bluuebunny/crossref_metadata_2025_split huggingface dataset:
FDA analysis of grade 3-4 safety events.
Authors: Smit Marie-Anne Damiette , Casak Sandra J. , Lemery Steven , Keegan Patricia , McKee Amy E. 
Published: September 2018

2544 Background: In new drug/biologics applications, safety data provided to FDA include serious adverse events (SAEs), defined as adverse events (AEs) resulting in death, life-threatening AE, inpatient hospitalization or prolongation of hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or congenital anomaly/birth defect. One limitation of the SAE definition is that hospitalization practices differ across localities and among medical practitioners. Therefore, a safety signal may not be adequately reflected when analyzing SAEs. We hypothesize that evaluating CTCAE Grade 3 (severe) and Grade 4 (life-threatening) AEs, independent of whether or not these were classified as serious, provides a more complete assessment of patient safety. Methods: We reviewed SAEs from all nine registrational trials for new molecular entities approved for the treatment of cancer by the FDA in 2014. Results: A total of 25,548 AEs were reported in 1,781 patients treated with an investigational agent. There were 2,943 Grade 3-4 AEs and 912 Grade 3-4 SAEs. Information regarding hospitalization was available in 62% of Grade 3-4 AEs. Fifty-five percent of Grade 3-4 SAEs vs. 5.5% of Grade 3-4 non-serious AEs resulted in hospitalization. Several clinically serious Grade 3-4 AEs, including sepsis and respiratory failure, were not classified as SAE. Conclusions: There is significant overlap in most common Grade 3-4 AEs and most common Grade 3-4 SAEs. Most AEs that are clinically serious were appropriately classified as SAE. However, some clinically serious AEs and some AEs resulting in hospitalization were not classified as SAE. With the exception of information regarding hospitalization, characterization of the reason why certain AEs were classified as SAEs was not possible. In this pooled analysis, data from the analysis of AEs by severity was more informative than the analyses by SAEs. [Table: see text]
A multicenter phase I trial of the DNA-dependent protein kinase (DNA-PK) inhibitor M3814 in patients with solid tumors.
Authors: van Bussel Mark , Mau-Soerensen Morten , Damstrup Lars , Nielsen Dorte , Verheul Henk M.W. , Aftimos Philippe Georges , De Jonge Maja J. , Berghoff Karin , Schellens Jan H.M. 
Published: September 2018

2556 Background: Agents that generate breaks in DNA are frequently used as cancer therapeutics. These agents induce different forms of DNA damage including double-strand breaks (DSBs), which are the most lethal if left unrepaired. M3814 targets tumor cell growth and survival by inhibiting DNA-PK, which is part of a critical DSB DNA damage repair mechanism. The purpose of the phase I, first in man trial was to evaluate the dose-limiting toxicity (DLT), establish a recommended phase II dose (RP2D), and assess the pharmacokinetic (PK) profile and single-agent clinical activity of M3814. Methods: Patients (pts) with potential aberrations in the DNA-damage and repair systemwere included. A standard 3+3 design was implemented with a starting dose of M3814 of 100 mg once daily, determined based on non-clinical safety. M3814 was given continuously and DLT was evaluated after 3 weeks. Throughout the trial rich PK sampling was taken. Tumor evaluation was performed every second cycle and treatment continued until progression, unacceptable toxicity, pt wish, or physician decision. Results: A total of 25 pts were enrolled at 6 dose levels (DL). Three pts were enrolled per DL, except at 300 and 400 mg BID where 9 and 4 pts were enrolled, respectively. At 300 mg BID one DLT (several low grade adverse events [AEs] lasting > 1 week) was seen. No DLTs were observed at 400 mg BID, which was declared as the RP2D; further dose escalation was not possible due to an impurity in the drug. An additional 6 pts were included at the RP2D. The most frequent AEs were nausea, vomiting, decreased appetite, constipation, diarrhea, pyrexia, fatigue, and rash, all seen in > 20% of pts. No pts discontinued due to AE and no grade 4 AEs were reported. Six pts (20%) had stable disease for at least 18 weeks; no pt had a partial remission. PK analysis demonstrated high variability of exposure with a tendency for skin rash in pts with the highest exposure. Conclusions: M3814 was found to be safe and tolerable at doses up to 400 mg BID, with limited single-agent activity in the studied population. Clinical evaluation of M3814 is ongoing in combination with radiotherapy as well as chemo-radiotherapy and planned in combination with chemotherapy. Clinical trial information: NCT02316197.
Patterns of failure on Ga PSMA (GaPSMA) and F18 FDG (FDG) PET CT in a prospective phase 2 trial of 177Lu DKFZ PSMA 617 (LuPSMA) in men with castrate resistant metastatic prostate cancer (mCRPC).
Authors: Joshua Anthony M. , Stricker Phillip , Epstein Richard J , Ho Bao , Nguyen Quoc , Kent Robert , Willowson Kathy P , Hofman Michael , Violet John A , Emmett Louise 
Published: September 2018

2562 Background: LuPSMA is emerging as an effective therapy in mCRPC, with retrospective series reporting high PSA response rates in men undergoing treatment (tx). However, not all men have prolonged tx responses. We report the prospective imaging (GaPSMA/FDG) and PSA response of men who progress biochemically during LuPSMA tx to gain information on characteristics of failure patterns, to determine optimal future tx strategies. Methods: Men with mCRPC, who had failed androgen blockade, failed/ ineligible/refused chemotherapy, with GaPSMA positive disease were enrolled in a prospective phase 2 trial. All men underwent LuPSMA therapy 6-8Gbq, 4 doses at 6 weekly intervals. Imaging with FDG, GaPSMA, bone scan and CT scans was at screening, at subsequent PSA rise, or 3 months post completion of 4 cycles of therapy. Results: 14 men met eligibility criteria and enrolled. 4/14 (28%) men had progressive disease (no PSA response). 10/14 (72%) PSA reduced by a mean 56% .Overall 9/14 (64%) men had >30% decline in PSA, and 5/15(36%) >50% reduction in PSA. 7/15 men were reimaged with GaPSMA, FDG at biochemical failure or 3/12 post tx completion. Imaging revealed 4 distinct patterns (P) of progression. Conclusions: PSMA acts as both target for radionuclide therapy and biomarker for effective tx response. PSMA and FDG imaging at PSA failure following or during LU PSMA therapy identifies phenotypic patterns of failure that have implications for determining next best tx options in men with mCRPC. [Table: see text]
The utility of genomics and functional imaging to predict irinotecan pharmacokinetics and pharmacodynamics: The PREDICT IR study.
Authors: Michael Michael , Liauw Winston , McLACHLAN Sue-Anne , Link Emma , Matera Anetta , Thompson Mick , Jefford Michael , Hicks Rodney J , Cullinane Carleen , Campbell Ian , Beale Philip James , Karapetis Christos Stelios , Price Timothy , Burge Matthew E. 
Published: September 2018

2564 Background: BSA-based dosing of Irinotecan (IR), does not account for its pharmacokinetic (PK) and pharmacodynamic (PD) variability. Given IR’s unique metabolism, functional hepatic nuclear imaging (HNI) with probes for hepatic transporters correlated with its PK. This study further evaluated the utility of HNI combined with extensive excretory/metabolic/PD pharmacogenomics (PG) to predict IR PK and PD in patients (pts) treated with FOLFIRI to enable dose individualization. Methods: Eligible pts had advanced colorectal cancer, suitable for 1st/2nd-line FOLFIRI± Bevacizumab. Pts had blood analyzed by Affymetrix DMET™ Plus Array and additional SNPs were genotyped. For HNI, pts were given IV 250MBq 99mTc-IDA and imaging data analyzed for hepatic extraction/excretion parameters (clearance [CL], 1hour retention [1hRET], deconvulutional CL [DeCL], hepatic extraction fraction [HEF]). Pts treated with chemotherapy, q2-weekly, and restaged after 4 cycles. Blood taken for IR and metabolite (SN38, SN38G) analysis on day 1 cycle 1, PK parameters derived by non-compartmental analysis. Statistical correlations were evaluated between (i) IDA HNI and (2) PGs, with IR PK, toxicity, objective response (ORR) and progression-free survival (PFS). Results: 32 pts analysed, 31 pts completed 4 cycles. (1) PK correlates: (a) HNI CL and 1hRET with SN38 Metabolic CL, (P = 0.04) and (b) HNI DeCL with IR AUC(0-∞) (P = 0.04). (2) Grade 3+ diarrhea (N = 4, 13%) predicted by SN38 AUC(0-∞) and Metabolic CL (P = 0.04), and gene variants for SCL22A2 and -28A3, ABCC2, UGT2B17, CYP2C18 and DPYD (P < 0.05). (3) Grade 3+ neutropenia (N = 9, 28%) predicted by SN38 PK exposure (P < 0.02), HNI CL and 1hRET (P < 0.0001) and variants for SLC7A7-, SLC22A2-, CHST1-, UGT1A1-, -2B7, ABCB1. (4) ORR (N = 6, 20%) predicted by Methylene tetrahydrofolate reductase (MTHFR) 677C > T (P = 0.002), SN38 exposure (P < 0.003), and variants in metabolic/transporter genes (P < 0.05). (5) PFS by SN38 PK exposure, MTHFR 677C > T, HNI CL, HNI HEF and variants in PK genes (P < 0.05). Conclusions: Hepatic functional imaging with extensive pharmacogenomics correlate with Irinotecan PK and PD enabling the development of nomograms to individualize dosing. Clinical trial information: ACTRN12610000898055.
The potential clinical impact of pre-emptive screening of multiple polymorphisms in gene-encoding DPD on patients candidate for fluoropyrimidine based-chemotherapy: An experience of the Northern Italy Cancer Centre.
Authors: Iachetta Francesco , Damato Angela , Bonelli Candida , Romagnani Alessandra , Banzi Maria , Nicoli Davide , Farnetti Enrico , Casali Bruno , Pinto Carmine 
Published: September 2018

2567 Background: Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluorouracil. Deleterious polymorphisms in gene-encoding DPD ( DPYD) results in a DPD deficiency that causes life-threatening toxicities when the standard dose of fluorouracil is used. DPYD*2A (IVS14+1G > A) is the most common single-nucleotide polymorphism (SNP) associated with critical DPD deficiency. At present, most of the evidence supports screening for at least 3 SNPs (DPYD*2A, c.2846 A > T, c.1679T > G). The aim of this study is to confirm that the detection of additional polymorphisms of DPYD could enhance prevention of fluoropyrimidine toxicity. Methods: In 2011, we began to screen DPYD*2A in patients candidate for fluoropyrimidine based-chemotherapy. As the first step of the evaluation, we selected all cases of DPYD*2A wild type, from 2011 to 2012, who developed CTC-NCI-V.3 toxicity ≥ G3. In these patients, we researched the other 3 SNPs (c.2846 A > T, c.1679T > G, c.2194C > A). Mutational status was analyzed with real Time PCR. Results: From 2011 to 2016 we pre-emptively screened DPD deficiency in 1,863 patients and 32 subjects (1.6%), with results mutated for DPYD*2A. As the first step of the evaluation, 548 subjects were assessed from 2011 to 2012. We found 7 patients who were carriers of the DPYD*2A mutation (1.27%). Of the 541 wild type cases, 114 presented toxicities ≥ G3. In this subgroup, 22 patients (19%) proved to be mutated for the other SNPs of DPYP, as reported in the table below. Conclusions: Preliminary data show that in 22 (19%) of 114 patients who presented severe toxicity which was not correlated with DPYD*2A, we found other polymorphisms of gene encoding DPD. Out of the 3 SNPs evaluated, c.2194 C > A proved to be the most frequent, although it is the polymorphism that is least known and least studied. Such results suggest that the evaluation of additional polymorphisms could enhance the prevention of fluoropyrimidine toxicity. The results are expected to be clarified further in the second step, which is ongoing. [Table: see text]
Molecular markers to predict response to selective fibroblast growth factor receptor inhibitors (FGFRinh) in patients (pts) with FGFR-amplified (amp) or mutated (mut) tumors.
Authors: Hierro Cinta , Serrano Marta , Ruiz-Pace Fiorella , Martin-Liberal Juan , Ochoa de Olza Maria , Azaro Analía , Brana Irene , Vieito Maria , Alsina Maria , Perez Garcia Jose Manuel , Verdaguer Helena , Macarulla Teresa , Sanchez Monica , Serra Violeta , Nuciforo Paolo , Vivancos Ana , Garralda Elena , Dienstmann Rodrigo , Tabernero Josep , Rodon Jordi 
Published: September 2018

2581 Background: Several FGFR and ligand (11q) alterations have been described in cancer. While FGFR fusions are recognized biomarkers of response to FGFRinh, it is still unclear to what extent FGFRamp, FGFR mRNA high expression (mRNAh) or FGFRmut predict sensitivity in the clinic. Methods: Retrospective analysis of pts with molecularly-selected FGFRamp/mRNAh/mut tumors treated with FGFRinh in phase 1 trials at our institution. Mut were detected with IlluminaÒ or Foundation OneÒ. FGFR1-2amp were analyzed by in situ hybridization and mRNA levels by qRT-PCR or nCounterÒ. Clinical benefit (ClinBen) was defined as any tumor shrinkage plus disease control for ³ 4 months (m). Time to progression (TTP) was defined as time between start of FGFRinh and end for any cause. Results: From 2011 to 2016, 36 pts with FGFRamp(25)/mRNAh(5)/mut(6) received an FGFRinh (irreversible- [11 cases (c)] or reversible-FGFR1-4inh [23 c], isoform-specific FGFRinh [3 c] or combo with PI3Kinh [1 c]). Median age 55 yrs (34-76); median prior palliative lines was 3 (0-8); tumor types: breast (17), colorectal (3), esophagus (3), liver (3), lung (3), others (7). Median TTP was 1.67 m (CI 95%; 1.40-2.87). In the FGFRamp/mRNAh population (30), 7 pts achieved ClinBen (23%). 4 out of these seven pts had mRNAh (1 FGFR2amp breast with FGFR2 mRNAh, 1 bladder FGFR3 mRNAh and 2 liver FGFR4 mRNAh without known amp), and 2 pts harboured 11q co-amplification (1 FGFR2amp breast, 1 FGFR2amp head and neck). There was no correlation between ClinBen and level of FGFRamp in the overall population (p = 0.51) or in the breast cancer group (p = 0.29). Of 6 FGFRmut pts, one with bladder cancer had ClinBen (clonal oncogenic FGFR3 S249C). The remaining 5 unresponsive FGFRmut pts had subclonal events, some of these FGFRmut were of unknown functional significance, and had coexisting oncogene mut in MAPK or PI3K pathways. Conclusions: Our results suggest that ClinBen with FGFRinh in the FGFRamp setting is enriched in pts with high mRNA expression and/or ligand co-amplification, and in the FGFRmut population may be dependent on clonality and functionality of the event and co-existence of driver mut.
Anticancer and immunostimulatory activity of the imipridone ONC201, a selective DRD2 antagonist, in advanced cancer patients.
Authors: Stein Mark N. , Chan Nancy , Silk Ann W. , Malhotra Jyoti , Aisner Joseph , Aiken Robert , Zloza Andrew , El-Deiry Wafik S. , Newman Jenna , Chesson Charles , Tarapore Rohinton , Allen Joshua E. , Oster Wolfgang , Saunders Tracie , Yu Bangning , Dickerson Siobhan , Rodriguez-Rodriguez Lorna , Haffty Bruce George , Kaufman Howard , Mehnert Janice M. 
Published: September 2018

2586 Background: ONC201 is an orally active, small molecule selective antagonist of the G protein-coupled receptor DRD2 that has established a new class of compounds referred to as imipridones. A first-in-human trial of ONC201 defined its recommended phase II dose (RP2D) as 625mg using once every three week administration that was very well tolerated at doses that yielded antitumor effects. ONC201 also showed stimulatory effects on immune cells in preclinical studies, including increased intratumoral NK cell infiltration in xenografts. Based on the exceptional safety profile of ONC201, weekly dosing has been evaluated. Methods: This open-label, 3+3 dose-escalation study used a starting dose of 375mg and escalated to 625mg using a weekly administration schedule. The primary endpoint was to determine the RP2D of ONC201 and secondary endpoints included PD, PK, toxicity, and anti-tumor efficacy. Based on signs of clinical activity and preclinical tumor type sensitivity studies of ONC201, the patient population was enriched for advanced glioblastoma, prostate cancer, and endometrial cancer. Six additional patients were treated at the weekly RP2D. Results: The RP2D for the weekly regimen was defined as 625 mg. Twelve evaluable patients were treated at this dose level and no drug-related AEs > grade 1 occurred. Five patients had stable disease by RECIST criteria for 21-29 weeks. A metastatic prostate cancer who received 375mg ONC201 weekly had significantly diminished intensity in bone scans after 6 doses. PK was consistent with previous reports: Cmax consistently reaches therapeutic micromolar plasma concentrations, ~11 hour half-life, evidence of sustained and delayed activity, no systemic accumulation. In agreement with preclinical observations of ONC201-induced NK cell populations, a 2-10 fold increase in circulating activated NK cells was observed in 5 prostate cancer patients. Conclusions: ONC201 is well tolerated at an oral dose of 625mg weekly, exhibits sustained and late anti-cancer activity, and increases circulating NK cells. Observation in this study, and other clinical studies, warrant further evaluation of the immune oncology effects of ONC201. Clinical trial information: NCT02250781.
Phase 1 study of the bone-targeting cytotoxic conjugate, etidronate-cytosine arabinoside (MBC-11), in cancer patients with bone metastases.
Authors: Zinnen Shawn , Rowinsky Eric Keith , Alexandrov Alexander , Plekhova Larisa , Roudas Marina , Karpeisky Alexander 
Published: September 2018

2589 Background: MBC-11 is a first-in-class therapeutic conjugate of the bone targeting bisphosphonate etidronate covalently linked to the antimetabolite cytosine arabinoside (Ara-C). In preclinical studies, MBC-11 localizes at the site of cancer-induced bone disease (CIBD) where it demonstrates both antiresorptive and antitumor activities following local release of Ara-C. Robust efficacy was observed in several rodent models of CIBD, as well as in spontaneous osteosarcoma in dogs. Herein, the results of the first-in-human study of MBC-11 are reported. Methods: Patients with advanced solid cancers and CIBD were treated with escalating doses (0.5-10 mg/kg/day) of MBC-11 administered as an intravenous infusion daily for 5 days every 4 weeks for up to 4 cycles. Fifteen patients (prostate cancer [PC; 7], breast cancer [BC; 7], cervical cancer [1]) received 38 total cycles. The study sought to characterize the safety, pharmacokinetics, and the effects of MBC-11 on bone turnover, and tumor response by 18F-FDG-PET/CT imaging and tumor biomarkers. Results: Myelosuppression was generally grade 1-2, involved all lineages, and was the principal toxicity of MBC-11. Two of three patients treated at the 10 mg/kg dose level had dose-limiting toxicity (DLT), each with both grade 4 neutropenia and thrombocytopenia, the maximum tolerated dose (MTD) was 5 mg/kg. Four of 5 patients with pretreatment elevations of the bone resorption marker Trap5b had persistent decrements. 18F-FDG-PET/CT imaging demonstrated partial metabolic responses in 3 patients; one BC patient treated at the 0.5 mg/kg and two CRPC patients treated at 1.0 mg/kg dose levels. An additional 3 patients had stable metabolic responses according to PERSIST. SUV values were reduced by at least 25% in 111 (53.8%) of 206 measurable bone lesions; significant activity was noted at all doses. Conclusions: At doses that were well tolerated and even much lower than the MTD, MBC-11 treatment resulted in substantial reductions in metabolic activity in CIBD patients, providing a foundation for further disease-directed studies to further assess efficacy. Clinical trial information: NCT02673060.
Association of the diversity and composition of the gut microbiome with responses and survival (PFS) in metastatic melanoma (MM) patients (pts) on anti-PD-1 therapy.
Authors: Wargo Jennifer Ann , Gopalakrishnan Vancheswaran , Spencer Christine , Karpinets Tatiana , Reuben Alexandre , Andrews Miles Cameron , Tetzlaff Michael T. , Lazar Alexander , Hwu Patrick , Hwu Wen-Jen , Glitza Isabella Claudia , Tawbi Hussein Abdul-Hassan , Patel Sapna Pradyuman , Lee Jeffrey Edwin , Davies Michael A. , Gershenwald Jeffrey E. , Futreal Andrew , Sharma Padmanee , Allison James Patrick , Jenq Robert R. 
Published: September 2018

3008 Background: Significant advances have been made in cancer therapy with immune checkpoint blockade. However, responses in pts with MM are variable, and insights are needed to identify biomarkers of response and strategies to overcome resistance. There is a growing appreciation of the role of the microbiome in cancer, and evidence in murine models that modulation of the gut microbiome may enhance responses to immune checkpoint blockade, though this has not been well studied in pts. Thus we evaluated the microbiome in a large cohort of pts with MM, focusing on responses to anti-PD-1. Methods: We collected oral (n = 234) and gut microbiome samples (n = 120) on a large cohort of of MM patients (n = 221). Of note, the majority of pts were treated with PD-1 based therapy (n = 105). Pts on anti-PD1 were classified as either responders (R) or non-responders (NR) based on RECIST criteria, and 16S rRNA and whole genome shotgun (WGS) sequencing were performed. Immune profiling (via immunohistochemistry, flow cytometry, cytokines and gene expression profiling) was also done in available pre-treatment tumors at baseline. Results: Significant differences in diversity and composition of the gut microbiome were noted in R vs NR to anti-PD-1, with a higher diversity of bacteria in R vs NR (p = 0.03). Differences were also noted in the composition of gut bacteria, with a higher abundance of Clostridiales in R and of Bacteroidales in NR. Immune profiling demonstrated increased tumor immune infiltrates in R pts , with a higher density of CD8+T cells; this correlated with abundance of specific bacteria enriched in the gut microbiome (r = 0.59, 0.014). Other features of enhanced immunity were also noted, and WGS revealed differential metabolic signatures in R vs NR. Furthermore, diversity (p = 0.009; HR = 7.67) and abundance of specific bacteria in R (p = 0.007; HR = 3.88) was associated with improved PFS to anti-PD-1 therapy. Conclusions: Diversity and composition of the gut microbiome differ in R vs NR pts with MM receiving anti-PD-1 therapy. These have potentially far-reaching implications, though results need to be validated in larger cohorts across cancer types.