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Item does not contain fulltext BACKGROUND: CI-994, an oral histone deacetylase inhibitor, has antineoplastic activity and synergism with gemcitabine preclinically. This randomized phase II trial explored whether CI-994 plus gemcitabine improves overall survival, objective response, duration of response, time to treatment failure and change in quality of life (QoL) or pain compared with gemcitabine alone. PATIENTS AND METHODS: A total of 174 patients received CG (CI-994 6 mg/m(2)/day days 1-21 plus gemcitabine 1000 mg/m(2) days 1, 8 and 15 each 28-day cycle) or PG (placebo plus gemcitabine 1000 mg/m(2) days 1, 8 and 15 of each 28-day cycle days 1-21). RESULTS: Median survival was 194 days (CG) versus 214 days (PG) (P = 0.908). The objective response rate with CG was 12% versus 14% with PG when investigator-assessed and 1% versus 6%, respectively, when assessed centrally. Time to treatment failure did not differ between the two arms (P = 0.304). QoL scores at 2 months were worse with CG than with PG. Pain response rates were similar between the two groups. There was an increased incidence of neutropenia and thrombocytopenia with CG. CONCLUSIONS: Adding CI-994 to gemcitabine in advanced pancreatic carcinoma does not improve overall survival, response rate or time to progression; CG produced decreased QoL and increased hematological toxicity and appears inferior to single-agent gemcitabine.

Single-agent gemcitabine remains the standard treatment for advanced pancreas cancer. Results of four phase III trials reported in 2004 indicated no survival benefit for single-agent exatecan or combinations of exatecan, pemetrexed, and oxaliplatin with gemcitabine compared with gemcitabine alone. It is unclear whether a trend toward improved outcome with the gemcitabine/oxaliplatin combination was attributable to use of a fixed-dose rate infusion regimen of gemcitabine in the combination arm, a method of administration that appears to be associated with benefits compared with standard gemcitabine infusion. Novel approaches to treatment currently under investigation include refining schedules of administration of combination therapy, combining gemcitabine with molecular targeted therapy, and combining gemcitabine with low-molecular-weight heparin.

Background: The primary objective of this study was to assess the antitumor activity of irofulven in patients with hormone-refractory prostate cancer by measuring a sustained decrease of 50% or greater in serum prostate-specific antigen (PSA) levels. Patients and Methods: Forty-two patients (median age, 73 years) received at least 1 dose of 10.6 mg/m 2 irofulven per day on days 1-5 of a 28-day course. Eligible patients had pathologically confirmed metastatic hormone-refractory adenocarcinoma of the prostate and had not received prior cytotoxic chemotherapy. Results: Forty-two patients received a median of 3 courses of irofulven. Thirty-two patients received at least 2 courses of therapy and were evaluable for efficacy. Four patients (13%) achieved partial response, with a median duration of 2.9 months (range, 2.6-5.8 months). Twenty-seven patients (84%) had disease stabilization and 1 patient (3%) progressed on study. Median progression-free survival was 3.2 months (95% confidence interval, 2.3-4.2 months), with a median progression-free survival of 4.2 months (range, 3.5-6.9 months) for responders. Grade 4 toxicities consisted of thrombocytopenia, anemia, and neutropenia, occurring in 1 patient each. The most common treatment-related grade 3 nonhematologic toxicities included asthenia (19% of patients), vomiting (14%), nausea (12%), and infection without grade 3/4 neutropenia (10%). Conclusion: Irofulven shows activity in hormone-refractory prostate cancer and has an acceptable safety profile, warranting further investigation of this drug, particularly in combination therapies.

The phytohormone gibberellin (GA) regulates the development and fertility of Arabidopsis flowers. The mature flowers of GA-deficient mutant plants typically exhibit reduced elongation growth of petals and stamens. In addition, GA-deficiency blocks anther development, resulting in male sterility. Previous analyses have shown that GA promotes the elongation of plant organs by opposing the function of the DELLA proteins, a family of nuclear growth repressors. However, it was not clear that the DELLA proteins are involved in the GA-regulation of stamen and anther development. We show that GA regulates cell elongation rather than cell division during Arabidopsis stamen filament elongation. In addition, GA regulates the cellular developmental pathway of anthers leading from microspore to mature pollen grain. Genetic analysis shows that the Arabidopsis DELLA proteins RGA and RGL2 jointly repress petal, stamen and anther development in GA-deficient plants, and that this function is enhanced by RGL1 activity. GA thus promotes Arabidopsis petal, stamen and anther development by opposing the function of the DELLA proteins RGA, RGL1 and RGL2.

Bioactive gibberellin (GA) regulates the growth and development of a wide array of plant species. GA exerts its effects via members of the DELLA protein family of putative transcriptional regulators. The GAI gene encodes GAI, a DELLA protein from Arabidopsis thaliana (L.) Heyhn. A mutant allele, gai, encodes a mutant protein (gai) that has altered properties, and confers a dominant, reduced GA-response, dwarf phenotype. Here we describe experiments to investigate the effects of transgenic expression of GAI and gai in tobacco. Constructs permitting the expression of the GAI and gai open reading frames (ORFs) at higher (driven by the cauliflower mosaic virus 35S promoter) and lower (driven by the original Arabidopsis GAI promoter) levels in tobacco were made. We show that low-level expression of GAI has no detectable effect on tobacco GA-responses. In contrast, high-level expression of GAI clearly affects the growth of adult tobacco plants and the GA-responsiveness of tobacco hypocotyls. Both low- and high-level expression of gai have effects on tobacco GA responses. Thus, tobacco GA-responses are affected by transgenic expression of GAI/gai, and the degree to which these responses are affected is related to the level of transgene expression.

Automated ‘open access’ mass spectrometry with liquid interfaces is now considered routine in our laboratories at Sandwich, UK. Synthetic chemists log samples into a queue on the mass spectrometer and return a short time later to take the mass spectrum and the sample away. The whole process occurs without any intervention by a mass spectroscopist (D. V. Bowen, M. Dalton, G. Perkins, F. Pullen and D. Richards, Rapid Commun. Mass Spectrom. Vol. 8, p. 632 (1994)). Fast response liquid chromatography/mass spectrometry is a further development in ‘open access’ mass spectrometry driven by the needs of chromatographers, for whom it is important that the identity of each component present in a high-performance liquid chromatographic separation is known. This Communication describes the development of such a system for our laboratories.

DELLA proteins are nuclear repressors of plant gibberellin (GA) responses. Here, we investigate the properties of SLN1, a DELLA protein from barley that is destabilized by GA treatment. Using specific inhibitors of proteasome function, we show that proteasome-mediated protein degradation is necessary for GA-mediated destabilization of SLN1. We also show that GA responses, such as the aleurone alpha-amylase response and seedling leaf extension growth, require proteasome-dependent GA-mediated SLN1 destabilization. In further experiments with protein kinase and protein phosphatase inhibitors, we identify two additional signaling steps that are necessary for GA response and for GA-mediated destabilization of SLN1. Thus, GA signaling involves protein phosphorylation and dephosphorylation steps and promotes the derepression of GA responses via proteasome-dependent destabilization of DELLA repressors.

Background Neutropenia is common in patients receiving myelotoxic chemotherapy. Pegfilgrastim, a sustained-duration filgrastim is a once-per-cycle therapy for prophylactic neutrophil support. Patients and methods Women, treated with four cycles of doxorubicin/docetaxel chemotherapy every 21 days, received pegfilgrastim or filgrastim 24 h after chemotherapy as a single subcutaneous injection per chemotherapy cycle (pegfilgrastim 30, 60 or 100 µg/kg) or daily subcutaneous injections (filgrastim 5 µg/kg/day). Safety, efficacy and pharmacokinetics were analyzed. Results The incidence of grade 4 neutropenia in cycle 1 was 95, 90 and 74%, in patients who received pegfilgrastim 30, 60 and 100 µg/kg, respectively, and 76% in patients who received filgrastim. Mean duration of grade 4 neutropenia in cycle 1 was 2.7, 2 and 1.3 days for doses of pegfilgrastim, and 1.6 days for filgrastim. The pharmacokinetics of pegfilgrastim were non-linear and dependent on both dose and neutrophil count. Pegfilgrastim serum concentration was sustained until the neutrophil nadir occurred then declined rapidly as neutrophils started to recover, consistent with a self-regulating neutrophil-mediated clearance mechanism. The safety profiles of pegfilgrastim and filgrastim were similar. Conclusions A single subcutaneous injection of pegfilgrastim 100 µg/kg provided neutrophil support and a safety profile comparable to daily subcutaneous injections of filgrastim during multiple chemotherapy cycles.

Bioactive gibberellin (GA) is an essential regulator of vascular plant development. The GAI gene of Arabidopsis thaliana (L.) Heynh. encodes a product (GAI) that is involved in GA signalling. The dominant mutant gai allele encodes an altered product (gai) that confers reduced GA responses, dwarfism, and elevated endogenous GA levels. Recessive, presumed loss-of-function alleles of GAI confer normal height and resistance to the GA biosynthesis inhibitor paclobutrazol. One explanation for these observations is that GAI is a growth repressor whose activity is opposed by GA, whilst gai retains a constitutive repressor activity that is less affected by GA. Previously, we described gai-t6, a mutant allele which contains an insertion of a maize Ds transposable element into gai. Here we describe the molecular and physiological characterization of two further alleles (gai-t5, gai-t7) identified during the Ds mutagenesis experiment. These alleles confer paclobutrazol resistance and normal endogenous GA levels. Thus the phenotype conferred by gai-t5, gai-t6 and gai-t7 is not due to elevated GA levels, but is due to loss of gai, a constitutively active plant growth repressor.

Background: The adoption of NGS platforms and development of targeted oncology drugs have enabled matching of patients and drugs. The authors undertook an observational, clinical study to explore the feasibility and potential clinical benefits of an upfront approach to the genomic profiling of tumors from metastatic colorectal cancer (mCRC) patients. The study sought to determine the number of drug targetable genomic changes, which occur within mCRC patients including a comparison of patients who progress early versus late. Methods: The study targeted enrollment of 50 mCRC patients within the US Oncology Network followed by collection of archival FFPE samples and genomic testing. Sample collection and processing was performed at Quintiles Central Laboratories followed by testing and bioinformatic analysis at the Quintiles Genomic Laboratory. Genomic profiling was performed on the Ion Torrent PGM following enrichment of tumor DNA via the AmpliSeq Cancer Hotspot Panel v2 assay, enriching for hotspots within 50 cancer-related genes. Clinical annotation and reporting to the doctors was provided by NofOne. Basic demographic and clinical information was collected but formal disease monitoring and follow-up was not performed. Clinicians were asked to report the impact of the genomic test report on patient recommendations. Results: The study enrolled and profiled 51 stage IV mCRC patients from July 2013 to October 2013 from 18 sites in the US. Subjects were stratified by time to progression prior to entering the study. The study population was evenly distributed across early (< 1yr) and late progressors (> 1yr) with a median age of 62. Test turn-around time averaged 15 days. 98% of the bases sequenced in the genomic analysis reached the target coverage necessary to identify 5% variant frequency in the sample. Genomic variants associated with approved therapies in mCRC were observed in 7.8% of patients while 64.7% of patients had variants associated with approved therapies in other indications. 84.3% of patients had variant associated with open clinical trials. Of these 43 patients, 32 had multiple biomarkers with associated trials. Overall, more than 100 mutations were identified including alterations in KRAS, BRAF, EGFR, PIK3CA, GNAS, TP53, APC and other genes. The number of actionable mutations was not associated with progressor status. Doctors recommended clinical trials following profiling and reporting of genomic alterations in 15 out of the 51 patients (29%), Conclusions: The outcome of this observational study demonstrates the feasibility of rapid screening and reporting of NGS genomic results targeting actionable mutations in mCRC. The lack of an association between early and late progressors, suggests that a greater sample size will be required for future studies. The reported impact on clinician recommendations indicates the value of the results to inform treatment and clinical trial decisions. Citation Format: Bradley L. Smith, Philip Breitfeld, Jennifer Cubino, Victor Weigman, Donald P. Richards, Ki Y. Chung. Feasibility study of genomic biomarker profiling for patients with metastatic colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5187. doi:10.1158/1538-7445.AM2014-5187

Background: We have previously reported that adjuvant treatment with a therapeutic vaccine targeting the mutated Ras oncogene product generated mutation-specific T cell responses associated with a trend toward improved survival in patients with post-operative residual disease (R1 resections) but no improvement in the overall population1. Initial analysis of 90 pretreatment plasma samples using matrix assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry (MS) showed the potential to predict improved RFS and OS for treatment with GI-4000/gemcitabine, but not placebo/gemcitabine. Methods: We have developed a novel technique, combining methods used in recent advances in learning theory (‘deep learning’) with newly-refined MS techniques that allow exploration deeper into the proteome to create diagnostic tests. Using 500,000 laser shot Deep MALDI spectra2 more than 700 mass spectral features were identified. A subset of these was used to create many multivariate classifiers that were filtered for performance and combined using dropout regularization. This method allows the use of smaller training sets and so left a test set with which performance of the signature could be independently assessed. This new methodology was used to create a test (BDX-001) to identify patients likely to benefit from the addition of GI-4000 to gemcitabine. Results: Using BDX-001 for stratification, subjects who are BDX-001(+) demonstrated a 499 day advantage in median OS when treated with GI-4000/gemcitabine vs. placebo/gemcitabine. Additionally, these subjects demonstrated a 351 day improvement in median RFS. BDX-001 did not predict response for placebo/gemcitabine treated subjects. These results were obtained using only test set data, and although the small sample size prohibited statistical significance, it should give an unbiased test performance estimate to be validated independently. Conclusions: BDX-001 is a test developed using novel proteomic and learning theory methods that appears to predict treatment response to GI-4000 in resected pancreas cancer patients, potentially identifying patients with improved RFS and OS in the GI-4000/gemcitabine arm. We plan to prospectively validate BDX-001 as a companion diagnostic in a future study of GI-4000 in pancreas cancer. References 1. Richards et al, ESMO GI. Annals of Oncology, June 2012 23 (suppl 4) 2. Duncan et al, ASMS 2013, http://asms.inmerge.com/Proceedings/2013Proceedings.aspx. Citation Format: Donald A. Richards, Peter Muscarella, Tanios Bekaii-Saab, Lalan S. Wilfong, Vic Velanovich, Julian Raynov, Patrick J. Flynn, William E. Fisher, Samuel H. Whiting, Constana Timcheva, Tom Holmes, Claire Coeshott, Alicia Mattson, Heinrich Roder, Joanna Roder, Allen Cohn, Timothy C. Rodell. A proteomic signature predicts response to a therapeutic vaccine in pancreas cancer; analysis from the GI-4000-02 trial. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5314. doi:10.1158/1538-7445.AM2014-5314

Aim: Activation of HER2/HER3 heterodimers by HER3's ligand heregulin (HRG) is a putative resistance mechanism for HER2-targeted therapies. MM-111 is a HER2/HER3 bispecific antibody fusion protein designed to inhibit HRG activated HER3 signaling in HER2+ tumors. This study evaluated biomarkers in patient samples from a multi-arm Phase 1 study of MM-111 combined with standard of care HER2-targeting regimens: capecitabine + cisplatin + trastuzumab (T); lapatinib (L) +/- T; paclitaxel (P) + T; L + P + T; docetaxel + T. All patients were required to have advanced HER2+ cancer. Methods: The following biomarkers were assessed in formalin fixed, paraffin-embedded archived tissue: HER2 by 5 methods including immunohistochemistry (IHC) scored using 0/1 + /2 + /3+ and image analysis (optical density) systems, quantitative immunofluorescence (qIF), fluorescent in situ hybridization (FISH), and reverse transcription polymerase chain reaction (PCR); HER3 by qIF and PCR; and HRG, betacellulin, and EGF receptor by PCR. Results: 86 patients [46 breast, 15 gastro-esophageal (GE), 11 bladder, 14 other cancers] were treated and archived tissue was received from 71 patients. All 71 samples were assessable by IHC, 69 by qIF, 64 by FISH, and 46 by PCR. The 5 HER2 assessments correlated well with each other and the correlations were independent of indication. Compared to other indications, patients with GE cancer tended to have higher HRG and HER3 expression. Stratified by indication and treatment, increased HER2 expression correlated with longer progression free survival (PFS) across all patients, particularly GE patients, but the relative contribution of MM-111 or trastuzumab could not be determined. Higher betacellulin expression was associated with longer PFS for regimens containing lapatinib. Conclusions: This study supports use of the described biomarker assays for analysis of samples from a randomized Phase 2 study of MM-111 in HER2+ GE cancer. Biomarker analyses of archived and newly acquired biopsy samples will be performed in the Phase 2 study to provide further insight for the role of HER2, HER3, and HRG in the response of HER2+ cancer to MM-111-containing therapy. Disclosure: A. Kudla, B. Adiwijaya, V. Paragas, K. Kawash, S. Frye, C.F. McDonaghand V. Moyo: Employee of Merrimack Pharmaceuticals with stock options; A.A. Garcia: Recipient of research funding from Merrimack Pharmaceuticals; C.S. Denlinger: Recipient of research funding from Merrimack Pharmaceuticals. P. Conkling: Recipient of funding from Virginia Oncology Associates and US Oncology. S. Anthony: Consultant for Paradigm.All other authors have declared no conflicts of interest.

4026 Background: Radioimmunotherapy (RAIT) is an option to avoid side effects of further chemotherapy for advanced metastatic pancreatic ductal cancer (mPC). This multicenter, phase Ib study aimed ...

8068 Background: DKN-01 is a high affinity neutralizing humanized Mab targeting extracellular dickkopf-1 (Dkk-1). Dkk-1 inhibits the canonical Wnt/β-catenin signaling pathway and modulates other bi...

TPS2646^ Background: Here we are introducing a novel signal-finding clinical trial protocol series, termed the Novartis “Signature” program. These are tissue-agnostic, mutation specific protocols t...

11109 Background: Next generation sequencing (NGS) of routinely fixed tissue from pts with advanced solid tumors may inform treatment planning. Foundation Medicine has developed a CLIA-certified, C...

651 Background: MM-111 (111) inhibits ligand activated HER3 signaling in HER2+ tumors. This study evaluated the safety of 111 combined with standard of care (SOC) HER2-targeting regimens (Rx): cape...

2588 Background: Dual inhibition of the PI3K and MAPK signaling pathways is a promising strategy for optimal anticancer therapy. In this phase 1b trial we determined the maximum tolerated dose (MTD...

537 Background: Treatment for locally advanced rectal cancer (LARC) includes preoperative radiation concurrent with fluoropyrimidine chemotherapy (CRT). Local recurrence is a problem. Cetuximab is active in colorectal cancer and is effective with radiotherapy in other diseases. This study evaluated the pathologic response rate for LARC treated with preoperative chemoradiotherapy w/wo cetuximab. Methods: LARC (T3/4 or LN+, M0) pts were randomized to Arm1/Arm2. Arm 1 received standard pelvic radiotherapy (5040-5400cGy in daily fractions) with continuous infusional 5-FU (225mg/m2/day); Arm 2 received identical chemoradiotherapy + concurrent cetuximab (400mg/m2 initial dose) 1 week before pelvic radiotherapy, followed by 250mg/m2 weekly for the duration of chemoradiotherapy. After study treatment completion, pts were re-evaluated clinically and radiographically for clinical response. After 6-8 weeks, patients underwent surgical resection. The primary end point was pathologic CR (pCR), and secondary endpoints included ORR, RFS, OS, and local recurrence rates. Results: 139 pts were enrolled (Arm 1=69/Arm2=70); Arm1/Arm2 median age 61/55 yrs, and stage II and III 59%, 39%/40%, 60%. In 124 postsurgery pts, pCR occurred in 17 Arm 1 pts (28.3%, 95% CI 17.5-41.4) and 17 Arm 2 pts (26.6%, 95% CI 16.3-39.1); TRG postsurgery was similar between treatment arms (Table). Grade 3 and 4 toxicities were largely nonhematologic: diarrhea 16%/22%, rash 0%/12%, dehydration 5%/8%, mucositis 5%/6%. The 5-yr RFS for Arm1/Arm2 was 61%/65%, 5-yr OS was 66%/83%, local recurrence was 3%/4%. Conclusions: The addition of cetuximab to preoperative CRT for LARC was associated with increased but manageable toxicities. pCR rates were similar between treatment arms, as were survival statistics and local recurrence rates. No association was found between KRAS status and pCR. Clinical trial information: NCT00527111. [Table: see text]

▪ Abstract Gibberellins are hormones that control growth and a wide variety of other plant developmental processes. In recent years, significant progress has been made on the biochemistry of gibberellin biosynthesis and on the mechanisms by which gibberellin levels are regulated in plants. There have also been major advances in the understanding of gibberellin signaling, with several key genes being cloned. This review discusses our current understanding of gibberellin signaling, as seen from the perspective of molecular genetic analysis, and relates these observations to previous biochemical studies. In particular, we highlight an important conclusion of recent years: that GAI/RGA and orthologs play major roles in gibberellin signaling in diverse plant species, and that gibberellin probably stimulates growth by derepression of GAI/RGA.

The purpose of this study is to determine immune recovery and function after treatment with docetaxel or paclitaxel. Peripheral blood mononuclear cells were harvested before chemotherapy and at weekly times afterwards for cycle 1. Leukocyte subsets ICD45hiCD14lo polymorphonuclear neutrophils, CD45hiCD14hi monocytes, CD45hiCD14- lymphocytes, CD3+CD4/CD8+ T cells, CD3-CD19+ B cells, CD3-CD16/CD56+ natural killer (NK) cells], and circulating cytokine levels [tumor necrosis factor-alpha, gamma-interferon (gamma-IFN), and interleukins (IL-2, IL-10, IL-12)] were followed. In addition, T-cell mitogenic function, NK function, and lymphokine activated killer (LAK) function was assessed. Ten patients were entered in the trial. T-cell frequency, B-cell frequency, and CD4/CD8 ratio did not change. IL-10 serum levels significantly decreased in paclitaxel-treated patients (4.4+/-1.3 pg/ml at week 4 versus 7.8+/-2.1 pg/ml at baseline; p < 0.05). IL-2, IL-12, and gamma-IFN levels were not detectable. NK cytotoxic activity decreased in docetaxel-treated patients. LAK cell activity was not altered. Four patients achieved a partial or complete response. They demonstrated higher than normal CD4:CD8 T-cell ratios and an improved phytohemagglutinin stimulation index (SI = 2.5). In conclusion, our findings suggest that immune function was affected more significantly after docetaxel treatment. Investigational approaches, which enhance cellular immunity, may be of greater relevance after treatment with docetaxel. Additional studies monitoring NK function after chemotherapy are recommended.

The geared servomechanism is an important device used in many industrial applications for transferring power and motion. Over time, the meshing of gear teeth will lead to wear and damage. In this paper, the dynamics of a spur gear pair with damage to a single tooth will be investigated. Damage associated with the formation of a fillet crack and spalling will be simulated. The dynamic forces induced often result in a higher level of noise and vibration within the gear system: The prime direction of the present work is to study the effects of damage on the transient and steady-state vibration response of a spur gear pair. Simulation results indicate that damage significantly affects the response of the system and may accelerate tooth failure.

GRAS is a recently discovered family of plant-specific proteins that play important regulatory roles in diverse aspects of plant development. Several of the motifs present in the GRAS proteins suggest that they function as transcription factors, although homology-searching programs have revealed no significant similarity to any non-plant proteins. Here we propose that the GRAS proteins are related to the Signal Transducers and Activators of Transcription (STAT) family of proteins. STATs are known in many non-plant species, and act as intracellular intermediaries between extracellular ligands and the transcription and activation of genes. Our hypothesis is that the GRAS proteins perform this function in plants, with mechanisms similar to those of the animal STATs. If true, this hypothesis has important implications for the evolution of phosphotyrosine based signal transduction systems in eukaryotic organisms. BioEssays 22:573-577, 2000.

Industrial exposure and pharmaceutical use of antimony compounds have been linked to altered cardiovascular function and pathology. Antimony compounds induce hypotension, bradycardia, and cardiac arrhythmias, all of which can arise from aberrations in myocyte regulation of intracellular free calcium concentration ([Ca 2+ ] i ). To determine if trivalent antimony affects [Ca 2+ ] i during excitation–contraction, we developed an in vitro cardiac myocyte model that was exposed for 24 hr to potassium antimonyl tartrate (PAT) at 0–10 μ m . Control myocytes received sodium potassium tartrate. Concentrations of up to 10 μ m PAT were without effect on total DNA and protein content of cultures, indicating that PAT exposures were not overtly toxic. However, spontaneous beating rates of myocytes were significantly reduced by 5 and 10 μ m PAT. Myocytes were paced by electric field stimulation at 0.5 Hz, and the effect of PAT on [Ca 2+ ] i transients during excitation–contraction was monitored with fura-2. PAT (2–8 μ m ) significantly reduced systolic [Ca 2+ ] i in a concentration-dependent fashion, but was without effect on diastolic [Ca 2+ ] i or on the first derivative of the transient rise ( d [Ca 2+ ] i / dt ). Myocytes from control cells responded to epinephrine (10 −8 –10 −5 m ) in concentration-dependent fashion with elevated systolic [Ca 2+ ] i and an increase in the rate of decay of transients. In PAT-exposed myocytes, the systolic response was blunted while the decay rate was enhanced. PAT-exposed cells also exhibited a reduced basal [Ca 2+ ] i when depolarized by 90 m m KCl and a reduced caffeine-releasable Ca 2+ pool of the sarcoplasmic reticulum. Both control and PAT-treated cells responded to ryanodine in a comparable fashion. Results indicate that a nonlethal exposure to PAT reduces Ca 2+ availability during excitation–contraction. Decreased influx of Ca 2+ across the sarcolemma and enhanced removal of Ca 2+ appear to be responsible.

Trivalent antimony, delivered as potassium antimonyl tartrate (PAT), has been previously shown to induce an oxidative stress and toxicity in cultured neonatal rat cardiac myocytes. The present study investigates the effect of PAT on intracellular free calcium ([Ca2+]i), which has been implicated in the toxicity of agents inducing oxidative stress, and explores its role in PAT toxicity. Exposure to 50 or 200 microM PAT led to progressive elevation in diastolic or resting [Ca2+]i and eventually a complete loss of [Ca2+]i transients that occurred well before cell death as assessed by LDH release. Prior loading of myocytes with the intracellular calcium chelator BAPTA (10 to 40 microM), protected against PAT toxicity in the presence and absence of extracellular calcium, and demonstrated a crucial role for [Ca2+]i in PAT toxicity. Exposure to 200 microM PAT in the absence of extracellular calcium slightly elevated [Ca2+]i, but only to levels comparable to resting [Ca2+]i for cells in 1.8 mM extracellular calcium. This demonstrated that although PAT toxicity was dependent on [Ca2+]i, a large increase above resting levels was not needed, and also that some calcium was mobilized from intracellular stores. However, the caffeine-releasable pool of sarcoplasmic reticulum calcium was increased, not depleted, by exposure to 200 microM PAT. These results demonstrate that PAT disrupts [Ca2+]i handling and support a role for a calcium-dependent event, but do not support the necessity of events in PAT-induced cell death that are mediated by a large elevation in [Ca2+]i.

The purpose of the present study was to determine if cardiac actions of dichloromethane (DCM) in vivo correlate with in vitro alterations of Ca2+ dynamics in cardiac myocytes. Neonatal rat ventricular myocytes were obtained from 2- to 4-day-old rats, and electrically induced fluctuations of cytosolic free Ca2+ concentration ([Ca2+]i) in single cardiomyocytes were investigated using spectrofluorometric analysis of fura-2-[Ca2+]i binding. In cultured myocytes, cumulative exposure to 0.64–40.96 mM DCM resulted in a concentration-dependent and reversible decrease in the magnitude of [Ca2+]i transients with IC10 and IC50 values of 7.98 and 18.82 mM, respectively. Total inhibition of [Ca2+]i transients and cessation of beating were observed at 40.96 mM DCM. Suffusion with DCM for 40 min did not cause morphological alterations of the myocytes. In a urethane-anesthetized rat model, left ventricular pressure was measured by introducing a tip catheter via the carotid artery into the left ventricle, the ECG was recorded by two needle electrodes applied subcutaneously to the chest wall, and arterial pressure was measured via the femoral artery. Oral administration of 3.1–12.4 mmol DCM/kg resulted in DCM blood concentrations between 1.0 and 1.6 mM, accompanied by a dose-dependent decrease in contractile force and heart rate without influencing blood pressure and ECG tracings. Moreover, DCM treatment provided significant protection against arrhythmia development due to CaCl2-infusion. In spite of the slight discrepancy between DCM blood concentrations and in vitro concentrations of DCM for [Ca2+]i transient inhibition, present data are consistent with the view that cardiac effects after DCM exposure are mediated by alterations of Ca2+ dynamics during excitation-contraction coupling.

Background Ligand-activated HER3 forms a potent signaling heterodimer with HER2 and is emerging as key tumorigenic node and mediator of drug resistance. MM-111 (111) is a novel molecule that inhibits ligand activated HER3 signaling in HER2+ tumors. Preclinically, MM-111 potentiates the anti-tumor activity of and mitigates resistance to trastuzumab, lapatinib and chemotherapies. This study evaluates the safety of MM-111 combined with standard of care (SOC) HER2-targeting regimens (Rx), namely; capecitabine (X), cisplatin (C), and trastuzumab (T) (Arm 1); lapatinib (L) + /- trastuzumab (Arm 2); and paclitaxel (P) with trastuzumab (Arm 3). Methods This was a multi-arm Phase 1, dose escalation study of MM-111 in combination with SOC regimens to evaluate safety, pharmacokinetics (PK), and anti-tumor activity. Patients were required to have documented advanced HER2+ cancer, with adequate organ function. Each arm was designed to run as a separate Phase 1 study to address safety and tolerability and each arm utilized a "3 + 3" design with standard dosing of the SOC regimen. MM-111 was dosed weekly at 10mg/kg and escalated up to 20mg/kg where possible. Results As of 30 March 2012, thirty patients had been enrolled across three arms. Dose-limiting toxicities (DLTs) included myelosuppression, infection, vomiting, diarrhea, mucositis, hypokalemia, hyponatremia, hypophosphatemia, hyperuricemia and one report of congestive heart failure (CHF). Serious Adverse Events (SAEs) included pneumothorax, confusion, hemiparesis, seizure, sepsis, diarrhea, disease progression and CHF (also DLT). The table below summarizes patient outcomes. Cohort 1 Arm 1 Arm 2 Arm 3 Rx (Dose) X (1000) C (80) T (4/2) L (1000 mg) T (4/2) P (80) T (4/2) 111 (10) 111 (10) 111 (10) Units 111 & T (mg/kg) X C & P (mg/m2) N 6 3 8 DLT 4 0 1 SAE 4 1 2 Cohort 2 XCT LT PT 111 (5) 111 (20) 111 (20) N 3 7 3 DLT 2 1 0 SAE 0 4 0 CR; PR; SD /N 1 CR;2 PR;2 SD /9 2 PR/10 4 PR;5 SD /11 MM-111 dosing required further reduction to 5mg/kg in arm 1 but was safely escalated to 20mg/kg in arms 2 and 3. Conclusion Overall, MM-111 could be safely combined with SOC HER2 regimens. Additional safety, PK and efficacy data will be provided. Disclosure C. McDonagh: Employed by Merrimack. Stock Ownership. S. Frye: employed by Merrimack. Stock Ownership. V. Moyo: Employed by Merrimack. Stock Ownership. All other authors have declared no conflicts of interest.

LBA3501 Background: Perifosine (P) is an oral, synthetic alkylphospholipid that inhibits or modifies signal transduction pathways including AKT, NFkB and JNK. A randomized phase II study examined P-CAP vs. CAP in pts with 2nd or 3rd line mCRC. This study showed improvement in mTTP (HR 0.254 [0.117, 0.555]) and mOS (HR 0.370 [0.180,0.763]). Based on these results, a randomized phase III study of P-CAP vs. CAP with a primary endpoint of overall survival (OS) in pts with refractory mCRC was initiated. Methods: The study was a prospective, randomized, double-blind, placebo-controlled randomized phase III trial. Eligible pts had mCRC which was refractory to all standard therapies. Pts randomized 1:1 to Arm A = P-CAP (P 50 mg PO QD + CAP 1000 mg/m2PO BID d1-14) or Arm B = CAP (placebo + CAP 1000 mg/m2 PO BID d 1-14). Cycles were 21 days. Baseline tumor block collection and a biomarker cohort of pts with pre- and on-treatment tumor and blood samples were performed. Results: Between 3/31/10 and 8/12/11, 468 pts were randomized, 234 pts were in each arm. Baseline demographics were balanced between the arms: age < 65y (A: 65%, B: 58.5%), male (A: 57.7%, B: 53.0%), ECOG PS 0 (A: 39.7%, B: 39.7%), K-ras mutant (A: 50.4%, B: 51.3%), and median number of prior therapies (A: 4, B: 4). As of 3/19/12, median follow up was 6.6 months. Median overall survival: Arm A = 6.4 mo, Arm B = 6.8 mo, HR 1.111 [0.905,1.365], p = 0.315. Median overall survival for K-ras WT pts: Arm A = 6.6 mo, Arm B = 6.8 mo, HR 1.020 [0.763,1.365], p = 0.894; K-ras mutant pts: Arm A = 5.4 mo, Arm B = 6.9 mo HR 1.192 [0.890,1.596], p = 0.238. Conclusions: Despite promising randomized phase II data, this phase III study shows no benefit in overall survival adding perifosine to capecitabine in the refractory colorectal cancer setting. Response rate, progression free survival, and safety data will be presented. Biomarker analysis is pending to see if subgroups of patients may have potential benefit.

Introduction Patients with resected pancreas cancer treated with standard of care gemcitabine have a median overall survival of 22 months (vs 20 months with observation). Activating mutations in ras occur in > 90% of pancreas cancer cases. GI-4000 is a proprietary immunotherapy designed to target cells with activating ras mutations using whole, heat-killed recombinant Saccharomyces cerevisiae yeast (called Tarmogens = Tar geted Mo lecular Immuno gens ). Tarmogens have demonstrated selective killing of target cells expressing a number of cancer antigens including mutated Ras in vivo by activating an antigen-specific T cell mediated response. This trial is designed to evaluate the efficacy, immunogenicity, and safety of GI-4000 plus gemcitabine in patients with Ras mutant positive resected pancreas cancer. Methods The study enrolled 176 subjects with Ras mutant positive adenocarcinoma of the pancreas post resection randomized 1:1 to GI-4000 plus gemcitabine or placebo plus gemcitabine (stratified by resection status; R0 or R1). Three weekly injections of GI-4000 or placebo were followed by 6 cycles of gemcitabine 1000 mg/m2 iv (day 1, 8, 15 every 28 days). Monthly GI-4000 or placebo were administered on the gemcitabine off-weeks and continued monthly until disease recurrence, intolerable toxicity, or death. The primary endpoint is recurrence-free survival. Data for the 39 R1 subjects (GI-4000 N = 19, Placebo N = 20) have been unblinded and analyzed. Results The GI-4000 group had an 11.4 week advantage in median overall survival (524 days vs 444 days), 16% advantage in 1 year survival (72% vs 56%), and a 4.6 week advantage in median RFS (287 days vs 255 days). The GI-4000 group showed a significantly higher rate of mutation specific T cell response to Ras by ELISpot assay; 7/15 (47%) vs 1/12 (8%), p = 0.032,with a more pronounced survival benefit in GI-4000 treated immune responders; 21.7 week advantage in median survival (596 Days vs 444 Days) compared to placebo. No significant novel toxicities have been observed to date. Conclusion GI-4000 in combination with adjuvant gemcitabine showed a clinically meaningful point estimate for the treatment effect on survival in R1 subjects with Ras mutant positive adenocarcinoma of the pancreas. GI-4000 was immunogenic and well tolerated. Ras specific immune response was associated with a more pronounced benefit in median survival. These data warrant further study in a definitively powered clinical trial for GI-4000 in the adjuvant setting in R1 subjects. The results for the R0 cohort will be reported when the data are mature.

e14501 Background: Patients with resected pancreas cancer treated with standard of care Gem have a median overall survival of 22 months (vs 20 months w/ observation). Activating mutations in ras occur in > 90% of pancreas cancer cases. GI-4000 is whole, heat-killed recombinant S. cerevisiae yeast that expresses mutated Ras proteins. This trial is designed to evaluate the efficacy, immunogenicity, and safety of GI-4000 plus Gem in patients with Ras mutant + resected pancreas cancer. Methods: The study enrolled 176 Ras mutant + pancreas cancer subjects post resection randomized 1:1 to GI-4000 plus Gem or placebo plus Gem (stratified by resection status; R0 or R1). Three weekly injections of GI-4000 or placebo were followed by 6 cycles of Gem 1000 mg/m2 iv (day 1, 8, 15 every 28 days). Monthly GI-4000 or placebo were administered on the Gem off-weeks and continued monthly until intolerance, disease recurrence, or death. The primary endpoint is RFS. Data for the 39 R1 subjects (GI-4000 n=19, Placebo n=20) have been unblinded and analyzed. Results: The GI-4000 group had an 11.4 week advantage in median overall survival (524 Days vs 444 Days), 16% advantage in 1 year survival (72% vs 56%), and a 4.6 week advantage in median RFS (287 Days vs 255 days). The GI-4000 group showed a significantly higher rate of mutation specific T cell response to Ras by ELISpot assay; 7/15 (47%) vs 1/12 (8%), p=0.032,with a more pronounced survival benefit in GI-4000 treated immune responders; 21.7 week advantage in median survival (596 Days vs 444 Days) compared to placebo. No significant novel toxicities have been observed to date. Conclusions: GI-4000 in combination with adjuvant Gem showed a clinically meaningful point estimate for the treatment effect on survival in R1 subjects with Ras mutant + pancreas cancer. GI-4000 was immunogenic and well tolerated. Ras specific immune response was associated with a more pronounced benefit in median survival. These data warrant further study in a definitively powered clinical trial for GI-4000 in the adjuvant setting in R1 subjects.

9117 Background: There are limited tx options for CIT. Epag, an oral, small molecule, thrombopoietin-receptor agonist that increases platelet (plt) production, is being explored for tx of CIT. Methods: This was the Ph I portion of a Ph I/II, blinded, pbo-controlled multicenter study in adults with solid tumors and baseline plts ≤300,000µL, who received up to 6 cycles of gem (1000-1250 mg/m2 IV) as monotherapy on Days 1, 8, and 15 Q28 days or Days 1 and 8 Q21 days in combination with cisplatin (50-80 mg/m2 IV Day 1 or divided 1 and 8) or carboplatin (AUC 4-7 IV Day 1). Patients received ctx alone for Cycle 1 and ctx plus epag or matching pbo (randomized 3:1) daily on Days -5 to -1 and 2 to 6 for subsequent cycles. Epag or pbo was interrupted for plts ≥400,000/µL. Results: 33 patients were randomized; 26 received epag or pbo (Table). Data review with an external, independent physician found no safety concerns, and there were sufficient plt increases with a dose of 100 mg epag vs pbo. No dose-limiting toxicities were reported for epag but 1 for pbo. Most AEs were grade 1 or 2. The most common AE in combined epag- and combined pbo-treated groups was neutropenia. Conclusions: Epag was well-tolerated and improved plt counts. Based on these encouraging Ph I results, Ph II using 100 mg epag in thrombocytopenic patients is planned. [Table: see text]

2516 Background: Skeletal muscle wasting (cachexia) is a prevalent and not readily managed condition in advanced cancer patients. LY2495655 is a humanized monoclonal antibody to myostatin, which has demonstrated positive effects on cachexia measures in animal models. We present phase I trial data on use of LY2495655 in healthy volunteers (Study 1) and interim data from an ongoing phase I study in patients with advanced cancer (Study 2). Methods: Study 1 was a randomized, placebo-controlled, blinded, single-dose, parallel, dose-escalation study evaluating the safety and tolerability of IV or SC LY2495655 (0.7 mg-700 mg). Study 2 is an ongoing nonrandomized, open-label study evaluating the safety and pharmacokinetics (PKs) of LY2495655 in patients with advanced cancer not receiving chemotherapy. Dose cohorts (2 mg-700 mg, ≥3 patients per cohort) were to be treated until the maximum tolerated dose (MTD) was met, or the highest dose (700 mg) cohort was completed. Final locked data from Study 1 and interim data from the dose escalation phase of Study 2 were used in the analyses. Results: In Study 1, 64 healthy volunteers were enrolled (48 LY2495655, 16 placebo). In Study 2, 22 patients had received treatment with LY2495655 at the time of the analysis. In both studies, all doses of LY2495655 were well tolerated (no DLTs were observed and MTD was not reached), and nonlinear PKs were observed (most evident in lower dose levels). In Study 1, thigh muscle volume generally increased with LY2495655. In Study 2, increased muscle volume was observed only at 21-mg and 70-mg doses. Consistent increases in hand grip strength and improvements in functional tests were observed at doses ≥21 mg. Conclusions: There were no unusual safety concerns in healthy subjects or cancer patients. PK results were consistent between the 2 studies. Increases in muscle volume were observed in both studies, with concomitant improvement in functional measures. However, there is no clear trend in dose-dependent efficacy, possibly due to extremely small sample sizes and patient heterogeneity. Enrollment in Study 2 continues with dose expansion cohorts. A Phase 2 study is ongoing in pancreatic cancer patients.

e18047 Background: IMO-2055 is a novel TLR-9 agonist with potential to enhance the efficacy of biologics and small molecules through immune stimulation. Xenograft data show anti-tumor synergy between IMO-2055, E and bev; E-bev has been evaluated in 2nd line NSCLC. Methods: Primary objective was to determine the recommended dose (RD) of IMO-2055 (dose range 0.08-0.48 mg/kg/w s.c.) with E 150mg/day p.o. and bev 15mg/kg q3w i.v. in a standard 3+3 design. An expansion cohort at the RD further determined safety and efficacy. Pts had AJCC stage 3/4 inoperable, histologically proven NSCLC where standard chemotherapy was not an option. Treatment was until progression (PD) or toxicity. Results: 36 pts were enrolled at 10 US sites from Nov ‘07 to Mar '11. 35 were treated/evaluable for safety; 33 for efficacy. Median age was 64, 58% were men, 81% white, 81% PS 1 with 69% adenocarcinomas and median 17 months since diagnosis. 44% pts were >2nd line. Pts received a median of 4.3 3-week cycles. 19 pts entered dose-escalation: 4 at 0.08 mg/kg, 6 at 0.16 mg/kg, 6 at 0.32 mg/kg, and 3 at 0.48 mg/kg IMO-2055. Two pts had DLTs: 1 grade 3 dehydration at 0.16 mg/kg, and 1 grade 3 fatigue at 0.48 mg/kg. RD was 0.32 mg/kg based on pharmacodynamic and clinical data: 17 more pts were treated at this dose. The most common AEs were diarrhea, nausea, fatigue and rash; most frequent grade 3-4 AEs were fatigue (9%), diarrhea (9%), anemia and dyspnea (both 6%), with no clear dose-relationship to IMO-2055. G3-4 hypertension was 0%, ATE 6% and hemorrhage 3%. Five pts died of PD on or within 30 days of study drug administration. Response rate was 12% with 79% disease control (SD+PR). Median PFS was 5.6 months (95% CI 3.9-7.2) and OS 16 months (95% CI 7.5-17.8) with 55% pts alive at 1 year. Conclusions: Addition of IMO-2055 to E-bev was well tolerated with no unexpected toxicity. The RD of IMO-2055 with E-bev is 0.32 mg/kg/w s.c. Median PFS and OS in this heavily pretreated population compare favorably with published E-bev data. IMO-2055 should be further explored in NSCLC.

TPS3111 Background: The HER2/HER3 oncogenic heterodimer is a potent HER receptor pairing with respect to strength of interaction, receptor tyrosine phosphorylation, and downstream signaling through mitogen activated protein kinase and phosphoinositide-3 kinase pathways. MM-111 is a novel bispecific antibody fusion protein that inhibits ligand activated HER3 signaling through abrogation of ligand binding specifically in HER2 overexpressing tumors. In preclinical models of HER2+ solid tumors, MM-111 inhibits ligand-induced HER3 phosphorylation, cell cycle progression, and tumor growth. HER2 is a well-established target of anticancer agents such as trastuzumab and lapatinib, specifically in breast and gastric tumors. Preclinical data demonstrate that MM-111 potentiates the antitumor activity of both trastuzumab and lapatinib and this phase I study seeks to determine if MM-111 can be safely used in combination with various standard of care HER2 targeting regimens, namely; (1) trastuzumab, cisplatin and, capecitabine, (2) trastuzumab and lapatinib, and (3) trastuzumab and paclitaxel. Methods: This is a multi-arm phase I, open label, multicenter, dose-escalation study of MM-111 in an add-on design that evaluates the safety, pharmacokinetics (PK), and anti-tumor activity of MM-111 in combination. Each arm is designed to run as a separate phase I study to address safety and tolerability of each combination. For eligibility, patients are required to have documented advanced HER2-positive cancer, with adequate bone marrow, hepato-renal and cardiac function. The dose escalation for each arm utilizes a standard “3 + 3” design with MM-111 dosed initially at a moderate dose of 10 mg/kg and escalated up to 20 mg/kg to identify a phase II dose in combination with each regimen. Once the maximum tolerated dose or phase II dose is identified, expansion cohorts will accrue to further evaluate these combinations. The flexibility of the design allows additional combinations arms to be added. Key exploratory analyses will include an evaluation of safety, PK, and efficacy as evidenced by best overall response and duration of response.

213 Background: IPI-926 is a novel, natural product-derived small molecule that targets the Hedgehog (Hh) pathway by inhibiting smoothened. In preclinical models of pancreatic cancer, repressing activation of the Hh pathway diminishes tumor-associated desmoplasia and improves chemotherapy delivery. Methods: This is the final report of the Phase 1b portion of a Phase 1b/2 trial evaluating the safety and efficacy of IPI-926 plus gemcitabine. Eligible patients (pts) with untreated metastatic pancreatic cancer and ECOG status 0-1 were administered oral IPI-926 daily (QD) for 28-day cycles, in 3 to 6 pt dose cohorts. Gemcitabine (1,000 mg/m2) was administered IV weekly for 3 weeks with 1 week off. DLTs were evaluated during Cycle 1. Results: 16 pts (median age 69 years; range 58-86) were enrolled at IPI-926 doses of 110, 130 or 160 mg QD (single agent MTD). Pts received a median of 5 cycles (1-13). Two pts remain on trial. No IPI-926-related serious AEs have been observed. One DLT of Grade 3 AST increase was observed (130 mg dose cohort) and was asymptomatic; it resolved with dose interruption, and did not recur with dose reduction. The most common AEs occurring were fatigue (75% total, 6% ≥ Grade 3), thrombocytopenia (63%, 25%), anemia (56%, 13%), nausea (50%, 0%), diarrhea (44%, 0%), vomiting (44%, 0%), peripheral edema (44%, 0%), pyrexia (44%, 0%), and AST increase (44%, 13%). Dose reductions of IPI-926 occurred in 3 (19%) pts. Dose reductions of gemcitabine occurred in 11 (69%) pts, primarily for thrombocytopenia (9 pts). One pt (6%) discontinued due to an AE (microangiopathic hemolytic anemia). Five (31%) radiographic partial responses were observed (1/3 at 110 mg, 2/6 at 130 mg, 2/7 at 160 mg). Median progression-free survival is > 7 months. 74% of pts were alive 6 months after study entry. Conclusions: IPI-926 plus gemcitabine is well tolerated in pts with untreated metastatic pancreatic cancer, with evidence of activity and no unexpected toxicity. Complete Phase 1b data, including final overall survival, will be presented. Clinical evaluation of this combination continues in the randomized, double-blind, placebo-controlled Phase 2 portion of the trial.

Individual halogenated hydrocarbons (HC) have recently been demonstrated to depress Ca2+ dynamics in cardiomyocytes during excitation-contraction coupling. In the present study, eight widely used HC were systematically compared for their effects on Ca2+ dynamics in neonatal rat cardiomyocytes by means of spectrofluorometric analysis of fura-2-Ca(2+)-binding. Cells were exposed to dichloromethane (DCM), dichloroethane (DCE), 1,1,2-trichloroethane (112-TCE), trichloroethylene (TRI), halothane (HAL), 1,1,1-trichloroethane (111-TCE), perchloroethylene (PER), or pentachlorethane (PCE) in an environmentally controlled chamber. All HC tested decreased the height of electrically induced cytosolic free Ca2+ ([Ca2+]i) transients in a concentration-dependent and reversible manner (IC50 0.15-18.06 mM) without significant effects on diastolic [Ca2+]i. The increase in [Ca2+]i induced by depolarization with 90 mM KCl was inhibited to a lesser degree. Investigations with thapsigargin (100 nM) and ryanodine (1 microM)-inhibitors of Ca2+ release from the sarcoplasmic reticulum-provided evidence that the tonic Ca2+ response after KCl depolarization depends mainly on sarcolemmal Ca2+ influx. The potency of the eight HC to inhibit Ca2+ dynamics in cardiomyocytes correlated with their octanol/water partition coefficients. Results support the hypothesis that alteration of Ca2+ dynamics in cardiomyocytes is a common mechanism of cardiotoxic HC actions.

Free radical-induced oxidative stress has been linked to ischemia-reperfusion injury of the myocardium. The .OH radical is considered the most damaging radical and can be increased in cells by treatment in vitro with H2O2. The purpose of the present study was to determine if aliphatic halocarbons enhance H2O2-induced oxidative injury in isolated cardiac myocytes from neonatal rats. Oxidative damage was assessed by measuring release of thiobarbituric acid-reactive substances (TBARS) from lipid peroxidation, loss of lactate dehydrogenase (LDH) through damaged sarcolemmal membranes, and alterations in intracellular calcium ([Ca2+]i) transients in electrically stimulated (1 Hz, 10 ms, 60 V) myocytes. H2O2 increased TBARS release and LDH leakage in a concentration-dependent (20-200 microM) manner. Continuous suffusion with H2O2 first altered the configuration of [Ca2+]i transients, then eliminated them, and finally caused [Ca2+]i overload (basal [Ca2+]i exceeded peak systolic [Ca2+]i of control). The time to [Ca2+]i overload was inversely associated with concentration, and the shortest time to overload was obtained with 100 microM H2O2. A 1-h preincubation of myocytes with the iron chelator deferoxamine inhibited all effects of H2O2. 1,1,1-Trichloroethane, carbon tetrachloride, or halothane at 1 mM significantly and reversibly reduced [Ca2+]i transients but did not influence TBARS release or LDH leakage. Simultaneous exposure of myocytes to H2O2 and halocarbons did not affect the myocyte response to H2O2 exposure. Results indicate that the three halocarbons tested do not enhance H2O2-induced oxidative injury in isolated cardiac myocytes.

4015 Background: Advanced adenocarcinoma of the gastroesophageal junction and/or stomach is standardly treated by combination chemotherapy with minimal improvements in survival. This study evaluated the value of adding cetuximab (C) to combination chemotherapy in this disease. Methods: The primary objective of this noncomparative study was progression-free survival (PFS); secondary objectives were 1-yr survival, response rate, time to response (TTR), duration of response (DOR), and safety. Treatment (Tx): Arm 1: DOCOX = docetaxel 60 mg/m2 plus oxaliplatin 130 mg/m2 on Day 1 of each 21-day cycle. Arm 2: DOCOX + C = DOCOX with C 400 mg/2 1st dose, then 250 mg/m2weekly. Key inclusion: stage IV adenocarcinoma of the GEJ/stomach; measurable disease; ECOG 0-2; and normal renal, hepatic, and marrow function; exclusion: any prior Tx other than adjuvant radiation with 5-FU/leucovorin. Results: 150 pts enrolled; 75/arm. Demographics Arm 1/2: male 79%/80%, median age 61/64 yrs; disease site: gastric 44%/41%, GEJ 51%...

6508 Background: Btk is essential to B-cell development and function. Btk is highly-expressed in CLL and its inhibition by the potent irreversible inhibitor PCI32765 (P) promotes apoptosis and inhi...

4018 Background: Docetaxel plus cisplatin and fluorouracil (TCF) improved time to progression and survival compared with CF in advanced gastric cancer (GC). We conducted a randomized phase II study of T plus oxaliplatin (E) with or without fluorouracil (F) or capecitabine (X) in advanced GC. Methods: The GATE study is a multinational, randomized, 3-parallel-arm, stratified study. Optimal doses for all regimens were determined in a pilot phase. Patients ≥18 of age, with a KPS >70 and histologically proven metastatic or locally advanced GC not treated with chemotherapy for advanced GC were randomized to TEF (T 50 mg/m² followed by E 85 mg/m² simultaneously with folinic acid 400 mg/m² followed by F 2400 mg/m² as a 46-hr continuous infusion on Day 1, q2w), TE (T 75 mg/m² followed by E 130 mg/m² on Day 1 q3w), and TEX (T 50 mg/m² followed by E 100 mg/m² Day 1, q3w and X 625 mg/m² BID continuously). The primary objective was time to progression (TTP) in the evaluable population; secondary objectives included re...

randomized discontinuation trial (NCT00940225), see Abstract 371 XL184 is administered orally at a daily dose of 100 mg (125 mg • salt equivalent) study endpoints

3635 Background: Preoperative chemoradiation (CRT) is the standard treatment for patients with localized rectal adenocarcinoma. This noncomparative study assessed the toxicity and efficacy of infus...

TPS226 Background: Patients with resected pancreas cancer treated with standard of care gemcitabine (Gem) have a median recurrence-free survival of 14 months, median overall survival of 22 months, and a survival rate of 20% at 5 years. The postresection patient population represents a compelling model of minimal residual disease for which targeted and active immunotherapy may decrease cancer recurrence and improve survival through elimination of microscopic disease. Activating mutations in ras occur early in the development of pancreas cancer and are subsequently maintained, being found in > 90% of pancreas cancer cases. This trial is designed to evaluate the efficacy, immunogenicity, and safety of GI-4000 plus Gem versus placebo plus Gem in patients with resected pancreas cancer and an activating ras mutation. GI-4000 is a proprietary immunotherapy designed to target cells with activating ras mutations using whole, heat-killed recombinant Saccharomyces cerevisiae yeast (called Tarmogens = targeted molecu...

e13515 Background: P and PLD are clinically active as single agents and synergistic in preclinical models. This phase I, open-label trial determined the maximum tolerated dose (MTD) and safety profile of P followed by PLD in patients (pts) with breast or gynecologic cancers. Methods: Using standard phase I (3+3 dose escalation) study design, cohorts of 3–9 pts received escalating doses of P followed by PLD in 28-day cycles: P 400–500 mg/m2 on Days 1 and 15 and PLD 30–45 mg/m2 on Day 1. All pts received folic acid (350–1000 μg daily) and vitamin B12 (1000 μg) until 21 days after last dose of P. Pts continued until dose-limiting toxicity (DLT) or disease progression (PD) occurred. Results: From 11/05 to 1/08, 29 pts were registered/treated. Median age: 60.6 years (range, 47.5–80.1); ECOG performance status 0/1: 28%/72%; primary disease sites: ovarian (55%), breast (35%), peritoneal (10%); prior therapies: chemotherapy (100%), surgery (72%), hormones/biologics (35%), radiation (21%). Dosing results are shown below. At dose level (L) 2 and L3, 1 pt/cohort had DLTs; L5 was added and 3/3 pts had DLTs; 4 more pts were treated at L4 (1 pt replaced). Most frequent drug-related Grade 3–4 hematologic toxicities: neutropenia (86%), leukopenia (59%), thrombocytopenia (48%), anemia (41%). Most frequent drug-related Grade 3–4 nonhematologic toxicities: hand-foot syndrome (14%), hypokalaemia (10%). Major reasons for discontinuation: PD (48%), toxicity (28%), pt request (14%). Overall best responses (n=24): 5 pts (21%) had partial response (PR), 14 pts (58%) had stable disease (SD), 2 pts (8%) had PD, 3 pts (13%) were not evaluable. All 5 PR and 8 SD pts were ovarian; 5 SD and both PD pts were breast. Conclusions: P followed by PLD was reasonably tolerated in this heavily-pretreated population. The MTD was P 500 mg/m2 and PLD 40 mg/m2. These dose levels may be carried forward to phase II studies in more specific patient populations. [Table: see text] [Table: see text]