The FDR4ATMOS Project

2020 ◽  
Author(s):  
Günter Lichtenberg ◽  
Sander Slijkhuis ◽  
Mourad Hamidouche ◽  
Melanie Coldewey-Egbers ◽  
Bernd Aberle ◽  
...  
Keyword(s):  
Time Series ◽  
Phase 1 ◽  
Atmospheric Composition ◽  
Data Preservation ◽  
Uncertainty Estimates ◽  
Data Record ◽  
Level 1 ◽  
Level 2 ◽  
Total Column

<p>The Fundamental Data Record for ATMOSpheric Composition (FDR4ATMOS) project is part of the ESA Long Term Data Preservation (LTDP) programme aimed at the preservation and valorization of data assets from ESA’s Earth Observation (EO) Heritage Missions. It has two objectives. The first one is to update the SCIAMACHY processing chain for better Ozone total column data. After the full re-processing of the SCIAMACHY mission with the updated processor versions 9 (Level 1) and version 7 (Level 2), ground-based validation showed that the total Ozone column drifted downward by nearly 2% over the mission lifetime. This drift is likely caused by changes in the degradation correction in the Level 1 processor, that led to subtle changes in the spectral structures. These are misinterpreted as an atmospheric signature. FDR4ATMOS will update the Level 0-1 processor accordingly with the final aim of a mission re-processing.</p><p>The main objective of the FDR4ATMOS project is to develop a cross-instrument Level 1 product for GOME-1 and SCIAMACHY for the UV, VIS and NIR spectral range, with focus on the spectral windows used for O3, SO2, NO2 total column retrieval and the determination of cloud properties. Contrary to other projects, FDR4ATMOS does not aim to build harmonised time series based on Level 2 products (geophysical parameters) but to build a Fundamental Data Record (FDR) of Level 1 products, i.e. radiances and reflectances. The GOME-1 and SCIAMACHY instruments together span 17 years of spectrally highly resolved data essential for air quality, climate, ozone trend and UV radiation applications. The goal of the FDR4ATMOS project is to generate harmonised data sets that allow the user to use it directly in long-term trend analysis, independently of the instrument. Since this was never done for highly resolved spectrometers, new methods have to be developed that e.g. take into account the different observation geometries and observation times of the instrument without impacting the spectral structures that are used for the retrieval of the atmospheric species. The resulting algorithms and the processor should also be as generic as possible to be able to easily transfer the methodology to other instruments (e.g. GOME-2 and Sentinel-5p) for a future extension of the time series. The project will support new applications and services and will enhance traceability of satellite-derived data with improved uncertainty estimates based on rigorous metrological principles.</p><p>FDR4ATMOS started in October 2019 and is currently in phase 1. We will present the motivation, goals and first results of the project.</p><p><br><br></p>

scholarly journals Construction of merged satellite total O<sub>3</sub> and NO<sub>2</sub> time series in the tropics for trend studies and evaluation by comparison to NDACC SAOZ measurements

2014 ◽  
Vol 7 (10) ◽  
pp. 3337-3354 ◽  
Author(s):  
M. Pastel ◽  
J.-P. Pommereau ◽  
F. Goutail ◽  
A. Richter ◽  
A. Pazmiño ◽  
...  
Keyword(s):  
Time Series ◽  
Lower Stratosphere ◽  
Atmospheric Composition ◽  
Data Sets ◽  
Composition Change ◽  
Long Time ◽  
Uv Visible ◽  
The Tropics ◽  
Lower Noise ◽  
Total Column

Abstract. Long time series of ozone and NO2 total column measurements in the southern tropics are available from two ground-based SAOZ (Système d'Analyse par Observation Zénithale) UV-visible spectrometers operated within the Network for the Detection of Atmospheric Composition Change (NDACC) in Bauru (22° S, 49° W) in S-E Brazil since 1995 and Reunion Island (21° S, 55° E) in the S-W Indian Ocean since 1993. Although the stations are located at the same latitude, significant differences are observed in the columns of both species, attributed to differences in tropospheric content and equivalent latitude in the lower stratosphere. These data are used to identify which satellites operating during the same period, are capturing the same features and are thus best suited for building reliable merged time series for trend studies. For ozone, the satellites series best matching SAOZ observations are EP-TOMS (1995–2004) and OMI-TOMS (2005–2011), whereas for NO2, best results are obtained by combining GOME version GDP5 (1996–2003) and SCIAMACHY – IUP (2003–2011), displaying lower noise and seasonality in reference to SAOZ. Both merged data sets are fully consistent with the larger columns of the two species above South America and the seasonality of the differences between the two stations, reported by SAOZ, providing reliable time series for further trend analyses and identification of sources of interannual variability in the future analysis.

The Two-Dimensional CCSMM

2021 ◽  
pp. 32-54
Keyword(s):  
Cyber Security ◽  
Phase 1 ◽  
Maturity Model ◽  
Two Dimensional ◽  
Four Dimensions ◽  
Level 1 ◽  
Level 2

The community cyber security maturity model (CCSMM) defines four dimensions and five implementation mechanisms in describing the relative maturity of an organization or an SLTT's cybersecurity program. These are used in defining levels of maturity and the cybersecurity characteristics of an organization or SLTT at each level. In order to progress from one level to the next, a variety of activities should take place, and these are defined in terms of five different mechanisms. In between two levels are a variety of activities that should take place to help the entity to advance from one level to the next. These groups of activities describe four phases, each of which takes place between two levels. Thus, Phase 1 defines the activities that should occur for an entity to advance from Level 1 to Level 2.

scholarly journals Long-Term Variations in the Pixel-to-Pixel Variability of NOAA AVHRR SST Fields from 1982 to 2015

2019 ◽  
Vol 11 (7) ◽  
pp. 844 ◽  
Author(s):  
Fan Wu ◽  
Peter Cornillon ◽  
Lei Guan ◽  
Katherine Kilpatrick
Keyword(s):  
Quality Data ◽  
Retrieval Algorithm ◽  
Ocean Fronts ◽  
Noaa Avhrr ◽  
Data Record ◽  
Along Track ◽  
Level 2 ◽  
Very High ◽  
Significant Effort

Sea surface temperature (SST) fields obtained from the series of space-borne five-channel Advanced Very High Resolution Radiometers (AVHRRs) provide the longest continuous time series of global SST available to date (1981–present). As a result, these data have been used for many studies and significant effort has been devoted to their careful calibration in an effort to provide a climate quality data record. However, little attention has been given to the local precision of the SST retrievals obtained from these instruments, which we refer to as the pixel-to-pixel (p2p) variability, a characteristic important in the ability to resolve structures such as ocean fronts characterized by small gradients in the SST field. In this study, the p2p variability is estimated for Level-2 SST fields obtained with the Pathfinder retrieval algorithm for AVHRRs on NOAA-07, 9, 11, 12 and 14-19. These estimates are stratified by year, season, day/night and along-scan/along-track. The overall variability ranges from 0.10 K to 0.21 K. For each satellite, the along-scan variability is between 10 and 20% smaller than the along-track variability (except for NOAA-16 nighttime for which it is approximately 30% smaller) and the summer and fall σ s are between 10 and 15% smaller than the winter and spring σ s. The differences between along-track and along-scan are attributed to the way in which the instrument has been calibrated. The seasonal differences result from the T 4 − T 5 term in the Pathfinder retrieval algorithm. This term is shown to be a major contributor to the p2p variability and it is shown that its impact could be substantially reduced without a deleterious effect on the overall p2p σ of the resulting products by spatially averaging it as part of the retrieval process. The AVHRR/3s (NOAA-15 through 19) were found to be relatively stable with trends in the p2p variability of at most 0.015 K/decade.

scholarly journals Estimation of Burned Area in the Northeastern Siberian Boreal Forest from a Long-Term Data Record (LTDR) 1982–2015 Time Series

2018 ◽  
Vol 10 (6) ◽  
pp. 940 ◽  
Author(s):  
José García-Lázaro ◽  
José Moreno-Ruiz ◽  
David Riaño ◽  
Manuel Arbelo
Keyword(s):  
Time Series ◽  
Boreal Forest ◽  
Burned Area ◽  
Data Record ◽  
Term Data

scholarly journals ACTR-63. PHASE I DOSE ESCALATION STUDY OF PROCASPASE ACTIVATING COMPOUND-1 (PAC-1) IN COMBINATION WITH TEMOZOLOMIDE IN PATIENTS WITH RECURRENT ANAPLASTIC ASTROCYTOMA OR GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi28-vi28
Author(s):  
Matthias Holdhoff ◽  
Martin Nicholas ◽  
Richard Peterson ◽  
Oana Danciu ◽  
Stefania Maraka ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Anaplastic Astrocytoma ◽  
Caspase 3 ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Dose Escalation Study ◽  
Level 1 ◽  
Level 2

Abstract BACKGROUND Procaspase activating compound -1 (PAC-1) is a small molecule that catalyzes conversion of procaspase-3 to caspase-3 which induces apoptosis in cancer cells. Glioblastoma (GBM) is among the tumors with high concentrations of procaspase-3 and low levels of caspase-3. PAC-1 crosses the blood brain barrier and has been shown to synergize with temozolomide (TMZ) in canine malignant glioma and meningioma that arise spontaneously. METHODS This is a multicenter phase 1 dose-escalation study to assess the maximum tolerated dose (MTD) of PAC-1 administered days 1–21 in combination with TMZ days 8–12 at a dose of 150 mg/m2 of each 28 day cycle in subjects with recurrent anaplastic astrocytoma (AA) or GBM. A modified Fibonacci 3 + 3 design is used with up to 4 dose levels of PAC-1 (375, 500, 625 and 750 mg/day). Neurologic toxicity, including cognitive function, is closely monitored throughout the trial. INTERIM DATA: A total of 14 subjects have been enrolled to-date. Of these, 7 at dose level 1, PAC-1 375 mg/day (6 GBM, 1 AA; median age 58y, range 25–75) and 7 at dose level 2, PAC-1 500 mg/day (5 GBM, 2 AA; median age 51y, range 35–60). Best responses to-date were 2 subjects with a partial response and 2 with stable disease. Grade 3 (hepatotoxicity) and 4 (cerebral edema) was reported as possibly related to PAC-1 in 1 patient at dose level 1. The median number of cycles received was 4 (range, 1–12+) at dose level 1 and 2 (range, 1–3) at dose level 2. Enrollment to dose level 2 has been completed and data analysis is ongoing. Updated response and toxicity as well as pharmacokinetic data will be presented.

Cyclosporine Modulation of Multidrug Resistance in Combination with Pravastatin, Mitoxantrone, and Etoposide for Adult Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML): A Phase 1/2 Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4343-4343
Author(s):  
Tara L Chen ◽  
Elihu H. Estey ◽  
Megan Othus ◽  
Kelda M. Gardner ◽  
Lauren Markle ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Multidrug Resistance ◽  
Dose Level ◽  
Phase 1 ◽  
Kidney Injury ◽  
Adult Patients ◽  
Hematologic Toxicity ◽  
Heavily Pretreated ◽  
Level 1 ◽  
Level 2

Abstract Abstract 4343 Background: Outcomes in relapsed/refractory AML are dismal. Given the high prevalence of multidrug resistance (MDR), many clinical studies have tested whether MDR reversal agents such as cyclosporine (CSA) could increase the efficacy of conventional chemotherapeutics but results have been inconsistent. More recently, HMG-CoA reductase inhibitors (e.g. pravastatin) have been investigated after demonstration that cholesterol synthesis inhibition can restore chemosensitivity of AML cells in vitro. As studies further suggested the HMG-CoA inhibitors could downregulate MDR function, we attempted to improve the efficacy of mitoxantrone and etoposide in patients with relapsed/persistent AML by combining CSA and pravastatin in a single-arm, open-label phase 1/2 trial. Patients and Methods: Adult patients with relapsed/refractory non-APL AML and a treatment-related mortality score of <9.2 (Walter et al. J Clin Oncol 2011) were eligible if they had an ECOG performance status (PS) ≤3 and adequate organ function. Prior hematopoietic cell transplantation (HCT) was permissible if relapse occurred >180 days post-HCT. Planned treatment included induction and consolidation therapy with pravastatin, CSA, and increasing doses of mitoxantrone and etoposide. All patients received pravastatin 320mg PO every 6 hours on days 1–10. The starting dose level (level 1) used etoposide 60mg/m2/day and mitoxantrone 5mg/m2/day via continuous infusion on days 5–9. CSA started 6 hours before the first doses of mitoxantrone/etoposide; after loading with 6mg/kg over 2 hours and 4mg/kg over 6 hours, CSA was infused at 18mg/kg/day on days 5–9. CSA levels were monitored on Day 6 and 8 to maintain levels <2,400ng/mL (by LCMS-MS). At dose level 2, identical doses of pravastatin and CSA were combined with etoposide (80mg/m2/day) and mitoxantrone (6mg/m2/day). Dose-limiting toxicities (DLTs) were defined as: 1) any Grade 3 non-hematologic toxicity lasting >48 hours except of febrile neutropenia (FN), infection, or hyperbilirubinemia; and 2) any Grade ≥4 non-hematologic toxicity except FN/infection, constitutional symptoms if recovery to Grade ≤2 within 14 days, and hyperbilirubinemia. An “adaptive” Bayesian phase 1–2 design that monitored both toxicity and response was used. The maximal acceptable rate of toxicity was 30%, the minimum acceptable rate of efficacy 20% (historical rate of 15% in this population), stopping when posterior probability >90%. A maximum of 45 patients would be treated in cohorts of 3. Results: Between October 2010 and February 2012, 10 patients (median age 52 [range 40–58] years) were treated, including 4 patients (all at dose level 1) who received therapy off protocol. Two patients had secondary AML, and 6 had complex cytogenetics. PS was 1 (7 patients) or 2 (3 patients). Average TRM score was 4.32 for on-study patients. All patients had received at least 2 prior regimens, and 7 received 3 prior therapies. One patient had undergone HCT. The average CSA level on Day 6 was 1,366.3ng/mL (range 713–2,082ng/mL) and 1,199.8ng/mL on Day 8 (range 526–1,593ng/mL). Efficacy (CR or CRi)/DLTs for on-study patients were: level 1 (n=3): 0/1 (grade 4 acute kidney injury); level 2 (n=3): 0/2 (grade 4 acute kidney injury; sepsis/multiorgan failure). Among the 7 patients treated at level 1, other toxicities included septic shock (n=1), FN (4), mucositis (2), and decreased left ventricular ejection fraction (1). One off-study patient achieved CR after 1 course and received 1 cycle of consolidation with pravastatin, etoposide, and mitoxantrone but experienced CNS relapse after CR duration of only 46 days. Based on the results of the on-study patients, the statistical monitoring mandated early study closure for lack of efficacy & excessive toxicity. Conclusion: In the targeted, heavily pretreated patient population, the study regimen was excessively toxic and failed to achieve acceptable efficacy. Further clinical testing, if any, should be limited to less heavily pretreated, otherwise “fit” patients with AML. This trial was registered at ClinicalTrials.gov as NCT01342887. Disclosures: No relevant conflicts of interest to declare.

Phase 1 Dose-Escalation Study of 90yttrium-Labeled Anti-CD22 Epratuzumab Tetraxetan in Adults with Refractory/Relapsed CD22+ B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3708-3708
Author(s):  
Patrice Chevallier ◽  
Thomas Eugene ◽  
Nelly Robillard ◽  
Françoise Isnard ◽  
Franck E Nicolini ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Whole Body ◽  
Organ Distribution ◽  
Hematologic Toxicity ◽  
Level 3 ◽  
Level 1 ◽  
Level 2

Abstract Background: Prognosis of relapsed/refractory acute lymphoblastic leukemia (ALL) in adults is dismal. CD22 is highly expressed in patients with B-ALL. Epratuzumab (hLL2) is a humanized monoclonal antibody targeting CD22 surface antigen. We performed a standard 3+3 phase 1 study to assess the feasibility, tolerability, and efficacy of a 90yttrium-labeled anti-CD22 epratuzumab tetraxetan (90Y-DOTA-hLL2) radioimmunotherapy (RIT) in adults with refractory/relapsed CD22+ B-ALL. Methods: After premedication with corticosteroid, 90Y-DOTA-hLL2 was administered twice on days 1 and 8 (+2), successively at 2.5 (level 1), 5.0 (level 2), 7.5 (level 3), and 10.0 (level 4) mCi/m². The first two patients also received 4 infusions of DOTA-hLL2 360 mg/m²/day before the RIT. This “cold phase” was terminated after observing no efficacy and full saturation of the CD22 target on the leukemic cells. Minimal residual disease (MRD) was assessed either by flow cytometry or by RQ-PCR for BCR-ABL1 analyses in Philadelphia chromosome positive (Ph+) B-ALL patients. Dose-limiting toxicity (DLT) was defined as any non-reversible grade >3 non-hematological toxicity or grade 4 pancytopenia with hypocellular bone marrow lasting for >6 weeks. Maximum tolerated dose (MTD) was defined as the dose level at which 2 of 3 or 2 of 6 patients experienced a DLT. Dosimetry, organ distribution and elimination of the radiotracer were studied between the two RIT infusions in all but one patient, using whole-body scintigraphy recorded after 111Indium-epratuzumab tetraxetan injection and blood pharmacokinetics. Patients were evaluated for response between 4 and 6 weeks following the first infusion of RIT. Findings: Between October 2011 and June 2014, 20 patients were enrolled. Three patients were not considered for analyses because of disease progression (n=2) or persistent non-blastic pancytopenia (n=1) before RIT. Overall, 17 cases were treated (5 at level 1 including 2 previously treated with the cold phase, 3 at level 2, 3 at level 3, and 6 at level 4). There were 10 males and 7 females with a median age of 62 years (range: 27-77). Two patients had primary refractory B-ALL; 10, 3 and 2 were in first, second or third relapse, respectively. Median percentage of blasts in the bone marrow was 75%. Karyotypes were as follows: Ph+ B-ALL n=6, complex n=3, MLL rearrangement n=1, hyperdiploidy n=1, hypodiploidy n=1, near-triploidy n=1, del4q (+ikaros mutation) n=1, normal (but ikaros mutation) n=1, and unknown n=2. Four patients were previously allotransplanted. Median interval between diagnosis and RIT was 16.5 months. Five patients presented immediate infusion reactions (3 grade 1, 1 grade 2 and 1 grade 3 in a patient with a previous history of severe allergic reactions) after the first RIT infusion, but received the second infusions without toxicities. All examined patients showed expected uptake of the radiotracer on potential disease sites (blood, spleen, liver, and bone marrow). No response was seen at levels 1 and 3. One molecular complete response was documented at level 2 (54-year old woman in third relapse of Ph+ B-ALL). At level 4, 2 patients achieved complete remissions (1 Ph+ ALL and 1 Ph- ALL), while all 6 cases presented with grade 4 hematologic toxicity. One DLT was documented at level 4 (non-blastic pancytopenia lasting 8 weeks), but MTD was not reached. Two patients in response received a second RIT cycle. Currently, only one non-responder is alive, while 2 of 3 responders are alive. One relapsed at 1 year and died of progression (level 2), while the two remaining are in persistent CR at 6 months post RIT, with low positive MRD. Interpretation: 90Y-DOTA-hLL2 RIT is well-tolerated and induced complete remissions even in heavily pre-treated CD22+ relapsed/refractory B-ALL patients, thus appearing to be a promising targeted therapy for CD22+ B-ALL. We recommend the dose of 10 mCi/m² given twice, one week apart/cycle, for phase 2 studies. The trial is registered at http://clinicaltrials.gov/ct no.NCT01354457. Funding: Immunomedics, Inc. Disclosures Goldenberg: immunomedics: Employment. Wegener:immunomedics: Employment.

scholarly journals Observed and simulated time evolution of HCl, ClONO<sub>2</sub>, and HF total column abundances

2011 ◽  
Vol 11 (12) ◽  
pp. 32085-32160 ◽  
Author(s):  
R. Kohlhepp ◽  
R. Ruhnke ◽  
M. P. Chipperfield ◽  
M. De Mazière ◽  
J. Notholt ◽  
...  
Keyword(s):  
Time Series ◽  
Northern Hemisphere ◽  
Time Series Data ◽  
Montreal Protocol ◽  
Irregular Sampling ◽  
Atmospheric Composition ◽  
Series Data ◽  
Anthropogenic Source ◽  
Time Range ◽  
Total Column

Abstract. Time series of total column abundances of hydrogen chloride (HCl), chlorine nitrate (ClONO2), and hydrogen fluoride (HF) were determined from ground-based Fourier transform infrared (FTIR) spectra recorded at 17 sites belonging to the Network for the Detection of Atmospheric Composition Change (NDACC) and located between 80.05° N and 77.82° S. These measurements are compared with calculations from five different models: the two-dimensional Bremen model, the two chemistry-transport models KASIMA and SLIMCAT, and the two chemistry-climate models EMAC and SOCOL. The overall agreement between the measurements and models for the total column abundances and the seasonal cycles is good. Trends of HCl, ClONO2, and HF are calculated from both measurement and model time series data, with a focus on the time range 2000–2009. Their precision is estimated with the bootstrap resampling method. The sensitivity of the trend results with respect to the fitting function, the time of year chosen and time series length is investigated, as well as a bias due to the irregular sampling of the measurements. For the two chlorine species, a decrease is expected during this period because the emission of their prominent anthropogenic source gases (solvents, chlorofluorocarbons (CFCs)) was restricted by the Montreal Protocol 1987 and its amendments and adjustments. As most of the restricted source gases also contain fluorine, the HF total column abundance was also influenced by the above-mentioned regulations in the time period considered. The measurements and model results investigated here agree qualitatively on a decrease of the chlorine species by around −1 % yr−1. The models simulate an increase of HF of around +1 % yr−1. This also agrees well with most of the measurements, but some of the FTIR series in the Northern Hemisphere show a stabilisation or even a decrease in the last few years. In general, for all three gases, the measured trends vary more strongly with latitude and hemisphere than the modelled trends. Relative to the FTIR measurements, the models tend to underestimate the decreasing chlorine trends and to overestimate the fluorine increase in the Northern Hemisphere. At most sites, the models simulate a stronger decrease of ClONO2 than of HCl. In the FTIR measurements, this difference between the trends of HCl and ClONO2 depends strongly on latitude, especially in the Northern Hemisphere.

scholarly journals Evaluation of the Influence of Disturbances on Forest Vegetation Using the Time Series of Landsat Data: A Comparison Study of the Low Tatras and Sumava National Parks

2019 ◽  
Vol 8 (2) ◽  
pp. 71 ◽  
Author(s):  
Premysl Stych ◽  
Josef Lastovicka ◽  
Radovan Hladky ◽  
Daniel Paluba
Keyword(s):  
Time Series ◽  
National Park ◽  
Vegetation Indices ◽  
Forest Vegetation ◽  
Vegetation Changes ◽  
Landsat Data ◽  
Climate Data ◽  
Data Record ◽  
Climate Data Record ◽  
Level 2

This study focused on the evaluation of forest vegetation changes from 1992 to 2015 in the Low Tatras National Park (NAPANT) in Slovakia and the Sumava National Park in Czechia using a time series (TS) of Landsat images. The study area was damaged by wind and bark beetle calamities, which strongly influenced the health state of the forest vegetation at the end of the 20th and beginning of the 21st century. The analysis of the time series was based on the ten selected vegetation indices in different types of localities selected according to the type of forest disturbances. The Landsat data CDR (Climate Data Record/Level 2) was normalized using the PIF (Pseudo-Invariant Features) method and the results of the Time Series were validated by in-situ data. The results confirmed the high relevance of the vegetation indices based on the SWIR bands (e.g., NDMI) for the purpose of evaluating the individual stages of the disturbance (especially the bark beetle calamity). Usage of the normalized Landsat data Climate Data Record (CDR/Level 2) in the research of long-term forest vegetation changes has a high relevance and perspective due to the free availability of the corrected data.

A Phase 1 Trial of Vorinostat and Pegylated Liposomal Doxorubicin In Relapsed or Refractory Lymphoma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2816-2816
Author(s):  
Frederick Lansigan ◽  
Stuart Seropian ◽  
Dennis L. Cooper ◽  
Von Potter ◽  
Noelle Sowers ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase 1 ◽  
Pegylated Liposomal Doxorubicin ◽  
Cell Transplant ◽  
Heavily Pretreated ◽  
Level 3 ◽  
Refractory Lymphoma ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 2816 Background: Vorinostat is a histone deacetylase inhibitor with activity in lymphoma and leukemia. Vorinostat has been reported to act synergistically with topoisomeraseII inhibitors such as anthracyclines (Ac) by facilitating an open chromatin configuration thus enhancing double-strand DNA breaks and apoptosis. We conducted a phase 1 study of escalating doses of vorinostat with pegylated liposomal doxorubicin (V+PLD) in patients with relapsed or refractory lymphoma. The primary objective was to determine the maximum tolerated dose (MTD). Other endpoints included safety, tolerability, and activity of V+PLD. Methods: Patients age ≥18 years with relapsed or refractory lymphoma were enrolled sequentially into 1 of 3 dosing levels using a standard 3+3 design for up to 8 cycles. The study was conducted in accordance with the Declaration of Helsinki, good clinical practice and regulatory guidelines. Vorinostat 200 (dose level 1), 300 (dose level 2), or 400mg (dose level 3) twice daily on days 1–7 and PLD 30mg/m2 on day 3 of a 21-day cycle were administered to eligible and consenting patients. CTCAE v.3.0 was used to determine toxicities, and the revised criteria for malignant lymphoma were used to determine response. Results: 14 patients have been enrolled; 2 men and 12 women; median age 69 years [range 27–88]; median prior therapies (4) [1-11]; prior Ac (13); median prior Ac dose (300mg/m2) [108-440mg/m2]; prior HDACi (1); Dose level 1 (7); Dose level 2 (4); Dose level 3 (3). Lymphoma subtypes included: Hodgkin's lymphoma (HL)(4), peripheral T-cell lymphoma (3), diffuse large B-cell lymphoma (DLBCL)(5), grey zone lymphoma (1), lymphoplasmacytic lymphoma (1). Median number of study cycles was two [1-8](2). Grade 3–4 hematologic toxicities included: neutropenia (3) and thrombocytopenia (1). Grade 3–4 non-hematologic toxicities included: fatigue (2), nausea (1), anorexia (1), dehydration (1), AST/ALT elevation (1), amylase/lipase elevation (1). No cardiac toxicities were observed. There was one death attributed to disease progression. Partial responses (PR) were documented in two HL patients, stable disease (SD) in one HL and one DLBCL patient. Three patients continued therapy beyond 2 cycles. One HL patient with a PR tolerated 8 cycles despite a prior anthracycline dose of 350mg/m2 and 9 prior systemic treatments including ABVD, ICE, GND, DICEP, BEAM and autologous stem cell transplant, Gem and C-MOPP. Another HL patient with a PR after 2 cycles is currently on cycle 3 at dose level 3 and had 5 prior treatments including autologous transplant. One other HL patient with SD discontinued therapy after 2 cycles to proceed with alternative chemotherapy including allogeneic stem cell transplant. One patient with cutaneous DLBCL obtained a skin response but had overall stable disease and completed 6 cycles before disease progression; prior treatment included R-CHOP, R-ICE, CEPP, and GemOx. In addition, one patient with lymphoplasmacytic lymphoma had a clinical response after 1 cycle but therapy was discontinued because of neutropenia and her disease progressed. Conclusions: The combination of V+PLD is well tolerated even among older and heavily pretreated patients. There were no cardiac toxicities even in patients heavily pretreated with anthracyclines. The MTD has not been reached and enrollment to dose level 3 is ongoing. Disease control was achieved in 4 of 14 patients (2 PR and 2 SD). Of interest, 3 of 4 patients with HL achieved disease control (2 PR and one SD), and treatment with vorinostat in combination with anthracycline-based therapy warrants further investigation in HL. Disclosures: Lansigan: Merck: Speakers Bureau. Off Label Use: Vorinostat in combination with pegylated doxorubicin is considered experimental in lymphoma. Foss:Merck: Speakers Bureau.

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