bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of RecurIndex (RI) for patients with early-stage breast cancer enrolled in a Taiwanese multicenter study.
Authors: Lee Yi-Hsuan , Pennarun Nicolas , Tseng Ling-Ming , Yang Po-Sheng , Liang Ji-An , Hsieh Chia-Ming , Chang Yuan-Ching , Wang Ming-Yang , Shih Kuan-Hui , Cheng Skye Hung-Chun , Huang Chiung-Sheng 
Published: May 2020

3560 Background: Numerous prospective studies, predominantly in Caucasian population, have proven the clinical utility of using multigene expression tests to prevent overtreatment in early breast cancer (EBC) patients. Since racial and ethnic disparities exist in genetic and biological factors that could influence the disease, the primary purpose of this study is to access the clinical utility of RecurIndex, a recurrence risk test, that is based on a genomic profiling derived from Asian women. Methods: A total of 298 patients with EBC, luminal subtype (85.6%), HER2 subtype (7.7%) and triple-negative subtype (6.7%), were enrolled in a retrospective study across Taiwan medical centers. Kaplan Meier and Cox Proportional Hazards model were used to, respectively, identify independent prognostic factors and calculate the survival rates. The prediction model was then tested using the area under the receiver operating characteristic curve (AUC). The primary endpoint was distant recurrence-free survival (DRFS). Results: The 10-year DRFS was significantly higher in the good-prognosis group than the poor-prognosis group (92.0% [95% CI, 86.1-98.2] versus 63.0% [95% CI, 49.9-79.5]) (Table). The overall hazard ratio for distant recurrence was 1.031 (95% CI, 1.017±1.046) per RI score increment. In addition, in a subset of 179 cases (60.1%), the model yielded an 82.3% correct classification rate for predicting DR with a sensitivity of 87.0%, a specificity of 68.6% and negative predictive values of 97.3%. Conclusions: The present study provides robust evidence of the clinical utility of RI-DR to predict clinical outcomes. RecurIndex could be used to determine the utility of chemotherapy in Asian patients, especially in hormone-receptor positive and HER2 negative disease, leading to a meaningful reduction in adjuvant chemotherapy recommendations. [Table: see text]
The utility of blood-based molecular tools-the NETest-to monitor and evaluate the efficacy of PRRT in neuroendocrine tumors.
Authors: Bodei Lisa , Kidd Mark S. , Singh Aviral , Drozdov Ignat A. , Malczewska Anna , Baum Richard P. , Krenning Eric , Modlin Irvin Mark 
Published: May 2020

3568 Background: Peptide receptor radionuclide therapy (PRRT) is an effective therapy for metastatic/inoperable neuroendocrine tumors (NETs). Tools to predict and monitor the efficacy of therapy are important adjuncts in the radio-oncology armamentarium. Standard blood biomarkers are not effective by new molecular based assays such as the PRRT Predictive Quotient (PPQ) and NETest are effective as real-time predictors and monitors of therapy. We aimed to prospectively evaluate whether: 1) the NETest functioned as a surrogate biomarker for image-based per RECIST evaluation of PRRT efficacy; 2) there was a correlation between changes in NETest levels during therapy, PPQ prediction and treatment efficacy. Methods: Three independent 177Lu-PRRT-treated GEP-NET and BPNEN cohorts (Rotterdam, Netherlands: n= 41; Bad-Berka, Germany: n= 44; Meldola, Italy: n= 72). Treatment response: RECIST1.1 [Responder (stable, partial/complete response) vs Non-Responder]. Blood sampling: pre-PRRT, prior to each cycle and 6 months (median) after completion of all cycles. PPQ (positive/negative) and NETest (0-100 score) by PCR. Stable<40; progressive > 40). CgA (ELISA) as comparator. Samples deidentified, measurement and analyses blinded. Kaplan-Meier survival and Mann-Whitney analyses. Results: 122 of 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly ( p< 0.0001) decreased in RECIST-“responders” (-47±3%); in “non-responders” it elevated (+79±19%, p< 0.0005). NETest monitoring accuracy 98% (119/122). Follow-up levels > 40 (progressive) vs stable (<40) significantly correlated with mPFS (not reached vs. 10 months; HR 0.04, 95%CI: 0.02-0.07). PPQ response prediction was accurate in 118 (97%); 99% accurate positive and 93% accurate negative prediction. NETest significantly ( p< 0.0001) decreased in PPQ-predicted responders (-46±3%) and remained increased in PPQ-predicted non-responders (+75±19%). Follow-up NETest categories stable vs progressive significantly correlated with PPQ prediction and mPFS (not reached vs. 10 months; HR 0.06, 95%CI: 0.03-0.12). In comparison, the standard biomarker, CgA, failed to predict or correlate with response to PRRT ( p= NS). Conclusions: NETest accurately (98%) monitors PRRT response and is an effective surrogate marker for radiological response (image concordance 98%). A NETest decrease identified responders (99%) and correlated ( > 97%) with the pretreatment PPQ response predictor.
Targetable immune checkpoint molecules may be significantly differentially expressed in minority ethnicities.
Authors: Adashek Jacob J. , Szeto Christopher , Sanborn J. Zack , Reddy Sandeep K. , Toor Amir A. , Danielides Stamatina , Smith Steven , Grossman Steven R. , Clevenger Charles V , Faber Anthony , Ferreira-Gonzalez Andrea , Boikos Sosipatros Alexandros 
Published: May 2020

3576 Background: Studies of immune checkpoint blockade therapy (ICT) outcomes have been largely performed in melanoma and lung cancer patients, both of which are enriched for White patients. For example, a National Cancer Database study found that 97% of first-line ICT treatments in melanoma have been administered to White recipients (Patel, ASCO-SITC 2020). Given expanding indication in tumor types affecting more diverse populations, we sought to study whether minority populations might be projected to have differing checkpoint blockade response rates. Methods: Ethnicity information and RNAseq expression profiles and primary site information were obtained for 7087 patients from TCGA. Ethnicity was tested for association with RNA expression of targetable checkpoint genes ( PD1, PDL1, PDL2, CTLA4, IDO1, LAG3, TIM3, TIGIT, OX40, VISTA, and GITR) in 5 tumor histology types by Wilcoxon methods with Benjamini-Hochberg correction for multiple hypothesis testing. A dataset of > 2700 cases was obtained from NantHealth, with paired whole exome/RNAseq data. Ethnicity for 579 patients was assigned using allele-fraction from ~250 single nucleotide polymorphic sites found exclusively in 6 populations within the 1000 Genomes project. Ethnicity/checkpoint associations found in TCGA were tested within this dataset. Results: Within the TCGA cohort, ethnicity was not a factor in differential expression of checkpoint molecules in lung cancer. Within melanomas, in Asian patients PDL1, CTLA4, and IDO1 were expressed at lower levels than in White patients (each p = 0.04). These associations did not remain significant after correction for multiple hypothesis testing. Breast cancers in Black patients had significantly higher PD1, CTLA4, IDO1, LAG3, GITR, and OX40 expression compared to White patients, all remaining significant after correction (adj. p 3.7e-5 to 6.4e-3). Among White patients, colon cancers showed higher expression of PDL1/2, IDO1, LAG3, TIM3, and GITR (p 0.04 to 0.0017). IDO1 was significantly higher in White patients even after correction (adj. p = 0.03), and lower in Black patients (adj. p = 0.03). Conclusions: Ethnicity may represent a significant factor for efficacy checkpoint blockade therapies. White breast cancer patients might be anticipated to exhibit reduced sensitivity to PD1/CTLA4 blockade, while Black colon cancer patients may exhibit reduced sensitivity to IDO1 therapies such as epacadostat. A biomarker-driven approach to patient selection may ameliorate ethnic disparities in ICT outcomes.
Phase I study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors.
Authors: Rha Sun Young , Beom Seung-Hoon , Shin Young Geun , Yim Dong-Seok , Moon Yong Wha , Kim Tae Won , Kim Sun Young , Kim Gun Min , Kim Hyo Song , Cheong Jae-Ho , Lee Young Woo , Geiger Barbara Jean , Yoo Sanghee , Rudoltz Marc S. , Janku Filip 
Published: May 2020

3590 Background: IM156, a novel oral potent biguanide OXPHOS inhibitor of Protein Complex 1 (PC1) of the mitochondrial electron transport chain, causes AMPK phosphorylation, the downstream effects of which are detrimental to OXPHOS-dependent cancer cells prone to energy stress. Preclinical experiments with IM156 demonstrated activity in solid tumor and hematologic malignancy models as a single-agent and in combinations. Methods: This was an open label, first-in-human, multi-center, dose-escalation study ( NCT03272256 ) using a 3+3 design. The primary endpoint was to determine the maximum tolerated dose and/or recommended Phase 2 dose (RP2D) based on dose limiting toxicities (DLT), safety and tolerability. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics (PD) and preliminary signals of efficacy. Eligible patients were adults with advanced solid tumors refractory to standard therapies with ECOG Performance Status <2, adequate organ function, and measurable disease (RECIST 1.1 or RANO [gliomas]). IM156 was administered orally every other day (QOD) or daily (QD) in 28-day cycles. Results: 22 patients (gastric cancer: N = 8; ovarian cancer: N = 3; colorectal cancer: N = 3; endometrial cancer: N = 2; sarcoma: N = 2; other: N = 4) were enrolled in 7 dose cohorts (100, 200, 400, 800, and 1,200 mg QOD; 800 and 1,200 mg QD). The most frequent treatment-related adverse events (TRAEs) were gastrointestinal (nausea [N = 16, 73%], diarrhea [N = 12, 55%], and vomiting N = 11, 50%]). Nausea, reported in 3 (14%) patients, was the only Grade 3 TRAE. No DLTs were reported; the RP2D declared was 800 mg as 1,200 mg QD was associated with Grade 2/3 nausea requiring dose modifications. PK demonstrated dose-proportional increases in Cmax and AUC0-last reaching the expected efficacious range. PD demonstrated a decrease in tumor growth rate in 3 patients (1,200 mg QOD: N = 2; 800 mg QD: N = 1), and a decrease in VEGF and tumor markers in a patient with gastric cancer with neuroendocrine differentiation treated at 800 mg QD who remains on study in Cycle 11. Best response was stable disease in 7 (32%) patients. Conclusions: IM156 is the first PC1 OXPHOS inhibitor to have been successfully tested in patients with cancer with the identification of a RP2D. It was well tolerated at dose levels active in preclinical models, and demonstrated modest clinical activity in an unselected population of patients. Subsequent development will focus on OXPHOS-dependent tumors and in combinations with agents in which OXPHOS metabolism is a mechanism of resistance. Clinical trial information: NCT03272256 .
IGM-8444 as a potent agonistic Death Receptor 5 (DR5) IgM antibody: Induction of tumor cytotoxicity, combination with chemotherapy and in vitro safety profile.
Authors: Wang Beatrice , Wang Ling , Kothambawala Tasnim , Calhoun Susan , Matthew Thomas , Hernandez Genevive , Peterson Marvin , Sinclair Angus , Humke Eric William , Keyt Bruce 
Published: May 2020

3595 Background: Death receptor 5 (DR5) is a member of the tumor necrosis factor (TNF) receptor superfamily that multimerizes when bound to its ligand, TNF-related apoptosis inducing ligand (TRAIL), to activate the extrinsic apoptotic pathway. DR5 is broadly expressed on solid and hematologic cancers and has been targeted with both recombinant TRAIL and agonistic antibodies in the clinic. However, these therapeutics have generally been unsuccessful due to toxicity or lack of efficacy. We have developed a multivalent IgM DR5 agonist, IGM-8444, that multimerizes DR5 to selectively and potently induce tumor cell apoptosis while maintaining tolerability. Methods: IGM-8444 is an engineered, pentameric IgM antibody with 10 binding sites specific for DR5. Human tumor cell lines or hepatocytes were evaluated in vitro for dose dependent IGM-8444 induced cytotoxicity. The efficacy of IGM-8444 was evaluated with or without chemotherapy, in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse tumor models, with IGM-8444 administered at various dose levels and schedules when tumors reached approximately 100 mm3. Sera and tumors were analyzed for biomarkers of tumor apoptosis. Results: In vitro cytotoxicity assays identified IGM-8444 activity across cell lines from 18 solid and hematologic malignancies. In IGM-8444 partially resistant cell lines, combination with chemotherapy or a Bcl2 inhibitor enhanced in vitro cytotoxicity. IGM-8444 was efficacious as a monotherapy in CDX and PDX tumor models including colorectal, lung, and gastric indications. In a gastric PDX model, IGM-8444 induced complete and durable dose-dependent tumor regressions. In vivo, combination of IGM-8444 with standard-of-care chemotherapies, such as irinotecan, led to enhanced efficacy. IGM-8444 administration increased markers of tumor apoptosis, identifying potential clinical pharmacodynamic biomarkers. At doses several log-fold higher than efficacious doses, IGM-8444 demonstrated a favorable single agent in vitro safety profile, with little to no in vitro cytotoxicity observed using primary human hepatocytes from multiple donors. Conclusions: These data support the clinical development of IGM-8444 in both solid and hematological malignancies as a single agent and in combination with standard of care therapy. IGM-8444 is projected for IND filing in 2020.
Preliminary clinical pharmacokinetics and dose-response to support a phase II dose selection for CX-2009: A masked probody drug conjugate to CD166.
Authors: Stroh Mark , Li Rachel , Lu Hong , Wada Russ , Richardson Jennifer Hope , Frye John W. , Peterson Amy C. 
Published: May 2020

3599 Background: PROBODY therapeutics are antibody prodrugs with cleavable peptide masks designed to reduce off-tumor, on-target toxicities. The mask blocks binding in the periphery and is removed by tumor-associated proteases resulting in intratumoral binding. CX-2009 is a PROBODY drug conjugate directed against CD166/ALCAM, which is a target overexpressed in carcinomas but not suitable for traditional ADC targeting because it is expressed in normal epithelium. CX-2009 is conjugated to DM4, a potent microtubule inhibitor. Here we report preliminary clinical pharmacokinetic (PK) and exploratory dose-response (DR) analyses for CX-2009 from the ongoing phase 1/2 PROCLAIM-CX-2009 study (NCT03149549). Methods: Human PK and anti-drug antibody (ADA) data were obtained at selected times post-dose following IV 0.25–10 mpk CX-2009 Q3W and of 6 mpk Q2W. Covariates were selected for population PK (POPPK) based on multivariate screening at P< 0.01. Preliminary exploratory DR analyses were conducted for selected endpoints including adverse events of special interest and response data (CR, PR, SD, and PD). Results: Preliminary CX-2009 PK data from 92 subjects were available as of October 2019. Median free DM4 levels circulated at ≤0.3% of Total CX-2009 (masked + activated CX-2009) levels across the 1–10 mpk dose levels. A two-compartment POPPK model with linear elimination was fit to the Intact (masked form) CX-2009 data. The preliminary CX-2009 POPPK model estimates for Intact CX-2009 clearance (CL), volume of distribution, and half-life were 0.47 L/day, 4.51 L, and 7.14 days, respectively, with 91% of CX-2009 circulating as Intact CX-2009. ADA was not a statistically significant covariate on Intact CX-2009 CL. Evidence of clinical activity was observed at doses of 4 mpk Q3W or higher. DR analysis suggested that the frequency of grade ≥3 ocular toxicity events increased significantly at dose equivalents ≥8 mpk Q3W. POPPK simulations suggested that the targeted 90 nM trough concentration (based on nonclinical data) would be contained within the 90% prediction interval of predicted Intact CX-2009 levels following CX-2009 7 mpk. Conclusions: Preliminary CX-2009 PK data following CX-2009 0.25-10 mpk suggest that CX-2009 circulates predominantly as Intact CX-2009, and that Intact CX-2009 PK is not strongly influenced by target-mediated drug disposition or ADA. Preliminary DR and POPPK simulations support further evaluation of 7 mpk CX-2009 Q3W in selected cohort expansions. Clinical trial information: NCT03149549 .
Efficacy and safety of entrectinib in patients (pts) with NTRK-fusion positive (NTRK-fp) solid tumors: An updated integrated analysis.
Authors: Rolfo Christian Diego , De Braud Filippo G. , Doebele Robert Charles , Drilon Alexander E. , Siena Salvatore , Patel Manish , Cho Byoung Chul , Liu Stephen V. , Ahn Myung-Ju , Chiu Chao-Hua , Farago Anna F. , Goto Koichi , Lee Jeeyun , Bazhenova Lyudmila , John Tom , Fakih Marwan , Simmons Brian P. , Pitcher Bethany , Huang Xinhui , Demetri George D. 
Published: May 2020

3605 Background: NTRK gene fusions lead to transcription of chimeric TRK proteins with overexpressed kinase function. Entrectinib is a potent inhibitor of TRKA/B/C. In phase 1/2 studies (ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267), entrectinib was effective in pts with NTRK-fp solid tumors. We present updated data in a larger population with longer follow-up. Methods: In this integrated analysis of adult pts from 3 phase 1/2 trials (data cut-off 31 Oct 2018), tumors were assessed by blinded independent central review (BICR) with RECIST v1.1 (end of cycle 1; then every 8 wks). Primary endpoints were overall response rate (ORR) and duration of response (DOR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), efficacy in pts with/without baseline CNS disease, and safety. Results: There were 74 evaluable pts with advanced/metastatic NTRK-fp solid tumors (Table). Median duration of survival follow-up in all pts was 14.2 mo (range 0.1–29.7). BICR ORR was 63.5% (95% CI 51.5–74.4), with 5 complete responses (6.8%). Median BICR DOR was 12.9 mo (95% CI 9.3–NE); median BICR PFS was 11.2 mo (95% CI 8.0–15.7); median OS was 23.9 mo (16.0–NE). In pts with no baseline CNS disease (investigator-assessed; n=55), BICR ORR was 65.5% (95% CI 51.4–77.8) and median BICR DOR in responders was 12.9 mo (95% CI 9.3–NE). In pts with baseline CNS disease (investigator-assessed; n=19), BICR ORR was 57.9% (95% CI 33.5–79.8) and median BICR DOR in responders was 6.0 mo (95% CI 4.2–NE). Safety was in line with that previously reported; the most common ≥grade 3 treatment-related AEs were weight gain (8, 7.1%), anemia (8, 7.1%), and fatigue (7, 6.2%). Conclusions: In this updated analysis, including more pts and longer follow-up, entrectinib continued to demonstrate clinically meaningful responses in pts with NTRK-fp solid tumors, with and without baseline CNS disease. Clinical trial information: NCT02097810, NCT02568267 . [Table: see text]
CTEP 9557: A dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF mutant solid tumors.
Authors: Mooradian Meghan , Cleary James M. , Cohen Justine Vanessa , Lawrence Donald P. , Buchbinder Elizabeth Iannotti , Giobbie-Hurder Anita , Parikh Aparna Raj , Shapiro Geoffrey , Darville Lancia , Smalley Keiran , Koomen John M , Newton Amber , Keer Harold N. , Ivy S. Percy , Chen Helen X. , Sullivan Ryan J. 
Published: May 2020

3609 Background: Combination BRAF and MEK inhibitor therapy is associated with response in patients (pts) with BRAF mutant (mut) solid tumors; however critical limitations for the durable activity of these agents remains. Preclinically, the addition of heat shock protein 90 (HSP90) inhibitors improves the efficacy of BRAF inhibitor (BRAFi) therapy in both BRAFi -sensitive and resistant mutant cell lines. Methods: CTEP study 9557 (NCT02097225) is a phase I study designed to determine the safety and efficacy of the small molecule HSP90inhibitor, AT13387, in combination with dabrafenib (dab) and trametinib (tram) in patients with BRAF V600E/K mut solid tumors. Prior chemotherapy, immunotherapy, BRAF and/or MEK exposure was permitted. The primary objective was to determine the maximum tolerated dose (MTD). Results: From July 2015 to June 2018, 22 patients with previously treated, metastatic BRAF V600E/K mut solid tumors were enrolled using a 3 + 3 design at four dose levels (DL) (Table). Pts were predominantly female (59%) with a median age of 57.5yrs (37 -75). The most common tumor type was BRAF V600Emut colon cancer (N=12). Dose limiting toxicities (DLTs) occurred in one patient in DL3 and one in DL4, specifically grade 3 myelosuppression and fatigue, respectively. The MTD was Dab 150mg [BID/PO], Tram 2mg [QD/PO] and AT1187 260mg/m2 [D1,8,15/IV]. Twenty-one of 22 pts were eligible for efficacy assessment. Best response, per RECIST 1.1, was partial response (PR) in 2 pts – one with colon ca (TKI-naïve), one with melanoma (TKI-resistant) - stable disease (SD) in 8 pts, and disease progression (PD) in 11 with a disease control rate (PR + SD) of 47.6% (90% CI: 29% - 67%). Median time to progression was significantly longer in DL3 (3.9 mths; 1.8-9.2) compared to DL1 (1.6mths; 0.9-1.7) or DL2 (1.5; 0.6-3.6). Median PFS and OS were 1.8mths (90% CI: 1.6 – 3.7mths) and 5.1 mths (90% CI: 2.5 -10.6mths), respectively. Median OS was not reached in DL3/4. Correlative data on the expression of the key signaling proteins relating to response will be presented at the meeting. Conclusions: HSP90 inhibition combined with BRAF/MEK inhibition was determined to be safe with evidence of disease control in a heavily pre-treated population of pts with BRAF V600E/K mut solid tumors. Clinical trial information: NCT02097225 . [Table: see text]