bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diurnal rhythms (DR) in gene expression in human oral mucosa: Implications for gender differences in toxicity, response and survival and optimal timing of targeted therapy (Rx)
Authors: Bjarnason G. A. , Seth A. , Wang Z. , Blanas N. , Straume M. , Martino T. A. 
Published: March 2020

2507 Background: DR in processes relevant to oncology, including cell cycle, apoptosis, and angiogenesis, have been demonstrated (Nat Rev Cancer 3:350, Cancer Res 63:7277). In rodents, 10–20% of the genome has a 24-hour (h) rhythm in RNA expression (Cell 109:307). A molecular clock consisting of transcription/translation feedback loops of clock-genes controls this rhythmicity (Nat Rev Neurosci 4:649). We studied, for the first time, daily whole genome RNA expression patterning in healthy human volunteers. Methods: RNA samples extracted from oral mucosa biopsies (bx) obtained every 4h over 24h (6 bx) from 5 males (M) and 5 females (F) were subjected to microarray analysis (Affymetrix HG_U133_Plus2 chip, 54,679 transcripts). COSOPT, designed for circadian microarray time series analysis (Methods Enzymol 383: 149) was used to detect genes with significant rhythms (pMMC-Beta = 0.1). Expression patterns were visualized in GeneSpring GX7.3 (Agilent) and validated by real-time PCR and ANOVA. Results: There were 801 and 810 rhythmic genes in M and F respectively, with most genes peaking at 4AM or 4PM in M but at 6AM or 11AM in F. Only 90 rhythmic genes (including core clock-genes and clock controlled genes) were common to M and F, with over 700 genes only rhythmic in M and not in F and vice versa. The profiles of clock- genes and clock-controlled genes were inverted relative to the nocturnal rodent data. There were 75 and 67 rhythmic transcription factor genes in M and F respectively, with 28 common to both M and F. There were 71 rhythmic human cancer genes (Nat Rev Cancer 4:177) with significant gender differences. This group includes rhythmic gene products involved in signaling pathways currently targeted for cancer Rx. Conclusions: We show for the first time a significant gender specific DR in gene expression involving multiple genes of interest in oncology. This may contribute to the documented gender differences in toxicity, response and survival (J Clin Onc 24: 3562, NEJM 353:133), and can inform future trials of optimal timing of antisense Rx and other targeted Rx. The inverted DR in rodents vs. humans has implications for translating rodent data to human Rx trials. No significant financial relationships to disclose.
Phase I study of LY573636-sodium, an acylsulfonamide anti-cancer compound with a novel mechanism of action, administered as 24-hour continuous infusion in patients with advanced solid tumors
Authors: Slapak C. A. , LoRusso P. M. , Mendelson D. , Sykes A. K. , De Alwis D. P. , Wagner M. M. , Ilaria R. L. , Gordon M. S. 
Published: March 2020

2542 Background: LY573636 -sodium (hereafter referred to as LY573636 ) is a novel anti-cancer compound that induces apoptosis by a mitochondrial-mediated mechanism. Methods: A phase I study was conducted to determine the maximum tolerated dose and pharmacokinetic (PK) profile of LY573636 administered as a 24-hour continuous intravenous (IV) infusion every 28 days. Results: 26 patients (pts) were enrolled on study, 12 males and 14 females, with a median age of 57 (range: 41–74). LY573636 was dose-escalated using a flat dosing-based schema. No dose limiting toxicity (DLT) was observed until the 2,000 mg cohort, when 1 pt developed CTCAE grade 3 hyperbilirubinemia. PK analysis revealed that LY573636 had a low total plasma clearance (CL = 0.02L/hr) and a terminal elimination half-life of approximately 340 hours due to high-albumin binding (∼99%). One additional pt in the 2,000 mg flat dose cohort developed grade 4 thrombocytopenia in cycle 2, possibly due to the accumulation of albumin-bound drug. Based on these PK and clinical data, the dosing strategy was revised to a flat loading/maintenance dose regimen of 2,500 mg/1,750 mg every 28 days by 24-hour continuous IV infusion. Thirteen pts were treated at this dose level, with 1 pt experiencing a DLT of grade 4 leukopenia. Overall, 8/26 pts had stable disease (SD) after 2 or more cycles, with 2 pts still on study. Five pts received ≥ 4 cycles (SD ≥ 4 mos), including heavily pre-treated pts with ovarian cancer, soft tissue sarcoma, and uterine cancer. Conclusions: LY573636 is a novel anti-cancer compound with a unique mechanism of action. The most common DLT was BM suppression. Because of the long half-life of LY573636 , and the encouraging findings of a separate IV bolus phase 1 study, an IV bolus-based regimen will be taken forward into phase 2 study. No significant financial relationships to disclose.
A phase I study of a novel taxane, TL310, orally administered every week in patients (pts) with advanced solid tumors
Authors: Glasspool R. M. , Boddy A. V. , Evans T. R. , Griffin M. J. , Anthoney A. , Barker A. , Longley R. E. , Twelves C. J. , Edwards C. J. , Wilcox H. E. 
Published: March 2020

2544 Background: TL310 is a novel, oral taxane with potent pre-clinical activity in taxane-resistant model systems. This is the first study to evaluate the safety, tolerability and pharmacokinetics (PK) of TL310 in pts with advanced refractory solid tumors. Methods: Pts with adequate hematologic, renal, and liver function received TL310 administered orally on days 1, 8 and 15 of a 28-day cycle. Pts were continuously assessed for safety and dose-limiting toxicity (DLT) was based on first cycle toxicity only. A rapid dose escalation schedule was used (1 pt per dose level until ≥ grade 2 toxicity then 3–6 patients per cohort). The maximum tolerated dose (MTD) was defined as the dose level below that at which ≥ 2 of 3–6 pts experienced DLT. PK sampling was performed on days 1, 2, 3–4, 8, 15, 16, 17–18, 22 of cycle one. Serial imaging with CT was performed every 8 weeks to assess response. Results: 18 patients [M=11, F=7], ECOG PS ≤ 2 were treated with doses of 5 (1 pt), 10 (1pt), 20 (1pt), 40(2pts), 80 (5pts), 120 (3pts) and 160 mg/m2 (5pts). 1 pt had grade 2 vomiting at 80mg/m2. This, and subsequent, dose levels were expanded to include 3 pts. 3 pts (2 at 80 and 1 at 160 mg/m2) vomited immediately after drug administration during cycle 1 and were replaced. 1/5 patients experienced a DLT at 160 mg/m2 with G5 neutropenic sepsis, G4 neutropenia and G4 thrombocytopenia. No other grade 3/4 toxicities attributed to study drug have occurred. Of 18 patients assessable for response, 1 had a partial response (gastric cancer) at 80 mg/m2 and 6 had stable disease for > 2 cycles (esophageal 3, melanoma 1, ovary 1, cervix 1). The maximum concentration (Cmax) increased with dose up to 120 mg/m2, but appeared to plateau (86±6 ng/ml) in 4 of 5 patients at 160 mg/m2. TL310 has a half-life of up to 80 hours, but PK were very similar on successive courses of treatment. Conclusions: TL310 can be administered orally up to 160 mg/m2 on day 1, 8, 15 of a 28 day cycle and shows promising activity at doses below the MTD. The MTD has not yet been defined and dose escalation continues. No significant financial relationships to disclose.
Phase II stopping rules employing response rates and early progression
Authors: Goffin J. R. , Tu D. 
Published: March 2020

2553 Background: Drug development in oncology has become increasingly resource intensive. Anything that might accelerate drug development would benefit patients and drug developers. Traditionally, tumour response rates (RR) have been used to assess the efficacy of new agents in phase II trials. High rates of early progression of disease (EPD) may also indicate lack of drug efficacy, and this endpoint has the potential to shorten trials compared to assessing RR alone. This work seeks to create a set of rules that will allow phase II drug assessment employing both RR and EPD. Previous work on this subject suffered from insufficient power, as determined by the authors [Freidlin et al, J Clin Oncol, 20:599, 2002]. Methods: Using TreeAge Pro Healthcare software, we created a computer model that would accept specified trial parameters and determine through simulations stopping rules based on observed number of responses and EPDs to achieve the desired power and alpha error for a single-armed two-stage study with 15 patients in each stage. The null hypothesis (H(nul)) specified the response rate (rr(nul)) and early progressive disease rate (epd(nul)) that would render a drug uninteresting for further development, such that: H(nul): rr LE rr(nul) & epd GE epd(nul), where rr is that actual response rate observed and epd is the actual rate of early progression. Similarly, the alternate hypothesis (H(alt)) specified the response rate (rr(alt)) and early progressive disease rate (epd(alt)) that would render a drug interesting for further development, such that: H(alt): rr GE rr(alt) or epd LE epd(alt). (LE, less than, equal to; GE, greater than, equal to) Results: Conclusions: The simulation was able to establish stopping rules for observed number of responses and EPDs to achieve the desired error rates. Variations on the rules based on other trial sample types and design parameters will be detailed. [Table: see text] No significant financial relationships to disclose.
A physiologically-based pharmacokinetic (PBPK) and pharmacodynamic (PD) model of docetaxel (Doc) and neutropenia in humans
Authors: Florian J. A. , Egorin M. J. , Zamboni W. C. , Eiseman J. L. , Lagattuta T. F. , Belani C. P. , Chatta G. S. , Scher H. I. , Solit D. B. , Parker R. S. 
Published: March 2020

2567 Background: We have scaled our previously described murine Doc PBPK model (Florian et. al, Proc. AACR, 2006) to humans to determine if it predicts human plasma Doc concentration. The resulting human plasma Doc predictions were then coupled to a low- order neutrophil model from the literature (Karlsson et. al, Clin. Cancer Res., 2006), and individual patient absolute neutrophil count (ANC) predictions were compared with actual ANC data. Methods: Plasma Doc concentration vs. time data were obtained from 75 patients given 1-h Doc infusions and sampled out to 48 h. 67 patients received 50–75 mg/m2 q3wk, and 8 patients received 35 mg/m2 weekly. Plasma Doc concentrations were determined by LC-MS, & ANC were measured weekly during cycle 1. Human organ volumes & blood flow rates for humans were obtained from the literature and scaled based on individual patient weight. Intra-tissue exchange rates & liver clearance rate from the mouse PBPK model were used unchanged as parameters in the scaled model. The PBPK model was used to drive the ANC model, which had been developed with data from patients treated on a q3wk schedule. Simulations were performed using MATLAB, and model predictions were compared with actual data based on a weighted sum squared error metric. Results: The initial, scaled PBPK model performed well in describing actual plasma Doc concentrations during the infusion & at times after 5 h, but not at the intermediate time points. Consequently, transition rates for the “other” compartment were estimated for the human population. The updated model was more accurate in predicting human plasma Doc concentrations (mean improvement 17%; range -3 to 70%). When the scaled PBPK model was coupled with the neutrophil model, the resulting predicted neutrophil profiles agreed with those from patients dosed on a q3w regimen, but not with those dosed weekly. Conclusions: This unique PBPK/PD model allows the prediction of human plasma Doc concentrations provided the patient weight & dose are known. Further validation of the coupled PBPK/PD model, including predicted tumor concentrations, is ongoing. No significant financial relationships to disclose.
Effects of a potent CYP3A inhibitor on the pharmacokinetics and safety of enzastaurin
Authors: Musib L. , Darstein C. , Suico J. , Baldwin J. , Welch P. 
Published: March 2020

2572 Background: Enzastaurin (ENZ) targets the PKCβ and PI3K/AKT pathways to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. ENZ is metabolized by CYP3A in vitro. This study examined the potential clinical effects of a potent CYP3A4 inhibitor, ketoconazole (KETO), on the pharmacokinetics and safety of ENZ. Methods: In this open-label, fixed-sequence, three-period, crossover study (duration = 6 weeks), healthy subjects received an oral, 200- mg, single dose of ENZ (period 1); 400-mg daily doses of KETO for 4 days to assess QT (period 2); and 400-mg daily doses of KETO for 14 days, with a 200-mg single dose of ENZ given on day 4 (period 3). Plasma samples for PK analysis were collected predose and after ENZ administration in periods 1 and 3 at scheduled intervals. Results: Of the 16 women enrolled, 13 completed the study. Changes in PK parameters of ENZ and its metabolite, LY326020, in the presence of KETO are summarized in the table . No serious adverse events (AEs) occurred. A similar number of AEs possibly related to enzastaurin occurred in period 1 (6) and period 3 (7). Headache (n=4) and nausea (n=3) were more frequent in period 3, but were also the most common AEs related to KETO. Three patients had hepatic transaminase elevations, but no consistent pattern with dosing period or ENZ exposures was observed. At 4 hours post-dose, QT intervals were prolonged by a mean 5.88 (95% CI: 1.767–10.00) msec after four daily doses of KETO and by a mean 9.29 (95% CI: 5.165–13.41) msec when coadministered with ENZ. Conclusion: In the presence of KETO, plasma concentrations of ENZ and its metabolites increased significantly. ENZ alone did not increase QT intervals. Ketoconazole plus ENZ caused a slightly greater increase in QT intervals compared to KETO alone, but this very small change may not be clinically significant. ENZ was generally well tolerated, alone or with KETO. [Table: see text] No significant financial relationships to disclose.
Effect of smoking on imatinib pharmacokinetics
Authors: van Erp N. P. , Gelderblom H. , van Glabbeke M. , van Oosterom A. , Verweij J. , Guchelaar H. , Peng B. , Judson I. 
Published: March 2020

2573 Background: Smoking is a potent inducer of the cytochrome P450 1A2 isoenzyme (CYP1A2) and may therefore effect the pharmacokinetics (PK) of drugs metabolized by CYP1A2. Indeed, clinical studies with erlotinib (metabolized by CYP3A4 and also partly by CYP1A2) have shown a major increase in erlotinib clearance in smokers versus non-smokers. The effect of smoking on the PK of imatinib, which is also metabolized by CYP3A4 and partly by CYP1A2, is unknown. We aimed to study the effect of smoking on imatinib PK in order to explain a part of the interpatient variation. Methods: The effect of smoking on the PK parameters was analyzed in 34 patients with gastro-intestinal stromal tumors or soft tissue sarcoma included in the EORTC-STBSG phase I and phase II trials. This cohort included 9 smokers and 25 non-smokers. The daily smoking habits of the study patients were retrieved retrospectively from the patient’s record. PK parameters assessed with NONMEM, version V were clearance (Cl), distribution volume (V), elimination half life (T1/2) and the dose standardized area under the concentration curve (AUC). We considered a 40% reduction in imatinib exposure clinically relevant and this study is adequately powered to detect this difference. Results: The mean PK parameters in the smokers versus the non-smokers group ± SD were: Cl; 9.6 ± 5.5 L/h vs 9.2 ± 4.6 L/h, V; 216.5 ± 114.3 L vs 207.0 ± 116.9 L, T1/2; 16.1 ± 6.0 h vs 16.5 ± 6.0 h, AUC; 133.6 ± 71.0 ng.h/ml.mg vs 142.3 ± 84.0 ng.h/ml.mg. There was no significant difference in PK parameters observed between the smokers and the non- smokers. Conclusion: This retrospective study suggest that the PK of imatinib was not affected by smoking and therefore does not explain the large variation in imatinib PK. No significant financial relationships to disclose.
A randomized phase II p53 vaccine trial comparing subcutaneous direct administration with intravenous peptide-pulsed dendritic cells in high risk ovarian cancer patients
Authors: Herrin V. E. , Achtar M. S. , Steinberg S. M. , Whiteside T. L. , Wieckowski E. , Czystowska M. , Visus C. , Berzofsky J. A. , Khleif S. N. 
Published: March 2020

3011 Background: 50% of ovarian cancers carry a p53 mutation, most of which can lead to overexpression of the protein, providing a unique target for vaccine therapy. Preclinical data shows cytotoxic T-lymphocytes can be generated against wild-type peptide and can lyse tumor cells overexpressing p53. There are many methods of antigen delivery for cancer vaccines and very few comparative studies have been conducted to determine the best of these. Here we report findings for this completed study comparing two methods of vaccination. Methods: Eligible patients had Stage III, IV, or recurrent ovarian cancer and were clinically NED at study entry. Elevated CA-125 was allowed. HLA-A2.1 and overexpression of p53 were required. A wild-type epitope (264–272) with high HLA-A2.1 affinity was utilized for vaccination. Two techniques were randomly compared: subcutaneous (SQ) peptide admixed with ISA-51 and GM-CSF adjuvants or peptide-pulsed dendritic cells given intravenously (IV). Both arms received 6 million IU/m2 IL-2 SQ for ten days beginning with cycle 3. Elispot analysis was utilized to assess immunologic response, the primary endpoint. After reaching statistical significance, accrual to the more technically difficult IV arm was halted. Results: Of 21 patients enrolled, 20 have evaluable data points; 13 on the SQ arm and 7 IV. On the SQ arm, 9 of 13 (69%) patients had evidence for immunologic response. On the IV arm, 5 of 7 (71%) patients had an immunologic response. 42% on each arm experienced some grade III or IV toxicity (increased liver enzymes on the SQ arm and fatigue and lymphopenia on the IV arm), but only one patient disenrolled due to toxicity, a cardiac arrhythmia exacerbated by IL-2. Mean overall survival (to date) on the SQ arm is 70.4 months and on the IV arm is 72.9 months. Conclusions: The patients on this study were mostly heavily treated patients with short disease-free intervals, yet we demonstrated that immune responses can be generated against a wild-type protein epitope in a significant number of patients. Both vaccine approaches were similarly effective. This result should lead to a trial of early vaccination in high- risk patients to potentially delay or even prevent recurrence. No significant financial relationships to disclose.
Comprehensive analysis of melanoma antigen specific T cell repertoire: EPIMAX (EPItope MAXimum)
Authors: Palucka A. , Banchereau J. , Vence L. , Connolly J. , Fay J. , Ueno H. 
Published: March 2020

3016 Background: We have demonstrated in phase I clinical trial treating 20 patients with metastatic melanoma that dendritic cells (DCs) loaded with killed allogeneic tumor cells can elicit immune and clinical responses. Loading DC vaccines with killed allogeneic tumor cells allows: i) presentation of antigens via both MHC class I and class II, ii) strong help, iii) applicability to any cancer, and iv) loading tumor antigen independent of HLA haplotype of the patient. However, this renders the immunomonitoring step complex as the antigens and their restriction elements are unknown. To address this issue, we developed EPIMAX. Methods: EPIMAX measures simultaneously cell proliferation and secretion of multiple cytokines that distinguish Type 1, Type 2 cytokines and IL-10 secretion using Luminex. Briefly, 5x105 CFSE-labeled PBMCs are plated with peptide pools of overlapping peptide libraries from appropriate antigens. After 48hrs, supernatants are transferred for cytokine determination. After an additional 6 days of culture, cell proliferation is analyzed by flow cytometry after staining for surface markers CD4 and CD8. Results: We demonstrated that EPIMAX permits us to assess: i) Specificity and breadth of induced immune responses, ii) Type of induced immunity (Type I, Type II, IL-10), and iii) Function of specific T cells as measured by cytokine secretion and proliferation. To date 8 patients with stage IV melanoma were analyzed at baseline and after vaccination with DCs loaded with killed allogeneic melanoma cells. We assessed epitopes derived from MART-1, NY-ESO1, TRP-1 and gp100. Analysis of CD8+T cells: We have identified 15 melanoma antigen CD8+T cell epitopes in 8 patients. These include: three Tc0 epitopes (IL2), and twelve Tc1 epitopes triggering IP-10 secretion. Analysis of CD4+T cells: We have identified 15 melanoma antigen CD4+T cell epitopes in 5 patients. These include: nine Th0 epitopes (IL2), four Th1 epitopes (IFNγ) and two Th2 epitopes (IL13). Finally, we analyzed secretion of IL-10 and found thus far IL-10 secreting CD4+T cells in seven patients. Further studies demonstrated that these T cells have regulatory function. Conclusions: EPIMAX permits comprehensive assessment of melanoma antigen specific T cell repertoire. No significant financial relationships to disclose.
XmAb Fc engineered anti-CD19 monoclonal antibodies with enhanced in vitro efficacy against multiple lymphoma cell lines
Authors: Zhukovsky E. , Chu S. , Bernett M. , Karki S. , Dang W. , Hammond P. , Edler C. , Polder N. , Chan C. , Jacinto J. , Desjarlais J. 
Published: March 2020

3021 Background: CD19 is a pan-B cell surface receptor that is expressed from early stages of pre-B cell development through terminal differentiation into plasma cells. It is an attractive immunotherapy target for cancers of lymphoid origin since it is also expressed on the vast majority of Non-Hodgkin Lymphoma (NHL) cells as well as some leukemias. Despite major improvements in response rates and progression free survival the majority of NHL patients will relapse under the current combination chemotherapy with anti-CD20. Thus salvage regimens with new non-cross resistant antibody therapies are warranted. Methods: We employ our XmAb antibody engineering technology to increase the affinity of IgG antibodies for Fc gamma receptors (FcγR), improve the effector function of antibodies, and significantly increases their antitumor potency; we also we humanize and affinity mature such antibodies. Results: The XmAb technology was applied to a humanized anti-CD19 antibody to engineer a variant with significantly enhanced (10- to 100-fold) antibody-dependent cell-mediated cytotoxicity (ADCC). The resulting XmAb CD19 variant was assayed for ADCC against multiple cell lines representative of follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), B-cell acute lymphoblastic leukemia (B-ALL), mantle cell lymphoma (MCL), hairy cell leukemia (HCL), chronic myelogenous leukemia (CML), and Burkitt’s lymphoma (BL). The ADCC activity of the XmAb CD19 was in striking contrast to a wild type IgG1 version of the antibody that mediates little ADCC. Moreover, ADCC potency and efficacy of the anti-CD19 Fc variant antibody were superior to that of rituximab: CLL - 10- and 1.5-fold higher, ALL - 10- and 100-fold higher, and HCL - 6- and 1.2-fold higher, respectively. Further, we observed no correlation between ADCC and antigen expression based on the measured cell surface density of CD19 for these cell lines. Conclusions: The increased affinity for FcγRs exhibited by the anti-CD19 Fc variant antibody overcomes much of the dependence of cytotoxicity on surface antigen density. Our data suggest that the anti-CD19 Fc variant antibody engineered for increased effector function could be a promising next-generation NHL immunotherapeutic. No significant financial relationships to disclose.