bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): Updated results from the BLOOM study.
Authors: Yang James Chih-Hsin , Cho Byoung Chul , Kim Dong-Wan , Kim Sang-We , Lee Jong-Seok , Su Wu-Chou , John Tom , Kao Stephen Chuan-Hao , Natale Ronald , Goldman Jonathan Wade , Overend Philip , Vishwanathan Karthick , Ye Xin , Yang Zhenfan , Ahn Myung-Ju 
Published: September 2018

2020 Background: LM due to NSCLC progression are associated with poor prognosis. Osimertinib is an oral, CNS-active, irreversible EGFR-TKI selective for sensitizing (EGFRm) and T790M resistance mutations. Methods: In the BLOOM study (NCT02228369), pts with EGFRm advanced NSCLC who had progressed on prior EGFR-TKI therapy and had LM confirmed by positive cerebrospinal fluid (CSF) cytology received osimertinib 160 mg once daily (qd). Response was assessed (by investigator) in 2 cohorts: T790M unselected and T790M positive (by central test); results are presented as a combined analysis set. Analyses were based on CSF cytology, brain MRI imaging, and neurological examination every 6 weeks (wk; relative to first dose) until progression. Adverse events (AEs) were graded according to CTCAE. EGFR-mutant DNA in CSF was determined by ddPCR. Plasma and CSF samples were collected for PK analyses. Results: As of 24 Sep 2016,32 pts had received treatment: 21 T790M unselected; 11 T790M positive. Max treatment duration was 17.5 months (m; median 6.0 m); 21 pts ongoing. 23/32 pts had a 12-wk brain image assessment: 10 had radiological improvement, 13 had stable disease (SD). The same 23 pts had a 12-wk neurological assessment: of 8 symptomatic pts, 7 improved, 1 had SD; of 15 asymptomatic pts, 2 worsened, 13 remained asymptomatic. The geometric mean decrease in EGFR-mutant DNA copy was 57% (95% CI 30, 74) in 22 pts with pre-dose and Cycle 2 Day 1 CSF samples. Most common AEs were skin effects (n = 20), diarrhea (n = 13), nausea (n = 11) and paronychia (n = 9). All were grade (G) 1/2 except 1 case each of diarrhea and nausea (both G3). 9 pts had dose interruptions and 4 had dose reductions to 80 mg qd. Osimertinib mean concentration in CSF was 7.51 nM (range 2.19–21.1 nM) at steady state (N = 16); CSF:free plasma ratio: 16%. Accrual is now complete (n = 41; 21 T790M unselected, 20 T790M positive) and updated data (including overall survival) will be presented. Conclusions: Osimertinib penetrates the blood-brain barrier. Encouraging activity and manageable tolerability in pts with LM from EGFRm NSCLC was observed at 160 mg qd, with a median treatment duration of 6.0 m; continued evaluation is ongoing. Clinical trial information: NCT02228369.
Comprehensive assessment of ATRX mutation, protein expression, and alternative lengthening of telomeres (ALT) phenotype in grade II and III gliomas.
Authors: Becker Aline P. , Bell Erica Hlavin , Fleming Jessica , McElroy Joseph P , Fabian Denise , Beyer Sasha , Salavaggione Andrea L , Graham Mindy K , Heaphy Christopher M , Oehlke Oliver , Staszewski Ori , Prinz Marco , Grosu Anca , Chakravarti Arnab 
Published: September 2018

2064 Background: ATRX mutations are key molecular markers for classification of gliomas. We aimed to evaluate ATRXmutations and protein expression and the ALT phenotype as potential biomarkers for grade II and III gliomas. Methods: Retrospective analysis of 156 adult gliomas, with long-term follow up. Gene sequencing ( IDH1/2 and ATRX), Oncoscan array (1p19q co-deletion), FISH assays (1p19q co-deletion and ALT phenotype) and immunohistochemistry (IDH1 R132H and ATRX) were performed and the results were correlated with OS and PFS. Results: Twenty-six out of 94 samples (27.7%) had ATRX mutations, commonly related to IDH1/2 mutant-1p/19q intact tumors (22/26 cases – p < 0.0001), however, 3 (11.5%) mutant tumors had concurrent 1p/19q co-deletions. ATRX loss of expression occurred in 66/150 cases (44%), consistently related to ATRX mutations (p < 0.0001). Intriguingly, 4/25 ATRX mutant tumors (2 frameshift and 2 point mutations with low/medium functional impact) showed weak/heterogeneous expression, while 18/65 (27.7%) ATRX wild type tumors had loss of protein expression. ALT phenotype was detected in 50/150 cases (33.3%), strongly related to ATRX mutations (23/32 cases), loss of protein expression (45/50 cases), and to IDH1/2 mutant-1p/19q intact tumors (35/41 cases). Two ATRX mutant tumors were ALT negative, while nine ATRX wild type tumors with loss of expression had ALT phenotype. ATRXmutations, loss of protein expression, and ALT phenotype were strongly related to longer OS in grade III gliomas (p = 0.006, 0.023 and 0.003, respectively). Further subset analyses were not completed due to small sample sizes. Conclusions: ATRX mutations and loss of protein expression as well as ALT phenotype are potential prognostic factors for grade III gliomas. Importantly, this study highlights possible discrepancies (although infrequent) between ATRX sequencing, immunohistochemistry, and FISH (ALT). In addition, other mechanisms of ATRX gene silencing should be further investigated in grade II and III gliomas. FUNDING: R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01 (NCI), Brain Tumor Funders Collaborative Grant, and The Ohio State University CCC (all to AC).
First-in-class oral ERK1/2 inhibitor Ulixertinib (BVD-523) in patients with advanced solid tumors: Final results of a phase I dose escalation and expansion study.
Authors: Li Bob T. , Janku Filip , Patel Manish R. , Sullivan Ryan J. , Flaherty Keith , Buchbinder Elizabeth Iannotti , Lacouture Mario E. , Varghese Anna M. , Wong Deborah Jean Lee , Sznol Mario , Sosman Jeffrey Alan , Keedy Vicki Leigh , Wang-Gillam Andrea , Ribas Antoni , Tolcher Anthony W. , Patel Sapna Pradyuman , Varterasian Mary Laura , Welsch Dean , Hyman David Michael , Infante Jeffrey R. 
Published: September 2018

2508 Background: Aberrant MAPK pathway activation is known to be an oncogenic driver in many solid tumors, making ERK inhibition an attractive therapeutic strategy. Ulixertinib is an oral ERK1/2 inhibitor that demonstrated potent activity in vitro and tumor regression in BRAF and RAS mutant xenograft models. Methods: This multi-center phase I trial enrolled patients (pts) with advanced solid tumors. Dose escalation utilized an accelerated 3+3 design; expansion cohorts included BRAF or NRAS mutant melanoma and other BRAF or MEK mutant cancers. Study objectives were to characterize dose limiting toxicities (DLTs), maximum tolerated dose (MTD), toxicity profile, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity by RECIST 1.1. Results: A total of 135 pts were enrolled. Dose escalation enrolled 27 pts (10-900 mg BID) and established the MTD and recommended phase 2 dose (RP2D) of 600 mg BID. DLTs included rash, diarrhea, elevated AST, and elevated creatinine. Drug exposure was dose proportional up to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108 pt expansion cohort, there were no drug related deaths; however, 32% of pts required a dose reduction. The most common adverse events were rash (49%), diarrhea (47%), fatigue (41%), and nausea (37%). In addition to 3 pts with partial responses during escalation (11%), an additional 9 of 83 (11%) evaluable pts at expansion had a partial response: 1 melanoma pt refractory to prior BRAFi/MEKi treatment, 3 NRAS mutant melanoma pts, 2 pts with BRAF V600E mutant lung cancers including response in brain metastases, 1 with BRAF V600E mutant glioblastoma multiforme, 1 with BRAF G469A head & neck cancer, and 1 with BRAFL485W gallbladder cancer. The duration of response ranged from 2 to 24+ months. Conclusions: Ulixertinib at 600 mg twice a day has an acceptable safety profile and has produced durable responses in pts with NRAS mutant melanoma, BRAF V600 and non-V600 mutant solid tumors including melanoma, glioblastoma multiforme, lung cancers with brain metastases, gallbladder and head & neck cancers. These data support further clinical development of ulixertinib. Clinical trial information: NCT01781429.
Preliminary results from a phase 1 study of the antibody-drug conjugate ABBV-221 in patients with solid tumors likely to express EGFR.
Authors: Calvo Emiliano , Cleary James M. , Moreno Victor , Gifford Maryella , Roberts-Rapp Lisa , Ansell Peter J , Mittapalli Rajendar K. , Lee Ho-Jin , Hu Beibei , Barch David , Ocampo Christopher Joseph , Tolcher Anthony W. 
Published: September 2018

2510 Background: ABBV-221 is a 2nd-generation antibody-drug conjugate (ADC) targeting EGFR based on the 1st-generation ADC ABT-414. ABT-414 shows efficacy in glioblastoma (GBM) patients (pts) with EGFR amplification in ongoing studies. ABBV-221 is an affinity matured monoclonal antibody against EGFR linked to the toxin MMAE. ABBV-221 has higher affinity for overexpressed EGFR than ABT-414, potentially allowing it to target a broader range of tumor types. Methods: This is a Phase 1, multicenter study to determine maximum tolerated dose (MTD) and recommended Phase 2 dose (RPTD) of ABBV-221. Pts are required to have an EGFR-dependent cancer to be eligible. Starting dose of ABBV-221: 0.3 mg/kg IV infused over 3 hrs for each 21-day cycle, with alternate dosing schedules utilized (2 wks on, 1 wk off or weekly) to mitigate infusion reactions. Results: As of 11 January 2017, 42 pts were treated (13 colon, 5 head & neck (H&N) cancer, 5 non-small cell lung cancer, 5 GBM, 2 breast, 12 other). Ten dose escalation cohorts have been completed with the last cleared dose 4.5 mg/kg per cycle. Tumor tissue samples were evaluated for EGFR protein expression by IHC, EGFR and EGFR ligand mRNA expression by RNAseq, and the results compared to outcome. The most common adverse event (AE) was infusion reaction in 18/42 pts (43%); 3 pts experienced severe infusion reactions. Several mitigation strategies were used to permit continued dose escalation. The other most common AE was fatigue in 17/42 pts (41%). Only 1 pt had keratitis (Grade 4). Sixteen pts (38%) had stable disease (SD), including 4 pts who remained on study longer than 6 months. One H&N pt who has received 2 cycles of ABBV-221 had an unconfirmed partial response and continues to be treated. This pt had high levels of both EGFR and EGFR ligand. Preliminary pharmacokinetics (PK) analysis suggests ABBV-221 exposures are approximately dose-proportional. Conclusions: Safety, PK, pharmacodynamics, and preliminary efficacy data of ABBV-221 warrant further study in this population. Infusion reactions have been manageable and primarily a first dose phenomenon. The duration of SD in pts with refractory solid tumors is encouraging. Clinical trial information: NCT02365662.
A phase I study of PT-112 in advanced solid tumors.
Authors: Karp Daniel D. , Camidge D. Ross , Bryce Alan Haruo , Jimeno Jose , Infante Jeffrey R. 
Published: September 2018

2519 Background: PT-112 is a novel platinum-pyrophosphate agent designed to avoid the toxicity and drug resistance mechanisms of conventional chemotherapy. Pre-clinical models show effects on multiple cell signaling components: p16 mediated G1/S cell cycle arrest; modulation of MDM2/p53 expression; extrinsic apoptosis initiation; and immunogenic cell death (ICD) induction. This Phase I first-in-human, multicenter, open label study assesses PT-112’s safety and pharmacokinetic (PK) profile in advanced solid tumor patients (pts), to determine the RP2D and signals of activity. Methods: Pts with advanced solid tumors and acceptable marrow / organ function received PT-112 IV over 1-hr on days 1, 8, and 15 every 4 wks in a 3+3 dose escalation design. Intra-subject escalation was allowed. PK samples from cycles 1-2 were analyzed by ICP-MS and LC-MS/MS. Results: 44 pts have been treated across dose levels (DL) from 12-300mg/m2. Cumulative dosing ranged from 1 to 60 infusions, and cumulative exposure from 96 to 5,244 mg/m2. PK parameters were dose proportional. Target Cmax and AUC levels were achieved, with constant VD. DLTs were observed at 150mg/m2 (G3 pancytopenia); 250mg/m2 (G2 renal injury in a cervical ca pt with hydro-nephrosis); and 300mg/m2 (G3 rash). The most common treatment-related AEs were G1-2 fatigue (26% pts), nausea (23%), vomiting (14%), constipation (12%), and diarrhea (12%). Numerous signals of activity were observed at DLs ≥ 125mg/m2. These include a confirmed PR in a NSCLC pt with 6 prior lines of therapy and no response to TKI inhibition or PD-1 blockade; PFS > 6 months (7-18 months) in 3 pts; metabolic response via PET scan in bone and liver mets (basal cell and pancreatic ca.); biomarker responses in ovarian and prostate ca.; and nodal/metastatic volumetric reduction in 3 pts. Conclusions: PT-112 is a well-tolerated novel agent with a pleiotropic mode of action and feasibility for long-term and combination treatment. Numerous signals of anti-cancer efficacy in heavily pre-treated pts suggest lack of cross-resistance with conventional agents. MTD has not yet been reached. PT-112’s profile makes it an attractive candidate for further development, including in combination with immunotherapy. Clinical trial information: NCT02266745.
Dose escalation results from a first-in-human, phase 1 study of the glucocorticoid-induced TNF receptor-related protein (GITR) agonist AMG 228 in patients (Pts) with advanced solid tumors.
Authors: Tran Ben , Carvajal Richard D. , Marabelle Aurelien , Patel Sandip P. , LoRusso Patricia , Rasmussen Erik , Juan Gloria , Upreti Vijay V. , Ngarmchamnanrith Gataree , Schöffski Patrick 
Published: September 2018

2521 Background: AMG 228 is an agonistic human IgG1 monoclonal antibody that binds to GITR (CD357), a TNFSFR costimulatory molecule expressed by effector/regulatory T cells. Dose escalation of this open label, first in human, phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and maximum tolerated dose (MTD) and recommended phase 2 dose of AMG 228 in pts with advanced solid tumors. Methods: Pts with refractory advanced colorectal cancer (n = 13), squamous cell carcinoma of head and neck (n = 10), non–small cell lung cancer (n = 2), urothelial transitional cell carcinoma (n = 4), and melanoma (n = 1) received AMG 228 IV Q3W. Dose escalation was in two stages: single-pt cohorts until AMG 228-related grade > 2 adverse events (AEs), efficacy, or 90 mg dose reached (4 cohorts: 3, 9, 30, and 90 mg), followed by rolling six design (n = 2 to 6) until MTD or highest planned dose of 1200 mg reached (5 cohorts: 180, 360, 600, 900, and 1200 mg). Primary endpoints included incidence of dose-limiting toxicities (DLTs) and AEs and PK. Additional endpoints were objective response (RECIST 1.1) and evidence of biological activity. Results: In total, 30 pts (median age 63 y) were treated (3, 9, 30, and 90 mg, n = 1; 180 mg, n = 6; 360 mg, n = 4; 600 mg, n = 6; 900 mg, n = 4; 1200 mg, n = 6). Twenty-seven (90%) pts had treatment-emergent AEs; the most common were hypophosphatemia (23%), fatigue (23%), anemia (23%), nausea (20%), and pyrexia (20%). No DLTs occurred; the MTD was not reached. AMG 228 exposure was dose-related, with PK profiles at low doses (3 to 90 mg) consistent with target mediated drug disposition; doses > 360 mg achieved serum levels needed for 95% receptor occupancy on activated PBMCs. No evidence of T cell activation was observed despite complete target coverage in both tumor and peripheral blood. Among 29 evaluable pts, none had an objective response. Conclusions: In this population of pts with advanced solid tumors, AMG 228 Q3W was tolerable up to the highest tested dose (1200 mg), showing favorable PK. However, no clinical or immunological activity was observed in this limited number of pts. Clinical trial information: NCT02437916.
A phase I study of LY3022855, a colony-stimulating factor-1 receptor (CSF-1R) inhibitor, in patients (pts) with advanced solid tumors.
Authors: Dowlati Afshin , Rugo Hope S. , Harvey R Donald , Kudchadkar Ragini Reiney , Carvajal Richard D. , Manji Gulam Abbas , Hamid Omid , Klempner Samuel Jacob , Tang Shande , Yu Danni , Kauh John S. , Schaer David Arlen , Tate Sonya Catherine , Wesolowski Robert 
Published: September 2018

2523 Background: Binding of CSF-1 to the CSF-1 receptor (CSF-1R) results in proliferation, differentiation, and migration of monocytes/macrophages. Intratumoral infiltration with macrophages correlates with increased invasiveness, growth, and immunosuppression. LY3022855 (LY) is a human IgG1 antibody (mAb) targeting CSF-1R. Methods: Eligible pts (ECOG 0-2) with advanced solid tumors were enrolled. Mandatory pre and post-treatment biopsies were obtained. LY was given on a 6-week cycle. Two escalation regimens (Part A: weight-based dosing; Part B: flat dosing) were investigated in a 3+3 design. Primary objective was to establish the safety and characterize the pharmacokinetics (PK) of LY. Secondary objectives were to establish recommended phase 2 dose (RP2D) and to characterize pharmacodynamics (PD). Results: As of Sept 6, 2016, 35 cancer pts (colorectal 14; lung 4; pancreas 3; others 14) were treated (29 in Part A; 6 in Part B) with median treatment duration 4 weeks (range 1-21). Common treatment-emergent adverse events (TEAEs) were fatigue (54%), hypoalbuminemia (40%), nausea (37%), AST increase (37%), anemia (34%), anorexia (34%), creatine kinase elevation (29%), and constipation (23%). Most common grade (G) 3/4 TEAEs were anemia (11%), fatigue (11%), ascites (9%), and lymphocyte count decrease (9%). 3/28 evaluable pts had DLTs: G3 left ventricular systolic dysfunction (1), G4 rhabdomyolysis and G4 acute renal failure (1), and G3 pancreatitis (1). Eight treatment unrelated deaths were reported. One pt (adenoid cystic carcinoma) had stable disease (~3 mo as of last visit), 19 pts had progressive disease, and 15 pts were non-evaluable for response assessment. PK profile of LY was consistent with IgG1 mAbs. An interim analysis following completion of Part A demonstrated a lack of relationship between weight and clearance, prompting evaluation of non-weight based dosing. PD analyses revealed dose-dependent increases in serum CSF-1 levels as well as suppression of circulating non-classical monocytes (CD14dim CD16bright), indicating biologic activity at studied doses. Conclusions: RP2D for LY monotherapy has been determined. Detailed PK and PD data will be presented. Clinical trial information: NCT01346358.
A call for global harmonization of phase I oncology trials: Results from two parallel, first-in-human phase I studies of DS-7423, an oral PI3K/mTOR dual inhibitor in advanced solid tumors conducted in the United States and Japan.
Authors: Yokota Tomoya , Bendell Johanna C. , LoRusso Patricia , Tsushima Takahiro , Desai Ved , Kenmotsu Hirotsugu , Watanabe Junichiro , Ono Akira , Murugesan Bhavani G. , Silva Joseph , Naito Tateaki , Greenberg Jonathan , Kumar Prasanna , Wang Yibin , Jikoh Takahiro , Shiga Ryota , Ho Alan Loh , Gounder Mrinal M. 
Published: September 2018

2536 Background: The aim of this study was to determine the safety, maximum-tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of DS-7423, a novel inhibitor of PI3K/mTOR, in US and Japanese population. We further compared toxicities and recommended phase 2 dose (RP2D) of DS-7423 and approved oncology drugs in the two populations. Methods: We conductedparallel, first-in-human studies in US and Japan in patients with advanced solid tumors. We conducted a Pubmed search of pivotal and corresponding phase I studies to compare the RP2D and final approval doses of molecularly targeted agents (MTA) between US and Japan. Results: 69 patients were enrolled (n = 42 from US and n = 27 from Japan). Between populations, the only difference at baseline was body weight (BW) and body mass index (BMI). Dose-limiting toxicities included grade 3 rash (48 mg), grade 3 stomatitis (240 mg), grade 3 lung infection (240 mg), grade 4 hyperglycemia (240mg), grade 3 fatigue (320 mg), and grade 3 dehydration (320mg). The MTD and RP2D was 240 mg/d in both populations. Frequent treatment-related adverse events included diarrhea, fatigue, decreased appetite, rash, and stomatitis. No remarkable difference in AUC and Cmax were observed between populations. Prolonged stable disease was seen in cholangiocarcinoma, thymic cancer, non-small cell lung cancer, squamous cell carcinomas, carcinoid, and sarcoma. DS-7423 demonstrated PD effects on serum glucose, C-peptide and Akt phosphorylation and 18F-FDG uptake in tumors. The final RP2D of 17 MTA approved in US and Japan from 2001 to 2015 was near identical. The approved doses in both regions were identical. Conclusions: Despite differences in BW, BMI, and ethnicity, DS-7423 showed no difference in PK, PD, toxicity or efficacy between populations. We found near identical RP2D in phase I oncology studies and approved doses in pivotal studies. This supports increased international collaboration in the conduct of phase I oncology trials. Clinical trial information: NCT01364844, Japic CTI, 12766.
Suitability factors of core needle biopsies for pharmacodynamic (PD) studies.
Authors: Parchment Ralph E. , Ferry-Galow Katherine , Makhlouf Hala R. , Wood Brad J. , Levy Elliott B. , Krishnasamy Venkatash P. , Chang Richard , O'Sullivan Coyne Geraldine H. , Meehan Robert S. , Kinders Robert J. , Doroshow James H. , Chen Alice P. 
Published: September 2018

2540 Background: There are different requirements of biopsies for diagnosis vs. pharmacologic evaluation of drug mechanism biomarkers. Evaluation of core needle biopsy pairs collected pre-dose and at a defined timepoint post-dose provides insight into the pharmacodynamics of agents in early development. Adequate biopsies are key for quantifying response of the tumor cell population to molecular drug action. Tumor heterogeneity and variable tumor content make many biopsy pairs unsuitable for biomarker evaluation with any assay platform (microscopy, immunoassay, etc.). We analyzed biopsies obtained from the Developmental Therapeutics Clinic (DTC) for suitability for PD assays. Methods: Specimens obtained from 2010-2016 across 4 trials were analyzed. For microscopy measurements, biopsy pairs collected using image guidance are snap-frozen, thawed under fixative, and embedded in paraffin with control tissues. The likelihood of finding optimal regions for analysis is maximized by preparing a series of sections with H&E stained flanking slides, and annotation by an anatomic pathologist. Results: Of 112 biopsies evaluated, 26% were found to contain < 5% tumor, making them inadequate for quantitative microscopy due to a mixture of factors, with the primary factor being predominantly non-neoplastic tissue, followed by extensive mucin content, necrosis, fibrosis, inadequate size and tissue artifact post-collection. Another 20% contained ≤25% tumor, and in this group, tumor segmentation methodology during image analysis increased the rate of evaluable biopsies. 56% of tissues had > 25% tumor and were suitable for analysis. Conclusions: Improved communication between oncologists, radiologists and pathologists is key to a better understanding of factors that affect suitability of biopsies for robust PD biomarker analyses. NCI’s DTC has implemented protocol modifications including increased tissue collection and frequent case reviews by the Phase 1 team, interventional radiologists and PD team aimed at understanding features during image guidance that relate to suitability. Implementation of a scoring system has allowed the assessment of suitability of biopsies for analysis. Funded by NCI Contract No HHSN261200800001E.