bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bispecific Fynomer-antibody fusion proteins targeting two epitopes on HER2.
Authors: Mourlane Frederic , Toller Isabella , Brack Simon , Grabulovski Dragan , Bertschinger-Ehrler Julian 
Published: March 2020

2575 Background: Fynomers are small binding proteins (7 kDa) derived from the SH3 domain of Fyn kinase. They can be engineered to yield specific and high-affinity binding domains to target proteins of interest. In the past, we have isolated Fynomers with excellent physico-chemical properties binding to 16 different antigens. One important application of the Fynomer technology represents the genetic fusion of a Fynomer to an antibody to provide bispecific fusion proteins. Methods: Using phage display technology we have isolated Fynomers binding to tumor-associated antigens. After genetic fusion of these Fynomers to antibodies of interest the resulting bispecific proteins were evaluated in vitro and in vivo for their antitumoral activity. Results: The fusion of Fynomers to the antibodies of interest did not alter the favorable biophysical properties of the antibodies. First, the Fynomer-antibody fusion proteins could be purified with the same high yields from the supernatant of transiently transfected CHO cells as the unmodified antibodies (in the range of 100 mg/L). Second, the purified fusion proteins were monomeric and showed no signs of aggregation even after four months of storage at 4 °C or -20 °C in PBS as determined by size exclusion chromatography. Third, the Fc-mediated effector functions of antibodies were not altered by their fusion with Fynomers. Antibody-dependent cellular cytotoxicity (ADCC) was maintained, and the affinity to the neonatal Fc-receptor (FcRn) was similar as observed for the unmodified antibody. In addition, the bispecific Fynomer-antibody fusion proteins demonstrated excellent growth inhibition of tumor cells in vitro and high efficacy in vivo in tumor xenograft mouse models. Conclusions: These encouraging preclinical results indicate that the bispecific Fynomer-antibody fusions have highly promising properties with a great potential for further preclinical and clinical development.
Development of an assay based on SOMAmer affinity reagents that detects drug-unbound serum EGFR in the presence of cetuximab and panitumumab.
Authors: Park Noh Jin , Wang Xiuqiang , Root Dana , Diaz Angelica , Sun Weimin , Morrone Robert j , Waldman Frederic , Strom Charles m 
Published: March 2020

2587 Background: EGFR is an oncogene product whose extracellular domain (ECD) can be either up-regulated or down-regulated in serum of patients with various cancers. In colon cancer patients with positive tissue EGFR expression, 2 EGFR ECD-targeting monoclonal antibody drugs, cetuximab (Erbitux) and panitumumab (Vectibix), are widely used chemotherapeutic agents. Patient responses to these drugs vary, and the mechanism of this variability remains unelucidated. Methods: A Slow Off-Rate Modified Aptamer (SOMAmer) targeting the EGFR ECD was selected via Systematic Evolution of Ligands by Exponential Enrichment (SELEX). Using this SOMAmer as a capturing reagent and based on published studies ( Gold et al. PLoS ONE; Dec 7, 2010:10.1371/journal.pone.0015004), we developed a quantitative serum EGFR assay to reliably quantify EGFR in serum. Results: Recovery tests using various amounts of purified EGFR spiked into serum demonstrated a full level of EGFR. Intra and inter assay variability were tested and showed minimum variability. The detection range is 0.95 ng/ml to 600 ng/ml. Interestingly, when serum samples from patients taking cetuximab or panitumumab at the time of blood collection were tested, we observed markedly lower levels of EGFR-captured SOMAmer. ELISA assays from 2 different vendors showed normal to high levels of EGFR in these samples. We further showed that pretreatment of normal serum with either cetuximab or panitumumab can dose-dependently reduce the EGFR SOMAmer signal. The data suggest that our EGFR SOMAmer assay detects serum EGFR molecules that are unbound by cetuximab or panitumumab. Some treated patient samples had more drastic reductions in circulating serum EGFR than others. Conclusions: Various assay development parameters such as accuracy, detection range, and intra and inter assay variability showed that a SOMAmer-based assay detecting serum EGFR can be used in a clinical setting. Our data suggest that this assay can accurately measure drug-unbound EGFR in patients, which may serve as a surrogate drug efficacy indicator, and this may help physicians to adjust the drug dosage. Further studies will be necessary to investigate this possibility.
Phase I and pharmacokinetic (PK) study of pazopanib (P) in combination with two schedules of ifosfamide (I) in patients (pts) with advanced solid tumors (STs).
Authors: Hamberg Paul , Boers-Sonderen Marye , Loos Walter J. , De Jonge Maja J. , Van Der Graaf Winette T.A. , Suttle Ben B , Eskens Ferry , Verweij Jaap , Van Herpen Carla , Sleijfer Stefan 
Published: March 2020

2593 Background: P is a tyrosine kinase inhibitor of PDGFR, VEGFR and KIT. This study aimed to determine the recommended phase II dose (RP2D) of P combined with I. To assess the impact of scheduling on tolerability, two I schedules were explored. Methods: Pts with progressive ST, no standard therapy available, PS 0-1 and good organ function were eligible. Pts received daily P with 3-weekly I, 9 g/m2/cycle, either continuously (Iciv) or as 3 hrs boluses (Ibolus) for 3 days. P was escalated in serial cohorts of 3-9 pts per I-schedule. If in 3-6 pts dose-limiting toxicity (DLT) of 33.3% within 1st cycle was seen 3 more pts at that dose level (DL) were enrolled. RP2D was exceeded if in > 1/3 pts, > 2/6 pts or ≥ 3/9 pts DLT occurred. P was maximized at 1000 mg/day. At RP2D, an expansion cohort of 6-9 pts was studied to confirm safety. PK samples of P and I were collected in all pts. Sampling allowed intra-individual comparison of I-PK with or without P and vice versa. Results: 47 pts were studied. For Iciv (25 pts), RP2D was the maximum dose of P (1000 mg), higher than the single agent RP2D. At RP2D 2 DLTs in 15 pts occurred: 1 febrile neutropenia (FN); 1 encephalopathy. With Ibolus (22 pts), P 400 mg with or without GCSF was not tolerated (5 DLTs in 10 pts: 3*FN, 1 encephalopathy; 1 proteinuria). At RP2D (P 200 mg + Ibolus + GCSF) 3 DLTs in 12 pts (FN; encephalopathy, renal insufficiency) were observed. Toxicity occurring in >30% of pts in Iciv (all grades/grade 3-4,%) were neutropenia (92/92) anemia (92/8); thrombocytopenia (35/12), elevated ASAT, ALAT, alkaline phosphatase (73/4; 73/0; 62/2), nausea (58/0), vomiting (73/0), diarrhea (54/0) and hypertension (31/12). 4/25 pts in Iciv evaluable for response had PR (2 sarcoma, 2 ovary) and 10 prolonged (≥3 mths) SD. In Ibolus, 6/20 pts had PR (2 urothelial, 1 sarcoma, 1 ovary, 1 CUP, 1 mesothelioma) and 3/20 prolonged SD. Preliminary PK analysis showed no effect of P on I-exposure, neither of Ibolus or Iciv on P. Conclusions: P is tolerated at a higher dose combined with Iciv compared to Ibolus (1000 vs 200 mg). PK cannot explain this difference. This study underlines the impact of scheduling on the tolerability of VEGFR-TKI and cytotoxic drug combinations.
Pharmacokinetic modeling and simulation (PK M&S) supported dose escalation of PF-03446962, a monoclonal antibody (mAb) against activin receptor like kinase 1, in patients with solid tumors.
Authors: Wang Erjian , Borghaei Hossein , Goff Laura Williams , Noberasco Cristina , Cohen Roger B. , Stampino Corrado Gallo , Williams James Andrew , De Braud Filippo , Berlin Jordan 
Published: March 2020

2595 Background: PF-03446962 is a first in class mAb. The PK of mAbs is complex, as their clearance (CL) can be linear or non-linear, besides extremely slow. Caution must be exercised when designing mAbs’ dose escalation schemes. Along with safety and activity evaluation, we used PK M&S in real time to ensure that subsequent recommended doses did not expose too many patients to subtherapeutic levels while preserving safety. Methods: The model incorporated both Michaelis-Menten approximation and linear components. A prespecified target exposure was defined by preclinically projected therapeutic and toxic concentrations. The PK M&S results were used to make dose escalation decisions. Results: Eight dose levels (0.5, 1, 2, 3, 4.5, 6.75, 10, and 15 mg/kg) were studied in 44 patients. CL of PF-03446962 exhibited nonlinear characteristics at low doses and linear at high doses. CL was saturated at dose levels of 3 mg/kg and above. Mean half-life was 2.6 days for the first dose level and 12-15 days after CL saturation. The dose ratio of 15 to 0.5 mg/kg was 30, while its corresponding Cmax and AUC ratios were 46 and 97, respectively. However, the PK M&S accurately predicted exposure following each dose. 95% of the observed drug concentrations across all dose levels were within the predicted values. Concentrations at the 4.5 mg/kg dose exceeded the predicted efficacious level over the dosing period. None of 44 patients in the study were exposed to the toxic level derived from a study in monkeys. PK data also implied a biologically active dose at 2 mg/kg dose and above, confirmed by observing target toxicities (ie, telangiectasia) and clinical tumor responses. One patient with PR was at the 2 mg/kg dose and 2 patients with PR were at the 10 mg/kg. The PK M&S well predicted the drug exposure following multiple doses in patients, indicating that patients did not develop antidrug immunogenicity. Conclusions: The PK M&S based approach ensured that the majority of patients were treated at or near the therapeutic dose. It can be readily implemented in the conduct of dose escalation trials of antitumor mAbs, while minimizing risk to patients and maximizing efficiency.
Docetaxel pharmacogenetics: The influence of RXRα and HNF4α genetic variations on docetaxel disposition in Asian nasopharyngeal carcinoma patients.
Authors: Chew Sin Chi , Singh Onkar , Chen Xiangai , Lim Wan-Teck , Tan Eng-Huat , Lee Edmund Jon Deoon , Chowbay Balram 
Published: March 2020

2598 Background: The transactivations of the metabolism enzymes (CYP3A4/5) and efflux transporters (ABCB1/ABCC2) involved in docetaxel disposition are regulated by the orphan nuclear receptors such as PXR, CAR, RXRα and HNF4α. This study aimed to explore the associations between the genetic variations present in the genes encoding the orphan nuclear receptors, RXRα and HNF4α, on docetaxel disposition. Methods: The DNAs from healthy Chinese, Malay and Indian subjects (n=56 each) were screened for RXRα and HNF4α SNPs in exons and intronic/exonic boundaries by direct sequencing. The high frequency SNPs (>1%) were profiled in a cohort of local nasopharyngeal cancer patients (n=54). Genotypic-phenotypic correlations were conducted using Mann-Whitney U-test and Kruskal-Wallis test. Results: Eighty-eight and sixty-nine SNPs were identified from the healthy screening of RXRα and HNF4α, respectively, across 3 populations. A total of 30 and 35 high frequency SNPs in RXRα and HNF4α, respectively, were profiled in the patients. Six RXRα SNPs [IVS2+33G>A (rs2234753), IVS7+70A>G (rs1536475),*846G>A (rs4240711), *+4458G>A (rs3132291), *+4768C>A (rs4842196) and *+4988A>G (rs4842198)] and 6 HNF4α SNPs [-728A>C (rs1800963), IVS2-278A>G (rs55934816), IVS6+141A>G (rs6103731), IVS7-88T>C (rs2273618), IVS9–145T>C (rs3746574) and IVS9-67C>G (rs3746575)] were significantly associated with higher clearance and lower AUC0-∞ and/or Cmax of docetaxel (P<0.05). Conversely, HNF4α SNP [IVS9+354G>T (rs3818247)] was associated with lower clearance and higher AUC0-∞ and Cmax of docetaxel (p<0.05). A high linkage pattern was observed among the abovementioned RXRα SNPs except for IVS2+33G>A (rs2234753) (D'≥0.74). Similarly, HNF4α SNPs were found to be highly linked, except for -728A>C (rs1800963) (D'≥0.62). Conclusions: The results highlight the contributions of RXRα and HNF4α pharmacogenetics in influencing the inter-individual variability in docetaxel disposition in Asian nasopharyngeal patients.
Biomarkers of vincristine neuropathy in Kenyan children.
Authors: Skiles Jodi L , Chiang ChienWei , Li Claire , Li Lang , Olbara Gilbert , Tallam Celestine , Njuguna Festus , Renbarger Jamie L. 
Published: March 2020

2601 Background: In a U.S. population, cytochrome P450 (CYP) 3A5 high-expressers metabolize vincristine (VCR) more efficiently than low-expressers and vincristine-induced peripheral neuropathy (VIPN) is less common in African-Americans than Caucasians. We test the hypothesis that more children in Kenya are CYP3A5 high-expressers compared to U.S. children and as such experience less VIPN. Methods: This study was conducted in Kenyan children with cancer (n=78) being treated with VCR at Moi University AMPATH Oncology Institute in partnership with Indiana University. Saliva Oragene kits for DNA extraction and genotyping were obtained. Whole blood was collected via finger stick on Whatman protein saver dried blood spot cards for analysis of VCR concentrations. VIPN was assessed prospectively using two neuropathy assessment tools (Modified Total Neuropathy Score (TNS) and National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0). Results: Compared to 14% in the U.S. sample, 94% of Kenyan subjects are CYP3A5 high-expressers (p<2.2x10-16). Kenyan children have significantly lower VCR plasma concentrations (11.15ng/ml/mg ± 1.051) compared to US (primarily Caucasian) children (13.26ng/ml/mg ± 2.897) one hour following the administration of VCR (p=0.011). By TNS VIPN assessment, 71% of Kenyan children developed VIPN compared to 100% of U.S. children (p=8.8x10-7). CYP3A5 high-expresser genotype is associated with lower TNS VIPN severity scores than low-expresser genotypes (p=0.006). TNS VIPN assessments show that height is positively correlated with severity of VIPN (p=0.025). CTCAE VIPN assessments also showed a positive correlation with height (p=0.036), but did not show any association with CYP3A5 genotype. Conclusions: Kenyan children are more likely to be CYP3A5 high-expressers than U.S. children and as such may metabolize VCR more efficiently. Supporting these data is that Kenyan children experience significantly less VIPN than U.S. children. CYP3A5 genotype and height are independent predictors of VIPN in Kenyan children with cancer. The CTCAE may lack sufficient sensitivity to detect VIPN for use in future studies aimed at optimizing VCR dosing strategies.
Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1 study.
Authors: Rummel Mathias J. , Niederle Norbert , Maschmeyer Georg , Banat Andre G. , von Gruenhagen Ulrich , Losem Christoph , Kofahl-Krause Dorothea , Heil Gerhard , Welslau Manfred , Balser Christina , Kaiser Ulrich , Weidmann Eckhart , Duerk Heinz A. , Ballo Harald , Stauch Martina , Barth Juergen , Hinke Axel , Brugger Wolfram ,   Study Group Indolent Lymphomas (StiL)
Published: March 2020

3 The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Sunday, June 3, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Phase I/II study of the investigational aurora A kinase (AAK) inhibitor MLN8237 (alisertib) in patients (pts) with non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), breast cancer (BrC), head/neck cancer (H&N), and gastroesophageal (GE) adenocarcinoma: Preliminary phase II results.
Authors: Lee Peter , Alvarez Ricardo H. , Melichar Bohuslav , Adenis Antoine , Bennouna Jaafar , Schusterbauer Claudia , Zhang Bin , Benaim Ely , Rosen Peter J. 
Published: March 2020

3010 Background: AAK is a key mitotic regulator that is amplified or overexpressed in multiple tumor types. MLN8237 is an investigational oral, selective AAK inhibitor being studied in both hematologic (phase III) and nonhematologic malignancies. In the phase 1 part of this study, MLN8237 was generally well tolerated in pts with solid tumors. The maximum tolerated dose was 50 mg BID for 7d + 2 wks rest in 21-d cycles; this dose was recommended for phase II evaluation. Here we report preliminary data from the 5-arm phase 2 part (NCT01045421). Methods: 20 pts each with one of 5 tumor types in the relapsed/refractory setting were enrolled in phase II for efficacy evaluation: NSCLC (inc. 8–10 pts with mainly squamous-cell histology), SCLC (inc. 8–12 chemotherapy refractory pts), BrC (inc. 8–10 pts with a basal-like intrinsic subtype, and 8–10 HER2+ pts), H&N (inc. 8–12 pts with tonsillar or base-of-tongue disease), or GE adenocarcinoma. Pts were aged ≥18 y, and had ECOG PS 0–1, measurable disease by RECIST, and ≤2 prior cytotoxic chemotherapy regimens (≤4 in BrC). Oral MLN8237 was administered as an enteric-coated tablet at 50 mg BID for 7d + 2 wks rest in 21-d cycles. The primary endpoint was overall response rate. Response was determined by RECIST v1.1. Each arm with ≥2 partial responses (PR) is being expanded with 25 additional pts. Results: In 100 efficacy-evaluable pts, median age was 59 y (range 33–88) and 89% were caucasian. Pts received a median of 3 cycles (range 1–9). PRs were observed in 11 pts: H&N, SCLC (each n=3), BrC, GE adenocarcinoma (each n=2), and NSCLC (n=1). 45 pts had a best response of stable disease. In the safety population (n=196), most frequent grade ≥3 drug-related AEs were neutropenia (37%), leukopenia (12%), fatigue, anemia, stomatitis, and thrombocytopenia (each 6%). Updated data will be presented. Conclusions: Preliminary phase II data suggest that oral MLN8237 is tolerable and has antineoplastic activity in a range of solid tumors studied. This study is currently ongoing to further evaluate MLN8237 in the expansion cohorts.
Molecular profiling of patients (pts) with colorectal cancer (CRC) and matched targeted therapy (MTA) in phase I clinical trials.
Authors: Dienstmann Rodrigo , Sanchez-Olle Gessami , Serpico Danila , Rodon Ahnert Jordi , Saura Cristina , Macarulla Teresa , Fernandez Maria Elena Elez , Alsina Maria , Perez-Garcia Jose Manuel , Capdevila Jaume , Argiles Guillem , Brana Irene , Cruz Cristina , Azaro Analia , Moreno-Fernandez Debora , Aura Claudia , Hernandez-Losa Javier , Vivancos Ana , Ramon y Cajal Santiago , Tabernero Josep 
Published: March 2020

3014 Background: Molecular prescreening and biomarker enrichment strategies in Phase 1 trials with targeted therapies are anticipated to improve the outcomes of affected pts. Methods: As part of our personalized oncology program, tumors from pts with advanced chemorefractory CRC were analyzed for specific molecular aberrations (KRAS/ BRAF/ PIK3CA mutations [mut], PTEN and pMET expression) at the Vall d'Hebron Molecular Pathology and Genomics Labs. Those whose tumors were found to have a dysregulation were offered a Phase 1 trial with MTA. Results: During 2010 and 2011, tumor molecular analysis was performed in 254 pts: KRAS mut (80/254, 31.5%), BRAF mut (24/196, 12.2%), PIK3CA mut (15/114, 13.2%), KRAS+PIK3CA mut (9/114, 7.9%), PTEN low (97/183, 53.0% - HSCORE<50; 45/183, 24.6% - PTEN null), KRAS mut + PTEN low (38/138, 20.8%), pMET high (38/64, 59.4% with HSCORE>30). In total, 68 pts (median, age 63 yrs; prior therapies 3), received 82 different matched therapies. Type of MTA: PI3K pathway inh (if PIK3CA mut, n=10; or PTEN low, n=32), MEK+PI3K pathway inh (if KRAS mut, n=10; or BRAF mut, n=1), second-generation anti-EGFR mAbs (if KRAS wild-type, n=11), anti-HGF mAb (if pMET high, n=10), mTOR inh + anti-IGFR-1R mAb (if PTEN low, n=5) and BRAF inh (if BRAF mut, n=3). Median time to treatment failure (TTF) with MTA was 7.9 weeks (CI95%:7.6-8.1) vs. 16.3 weeks (CI95%:13.9-18.7) for their prior systemic antitumor therapy (p<0.001). If prior therapy non-standard (according to NCCN guidelines, n=39), TTF with MTA 7.9 weeks (CI95%:6.8-8.9) vs. TTF with prior therapy 8.7 weeks (CI95%:7.3-10.1). If an approved standard regimen (n=43), TTF with MTA 7.9 weeks (CI95%:7.6-8.1) vs. TTF with prior therapy 21.9 weeks (CI95%:15.0-28.7). Partial response was seen in one pt (1.2%, PI3K inh with PIK3CA mut) and stable disease > 16 weeks in 10 cases (12.2%). Clinical benefit, defined as a TTF ratio ≥ 1.3 (TTF on MTA/ TTF on prior therapy), was seen with 15.9% of the therapies (13/82). Conclusions: Preliminary results suggest that matching chemorefractory CRC patients with targeted agents in early clinical trials based on the current molecular profile does not result in longer TTF compared to their prior therapy.
A phase I, single-institution, open-label, dose escalation trial with an expansion cohort evaluating the safety and tolerability of AZD6244 and IMC-A12 in subjects with advanced solid malignancies.
Authors: Ahmed Shabina Roohi , Ball Douglas Wilmot , Cosgrove David , Scardina Angela , Petito Emily , Downs Melinda , Nelkin Barry , Chen Helen X. , Doyle Laurence A , Donehower Ross C. , Carducci Michael Anthony , Azad Nilofer Saba 
Published: March 2020

3020 Background: Significant crosstalk exists between the PI3K and Raf/MEK/ERK pathways and treatment of select cell lines with a MEK inhibitor and an IGF1-R inhibitor has been shown to cause greater inhibition of growth than either agent alone. IMC-A12 (I) is a recombinant human monoclonal antibody directed IGFI-R; it blocks interaction between IGF-1R and its ligands, IGF-I and -II. AZD6244 (A) is a highly selective, non-competitive MEK ½ inhibitor. Methods: The study is a phase I, dose-escalation with a standard 3+3 design. Eligible patients had advanced solid tumor, good end organ function and performance status with exclusion for poorly controlled diabetes or growth hormone abnormalities. Part 1: open label, dose escalation. Pts were treated with A at 50 mg BID, then 75 mg BID; I at 12mg/kg q2wk held constant. DLTs were defined as grade (G) 3 or 4 toxicities during cycle 1. Part 2: expansion cohort of 15 pts for correlative endpoints and PK studies; serial tumor biopsies will be evaluated for changes in signaling in the IGF pathway, including p-ERK, p-Akt and RAS. Mutational analysis of RAS and RAF will be done to correlate with PD endpoints and disease response. Results: Part 1: 16 patients accrued with 6 treated at DL1 and 10 treated at DL2. Multiple tumor types were represented, including 4 colon, 2 thyroid, 2 pancreatic, and 1 breast. At 75 mg of A, there was 1 DLT of visual changes. G3 AEs included nausea/vomiting (n=2, 12%), visual changes/retinopathy (n=2, 12%), MRSA skin infection (n=1, 6%), (n=1, 6%), hyperglycemia (n=1, 6%), and stroke (n=1, 6%). Other common AEs included acneform rash (n=10, 63%), nausea/vomiting (n=6, 37%), anorexia (n=4, 25%), and diarrhea (n=3, 19%). Of 10 evaluable patients in Part 1, 1 had a partial response and 4 patients had stable disease (40%). Sustained responses of 10 and 14 months were seen in the DTC patients. 3 patients are currently enrolled in the expansion cohort. The RP2D is 50 mg of A, due to the visual changes seen with 75 mg, and 12mg/kg of I. Conclusions: A at 50 mg QD combines safely with I 12mg/kg. An expansion cohort is underway to determine if this combination warrants further investigation.