bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bioavailability of sorafenib tablets administered as a liquid suspension
Authors: Lettieri J. T. , Dubowy R. , Xia C. , Rotolo C. , Zinny M. A. 
Published: August 2020

e14549 Background: Sorafenib is a multikinase inhibitor currently approved by the FDA for the treatment of advanced renal-cell carcinoma (RCC) and unresectable hepatocellular carcinoma (HCC), and by the EMEA for the treatment of HCC and advanced RCC. Sorafenib is available as a tablet formulation. Some patients who are unable to swallow tablets have suspended sorafenib tablets in a liquid for ease of administration. We performed a study to assess whether this process alters the bioavailability of sorafenib. Methods: Twenty-six healthy male volunteers were enrolled. Utilizing a randomized, crossover design, subjects received either two 200-mg intact tablets (IT) with 8 ounces water, or two 200-mg tablets disintegrated over 10 minutes in 2 ounces of water (ST), with an additional 6 ounces of water swallowed as a rinse of the dosing vessel. Doses were separated by a 10- to 14-day washout period. Following each dose, blood samples were collected at designated times up to 144 hours after dosing for measurement of sorafenib plasma concentrations. Sorafenib was assayed by a validated liquid chromatography/mass spectrometry method. The pharmacokinetic parameters area under the curve (AUC), maximum concentration (Cmax) and time to Cmax (Tmax) were assessed by noncompartmental analysis. Results: Geometric mean (percentage coefficient of variation) or median results for these pharmacokinetic assessments are shown in the table. Conclusions: The pharmacokinetics of sorafenib, when administered as a liquid suspension of tablets in water, were similar to the pharmacokinetics of tablets swallowed whole. [Table: see text] [Table: see text]
Correlation of immunological effects of anti-VEGF therapy with progression-free survival of advanced colorectal cancer patients
Authors: Manzoni M. , Rovati B. , Delfanti S. , Bencardino K. , Chatzileontiadou S. , Brugnatelli S. , Loupakis F. , Villa E. , Falcone A. , Danova M. 
Published: August 2020

e14559 Background: The clinical efficacy of Bevacizumab (BEV) in advanced colorectal cancer (mCRC) could be related not only to its well-established effect on tumor neoangiogenesis but also to a counteraction of VEGF-mediated dendritic cell (DC) abnormalities. The addition of BEV to chemotherapy (CT) may improve the number and function of blood DCs in cancer pts. We have focused on the correlation between this effect and the clinical efficacy of a BEV-based, 1st-line treatment for mCRC. Methods: Starting from January 2007 we performed a flow cytometric analysis of PB lymphocytes and DC subsets in 53 mCRC pts who had not received prior CT for metastatic disease or for whom 6 months had elapsed since adjuvant CT (M/F: 31/22, median age: 59yrs; range 32–75; ECOG PS <2), before and every 3 courses of a BEV+CT (5-FU± CPT11± Oxaliplatin) program. Biological data of the 42 evaluable pts that received all the planned treatment were correlated to both tumor response (OR) and progression free survival (PFS). Results: During treatment, DCs and their subsets showed a progressive, significant increase in absolute number, with respect to baseline, both in responder (CR,PR,SD) (67%) and in non responder pts. This effect on the DC profile was evidenced in responder pts up to 4 weeks since the last treatment course. After therapy completion, pts with PFS > 15 months (58%) showed DC and DC1 absolute number significantly higher with respect to pts with shorter PFS (p< .02). Conclusions: The recovery of blood DCs induced by 1st- line, BEV-based therapy in mCRC pts indicates a potential additional anticancer mechanism of this drug. The improvement of DC number does not influence OR but correlates with longer PFS. This suggests that BEV can influence tumor regrowth by contributing to overcome the impairement of the host immune surveillance induced by VEGF. No significant financial relationships to disclose.
A prospective PGx and PK/PD dose-finding study of irinotecan based on UGT1A1*6 and *28 genotyping (UGT0601)
Authors: Esaki T. , Satoh T. , Ura T. , Tsujinaka T. , Sasaki Y. , Yamazaki K. , Yamada Y. , Ishizuka N. , Hyodo I. , Sakata Y. 
Published: August 2020

e14560 Background: UGT1A1*6 as well as UGT1A1*28 polymorphisms is associated with decreased glucuronidation of SN-38, the active metabolite of irinotecan (CPT-11). Although the maximum tolerated dose (MTD) and the recommended dose (RD) in Hetero was determined 150 mg/m2 (approval dose in Japan), those of Homo were unknown. Methods: Pts received prior chemotherapies except for CPT-11 for metastatic gastrointestinal cancer were enrolled. UGT1A1 polymorphisms were categorized into Wild(*1/*1), Hetero(*1/*28, *1/*6), and Homo(*28/*28, *6/*6, *28/*6). CPT-11 was administered biweekly. Starting doses were 150 mg/m2 in Wild, 100 mg/m2 in Hetero, and 75 mg/m2 in Homo. DLT was defined as grade 4 hematological, or grade 3 non-hematological toxicity. MTD closest to dose-limiting toxicity (DLT) appearance of 30% was guided by the continual reassessment method in the cohort of Hetero and Homo. DLT and pharmacokinetic (PK) sampling was evaluated during the 1st cycle. Results: Eighty-two pts were enrolled from November 2006 to November 2008 (Wild, Hetero, Homo: 41, 20, and 21, respectively). The dose level reached at 150 mg/m2 in Homo. At 150 mg/m2, DLT was observed in six pts of Homo (grade 4 neutropenia, grade 3 diarrhea: 6 and 1, respectively). The probability of DLTs were 22.2% at 125 mg/m2, and 37.4% at 150 mg/m2. The MTD was determined 150 mg/m2 in pts with Homo group. However, the incidences of grade 3/4 neutropenia at 150 mg/m2 during the 1st cycle were 9.8% (4/41), 18.8% (3/16), and 62.5% (10/16) in Wild, Hetero, and Homo, respectively. And the second administration was delayed 7 days or more in most pts in Homo (63% at 150 mg/m2). In one pt of Homo for *28/*28 died of septic shock during the 2nd cycle. SN-38 AUC (0–24h, ng*hr/mL, median) was 239 in Wild, 237 in Hetero, and 410 in Homo. Pts with Homo showed the different trend of PK/PD compared to those with Wild and Hetero. Conclusions: The MTD was 150 mg/m2 in pts with Homo group and the most frequent DLT was grade 4 neutropenia. However, our findings suggest that 150 mg/m2 q2w is difficult to recommend and the initial dosage and administration should be considered carefully for pts with Homo. [Table: see text]
Synergistic effect of SNDX-275 with lapatinib or erlotinib in breast, lung, or head and neck cancer cell lines expressing HER- 2
Authors: Witta S. E. , Franekova V. , Yoshida K. , Igolnikov I. , Frederick B. , Varella-Garcia M. , Bunn P. A. , Hirsch F. R. 
Published: August 2020

e14566 Background: We previously demonstrated the synergistic effect of the histone deacetylase inhibitor SNDX-275 and gefitinib in non-small cell lung cancer (NSCLC) cell lines lacking E-cadherin expression. We evaluated the combination effect of SNDX- 275 with erlotinib or lapatinib in lung, head and neck (H&N) and breast cancer cell lines resistant to erlotinib or lapatinib(IC50> 1uM) and expressing Her2. Methods: This study included 10 H&N and 17 NSCLC cell lines, 2 breast cancer cell lines with expressing Her2 (SK BR3, MCF7) and one lacking Her2 expression, MDA-MB231. Cell lines were incubated for 5 days with increasing concentrations (0.16, 1 and 6μM) of SNDX-275, lapatinib and erlotinib alone or in combination. The growth inhibitory effect was analyzed with MTT assay. The combination drug effect was evaluated using CalcuSyn (Cambridge, UK). E-cadherin and Her2 expression was evaluated using microarray analysis and RT-PCR. Her2 was considered positive if the relative expression was >300 by RT-PCR. Protein expression was analyzed with western blots. Results: Among the 17 NSCLC and 10 H&N cell lines 16 (12 NSCLC and 4 H&N) had positive Her2 RNA expression. 2 NSCLC (A549, H1703) and 2 H&N (UMSCC10, UMSCC19) were resistant to erlotinib or lapatinib (IC50>1μM). The 2 breast cancer cell lines 2, MCF7 and MDA-MB-321, were resistant to erlotinib and lapatinib. SNDX-275 increased the expression of E-cadherin in 5 of the 6 cell lines selected (A549, H1703, UMSCC19, MCF7 and MDA- MB-321). Synergistic effect of SNDX-275 1μM and lapatinib 1μM was detected in the MCF7, UMSCC10, UMSCC19 cell lines (Combination Index, CI: 0.09, 0.9, 0.67; respectively), while SNDX-275 1μM and erlotinib 1μM were synergistic in MCF7, MDA-MB-321, H1703 and A549 (CI: 0.2, 0.95, 0.58, 0.32; respectively). Conclusions: The combination of SNDX-275 and erlotinib or lapatinib is active in breast, NSCLC, H&N cell lines resistant to either drug alone. [Table: see text]
Phase I study of nimotuzumab, a humanized anti-epidermal growth factor receptor (EGFR) IgG1 monoclonal antibody in patients with solid tumors in Japan
Authors: Boku N. , Yamazaki K. , Yamamoto N. , Takahashi T. , Fukutomi A. , Miyazaki M. , Satoh T. , Okamoto I. , Nakagawa K. , Fukuoka M. 
Published: August 2020

e14574 Background: Nimotuzumab, a humanized IgG1 monoclonal antibody targeting EGFR, has been used in head & neck cancer or malignant glioma outside Japan, and MTD including severe skin rash were not observed up to 800mg/body. This phase I study of nimotuzumab was conducted to investigate the safety profile, MTD, DLT, PK, human antibody against nimotuzumab (HAHA) in Japanese patients (pts), and PD analysis (activation of EGFR, Akt, MAPK, Ki67) was done. Methods: Pts with advanced solid tumors having no available standard therapy were enrolled. Nimotuzumab was given intravenously at dose levels of nimotumumab 100, 200 and 400mg/body, weekly. Blood, skin samples before treatment and after 4th infusion and pre-treatment tumor were collected for PD analysis. Results: 4 pts were enrolled in each level (total 12 pts). Pt characteristics were M/F 5/7, median age 57 years, ECOG PS 0/1 7/5. No grade 3 or 4 toxicities and no DLT were observed, and MTD was not determined. The major adverse event was grade 1 or 2 skin rash (58%, 7/12). Neither infusion reaction nor HAHA was observed. AUC0-inf, Cmax and t1/2 increased and CL deceased by dose dependent manner, indicating nonlinear PK characteristic. SD and PD were observed in 8 patients (67%) and4 patients (33%), without objective responses. Median time to progression was 4 months. Time to progression seemed to be longer in the pts with amplified gene copy number of EGFR though the number of pts was limited. Conclusions: Weekly infusion of nimotuzumab was well tolerated up to 400 mg/body in Japanese pts. A correlation between anti-tumor activity and EGFR amplification was speculated. Additional PD analysis is currently ongoing. No significant financial relationships to disclose.
Prediction of the benefit of trastuzumab (T)-based therapy by the change of gene expression of peripheral blood mononuclear cells (PBMC)
Authors: Shimizu C. , Tamura K. , Koizumi F. , Komori O. , Pritchard M. , Mollah M. H. , Eguchi S. , Fujiwara Y. 
Published: August 2020

e14578 Background: Identification of molecular predictors of response is important in the aspect of personalization of treatment, especially in the era of molecular targeted drugs. Antibody-dependent cell-mediated cytotoxicity (ADCC) is suggested as one of the main mechanism of action of T. Moreover, PBMC specimens can securely be obtained with minimal invasion. We therefore hypothesized that gene expression changes induced by T of PBMC may be useful for prediction of response of T. Methods: 36 HER2-positive metastatic breast cancer (BC) patients were enrolled in this prospective biomarker study. The patients were treated with single-agent T (q1w) for chemotherapy-naïve, hormone refractory metastatic disease. The clinical response was measured after 8 cycles of single-agent T. PBMC were collected prior to and 1-week after the first administration of T. Gene expressions of PBMC were measured using Affimetrix GeneChip Human Genome U133 Plus 2.0 array. Change of gene expressions before and after T was correlated with clinical response using Wilcoxon rank sum test. A multi-gene predictor of response to T was generated using the highly ranked genes. The performance of the predictor was then assessed in patients prospectively treated with neoadjuvant chemotherapy (NAC): HER2- positive BC patients recieved NAC containing T. PBMC were collected prior to NAC and 1-week after the first administration of T. Results: 34 patients were evaluable for clinical outcome. 15 and 19 patients were classified as responders and non- responders, respectively. The top 4 genes differentially regulated by T between responders and non-responders were selected for development of a predictor by leave-one-out cross validation. The 4-gene predictor correctly predicted the pathological complete response (pCR) in 5 out of 5 patients who achieved pCR and residual disease (RD) in 10 out of 12 patients with RD (error rate 12 %) in HER2-positive breast BC patients treated with NAC containing T. However, it was not associated with pathological response in 19 HER2- negative patients treated with NAC without T (error rate 39 %). Conclusions: Change in PBMC gene expression after single dosage of T may be useful as a predictor of response to T-based therapy. No significant financial relationships to disclose.
Cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) against tumor cell lines characterized for EGFR expression and K-ras mutation
Authors: Barriere J. , Fischel J. , Formento P. , Renée N. , Francoual M. , Formento J. , Chefrour M. , Etienne-Grimaldi M. , François E. , Milano G. 
Published: August 2020

e14583 Background: Mutated K-ras protein is a strong predictive factor of cetuximab resistance, bypassing the classical direct inhibitory effect on epidermal growth factor receptor (EGFR) signaling. However, cetuximab is also able to mediate ADCC, which may be part of the clinical response. The aim of this ex-vivo study was to quantify cetuximab-mediated ADCC on various human cancer cell lines characterized for EGFR-expression and K-ras mutation. Methods: Two K-ras mutated cell lines over-expressing EGFR and resistant to anti-EGFR tyrosine kinase inhibitor were tested (Capan-1 and Capan-2, pancreatic), along with 2 K-ras wild-type cell lines over- expressing EGFR (CAL166, head and neck; A431, epidermoid carcinoma) and an EGFR-negative cell line (OCM1, uveal melanoma). The tested monoclonal antibodies (mAbs) were: cetuximab (Merck, anti-EGFR IgG1 mAb), panitumumab (Amgen, anti-EGFR IgG2 mAb), and as a negative control, rituximab (Roche, IgG1 anti-CD20 mAb). ADCC (51Cr release assay) was performed using freshly- isolated peripheral blood mononuclear cells from a healthy donor. Results were expressed as % of potentially maximum 51Cr release. Results: Cetuximab mediates ADCC against EGFR-over-expressing cell lines CAL166 (38.4 ± 3.1 %), A431 (13.5 ± 1.7 %), Capan-1 (31.2 ± 0.8 %) and Capan-2 (27.8 ± 8.6 %) irrespective of the K-ras mutational status, but not against EGFR-negative OCM-1 (6.2 ± 1 %). Conversely, unlike IgG1 cetuximab, the anti-EGFR IgG2 panitumumab and the irrelevant antibody rituximab were both unable to induce significant ADCC (< 10 % on all tested cell lines). Conclusions: Cetuximab-mediated ADCC is independent of the K-ras mutational status of the tumor cell lines. Present data suggest that cetuximab may remain of clinical interest in K-ras-mutated patients. Immunostimulation, as well as new generation anti-EGFR mAbs with improved ability to induce ADCC, may be promising in the management of K-ras-mutated patients. No significant financial relationships to disclose.
A three-part, phase I, dose-escalation study of GSK1120212, a potent MEK inhibitor, administered orally to subjects with solid tumors or lymphoma
Authors: Thompson D. S. , Flaherty K. , Messersmith W. , Harlacker K. , Nallapareddy S. , Vincent C. , DeMarini D. J. , Cox D. S. , O'Neill V. J. , Burris H. A. 
Published: August 2020

e14584 Background: GSK1120212 is a potent and highly selective inhibitor of MEK1, a component of the MAP kinase pathway. GSK1120212 demonstrates efficient inhibition of p-ERK which correlates with inhibition of cell proliferation and induction of apoptosis. PO administration of GSK1120212 achieved tumor regression in multiple mouse xenograft models. The objectives of this study are to define the maximum tolerated dose (MTD) and to evaluate the pharmacokinetics (PK) and pharmacodynamic (PD) effects of GSK1120212. Methods: In Part 1, patients (pts) with solid tumors or lymphoma are enrolled in successive cohorts and receive a single PO dose of GSK1120212 followed by QD doses on days 1 - 21 of each 28-day cycle. Tumor response is assessed Q 8 weeks. PK blood samples are collected from all pts. Ophthalmic exams are administered at baseline and as clinically warranted. Dose escalation occurs via an accelerated titration followed by a standard 3+3 escalation. In Part 2, pts with pancreatic or K-Ras mutant CRC will be enrolled at the MTD. In Part 3, pts with biopsiable tumors will enroll at MTD and sub-MTD doses. Tumor biopsies will be taken pre- and post-dose to measure pERK and other markers of cell proliferation. Results: Six pts with advanced malignancies (neuroendocrine, thyroid, colorectal (n=2), melanoma (n=2) have been treated with tablets at four dose levels: 0.125 (n=2), 0.25 (n=1), 0.5 (n=2), and 1.0 mg (n=1). No DLTs or grade 2 toxicities have been reported. One patient was on study for over 17 weeks. Based on mean AUC and Cmax, GSK1120212 exposures following 15 days of repeat-dose administration were approximately dose proportional across the dose range (0.125–0.5 mg) with a median Tmax of approximately 1.5 hours. Conclusions: GSK1120212 has been well tolerated to date. Dose escalation is ongoing. [Table: see text]
Targeting tumor metabolism: biguanides as anti-neoplastic agents
Authors: Knoblauch R. E. , Thompson C. B. 
Published: August 2020

e14592 Background: During the process of malignant transformation, the tumor cell adopts a new form of metabolism, characterized by aerobic glycolysis and altered TCA cycle flux, that enable it to meet the energetic and biosynthetic demands of proliferation. This shift to anabolic metabolism results from oncogene-driven activation of signaling pathways, and therefore represents a potential therapeutic target that lies downstream of these genetic events. Methods: We have characterized the proliferative and metabolic effects of phenformin, a member of the biguanide family of compounds used in the treatment of diabetes, on the bcr-abl expressing K562 erythroleukemia cell line, and compared the resulting phenotype to those of imatinib and rapamycin, two targeted agents used in the treatment of malignant disease. Results: Phenformin induced the most profound growth inhibition of K562 cells, in a manner distinct from the targeted agents. Phenformin treatment eliminated the mitochondrial contribution to anabolic metabolism, through inhibition of Complex I of the Electron Transport Chain, as demonstrated by reduced oxygen consumption and intracellular ATP levels. Glutamine metabolism was also inhibited, consistent with TCA cycle inhibition as a secondary effect. The phenformin-induced mitochondrial dysfunction made K562 cells dependent upon glycolysis for survival. In contrast, the growth arrest resulting from imatinib treatment was associated with a complete reversion from the anabolic phenotype, as demonstrated by dramatically decreased glucose and glutamine consumption. Rapamycin, a poor inhibitor of K562 proliferation, decreased glycolysis but left mitochondrial function intact. Conclusions: Our results confirm the importance of metabolism to the proliferation of malignant cells, thereby validating anabolic metabolism's potential for therapeutic intervention. The direct inhibition of tumor cell metabolism by phenformin warrants further clinical study as a promising new approach to cancer therapy. No significant financial relationships to disclose.
Susceptibility of head and neck cancer to an attenuated model of the oncolytic vesicular stomatitis virus expressing suicide genes
Authors: Porosnicu M. , Liu J. , Lyles D. 
Published: August 2020

e14604 Background: The predominant loco-regional progression of head and neck squamous cell carcinoma (HNSCC) makes it suitable for testing oncolytic viruses. Recent work from several laboratories including ours has focused on developing vesicular stomatitis virus (VSV) as a replication-competent anticancer viral vector. Attenuated strains, such as M protein mutant VSV (M51R) are more likely to be promoted in clinical research. The major shortcoming of viral therapy is related to the large proportion of tumor cells remaining uninfected. We are addressing this limitation in two ways: the expression of the cytosine deaminase-uracil phosphoribosyltransferase (C:U) suicide gene by the rVSV vector, expected to produce a strong bystander effect and the exploitation of the radiosensitizing potential of the 5-FU chemo-drug produced intratumorally, as well as of the VSV virus itself. Methods: We determined the extent of defectiveness in interferon pathways and susceptibility to oncolytic VSV in a collection of HNSCC cell lines and in patient HN primary tumor cells. We employed gene array to screen for differences in gene expression in sensitive and resistant models. We have generated the rVSV-C:U and M51R-C:U viruses and we tested our collection of HNSCC cell models to infection with these viruses in the presence and absence of 5-FC. In vivo experiments were performed on a localized and on a metastatic SQ-20B model of HNSCC in nude mice. Results: 1) the primary patient HNC cells are more resistant than the HNC cell lines to the M51R-VSV; 2) the activation of IFN pathways and /or alterations of AKT pathway is contributing to resistance to VSVs. 3) Addition of the suicide gene to the attenuated VSV provided significantly more oncolytic effect in vitro and in vivo. The efficacy and the radiosensitizing potential of M51R- C:U on a nude mice model of HNSCC (SQ-20B) will be presented. Conclusions: M51R-VSV has increased efficiency and radiosensitizing effect on HNSCC models. We can define an optimal approach to testing VSV vectors for treatment of HNSCC, with a clinical trial in HNSCC patients as our next goal. Finally, we have important new information, both from cell lines and patient tissues, for proof-of-principle that cancers can down-regulate antiviral responses. No significant financial relationships to disclose.