A randomized Bayesian phase 1 design combining an MPS-1 inhibitor with paclitaxel: A strategy to improve determination of the incremental toxicity of a novel compound over a known backbone therapy.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 2537-2537
Author(s):  
Florence Atrafi ◽  
Oliver Boix ◽  
Prabhu Rajagopalan ◽  
Anthony W. Tolcher ◽  
Patricia LoRusso ◽  
...  
Keyword(s):  
Phase 1 ◽  
Improve Determination

scholarly journals Navigating the Quagmire: Comparison and Interpretation of COVID-19 Vaccine Phase 1/2 Clinical Trials

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 746
Author(s):  
Luca Tudor Giurgea ◽  
Matthew James Memoli
Keyword(s):  
Adverse Events ◽  
Protective Efficacy ◽  
Phase 1 ◽  
Phase 3 ◽  
Serious Adverse Events ◽  
Safety Studies ◽  
Antibody Titers ◽  
Public Health Strategies

Vaccines against Coronavirus Disease 2019 Originated-19) have been developed with unprecedented rapidity, many utilizing novel strategies. As of November 2020, a series of publications have outlined the results of phase 1/2 studies of nine different vaccines planned to move forward to phase 3 trials. The results are encouraging, demonstrating a paucity of severe or serious adverse events and robust induction of antibody titers. Determination of the vaccine candidates with the highest protective efficacy and best adverse event profiles will be essential in refining public health strategies. However, differences in study design and reporting of data make comparisons of existing phase 1/2 studies difficult. With respect to safety, studies have variable follow-up times and may use different definitions for adverse events. Immunogenicity outcomes are even more inconsistent, with variations in timepoints and critical differences in the types of antibodies studied as well as methodological differences in assays. Furthermore, the correlates of protection in COVID-19 are not known. Harmonization of phase 3 trial designs and use of objective and meaningful clinical outcomes will be crucial in streamlining future global responses to the pandemic.

scholarly journals Controlled Human Hookworm Infection: Accelerating Human Hookworm Vaccine Development

2018 ◽  
Vol 5 (5) ◽  
Author(s):  
David Diemert ◽  
Doreen Campbell ◽  
Jill Brelsford ◽  
Caitlyn Leasure ◽  
Guangzhao Li ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Phase 1 ◽  
Gastrointestinal Symptoms ◽  
The United States ◽  
Good Manufacturing Practice ◽  
Application Site ◽  
Central Component ◽  
Hookworm Infection ◽  
Patent Infection

Abstract Background Controlled human hookworm infection (CHHI) is a central component of a proposed hookworm vaccination-challenge model (HVCM) to test the efficacy of candidate vaccines. Critical to CHHI is the manufacture of Necator americanus infective larvae (NaL3) according to current Good Manufacturing Practice (cGMP) and the determination of an inoculum of NaL3 that is safe and reliably induces patent infection. Methods cGMP-grade NaL3 were produced for a phase 1 trial in 20 healthy, hookworm-naïve adults in the United States, who received either 25 or 50 NaL3. Participants were monitored for 12–18 weeks postinfection for safety, tolerability, and patency of N. americanus infection. Results Both NaL3 doses were well tolerated. Early manifestations of infection included pruritus, pain, and papulovesicular rash at the application site. Gastrointestinal symptoms and eosinophilia appeared after week 4 postinfection. The 50 NaL3 inoculum induced patent N. americanus infection in 90% of this dose group. Conclusions The inoculum of 50 NaL3 was well tolerated and consistently induced patent N. americanus infection suitable for future HVCM trials. Clinical Trials Registration NCT01940757.

Shift of ionization equilibrium in spatially confined laser induced plasma

2019 ◽  
Vol 34 (10) ◽  
pp. 1975-1981 ◽  
Author(s):  
Aleksandr S. Zakuskin ◽  
Andrey M. Popov ◽  
Timur A. Labutin
Keyword(s):  
Ionization Equilibrium ◽  
Spatial Confinement ◽  
Laser Induced Plasma ◽  
Atomic Lines ◽  
Improve Determination

Spatial confinement of laser-induced plasma leads to shift of ionization equilibrium and can improve determination of elements by their resonant atomic lines.

Oral weekly MLN9708, an investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma (MM): A phase I/II study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8033-8033 ◽  
Author(s):  
Paul Gerard Guy Richardson ◽  
Jesus G. Berdeja ◽  
Ruben Niesvizky ◽  
Sagar Lonial ◽  
Vivek Roy ◽  
...  
Keyword(s):  
Proteasome Inhibitor ◽  
Phase 1 ◽  
Fixed Dose ◽  
Hematologic Toxicity ◽  
Phase 2 ◽  
Nonhematologic Toxicity ◽  
Immunomodulatory Drug ◽  
Grade 3 ◽  
To Receive

8033 Background: MLN9708 is an oral, reversible 20S proteasome inhibitor. The feasibility of combining a proteasome inhibitor with an immunomodulatory drug and a steroid in previously untreated MM has been demonstrated with the RVD regimen. This is the first study of MLN9708 in combination with lenalidomide and dexamethasone (NCT01217957). Here we report the phase (Ph) 1 MTD and preliminary Ph 2 results. Methods: Pts with previously untreated MM, aged ≥18 yrs with measurable disease received oral MLN9708 (phase 1: 1.68–3.95 mg/m2) days 1, 8, and 15, lenalidomide 25 mg days 1–21, and dexamethasone 40 mg days 1, 8, 15, and 22, for up to twelve 28-day cycles. Primary objectives were determination of safety, MTD, and recommended phase 2 dose (RP2D) (Ph 1), and CR+VGPR rate (Ph 2). Results: At data cut-off (Dec 1, 2011), 29 pts had been enrolled (15 Ph 1, 14 Ph 2). Median age was 64 yrs (range 40–82); 69% ISS stage II/III. In Ph 1, the MLN9708 MTD was determined as 2.97 mg/m2 and the RP2D as 2.23 mg/m2; for Ph 2, the RP2D was converted to a 4.0 mg fixed dose based on population PK results. Ph 1 pts have received a median of 6 treatment cycles (range 1–11), 8 received ≥6 cycles; 6 stopped to receive ASCT, 7 are ongoing. Ph 2 pts received a median of 1 (range 1–2), all are ongoing. Grade ≥3 hematologic toxicity was reversible and included anemia (n=2) and thrombocytopenia (n=1). Grade ≥3 nonhematologic toxicity included erythematous rash, syncope, and vomiting (2 pts each). All-grade drug-related peripheral neuropathy was seen in 6 pts (21%), including grade 2 with pain in 2 (both Ph 1 at doses above the MTD). Two pts discontinued due to AE; there were 5 pts who had serious drug-related AE (all Ph 1). Of 19 response-evaluable pts (Ph 1 + Ph 2), all achieved ≥PR, including 5 CR (1 sCR), 4 VGPR, and 10 PR; all remain in response with duration of confirmed response of up to 9.5 months. Of 4 response-evaluable Ph 2 pts, 1 has achieved VGPR and 3 PR to date. Conclusions: Oral MLN9708 plus lenalidomide and dexamethasone appears well tolerated with manageable toxicity. These data show antitumor activity at the RP2D in pts with previously untreated MM, with ≥PR in all pts to date.

Modeling of Ethylene in Pipeline Leak Detection System

2004 ◽  
Author(s):  
Jakob Bu¨chert
Keyword(s):  
Real Time ◽  
Detection System ◽  
Leak Detection ◽  
Practical Experience ◽  
Time Model ◽  
Pump Stations ◽  
Pipeline Model ◽  
Improve Determination

This paper describes experiences with an improved equation of state (EOS) for ethylene for an existing real time pipeline model. The main scope of the model is leak detection, batch, contaminant and pig tracking. Altogether the pipeline model includes transportation of batched liquid ethylene, ethane, propane, butane and natural gas liquids (NGL). The pipeline is approximately 1900 miles miles long and includes laterals, 33 pump stations, 9 injection/delivery stations and 5 propane terminals. Originally the model used a BWRS EOS for all the above products. At that time a number of false leak alarms were experienced related to pipeline sections containing ethylene. A case study was carried out, specifically for ethylene, to investigate the effect of replacing the BWRS EOS with a modified Helmholtz EOS. The study showed that replacing the EOS on average would improve determination of the ethylene densities by 1.6%–5.6% with an expected reduction in the alarm rate for ethylene cases by approximately 50%. As a result the modified Helmholtz EOS was implemented in the real time model. Results are presented to show the practical experience with the new EOS gained over the last years.

scholarly journals HPLC method for simultaneous determination of impurities and degradation products in Cardiazol

Pharmacia ◽  
2020 ◽  
Vol 67 (1) ◽  
pp. 29-37
Author(s):  
Iryna Drapak ◽  
Borys Zimenkovsky ◽  
Liudas Ivanauskas ◽  
Ivan Bezruk ◽  
Lina Perekhoda ◽  
...  
Keyword(s):  
Flow Rate ◽  
Mobile Phase ◽  
Degradation Products ◽  
Phase 1 ◽  
Simultaneous Detection ◽  
Hplc Method ◽  
Column Temperature ◽  
Degree Of Separation ◽  
Determination Of Impurities

Aim. The aim of study was to develop a simple and accurate procedure that could be applied for the determination of impurities and degradation products in cardiazol. Materials and methods. Separation in samples was carried out with Acquity H-class UPLC system (Waters, Milford, USA) equipped with Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 μm) (Waters, Milford, USA). Xevo TQD triple quadrupole mass spectrometer detector (Waters Millford, USA) was used to obtain MS/MS data. Mobile phase A: 0.1% solution of trifluoroacetic acid R in water R; Mobile phase B: acetonitrile R. Samples were chromatographed in gradient mode (Table 1). Flow rate of the mobile phase: 1 ml / min. Column temperature: 30 °С. Detection: at 240 nm wavelength. Injection volume: 10 μl. Results. The retention time of the main substance is about 18.5 minutes. The order of the peak, the retention times and relative retention times: impurity B (12.04, 0.65); impurity А (18.5; 0.98); Cardiazol (18.87; 1.00). The LOD and LOQ values obtained were in the range of 30 ng/mL to 100 ng/mL and 80 ng/mL to 310 ng/mL respectively (with respect to sample concentration of 2 mg/ml). Linearity was established in the range of LOQ level to 0.2% having regression coefficients in the range of 0.9996 to 0.9999. The change in the temperature of the column affects the degree of separation of cardiazol and the impurity A, and thus, with a decrease of 5 ° C, the degree of separation is (1.06), while with increasing this index (3.43). When changing the flow rate of the mobile phase, the degree of separation changes in the following order, with a decrease to 0.9 ml / min separation (1.90), with an increase in speed to 1.1 ml / min (2.45). When the number of mobile phase B decreases by 5%, the degree of separation varies by (2.65), with an increase of 5% (1.82). In comparison with the chromatogram of the tested solution, the substance is not resistant to the action of peroxide, alkaline and acid decomposition. Conclusion. 1) HPLC method was developed and validated for the simultaneous detection and quantitation of impurities formed during the synthesis of cardiazol. 2) The method proved to be sensitive, selective, precise, linear, accurate and stability-indicating.

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