed with Budd-Chiari syndrome. Her protein C antigen and activity were 37% and 50%, respectively, corresponding to type 1 protein C deficiency. Conservative treatment by continuous oral treatment of spironolactone (25 mg/day), furosemide (20 mg/day) and prophylactic warfarin (2 mg/day) much improved the ascites.

Pharmacokinetic (PK) analysis of a phase I study of continuous oral treatment with the angiokinase inhibitor BIBF 1120, in combination with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer (NSCLC)

3567 Background: BIBF 1120 is a potent, orally available tyrosine kinase inhibitor (VEGFR 1/2/3, PDGFR α/β and FGFR 1/3) that suppresses tumor growth by angiogenesis inhibition. Recently, the combination of a VEGF inhibitor with standard chemotherapy improved the therapeutic outcome of first line NSCLC patients. Methods: The primary objectives of this Phase I trial were to determine the safety, tolerability, the maximum tolerated dose (MTD) and the PK of BIBF 1120 in combination with paclitaxel and carboplatin in previously untreated NSCLC patients. The BIBF 1120 dose was increased by 50 mg per cohort until the MTD was determined. BIBF 1120 was taken on Days 2–21 with carboplatin (AUC= 6 min·mg/mL) and paclitaxel (200 mg/m2) administered on Day 1 of each 21-day cycle. PK samples were taken on Days 1 and 2 of treatment cycle (TC) 1 and 2. PK parameters were analysed by non-compartmental techniques. Results: Twenty-five patients with stage IIIB/IV NSCLC, performance score 0–1, were enrolled and treated at doses of 50 mg/day (n=3), 100 mg/day (n=3), 150 mg/day (n=3), 200 mg/day (n=13) and 250 mg/day (n=3). The MTD of BIBF 1120 was 200 mg bid. BIBF 1120 steady state was reached after 7 days of bid dosing. No systematic change in trough plasma concentrations or deviation from dose linearity of BIBF 1120 was observed in combination with carboplatin and paclitaxel. PK parameters of carboplatin and paclitaxel are displayed in the table. Conclusions: 200 mg of BIBF 1120 bid in combination with standard doses of carboplatin and paclitaxel is considered the recommended dose for continuous daily treatment for patients with advanced or metastatic NSCLC. There were no clinically relevant changes to the PK parameters of paclitaxel or carboplatin after 20 days administration of 200 mg BIBF 1120 bid, showing that this may be a viable combination in future studies. TC1 (before BIBF 1120 dosing) TC2 (after 20 days of BIBF 1120 dosing) N gMean gCV[%] N gMean gCV[%] Paclitaxel AUC0-∞ ng·h/mL 8 18,800 21.6 7 21,900 27.9 Cmax ng/mL 8 6,020 29.2 8 7,260 25.9 Carboplatin AUC0- ∞ ng·h/mL 6 66,300 21.8 5 78,300 32.9 Cmax ng/mL 6 16,900 19.5 6 18,300 37.1 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Boehringer Ingelheim Pharma GmbH & Co. KG, Boehringer Ingelheim Pharmaceuticals Inc. US Oncology Boehringer Ingelheim

P3-138: A Phase I open label study of continuous oral treatment with BIBF 1120 together with carboplatin and paclitaxel treated patients with non–small cell lung cancer (NSCLC)

P3-138: A Phase I open label study of continuous oral treatment with BIBF 1120 together with carboplatin and paclitaxel treated patients with non–small cell lung cancer (NSCLC)

P3-091: A Phase I study of continuous oral treatment with the triple angiokinase inhibitor BIBF 1120 together with pemetrexed in previously treated patients with non-small cell lung cancer

P3-091: A Phase I study of continuous oral treatment with the triple angiokinase inhibitor BIBF 1120 together with pemetrexed in previously treated patients with non-small cell lung cancer

Bortezomib in combination with intermediate‐dose dexamethasone and continuous low‐dose oral cyclophosphamide for relapsed multiple myeloma

A phase 2 trial was performed to study the combination of bortezomib (VELCADE) with intermediate-dose dexamethasone (DEX), and continuous low-dose oral cyclophosphamide (CY) in patients with relapsed multiple myeloma (MM). Fifty-four patients with advanced MM were enroled to receive eight 3-week treatment cycles with bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, followed by three 5-week cycles with bortezomib 1.3 mg/m(2) on days 1, 8, 15, and 22. Within all cycles, DEX 20 mg/d was given orally on the day of bortezomib injection and the day thereafter. In addition, patients received CY continuous oral treatment at a dose of 50 mg/d p.o. once daily. Fifty patients completing at least one treatment cycle were evaluable for response. Complete, partial, and minor responses occurred in 16%, 66% and 8% of patients, respectively; overall response rate 90% (efficacy analysis). Median event-free survival was 12 months, with a median overall survival of 22 months. Adverse events (AE) of grades 3 or 4 occurring in at least 10% of patients comprised leucopenia, infection, herpes zoster, thrombocytopenia, neuropathy and fatigue. Bortezomib combined with DEX and CY is a highly effective treatment for relapsed MM at an acceptable rate of grade 3/4 AE. Antiviral prophylaxis appears to be mandatory.

Single center phase II trial analysing the role of imatinib/hydroxyurea in patients (pts) with pretreated non-progressive glioblastoma (GBM) as maintenance treatment

2055 Background: In GBM the highest malignant brain tumor with a median survival of about 15 months dysregulated signalling of platelet derived growth factor receptors (PDGF-Rs) is implicated in pathogenesis. I/HU showed impressive efficacy and tolerability in patients (pts) with recurrent progressing GBM. In 30 pilot pts with recurrent GBM the progression free survival (PFS) at 6 and 24 months (m) was 32% and 16% respectively. Disease stabilisation (SD) in 37% was an important result. SD for more than 2 years was possible. In GBM a short period of SD after primary or relapse treatment is typical. In this phase II study the efficacy of I/HU as maintenance treatment in pts with GBM in stage of SD was analysed. Methods: From December 2003 up to June 2005 30 GBM pts with documented SD for more than 6 weeks following prior treatment, including surgery, radiotherapy and at least one chemotherapeutic regimen were included,. No enzyme-inducing anticonvulsive drugs were allowed. I dose was 600 mg od, HU dose was 1000 mg (500 mg bid) as continuous oral treatment, pts were followed up by blood cell count weekly and magnetic resonance imaging every 6 weeks. Results: All 30 pts were eligible for safety and for 6, 12 and 18 m PFS and overall survival (OS); 25 pts were male, 5 pts female, median age was 44 years (32 to 71), 24 pts had primary (de novo) and 6 pts secondary GBM. All 30 pts had prior radiotherapy, 21 pts had prior temozolomide and 9 pts non- temozolomide containing regimens. 8 pts were free from relapse, 17 pts after first and 5 pts after second relapse. The median observation time is 28 m. 6, 12 and 18 m PFS was 60% (18/30), 40% (12/30) and 30% (9/30) respectively. 6, 12 and 18 m OS is 90% (27/30), 67% (20/30) and 53% (16/30) so far. PFS for more than 24 m occurred in 3/6 pts with secondary and in 2/24 pts with primary GBM. Toxicity was low (anemia grade 3: 2 pt; grade 2: 4 pts; leucocytopenia grade 3:2 pts; grade 2: 7 pts; thrombocytopenia grade 2: 4 pts), HU dose was reduced in 8 pts, I dose in 1 pt and G-CSF was given in 8 pts, no treatment related death occurred. Conclusion: I (600 mg/d)/ HU (1000 mg/d) was well tolerated in this study. Long-term disease stabilisation was possible - especially in pts with secondary GBM. Confirmation in further investigation is required. [Table: see text]

Tolerability of β‐Blockers in Outpatients with Refractory Heart Failure Who Were Receiving Continuous Milrinone

To investigate the dosing, tolerability, and outcomes associated with the use of concomitant beta-blockers and inotropic therapy in patients with refractory heart failure during the first 6 months of their therapy. Retrospective review. University-based, tertiary care heart failure and transplant center. Sixteen inotrope-dependent outpatients with end-stage refractory heart failure who were receiving continuous intravenous milrinone. Of these patients, 12 also received an oral beta-blocker; the remaining four patients who did not receive beta-blockers served as the comparator group. For each patient, the initial and final study drug doses of continuous intravenous milrinone and oral beta-blocker treatment, when applicable, were recorded over the 6-month period. Mean heart rate, blood pressure, ejection fraction, and oxygen consumption were measured, and 95% confidence intervals were calculated. Serum sodium and creatinine concentrations, as well as the creatinine clearance, were measured. In the 12 patients who received concomitant milrinone and beta-blockers, the mean baseline ejection fraction was approximately 18%, and they received milrinone for 18.6 weeks. Seven patients received carvedilol for 16.1 weeks, and five received metoprolol tartrate for 17.6 weeks. Dosages of the beta-blockers were titrated. Final daily doses were carvedilol 42.8 mg (95% confidence interval 20.3-65.4) and metoprolol 42.5 mg (95% confidence interval 28.0-57.2). Patients continued to receive other standard oral drug therapy for heart failure. One patient discontinued metoprolol and one discontinued carvedilol because of hypotension and/or worsening heart failure. Cardiac adverse events in the concomitant milrinone plus beta-blocker group were heart failure requiring hospitalization in 10 patients and ventricular arrhythmias in one. Inotrope-dependent patients with refractory end-stage heart failure tolerated continuous intravenous milrinone plus beta-blockers in addition to diuretics and vasodilators for the 6-month observation period. Beta-blocker dosages were titrated, and three patients achieved the target beta-blocker dosage established for stage A-C heart failure. Additional studies are needed to determine the optimal selection and dosing of drug combinations in this population.