bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of IGF-1R inhibitor BMS-754807 on tumor glucose metabolism and proliferation in Sal-IGF xenografts by FDG and FLT- PET imaging
Authors: Chow P. L. , Ho C. P. , Kan D. , Attar R. M. , Graf Finckenstein F. , Carboni J. M. , Galbraith S. M. , Lee F. Y. , Gottardis M. M. , Krishnan B. S. 
Published: August 2020

e14501 Background: The type 1 insulin-like growth factor receptor (IGF-1R) plays a critical role in mitogenesis and survival in a variety of human tumor cells. IGF-1R is also closely related to the insulin receptor (IR). It is becoming increasingly evident that stimulation of IR or IR/IGF-1R hybrid receptors by insulin or IGF-1/2 may contribute to cancer growth, suggesting that both IGF-1R and IR may be targets for cancer therapy. BMS-754807 (‘807) is an oral IGF-1R tyrosine kinase antagonist under development that also blocks IR activity. This study explores the feasibility of fluorodeoxyglucose (FDG) and fluorothymidine (FLT) positron emission tomography (PET) as pharmacodynamic imaging biomarkers in a xenograft model. Methods: Mice were implanted with fragments of Sal-IGF, a transgenic salivary gland tumor expressing constitutively active IGF-1R. Once tumors reached desired size, the mice were divided into 3 treatment groups (vehicle, 6.25 mg/kg ‘807, & 50 mg/kg ‘807 on days 1–4). FDG-PET scans were performed on day -2 (prior to treatment), days 1 & 2 (max/min concentrations post day 1 dose), and days 4 & 5 (max/min day 4 dose). FLT-PET scans were performed on days -2, 2 (min day 1 dose), & 5 (min day 4 dose). Results: With FDG-PET imaging, a 66% reduction (P<0.05, paired t-test) in tumor SUVmean was observed at the end of the 50 mg/kg therapy (day 4) and sustained for 24h (day 5) with a concomitant reduction of 37% in tumor burden by day 5 (P<0.05). FLT-PET studies demonstrated a 45% reduction (P<0.05) in tumor SUVmean observed 24h after the end of 50 mg/kg therapy (day 5) with a concomitant reduction of 50% in tumor burden (day 5, P<0.05). Conclusions: Correlation with tumor growth inhibition suggests feasibility of FDG- PET despite IR blockade. These results support the use of both FDG and FLT PET imaging in clinical trials with ‘807. [Table: see text]
Tolerability and safety of oral neratinib (HKI-272) in Japanese patients with advanced solid tumors
Authors: Ito Y. , Hatake K. , Takahashi S. , Yokoyama M. , Suenaga M. , Ota M. , Onozawa Y. , Yamazaki K. , Hironaka S. , Boku N. 
Published: August 2020

e14505 Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor. In non-Japanese pts, neratinib was found to have clinical activity against solid tumors and dose-limiting toxicity (DLT) of diarrhea. The maximum tolerated dose (MTD) was 320 mg daily and the recommended dose (RD) was 240 mg because of the diarrhea. In this phase 1 study, the MTD was determined and safety and preliminary efficacy were assessed in Japanese pts with advanced solid tumors. Methods: Pts (3- 6/cohort) received 80, 160, 240, or 320 mg oral neratinib. Each pt participated in only 1 dose group and received single doses of neratinib followed by 1 wk of observation; pts then received daily continuous administration at the same dose. DLTs were assessed from the first single dose to the end of 14 days of continuous treatment. Pharmacokinetics (PK) will be analysed via a noncompartmental method. Tumor measurements were made at screening and at the end of every 8 weeks (2 cycles) by RECIST. Results: Preliminary data for 21 pts as of 30 Oct 2008 are presented. Pts had a median age [range] of 61 yrs [39–78], were 62% male, and had all received ≥2 prior chemotherapy regimens. Tumor types at primary diagnosis were advanced colorectal (81%), breast (14%), and gastric (5%) cancer. Median duration of neratinib treatment [range] was 10 wks [3–29].Two patients at the 320-mg dose had DLTs of diarrhea plus anorexia. Therefore the MTD was determined to be 240 mg. Neratinib-related AEs, any grade in ≥25% of pts included diarrhea (95%), fatigue (67%), anorexia (43%), nausea (43%), abdominal pain (38%), decreased hemoglobin (38%), increased AST (33%), and rash (29%). Neratinib-related AEs, grade ≥3 in ≥1 pts were anorexia (3 pts) and diarrhea (2 pts). Two pts had partial response (PR), 8 pts had stable disease (SD) ≥8 wks, 2 had SD≥16 wks, 9 had progressive disease. The 2 pts with PR had ErbB-2+ advanced breast cancer. PK analysis is still ongoing. Conclusions: In Japanese pts, the MTD for neratinb was determined to be 240 mg and the RD will be confirmed as 240 mg. Neratinib is tolerable and demonstrates preliminary antitumor activity in pts with solid tumors. [Table: see text]
Sunitinib in combination with paclitaxel and carboplatin in patients with advanced solid tumors: Updated phase I study results
Authors: Heath E. I. , Blumenschein G. R. , Cohen R. B. , LoRusso P. M. , LoConte N. , Kim S. T. , Chao R. , Wilding G. 
Published: August 2020

e14509 Background: Sunitinib (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, and RET, approved for the treatment of advanced RCC and imatinib-resistant/intolerant GIST. Safety and antitumor activity of SU in combination with paclitaxel (P) and carboplatin (C) were evaluated. Methods: Successive pt cohorts with advanced solid tumors (STs) received oral SU at 25, 37.5, or 50 mg for 2 wks during 3-wk cycles (Schedule 2/1) or for continuous 3 wk cycles (CDD schedule) with P (175–200 mg/m2) plus C (AUC=6 mg·min/mL) on day 1 of each of 4 cycles. Dose limiting toxicities (DLTs) and adverse events (AEs) were evaluated to determine the maximum tolerated dose (MTD). Response was evaluated for pts with measurable disease. Pts with clinical benefit continued on SU after 4 cycles under a continuation protocol. Results: Forty-three pts were enrolled (25 in Schedule 2/1 and 18 in CDD schedule). Median age was 58 yrs (range: 32–76), and 74% of pts had ECOG PS of 1. Tumor types included NSCLC (n=10), SCLC, esophageal, and pancreatic (n=4 of each), and other (n=21). In initial dose escalation cohorts, 4 DLTs were observed out of 23 pts (Heath et al. ASCO 2008). Based on overall tolerability, additional pts were enrolled on both schedules at SU 37.5 mg with P 175 mg/m2 plus C. In these expanded cohorts, 2 more DLTs were observed in Schedule 2/1 (Gr 4 thrombocytopenia) out of 7 pts; dose escalation and further enrollment was stopped (Table). Gr 3/4 AEs (all cohorts) included neutropenia (63%), thrombocytopenia (47%), and leukopenia (35%). Of 35 pts evaluable for response, there were 4 confirmed partial responses and 3 additional patients with unconfirmed PRs. Conclusions: SU in combination with P/C may represent a clinically useful treatment option in pts with advanced STs. The determination of MTD based on observed DLTs/tolerability is ongoing. [Table: see text] [Table: see text]
A phase I clinical trial of FOLFIRI in combination with the pancyclin–dependentkinase (CDK) inhibitor flavopiridol
Authors: Dickson M. A. , Carvajal R. D. , Shah M. , Tse A. N. , Dials H. , Cane L. M. , Schwartz G. K. 
Published: August 2020

e14511 Background: Preclinical data indicate that sequential treatment with flavopiridol (F) increases irinotecan- and 5-FU-induced apoptosis. Clinically, F showed promising activity when combined with irinotecan (Shah et al CCR 2005). Methods: We conducted a phase I trial of FOLFIRI + F every 2 weeks in patients (pts) with advanced solid tumors. Based on sequence- dependent inhibition, F was given 3 h after irinotecan but before 5-FU. Two maximum tolerated doses (MTD) were determined: MTD1 (F over 1 h) and MTD2 (F 30-min bolus + 4 h infusion). F pharmacokinetics (PK) were determined. Results: Of 74 pts treated, 63 were evaluable for toxicity and 56 for response. Pt characteristics: median age 60 (range 19–83), KPS 90 (70–90), prior regimens 3 (1–10). 39 pts received prior irinotecan. Tumor types: colorectal, gastric, HCC, GE junction, small bowel, pancreas, bile duct, breast, bladder, ovarian, sarcoma, melanoma, anal, urethral, thymic, head & neck, unknown primary. MTD1: F 80mg/ m2 with irinotecan 180mg/m2, LV 400mg/m2, 5FU: 400mg/m2 bolus + 2400mg/m2 over 48 h. Dose-limiting toxicities (DLT) were diarrhea, fatigue, neutropenia, neuropathy. MTD2: F 35mg/m2 bolus + 35mg/m2 over 4 h with the same FOLFIRI dose. DLTs were diarrhea, neutropenia, and fatigue. Clinical activity included 2 partial responses (small bowel cancer, 10.3 m; bladder cancer, 10 m) and 1 complete response (mucosal melanoma 10.3 m). 22 pts had stable disease (median 5.9 m; range 1.5–25.7 m). Clinical benefit rate (CR + PR + SD for > 3 m) was 39% (22/56). Of 25 pts with colorectal cancer, 11 had as best response SD for > 3m (median 6 m, range 4.2–15.4 m), despite failing ≥ 1 irinotecan-containing regimen. 6 of those had significant decreases (36–78%) in CEA. F PK showed interpatient variability with no significant interaction between FOLFIRI dose and F Cmax. F Cmax increased with increasing F dose. At MTDs, there was higher Cmax in pts who experienced DLT (3.48μM) vs those who did not (2.21μM). Conclusions: F can be safely given as a bolus (80mg/m2) or split dose (35mg/m2 bolus + 35mg/ m2 over 4 h) in combination with irinotecan 180mg/m2, LV 400mg/m2, 5FU: 400mg/m2 bolus + 2400mg/m2 over 48 h. Promising clinical activity is seen in mucosal melanoma and irinotecan-refractory colon cancer. (Supported by NCI R01CA67819) [Table: see text]
Phase I, pharmacokinetic, and pharmacodynamic evaluation of BNC105P, a novel anticancer agent that is both a vascular disrupting agent (VDA) and an inhibitor of cancer cell proliferation
Authors: Desai J. , Wong S. , Chong G. , Bibby D. , Leske A. , Kremmidiotis G. , Rosen M. , Rischin D. 
Published: August 2020

e14512 Background: BNC105P is a novel anticancer agent that inhibits tubulin polymerization and acts as a VDA. BNC105P is a phosphorylated parent compound which rapidly becomes the active agent BNC105. BNC105 exhibits 100-fold specificity for activated endothelial cells compared to quiescent endothelial cells. Methods: BNC105P (2.1 to 18.9 mg/m2) was given IV over 10 min on day 1 and 8 every 21 days to patients (pts) with advanced solid tumors (ECOG 0–2) and adequate organ function. The objectives were to determine safety, tolerability, MTD and pharmacokinetics (PK). A pharmacodynamic response was evaluated using DCE-MRI with two baseline and two post dose assessments (3–6, 24 h). DLTs were determined during the first 21 days. Results: 9 pts (7 M; 2 F), median age 60 years have been enrolled with one pt each at 2.1 and 4.2 mg/m2. At 8.4 mg/m2, one pt experienced Grade 2 (Gr 2) mucositis and a switch to a ‘3+3’ design occurred. No DLTs have been observed in 3 pts at 12.6 mg/m2 and 1 pt at 18.9 mg/m2. Notable toxicity includes one episode of Gr 1 febrile episode possibly related to infusion, two episodes of Gr 1 fatigue and one Gr 1 rash. PK data of BNC105 indicates a linear increase in plasma AUC levels (Table) and plasma half life of < 0.5 h. Best observed responses were SD in 2/9 pts including one pt with mesothelioma (progression at entry) with SD up to week 22 (8.4 mg/m2). At doses ≥ 8.4 mg/m2, DCE-MRI images indicate changes in tumor perfusion post-dose. Two pts at 12.6 mg/m2 had a decrease in Ktrans values of 6 and 15 % compared to baseline. Conclusions: Pharmacodynamically active doses have been achieved with plasma drug levels correlating with active preclinical plasma exposure. To date, no excess toxicity has been observed at doses up to 18.9 mg/m2. [Table: see text] [Table: see text]
Results of a phase II study to evaluate the biological effects of intratumoral (ITu) reolysin in combination with low dose radiotherapy (RT) in patients (Pts) with advanced cancers
Authors: Saunders M. , Anthoney A. , Coffey M. , Mettinger K. , Thompson B. , Melcher A. , Nutting C. M. , Harrington K. 
Published: August 2020

e14514 Background: Reolysin, a wild type reovirus serotype 3 Dearing strain, replicates preferentially in Ras-activated cancer cells. In vitro and in vivo data have shown that combining reolysin and radiation (RT) significantly increases RT-induced cytotoxicity. A completed phase I trial of ITu reolysin and RT demonstrated that the combination was well tolerated and resulted in local and systemic responses. Methods: This open-label, single-arm, multicenter Phase 2 study combined ITu reolysin with low-dose fractionated RT. 20 Gy was given in 5 consecutive daily 4 Gy fractions combined with 2 ITu injections of reolysin (1x1010 TCID50) on days 2 & 4. The primary endpoint was objective tumor response rate in treated lesions. Secondary endpoints were to evaluate: viral replication, immune response and safety. Pts with ECOG performance status ≤2, with refractory advanced or metastatic cancers were eligible. Results: 16 heavily pre-treated pts (9 male, median age 66 yrs, ECOG 0:4pts; 1:12pts) with advanced cancer: melanoma (5), colorectal (4), gastric (1), ovarian (1), pancreas (1), lung (1), cholangiocarcinoma (1), sinus (1), and thyroid (1) were enrolled since Dec 2006. Most pts had received prior chemotherapy (13 pts) or RT (5 pts). No related serious adverse effects were observed during the study. Toxicities related to treatment were Grade 1 or 2: chills, pyrexia, headache, lethargy, anorexia, vomiting, shivering, nausea, and mild injection site pain. Of 14 pts evaluable for response, 13 pts had stable disease or better in the treated target lesion. Of these, partial responses were observed in 4 pts (lung, melanoma x 2, gastric) and minor responses were observed in 2 pts (thyroid, ovarian). Antibody responses to reolysin were delayed compared to previous results with intravenous administration. Conclusions: The combination of ITu reolysin and low dose RT was well tolerated and resulted in marked responses or stabilization in the treated target lesions for most of the pts evaluated to date. Further study in the radical setting is warranted. [Table: see text]
Phase I study of MGCD265 administered intermittently to patients with advanced malignancies (Study 265–102)
Authors: Hong D. , LoRusso P. , Kurzrock R. , Maroun C. , Mehran M. , Drouin M. , Martell R. , Wheler J. 
Published: August 2020

e14516 Background: MGCD265 is an orally-available small molecule designed to inhibit c-Met, VEGFR-1, -2, -3, Tie-2 and Ron kinases. These targets are potentially relevant for the treatment of a variety of cancers. The objective of this Phase I study is to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of MGCD265 using an intermittent schedule of administration in patients with solid tumors. Methods: This is a multicenter, open-label, dose escalation study of oral MGCD265 administered on days 1–7 and 15–21 (1 week on, 1 week off schedule) of each 28-day cycle. Cohorts of 3–4 patients were enrolled per dose level, initially with dose doubling between cohorts, followed by smaller increments once grade 2 drug-related toxicity is observed. Dose limiting toxicity (DLT) was defined as: grade 4 neutropenia; grade 4 thrombocytopenia; any > grade 3 nonhematologic toxicity; severe/sustained hypertension; or any toxic effect leading to a patient missing > 4 doses of MGCD265. Treatment would continue until disease progression or toxicity. Results: Eleven patients with advanced solid tumors have been treated. Characteristics: age range 40–72; gender: 3 M/8F; ECOG: 1 (7 patients); 2 (4 patients). At dose levels of 24, 48 and 96 mg/m2, no DLTs nor grade 2 or greater drug-related AEs have been reported during cycle 1. Six patients received treatment for 2 or more cycles. Preliminary PK profile after the first dose of administration shows a dose dependent increase in AUC and Cmax (Table below) with an approximate mean half-life of 30 hours and an approximate mean Tmax of 7 hours. At the 96 mg/m2 dose, exposure was in the range of the lower end of the efficacious exposure in certain xenograft models. PD markers including plasma HGF and VEGF and shed/soluble receptors s-Met and s-VEGFR2 have been evaluated. Conclusions: Intermittent administration of MGCD265 was found to be well tolerated at doses of 24, 48, and 96 mg/m2. Treatment of patients at 192 mg/m2 is underway. [Table: see text] [Table: see text]
Bevacizumab-related hypertension: Search for underlying mechanisms
Authors: Steeghs N. , Rabelink T. J. , op ’t Roodt J. , de Koning E. , Gelderblom H. 
Published: August 2020

e14520 Background: Hypertension is a commonly observed side effect of inhibitors of VEGF/VEGFR-2 signaling such as bevacizumab. The mechanisms leading to this increase in blood pressure during anti-angiogenic therapy have not been elucidated. Recent studies suggest that functional rarefaction (a decrease in perfused microvessels) or anatomic rarefaction (a reduction in capillary density) may play an important role. The purpose of this study was to search for possible mechanisms that cause hypertension in patients treated with anti-angiogenic therapy and to confirm our hypothesis that systemic inhibition of VEGF inhibits vascular function and causes rarefaction. Methods: Patients treated with bevacizumab for any type of cancer were eligible. Measurements of blood pressure, flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD), aortic pulse wave velocity (PWV), and capillary density and diameter with sidestream dark field (SDF) imaging of the mucosal microcirculation of the lip were performed at baseline, after 6 weeks of treatment, and 3 months after discontinuation of bevacizumab treatment. Results: Fourteen patients were included in this study. During bevacizumab treatment the mean systolic and diastolic blood pressure values increased, +3.4 mmHg (p=0.406), and +5.6 mmHg (p=0.023) resp. Mean FMD showed a statistically significant decrease of -3.1% (p=0.006). Mean NMD was unchanged. After 6 weeks treatment mean PWV increased significantly +0.7 m/s (p=0.0.027). A significant reduction in capillary density was seen from 18.0 capillary loops per image at baseline to 12.7 after 6 weeks (p=0.000007). Also a significant reduction in capillary diameter was seen, from 6.9 to 5.6 μm (p=0.002). Results after discontinuation of bevacizumab treatment were not yet available. Conclusions: Rarefaction (reduction in capillary density) and endothelial dysfunction observed in this study provide a plausible mechanism for the increase in blood pressure which results from treatment with bevacizumab. No significant financial relationships to disclose.
Interest of DCE-US with quantification to demonstrate the VDA effect on vascularization in patients with advanced solid tumors treated with AVE8062
Authors: Chebil M. , Soria J. , Chami L. , Massard C. , Benatsou B. , Roche A. , Armand J. , Lassau N. 
Published: August 2020

e14522 Background: To determine the optimal time for the assessment of the perfusion in patients receiving AVE8062 (Vascular Disrupting Agent) at different doses combined with a fixed dose of cisplatin and then to correlate these results with the tumor response. Methods: Patients (pts) with advanced solid tumors, treated with AVE8062 (from 11.5 to 30 mg/m2) in combination with 75 mg/m2 cisplatin given every 3 weeks, were prospectively followed by DCE-US. DCE-US was performed before treatment, at 3 time points (0, 6 and 24 hours (h)) on Day 1 of the first (C1) and second cycle (C2), then every 2 cycles thereafter. Contrast uptake was acquired using VRI perfusion software after SonoVue bolus injection. Time-Intensity Curves (TIC) were determined using linear raw- data from CHI-Q (Toshiba) software. Peak Intensity (PI) representing the blood volume was calculated from automatic modeling of TIC. CT-scans performed before treatment and every 2 cycles were reviewed and tumor response assessed (RECIST). Results: A total of 96 DCE-US were performed in 13 pts, 11 of whom had data for both cycle 1 and cycle 2. Among these 11 patients, 8 presented with a dramatic decrease of PI and 3 with an increase of PI. At cycle 1, mean change from baseline in PI was -36% at 6h and -47% at 24h after AVE8062 infusion. Greater decreases were observed at cycle 2, -70% at 6 h and 78% at 24 h. No pt had a clinical response, but by cycle 2, the 8 pts with a decrease in PI at 24h went on to have stable disease as best response; 3 pts with increased PI 24h after their second treatment all had disease progression as best response. Conclusions: The best timing to observe the effect of AVE8062 on the PI seems to be 24 hours after drug administration at cycle 2. These preliminary results suggest that 24 hr PI at cycle 2 could be useful for determining pts who are more likely to have disease progression as best response to AVE8062. If confirmed, the assessment of PI variation may predict the clinical response to AVE8062. Further studies are needed to assess the possible predictive value of DCE-US on duration of progression-free survival. No significant financial relationships to disclose.
Plasma biomarkers predictive for disease control duration in the phase I study of E7080, a multitarget kinase inhibitor
Authors: Yamamoto N. , Yamada Y. , Nokihara H. , Goto Y. , Tanioka M. , Yamada K. , Koizumi F. , Koyama N. , Tamura T. 
Published: August 2020

e14524 Background: E7080 is an oral multi-targeted kinase inhibitor of VEGFRs, PDGFRs, FGFRs and c-kit. In the phase I study for advanced solid tumors, E7080 was repeated every 3 weeks (twice daily by 2 wks-on/ 1 wk-off). The toxicities were manageable and the preliminary antitumor activity including one partial response was observed at doses up to MTD [ASCO 2008; abstract 3527]. This study was conducted to evaluate whether the change of plasma biomarkers in the E7080 phase I study could predict the antitumor activity or the disease control duration. Methods: The treatment duration was determined as a period from the first dosing to treatment failure. Plasma angiogenic proteins and circulating endothelial cells (CEC)/ progenitor cells (CEP) were measured in blood samples collected on Days 1 (pre-dose), 8 and 15 of Cycles 1 and 2. CEC and CEP population with (+) or (-) c-kit expression were analyzed by FACS. Correlation was determined by Spearman's rank correlation coefficient (r) and test for non-correlation (p). Results: 19 (76%) out of 25 evaluable patients had PR/SD including 6 (24%) patients with the treatment duration of ≥180 days. VEGF increase and sVEGFR1 and -R2 decreases in plasma were seen with the increased dose of E7080. But these changes had no correlations with disease control. E7080 decreased c-kit(+) CEC and CEP, but not c-kit(-) population. Importantly, patients showing the decrease of c-kit(+) CEC in Cycle 1 had received E7080 treatment for significantly longer duration (r=-0.468, p=0.018). The decrease of c- kit(+) CEC diminished during treatment-off for final 7 days in Cycle 1 and repeatedly decreased in Cycle 2 treatment. The decrease of c- kit(+) ratio in CEP correlated with the increase of plasma SCF (r=-0.457, p=0.021) and SDF1 (r=-0.466, p=0.018), but not with VEGF or thrombopoietin. Conclusions: The change of c-kit(+) CEC correlated with the disease control duration in the phase I study of E7080. SCF and SDF1 may play a role in c-kit(+) CEP accumulation. C-kit(+)-selective changes of CEC could be a candidate biomarker to predict the disease control duration in anti-angiogenic therapy of E7080. [Table: see text]