bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and pharmacokinetics (PK) of AMG 706 in combination with gemcitabine for the treatment of patients (pts) with solid tumors
Authors: Price T. J. , Lipton L. , Williams J. , McGreivy J. , McCoy S. , Sun Y. , Aguero-O’Neill B. , Rosenthal M. A. 
Published: March 2020

14005 Background: AMG 706 is an oral, investigational multikinase inhibitor (MKI) with antiangiogenic and direct antitumor activity achieved by selectively targeting VEGF, PDGF and Kit receptors. Methods: This is a fully enrolled, phase 1b, open-label, dose- finding study. The objectives are to determine the maximum tolerated dose and to assess safety and PK of AMG 706 in pts with solid tumors receiving AMG 706 plus gemcitabine. Pts =18 years with ECOG 0–2 and no prior treatment with bevacizumab or VEGFr MKIs were assigned to cohorts receiving escalating doses of AMG 706 (50mg QD, 125mg QD or 75mg BID continuously from day 2 of cycle 1) plus gemcitabine (1000mg/m2 weekly for 7/8 wks, then 3/4 wks per cycle) for up to 11 cycles. Assessments include dose-limiting toxicities (DLT) (weeks 1–4) and tumor response (every 3 months). Results: 26 pts were enrolled and received at least 1 dose of AMG 706 (50mg QD n=11; 125mg QD n=6; 75mg BID n=9). All but 2 pts have completed the study. Median (range) age was 57 (25–77) yrs. 65% of pts received prior chemotherapy; 4 pts received prior gemcitabine (50mg QD n=2; 125mg QD n=1; 75mg BID n=1). There were 2 DLTs: grade 4 neutropenia (125mg QD), grade 3 deep vein thrombosis (75mg BID). Treatment-related adverse events (AE) occurring in = 10% of pts are shown in the table . The mean AMG 706 PK profiles were not markedly different when AMG 706 was dosed on the same day or 24 hours after gemcitabine administration. Objective tumor responses per RECIST for 26 evaluable pts were: 2 unconfirmed PR (50mg QD n=1; 125mg QD n=1), 7 SD (50mg QD n=3; 125mg QD n=1; 75mg BID n=3), 11 PD (50mg QD n=7; 125mg QD n=3; 75mg BID n=1), and 6 not available (125mg QD n=1; 75mg BID n=5). Conclusions: These preliminary data suggest that, in pts with solid tumors, AMG 706 combined with gemcitabine had an expected AE profile at the target once-daily dose of 125mg QD, with little effect on AMG 706 PK. The data provide a foundation for conducting further trials, potentially including biliary tumors. Final data will be presented. [Table: see text] No significant financial relationships to disclose.
Suppression of HOX A cluster genes inhibits proliferation and induces cell death in human mixed-lineage leukemias
Authors: Faber J. , Krivtsov A. , Stubbs M. , Wright R. , van den Heuvel-Eibrink M. , Kung A. , Zwaan C. , Armstrong S. 
Published: March 2020

14020 Background: Leukemias harboring translocations of the mixed lineage leukemia locus (MLL) are generally associated with poor clinical prognosis. Using gene expression profiling we and others have previously shown that Homeobox (HOX) A cluster genes are highly expressed in leukemias with MLL rearrangements. Methods: Here we studied the role of aberrant HOXA9 expression in human MLL- rearranged and non-rearranged leukemias utilizing an shRNA mediated knockdown approach. Results: Three different shRNA constructs targeting human HOXA9 were synthesized and stably introduced into t(9;11) MOLM14 cells utilizing a lentiviral vector system. 75–80% HOXA9 RNA knockdown was confirmed by quantitative PCR and Western Blot analysis. In a panel of 17 AML/ALL cell lines (7 MLL rearranged, 10 non rearranged), HOXA9 directed shRNA inhibited cell proliferation starting as early as 48h after transduction, and induced apoptosis beginning at 72h. Interestingly, impaired cell proliferation and induction of apoptosis was significantly higher in the MLL rearranged cell lines (mean viability: 51.88%) than in the non-rearranged cells (mean viability: 90.98%; p=0.007) and also significantly correlated with the baseline HOXA9 mRNA expression before knockdown (R= 0.8, p=0.00017). We then further analyzed the effect of HOXA9 knockdown in MLL rearranged and non-rearranged primary human AML cells. Similar to our findings in cell lines, a marked induction of cell death was observed, which was significantly higher in leukemias with an MLL translocation (p=0.005) and also significantly correlated with the baseline HOXA9 mRNA expression (R= 0.8, p=0.001). Next, the in vivo effect of HOXA9 knockdown was assessed by transplanting luciferase-expressing SEMK2 (t4;11) cells into SCID-beige mice followed by in vivo bioluminescent imaging. Leukemia burden was significantly reduced in HOXA9 shRNA treated mice (n=10) with a peak difference at day 15 (p=0.000059) shortly before mice of the control group (n=10) succumbed from overt leukemia. At this point all mice of the HOXA9 shRNA treated group were still healthy with no signs of leukemia. Conclusions: Taken together our data implicates that depletion of HOXA9 might be a novel approach for targeted therapy in human MLL rearranged leukemias. No significant financial relationships to disclose.
Comparison of enzastaurin pharmacokinetics and safety in the once daily (QD) and twice daily (BID) dose regimens: A phase I study
Authors: Hanauske A. , Musib L. , Weigang-Köhler K. , Yilmaz E. , Graefe T. , Kuenen B. , Thornton D. , Lahn M. , Darstein C. , Giaccone G. 
Published: March 2020

14021 Background: Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCβ and the PI3K/AKT pathway to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. Objectives of this phase 1b study included the comparison of safety and PK data for enzastaurin and its active metabolites in the QD (once daily) and BID (twice daily) regimens. Methods: Patients (pts) with advanced or metastatic cancer were enrolled. In cycle 1, pts received 500 mg enzastaurin QD from days 1–15 and 250 mg BID from days 16–30. In subsequent 21-day cycles, 500 mg/m2 pemetrexed was administered as a 10-minute intravenous infusion on day 1, with 250 mg enzastaurin BID. Folic acid and vitamin B12 supplementation was given to pts prior to and during pemetrexed administration. For comparison of enzastaurin QD versus BID, PK sampling was performed on days 15 and 29 of cycle 1. Results: Interim data for cycle 1 are presented for 26 patients who received 1 dose of enzastaurin. Twenty patients (9 F, 17 M; median age 60 years [range: 43–80]; ECOG =2) completed cycle 1. Hematological toxicities (grade [Gr] =3) were reported on a total of 9 pts. Lymphopenia occurred in 8 pts in BID regimen (1 Gr 3) and 2 pts in QD. Leukopenia (n=1), neutropenia (n=1), hypokalemia (n=1) and SGPT increase (n=1) were reported only in BID regimen. Chromaturia (n=15) was observed in both regimens. Hypoalbuminemia (n=2) and fatigue (n=2) were equally common in both regimens. Pharmacokinetic data for the two regimens is shown in the table . Exposures increased by approximately 50% and 40% for enzastaurin and total analyte (enzastaurin + metabolites), respectively. Conclusions: In comparison to QD dosing, enzastaurin exposures are increased modestly after BID dosing. This increase in exposure did not cause any clinically significant worsening of toxicities in most patients. [Table: see text] [Table: see text]
Poly-adeninosinediphosphate-ribose polymerase inhibitors as sensitizers for therapeutic treatments in human tumor and blood mononuclear cells
Authors: Ji J. , Redon C. , Pommier Y. , Kinders R. , Parchment R. , Hollingshead M. , Yang S. , Murgo A. , Tomaszewski J. , Doroshow J. 
Published: March 2020

14024 Background: Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) is a molecular sensor of DNA breaks that facilitates DNA repair and controls genomic stability. Treatment with single doses of ABT-888, a novel potent PARP-1 inhibitor, reduced PAR levels in peripheral blood mononuclear cells (PBMCs) and tumor biopsies in an on-going Phase-0 trial at the NIH Clinical Center. As a corollary to this study, we investigated whether ABT-888 can act as a sensitizer for radiation therapy and chemotherapy in human cancer cell culture, xenograft tumors and PBMCs to support future combination clinical trials. Methods: Inhibition of PARP-1 by ABT-888 was determined by a quantitative PAR chemiluminescence immunoassay validated for the Phase 0 trial. Since gamma-H2AX (?-H2AX) is a marker of DNA damage, we also developed and validated ?H2AX assays to monitor the effects of PARP-1 inhibition during treatment with Topo I inhibitors and radiation. Human monocytic leukemia (THP-1) and breast carcinoma (MCF-7) cell lines were treated with Topo I inhibitors including indenoisoquinoline, camptothecin and topotecan or irradiated with 0.5 to 10 Gy in the presence of ABT 888. We further evaluated these effects in human blood ex vivo to confirm the observations made in cell culture. Results: We found that ABT-888 inhibited PAR, but did not significantly increase DNA damage. Combination of ABT-888 with a Topo I inhibitor produced over 275% increase of DNA damage in THP-1 leukemia cells compared to indenoisoquinoline alone. ?H2AX foci per cell were 9.5 ± 0.8 in MCF-7 treated with 0.5 Gy/50 nM ABT-888 in comparison to 4.0 ± 0.6 with radiation alone. When whole blood was treated in the presence of ABT-888, camptothecin- induced DNA damage in PBMCs was also increased 2–3 fold, with maximum ?H2AX expression at 2 hours post treatment. Conclusions: We conclude that ABT-888 is a highly potent PARP-1 inhibitor that can enhance the DNA damaging effects of chemotherapy and radiation therapy of human cancer. Funded by NCI Contract N01-CO-12400. No significant financial relationships to disclose.
A phase I trial of AVN944 in patients with advanced hematologic malignancies
Authors: Klisovic R. B. , Tricot G. , Coutre S. , Kovacsovics T. , Giles F. , Genna T. , Bol D. K. , Strovel J. W. , Hamilton J. M. , Mitchell B. 
Published: March 2020

14026 Background: AVN-944 is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme that catalyzes the rate- limiting step in guanine nucleotide synthesis, and induces apoptosis in malignant hematopoietic cell lines in vitro. Methods: This phase I study employed open-label dose escalations in patients (pts) with relapsed, refractory hematologic cancers with safety, pharmacokinetic (PK), pharmacodynamic, & efficacy endpoints. Between 12/05 and 1/07 a total of 70 cycles of AVN944 at 25 (7pts), 50 (6pts), 75 (7pts), 100 (7pts) or 125 mg (3pts) b.i.d. orally X 21d every 28d were administered to 30 pts with AML (12), ALL (2), CLL (3), and multiple myeloma (13). Peripheral blood mononuclear cell (PBMC) or leukemic blast samples were obtained from all pts pre and post-receiving AVN944 to determine effects on GTP pools, IMPDH activity, and to correlate these changes to response in a 32-gene set that relates directly to cellular pathways dependent upon guanine nucleotide biosynthesis. Results: Pharmacokinetics were dose proportional with mean Tmax=1 hour, T1/2=1.5 hours, Cmax=2800 ng/ml and AUC=7228 hr.ng/ml at the 100 mg b.i.d. dose. Toxicities were generally mild-moderate and/or not attributed to AVN944. Twelve serious adverse events (SAEs) occurred in 8 pts; 7 of 8 had AML. No SAEs was attributed to AVN944. DLT was not seen. No protocol defined responses were seen. Twelve of 24 assessable pts had stable disease of 2 to 10 months duration. Changes in the gene expression set correlated with disease stability. Conclusions: AVN944 is well tolerated with oral b.i.d. dosing. Stabilization of disease was observed in half of the pts. Gene expression correlated with stable versus progressive disease. [Table: see text]
A single agent, phase I pharmacodynamic study of nimotuzumab (TheraCIM-h-R3) in patients with advanced refractory solid tumors
Authors: Brade A. M. , Magalhaes J. , Siu L. , Oza A. , Lovell S. , de Borja M. , Pond G. , Sherman I. , Hedley D. , Chen E. 
Published: March 2020

14030 Background: Nimotuzumab (N) is a humanized mAb against the EGFR extracellular ligand binding domain. Although well tolerated when combined with radiotherapy in previous studies and lacking usual toxicities of EGFR-targeting agents, the pharmacodynamics (PD) of N has not been elucidated. This phase I study was designed to evaluate the safety, tolerability and PD of N. Methods: Eligibility criteria included advanced solid tumors refractory to standard therapy and ECOG PS = 0 - 2. IV N was administered weekly x 6 and then every other week (6 weeks = 1 treatment cycle). Tumor, skin and liver biopsies obtained pre- and 2 and 7 weeks post-treatment were evaluated using computer-based, whole mount assessment of immunohistochemical staining. Results: Accrual was completed 21/09/06, 17 patients (11m/6f, median age 63, 13 colorectal cancer, ECOG 0:1:2 = 6:10:1, prior therapy 1:2:3+ = 2:6:9) were registered and 16 patients were treated on 4 dose levels (100, 200, 400 and 800 mg) for a total of 43 treatment cycles (1 patient deemed ineligible after registration did not receive study therapy). Treatment was well tolerated. One dose-limiting toxicity was observed (dose level 1 - grade 3 fatigue possibly attributable to N) . Skin toxicity was mild (Gr 1/2 in 7/1 patients). Confirmed stable disease was seen in 6 patients, a confirmed partial response in 1 patient with prolonged progression-free status observed in 3 patients for 5.8, 14.1 and 18.7 months (the latter two remain on study). Baseline and week 2 biopsies of tumor/skin/liver were evaluable in 12/13/7 pts. Week 7 tumor/skin/liver biopsies in initially responding or stable patients were evaluable in 6/8/6 pts. Post treatment (week 2), EGFR staining decreased in 8/12 matched tumor [mean ratio (post/pre): 0.79 range: (0.37, 1.91)], 8/13 skin [0.96 (0.40, 1.31)] and 5/7 liver [0.88 (0.62, 1.17)] biopsies. No significant relationship was detected between pre/post-treatment EGFR expression with either response or toxicity. Evaluation of downstream targets of EGFR (in tumor, skin and liver) is ongoing and will be presented. Conclusions: Overall nimotuzumab was well tolerated and exhibits mild skin toxicity. Prolonged progression free-survival was observed in 3/16 of these heavily pre-treated patients. No significant financial relationships to disclose.
Statistical considerations for a phase 0 trial
Authors: Rubinstein L. V. , Steinberg S. M. , Kummar S. , Low J. , Parchment R. , Kinders R. , Gutierrez M. , Murgo A. J. , Doroshow J. H. , Tomaszewski J. 
Published: March 2020

14038 Background: Phase ‘0’ clinical trials are small first in man studies to determine a dose or dose range which results in a desired biologic effect. Novel statistical designs are needed due to the limited number of patients and the complexities of analyzing primary pharmacodynamic endpoints. Methods: In general, the effect of the agent will be evaluated, based on a biologic endpoint(s), at two levels, the individual participant level (for a given dose amount), and the agent dose amount level (across individual participants). At the participant level, the effect is preferably defined as a dichotomous outcome. The statistical criteria should be such that the threshold is not surpassed with more than .10 probability, for a given participant, at a given dose amount, for the null hypothesis case of no true biologic effect. At the dose amount level, the effect rate is defined as the probability that a randomly chosen participant will satisfy the participant level threshold. The statistical criteria for declaring an observed effect rate to be significant should be such that the over-all probability of declaring the agent effective (summed across all dose amounts) should not exceed .10 for the null hypothesis case of no true biologic effect. A target effect rate, measured across participants, should be given, and the power to detect it, for a given dose amount, should be estimated. Ideally, there will be multiple pre-agent administration endpoint measurements, per participant, to define variability. Examples: 1. If 10 participants are accrued to a single dose amount, an observed effect rate for that dose amount could be defined to be significant if at least 2 of the 10 participants satisfy the participant threshold, yielding 85–90% power to detect a 35% effect rate. 2. If 5 participants are accrued to each of 2 dose amounts, an observed effect rate for a particular dose amount could be defined to be significant if at least 2 of the 5 participants satisfy the participant threshold, yielding approximately 90% power to detect a 60% effect rate. 3. If 3 participants are accrued to each of 4 dose amounts, an observed effect rate for a particular dose amount could be defined to be significant if at least 2 of the 3 participants satisfy the participant threshold, yielding approximately 90% power to detect an 80% effect rate. No significant financial relationships to disclose.
EPC2407, a new beta-tubulin vascular disrupting agent with potent apoptosis and cell growth inhibition
Authors: Anthony S. P. , Von Hoff D. , Whisnant J. K. , Tseng B. Y. 
Published: March 2020

14043 Background: Compounds which bind to colchicine-like sites of microtubules have contributed greatly to the armamentarium of cancer therapies. But new modes of administration of taxanes and potent new vascular disruption agent molecules such as combretastatin continue to challenge drug development for ways to improve the therapeutic index in this important class. EPC2407 is a novel 4-aryl chromene of nM anti-tumor potency; it is crossing the translational bridge based on an array of preclinical anti-tumor pharmacology and supported by multiple toxicology trials which included drug exposure data. Methods: Vascular disrupting agents demand careful preclinical workup. What we have done is summarized in the table below. This data is from cellular metabolic, cell proliferation, vascular endothelial, in vivo tumor, and animal toxicokinetic and safety studies. Results: Please see table below of the preclinical experiments. Conclusions: A Phase I clinical trial has been designed and initiated to replicate the safety margin shown by the analysis of preclinical drug exposure data. The critical safety issue for human dosing was the dose exposure which might produce the well known ECG abnormality of delayed repolarization or prolonged QTc. A dose related QTc effect was demonstrated in cynomolgus monkeys after a 2 min infusion which achieved acute plasma exposures higher than 3836 nM. These effects were dose related and persisted only through 4 short half-lives of the parent compound. Initial human analysis fails to show any prolongation of the QTc. [JW1] [JW1]THE END HERE, all else was draft. [Table: see text] No significant financial relationships to disclose.
Combination of fulvestrant and lapatinib in non-HER2-overexpressing and adriamycin-resistant breast cancer cell lines
Authors: Emde A. M. , Maslak K. , Liu H. , Reles A. E. , Possinger K. , Eucker J. 
Published: March 2020

14050 Background: We evaluated whether combination of lapatinib, a dual tyrosine kinase inhibitor against EGFR and HER2, and fulvestrant, a full estrogen receptor antagonist, is superior in EGFR and HER2 overexpressing and non-overexpressing breast cancer cell lines regarding cell growth inhibition and effects on the protein expression level on special proteins such as PDK1 and ERK1/2. Methods: MTT assay and western blot analysis were performed in the different breast cancer cell lines BT474, T47D, MCF-7 and Adriamycin resistant MCF7 cells. Incubation time was 72h. Concentration of both agents in western blot: 1x10exp-7M, in MTT assay 10exp-11M to 10exp-5M. Results: MTT assay showed a significant stronger proliferation inhibition by lapatinib and fulvestrant in BT474 cells and non- overexpressing T47D cells at a concentration of 10E-7M compared to single agent treatment. By western blot analysis, we found a synergistic downregulation of PDK1 in the combination treatment both in BT474 and AR MCF7 cells, whereas not in T47D cells. In MCF7 cells a downregulation of p-PDK1 was observed after treatment with fulvestrant alone as well as lapatinib plus fulvestrant. Regarding ERK1/2, a synergistic downregulation could be observed in AR MCF7 cells. A downregulation of a p-ERK was detected in MCF-7 cells after treatment with lapatinib, fulvestrant or both. Conclusion: A synergistic action of lapatinib and fulvestrant was observed in all 4 cell lines despite their different receptor status regarding EGFR, HER2 and ER alpha. Shadeo et al. (2005) showed different copy number profiles in these breast cancer cell lines regarding the examined pathways. We could show by western blot analysis that the combination treatment had inhibitory effect on these cell lines according to their individual up-regulated pathways. Altogether, this suggests that the combination is a promising treatment not only in EGFR and HER2 over-expressing breast cancer and that treatment effect is also dependent on up-regulated pathways more likely than receptor status. No significant financial relationships to disclose.
A randomized phase 2 trial of combretatstatin A4 phosphate (CA4P) in combination with paclitaxel and carboplatin to evaluate safety and efficacy in subjects with advanced imageable malignancies
Authors: Akerley W. L. , Schabel M. , Morrell G. , Horvath E. , Yu M. , Johnsson B. , Arbogast K. 
Published: March 2020

14060 Background: CA4P is the lead compound in a class of agents termed Vascular Disrupting Agents. Phase I studies of CA4P demonstrated toxicities that do not overlap those of chemotherapy. In vitro studies show synergistic cytotoxicity for CA4P and chemotherapy. This study was designed to assess safety, toxicity and tumor perfusion of CA4P at 2 doses when combined with paclitaxel and carboplatin at fixed doses. Methods: A one stage, randomized trial for subjects with imageable tumors by DCE-MRI for perfusion. Subjects received either 45 or 63 mg/m2 CA4P IV on Days 1, 8, and 15, then 200 mg/m2 paclitaxel and AUC 6 carboplatin on Day 2 of each 21 day cycle. After completion of 6 cycles, subjects could continue with CA4P alone. DCE-MRI was measured prior and 24 hours after the first dose of CA4P. Results: 13 subjects were accrued from 3/05–11/05. 78 cycles were administered and 1 subject continues active therapy on cycle 19. The median number of cycles administered was 6. Both 45 and 63 CA4P with paclitaxel/carboplatin were well tolerated. The most frequent adverse events are listed in Table 1 . Grade 3–4 AEs were similar between the two dose groups. Table 1 : Most Frequent AEs by CA4P Dose DCE-MRI data showed a mean reduction in blood flow for both dose groups (46% vs. 19% respectively) confirming CA4P’s tumor vascular disrupting capabilities. Tumor responses were observed and were similar between both dose groups. Best overall response through cycle 6 was 3 PR, and 6 SD. Two subjects with thyroid cancer were randomized to the low dose group and completed cycle 6. The 1st had SD and progressed after cycle 6. The 2nd achieved PR and progressed after 8 cycles. These subjects also had the greatest reduction in tumor blood flow. Ktrans was reduced by 73 and 79% 24 hours post CA4P. Conclusion: These doses of CA4P in combination with paclitaxel and carboplatin were well tolerated, demonstrated anti-tumor activity and reduction of tumor blood flow. [Table: see text] No significant financial relationships to disclose.