Mapping GLAMs: creating a national dataset of GLAMs to develop a categorical climate-change risk assessment scale

Introduction. The PROTECCT-GLAM project aims to assess and address climate risks for U.S. galleries, libraries, archives, and museums (GLAMs). The project team began with creating a national dataset of GLAMs. Method. The project team used existing datasets that required different auditing and manipulation techniques to align its data. Following the data normalization, the master file included 77,960 entries. Analysis and Results. The project team used ArcGIS Pro to analyze a dataset of galleries, libraries, archives, and museums (GLAMs) for risk from sea level rise, finding 16,877 GLAMs within 30 kilometres of the U.S. coast, with California, New York, Maryland, Florida, and New Jersey having the highest numbers. They also assessed GLAMs per capita by state using 2020 census data, reporting results per 10,000 people. Conclusion. The dataset creation was successful and is being utilized to create a five-point scale based on the average of five climate variables for each GLAM

Oncolytic DNX-2401 Virotherapy Plus Pembrolizumab in Recurrent Glioblastoma: A Phase 1/2 Trial

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients

Interface software can markedly reduce time and improve accuracy for clinical trial data transfer from EMR to EDC: The results of two measure of work time studies comparing commercially available clinical data transfer software to current practice manual data transfer.

1573 Background: Clinical studies and new drug approvals are delayed by slow data transfer and transcription errors from site entered data. These delays have been compounded by a shortage of data entry personnel at sites such that data entry approaches 10-30 days post visit. Data transfer is largely performed by manual keyboard entry from electronic medical records (EMR) into electronic case report forms (ECRF). Methods: We conducted two separate measure-of-work time studies to compare a commercially available interface software product, ProXimity to the current manual data entry. The clinical trial data from two different EMRs (ARIA and IKM G2) to an EDC (Medidata Rave). The EDC mirrored an IRB approved clinical study. Time to transfer data and error rates were the primary and secondary endpoints, respectively. For study 1 Aria EMR data from 3 subjects and 1497 data fields including demographics, vital signs, ECOG PS, physical findings, adverse events, and lab results including CBC, CMP, urinalysis, coagulation, serology were selected for visits from Screening and C2D1. For Study 2 IKM G2 data from 6 subjects and 834 data fields included demographics, vitals, and lab results. The data entry personnel were aware of the timed nature of the study. Results: Study 1 ProXimity took 13.2 min to transfer the data compared to 73.4 min for manual entry, with error rates of 0.8% compared to 3.5%, respectively. In Study 2 Proximity took 6.5 min compared to 29 min for manual entry, with error rates of 1.4% each due to non- conformant data (text). Conclusions: Software data transfer interfaces can markedly shorten the time for data entry, reduce error rates and reduce operational costs. </jats:p

Phase 1/2 Study of Oral TP-0184 for the Treatment of Anemia in Adults with Low- or Intermediate-Risk Myelodysplastic Syndromes

Abstract Patients with anemia due to lower-risk myelodysplastic syndromes (MDS) have limited treatment options. The transforming growth factor β (TGF-β) pathway has been implicated in contributing to ineffective hematopoiesis in patients with MDS. Members of the TGF-β superfamily include activin receptor-like kinase 2 (ALK2) and ALK5. ALK2 signaling plays a key role in modulating hepcidin, an important regulator of iron homeostasis (and thus erythropoiesis). Increased levels of hepcidin have been linked to anemia in patients with chronic inflammation and cancer, including multiple myeloma (Maes K, et al. Blood. 2010;116:3635-44). The role of hepcidin in MDS-related anemia is unknown and needs to be explored. ALK5 signaling through SMAD2/3 phosphorylation is constitutively active in bone marrow precursor cells from patients with MDS (Zhou L, et al. Blood. 2008;112:3434-43). Inhibition of ALK5 suppresses phosphorylation of SMAD2 in MDS hematopoietic progenitor cells and stimulates hematopoiesis in cells derived from patients with MDS. Collectively, these data suggest that blockade of the TGF-β-SMAD2/3 signaling pathway with an ALK5 inhibitor has the potential to benefit patients with anemia due to MDS. TP-0184 is a small-molecule, dual inhibitor of ALK2 and ALK5. In vitro, TP-0184 inhibits downstream signaling from ALK2 by reducing the phosphorylation of SMAD1/5/8 and blocks hepcidin expression (Peterson PW, et al. Blood. 2017;130 [suppl_1]: 937). Ex vivo, TP-0184 inhibits downstream signaling from ALK5 by reducing SMAD2/3 phosphorylation (data on file). By inhibiting both the ALK2 and ALK5 signaling pathways, TP-0184 may reduce ineffective erythropoiesis in patients with MDS. An open-label, single-arm, phase 1/2 study (NCT04623996) is being undertaken to evaluate the preliminary safety and efficacy of TP-0184 in treating anemia in adults (aged ≥18 years) with MDS. To be eligible, patients must have low- or intermediate-risk MDS (de novo or secondary) per the Revised International Prognostic Scoring System and have relapsed, exhibited an inadequate response to, or been refractory, resistant, or intolerant to treatment with an erythropoiesis-stimulating agent. Patients may have low or high red blood cell transfusion burden, must exhibit adequate major organ function, and must have an Eastern Cooperative Oncology Group performance status of 0-2. Key exclusion criteria include the presence of concomitant severe cardiovascular disease, such as congestive heart failure, myocardial infarction, angina, and/or uncontrolled cardiac arrhythmia; history of stroke, deep venous thrombosis, or pulmonary or arterial embolism; presence of clinically significant anemia due to iron, vitamin B12, or folate deficiencies, autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding; and prior allogeneic or autologous stem cell transplant. In this study, TP-0184 will be administered orally once daily for 24 weeks. The primary and secondary endpoints of each study phase are summarized in the table. Recruitment is ongoing, with approximately 30 patients targeted for enrollment in phase 1 and 10-60 patients targeted for enrollment in phase 2. In phase 1, increasing dose levels of TP-0184 ranging from 20 to 270 mg will be evaluated, with 1-6 patients dosed at each level. Dose escalation will be performed using a two-parameter Bayesian logistic regression model. Determination of the recommended phase 2 dose (RP2D) will be informed by the maximum tolerated or maximum administered dose in phase 1. In phase 2, the efficacy of TP-0184 at the RP2D will be monitored using Bayesian posterior probability to optimize enrollment with Bayesian stopping rules. Bayesian monitoring of responses will be started after the first 10 enrolled patients are evaluable for efficacy. Figure 1 Figure 1. Disclosures Verma: Medpacto: Research Funding; Curis: Research Funding; Eli Lilly: Research Funding; Stelexis: Consultancy, Current equity holder in publicly-traded company; Novartis: Consultancy; Acceleron: Consultancy; Celgene: Consultancy; Stelexis: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company; Incyte: Research Funding; GSK: Research Funding; BMS: Research Funding. Brunner: Celgene, Forty Seven Inc, Jazz: Other: Advisory Board; Novartis, Celgene, Takeda, AstraZeneca: Research Funding. Pennock: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. McMullen: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Wade: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Yang: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Xie: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Whatcott: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Foulks: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Melear: Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau. </jats:sec

MAGNIFY: Phase IIIb Randomized Study of Lenalidomide Plus Rituximab (R2) Followed By Lenalidomide Vs. Rituximab Maintenance in Subjects with Relapsed/Refractory Follicular, Marginal Zone, or Mantle Cell Lymphoma

Abstract Background:Lenalidomide is an immunomodulatory agent with direct and immune-mediated mechanisms of action, as well as clinical activity in NHL. Recent studies in frontline and relapsed/refractory NHL show high activity for lenalidomide plus rituximab (R2), supporting further study of this combination. Methods: MAGNIFY (NCT01996865) is a phase IIIb, multicenter, open-label study of subjects with grades 1-3b FL (including transformed lymphoma [TL]), MZL, or MCL who received &gt;=1 prior therapy and had stage I-IV, measurable disease (&gt;1.5 cm). Subjects received 12 cycles of R2 induction, consisting of oral lenalidomide 20 mg/day, days 1-21 per 28-day cycle (d1-21/28) plus intravenous rituximab 375 mg/m2, days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3, 5, 7, 9, and 11 (28-day cycles). Subjects with stable disease (SD) or better after induction were then were randomized 1:1 to R2 vs. rituximab maintenance. Stratification to the 2 maintenance arms was based on histology (FL grade 1-3b and TL vs. MZL vs. MCL), number of prior lines of antilymphoma therapy (&lt;=2 vs. &gt;2), and age (&lt;65 vs. &gt;=65 years).Maintenance R2 consisted of lenalidomide 10 mg/day, d1-21/28, cycles 13-30 plus rituximab 375 mg/m2, day 1 of cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 (Arm A). Rituximab maintenance alone was on the same schedule (Arm B). Subjects receiving R2 maintenance after 18 cycles are eligible to continue maintenance lenalidomide monotherapy 10 mg/day, d1-21/28 (optional per subject and/or investigator discretion) until disease progression as tolerated. The primary endpoint isprogression-free survival (PFS) comparing maintenance arms using a two-sided test with alpha=0.05 and HR=0.67. Secondary endpoints include safety, overall survival, and response rates. Efficacy is evaluated per modified 1999 IWG criteria and safety per NCI CTCAE version 4.03. Results: As of Jan 11, 2016, 135 subjects have been enrolled, including 91 (67%) with FL, 24 (18%) with MZL, 19 (14%) with MCL, and 1 (1%) with TL. At the time of enrollment, subjects had a median age of 66 years (range, 41-91); 81% had stage III/IV disease. Subjects had received a median of 2 prior therapies (range, 1-10), with 36% refractory to rituximab (defined as SD/PD to or PR/CR for &lt;6 months with prior rituximab). The most common prior regimens were rituximab (41%), BR (25%), R-CHP (14%), R-CHOP (11%), and R-CVP (7%). At data cut-off, 45 (33%) subjects discontinued treatment before the maintenance period. Primary reasons for discontinuation of lenalidomide and/or rituximab, respectively, were due to AEs in 16 (12%) and 14 (10%) subjects, PD in 15 (11%) subjects for either treatment, withdrawal by subject in 6 (4%) and 7 (5%) respectively, and death 3 (2%) in either treatment. In the safety population (n=124), treatment-emergent adverse events (AE) during induction that led to dose reduction/interruption of lenalidomide or rituximab occurred in 55% or 24% of subjects, respectively, mainly due to neutropenia for lenalidomide and infusion-related symptoms for rituximab. The most common grade 3/4 AEs during induction were 27% neutropenia, 9% leukopenia, 6% thrombocytopenia, and 5% fatigue. 11 subjects have died (5 due to PD, 3 AEs, 3 other). At a median duration of 23.1 weeks (range, 0.1-51.1) of induction, 90 subjects were evaluable for response. Best responses to induction were 56 (62%) subjects with ORR, 8 (9%) CR, 12 (13%) CRu, 36 (40%) PR, and 22 (24%) SD. Responses with R2 treatment were observed in all histologies (Table 1). At data cut-off, 19 subjects have completed induction and 18 have proceeded to maintenance (n=7 R2, n=11 rituximab alone). Continued study and follow-up are ongoing to enroll more subjects in the induction and maintenance arms. Conclusions: R2 induction therapy shows favorable activity and a tolerable safety profile in subjects with advanced-stage, relapsed/refractory FL, MZL, MCL, and TL. Continued study is ongoing to determine the effect of R2 vs. rituximab maintenance following 1 year of R2 induction. Disclosures Andorsky: Gilead: Research Funding; Celgene: Consultancy, Research Funding; CTI: Research Funding. Yacoub:Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Alexion: Honoraria. Bitran:Oncology Specialists: Employment. Melear:Texas Oncology: Employment. Foon:Celgene: Employment. Rizvi:Celgene: Employment, Equity Ownership. Llorente:Celgene: Employment. Li:Celgene: Employment, Equity Ownership. Sharman:Genentech: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy; Gilead: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy. </jats:sec

SEA-BCMA, an Investigational Nonfucosylated Monoclonal Antibody: Ongoing Results of a Phase 1 Study in Patients with Relapsed/Refractory Multiple Myeloma (SGNBCMA-001)

Abstract Background Patients (pts) with relapsed/triple-class refractory (R/R; refractory to a proteasome inhibitor, immunomodulatory drug or anti-CD38 antibody) multiple myeloma (MM) have limited treatment options. A need remains for novel combination therapies with manageable toxicity and non-cross-resistant mechanisms of action. B-cell maturation antigen (BCMA) is expressed in most MM pt tumors. SEA-BCMA is an investigational, humanized, nonfucosylated IgG1 monoclonal anti-BCMA antibody. Proposed mechanisms of action of SEA-BCMA include blocking of BCMA-mediated pro-survival and proliferative signaling, mediating antibody-dependent cellular phagocytosis, and displaying enhanced antibody-dependent cellular cytotoxicity. Preclinical data demonstrate promising antitumor activity and versatile combinability. Here, we present preliminary data from the first-in-human Phase 1 clinical trial. Methods SGNBCMA-001 (NCT03582033) is an ongoing phase 1, open-label, multicenter, dose-escalation and expansion study to evaluate the safety, tolerability and antitumor activity of SEA-BCMA in adults with R/R MM not previously exposed to any other BCMA-directed therapy. Part A tested monotherapy safety and tolerability with dose escalation (100-1600 mg flat dosing once every 2 weeks [Q2W] by intravenous infusion), and dose expansion at the highest tolerated dose. Parts B and C aim to optimize efficacy by testing intensified dosing (Part B; weekly [Q1W] induction dosing of SEA BCMA for 8 weeks is followed by Q2W maintenance dosing) and dexamethasone (DEX) combination therapy (Part C) in pts who have received ≥3 prior lines of therapy for MM and are triple-class refractory. Responses are assessed per the 2016 International Myeloma Working Group criteria. Results As of June 15, 2021, Part A completed enrollment. A total of 55 pts received SEA-BCMA (see Table 1 for pt characteristics). SEA-BCMA was generally well tolerated, and the maximum tolerated dose was not reached in the 5 dose levels tested in Part A (100, 200, 400, 800, or 1600 mg Q2W; n=2, 2, 2, 7, and 7, respectively). At 800 mg, 1 of 7 pts reported a Grade 3 infusion-related reaction (IRR), which met dose-limiting toxicity (DLT) criteria by lasting &amp;gt;24 hours despite supportive care. This constituted the single DLT observed during dose escalation. Subsequently, dose expansion (n=15) proceeded at 1600 mg Q2W. The most common treatment-emergent adverse events (TEAEs) observed with 1600 mg Q2W (n=22) were fatigue (32%), pyrexia (23%), IRR (23%), and hypertension (23%) for non-hematological events, and anemia (14%) for hematologic events. The most common ≥Grade 3 TEAEs with 1600 mg Q2W were anemia and syncope (9% each). Following a safety monitoring review, premedication with acetaminophen + antihistamine was introduced to mitigate IRRs in expansion cohorts. Parts B and C completed parallel safety run-ins (n=6 each) at the 1600 mg dose with no DLTs observed and with similar tolerability. Pharmacokinetic (PK) analyses indicate serum SEA-BCMA exposures increased proportionally with increasing dose with a half-life of approximately 10 days. Preliminary analyses suggest the PK profile of SEA-BCMA in combination therapy with DEX (n=5) is comparable to monotherapy and is unaltered with a change in schedule from Q2W to Q1W. Three of 22 pts who received 1600 mg SEA-BCMA Q2W monotherapy (Part A) achieved a confirmed objective response (OR; OR rate: 14% [95% confidence interval: 2.91, 34.91]; 2 partial responses [PR], 1 very good PR [VGPR]). To date, 3 pts remain on treatment (2 PRs and 1 stable disease). The median duration of treatment was 12 weeks (Figure 1; range 4-88). In Parts B and C, 2 of 8 (2 PR) and 2 of 12 (1 VGPR, 1 PR) pts reported a confirmed OR; 3 of the 4 responding pts remain on treatment in cycle 7, 8, and 9, respectively. Conclusions Preliminary results for SGNBCMA-001 suggest a favorable safety profile and combination potential. SEA-BCMA also showed encouraging duration on treatment and initial antitumor activity in a heavily pre-treated late-line R/R MM pt population. Expansion cohorts testing intensified SEA-BCMA dosing and the addition of DEX are underway to further assess the safety, tolerability, and estimate of SEA-BCMA activity in the context of these treatment approaches. An additional expansion cohort (Part D), testing the combination of SEA-BCMA with pomalidomide and DEX in pts who have received ≥2 prior lines of therapy, is now enrolling. Figure 1 Figure 1. Disclosures Hoffman: BMS, Celgene: Honoraria. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Melear: Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau; Janssen: Speakers Bureau. Liedtke: Pfizer: Honoraria; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Niesvizky: Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; GSK: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding. Tomasson: Pfizer, Inc.: Research Funding; Rafael Pharmaceuticals: Research Funding; syros Pharmaceuticals: Research Funding; Janssen R&amp;D: Research Funding; Seagen, Inc.: Research Funding. Yasenchak: Seagen Inc.: Research Funding. Green: Seagen Inc.: Research Funding; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees, Patents &amp; Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents &amp; Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding. Li: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Wang: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Ho: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. </jats:sec

Daratumumab, bortezomib, cyclophosphamide and dexamethasone in newly diagnosed and relapsed multiple myeloma: LYRA study.

This United States community study evaluated the combination of daratumumab, bortezomib, cyclophosphamide and dexamethasone (D-VCd) in newly diagnosed multiple myeloma (NDMM) and relapsed multiple myeloma (RMM). Patients received 4-8 induction cycles of bortezomib 1·5 mg/