bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antitumor activity of a new cholesterol derivative (24-ethyl-cholestane- 3β, 5α,6α-triol) in solid tumors
Authors: Habib N. , Daaboul H. , Hajj G. , Jabbour A. , Kassem N. 
Published: August 2020

e13541 Oxysterols are oxygenated derivatives of cholesterol. They have nuclear receptors and have been shown to pass cell membranes and the blood-brain barrier at a faster rate than cholesterol itself. In addition, oxysterols have been ascribed a number of important roles in connection with cholesterol turnover, atherosclerosis, apoptosis, and necrosis. Oxysterols have been shown to have antitumor effects on experimental models. These compounds however may be toxic and to our knowledge, although some derivatives have been tested in animals, none have reached the clinical level. 24-ethyl-cholestane- 3β,5α,6α-triol is a new oxysterol developed in our lab. An oral form of this compound has been tested in mice and rats and has shown neither acute nor chronic toxicity. It has also been tested on animal tumor models and on human cancer xenografts. The results of these tests were very promising showing an anti-tumor activity on a panel of tumor cell lines. Our experiments on humans have shown no toxicity for this drug. Many patients with a variety of solid tumors all of whom have received many lines of chemotherapy and considered refractory to any conventional therapy have received this new drug. We observed in most of these patients a rapid and dramatic improvement in their quality of life and a fast pain control. Some patients could stop taking high doses of opioids within 1 or 2 days. A high rate of clinical benefit has also been observed in a variety of solid tumors including lung, breast, pancreatic, ovarian and uterine cancers, associated in some cases with a sharp decrease in tumor markers. Some patients with brain tumors (glioblastomas) have also responded to this therapy. No significant financial relationships to disclose.
The comparison of epirubicin-treated MCF-7 mammosphere cells to the treated monolayer cells
Authors: Huang M. , Zhang F. , Xu Y. , Wang H. , Lin S. , Zhang Y. 
Published: August 2020

e13542 Objective: To explore the different effects of epirubicin on the MCF-7 mammosphere cells and the monolayer cells. Methods: MCF-7 cells were cultured in suspension to generate primary mammospheres. The inhibitory effects of epirubicin on MCF-7 mammosphere cells and the monolayer cells by were measured by MTT assay. The change of CD44+CD24- expression and cell cycle distribution in MCF-7 mammosphere cells and the monolayer cells under epirubicin condition was analyzed by flow cytometry. Results: The cell inhibition was lower in MCF-7 mammosphere cells than that in the monolayer cells when induced by the same concentration of epirubicin (>100 ng/ml),(P<0.01). The CD44+CD24- expression was significantly higher in MCF-7 mammosphere cells than that in the monolayer cells under 400 ng/μl epirubicin for 72 h, (22.8% ± 4.8% Vs 3.3% ± 0.8%),(P<0.01). The cell cycle indicated that MCF-7 mammosphere cells had higher proportion of G0/G1 phase than the monolayer cells, (74.33% ± 3.20% Vs 53.40% ± 3.45%) (P<0.01). Epirubicin had little effect on the G0/G1 phase of MCF-7 mammosphere cells and the monolayer cells, but the S phase and G2 phase was not the case. Conclusion: Epirubicin had lower inhibitory effects on MCF-7 mammosphere cells and it can be used to enrich breast cancer stem cell. Epirubicin had lower effect on the G0/G1 phase of MCF-7 mammosphere cells as compared with control. No significant financial relationships to disclose.
Clinical benefit of catumaxomab in malignant ascites in patient subpopulations in a pivotal phase II/III trial
Authors: Parsons S. , Hennig M. , Linke R. , Klein A. , Lahr A. , Lindhofer H. , Heiss M. 
Published: August 2020

e14000 Background: Parsons et al. (ASCO 2008) reported the results of a pivotal phase II/III trial in patients with malignant ascites due to epithelial cancer. Treatment with the trifunctional antibody catumaxomab resulted in a clinically relevant prolongation of puncture-free survival, defined as the time to the next therapeutic puncture or the time to death, whichever occurred first. Malignant ascites is a typical late-stage manifestation of cancer associated with a poor prognosis and survival. Effective treatment options are limited. It is thus of special interest if all patient subgroups derive objective benefit from treatment. Methods: A post-hoc analysis was performed on the 258 patients with epithelial tumors treated with catumaxomab + paracentesis or paracentesis alone (control) in the pivotal trial to investigate any association between the primary endpoint (puncture-free survival) and the primary tumor, metastases, or other prognostic parameters. Results: Puncture-free survival was lower in patients with non-ovarian vs ovarian tumors and those with a poor prognosis (metastases vs no metastases, elderly vs younger, or low vs serum protein level). However, there was always a statistically significant treatment effect for catumaxomab compared with the respective control group (p≤0.0001, log rank test, for all comparisons) (see table). Conclusion: Catumaxomab demonstrated a significant clinical benefit in patients with malignant ascites independent of the primary tumor or other prognostic factors. Therefore, catumaxomab could be considered as a treatment option for patients with a poor prognosis. [Table: see text] [Table: see text]
Association of copy number variants in colorectal liver metastases with 5-fluorouracil resistance
Authors: Watson R. G. , Muhale F. , Thorne L. , Yu J. , O’Neil B. , Hoskins J. M. , Myers M. O. , McLeod H. L. , Auman J. T. 
Published: August 2020

e14502 Background: Resistance to 5-fluorouracil (5-FU) represents a major contributor to cancer-related mortality in advanced colorectal cancer patients. Previous work has shown that thymidylate synthase (TYMS) copy gains were associated with significantly shorter survival, while increased expression of thymidine phosphorylase (TP) led to greater sensitivity to 5-FU in vitro. We assessed TYMS and TP copy number in colorectal liver metastases from untreated patients and patients treated with 5-FU in an effort to elucidate the underlying molecular mechanisms for 5-FU resistance. Methods: Liver metastases were procured from 59 patients who had received 5-FU within 6 months preceding liver resection (treated samples) and from 46 patients who had received no 5-FU treatment in the 6 months prior to their liver resections (untreated samples). DNA copy number of TYMS and TP was evaluated in frozen colorectal liver metastases using quantitative real time PCR. Results: For TYMS, 8.9% of the treated samples showed copy number gain, as compared to 4.8% of the untreated samples. Loss of TYMS was rare, with only 1 and 2 occurrences seen in the treated and untreated samples, respectively. For TP, both groups exhibited similar copy number gains (25% for treated, 29% for untreated); however, a greater proportion of the treated samples exhibited loss of TP (20% vs. 10%). Collectively, the treated samples have a much higher incidence of genetic alterations potentially associated with resistance (TYMS gain or TP loss) than untreated samples (30% vs. 10%, p = 0.03 Fisher exact test). Conclusions: Colorectal liver metastases treated with 5-FU exhibit DNA copy variants that may reduce 5- FU's efficacy. Our data suggest that these genetic alterations may have important implications for the management of advanced colorectal cancer patients with recurrent disease. No significant financial relationships to disclose.
A phase I trial using patupilone (epothilone B) and concurrent radiotherapy for CNS malignancies
Authors: Fogh S. E. , Machtay M. , Werner-Wasik M. , Curran W. , Bonanni R. , Mallon G. , Axelrod R. , Andrews D. , Dicker A. 
Published: August 2020

e14504 Background: Based on pre-clinical data indicating the radiosensitizing potential of Epothilone B, this study was designed to evaluate the toxicity and response rate of patupilone (EPO906), an anti-microtubule stabilizing agent, with concurrent radiotherapy in the treatment of patients with CNS malignancies. Methods: This phase I study evaluated the toxicities associated with patupilone in combination with radiotherapy for the treatment of CNS malignancies in order to establish maximum tolerated dose (MTD). Eligible patients had recurrent gliomas (10), primary (5), or metastatic (17) brain tumors. Dose escalation occurred if no dose limiting toxicities (DLT) defined as any Grade 4–5 toxicity or Grade 3 toxicity requiring hospitalization or interruption of radiation therapy. Results: A total of 32 patients were enrolled. Five patients were treated with weekly patupilone at 1.5 mg/m2, 4 patients at 2.0 mg/m2, 4 patients at 2.5 mg/m2 and one patient at 4mg/m2. Based on sponsor recommendations, the protocol was changed to a q-3 week dosing schedule with a starting dose of 6 mg/m2. Seven patients were treated in the 6 mg/m2 group, 6 patients in the 8 mg/m2 cohort and 5 patients in the 10 mg/m2 group. Radiation treatment was determined by the patient's diagnosis. Primary CNS malignancies received a median dose of 60 Gy in 1.8–2.0 Gy fractions. CNS metastases received whole brain radiation with a median dose of 37.4 Gy in 1.8–2.5 Gy fractions and patients with recurrent gliomas received stereotactic radiotherapy with a median dose of 37.5 Gy in 2.0–3.5 Gy fractions. No DLTs were observed in patients who received weekly patupilone or in the 6 mg/m2 q3wk cohort. One DLT (pneumonia/infection without neutropenia) was observed at the 8 mg/m2 q3wk group. In the subsequent dose level (10 mg/m2), two grade 4 DLTs occurred (renal failure and pulmonary hemorrhage) making 8 mg/m2 q3wk the MTD and recommended phase II dose. Median overall survival was 12 months for recurrent gliomas, 15 months for primary brain tumors and 4 months for CNS metastasis. Conclusions: Combined with a variety of radiation doses and fractionation schedules, concurrent patupilone is well tolerated and safe with a MTD of 8 mg/m2 q3wk. A phase II study to characterize efficacy should be considered. No significant financial relationships to disclose.
Phase I/II trial of oncolytic reovirus (Reolysin) in combination with carboplatin/paclitaxel in patients (pts) with advanced solid cancers
Authors: Karapanagiotou E. , Pandha H. S. , Hall G. , Chester J. , Melcher A. , Coffey M. , de Bono J. , Gore M. E. , Nutting C. M. , Harrington K. J. 
Published: August 2020

e14519 Background: Reolysin, a wild type reovirus (Dearing strain), replicates preferentially in Ras-activated cancer cells. Preclinical data have demonstrated synergistic tumor kill when reolysin is combined with standard chemotherapies including platinum agents and taxanes, justifying the clinical evaluation of this drug combination. Methods: Pts were initially treated in an open-label, dose-escalating, phase I trial and received iv reolysin, d1–5, iv carboplatin (AUC5), d1, and paclitaxel (175mg/m2), d1, qw3. Reolysin was administered at a starting dose of 3x109 TCID50 and then increased to 1x1010 and 3x1010 TCID50 in cohorts of 3 pts. Primary endpoints for the dose escalation trial were to determine the maximum tolerated dose, dose limiting toxicity (DLT) and to recommend a dose for phase II studies. Secondary endpoints were to evaluate pharmacokinetics, immune response and anti-tumour activity. The primary endpoint for the phase II expansion cohort in head and neck (H&N) pts is to characterize response rate. Results: 17 heavily pre-treated pts (11 M, median age 55 yrs) with advanced cancer: H&N (10), melanoma (4), peritoneal/endometrial cancer (2), and sarcoma (1) have received 82 cycles of treatment to date; 4 pts are still on study. There were no DLTs in the dose escalation. Toxicities were mainly grade 1 and 2 and included: nausea, fatigue, vomiting, myalgia, fever, neutropenia, lymphopenia, thrombocytopenia and hypotension. This combination resulted in a blunting of antiviral immune response as compared to monotherapy virus. Response rates in 15 evaluable patients were partial response (PR) (4 pts), stable disease (SD) (6 pts) and progressive disease (5 pts). Of note, all PRs and 4/5 SDs were in H&N disease. Conclusions: The combination of reolysin and carboplatin/paclitaxel was well tolerated and resulted in disease control in the majority of pts. Significant responses in refractory H&N pts recommended this combination for phase II evaluation. Enrollment is ongoing and randomized studies are planned. [Table: see text]
Development of radiolabeled mapatumumab and imaging in solid tumor patients who are treated with gemcitabine, cisplatin, and mapatumumab
Authors: Oldenhuis C. , Dijkers E. C. , Duiker E. W. , Fox N. L. , Klein J. L. , Gietema J. A. , Brouwers A. H. , Lub-de Hooge M. N. , de Vries E. G. 
Published: August 2020

e14521 Background: Mapatumumab is a fully human agonistic monoclonal antibody (mAb) to the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1). Mapatumumab combined with gemcitabine and cisplatin increased cytotoxicity in preclinical models and was safe in a phase 1 study. To study its biodistribution, 111Indium (111In) labeled mapatumumab was developed for γ-camera imaging and tested in mice. Subsequently, 111In-mapatumumab scintigraphy was performed in patients (pts). Methods: Mapatumumab was labeled with 111In. Labeling efficiency, radiochemical purity, stability and binding properties were determined in vitro. Biodistribution was studied at multiple time points in nude mice bearing human xenografts (SKBR3 or SW948). Tissue activity was expressed as % injected dose/gram tissue (%ID/g). In a feasibility study, gemcitabine 1250 mg/m2 IV on days 1 and 8, cisplatin 80 mg/m2 IV and mapatumumab 20 mg/kg on day 1 was administered to advanced solid tumor pts every 21 days. In cycles 1 and 3, pts underwent γ-camera imaging directly, and at day 1, 3, and 6 after 150 MBq 111In-mapatumumab IV (planar and single-photon emission computed tomography (SPECT)). Results: Labeling efficiency was 92.0% and radiochemical purity 96.0%. 111In-mapatumumab was stable in serum for 1 week at 37°C and specific TRAIL-R1 binding was maintained after labeling. In mice, high uptake was seen in liver (8.14 ± 0.75 %ID/g), kidneys (16.30 ± 1.75 %ID/g), spleen (7.25 ± 2.64 %ID/g) and bone (5.68 ± 1.31 %ID/g), with a maximum 24–72 hours (h) after tracer injection. Maximum uptake in the xenografts was observed after 72 h (7.55 ± 3.54 %ID/g for SKBR3 and 6.21 ± 2.03 %ID/g for SW948). Five pts have been enrolled in the ongoing clinical study. Known tumor lesions (by CT-scan) showed variable tracer uptake in 3 pts, while within pts not all known tumor lesions were positive on SPECT. Conclusions: Mapatumumab can be efficiently radiolabeled for clinical use. Preliminary results show that mapatumumab scintigraphy identifies some but not all tumor lesions in pts. This is the first demonstration that mAb targeting a TRAIL-R distributes to tumor tissues in patients and could potentially guide mapatumumab therapy. [Table: see text]
Population pharmacokinetic (PK)/pharmacodynamic (PD) modeling and simulations for exposure‐;tumor response relationships: Motesanib in a phase II thyroid cancer (TC) trial
Authors: Lu J. , Claret L. , Sutjandra L. , Kuchimanchi M. , Stepan D. , Bruno R. , Melara R. , Sun Y. 
Published: August 2020

e14528 Background: Motesanib is a highly selective, oral inhibitor of VEGF receptors 1, 2, and 3; PDGFR; and Kit that is being investigated for its antitumor activity. In a phase 2 monotherapy study, a response rate of 14% (per RECIST) was observed in patients (pts) with differentiated thyroid cancer (DTC; NEJM 359:31–42, 2008) compared with 1% in pts with medullary TC (MTC; Endocr Soc Ann Meeting 2007, abstract OR39–3). We evaluated the relationship between motesanib PK and tumor response, investigated whether differences in PK between MTC and DTC pts contributed to the observed difference in response, and simulated tumor response with different dose regimens in pts with TC. Methods: Data from the phase 2 TC trial were used for PK/PD modeling. The study enrolled 93 DTC and 91 MTC pts who received motesanib 125 mg once daily (QD). Motesanib concentrations were fitted to a 2- compartment population PK model. Estimates of pts’ PK parameters were used to calculate concentration and steady-state area under the curve values for motesanib, which were used as the exposure measures in population PK/PD modeling (ie, longitudinal exposure-tumor response modeling of drug effect on tumor growth dynamics). Monte Carlo simulations were used to evaluate the potential effect of doses other than 125 mg QD (75 mg and 100 mg QD) on tumor response in TC pts. Results: Clearance in MTC pts was 40% faster than in DTC pts (74 vs 44 L/h). The fit was significantly improved (P<0.001) when exposure instead of dose was used in the model. The exposure-tumor response model that incorporated the difference in exposure described change in tumor size well in both MTC and DTC populations. Clinical trial simulations using the preliminary model based on week 24 data predicted that DTC pts would achieve 19.7%, 15.7%, and 11.3% reductions in tumor size at week 24 following doses of 125 mg QD, 100 mg QD, and 75 mg QD, respectively. The actual change in median tumor size at week 24 following 125-mg QD dosing in DTC pts included in the PK/PD analysis was 17.9%. Conclusions: The use of 125 mg QD motesanib in DTC pts was supported by PK/PD modeling and Monte Carlo simulations. Differences in PK may explain the difference in tumor response observed in MTC and DTC patient populations. [Table: see text]
A modeling framework to simulate motesanib efficacy in thyroid cancer
Authors: Claret L. , Lu J. , Sun Y. , Stepan D. , Bruno R. 
Published: August 2020

e14553 Background: Motesanib is a highly selective, oral inhibitor of VEGF receptors 1, 2, and 3; PDGFR, and Kit with antiangiogenic and direct antitumor activity. A modeling framework that simulates clinical endpoints, including objective response rate (ORR; per RECIST) and progression-free survival (PFS), was developed to support clinical development of motesanib. This study evaluated the framework using results from a trial of motesanib in thyroid cancer (TC). Methods: Models for tumor growth inhibition (J Clin Oncol 24[18S]:abstract 6025, 2006) with drug effect driven by area under the curve (AUC) (as predicted by a population pharmacokinetic model), overall survival, and probability and duration of dose reductions were developed based on data from 93 differentiated TC (DTC) and 91 medullary TC patients who received motesanib monotherapy (125 mg once daily [QD]) in a phase 2 study (Horm Res 68[suppl 3]:28–9, 2007; NEJM 359:31–42, 2008). The full simulation framework was assessed in predicting dose intensity (starting dose of 125 mg QD), tumor size over time, ORR, and PFS. Dose-response simulations were performed in DTC patients. Results: Survival times followed a Weibull distribution with ECOG performance status, baseline tumor size, and change in tumor size from baseline at week 7 as predictors. The probability of dose reductions was dependent on time and AUC. Time to event Weibull models predicted the duration of dose reductions and dose interruptions. The models correctly predicted median daily exposure intensities up to week 24. The predicted ORR in DTC patients was 15.0% (95% prediction interval [PI], 7.5%-23.7%) compared with the observed ORR of 14.0%. Predicted median PFS was 40 weeks (95% PI, 32–49 wk) compared with the observed median PFS of 40 weeks. Dose- response simulations confirmed the appropriateness of 125-mg QD dosing in DTC: the modeling framework predicted no clinically relevant improvement in PFS would be obtained by dose intensification. Conclusions: This modeling framework (dose reduction/tumor growth inhibition/survival) will be an important tool to simulate clinical response and support clinical development decisions. Further evaluation of the model using additional datasets will be required. [Table: see text]
LX1032: A potential new therapy for carcinoid syndrome (CS)
Authors: Pappas C. , Turnage A. , Frazier K. S. , Liu Q. , Brown P. 
Published: August 2020

e14555 Background: Patients with metastatic CS experience a variety of symptoms due to increased serotonin (5-HT) produced by metastatic GI tumor cells. The enzyme tryptophan hydroxylase (TPH) catalyzes the rate-limiting step in the synthesis of 5-HT. Reducing 5-HT synthesis by TPH inhibition represents a new mechanism for potentially managing symptoms associated with CS. LX1032 is a novel, orally bioavailable TPH inhibitor designed to afford systemic exposure without affecting 5-HT synthesis in the CNS. Preclinical studies of LX1032 in multiple species confirmed systemic inhibition of 5-HT synthesis without changes in brain 5-HT levels. Methods: Single (n=47 subjects) and multiple (n=40 subjects) ascending dose studies with LX1032 were completed in normal volunteers; 24-hr urinary 5-HIAA and blood 5-HT were measured as biomarkers of 5-HT metabolism. Results: LX1032 produced a significant dose-dependent reduction in urinary 5-HIAA and blood 5-HT levels, with maximal reductions observed at doses at or above 500 mg, once daily, in the 14 day multiple ascending dose (MAD) study; the mean change from baseline in blood 5-HT was -30% for the 1500 mg (500 mg TID) dose group. Single doses up to 500 mg were well tolerated with no evidence of dose limiting toxicity or tolerability; GI related adverse events (nausea, emesis, and diarrhea) started to emerge at the 1,000 mg dose level and became dose-limiting at the 1,500 mg single dose level. Multiple doses were well tolerated at all dose levels up to 1.500 mg (500 mg TID). Adverse events (AEs) were mild to moderate and no serious AEs occurred; a dose-dependent, mild increase in hepatic transaminase levels was observed in the MAD study. Conclusions: Inhibiting TPH, and thereby reducing peripheral 5-HT production, represents a potential new approach for managing symptoms in CS patients. LX1032 is a novel, orally bioavailable TPH inhibitor that significantly reduced 5-HT production at well tolerated dose levels. The favorable safety profile and observed decrease in urinary 5-HIAA and blood 5-HT levels indicate that LX1032 could be used to lower 5-HT as a potential new approach for managing hyperserotoninemia-related complications of CS, and support studies of the compound in CS patients. [Table: see text]