bluuebunny/crossref_metadata_2025_split huggingface dataset:
Global drug development in cancer: A cross-sectional study of clinical trial registries
Authors: Hertz P. , Seruga B. , Le L. W. , Tannock I. F. 
Published: August 2020

2520 Background: Clinical trials are increasingly funded by industry. High costs of drug development may lead to attempts to develop new drugs in more ‘profitable’ (i.e., more prevalent) as compared to ‘less profitable’ (i.e., more deadly) cancers. Here we determine the focus of current global drug development. Methods: We determined characteristics of phase II and III clinical trials evaluating new drugs in oncology, which were registered with WHO International Clinical Trial Registries between 01/2008 and 06/2008. Estimates of incidence, mortality, and prevalence in the more- and less-developed world (MDW, LDW) were obtained from GLOBOCAN 2002. Simple correlation analysis was performed between the number of clinical trials and incidence, mortality and prevalence per cancer site after log transformation of variables. Results: We identified 399 newly registered trials. Of 374 trials with information about recruitment, 322 (86.1%) and 39 (10.4%) recruited patients only from the MDW and LDW, respectively, while 13 (3.5%) had worldwide recruitment. 229 (58%) of trials were sponsored by industry and 324 trials were phase II (81%). Most trials (and most phase III trials) evaluated treatments for globally prevalent cancers: breast, lung, prostate, and colorectal cancer (Table). Prevalence of a particular cancer type in both the MDW and LDW correlated significantly with the number of clinical trials (Pearson r = 0.63 and 0.55; p = 0.01 and 0.03, respectively). In contrast, mortality in the MDW (Pearson r = 0.73; p= 0.002), but not in the LDW (Pearson r = 0.38; p= 0.17), correlated significantly with the number of clinical trials. Conclusions: Global drug development in cancer predominates in globally prevalent cancers, which are a more important cause of mortality in the MDW than in the LDW. Cancer sites that are major killers globally, and especially in the LDW (e.g., stomach, liver, and esophageal cancer) should receive priority for clinical research. [Table: see text] No significant financial relationships to disclose.
Population pharmacokinetics (PPK) of eribulin mesylate in patients with locally advanced or metastatic breast cancer (MBC)
Authors: Jansen M. , Vernaz-Gris M. , DesJardins C. , Wong N. , Campone M. , Cortes J. , Wanders J. , Shuster D. , Fuseau E. 
Published: August 2020

2524 Background: Eribulin mesylate (E7389) is a non-taxane microtubule dynamics inhibitor with a novel mechanism of action. A study was conducted to evaluate efficacy, safety and pharmacokinetics of eribulin at a dose of 1.4 mg/m2 for locally advanced or MBC in patients previously treated with an anthracycline, a taxane, and capecitabine. Methods: Eribulin was administered intravenously over 2–5 minutes at a dose of 1.4 mg/m2 on days 1 and 8 of a 21- day cycle to 291 patients. Four plasma samples were collected between 5 min and 120 hours after the first dose. Plasma eribulin concentrations were determined by LC/MS/MS. A total of 774 samples, from 209 patients with complete dose and sampling information were included in the PPK analysis, which was conducted using nonlinear mixed effects modeling (NONMEM). Results: Eribulin PKs were best described by a three-compartment model, with elimination from the central compartment. Distribution was rapid and elimination slow. For a typical patient with AST<ULN and CLCR=101mL/min (Cockroft-Gault), clearance (CL) was 2.98 L/h and central volume of distribution 3.72 L (V1). Volumes and inter-compartmental clearances for the two peripheral compartments were 3.60 L (V2), 126 L (V3), 2.7 L/h (Q2) and 5.6 L/h (Q3). Inter-patient variability on CL was 57%, and ranged from 26- 98% for other parameters. Residual error was 21% (proportional). CL was on average 38% lower in patients with AST>ULN and positively correlated with renal function. The covariate effects only explained a minor fraction of inter-patient variability in this single study dataset. Conclusions: Eribulin PKs were described by a three-compartment model with rapid distribution and slow elimination. Appreciable interpatient PK variability exists, a minor fraction of which was explained by measures of liver and renal function. [Table: see text]
Interethnic differences in Cyp3A4 inhibition by ketoconazole on docetaxel pharmacokinetics (PK) and pharmacodynamics (PD)
Authors: Lim Y. , Goh B. , Wang L. , Cordero M. T. , Chuah B. Y. , Lim S. , Tan S. , Buhari S. A. , Soo R. , Lee S. 
Published: August 2020

2526 Background: Use of concomitant medications that inhibit drug metabolizing enzymes such as Cyp3A4 is common and may affect chemotherapy PK/PD. We studied the effects of Cyp3A4 inhibition with ketoconazole on docetaxel PK/PD in 3 Asian ethnic groups. Methods: Two cohorts of chemonaive breast cancer patients were compared. The first cohort comprised of 95 patients (62 Chinese, 26 Malay, 7 Indian) treated with 75mg/m2 docetaxel unmodulated by ketoconazole, while the second cohort comprised of 31 patients (14 Chinese, 14 Malay, 3 Indian) treated with docetaxel 70mg flat dose modulated by oral ketoconazole, a regimen we previously reported to result in comparable docetaxel AUC as 75mg/m2 docetaxel. Plasma docetaxel concentrations were obtained at 0, 0.5, 1, 2, 5, 7 and 24 hours, and blood counts monitored on days 8 and 15 of cycle 1. Results: No significant differences in docetaxel PK or neutropenia between the races were observed in response to 75mg/m2 docetaxel unmodulated by ketoconazole (docetaxel clearance 36.4±16.9, 34.3±12.5, 44.2±27.7L/h, p=0.702; docetaxel AUC 3.6±2.7, 3.5±1.2, 2.9±1.3mg/L h, p=0.418; day 8 neutrophil count 0.5±0.6, 0.8±0.8, 0.4±0.3x109/L, p=0.138; grade 4 neutropenia 66%, 50%, 86%, p=0.157). In contrast, when docetaxel was administered with ketoconazole to inhibit Cyp3A4, inter-ethnic differences in docetaxel PK/PD were observed, with Chinese having the lowest docetaxel clearance and highest docetaxel AUC, followed by Malays and Indians (docetaxel clearance 18.6±5.7, 23.7±9.3, 30.6±6.7L/h, p=0.048; p=0.017 trend test; docetaxel AUC 4.2±1.4, 4.1±3.9, 2.4±0.5 mg/L h, p=0.048, p=0.017 trend test), although there were no statistically significant differences in body weight or surface area between the races. In concordance, Chinese patients experienced greatest degree of myelosuppression, followed by Malays and Indians (day 8 neutrophil count 0.8±0.8, 1.5±1.1, 1.7±1.1x109/L, p=0.046, p=0.013 trend test), and were more likely to develop grade 4 neutropenia (57%, 14%, 0%, p=0.024) from docetaxel + ketoconazole. Conclusions: Inter-ethnic differences in CYP3A inhibition by ketoconazole exist, and are important when evaluating the impact of concomitant medications with chemotherapy that may inhibit Cyp3A4. No significant financial relationships to disclose.
Repeatability of [18F] fluoro-deoxyglucose positron emission tomography (FDG-PET) in a multicenter phase I oncology study in patients with gastrointestinal malignancies
Authors: Velasquez L. M. , Kollia G. , Hayes W. , Galbraith S. 
Published: August 2020

2530 Background: FDG-PET is used to monitor response in multi-center oncology clinical trials. This study assessed the repeatability of select semi-quantitative standardized uptake values (SUV) as measured by double baseline FDG-PET studies in a multi-center phase I oncology trial. Methods: Double baseline FDG-PET studies were acquired on 62 sequentially enrolled patients. Tumor metabolic activity was assessed by SUVmean, SUVmax, SUVpeak and SUV70%. Compliance with image acquisition guidelines and quality assurance (QA) standards were assessed as to their effect on SUV repeatability. Summary statistics for baseline absolute differences relative to the average of baseline values and repeatability analysis were performed for all patients (full dataset) and a subset with scans that passed QA (QA dataset), analyzed in both a multi-observer (site-reported) and single-observer (central-read) setting. Intra-subject precision of baseline measurements was assessed by repeatability coefficients, intra-subject coefficients of variation, and confidence intervals for all SUV parameters. Results: No statistically significant difference was noted between the two baseline measurements for any of the SUV parameters. Mean baseline differences for SUVmean, SUVmax, SUVpeak and SUV70% were not statistically significant for either dataset, in the multi- or the single-observer setting. The intra-subject coefficient of variation of the SUV parameters ranged from 11–14% (QA dataset) to 16% (full dataset). The 95% repeatability coefficients for individual patient differences, ranged from (-25%, 34%) to (-34%, 52%) for all SUV parameters. Conclusions: Repeatability results of double baseline FDG-PET scans were similar for all SUV parameters assessed in a variety of analysis settings. The variability was acceptable even in the absence of close compliance with current consensus recommendations, supporting the use of FDG-PET imaging as a robust tumor assessment tool in multi-center oncology clinical trials. The results of this study suggest thresholds for determining metabolic response may be on the order of -35%, 50%, allowing increased confidence that a true change from baseline has occurred. [Table: see text]
A phase I study of vorinostat in combination with bortezomib in refractory solid tumors
Authors: Ninan J. A. , Bailey H. , Kolesar J. , Marnocha R. , Eickhoff J. , Wright J. , Espinoza-Delgado I. , Alberti D. , Wilding G. , Schelman W. 
Published: August 2020

2531 Background: Vorinostat (suberoylanilide hydroxamic acid, SAHA) is an oral histone deacytlase (HDAC) inhibitor that has anti-tumor activity in hematologic malignancies and advanced solid tumors. Vorinostat has been postulated to act synergistically with bortezomib at the level of aggresome inhibition with creation of reactive oxygen species. We previously conducted a study of this combination with once-daily dosing of vorinostat with bortezomib (Step A). This study (Step B) was conducted to evaluate twice daily dosing of vorinostat during administration of bortezomib to determine safety and efficacy, pharmacokinetics, and activity this combination. Methods: This study used standard eligibility criteria except patients must have had no prior bortezomib. The treatment plan initially consisted of vorinostat given orally twice daily on days 1–14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at level 1, and the protocol was amended to administer vorinostat twice daily on days 1–4 and 8–11. Starting dose was vorinostat 200 mg and bortezomib 1 mg/m2. RECIST was used to measure response. Results: 29 pts have been enrolled; 13 men and 16 women. Tumor types include: Prostate (1), Colorectal (3), Pancreatic (6), Sarcoma (7), Biliary (1), Thymus (1), GIST (2), Mesothelioma (1), ovarian (1), Neuroendocrine (1), Lung (1), Head and Neck (1), Breast (2), and Cervical (1). Grade 3–4 toxicities possibly related to SAHA at any dose level were as follows: thrombocytopenia (5), fatigue (3), increased ALT (1), elevated INR (1), anemia, (1), hypotension (1), diarrhea (3), anorexia (1), dizziness (1), nausea/vomiting (1), and hypoalbuminemia (1). The only dose limiting toxicities included elevated ALT (1), fatigue (1). There were two deaths but neither was felt to be related to the drug. The MTD for Step B was established at vorinostat 300 mg BID and bortezomib 1.3 mg/m2. Conclusions: The MTD for Step B was established at vorinostat 300 mg BID and bortezomib 1.3 mg/m2. Subjective evidence of clinical activity has been observed in patients with refractory solid tumors. These studies were supported by NCI, UO1, CA062491, SAIC 25XS097, and 1ULRR025011. No significant financial relationships to disclose.
Is positron emission tomography (PET) with FDG an early predictor of the RECIST morphological response to chemotherapy in metastatic colorectal cancer patients (mCRC)?
Authors: Hendlisz A. , Emonts P. , Covas A. , Ameye L. , Paesmans M. , Castany Prado Maria del Rosario R. , Machiels G. , Van den Eynde M. , Vanderlinden B. , Flamen P. 
Published: August 2020

2533 Background: Reliable early assessment of response would help identify active treatments and avoid unnecessary side effects. Our hypothesis was that FDG-PET metabolic changes 2 weeks after the first dose of chemotherapy predict standard morphological response. Methods: 45 mCRC patients undergoing 1st or 2nd-line chemotherapy are planned to be included in a prospective trial comparing early metabolic changes, as measured by serial FDG-PET, with the standard RECIST- based response assessment using multi-slice CT. A signed informed consent was obtained in all cases. For the lesion-by-lesion analysis, according to the EORTC recommendations, a metabolic response was defined as a ≥ 15% decrease of the standardized FDG uptake (SUVmax) on day 14. A patient was classified as having overall metabolic responsive disease if the majority or all lesions observed on the baseline PET showed a metabolic response, without any progressive lesion ( ≥25% increase). Results: At interim analysis, 28 patients (median age 65.9 yrs) were available for comparative metabolic and morphological analysis of 88 lesions. Mean number of lesions per patient was 3 (range 1–8). Patients received FOLFOX (18), FOLFIRI (9), and capecitabine (1) as first- (19) or second-line (9) treatments. Metabolic assessment showed 49 (56%) responding and 39 (44%) nonresponding lesions. The morphological response rate in metabolically non-responding lesions (5/39; 13%) was lower than in responding lesions (22/49; 45%) (p = 0.001; Fisher's exact test). A mixed metabolic response, combining responding and non-responding lesions within the same patient, was seen in 21/28 (75%) pts. A RECIST response was observed in 6/14 (43%) PET responding and in 0/14 (0%) PET nonresponding patients (p = 0.02; Fisher's Exact test). Updated results of this ongoing trial will be presented. Conclusions: Serial FDG PET seems able to identify non-responding mCRC disease after one course of chemotherapy. No significant financial relationships to disclose.
Clinical and pharmacokinetic (PK) findings in a phase I study of 7-t-butyldimethylsilyl-10-hydroxycamptothecin (AR-67) in patients with refractory solid tumors
Authors: Arnold S. M. , Horn J. , Eckardt J. R. , Rinehart J. J. , DeSimone P. , Fields S. Z. , Kee B. K. , Moscow J. A. , Houchins J. C. , Leggas M. 
Published: August 2020

2534 Background: AR-67 is a 3rd generation camptothecin analog selected for development based on the high in vitro stability of its pharmacologically active lactone form and high potency in preclinical models. This report describes the initial phase I study of intravenous AR-67 in adults with refractory solid tumors. Methods: AR-67 was infused over 1 hour for 5 days of a 21-day cycle using an accelerated titration phase I trial design. PK was performed on the 1st and 4th day of cycle 1. AR-67 was assayed with a validated chromatography method. Toxicity and response were assessed using NCI CTC (v3) grading scale and RECIST. Results: In total, 26 patients were treated at 9 dose levels (mg/m2/day): 1.2 (n=2), 1.67 (n=3), 2.34 (n=3), 3.2 (n=3); 4.5 (n=1), 6.3 (n=1), 7.5 (n=7), 8.9 (n=4) and 12.4 (n=2). Median age 62 (range 31–79), 15M/11F, median prior therapies 3 (range 1 to 6). Tumor types included: colorectal (8), non-small cell lung (NSCLC) (4), small cell lung (3), soft tissue sarcoma, (3), head and neck (2), prostate (2), and other (4). 21 subjects completed 2 or more cycles of therapy, 5 subjects received 1 cycle of therapy and had rapid disease progression (1 received 2d of drug prior to PD), 1 subject is still under treatment after 9 cycles. DLTs were observed in 5 patients: 2 of 2 at 12.4 mg/m2/day (Gr 4 febrile neutropenia, Gr 3 fatigue); 2 of 4 at 8.9 mg/m2/day (Gr 4 thrombocytopenia), 1 of 7 at 7.5 mg/m2/day (Gr 4 thrombocytopenia). Common C1 worst-grade drug related toxicities (CTC I/II % vs III/IV %): Hg (27/8), WBC (11/19), ANC (19/8), platelets (19/12), fatigue (15/8) insomnia (8/0), flushing (15//0), constipation (8/0), nausea (23/0), ALT elevation (12/0), hiccups (8/0). Antitumor activity, assessed by development of PR and SD, was observed in NSCLC, SCLC, colon and bladder cancer. The lactone form was predominant in plasma (>85% of AUC) at all time points. Clearance was constant with increasing dose and exposure (AUC) correlated with toxicity. Conclusions: AR-67 has superior lactone stability compared to approved analogs, has a predictable toxicity profile that did not include diarrhea and has activity in NSCLC. The RP2D is 7.5 mg/m2/day for 5 days of a 21-day cycle. This work was supported by R21-CA-123867 and Arno Therapeutics. [Table: see text]
Evaluation of indibulin, a novel tubulin targeting-agent, in combination with capecitabine, with mathematically optimized dose scheduling
Authors: Lewis J. J. , Galsky M. D. , Camacho L. H. , Loesch D. M. , Komarnitsky P. B. , Norton L. 
Published: August 2020

2538 Background: Indibulin (IDB) is a novel, orally available tubulin-targeting molecule that perturbs cancer cell migration and mitosis. It is active against taxane-resistant cell lines and is synergistic with 5-FU in vitro and in vivo. Two translational studies have been conducted: a Phase IB study of IDB in combination with capecitabine (CAP) in patients with advanced solid tumors, and mathematical modeling applying Norton-Simon models to breast carcinoma MX-1 xenografts to further develop Phase II dose. Methods: IDB is administered continuously starting at 400 mg BID. CAP is administered for 2 weeks with 1 week rest, starting at 875 mg/m2 BID. IDB and CAP are escalated to MTD: IDB 600 mg BID & CAP 1000 mg/m2 BID. Efficacy is evaluated every 9 weeks using RECIST. In the xenograft model indibulin is administered at dose levels from 12 to 28.7 mg/kg/day to nude mice carrying MX-1 breast carcinoma. Tumor growth is analyzed using a Gompertzian-type growth model to determine via calculus of variations the optimal schedule to maximize the efficacy/toxicity ratio. Results: To date, 7 patients have been treated and are evaluable for safety. Median age 62 yrs; ECOG ≤1; median prior therapies 3. Four patients are evaluable for efficacy and all have stable disease (3 for 6 cycles, 1 for 3 cycles). AEs include hand-and-foot syndrome (CAP), fatigue, vomiting, anorexia, and headache. Neither DLTs nor grade ≥3 AEs have been observed. In MX-1 xenografts, indibulin demonstrates linear dose-efficacy relationship over the range of 12 to 22 mg/kg. At all dose levels the first 5 days of administration are associated with a rapid accumulation of anticancer effect with lesser effects over the next 5 days to a peak of efficacy at day 10 Conclusions: IDB + CAP is well tolerated, without neurotoxicity. There is preliminary evidence of clinical activity even with this sub-optimal, continuous schedule of IDB. Formal analyses suggest that an intermittent schedule could optimize efficacy, minimize acquired resistance and allow for host recovery from drug-induced toxicity. Pre- clinical evaluation in a breast cancer model supports an intermittent dosing schedule to further increase the activity of IDB. [Table: see text]
Decitabine effect on human tumor expression of various transporters
Authors: Stewart D. J. , Nunez M. I. , Jelinek J. , Guo Z. , Hong D. , Gupta S. , Oki Y. , Issa J. , Kurzrock R. , Wistuba I. I. 
Published: August 2020

2540 Background: We reported that immunohistochemistry (IHC) expression of the platinum/copper transporter CTR1 in human tumors correlated inversely with DNA methylation and was increased by the DNA demethylating agent decitabine (D. Stewart et al, Proc ASCO 2008). Decitabine also increased expression of folate transporters in platinum-resistant cell lines that have decreased expression of folate transporters and of small GTPases such as RHOA that regulate endocytosis (D Shen et al. Br J Cancer 2004). Methods: Tumors were biopsied pre decitabine and on cycle 1 day 12 in 31 patients with refractory malignancies in a phase I study of decitabine given days 1–5 ± 8–12 each cycle. We used IHC to assess the folate carriers FOLR1 and RFC1, the glucose transporter GLUT4 and the endocytosis regulating small GTPase RHOA. Scores of 0–300 were calculated by multiplying staining intensity (0–3) by % cells staining. LINE assays were used to assess % global DNA methylation. Results: DNA methylation did not correlate with FOLR1, RFC1 and GLUT4 scores but did correlate inversely with RHOA (r= -0.58, p=0.006). Median tumor IHC scores post vs pre decitabine were 80 vs 80 (range, 0–270 vs 0–210, p=0.89) for FOLR1, 90 vs 90 (range, 15–300 vs 0–300, p=0.17) for RFC1, 0 vs 0 (range 0- 140 vs 0–70, p=0.61) for GLUT4, and 77.5 vs 50 (range, 0–210 vs 0–210, p=0.03) for RHOA. If only tumors with pre decitabine scores <150 were included, post vs pre RFC1 differences were significant (95 vs 80, p=0.004). Outcomes were similar whether or not 4 melanoma patients (in whom melanin pigment decreased the reliability of IHC scoring) were included. Conclusions: As previously noted with the copper/platinum transporter CTR1, treatment with the DNA demethylating agent decitabine was associated with a significant increase in tumor expression of the endocytosis regulator RHOA in resistant human tumors. Expression of the folate transporter RFC1 was also increased if only patients with levels that were initially low were included. This suggests that decitabine should be tested for its ability to increase uptake of chemotherapy in resistant tumors. Promoter methylation for these transporters has not yet been assessed. Supported in part by NIH grant UO1 CA062461–10 & R21 CA112895–01A1. No significant financial relationships to disclose.
Impacts of microRNA-215 on cell proliferation and chemotherapy resistance in colon cancer and osteosarcoma
Authors: Ju J. , Song B. , Wang Y. 
Published: August 2020

2542 Background: Translational control plays a key role in resistance to anti-cancer drug treatment. MicroRNAs regulate gene expression at the post-transcriptional level, mainly by interacting with 3'-UTR of their mRNA targets. Methods: miR-215 was ectopically expressed by transient transfection in both human colon cancer cell lines and osteosarcoma cell lines. The impact of miR-215 on cell proliferation, cell cycle control, chemosensitivity and down stream targets were characterized. The expression of miR-215 in colorectal cancer specimens and normal adjacent tissues was quantified by real time-qRT-PCR analysis. Results: In this study, we discovered that miR-215 down-regulates the expression of both dihydrofolate reductase (DHFR) and thymidylate synthase (TS), two of the most important chemotherapeutic targets, in human osteosarcoma U-2 OS and colon cancer HCT-116 (wt-p53) cell lines. Cells with elevated miR-215 expression are more resistant to DHFR inhibitor methotrexate (MTX) or TS inhibitor Tomudex (TDX) treatment. Ectopically over-expressing miR-215 triggers reduced cell proliferation and increased G2 arrest, at least in part, through the induction of p53 and p21. miR-215 transfected cells with reduced proliferating phenotype were resist to MTX or TDX treatment due to deceased cell cycle in S phase. The expression of endogeneous miR-215 was highly elevated in CD133+/HI CD44+/HI colon cancer stem cells compared to CD133- CD44- colon cancer cells, suggesting that tumor stem cells may be avoiding cellular and DNA damage caused by chemotherapy with a reduced proliferating phenotype mediated by certain miRNAs such as miR-215. The elevated expression of miR-215 in colon cancer stem cells with slow proliferation rate and resistance to chemotherapy further supports the role of miR-215 in cell proliferation and chemotherapy resistance. Conclusions: miR-215 may have a unique potential as a novel therapeutic target and biomarker candidate in cancer. No significant financial relationships to disclose.