tbuckley/cabot-search huggingface dataset:
A phase I study of BOS172738 in patients with advanced solid tumors with RET gene alterations including non-small cell lung cancer and medullary thyroid cancer.
Authors: Patrick Schoffski, Philippe Georges Aftimos, Christophe Massard, Antoine Italiano, Christiane Jungels, Karen Andreas, Mitchell Keegan, Peter T.C. Ho
Journal: Journal of Clinical Oncology (2019)

TPS3162 Background: RET gene alterations (mutations and fusions) leading to constitutive kinase activity have been identified in various tumor types including non-small cell lung cancer (NSCLC), medullary thyroid (MTC), colon, breast and ovarian cancer. The current generation of multi-kinase inhibitors approved for treatment of such tumors, do not selectively target RET and exhibit significant off-target activity especially against vascular endothelial growth factor receptor 2 (VEGFR2), resulting in dose-limiting toxicities that prevent the full inhibition of RET in those tumors. Recently, early clinical data from a class of more selective RET inhibitors have shown promising results with a more favorable safety profile in patients with RET alterations. BOS172738 is a novel RET inhibitor with nanomolar potency against RET and approximately 300-fold selectivity against VEGFR2. This phase 1 study is assessing the safety and tolerability of BOS172738 in patients with advanced solid tumors with RET alterations. Methods: NCT03780517 is a phase 1, open label, multicenter, dose escalation trial to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of BOS172738, an orally dosed RET kinase inhibitor, in patients with advanced solid tumors with RET gene alterations. RET gene alteration status will be assessed locally but confirmed centrally. The study is comprised of 2 parts: in Part A (dose escalation), patients with advanced solid tumors with RET gene alterations will receive BOS172738 orally once daily in each 28-day cycle. Select patients in Part A are eligible for intrapatient dose escalation. On establishing the recommended phase 2 dose (RP2D), Part B (expansion) will enroll up to an additional 60 patients to 1 of 3 tumor type-specific cohorts. The 3 expansion cohorts will each consist of up to 20 advanced cancer patients with: 1) RET gene-fusion NSCLC; 2) RET gene-mutant MTC; and 3) other RET gene-altered advanced tumors or NSCLC/MTC with prior specific RET gene-targeted therapy. Patients in expansion cohorts will receive BOS172738 daily at the RP2D until disease progression or other discontinuation criteria have been met. The study is currently open to enrollment globally with the first patient entered in 01/2019. Clinical trial information: NCT03780517.
Case 20-1988
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Roger S. Williams, Edward P. Richardson
Journal: New England Journal of Medicine (1988)

Presentation of CaseA 10-year-old boy was admitted to the hospital because of headache, vomiting, and papilledema.The child was well until 12 days earlier, when he began to experience pain in the right ear and anorexia. A physician made a diagnosis of otitis externa and prescribed polymyxin–neomycin–hydrocortisone ear-drops. Four days later nausea, vomiting, and diarrhea developed, with a bifrontal headache, and the boy felt lightheaded on standing. Three days later his temperature rose to 38.9°C, with pain in the right side of the neck and the right tonsil, persistent headache, and stiffness of the neck. A physician found that . . .
FAIRLANE, a double-blind placebo-controlled randomized phase II trial of neoadjuvant ipatasertib plus paclitaxel for early triple-negative breast cancer
Authors: M. Oliveira, C. Saura, P. Nuciforo, I. Calvo, J. Andersen, J.L. Passos-Coelho, M. Gil Gil, B. Bermejo, D.A. Patt, E. Ciruelos, L. de la Peña, N. Xu, M. Wongchenko, Z. Shi, S.M. Singel, S.J. Isakoff
Journal: Annals of Oncology (2019)
Evaluating the role of the COX2/PGE2 pathway in anti-melanoma immunity.
Authors: Michelle Ferreira, Irina Krykbaeva, William Damsky, Harriet M. Kluger, Marcus Bosenberg
Journal: Journal of Clinical Oncology (2019)

e14114 Background: Checkpoint inhibitors such as anti-PD1 (aPD1) have revolutionized treatment of metastatic melanoma. However, a large subset of patients receiving such treatment fails to respond to aPD1 monotherapy due to mechanisms such as PD-L1 upregulation within the tumor and T cell exhaustion in the tumor microenvironment. The PGE2/COX2 signaling pathway is one of the pathways implicated in T cell exhaustion and PD1/PD-L1 upregulation and thus represents an attractive pharmacologic target to enhance effects of aPD1 therapy due to the availability and safety of inhibitors such as aspirin or NSAIDs. There is evidence that PGE2/COX2 pathway inhibitors act synergistically with aPD1 therapy in murine melanoma and breast cancer models. Here we aimed to further characterize this synergism using the YUMMER (Yale University Mouse Melanoma Exposed to Radiation) 1.7 model, an irradiated, syngeneic cell line originating from Braf V600E ; Pten -/- ; and Cdkn2a -/- genetically engineered mouse melanomas. YUMMER1.7 cells implanted into the flanks of C57BL6/j mice show reproducible but partial responses to intraperitoneal aPD1 therapy and thus serves as an ideal platform to study whether concurrent PGE2/COX2 pathway blockade may result in additive effects to aPD1 therapy. Methods: 6-7 week old male C57BL6/j mice (n = 20) were injected with 500K YUMMER1.7 cells and treated with aPD1 therapy alone starting on day 7 after tumor implantation (n = 10) or with aPD1 therapy starting on day 7 in addition to ibuprofen dissolved in drinking water at a concentration of 1 mg/mL started on the day of tumor implantation (n = 10). Using an average daily water consumption estimate of 6 mL/day, this translates to a human equivalent of roughly 1200 mg/day, a moderate dose of ibuprofen. Tumor growth was monitored and tracked to an endpoint of 1cm 3 . Results: Tumor volume at day 17 significantly differed between the two groups (p &lt; 0.0001). Survival curves were significantly different between the two groups (p &lt; 0.0001); all tumors treated with aPD1 alone grew to endpoint by day 32, while all tumors treated with aPD1 + ibuprofen regressed with 8 out of 10 showing complete regression by day 32. Conclusions: We have shown that ibuprofen strongly synergizes with aPD1 therapy in a murine model of melanoma, complementing existing evidence. This suggests that PGE2/COX2 inhibitors such as NSAIDs, which are over-the-counter agents with a well-studied safety profile, may serve as a promising means of enhancing the response to aPD1 therapies such as nivolumab in melanoma patients who initially fail aPD1 monotherapy.
Dose-escalation study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), in postmenopausal women with ER+/HER2- metastatic breast cancer (mBC).
Authors: Aditya Bardia, Hannah M. Linden, Gary A. Ulaner, Sarat Chandarlapaty, Alice Gosselin, Séverine Doroumian, Marina Celanovic, Mario Campone
Journal: Journal of Clinical Oncology (2019)

1054 Background: SERDs result in ER competitive antagonism and degradation and can block signaling in ER-dependent tumors resistant to other endocrine therapies. This study investigates SAR439859, a potent oral SERD, +/- palbociclib in ER+/HER2- mBC. Here are preliminary results, as of 28 Nov 2018, for single-agent SAR439859 dose escalation. Methods: Part A of this Phase 1/2 study (NCT03284957; TED14856) assessed SAR439859 dose escalation (dose range: 20–600 mg once daily [QD]; 3 + 3 design) in postmenopausal women with ER+/HER2- mBC treated for ≥ 6 months with prior endocrine therapy and ≤ 3 chemotherapies in the advanced setting. Endpoints: dose-limiting toxicities (DLTs); maximum tolerated dose (MTD); safety; pharmacokinetics (PK); tumor response (RECIST 1.1); pharmacodynamic (PD) inhibition of ER occupancy ( 18 FES-PET scan). Results: Patients (pts; n = 16) had a median age of 59.5 years (range 40–79), ECOG performance status of 0 (62.5%) or 1 (37.5%) and a median of three prior anticancer therapies (range 1–8) in the advanced setting (endocrine therapy n = 16; chemo/targeted therapy n = 13). All pts had ≥ 1 treatment emergent adverse event (mostly grade 1–2); most frequent were asthenia/fatigue (43.8%), hot flushes (37.5%), nausea (37.5%), diarrhea (31.3%), constipation (31.3%), and decreased appetite (31.3%). There were no DLTs at any of the five dose levels (maximum administered dose: 600 mg QD); MTD was not reached. In 18 FES-PET scans, signal inhibition &gt; 87% occurred with plasma concentrations &gt; 100 ng/mL. There was a dose proportional increase of exposure up to 400 mg after repeated QD doses. Average C trough was reached after repeated 400 mg QD allowing 90% of 18 FES-PET signal inhibition. One pt (6.3%) had confirmed partial response (150 mg QD); eight (50%) had stable disease (SD) including three (18.8%) long-term SD (≥ 24 weeks); seven (43.8%) had progressive disease. Conclusions: SAR439859 had a favorable safety profile, high ER occupancy and encouraging antitumor activity (to be confirmed in dose expansion) in pretreated pts with ER+/HER2- mBC. With no DLTs and MTD, 400 mg QD was selected for expansion cohorts based on safety, PD and PK data. Funding: Sanofi. Clinical trial information: NCT03284957.
PD-1/PD-L1 immunotherapy for advanced lung cancer: An electronic medical database based real world study in China.
Authors: Xiao Zhao, Qiong Sun, Sheng Jie Sun, Weiwei Shi, Shun Chang Jiao
Journal: Journal of Clinical Oncology (2019)

e20543 Background: Immunotherapy has shown promising results for clinical management of various cancers. We reported our real world experience with PD-1 or PD-L1 immunotherapy in management of advanced lung cancer patients in China. Methods: This is a single-center retrospective study based on the de-identified electronic medical data collected in routine clinical practice. A total of 198 advanced lung cancer (stage IIIA-IV) patients who underwent anti-PD-1/PD-L1 therapy at Chinese People's Liberation Army General Hospital between 2015 and 2018 were included. Progression free survival and overall survival of patients were estimated by Kaplan-Meier methods. The treatment-related adverse events were also analyzed. Results: Median age of patients was 60.0 years (33.0-88.0 years). Most patients were male (150, 75.8%), smokers (116, 61.7%) and had a KPS score ≥70 (169, 97.7%). Of 198 patients, 106 (53.5%) had adenocarcinoma and 54 (17.3%) had squamous cell carcinoma. Thirty-one (15.7%) patients had CNS metastases. Seventy-one (38.8%) patients received two or more prior therapies. Estimated progression free survival was 5.6 months and overall survival was 24.5 months. One-hundred twenty-seven (64.1%) patients had documented to suffer adverse events, most commonly gastrointestinal adverse events and liver damage (Table). Conclusions: Our study showed survival benefits of PD-1/PD-L1 immunotherapy in advanced NSCLC patients in clinical practice. Safety profile was comparable to the previous studies. Our study supports the benefits of PD-1/PD-L1 immunotherapy in clinical management of advanced lung cancer patients. [Table: see text]
Utilization of value stream mapping to improve chimeric antigen receptor (CAR) T-cell patient experience at an academic medical center (AMC).
Authors: Julie Porter, Katherine A. Kong, Theresa Latchford, Debbie Bergman, Sonni Doran, Nimfa Fajardo, Gary Goldstein, Melissa Rodin, Andrea Segura Smith, Jay Y. Spiegel, David Bernard Miklos
Journal: Journal of Clinical Oncology (2019)

6607 Background: Value Stream Mapping (VSM) is commonly used to identify waste, reduce process cycle times and implement process improvements in the product and manufacturing space. VSM was applied to analyze and improve the patient experience for individuals receiving CAR T cell therapy at this AMC, with emphasis on safety and quality of care, efficient patient flow and improved communication across the care team. Methods: Fifty-three multidisciplinary representatives from 21 teams across the AMC participated in at least one of the five 4-hour VSM sessions. Comprehensive VSM workflows were created for each step in the current CAR T cell patient journey, from initial referral through post-infusion care. Future state analysis was performed, with emphasis on identification of information technology improvements, communication and pain points. Baseline outcome metrics were established to assess effectiveness of future state VSM improvements. Results: Visual mapping of the CAR T cell patient journey identified several opportunities for improvement. A total of 72 improvement projects were outlined, which could be grouped into four main categories: (1) establish channels for improved care team communication, (2) build information technology infrastructure to support efficient patient flow and quality of care, (3) develop teaching tools for patient and care team education, and (4) delineate standard of care and clinical trials operational workflows. Baseline outcome metrics were measured across the patient population (n = 33), including time from consent to cell collection, length of inpatient stay, intensive care unit (ICU) utilization, and percent of readmissions within 7 days. Outcome metrics will be tracked and reported after future state changes to determine effectiveness of VSM-based process improvements. Conclusions: CAR T cell therapy is a novel therapy, which poses new challenges for coordination across a multidisciplinary care team at an AMC. The VSM approach is a useful tool to identify process and infrastructure improvements that can improve the patient journey. This approach can be generally applied to drive process improvements across clinical care.
Avoiding peg-filgrastim (Peg-F) prophylaxis during the paclitaxel (T) portion of the dose-dense (DD) doxorubicin-cyclophosphamide (AC)-T regimen: A prospective study.
Authors: Romualdo Barroso-Sousa, Ines Maria Vaz Duarte Luis, Antonio Di Meglio, Jiani Hu, Rebecca Rees, Natalie Faye Sinclair, Lindsey Milisits, Jose Pablo Leone, Michael Constantine, Meredith Gail Faggen, Frederick Briccetti, Caroline Cole Block, Ann H. Partridge, Harold J. Burstein, Adrienne Gropper Waks, Lorenzo Trippa, Sara M. Tolaney, Michael J. Hassett, Eric P. Winer, Nancy U. Lin
Journal: Journal of Clinical Oncology (2019)

517 Background: Use of growth factors (GF) adds considerable expense and some toxicity to adjuvant breast cancer chemotherapy. We tested the feasibility and safety of omitting routine GF use during the T portion of DD AC-T. Methods: This is a prospective, single-arm study in which patients (pts) who completed 4 cycles of DD-AC proceeded to DD-T 175 mg/m2 every two weeks (wks) without routine GF (NCT02698891). Key inclusion: age≤ 65, ECOG PS≤1, absolute neutrophil count (ANC) ≥1500/mm3, and no febrile neutropenia (FN) during DD-AC. Criteria to treat for T included ANC ≥1000/mm3. Peg-F was given only if pts had FN in a prior cycle, or at investigator discretion if infection or treatment delay &gt; 1 wk. Once Peg-F was given, pts received it in all future cycles. The primary endpoint was the rate of T completion ≤ 7 wks from cycle 1 day 1 (C1D1) to C4D1. Secondary endpoints included total use of Peg-F, rates of hematologic toxicity and FN, reasons for dose modification or hold. If ≥85% of pts completed T on time, the regimen would be considered feasible. If the true on-time completion rate is 75%, the chance the regimen would be declared infeasible is 91%, and if it is 85% the chance that the regimen is falsely declared infeasible is 10% (power = 0.899). ≥100/125 pts had to complete T on time for the regimen to be deemed successful. Results: Among 127 pts enrolled, 125 received ≥1 dose of protocol therapy and are included in the analysis. Median age at registration was 46 (range 21-65). Median C1D1 ANC was 7500/mm3 (range 1500-20500). 112 (90%) (95% CI 83-94%) pts completed DD-T ≤ 7 wks, and 3 (2%) completed within &gt; 7 wks (2 due to neutropenia); 10 (8%) did not complete all cycles of T. Omission of Peg-F was not causally related to non-completion of T in any pts. The most common reasons for dose reduction or delays were non-hematologic. One pt had FN but was able to complete T on time. Eight (6.4%) pts received Peg-F during the trial. Conclusions: Omission of routine GF use during DD-T according to a pre-specified algorithm appears safe, feasible, and was associated with a 95.7% reduction in use of Peg-F, relative to the current standard of care. Additional analyses including cost implications are ongoing. Clinical trial information: NCT02698891.
Immune landscape of the tumor microenvironment to predict prognosis and DNA mutations in patients with lung adenocarcinoma.
Authors: Sunyoung S. Lee, Ahmed Elkhanany, Andrew Baird, Jillian Dolan, Dong Chan Lee, Shinyoung Park, Stuart Baird
Journal: Journal of Clinical Oncology (2019)

8544 Background: The tumor microenvironment (TME) influences prognosis and response to therapy. The correlation between immune profiles in the TME and cancer DNA mutations is not well established. Methods: Clinical outcomes data, mRNA-seq, and DNA mutation of 480 patients (pts) with lung adenocarcinoma (LAD) were obtained from TCGA. Pts were clustered into 4 groups using unsupervised machine learning, based on mRNA expression of genes related to antigen presentation (AP) and cytolytic activity (CA): group (G) 1 with high AP and CA (52 pts); G2, high AP, low CA (82); G3, low AP, high CA (66); G4, low AP and CA (280). Analysis of the immune landscape was performed using mRNA-seq of 191 genes enriched in cellular and structural elements of TME. DNA mutations were analyzed using the R package ggpubr and correlated in G1-G4. Results: Pts in G1 have high expression of genes related to immune activation (IA) and decreased expression of immune suppression (IS) and have the best prognosis. Pts in G2 have intermediate prognosis with decreased IA genes and intermediate expression of genes related to IS and immune checkpoints. Pts in G3 have the worst prognosis with very high expression of genes related to immune checkpoints, desmoplasia, T cell co-inhibition, and IS. They also have low CD39 expression implying low cancer antigen-driven T cells. Pts in G4 have intermediate prognosis with highly depressed IA genes. Out of 70,199 non-synonymous mutations, the top 50 mutated genes in each pt group were identified: 36, 26, 31, and 17 DNA mutations were only found in G1, G2, G3, and G4 (refer to presentation). EGFR mutation was only found in G2; KRAS in G2/4; TP53 in G2/3/4. Conclusions: Our correlation analysis of mRNA-seq and DNA mutation shows that the immune landscape of TME can predict DNA mutations and prognosis. It further demonstrates a close connection between DNA mutations and changes in TME mRNA expressivity which appear to have valuable prognostication potential in the clinical setting with now widely available genomic testing.
Sustaining the gains in cancer care from the oncology care model.
Authors: Valerie P Csik, Jared Minetola, Andrew E. Chapman, Neal Flomenberg
Journal: Journal of Clinical Oncology (2019)

6632 Background: The Oncology Care Model (OCM) is a 5-year demonstration project led by the Centers for Medicare and Medicaid Services (CMS) to create a framework for the future of oncology care in the United States. More than half way through the project, our large, urban NCI-designated cancer center chose to focus on and invest in resources and personnel for patient navigation and the development of clinical pathways. Although navigation has shown to reduce emergency department (ED) visits by as much as 6% per quarter compared to non-navigated patients, sustaining it is a challenge because it is a nonbillable service. Clinical pathways are a tool to reduce care variation by addressing drug expenditures, and represent an opportunity to reduce outpatient costs by as much as 35% when patients are treated on pathway. 3 Many OCM practices made similar investments and all are facing the question: How will the infrastructure and efforts developed during OCM be sustainable after the demonstration project ends? Methods: An analysis of average ED cost and utilization as well as drug expenditures was conducted using OCM feedback data (Q1-Q8). Total utilization of ED visits and ED admits were used to determine a projected annualized cost which was compared to a budgeted navigation team. Similarly, projected annualized drug expenditures were compared to the annual cost of the pathways tool. Results: We found that ED visits and ED admits would need to be reduced by 11% to cover navigation costs. Similarly, a 0.7% reduction in total drug expenditures would cover the cost of clinical pathways. The OCM data represents a timeframe prior to implementation of these programs and an average increase of 1.6% per quarter for ED admits, a 0.6% decrease in ED visits and 2.7% increase in drug expenditures. This will serve as a baseline to measure progress towards our sustainability targets. Conclusions: Long term sustainability of the infrastructure developed during OCM to support cancer care transformation will be dependent on reducing high cost and highly utilized services. Aligning impact areas with resources/tools to ensure sustainability is an approach that can help define targets for OCM practices.
First-in-human imaging of nanoparticle entrapped docetaxel (CPC634) in patients with advanced solid tumors using <sup>89</sup>Zr-Df-CPC634 PET/CT.
Authors: Iris H.C. Miedema, Gerben J.C. Zwezerijnen, Daniela E. Oprea-Lager, Henk M.W. Verheul, Danielle J. Vugts, Marc C. Huisman, Ron H.J. Mathijssen, Cristianne J.F. Rijcken, Qizhi Hu, G.a.M.S. van Dongen, Catharina Wilhelmina Menke
Journal: Journal of Clinical Oncology (2019)

3093 Background: CPC634 is a nanoparticle entrapping docetaxel designed to improve tumor accumulation and tolerability compared to conventionally administered docetaxel by taking advantage of the presumed enhanced permeability and retention (EPR) effect. In vivo imaging with zirconium-89 ( 89 Zr)-desferal (Df)-CPC634 will provide valuable information on its biodistribution and will quantify tumor retention. Methods: Patients with solid tumors not amenable to standard therapy received 37 MBq, 0.1-2mg of 89 Zr-Df-CPC634 tracer and whole body PET/CT scans were obtained at 2, 24 and 96h post-injection (p.i.). Patients were administered CPC634 (60mg/m 2 ) two weeks later followed by a second tracer injection and scans at 24 and 96h p.i. Biodistribution was quantified by delineating organs of interest and calculating mean %ID/kg. Visual tumor retention was defined as focal uptake in tumor lesions exceeding local background and quantified as standardized uptake peak values (SUV peak ) in volumes of interest. Results: Five patients were included. Biodistribution of 89 Zr-Df-CPC634 showed significant retention in healthy liver, and spleen compared to lung (respectively 2.54, 1.61 and 0.56 mean %ID/kg at 96h p.i.), supporting apparent opsonization of nanoparticles in cells of the reticuloendothelial system. Visual retention was observed in 16/37 evaluable tumor lesions with the highest intensity at 96h p.i, compatible with the assumed EPR effect. Tumor retention showed intra- and interpatient heterogeneity, with a mean %ID/kg of 3.43 [1.14-9.32]. Pre-administering unlabeled CPC634 did not change the mean tumor retention of 89 Zr-Df-CPC634 (at 96h p.i. mean 3.50 %ID/kg [1.64-9.97]), however, four additional lesions were visible in comparison to tracer only. Conclusions: The biodistribution of 89 Zr-Df-CPC634 was consistent with a prolonged exposure of nanoparticle containing docetaxel. 89 Zr-Df-CPC634 showed high retention in tumors confirming the EPR effect of these nanoparticle in humans, and supporting their further development for tumor targeting of therapeutic agents. A Phase II efficacy study in platinum resistant ovarian cancer (NTC03742713) is currently ongoing. Clinical trial information: NCT03712423.