bluuebunny/crossref_metadata_2025_split huggingface dataset:
Talazoparib beyond BRCA: A phase II trial of talazoparib monotherapy in BRCA1 and BRCA2 wild-type patients with advanced HER2-negative breast cancer or other solid tumors with a mutation in homologous recombination (HR) pathway genes.
Authors: Gruber Joshua James , Afghahi Anosheh , Hatton Alyssa , Scott Danika , McMillan Alex , Ford James M. , Telli Melinda L. 
Published: May 2019

3006 Background: Talazoparib, a PARP inhibitor, is active in germline BRCA1/2 mutant advanced HER2-negative breast cancer, but its activity beyond BRCA1/2 is unknown. We conducted a single institution phase II trial to evaluate talazoparib in patients (pts) with advanced HER2-negative breast cancer or other solid tumors with a germline (g) or somatic (s) alteration in HR pathway genes not including BRCA1/2. Methods: Eligible pts had measurable disease, lacked a germline or somatic mutation in BRCA1/2, received at least one prior therapy for advanced HER2-negative breast cancer or other solid tumor and had a HR pathway gene mutation: PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, RAD51C, RAD51D, MRE11, ATR, PTEN, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL. Pts with no progression on or within 8 weeks of their last platinum dose were eligible. Pts were treated with talazoparib 1 mg po daily until disease progression. Response was assessed every 8 +/- 1 weeks. If 2 or more responses were observed in 10 pts in stage I, the study would proceed to stage II and enroll 10 additional pts. The null hypothesis of a ≤ 5% objective response rate would be rejected if at least 3 of 20 respond. Results: Twenty pts were enrolled; 13 breast cancer (12 HR+/HER2-, 1 TNBC) and 7 non-breast cancer (pancreas, colon, uterine, testicular, parotid salivary). Median age was 54 years. Of 12 response evaluable pts with breast cancer, 3 had a RECIST response (ORR = 25%, 2 g PALB2, 1 g CHEK2/g FANCA/sPTEN) and 3 additional pts (g PALB2, s ATR, s PTEN) had SD ≥ 6 months (CBR = 50%). No responses were seen in non-breast tumors; 2 (g CHEK2 testicular, g ATM colon) had SD ≥ 6 months. Talazoparib was well tolerated; 5 patients required dose reduction for hematologic toxicity. Results of tumor HR deficiency status assessment from metastatic biopsies and serial ctDNA profiling will be presented. Conclusions: In this proof-of-concept phase II study, single agent talazoparib demonstrated activity in HER2-negative advanced breast cancer pts with a HR pathway mutation beyond BRCA1/2. Further evaluation of talazoparib in this population is warranted. Clinical trial information: NCT02401347.
A phase 0 first-in-human study using NU-0129: A gold base spherical nucleic acid (SNA) nanoconjugate targeting BCL2L12 in recurrent glioblastoma patients.
Authors: Kumthekar Priya , Rademaker Alfred , Ko Caroline , Dixit Karan , Schwartz Margaret A. , Sonabend Adam M. , Sharp Laura , Lukas Rimas Vincas , Stupp Roger , Horbinski Craig , McCortney Kathleen , Stegh Alexander H. 
Published: May 2019

3012 Background: Glioblastoma is a difficult to treat tumor with therapeutics limited by their ability to cross the blood brain barrier. SNAs, i.e., gold nanoparticle cores covalently conjugated with a corona of densely packed, highly oriented siRNA oligonucleotides targeted to the GBM oncogene BCL2L12, represent a novel class of blood-brain and blood-tumor barrier-permeable nanomedicinal conjugates, for suppressing gene expression in the tumors of GBM patients. Methods: This is a single-arm, open-label, “window of opportunity” phase 0 first-in-human trial to determine the safety and bioavailability of a novel nanotherapeutic compound, NU-0129. Enrolled patients were treated with intravenous NU-0129 at the dose of 0.04mg/kg. This treatment dosing was considered microdosing defined as 1/50ththe NOAEL (no observed adverse event level) from non-human primate studies. Treatment was followed by tumor resection 8-48 hours later. Primary outcome patient safety and toxicity was monitored weekly for 3 weeks post-infusion. Secondary objectives included biodistribution of NU0129 in tissue, evaluation of pharmacokinetics of NU0129 and the feasibility of NU0129 administration. Exploratory objectives included Bcl2L12 expression and post treatment apoptotic markers as well as progression free survival and overall survival rates. Results: 8 patients were enrolled, treated and subsequently underwent surgical resection. No significant treatment related toxicities were seen. Severe ( > grade 3) adverse events were observed in two patients: hypophosphatemia (one grade 3, one grade 4) and one patient with grade 3 lymphopenia, all were considered as “possibly related” by treating oncologists. In 6 of the 8 patients sufficient tumor tissue was available for analysis of gold accumulation by ICP-MS (inductively coupled plasma-mass spectrometry), and gold accumulation was seen in the tumor tissue of all 6 of these patients. Conclusions: Macrodosing of the nanotherapeutic NU-0129 was well tolerated in glioblastoma patients with no unexpected adverse effects and showed initial evidence of crossing blood brain barrier. Immunohistochemistry for Bcl2L12 expression, apoptotic markers, and PK studies are pending. The demonstration of gold nanoparticles in the tumor tissue validates this approach for drug delivery. Clinical trial information: NCT03020017.
Design and development of the molecular analysis for Therapy Choice (NCI-MATCH) Designated Laboratory Network.
Authors: Tricoli James V. , Zane Linda , Harrington Robin , Yee Laura , Harper Kneshay N. , Chang Ting-Chia , Harris Lyndsay , Chen Alice P. , Flaherty Keith , O'Dwyer Peter J. , Conley Barbara A. , Winter Cynthia , Lee Jennifer , Williams Paul M. , Sklar Jeffrey , Patton David , Tsongalis Gregory J. , Hamilton Stanley R. , Iafrate A. John , Karlovich Chris Alan ,   The NCI MATCH Designated Laboratory Network
Published: May 2019

3016 Background: NCI-MATCH is a precision medicine trial that assigns treatment to refractory cancer patients by tumor mutation profile rather than by histology. After screening fresh tumor biopsies from nearly 6000 patients many treatment arms did not meet accrual due to the low prevalence of the eligible variants. NCI MATCH developed an approach to identify patients for the remaining arms utilizing a network of academic and commercial CLIA-certified labs that perform NGS assays as routine care at MATCH participating sites. Methods: Candidate labs were recruited through a notice in the Federal Register and posted on the NCI and ECOG ACRIN web sites. Twenty-seven labs (17 academic/10 commercial) submitted applications. After acceptance each lab analyzed a common set of 10 DNAs extracted from 8 cell lines and 2 clinical samples for concordance with the central NCI-MATCH NGS assay. Results: For the 17 labs with concordance results, a median of 8 (range 2 – 58) copy number variants (CNVs) were evaluated by the NGS assay of each DL, with the number evaluated depending on each lab’s clinical assay panel content. CNV concordance between central and DL assays, as measured by positive percent agreement (PPA), averaged 98.7% (range 87.5% - 100%) with the central assay as referent and 94.1% (range 77.8% – 100%) with the DL assay as referent. For single nucleotide variants (SNVs) and Insertion/deletions (Indels) combined, a median of 19 variants (range 11 – 26) were evaluated by each DL for concordance. PPA between central and DL assays averaged 98.0% (range 87.5% – 100%) and 98.6% (range 90.0% – 100%) with central and DL assay as referents, respectively. Strong correlations were observed between central and DL assays for both CNVs (median r = 0.93; 0.33 – 1.00) and SNV/Indels (median r = 0.98; 0.67 – 0.99). Conclusions: Our results suggest that different NGS assay platforms using diverse strategies for target enrichment and data analysis may still achieve high concordance if pre-analytical variables are minimized and the common genomic regions interrogated by each assay are well-understood. The designated lab network allows for a wider search for rare variants in tumors and provides a model for conducting future clinical trials. Clinical trial information: NCT02465060.
Efficacy of entrectinib in patients (pts) with solid tumors and central nervous system (CNS) metastases: Integrated analysis from three clinical trials.
Authors: Siena Salvatore , Doebele Robert Charles , Shaw Alice Tsang , Karapetis Christos Stelios , Tan Daniel Shao-Weng , Cho Byoung Chul , Kim Dong-Wan , Ahn Myung-Ju , Krebs Matthew , Goto Koichi , Garrido Lopez Pilar , Farago Anna F. , Loong Herbert H. F. , Tosi Diego , Barve Minal A. , Simmons Brian P. , Ye Chenglin , Eng Susan , Drilon Alexander E. 
Published: May 2019

3017 Background: Entrectinib potently inhibits kinases encoded by the NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated data (31 May 2018 cut-off) from 3 Phase 1/2 entrectinib trials (ALKA-372-001, EudraCT 2012-000148-88; STARTRK-1, NCT02097810; STARTRK-2, NCT02568267) for a large cohort of adults with ROS1 fusion-positive NSCLC ( ROS1+) or NTRK fusion-positive solid tumors ( NTRK+), with/without baseline CNS metastases. Methods: Pts had locally advanced/metastatic NTRK+ or ROS1+ tumors by nucleic acid-based confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were at wk 4, then every 8 wk by blinded independent central review (RECIST v1.1). Primary endpoints: ORR, DOR. Secondary endpoints: CBR, PFS, OS, intracranial efficacy and safety. Results: Most pts had ≥1 prior therapy; 33% had baseline CNS metastases. Outcomes for the ROS1+ NSCLC (n = 53) and NTRK+ solid tumors (n = 54; 24% sarcoma, 18% NSCLC) efficacy evaluable data sets are shown (table). Entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2. Conclusions: Entrectinib induced clinically meaningful durable responses in pts with ROS1+ NSCLC or NTRK+ solid tumors with or without CNS disease. Clinical trial information: NCT02097810; NCT02568267. [Table: see text]
The dynamic detection of drug area under curve (AUC) guides clinical usage of docetaxel in solid tumors.
Authors: Zhang Yan , Wu Yuan , Zhang Xiaomei , Yang Deliang , Shen Bo , Liang Geyu , Qi Martin 
Published: May 2019

3024 Background: The dosage of most chemotherapy drugs were performed based on the patients’ body surface area (BSA), including docetaxel (DTX). Previous studies showed that this conventional administration of DTX might cause adverse event, such as neutropenia, and neutropenia was proved to associate with DTX area under curve (AUC). This study was designed to evaluate the effect of dose-administration of DTX based on dynamic detection of DTX AUC on clinical outcomes. Methods: A total of 209 patients with DTX chemotherapy (one cycle every 3 weeks) were enrolled, and all patients received 2-6 cycles of treatment. In the first cycle, dosage of DTX based on BSA was administrated in all study population. From the second cycle, one group patients (control group) received DTX according to traditional BSA and the other group patients (experimental group) on the basis of dynamic detection of DTX AUC. The primary outcome was incidence rate of neutropenia and the second outcome was disease control rate (DCR). Results: Patients with grade 3 or higher neutropenia from the fourth to sixth cycle of DTX chemotherapy were significantly lower in the experimental group compared with the control group (P= 0.039, 0.012, and 0.001, respectively). In the experimental group, compared with the first cycle, and the number of patients falling within the therapeutic window increased by 27.19% in the sixth cycle after dose adjustment according to the AUC value of previous cycle. The DCR in the experimental and control group is 85.32% and 72.00%, respectively (P= 0.018). Conclusions: The administration method based on dynamic detection of AUC of DTX could significantly reduce incidence rate of neutropenia and received a higher DCR, but the result needed to be confirmed in further studies.
Prospective cohort study of the impact of hospital-wide dihydropyrimidine dehydrogenase (DPYD) genotype testing for fluoropyrimidine-based chemotherapy on adverse events and hospital costs.
Authors: Wigle Theodore John , Povitz Brandi , Teft Wendy , Legan Robin , Lenehan John Gordon , Gulilat Markus , Nevison Stephanie , Kritzinger Justin , Punaganty Veera , Keller Denise , AlShanteer Suhair , Francis Robin , Siebring Victoria , Sarma Sisira , Choi Yun-Hee , Welch Stephen , Winquist Eric , Schwarz Ute , Kim Richard B. 
Published: May 2019

3028 Background: Fluoropyrimidines remain integral components of modern chemotherapy for solid tumors, and their toxicities can be reduced by pretreatment DPYD genotyping. Our main objective was to demonstrate the feasibility of implementing a hospital-wide pretreatment DPYD testing service based on the CPIC 2013 guideline on fluoropyrimidines and DPYD. Methods: We enrolled participants prior to planned fluoropyrimidine treatment as well as those who had experienced adverse events (AEs) after initiation of therapy, from December 1, 2013 to November 30, 2018. The patients tested pretreatment were analyzed as a prospective cohort to assess AEs within 90 days of fluoropyrimidine initiation and associated hospital cost. The primary outcome was the rate of severe global fluoropyrimidine-related toxicity in the pretreatment cohort (grade≥3, CTCAE v.4.0.3). Results: Of 1362 patients genotyped for DPYD within the study period 1041 were enrolled pretreatment and included in the primary analysis. The median age was 65 years (19-90), 57% male, 51% 5-FU, and 49% capecitabine. Dose reductions were recommended for 21 DPYD variant carriers who were detected pretreatment. There was no significant difference in the primary outcome between DPYD variant (29%) and wild type (18%) patients (Fisher’s exact test p = 0.25). Costs associated with ER visits and hospitalizations at our tertiary care centre were $1,268 (89-8,562) (Median (IQR)) and $2,961 (341-13,567) for DPYD variant (n = 4) and wild-type (n = 99) patients respectively. Post-AE genotyping (n = 70) found five DPYD variant patients; all experienced grade≥3 toxicity, costs were $15,825 (10,962-25,310), and one poor metabolizer died due to complications. Targeted next generation exome sequencing of DPYD wild-type patients who experienced severe AEs identified five potentially deleterious genetic variants in ABC efflux transporters. Conclusions: Pretreatment DPYD genotype guided dosing of fluorouracil and capecitabine is feasible and benefits patients, health care providers, and hospitals. Our data supports adoption of pretreatment DPYD genotyping as a standard of care.
Phase I study of the Aurora A kinase (AurA) inhibitor TAS-119 with paclitaxel (P) in advanced solid tumors.
Authors: Cardin Dana Backlund , Park Haeseong , Diamond Jennifer Robinson , Drilon Alexander E. , VerMeulen Wendy L. , He Xiaomin , Hirai Hiroshi , Soni Nital , Berlin Jordan 
Published: May 2019

3031 Background: AurA is a key regulator of cell division, including mitotic spindle assembly. However, elevated levels of AurA have been reported to abrogate the mitotic spindle checkpoint activated by taxanes leading to treatment resistance. Preclinical studies of TAS-119 + P showed enhanced antitumor activity and suggested an optimal timing window of the combination. Study objective was to assess the safety of TAS-119 + P in adult patients (pts) with advanced solid tumors. Methods: Dose escalation used a 3+3 design to determine the maximum tolerated dose (MTD); 7 dose levels (DLs) were explored, starting with 25 mg TAS-119 BID dosed 4 days/week (d/wk) and weekly 90 mg/m2 P for 3 weeks of a 4 week cycle (DL1). Plasma samples were collected during cycle 1 to evaluate pharmacokinetics. In expansion, pts with advanced breast/ovarian cancers were treated at the MTD. Results: Dose escalation enrolled 26 pts with various cancers, the majority being pancreas, colon, and ovarian; 2 pts were not evaluable for DLT assessment and replaced. A DLT (neutropenia and elevated AST) was observed in 2/3 pts in DL1. Dosing was modified to 25 mg TAS-119 BID 2 d/wk and P 70 mg/m2 (DL2) and no DLTs were observed. Zero DLTs were observed in the next 4 doses: 70 mg/m2 P + TAS-119 2 d/wk at 50 mg BID (DL3) or 75 mg BID (DL4), or 80 mg/m2 P + TAS-119 at 75 mg BID 2 d/wk (DL5) or 75 mg BID 3 d/wk (DL6). TAS-119 was escalated to 100 mg BID 3 d/wk (DL7) and 3 DLTs (n=1, elevated ALT; n=1, diarrhea and mucositis) occurred in 2/3 pts. Three additional pts were then enrolled at DL6 to confirm the MTD. One breast and 2 ovarian pts were enrolled in expansion before the trial was suspended by the company. Toxicities observed in ≥30% of pts were diarrhea, nausea, and fatigue (most ≤Gr2). Plasma TAS-119 exposure increased dose-proportionally in 2 d/wk and 3 d/wk schedules; no impact of TAS-119 on PK of paclitaxel was found. The disease control rate was 59% (17/29); 4 of these pts had a partial response. Conclusions: The combination had a manageable toxicity profile at the MTD of 80 mg/m2 P + TAS-119 at 75 mg BID 3 d/wk. Preliminary clinical activity was seen in 59% of pts, including tumor responses in a majority (4/7) of pts with ovarian/fallopian tube cancers. Clinical trial information: NCT02134067.
A phase I study of the oral administration of irinotecan in combination with the potent P-glycoprotein (P-gp) inhibitor HM30181A.
Authors: Jimeno Antonio , Opyrchal Mateusz , Diamond Jennifer Robinson , Fountzilas Christos , Corr Bradley , Bezi Ildiko , Wang Hui , Kwan Rudolf , Zhi Jay , Cutler David , Boland Patrick McKay 
Published: May 2019

3032 Background: Irinotecan is a prodrug of the potent topoisomerase inhibitor SN-38. In animals, oral administration of irinotecan with the selective minimally absorbed P-gp inhibitor HM30181A increased the bioavailability of irinotecan. Oral administration of irinotecan may also increase the conversion to SN-38. Objectives: To determine the MTD and DLT of orally administered irinotecan in combination with HM30181A 15 mg on day 1 of a 21-day cycle. Additional objectives include determining the recommended phase 2 dose and the PK of irinotecan and SN-38. Methods: This was a phase 1 dose escalation study enrolling cohorts of 3-6 patients with advanced malignancies. Patients had Hb ≥9 gm/dL, ANC ≥ 1.5x109/L, platelets ≥ 100x109/L, adequate hepatic and renal function, ECOG 0-1 and were not homozygous for UGT1A1*28. Patients were administered HM30181A 15 mg and oral irinotecan 20, 40, 80, 120, 160, 200, 240, 280 and 320mg/m2. Results: Thirty male and female patients, mean age 60.9 (range 33-78) were enrolled into this ongoing study. The most common cancers were ovarian (6), colorectal (4), breast (4), endometrial (3), and pancreatic (3). The median number of cycles administered was 3 (range 1-9). Treatment-related Grade 3-4 AEs were experienced by 12 (40%) subjects. The most common were nausea 7 (23%), vomiting 6 (20%) and abdominal pain 3 (10%). Treatment-related SAEs were experienced by 6 (20%) patients (nausea or vomiting in 4 subjects). DLTs occurred in 2 patients at the 320 mg/m2 dose level (neutropenia and C. Difficile diarrhea) and additional patients are being enrolled at the 280mg/m2 dose level to define the MTD. Acute cholinergic diarrhea has not been observed. The best response was stable disease in 9/21 evaluable patients. PK at the three highest dose levels is summarized below. Conclusions: Oral administration of HM30181A in combination with irinotecan tablets results in pharmacologically active concentrations of SN-38. Confirmation of the MTD when dosed on a 21-day cycle is ongoing. Phase 2 studies are being planned. Clinical trial information: NTC02250157. [Table: see text]
Tumor specific DNA in bronchial lavage as a new diagnostic tool in lung cancer.
Authors: Thomsen Caroline Brenner , Hansen Torben , Andersen Rikke Fredslund , Hager Henrik , Rasmussen Kristian , Jakobsen Anders Kristian Moeller , Hilberg Ole 
Published: May 2019

3047 Background: A considerable fraction of lung cancer patients raise diagnostic challenges requiring invasive procedures with a certain risk of complications. Therefore, new diagnostic tools are of major interest. Aberrant methylation of the HOXA9 gene occurs in almost all malignant lung tumors and HOXA9 methylated DNA (meth-ctDNA) is shed into the circulation. The present study aimed at a prospective investigation of the possible diagnostic value of HOXA9 meth-ctDNA in bronchial lavage (BL). Methods: Patients enrolled were referred from the general practitioner suspecting lung cancer. The diagnostic package according to national guidelines includes chest and abdominal CT scan, bronchoscopy, relevant blood tests, and histopathological or cytological verification. Twelve ml liquid was collected at bronchoscopy for analysis of meth-ctDNA based on ddPCR technology according to our published method. The analysis was performed blinded to the clinical data and compared to the final diagnosis. Results: Eighty-nine patients were consecutively included from the 1 November 2018 to 31 January 2019. Fifty-six patients (62.9%) were diagnosed with lung cancer and 33 (37.1%) with a variety of benign diseases. Meth-ctDNA was found in 42/56 of the patients with a malignant tumor, sensitivity = 75.0% (95%CI=61.6-85.6%), whereas 31/33 of the patients without cancer were negative, specificity = 93.9% (95%CI= 79.8-99.3%). Table summarizes the results. The false negative samples were mainly from patients with peripheral tumors. The two false positive patients included one patient with Cryptogenic Organizing Pneumonia and one with unspecific nodule. Conclusions: The presence of meth-ctDNA in BL has a high sensitivity and specificity. If validated, the analysis represents a valuable adjunct in the diagnosis of lung cancer. Potentially, it could save the patients from numerous examinations with potential harmful risks and ensure a fast diagnosis. The relation between meth-ctDNA and final lung cancer diagnosis (N= 89). [Table: see text]