Schedule Of Day Research Articles

Trial in Progress: Phase I Open-Label Study of Metformin and Nelfinavir in Combination with Bortezomib in Patients with Relapsed and/or Refractory Multiple Myeloma

Background:GLUT4 inhibition is an attractive therapeutic option in multiple myeloma (MM) given the dependence of MM cells on glucose transport. Furthermore, combining a GLUT4 inhibitor with an oxidative phosphorylation inhibitor in MM cells to counter the possibility of therapeutic resistance to GLUT4 inhibition has demonstrated synergistic promise (Dalva-Aydemir et al, Clin Can Res 2015). Using a GLUT4 inhibitor such as the HIV protease inhibitor nelfinavir is an attractive choice since it not only inhibits the transport function of GLUT4, but it also lowers the cytotoxicity resistance of MM cells against proteasome inhibitors such as bortezomib (Driessen et al, Blood 2018). Thus, in summary the FDA-approved oral HIV-PI nelfinavir, long used for the treatment of HIV disease, can bind to glucose transporters (GLUT4) on MM cells and reversibly inhibit glucose uptake, thus disrupting the Warburg effect. Nelfinavir can also enhance the activity of PIs such as bortezomib overcome its resistance in MM cells. Metformin, an oral FDA-approved drug for the treatment of Type II Diabetes has the ability to disrupt the electron transport chain of defective mitochondria within MM cells, thus blocking the ability of such mitochondria to generate energy and anabolic substrates as compensatory mechanisms required for proliferation in the setting of GLUT4 inhibition. Thus, this study will look at the safety and tolerability of repurposing the existing FDA-approved drugs for Type II diabetes and HIV in combination with bortezomib for the treatment of relapsed and/or refractory myeloma.Methods:This study is a phase 1 clinical trial of metformin and nelfinavir in combination with bortezomib for patients with relapsed and/or refractory myeloma. Part A of this trial is a 3+3 dose escalation design with 3 dose levels planned. Part B is a dose expansion cohort at the Maximal Tolerated Dose (MTD) determined in Part A. Up to a maximum of 36 patients will be enrolled and treated for a maximum of six 21-day cycles. Bortezomib is administered in its usual weekly subcutaneous dosing schedule of days 1, 8 and 15 of a 21-day cycle at a dose level of 1.3 mg/m2. Metformin will be administered for 14 days of a 21-day cycle and started at a dose level of 500 mg twice daily and will be investigated to a maximum dose of 1000 mg twice daily. Nelfinavir will also be administered for 14 days of a 21-day cycle and started at a dose level of 1250 mg twice daily and will be investigated to a maximum dose of 2500 mg twice daily. Key inclusion criteria include having relapsed/refractory myeloma with at least 2 prior lines of therapy and prior exposure to PIs, immunomodulators and Anti-CD38 monoclonal antibodies, adequate hematologic reserve, kidney function and liver function. This trial especially allows patients with non-secretory disease yet measurable by bone marrow assessments or cross-sectional imaging of plasmacytomas to be enrolled which constitutes an unmet need in the real-world MM population. Finally, this allows patients to be treated with a dexamethasone-free regimen. The primary objective of this trial is to determine the MTD of metformin and nelfinavir in combination with bortezomib. The secondary objective is to evaluate the safety and tolerability as well as the overall response rate (ORR) associated with this combination. Potential predictive biomarkers as well as resistance mechanisms using genomic RNA, immunohistochemistry and metabolomics-based assessment platforms will be evaluated in this study. Recruitment is ongoing with no safety concerns. This trial is registered on clinicaltrials.gov: NCT03829020. This investigator-initiated trial was funded by the generous gift of the Helen Diller Family Foundation. DisclosuresKumar: Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Novartis: Research Funding; Carsgen: Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Merck: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy.

Urban Trees and Environmental Variables: Relationships in a City of Central Chile

We identified relationships between ecosystem services provided by trees and environmental variables, including temperature (°C at ground level and 1.5 m), relative humidity (%), particulate matter (PM10, maximum and average), noise (dBA), and ultraviolet radiation (UV at 1.5 m). This study was carried out in Talca, Chile, a mid-sized city. Measurement locations were selected in three areas based along three main avenues in the center of the city during three different seasons and three different schedules of day, generating 15,515 data in total. In circular plots, with 8 meter radiuses, measurements were recorded at the center and at a point on the perimeter. A correlation matrix was calculated and an ANOVA was conducted with canopy cover, schedule of day, and season as variation sources. The results show a high dispersion, and the correlation matrix that canopy coverage has a weak relationship with variables was studied. The results of the ANOVA showed the least number of significant differences associated with the canopy cover, schedule of day, and season, which showed significant differences for all variables. Tree coverage showed significant differences for all variables using the Tukey Test, with the exception of minimum noise. Plots with greater coverage were associated with increases in the particulate matter and relative humidity and decreases in maximum noise, temperature, and ultraviolet radiation. During mornings, the highest measurements of particulate matter, noise, and relative humidity were reported, whereas temperature maximums occurred at mid-day. The results confirm the importance of urban trees, specifically the canopy coverage, in mitigating negative environmental aspects in urban areas.

Trial in Progress: Phase I Dose-Escalation and Dose-Expansion Trial of a Novel Glutaminase Inhibitor (CB-839 HCl) in Combination with Carfilzomib and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma

Background: c-MYC activation is an early event of myeloma pathogenesis. It upregulates the expression of the glutaminase 1 (GLS1) enzyme which converts glutamine to glutamate in the mitochondria. Glutamate is required for the biosynthesis of various molecules in the tricarboxylic acid (TCA) cycle (i.e., glutamine anaplerosis). CB-839 HCl is a first-in-class, orally available, selective, noncompetitive inhibitor of GLS1. This inactivation of GLS1 results in an increase of glutamine and a decrease of glutamate and several TCA cycle intermediates within cancer cells, leading to a decrease in their proliferation and/or an increase in cell death. In the phase 1 study, CX-839-002, the safety and tolerability of CB-839 HCl was evaluated in patients with hematological tumors (multiple myeloma (MM) and non-Hodgkin's lymphoma), either as monotherapy or in combination with pomalidomide and dexamethasone or with dexamethasone alone. It was determined to be well tolerated and the maximal tolerated dose (MTD) was not reached. Proteasome inhibitors (PI) are the cornerstone agents in the treatment of myeloma. They disrupt normal protein homeostasis causing an induction of cellular proteotoxic stress, thus, making it an effective strategy against myeloma plasma cells, which naturally mass-produce large quantities of immunoglobulin proteins. PI-resistant MM cells are associated with changes in cellular bioenergetics that favor the increased use of mitochondrial respiration for energy production. Given the increased reliance of PI-resistant MM cells on mitochondrial respiration, and the critical role of glutamine for cellular respiration, inhibition of glutamine metabolism is a rational molecular strategy for the treatment of PI-resistant MM. Furthermore, pre-clinical studies demonstrate the in vitro and ex vivo synergism of CB-839 HCl with carfilzomib (CFZ) in terms of its cytotoxicity and anti-proliferation capacity in various primary human myeloma cell lines and primary patient myeloma cells respectively. As a result, this novel combination of glutaminase inhibition with proteasome inhibition appears promising as a therapeutic combination in MM and warrants further clinical investigation. Methods: This study is a phase 1, multicenter clinical trial of CB-839 HCl in combination with carfilzomib and dexamethasone for patients with relapsed and/or refractory myeloma. Part A of this trial is a 3+3 dose escalation design and Part B is a dose expansion cohort at the RP2D determined in Part A. Up to a maximum of 42 patients will be enrolled at participating ETCTN sites. CFZ will be administered in its usual weekly dosing schedule of days 1, 8 and 15 of a 28 day schedule along with dexamethasone on days 1, 8, 15 and 22. CB-839 will be started at a dose level of 400 mg twice daily and will be investigated to a maximum dose of 800 mg twice daily. Prior to day 1 of Cycle 1, we will administer a 7 day lead in of CB-839 monotherapy before combining it with CFZ. Key inclusion criteria are having relapsed/refractory myeloma with at least 2 prior lines of therapy and prior exposure to PIs, immunomodulators and Anti-CD38 monoclonal antibodies, having measurable disease, adequate hematologic reserve, kidney function and liver function. Key exclusion criteria are being refractory or intolerant to CFZ, adverse cardiac history, central nervous system disease and AL amyloidosis. The primary objective of this trial is to determine the MTD or recommended phase II dosing (RP2D) of CB-839 HCl in combination with carfilzomib and dexamethasone. The secondary objective is to evaluate the safety and tolerability as well as the overall response rate (ORR) associated of CB-839 HCl in combination with carfilzomib and dexamethasone. Correlative objectives will evaluate plasma pharmacokinetic profiles of CB-839 HCl and carfilzomib when used in combination. They will also evaluate potential predictive and prognostic biomarkers as well as resistance mechanisms using genomic DNA, RNA, flow cytometry, immunohistochemistry and metabolomics-based assessment platforms. Recruitment is ongoing and this trial is registered on clinicaltrials.gov: NCT03798678. Disclosures Baz: Bristol-Myers Squibb: Research Funding; Sanofi: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Merck: Research Funding. Neparidze:Janssen Scientific Affairs, LLC: Research Funding; Eidos Therapeutics: Other: Member of Independent Diagnostic Committee; MMRF/Synteract: Membership on an entity's Board of Directors or advisory committees. Kumar:Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Research Funding.

Long-Term Efficacy and Safety of Copanlisib in Multiply Relapsed or Refractory Patients with Marginal Zone Lymphoma

Long-Term Efficacy and Safety of Copanlisib in Multiply Relapsed or Refractory Patients with Marginal Zone Lymphoma

2773. Safety and Immunogenicity Study of Eastern Equine Encephalitis Vaccine

BackgroundEastern equine encephalitis virus (EEEV) is an alphavirus with a high mortality rate and serious neurological sequelae in infected persons making this virus an important human pathogen.MethodsFollowing written informed consent, eligible subjects received two priming doses of EEEV vaccine, inactivated, TSI-GSD 104, 0.5 mL subcutaneously on days 0 and 28 days followed by a mandatory booster, 0.1 mL intradermal, at 6 months. Serum samples were collected pre-vaccination, days 21–35 following dose 2, as well as before and 21–35 days after dose 3. Sera with a Plaque Reduction Neutralization Test80 titer (PRNT80) ≥ 1:40 were considered responders with adequate titers for the purpose of biocontainment suite entry.ResultsSixty-seven (67) subjects were enrolled in this study to receive the primary vaccination series. All 67 subjects received at least 1 primary vaccination; 66 completed the 2 primary doses; 58 completed the 2 primary doses and the 6-month dose. Of these, 38 (56.7%) reported one or more adverse events. Fatigue was reported in 13 (19.4%), headache in 9 (13.4%), upper respiratory tract infection in 6 (9.0%), nausea in 5 (7.5%), pyrexia in 5 (7.5%), oropharyngeal pain in 4 (6.0%), myalgia in 4 (6.0%), injection site pain in 7 (10.4%), injection site hematoma in 4 (6.0%) and injection site erythema in 3 (4.5%) subjects. Adverse events were mostly mild or moderate and transient. PRNT80 titers ≥ 1:40 was observed in 39/65 (60%) subjects who received both primary doses of EEEV vaccine compared with 48/57 (84%) subjects who completed the 2-dose primary series and the 6-month dose and also had blood drawn for titer. Females had a higher response rate (61.5%) at the pre 6-month boost titer than did males (34.3%) (p = 0.0231). Similarly, the pre 6-month boost geometric mean titer (GMT) for females was 35.5 vs. 21.9 for males (p = 0.0231). The post 6-month boost GMT for females was 146.7 and 181.5 for males (P = 0.13).ConclusionInactivated Eastern Equine Encephalitis Virus vaccine, TSI-GSD 104, Lot 2-1-89 appears to be safe and immunogenic. This Phase 2 vaccine study supports a priming dose schedule of Days 0 and 28 and 6-month. The 6 month dose is anamnestic improving the overall response rate and level of antibody for this primary dosing schedule.Disclosures All authors: No reported disclosures.

AEOL 10150 Mitigates Radiation-Induced Lung Injury in the Nonhuman Primate: Morbidity and Mortality are Administration Schedule-Dependent.

Pneumonitis and fibrosis are potentially lethal, delayed effects of acute radiation exposure. In this study, male rhesus macaques received whole-thorax lung irradiation (WTLI) with a target dose of 10.74 Gy prescribed to midplane at a dose rate of 0.80 ± 0.05 Gy/min using 6 MV linear accelerator-derived photons. The study design was comprised of four animal cohorts: one control and three treated with AEOL 10150 (n = 20 animals per cohort). AEOL 10150, a metalloporphyrin antioxidant, superoxide dismutase mimetic was administered by daily subcutaneous injection at 5 mg/kg in each of three schedules, beginning 24 ± 2 h postirradiation: from day 1 to day 28, day 1 to day 60 or a divided regimen from day 1 to day 28 plus day 60 to day 88. Control animals received 0.9% saline injections from day 1 to day 28. All animals received medical management and were followed for 180 days. Computed tomography (CT) scan and baseline hematology values were assessed prior to WTLI. Postirradiation monthly CT scans were collected, and images were analyzed for evidence of lung injury (pneumonitis, fibrosis, pleural and pericardial effusion) based on differences in radiodensity characteristics of the normal versus damaged lung. The primary end point was survival to 180 days based on all-cause mortality. The latency, incidence and severity of lung injury were assessed through clinical, radiographic and histological parameters. A clear survival relationship was observed with the AEOL 10150 treatment schedule and time after lethal WTLI. The day 1-60 administration schedule increased survival from 25 to 50%, mean survival time of decedents and the latency to nonsedated respiratory rate to >60 or >80 breaths/min and diminished quantitative radiographic lung injury as determined by CT scans. It did not affect incidence or severity of pneumonitis/fibrosis as determined by histological evaluation, pleural effusion or pericardial effusion as determined by CT scans. Analysis of the Kaplan-Meier survival curves suggested that treatment efficacy could be increased by extending the treatment schedule to 90 days or longer after WTLI. No survival improvement was noted in the AEOL 10150 cohorts treated from day 1-28 or using the divided schedule of day 1-28 plus day 60-88. These results suggest that AEOL 10150 may be an effective medical countermeasure against severe and lethal radiation-induced lung injury.

Clinical Pharmacokinetics of Apto-253 Support Its Use As a Novel Agent for the Treatment of Relapsed or Refractory Hematologic Malignancies

APTO-253 is a novel anticancer small molecule currently in a multicenter open-label, Phase I dose escalation study in patients with relapsed or refractory hematologic malignancies. APTO-253 has potent cytotoxic activity against leukemia, lymphoma and myeloma cell lines IC50s of 6.9 - 305 nM. APTO-253 produces significant tumor growth inhibition in the KG-1, THP-1 and Kasumi-1 xenograft models of human acute myeloid leukemia (AML). The anticancer activity of APTO-253 is mediated through induction of Krüppel-like factor 4 (KLF4), a tumor suppressor that is epigenetically silenced in many solid tumors and hematologic cancers. KLF4 expression is often downregulated in AML due to repressive binding of CDX2 to the KLF4 promoter. Increased levels of CDX2 are found in the majority of patients with AML and ALL, as well as in 40% of MDS patients, whereas CDX2 is not expressed in normal hematopoietic cells. Treatment of cultured AML cells with APTO-253 reverses the KLF4 silencing, resulting in induction of p21 and cell death by apoptosis. KG-1 AML cells treated with APTO-253 showed time- and concentration-dependent induction of KLF4 and a concentration-dependent increase in p21 mRNA levels following induction of KLF4. APTO-253 treatment of KG-1 cells for 24 h induced a 14-fold increase in KLF4 mRNA and 16-fold increase in p21 mRNA over basal levels. Following washout of APTO-253, the level of KLF4 mRNA decayed to approximately 50% of maximum induction level over a 24 h period.The potential for APTO-253 as a therapeutic option in AML was further supported by safety and pharmacokinetics data from an earlier Phase I trial of APTO-253 in patients with advanced or metastatic solid tumors during which APTO-253 was administered at doses of 20 - 387 mg/m2 using a dosing schedule of days 1 and 2, and 15 and 16 of a 28 day cycle. APTO-253 showed a dose-dependent increase in Cmax and AUC, and as the dose was escalated from 80 to 176 mg/m2 the Cmax ranged from 1,800 - 4,960 nM on day 1 and 1,600 - 6,100 nM on day 2. These results suggest that exposure levels from these doses of APTO-253 should be sufficient for single agent activity in patients with AML and other hematologic malignancies.APTO-253 demonstrated a favorable safety profile when tested against 5 major cytochrome P450 enzymes (1A2, 2C19, 2C9, 2D6 and 3A4), against a panel of proteins and receptors, and in the hERG tail current density assay. Metabolic profiling of APTO-253 at 50 μM in human liver microsomes showed no glutathione or glucuronide conjugation and only a minor hydroxylated metabolite. Finally, 1 μM APTO-253 did not inhibit kinases in a safety panel (40 kinases) or in a broad oncology panel (98 kinases), demonstrating that APTO-253 activity is not driven by kinase inhibition.Taken together, our results demonstrate that APTO-253 has substantial potential for the treatment of AML and other hematologic malignancies and is of particular interest due to its ability to modulate the expression of the KLF4 master transcription factor that plays a central role in restraining the growth of leukemic cells. DisclosuresHowell:Aptose Biosciences: Consultancy, Equity Ownership; Angstrom: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abeoda: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; InhibRx: Equity Ownership.

APTO-253 Induces KLF4 to Promote Potent in Vitro Pro-Apoptotic Activity in Hematologic Cancer Cell Lines and Antitumor Efficacy As a Single Agent and in Combination with Azacitidine in Animal Models of Acute Myelogenous Leukemia (AML)

APTO-253, a small molecule that mediates anticancer activity through induction of the Krüppel-like factor 4 (KLF4) tumor suppressor, is being developed clinically for the treatment of acute myelogenous leukemia (AML) and high risk myelodysplastic syndromes (MDS). APTO-253 was well tolerated in a Phase I study in patients with solid tumors using a dosing schedule of days 1, 2, 15, 16 of a 28 day cycle (2T-12B-2T-12B), but recent scientific observations guided APTO-253 toward AML and high risk MDS. Indeed, suppression of KLF4 was reported as a key driver in the leukemogenesis of AML and subsets of other hematologic diseases. The vast majority (~90%) of patients with AML aberrantly express the transcription factor CDX2 in human bone marrow stem and progenitor cells (HSPC) (Scholl et al., J Clin Invest. 2007, 117(4):1037-48). The CDX2 protein binds to CDX2 consensus sequences within the KLF4 promoter, thereby suppressing KLF4 expression in HSPC (Faber et al., J Clin Invest. 2013, 123(1):299-314). Based on these observations, the anticancer activity of APTO-253 was examined in AML and other hematological cancers. APTO-253 showed potent antiproliferative activity in vitro against a panel of blood cancer cell lines, with ηM IC50values in AML (6.9 - 305 ηM), acute lymphoblastic leukemia and chronic myeloid leukemia (39 – 250 ηM), non-Hodgkin’s lymphoma (11 – 190 ηM) and multiple myeloma (72 – 180 ηM). To explore in vivo efficacy, dose scheduling studies were initially conducted in the H226 xenograft model in mice. In the H226 model, APTO-253 showed improved antitumor activity when administered for two consecutive days followed by a five day break from dosing (2T-5B) each week, i.e. on days 1,2, 8,9, 15,16, 22,23, compared to the 2T-12B-2T-12B schedule. The 2T-5B schedule was used to evaluate antitumor activity of APTO-253 in several AML xenograft models in mice. In Kasumi-1 AML and KG-1 AML xenograft models, APTO-253 showed significant antitumor activity (p = 0.028 and p=0.0004, respectively) as a single agent when administered using the 2T-5B schedule each week for four weeks compared to control animals. Mice treated with APTO-253 had no overt toxicity based on clinical observations and body weight measurements. Mice bearing HL-60 AML xenograft tumors were treated with APTO-253 for one day or two consecutive days per week for three weeks, either as a single agent or combined with azacitidine, or with azacitidine alone twice per week (on days 1,4, 8, 11, 15 and 18). APTO-253 as a single agent inhibited growth of HL-60 tumors to approximately the same extent as azacitidine. Furthermore, both once weekly and twice weekly dosing of APTO-253 in combination with azacitidine resulted in significantly enhanced antitumor activity relative to either single agent alone (p = 0.0002 and p = 0.0006 for 1X and 2X weekly APTO-253 treatment, respectively, compared to control). Likewise, using a THP-1 AML xenograft model, APTO-253 administered as a single agent using the 2T-5B per week schedule showed significant efficacy, similar to that of azacitidine, while the combination of APTO-253 and azacitidine demonstrated greatly improved antitumor effects relative to either drug alone. APTO-253 was effective and well tolerated as a single agent or in combination with azacitidine in multiple AML xenograft models, plus APTO-253 does not cause bone marrow suppression in animal models or humans. Taken together, our results indicate that APTO-253 may serve as a targeted agent for single agent use and may provide enhanced efficacy to standard of care chemotherapeutics for AML and other hematological malignancies. DisclosuresRice:Lorus Therapeutics Inc.: Employment. Vellanki:Lorus Therapeutics Inc.: Employment. Lee:Lorus Therapeutics Inc.: Employment. Lightfoot:Lorus Therapeutics Inc.: Employment. Peralta:Lorus Therapeutics Inc.: Employment. Jamerlan:Lorus Therapeutics Inc.: Employment. Jin:Lorus Therapeutics Inc.: Employment. Lum:Lorus Therapeutics Inc.: Employment. Cheng:Lorus Therapeutics Inc.: Employment.

Phase II study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced non-small cell lung cancer (NSCLC)

7546 Background: Eribulin is a structurally-simplified, fully synthetic analog of the marine sponge natural product halichondrin B. Eribulin inhibits microtubule dynamics via a mechanistically novel mode of action. Methods: An open-label, single-arm, Phase II study of eribulin was conducted in patients with advanced NSCLC (ECOG of 0 or 1) who were treated with platinum-based doublet chemotherapy and stratified by prior taxane exposure. A total of 103 patients (83 with prior taxanes and 20 taxane naïve) were treated with eribulin (1.4 mg/m2), administered as a bolus infusion over 2 –5 minutes on Days 1, 8, and 15 of a 28-day cycle (N=77). Due to delays or skipped doses secondary to myelosuppression at Day 15 with recovery by Day 21, the protocol was amended to a schedule of Days 1 and 8 of a 21-day cycle (N=26). The primary efficacy endpoint was objective response rate. Independent radiologic review was used to confirm responses. Results: Of 106 enrolled patients, 103 received eribulin. Median age was 65 years and median number of prior therapies was 2, including taxanes (81%), gemcitabine (40%), pemetrexed (23%), and EGFR inhibitors (34%). Median number of cycles administered was 3 (range 1–15). Drug related toxicities included neutropenia grade 3 (23%) and 4 (26%), febrile neutropenia (4%), grade 3 fatigue (11%), grade 3 nausea (2%), and peripheral neuropathy grade 1/2 (37%) and 3 (2%). Based on RECIST criteria, the overall response rate (all partial responses) was 9.7% (95% CI: 4.0–15.4 %), with 10.8% PR in taxane pre-treated, and 5% PR in taxane naïve patients. Overall disease control rate (PR + SD) was 55.3%. 12-week progression free survival (PFS) rate was 53.0% (95% CI: 42.6–63.3%) and median PFS was 102 days (range 1–408+). Median duration of response was 176 days (range 50–291+), and median overall survival was 287 days (range 16–423+). The one year survival rate was 46.4% (95% CI: 34.9–58.0%). Conclusions: In this group of NSCLC patients who were treated with a median of two prior therapies, consisting in the majority of cases of two cytotoxic regimens, eribulin demonstrated an overall PR rate of 9.7% (10.8% in the taxane pre-treated) and 9.6 months median survival. No significant financial relationships to disclose.

A phase I/II trial of weekly docetaxel and gefitinib in elderly patients with stage IIIB/IV non-small cell lung cancer

Phase III trials in elderly patients with advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC) reveal treatment with single agent chemotherapy improves survival. The role of double agent therapy in this patient population is an area of investigation. A phase I/II trial was performed in elderly patients (age>or=70 years) with stage IIIB/IV disease and Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients were treated with gefitinib 250 mg daily. Patients received docetaxel on a treatment schedule of days 1, 8, 15 of an every 28 days schedule. The phase I portion of the trial consisted of dose escalation docetaxel from 30 to 36 mg/m2 using a three patient cohort design. The trial design contained continuous monitoring for excessive toxicity with pre-selected toxicity boundaries. Twenty-six patients were evaluable for efficacy and toxicity analysis. The median age was 75.5 years. The majority of the patients had stage IV disease (85%), ECOG functional status of 0-1 (81%), were male (65%), and current or former smokers (88%). Eleven patients experienced National Cancer Institute Common Toxicity Criteria grades 3-5 non-hematologic toxicity during the first cycle. The toxicity was determined to be unexpected, and the trial was discontinued. Overall response rate (complete+partial responses) was 31%, and the median survival was 6.5 months (95% confidence interval (CI) (3.6-9.0)), and estimated 1-year survival rate was 27% (95% CI (13-55%)). The combination of weekly docetaxel and gefitinib had activity; however, unexpected toxicity was observed in the elderly patient population.

Results of cardiac monitoring during phase I trials of a novel histone deacetylase (HDAC) inhibitor LBH589 in patients with advanced solid tumors and hematologic malignancies

3106 Introduction: LBH589 is a novel cinnamic acid hydroxamate that inhibits HDAC activity, IC50 of 0.03 μM, and inhibits hERG channel with an IC50 of 3.9 μM. Methods: In 2 phase I studies, LBH589 was administered as a 30 minute intravenous infusion on 2 schedules, days 1–3 and 8–10 of a 21 day cycle or days 1–3 and 15–17 of a 28 day cycle to adult pts with advanced solid malignancies (study 2101) or on a schedule of days 1–7 of a 21 day cycle to adult pts with hematologic malignancies (study 2102). Patients with impaired heart function were excluded, and drugs known to prolong QT interval were prohibited. Serial digital ECGs were performed at baseline (6 ECGs), and on days of dosing. ECG data were processed in a core lab by manual analysis. Results: 45 pts (median age: 60 yrs; 23 males, 22 females) were treated at 10 dose levels, range 1.2 - 20.0 mg/m2/day. PK analysis showed dose proportionality, T1/2 of 6 - 26 hr, and approximately 1.5 fold accumulation at steady state (day 3). PD analysis of PBL showed increased histone acetylation for 24 hours post-last dose at doses ≥ 4.8 mg.m2. A total of 1475 post-dose ECGs were performed. Central tendency analysis showed no change in QTcF on day 1; however, on day 3 of dosing, there was a dose related increase in QTcF of at most 20 msec. Frequency of outliers, QTcF > 500 msec and/or > 60 msec change from baseline, was 28% (12 pts) and occurred over a broad dose range, 4.8 mg/m2 - 20.0 mg/m2. Outlier ECGs occurred primarily on day 3 (7/12 pts) or later (3/12 pts) on days 4 or 5). Only 2 pts had outliers ECG on day 1. Six patients (14%) had QTc > 500 msec. Frquency of QTcF > 500 msec increased with dose. At doses ≤ 9 mg/m2, only 1 patient (1/33) had QTcF > 500 msec; while at doses > 9 mg/m2, 5 of 12 patients had QTcF > 500 msec. T wave and ST-T wave changes, primarily T wave flattening were frequently observed and were non-specific.Conclusions: LBH589 is a novel, potent HDAC inhibitor which was found to induce dose-related increases in QTcF of 20 msec or less at doses up to 20.0 mg/m2. Cardiac repolarization changes were delayed until day 3 perhaps due to a different mechanism effecting the hERG channel. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis

The place of accelerated schedules for hepatitis A and B vaccinations.

The availability of accelerated schedules of vaccination, as well as the development of combination vaccines, has enhanced the methods of protection against infectious disease, in particular that of hepatitis A and B viruses. The benefits of using accelerated schedules include: (i) enhanced adherence to and subsequent completion of vaccine courses; (ii) convenience for the recipient of the vaccine; (iii) reduced administration costs of providing the vaccine; and, most importantly, (iv) the ability to provide protection against these serious infections to those who will be imminently exposed to the risk and so require protection as quickly as possible. Active immunisation against both hepatitis A and B viruses has only been recognised within the last 20 years. During this time clinical studies have demonstrated the safety and efficacy of administering the monovalent hepatitis B vaccine by way of accelerated schedules. There are now several accelerated schedules of administration of hepatitis B vaccine which can be tailored to the needs of the individual at risk of exposure to infection. One such schedule allows the primary course to be administered within a period of 1 month. This schedule of day 0, 7 and 21, with a booster at 12 months, is licensed for use with the recombinant hepatitis B vaccine Engerix B and results in a seroprotection rate of 65% at day 28 which increases to 99% at month 13. In more recent years, the development of a multivalent or combination vaccine against hepatitis A and B (Twinrix) has been a welcome advance in the protection against viral hepatitis, and has been of particular benefit to those who are at risk of infection with both viruses. The advantages of accelerated schedules have also been recognised with this combination vaccine. The primary course may be administered within a period of 1 month so providing protection for those at risk and, in particular, the last minute traveller.

Combined carboplatin and cisplatin. Limited prospects for dose intensification.

The relative lack of overlapping toxicities and less-than-complete cross-resistance of tumors treated with both carboplatin and cisplatin may allow these two analogues to be given in combination to exploit platinum dose intensity therapeutics. Early experience with combined platinum regimens, however, found myelosuppression, particularly severe thrombocytopenia, to be dose-limiting. It was postulated that a 2-day interval between carboplatin and cisplatin would allow for near complete clearance of the former before cisplatin administration and a potential gain in dose intensity. Other carboplatin-cisplatin regimens produced Grade 3-4 toxicity in 20% of patients. By defining 95% confidence limits around this observed rate of Grade 3-4 toxicity, the accrual needs of this study were determined in a two-stage process. Sixteen patients with advanced malignancies were entered onto a trial of 300 mg/m2 of carboplatin on day 1, followed by 125 mg/m2 of cisplatin on day 3 every 28 days. Hematologic and nonhematologic toxicity was closely monitored, including the use of serial audiograms, to allow appropriate dose modification. A total of 40 courses of combination platinum therapy was administered to 15 patients who were evaluable for toxicity. Higher-than-anticipated ototoxicity and neurosensory toxicity was observed. WHO Grade 3 ototoxicity (hearing loss) was documented in 12 of 15 patients (80.0%, 95% confidence interval [CI]: 52.0-97.0%) and emerged as the dose-limiting side effect of this regimen. High-frequency hearing loss, as demonstrated by conventional audiograms, was universal among all 12 patients who received at least 2 courses of combination platinum therapy (100%, 95% CI: 73.5-100%). Grade 2 or 3 neurosensory toxicity also was observed in 4 of 15 patients. Hematologic toxicity was manageable. WHO Grade 3-4 neutropenia or thrombocytopenia occurred in only 14% and 11%, respectively, of 40 courses. There was no evidence of cumulative marrow toxicity. Calculated dose intensities (mg/m2/week) were 94 +/- 26.0 for carboplatin, 39.3 +/- 12.4 for cisplatin, and 64.0 +/- 19.2 for the combination (expressed as cisplatin equivalents). Objective responses (complete response+partial response) occurred in 8 of 16 subjects (50.0%, 95% CI: 24.7-75.4%), with 1 patient achieving a complete response of 14+months. The schedule of day 1 carboplatin plus day 3 cisplatin every 4 weeks appeared to allow a higher platinum dose intensity with less myelotoxicity than previously reported schedules combining these two analogues. Ototoxicity, however, was unexpectedly severe and limits future prospects for the use of combined platinum analogues to achieve dose intensification.

Field efficacy trial of inactivated hepatitis A vaccine among children in Thailand (an extended abstract)

The Norwegian population is basically seronegative regarding anti-hepatitis A antibodies. For this reason they are particularly vulnerable when esposed to hepatitis A virus when staying in highly endemic areas. Norwegian UN-personnel have so far been protected with serum immunoglobulins (Ig). Two studies are reported, one followed a schedule of 0, 1 and 2 months with a booster at month 12, while the other followed a schedule of day 0 and 14 with a booster at month 7

Field evaluation of a hepatitis A vaccine in a Norwegian contingent to the United Nations Interim Force in Lebanon

The Norwegian population is basically seronegative regarding anti-hepatitis A antibodies. For this reason they are particularly vulnerable when exposed to hepatitis A virus when staying in highly endemic areas. Norwegian UN-personnel have so far been protected with serum immunoglobulins (Ig). Two studies are reported, one followed a vaccination schedule of 0.1 and 2 months with a booster at month 12, while the other followed a schedule of day 0 and 14 with a booster at month 7. Both were field trials evaluating the new hepatitis A vaccine, from SmithKline Beecham Biological, in Norwegian UN soldiers serving in Lebanon. Both trials showed 100% seroconversion following the initial vaccination course, with low reactogenicity and no clinical or subclinical sign of hepatitis. The new vaccine has decisive advantages over immunoglobulins on medical, practical and economic grounds.

Standardization of age and route for duck plague vaccine in local ducklings of vaccinated and non- vaccinated parent origin

The study was carried out to determine the appropriate age and route of vaccination with duck plague vaccine (LRI, Mohakhali) in experimentally reared local ducks during the period from September 2006 to May 2007. A total of 90 local ducklings were divided into eight groups namely A, C, D and E for vaccinated parent origin and B, F, G and H for non-vaccinated parent origin. Again Group C, D, E, F, G and H were divided into subgroups C1 & C2; D­1& D­2; E1& E2; F1 & F2; G1 & G2; H1 & H2 respectively and contained 5 ducklings each. Group A and B contained 15 ducklings in each group and were used as unvaccinated control and also for studying persistence of maternally derived antibody level. Highest mean MDA titre in ducklings of Group A was found 53.33 ± 4.03 at the age of day 1 that declined to a negligible level (≤4) at the age of day 21 and highest mean MDA titre in ducklings of Group B was found 29.86 ± 1.45 at the age of day 1 that declined to a negligible level (≤4) at the age of day 16. Ducklings of different sub-groups were vaccinated with duck plague vaccine at day 14, day 21 and day 28 through intramuscular (breast) and subcutaneous route at the dose rate of 1ml per duckling. Sera were collected from vaccinated ducklings on day 7, day 14 and day 21 after vaccination and antibody titre was measured by passive hemagglutination test. Among the vaccinated subgroups, the highest mean PHA titre was found 89.60 ± 15.67 and 83.20 ± 19.20 in subgroups E1 (vaccinated at day 28) and F1 (vaccinated at day 14) respectively. At challenge, ducklings of vaccinated subgroups showed 100% protection except C1 and C2 (showed 80% protection) and control subgroups showed 0% protection. From the results of protection test it may be concluded that both intramuscular (breast) and subcutaneous routes are equally suitable for duck plague virus vaccination in ducklings and the optimum age for vaccination to ducklings originated from vaccinated parent to duck plague vaccine might be at day 21 or 28 and ducklings originated from non-vaccinated parent at day 14 or 21 instead of usual schedule of day 28. Key words: Vaccination, duck plague vaccine, age, route, ducklings DOI = 10.3329/bjvm.v6i1.1335 Bangl. J. Vet. Med. 2008. 6 (1): 27-30

Fertility control with oral medication

As the outstanding findings resulting from this investigation, we may state the following: 1.1. Length of the Menstrual Cycle.— 1.1.A. The ingestion of 10 mg. of norethynodrel, supplemented by varying amounts of estrogen, on a prescribed day 5 through day 24 regime, resulted in a normal distribution of lengths of menstrual cycles.1.2.B. If this regime is altered by omission of medication, there may ensue either shortened menstrual cycles, caused presumably by withdrawal bleeding, or lengthened menstrual cycles, resulting from adequate maintenance of the endometrium despite intermittent lack of medication or from prolonging of the treatment by use after the twenty-fourth day of the tablets missed earlier.2.2. Ovulation.— 2.1.A. Presumption of suppression of ovulation is strengthened by the fact that conception did not occur in any instance in which the medication schedule of day 5 through day 24 was followed faithfully.2.2.B. Among those who omitted medication for 3 or more days, the low incidence of pregnancy was roughly proportional to the number of unused tablets.3.3. Endometrium.— 3.1.A. This compound appeared to exert a prompt progestational effect on the endometrium which, after 5 to 7 days of medication, did not progress in terms of glandular response, but did advance with reference to the stromal reaction.3.2.B. No pathological endometrial changes were observed in specimens taken at different times in the cycle and after varying periods of medication up to 10 months. The sequence of endometrial response to medication, as well as of regression following medication, was generally quite regular, and no distinction could be made between endometrium from short-term and that from long-term treated subjects.4.4. Steroid Excretion.—Studies of urinary excretion of steroids indicated a decrease in 17-hydroxycorticosteroids and, to a questionable extent, of 17-ketosteroids. This decline did not seem to vary with the number of medication cycles, nor did it appear to be accompanied by any discernible signs of adrenocortical hypofunction.5.5. Blood Studies.—No significant differences in hemoglobin level were noted during or after medication as compared with those of untreated women. The average bleeding time, however, both during and after medication, was found to be significantly shorter than in the controls, while the clotting time in the postmedication subjects was significantly less than in either the control or the medicated group.6.6. Side Effects.— 6.1.A. The treated subjects reported certain untoward reactions, the incidence of which did not vary with 0.8 to 1.8 per cent estrogen supplementation of the 10 mg. dose of norethynodrel.6.2.B. It had been calculated that, over an 18 cycle span of medication, troublesome symptoms would cause approximately 27 per cent of the subjects enrolled in the project to discontinue treatment. Actually, in the course of the study to date, only 18 per cent have ceased medication because of side effects.6.3.C. The administration of a magnesium aluminum glycinate antacid has led to the reported disappearance of untoward reactions in 82 per cent of the subjects who took the antacid.7.7. Fertility Control.—In practice, several difficulties have been encountered in maintaining complete fertility control, so that there have occurred 19 pregnancies, 5 of which were in women who had omitted 3 to 17 tablets from the advised regimen, and 14 in individuals who had stopped medication because of “reactions” or carelessness. These 19 produced a pregnancy rate of 13 per 100 marriage years, which may be compared with an expected incidence of 67 pregnancies per 100 marriage years from Puerto Rican women of this age range not known to be practicing contraception; or an actual incidence of 63 per 100 marriage years among these women (some of whom had been using contraceptives) before entering on the study.We believe that our data demonstrate the action of a powerful agent for fertility control among the women utilizing it. Thus far, in the subjects of our study, it has clearly lowered the pregnancy rate. The fact that 14 women who had discontinued medication after 1 to 17 cycles became pregnant within 1 to 3 months thereafter suggests that the drug, as thus used, does not interfere with subsequent fertility.