bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidermal growth factor receptor (EGFR) status in different stages of resected non-small cell lung cancer (NSCLC): Implications for treatment with EGFR-targeted monoclonal antibodies
Authors: Berardi R. , Scartozzi M. , Squadroni M. , Santinelli A. , Brunelli A. , Gasparini S. , Valeri G. , Marmorale C. , Fianchini A. , Cascinu S.
Published: March 2020

20015

Background: Aim of our study was to verify potential changes in EGFR status in different stages of resected NSCLC. This was done in order to find out whether assessing the EGFR status could be considered an effective tool for planning therapy with EGFR-targeted monoclonal antibodies in different setting of patients. Methods: From January 1996 through December 2001, 439 patients underwent radical surgery for NSCLC at the Department of Thoracic Surgery of Università Politecnica delle Marche. EGFR expression was evaluated with an immunohistochemical technique on five micron-thick tissue sections obtained from specimens fixed in 10% (v/v) neutral buffered formalin and paraffin embedded.EGFR expression was detected as membranous and/or cytoplasmic brown staining of neoplastic cells with various intensity. Positivity for EGFR expression was defined as any membrane staining above background level. Both the primary and metastatic neoplasm were considered positive when ≥ 1% of the tumour cells had membranous staining. Results: Table 1 summarizes patients’ characteristics. Samples from 423 patients were available for EGFR analysis. EGFR immunohistochemical expression was found positive as follows: 15.8% in stage IIIB, 12.2% in IIIA, 2.3% in IIB, 5.3% in IIA, 4.8% in IB and 5% in IA. At multivariate analysis, EGFR status resulted indicator of prognosis both when considering all the patients and in the groups of patients with different stages of disease. Conclusions: Globally our findings seem to confirm the role of EGFR as a prognostic indicator in NSCLC. Furthermore the observation that EGFR is more frequently overexpressed in the advanced stages may suggest that EGFR-targeted treatment strategies could be more appropriated in this subgroup of patients.

[Table: see text]

No significant financial relationships to disclose.
Investigation of estrogen receptor α phosphorylation in breast cancer
Authors: Sarwar N. , Jiang J. , Shousha S. , Coombes R. C. , Ali S.
Published: March 2020

20046

Background: Estrogen receptor α (ERα) is an important predictive marker for response to endocrine therapy in breast cancer. Phosphorylation of ERα, in particular on serine 118 (S118), can result in ligand independent activation, thereby possibly contributing to resistance to endocrine therapies. The clinical significance of ERα phosphorylated at serine 118 (P-S118) in breast cancer was examined. Methods: Immunohistochemistry was performed on 301 primary breast tumor biopsies and on a small subset that had become resistant to endocrine therapy. P-S118 levels were scored using the modified McCarty’s H scoring system. Results: 282 (94%) of the 301 tumors were ERα positive. Of the 282 ERα positive patients, 282 (83%) had detectable nuclear staining for P-S118. There was no association between P-S118 staining and tumor size, nodal status, progesterone receptor and c-erbB2 status. There was however a positive correlation of P-S118 with ERα expression, (p < 0.001) and activated (phosphorylated) mitogen-activated protein kinase (MAPK) expression (p < 0.001). There was a clear inverse relationship with tumor grade and P-S118 staining (p < 0.001). Lower grade tumors being associated with higher H-scores for P-S118 staining. There was also some evidence of an association between P-S118 and age (P = 0.08). No association was found between P-S118 expression and survival. There was however a statistically significant difference in the distribution of P-S118 expression before and after becoming resistant to hormonal therapies (z = −2.357 p-value = 0.02). Comparison of H-scores showed that P-S118 levels were elevated following tumor regrowth. Conclusion: This analysis shows that S118 phosphorylation is higher in more differentiated tumors, suggesting that phosphorylation at this site is associated with a better prognosis. However, S118 phosphorylation is elevated in biopsies taken from patients who had relapsed on tamoxifen, compared to pre-treatment biopsies. Collectively these data indicate a complex role for ERα phosphorylation at least at S118, in breast cancer progression.

No significant financial relationships to disclose.
Prognostic significance of leptin (L) and leptin receptor (OB-R) expression in human breast cancer (BC)
Authors: Kulkarni S. , Saxena S. , Watroba N. , Groth J. , Brady W. , Edge S. , Geradts J.
Published: March 2020

20054

Background: L is a cytokine-like hormone that controls adipocyte mass and energy balance by binding to OB-R. Both L and OB-R have been implicated in carcinogenesis and were recently identified in human BC. The clinical significance of increased expression of L and OB-R in human BC is unclear. Methods: The anti-L rabbit (A-20) and anti-OB-R goat (M-18) polyclonal antibodies (ABs) from Santa Cruz Biotechnology were applied in indirect immunohistochemical (IHC) assays. Following antigen retrieval, ABs were reacted with 5 μm paraffin sections of tissue microarrays (TMAs). TMAs included 1mm cores of 316 women with operable BC and contained invasive cancer (IC), ductal carcinoma insitu (DCIS), surrounding histologically normal tissue (N) and nodal metastases (M). For L, nuclear (LN) and cytoplasmic (LC) staining were evaluated separately. For OB-R, one qualitative score (0, +1, +2, +3) was applied to each case. For analysis, 0, +1 were considered low and +2, +3 were considered high expression. Expression of LN, LC, and OB-R were evaluated with respect to clinicopathologic variables; disease free survival (DFS) and survival (S) were evaluated using Cox regression. Results: Median S and DFS were 11.4 and 10.1 years. Tissue from 113 patients with IC, 93 patients with N, 49 patients with M, and 36 patients with DCIS were evaluable for LC, LN and OB-R. OB-R expression was significantly higher in lobular vs. ductal carcinomas (p < .001). Increased expression of LC, LN, or OB-R was not associated with aggressive pathologic features studied in IC and DCIS. On multivariate analysis, highest expression of LN (+3) in IC was significantly associated with poor survival, p = .038, HR 3.51 (1.07–11.51 95% CI). Strong expression of LN in N was also associated with decreased survival, p = .043, HR 8.43 (1.07, 66.30 95% CI). Strong expression of OB-R expression in N was significantly associated with increased DFS and S, p = .004, HR 0.21 (.07–0.61 95% CI) and p = .007, HR .29 (.11–.71 95% CI). Conclusions: In this limited study, LN appears to have a negative impact on survival in women with invasive BC when elevated in IC and N. Elevated levels of LR appear to have a protective effect when elevated in N. Larger studies are needed to confirm our findings and elucidate the mechanisms responsible for these observations.

No significant financial relationships to disclose.
Impact of preoperative CEA levels on the prediction of lymphnode (LN) metastasis
Authors: Danno K. , Sugimoto T. , Ikeda M. , Ikeda K. , Ohnishi T. , Fukunaga M. , Ohta H. , Mishima H. , Watase M. , Sekimoto M. , Monden M.
Published: March 2020

20070

Background: Although CEA is the most commonly used tumor marker for colorectal carcinoma (CRC) and it may correlate with poorer prognosis, data are insufficient to support its use to determine adjuvant therapy. Monitoring preoperative CEA might be useful if it would assist in staging and treatment planning. Methods: This study was a pooled data analysis of 1791 CRC patients (pts) collected prospectively from 25 hospitals participating in the MCSGO. The purpose of this study was to investigate the impact of preoperative CEA on the prediction of the number of LN metastasis (#LN). Data of 1328 pts were completed with preoperative CEA and clinicopathological (CP) data (number of dissected LN, #LN, tumor size, distant metastasis, macroscopic type, depth of invasion, histological type, and lymphatic and vessel invasion). Data of 582 pts with the number of dissected LN 12 were analyzed in this study. #LN was categorized in 5 levels (0, 1, 2, 3, and ≥4), and relationship between #LN and CEA was first investigated via a multivariate analysis based on adjusting for the other CP factors. Discrete logistic regression analysis was used, in which a random effect was incorporated to adjust some bias between hospitals. The linear effects for the factors were evaluated via the regression model. The multivariate adaptive regression spline (MARS), the most powerful tool in the statistical prediction, was employed for the prediction of #LN. Results: The effect of the CEA adjusted by the other CP factors had a positive trend with two-sided P-value of 0.0394 for #LN. The adjusted R-squared measure (R2*) by the MARS fitting, a prediction performance index of #LN, was 0.369, and that averaged based on Bootstrap sampling (Bagging method) was R2* = 0.405. The relative importance of each factor in the prediction of #LN estimated by the decrease rate of R2* on masking each factor is shown in the Table . The relative importance of CEA in the prediction of LN# was ranked second next to lymphatic invasion. Conclusions: Preoperative CEA has a significant impact on the prediction of #LN.

[Table: see text]

No significant financial relationships to disclose.
RELMb is a hypoxic induced mitogenic factor in human adenocarcinoma A549 celline
Authors: Rose F. , Renigunta A. , Grimminger F. , Seeger W. , Hänze J.
Published: March 2020

20072

Background: RELMb (resistin-like molecule) represents the closest related human homologue of mouse RELMa, also known as hypoxic-induced-mitogenic-factor (HIMF). However, no orthologous gene of mouse HIMF exists in human. Results and Methods: In this study, we cloned human RELMb cDNA from lung and performed regulatory and functional expression studies in adenocarcinoma A549 cell line. RELMb mRNA was found to be strongly upregulated in hypoxia in these cells. Upon transfection of a RELMb encoding expression plasmid, we observed significant induction of proliferation in A549 cells, which could be blocked by phosphatidyl-inositol 3-kinase (PI3K) inhibitors LY294002 and wortmannin. Conclusions: The results suggest that human RELMb may contribute to hypoxic-induced proliferative responses in adenocarcinoma cells via PI3K dependent signal transduction.

No significant financial relationships to disclose.
Glycodelin: A possible new biological marker in colorectal cancer
Authors: Govindarajan R. , Parthasarathy S.
Published: March 2020

20081

Background: Glycodelin is a 28 kDa glycoprotein expressed in normal human reproductive tract. It is over expressed in various gynecological malignancies and vascular endothelium. Since angiogenesis has been associated with and antiangiogenic therapy is effective in colorectal cancer, it is possible that glycodelin could be a mediator in the pathogenesis and be a potential target in the treatment of this disorder. To assess whether the serum glycodelin was expressed in metastatic colorectal cancer, analysis of serum samples obtained from patients participating in a clinical trial were analyzed. Methods: Serum glycodelin levels from 19 controls (5 males, 9 premenopausal females and 5 postmenopausal females) and 24 patients with metastatic colorectal cancer (15 males and 9 females) enrolled into a phase II treatment protocol were measured. All patients had progressed on prior chemotherapy. Samples were obtained prior to the initiation of any further therapy. Glycodelin levels were measured by an Elisa based immuno assay using polyclonal antibodies raised against a peptide derived from the sequence of human glycodelin. Results: The median age of the patient populatin was 62.5 yrs. (range 29–78); of the males was 65 yrs. (range 57–78); of females was 58 yrs. (range 29–66). The median serum glycodelin level of whole control group was 41 nG/50μL (range 26–61); of 5 males 27 nG/50 μL (range 13–41); of 9 premenopausal females was 64 nG/50 μL (range 46–86); and of 5 postmenopausal women was 38 nG/ 50 μL (range 27–49). The median serum glycodelin level of patients with metastatic colorectal cancer was 128 nG/ 50 μL (range 51–523); of men was 128 nG/50 μL (range 51–523) and of women was 120 nG/50 μL(range 51–377). Serial glycodelin levels dropped by more than 50% in patients who had a clinical response or those who had stable disease. Conclusions: Serum glycodelin level was elevated in patients with metastatic colorectal cancer compared to controls. Whether glycodelin plays a role in the pathogenesis of colorectal cancer; can be a useful index to measure response and be useful as a potential target in the management of patients with colorectal cancers needs further evaluation.

No significant financial relationships to disclose.
Inhibition of tumor growth in a murine xenograft model by thalidomide
Authors: Horn L. , Hermes M. , Schwock J. , Brulport M. , Hengstler J. G.
Published: March 2020

20083

Background: Limitations in the treatment of recurrent disease in cervical carcinoma are for radiation therapy large tumor size and pelvic side wall involvement and for exenteration procedurde previous radiation therapy, bulky disease, and others. Alternative approaches including chemotherapy, chemo-radiation, radiation plus hyperthermia and others are accompanied by a failure rate of 50 to 80%. Recent research has shown that the antineoplastic effect of thalidomide (TD) is due to the inhibition of neo-angiogenesis, a decrease of TNF-a, blocking of nuclear factor κβ-kinase activity, stimulation of the IL-2 and downregulation of cell adhesion molecules. Here, we have studied the effect of TD on a cervical cancer cell line in a murine xenograft model. Methods: We injected 7 × 106 HELA cells s.c. into the dorsal skin of 6–8 week-old male nude mice (cd nu−/nu−; Charles River, Sulzfeld, Germany). The tumor diameter was measured with a caliber rule. The maximum and minimum diameters of the tumor were determined. Tumor volume (V) was calculated by the formula: V = a × b × b/2, where a represents the minimum and b the maximum tumor diameter. As soon as tumors reached a volume of 0.25 cm3 the mice were randomized into a treatment (n = 9) and a control group (n = 9). The mice in the treatment group received 14 daily injections of 300 mg/kg (i.p.) thalidomide for 14 days. Animals were housed under specific pathogen-free conditions. The experiments have been approved by the local animal welfare committee. Results: Thalidomide caused a clear delay in tumor growth. Already 7 days after onset of thalidomide therapy the mean tumor volume was smaller in the treated (0.24 ± 0.03 cm3) compared to the control mice (0.73 ± 0.15 cm3; mean ± standard error; p < 0.01). After 14 days of thalidomide treatment the mean tumor volumes were 0.37 ± 0.05 and 1.05 ± 0.19 cm3 in the treated and in the control mice, respectively (p < 0.01). However, after the end of the 14 days treatment period a new onset of tumor growth was observed. In conclusion, thalidomide delayed tumor growth but did not cause tumor remission. Conclusions: TD is effective in inhibition of tumor growth of a cervical cancer cell line in a mouse xenograft model and might be an alternative drug in patients with recurrent cervical carcinoma without any options for established standard therapy.

No significant financial relationships to disclose.
Cross-activity of various established antineoplastic regimens in primary breast cancer cells evaluated by the ex vivo ATP tumor chemosensitivity assay
Authors: Nagel W. J. , Luecke J. , Cree I. A. , Reinhold U. , Kurbacher J. A. , Reichelt R. , Bruch H. R. , Kurbacher C. M.
Published: March 2020

20086

Recently, various chemotherapy (Ctx) regimens are established in operable breast cancer (BC). Whereas anthracylines are now standard in high-risk patients (pts), the future role of taxanes or classical CMF is still controversial. Moreover, little is known which Ctx will be individually beneficial. This particular information is unlikely to be obtained from randomized trials because simultaneous treatment of one single pt with different competing protocols is inappropriate. Thus, we used ex vivo sensitivity profiles from native primary BC assessed with the ATP tumor chemosensitivity assay (ATP-TCA) to analyze the cross-activity of different standard regimens in individual pts. Each Ctx was tested at six different levels over 1.5 log range including both therapeutical and supra-therapeutical concentrations. Resistance, complete, and incomplete sensitivity were determined using a semiquantitative score. The following head-to-head comparisons of ex vivo activity were made: CMF, 4-OOH-cyclophosphamide (4-HC)+methotrexate (MTX)+5-Fluorouracil (5-FU) vs. EC, epirubicin (EPI)+4-HC, n = 56; CMF vs. paclitaxel (PCT), n = 34; CMF vs. docetaxel (DCT), n = 49; EC vs. PCT, n = 51; EC vs. DCT, n = 35; EC vs. EPI+PCT (ET), n = 45; PCT vs. DCT, n = 34. The ex vivo response rates were in good agreement with the expected clinical activity: CMF 52%, EC 63%, ET 85%, PCT 52%, DCT 49%. CMF and EC were equally active (=) in 68% BCs, CMF was superior (>) to EC in 16% and inferior (<) in 16%. The corresponding proportions (=/>/<) for the other comparisons were: CMF vs. PCT, 45%/31%/24%; CMF vs. DCT, 40%/40%/20%; EC vs. PCT, 49%/31%/20%; EC vs. DCT, 40%/40%/20%; EC vs. ET, 53%/ 9%/38%; PCT vs. DCT 55%/21%/24%. Generally, ET was the most active regimen, being equal or superior to EC in the majority of cases. However, CMF is clearly not inferior to EC or single agent taxanes. PCT and DCT are apparently not always the same. Facing the broad heterogeneity of chemosensitivity demonstrated in this study, we were able to show that the results of randomized trials cannot always be translated to an individual pt. Cross-activity analyses using the ATP-TCA may thus prove useful to allow for a more rational design of clinical trials in primary BC.

[Table: see text]
Microtubule-associated protein tau and in vitro paclitaxel sensitivity in primary breast cancer
Authors: Schmidt M. , Bremer E. , Victor A. , Gehrmann M. , Hengstler J. G. , Koelbl H.
Published: March 2020

20088

Background: Paclitaxel has an important role in the adjuvant therapy of primary breast cancer. Recently, microtubule-associated protein tau was described as a marker of paclitaxel sensitivity. We attempted to validate these findings in vitro utilizing the ATP tumorchemosensitivity assay (ATP-TCA). Methods: The in vitro drug sensitivity to paclitaxel was evaluated in 48 fresh primary breast cancer specimens using the ATP-TCA. ATP-TCA results were analysed using the area under the curve (AUC) of growth inhibition. These results were correlated with the expression of tau mRNA measured by quantitative RT-PCR (Spearman’s correlation coefficient). Tau was also compared between progesterone receptor (PgR) positive and negative and estrogen receptor (ER) positive and negative tumors, respectively (Wilcoxon test). Results: The correlation of tau with the AUC for paclitaxel was weak (r = −0.20) and disappeared when considering PgR positive and negative tumors separately (r = −0.004 and r = −0.048, respectively). Tau was found to be differentially expressed between PgR positive and negative as well as between ER positive and negative tumors (p < 0.0005 in both tests). Conclusions: The expression of tau does not show independent predictive value for the in vitro paclitaxel sensitivity in primary breast cancer.

No significant financial relationships to disclose.
Presentation of splice variants of 1-alpha-hydroxylase in MCF-7 breast cancer cells
Authors: Cordes T. , Diesing D. , Becker S. , Fischer D. , Diedrich K. , Friedrich M.
Published: March 2020

20097

Background: Calcitriol (1,25-dihydroxyvitamin D3) is the most active metabolite of vitamin D. It is known for its antiproliferative and differentiating effects on many cell populations including MCF-7 and other breast cancer cells. 1α-hydroxylase (CYP27B1) one of the key enzymes has been found in breast cancer cells suggesting an autocrine regulation of producing calcitriol. An alternative splicing of the encoding genes for the1α-hydroxylase might play a role in regulating enzyme levels and can explain tissue specific variations of the enzyme activity. Splice variants containing intron 1 may encode for truncated proteins with deletion of protein domains which are essential for its enzymatic activity. Methods: In order to obtain more information on the abundance of 1α-hydroxylase splice variants, we performed a highly specific nested touchdown PCR in MCF-7 cells. The protein products of the full length enzyme and its slice variants were confirmed by Western Blot. Results: The full length sequence of 1α-hydroxylase and two different splice variants including intron 1 were isolated. Conclusion: We hypothesize that the expression of the splice variants can lead to a quantitatively lower expression the mRNA of the full length enzyme. The abundance of less active 1α-hydroxylase protein products can alter the local synthesis of calcitriol in the cells and may explain variations of enzymatic activity in different cells and tissues.

No significant financial relationships to disclose.
Epidermal growth factor receptor (EGFR) expression in colorectal cancer in Slovakia
Authors: Salek T. , Mardiak J. , Ondrias F. , Bodnar J. , Klimcakova L.
Published: March 2020

20103

Background: EGFR is involved in the epidermal growth factor pathway that regulates cellular processes and is associated with the development of malignancy.EGFR targeted therapy could be an alternative option to improve clinical outcome in tumors with EGFR expression. Methods: From 09/2004 till 12/2005 we evaluated histologic specimens of 130 patients (89 male, 41 female) with colorectal cancer. EGFR expression was examined by immunohistochemistry using theEGFR Detection Kit (Dako Corporation) in paraffin-embedded colon/rectum tumors and graded as percentage of cells stained. Results: EGFR positivity (1% and more) was observed in 106 pts (81.5%) and EGFR negativity in 24 pts (18.5%). Median of positivity in percentage is 40 (1–95). Conclusions: The EGF receptor is overexpressed in many human tumors and is a promising therapeutic target.

No significant financial relationships to disclose.
Results of a clinical pharmacokinetic (PK) bioequivalence (BE) study of liposomal paclitaxel (LEP-ETU) versus paclitaxel (T) in patients with advanced cancer
Authors: Tan A. R. , Hanauske A. R. , Gelderblom H. , Scheulen M. E. , Van Warmerdam L. J. , Rosing H. , Fetterly G. J. , Shu V. S. , Sherman J. W. , Rubin E. H.
Published: March 2020

2017

Background: LEP-ETU is an easy-to-use liposomal formulation of paclitaxel developed to reduce toxicities associated with the excipient polyoxyethylated castor oil that is used in paclitaxel (Taxol [T]), while maintaining or enhancing efficacy. A phase I study of LEP-ETU demonstrated an MTD of 325 mg/m2 and a similar PK profile at a dose of 175 mg/m2 compared to published T data (Damjanov et al, J Clin Oncol 2005;23 Suppl:147s). Methods: This randomized, two-period crossover, clinical BE study was designed to directly compare the PK of paclitaxel following intravenous administration of LEP-ETU and T delivered over 180 minutes at a dose of 175 mg/m2 in patients with a variety of advanced solid tumors. Patients were randomized to receive either one treatment cycle of LEP-ETU followed by one cycle of T, or one cycle of T followed by one cycle of LEP-ETU. Eligible patients were permitted to continue LEP-ETU treatment in an extension study. Results: Fifty-eight patients were treated, and 32 evaluable patients were analyzed for BE. The latter group of patients met pre-specified evaluability criteria of having received 100% of each dose during the specified administration interval and having had the necessary blood samples drawn to determine Cmax and AUC. Mean total paclitaxel Cmax values for LEP-ETU and T were 4955.0 ng/mL and 5108.8 ng/mL, respectively. Mean total paclitaxel AUC0–8 values for LEP-ETU and T were 15853.8 ng·h/mL and 18550.8 ng·h/mL, respectively. Ratios of the geometric means of LEP-ETU divided by T for Cmax were 97% (90% CI, 91%-103%) and for AUC0–8 were 84% (90% CI, 80%-90%). These results meet the established 80–125% BE criteria. The most frequently reported adverse events were fatigue, alopecia, and myalgia. Of the 37 patients deemed suitable to continue LEP-ETU treatment in the extension study, 57% have received = 4 cycles of LEP-ETU with at least stable disease. Conclusion: LEP-ETU has met BE criteria compared to T. A comparative efficacy and safety study of LEP-ETU and T at a dose of 175 mg/m2 has been planned to confirm the potential of LEP-ETU to have comparable or improved treatment effect with a better safety profile than T.

[Table: see text]
Determination of uracil/UH2 ratio as a potential surrogate for DPD status in cancer patients presenting with severe toxicities during fluoropyrimidine treatment
Authors: Mercier C. , Yang C. , Ciccolini J. , Balti M. , Evrard A. , Blesius A. , Dahan L. , Richard K. , Seitz J. , Lacarelle B. , Favre R.
Published: March 2020

2020

Background: DPD deficiency is a rare pharmacogenetic syndrome leading to overexposure to fluoropyrimidine drugs, with subsequent exacerbation of toxicity and, possibly, fatal outcome in the most severe cases. Methods: We developed a simple and rapid surrogate method for evaluating the DPD status of cancer patients. This method was retrospectively validated by following 860 patients treated with fluoropyrimidines over a 3-year period at our institute. We applied the Uracil to UH2 ratio measurement as an indirect insight into DPD functionality in a subset of 120 patients (14%), who had presented with severe toxicity (grade 3–5, WHO) after fluoropyrimidine administration. We also searched for the canonical IVS14+1G>A single nucelotide permutation (SNP), which is associated with severe DPD deficiency. Results: More than 70% of the patients with severe toxicity and 80% of those with fatal outcome displayed U/UH2 ratios out of the range previously defined with a separate reference, non-toxic population thus strongly suggesting a correlation. In contrast, IVS14+1G>A SNP was not found to be a reliable marker for predicting toxicities. Conclusions: Taken together, our data indicate U/UH2 ratio appears to be frequently implicated in the occurrence of iatrogenic events with fluoropyrimidine therapy. In addition, our simple and rapid HPLC method may meet the requirements of routine screening, allowing identification of patients who might be at risk of severe toxicity during fluoropyrimidine administration, at relatively low cost. The predictive value of our test is being investigated in a prospective study with pharmacokinetic support.

No significant financial relationships to disclose.
Phase I study of ispinesib in combination with carboplatin in patients with advanced solid tumors
Authors: Jones S. F. , Plummer E. R. , Burris H. A. , Razak A. R. , Meluch A. A. , Bowen C. J. , Williams D. H. , Hodge J. P. , Dar M. M. , Calvert A. H.
Published: March 2020

2027

Background: Kinesin spindle protein (KSP) is required for establishment of mitotic spindle bipolarity and cell cycle progression. Ispinesib (SB-715992), a KSP inhibitor, blocks assembly of a functional mitotic spindle leading to G2/M arrest. Carboplatin is a platinum compound that produces predominantly interstrand DNA cross-links. In vivo combination of a platinum-containing agent (cisplatin) and ispinesib resulted in synergistic activity and an increase in maximum tolerated dose (MTD) of ispinesib. In a phase I study of single agent ispinesib on a once every 21-day schedule, the MTD was 18 mg/m2 with prolonged gr 4 neutropenia and febrile neutropenia as DLTs. Methods: Patients (pts) with advanced solid tumors, PS ≤ 1, and ≤ 3 prior chemotherapy regimens were eligible for this study. Escalating doses of carboplatin (AUC 4-6) were administered over 30 minutes followed by a 1-hour infusion of escalating doses of ispinesib (9– 21 mg/m2) on a 21-day schedule. At least 3 pts were treated at each dose level. The primary objectives of this study included characterizing safety and tolerability and defining the optimally tolerated regimen (OTR). Limited pharmacokinetic (PK) samples were obtained. Clinical response assessments per RECIST criteria were performed every 2 cycles. Results: 24 pts [15 M/9 F; median age 63yrs, ECOG PS 1], were treated at 6 dose levels. The most common tumor types were prostate (7) and breast (4). A median of 3 cycles were administered (range 1–7; total 75 cycles). In 17 pts, the most common toxicities were (# pts, [grade]): nausea (10, Gr 1–2), vomiting (8, Gr 1–3), fatigue (8, Gr 1–2), neutropenia (8, Gr 2–4), anemia (7, Gr 1–3), and thrombocytopenia (7, Gr 1–4). Gr 4 thrombocytopenia was the observed DLT in 2 pts [ispinesib (mg/m2)/carboplatin (mg/ml·min) (# pts): 15/6 (1); 18/6 (1). PK assessment of ispinesib and carboplatin will be completed when the OTR has been defined. Unconfirmed minor responses have been observed in 3 pts (breast, prostate, NSCLC) starting at doses of 18/6. Conclusions: Determination of an OTR is ongoing. Ispinesib doses ≥ single agent MTD when combined with carboplatin AUC 6 have an acceptable tolerability profile and demonstrate preliminary evidence of anti-tumor activity.

[Table: see text]
Population pharmacokinetics of trabectedin (ET-743) in subjects with cancer
Authors: Perez Ruixo J. J. , Zannikos P. , Hirankarn S. , Stuyckens K. , Liolios K. , Soto-Matos A. , Lopez-Lazaro L. , Pico C. , Yver A. , Owen J.
Published: March 2020

2030

Background: Trabectedin (T) is a DNA minor-groove intercalating agent. The objective of this study is to characterize the population pharmacokinetics of T in cancer subjects. Methods: A total of 603 subjects (945 cycles) receiving intravenous T as monotherapy at doses ranging from 0.024 to 1.8 mg/m2 and given as 1, 3 or 24 hrs infusion every 21 days; 3 hrs infusion on day 1, 8, 15 every 28 days; or 1 hr infusion daily for 5 consecutive days every 21 days were included in the analysis. An open four-compartment pharmacokinetic model with linear elimination, linear and non-linear distribution to the deep and shallow peripheral compartments, respectively, and a catenary compartment off the shallow compartment was developed to best describe a total of 4251 concentrations from 274 subjects (Index Dataset) using NONMEM V. The effect of selected covariates on T pharmacokinetics was investigated. Model was evaluated using goodness of fit plots and relative error measurements for 2362 concentrations from 329 subjects (Test Dataset). Computer simulations were undertaken to evaluate the covariate effects on T pharmacokinetics. Results: Mean (SD) of T terminal half-life was ≈180 (61.4) h. Plasma accumulation was limited when T was given every three weeks. Systemic clearance, 31.5 L/h (CV = 51%), was 19.2% higher in subjects receiving concomitant dexamethasone. Typical values of volume of distribution at steady-state for males and females were 6070 L and 5240 L, respectively. Age, body size variables, AST, ALT, LDH, creatinine clearance, albumin, total protein and presence of liver metastases were not related to T pharmacokinetics. No difference in model parameters was observed for the infusion durations evaluated. T AUC and Cmax were dose proportional for each schedule evaluated and consistent across cancer types. Conclusions: The integration of phase I/II pharmacokinetic data demonstrated T linear elimination, dose-proportionality up to 1800 μg/m2, and time-independent pharmacokinetics. Given the moderate to large interindividual variability in T pharmacokinetics, the clinical relevance of dexamethasone and gender covariates is probably limited since a substantial overlap in simulated concentration-time profiles was observed.

[Table: see text]
Phase I study of the effects of hepatic impairment on the pharmacokinetic (PK) and safety of satraplatin in patients with refractory non-hematologic cancer
Authors: Setlik R. F. , Preston G. , Jones C. B. , Sarantopoulos J. , Dufresne T. , Petrone M. E. , Nathan F. E. , Greene D. , Anthony T. , Takemoto C.
Published: March 2020

2045

Background: Satraplatin (S) is a third-generation oral platinum analog that has demonstrated activity in the treatment of patients with platinum-sensitive malignancies. A worldwide double-blind, placebo controlled randomized phase III trial evaluating S as 2nd line therapy for HRPC has recently completed enrollment. The current study was designed to determine the effect of hepatic impairment on S pharmacokinetics in patients with refractory cancer, as well as treatment efficacy and toxicity. Methods: S was administered orally at a dose of 80mg/m2/day (d) on d1–5 every 35 days. Study groups (cohorts) were defined at 4 levels of hepatic impairment - Group 1 (G1) = control; G2 = Child-Pugh Class A; G3 = Child-Pugh Class B; and Group 4 = Child-Pugh Class C. Results: 19 pts have been enrolled to date (11 M/ 8 F); median age is 57 (range 44–80). Pts with prostate (2), pancreas (4), colorectal (3), adenocystic (2), and 1 each neuroendocrine, hepatocellular, melanoma, breast, ovarian, SCLC, and anal cancers were enrolled. 8 pts were in G1, 3 pts in G2, 4 pts in G3, and 5 pts in G4. Accrual is ongoing in this study with a total of 8 pts planned for each group. The median number of prior regimens was 5 (range 2–8). A total of 35 cycles of S have been given: median 2/pt (range 1–4). 9 pts have completed 2 cycles of S. Hematologic toxicities during the first 2 cycles included grade (G) 3/4 thrombocytopenia in 15 %. There were no cases of G 3/4 neutropenia or anemia. One case of G3 hypokalemia, was reported. Two patients developed acute renal failure; one of which was due to uncontrolled nausea (N) and vomiting (V) and the other was associated with rapid disease progression in the liver. Both were G4 patients. Otherwise, N, V, and diarrhea were mild to moderate, and controlled with oral therapy. Conclusions: S is, in general, well tolerated in patients with mild or moderate liver impairment. Severe thrombocytopenia is the most common side-effect. Of the patients enrolled to date 15% did not have progression of disease. PK data will also be presented.

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Phase I and pharmacokinetic evaluation of enzastaurin combined with gemcitabine and cisplatin in advanced cancer
Authors: Beerepoot L. , Rademaker-Lakhai J. , Witteveen E. , Radema S. , Viseren-Grul C. , Musib L. , Van Hal J. , Beijnen J. , Schellens J. , Voest E.
Published: March 2020

2046

Background: Enzastaurin (Enz), an oral PKC inhibitor that also suppresses PI3K/AKT pathways, blocks tumor angiogenesis and tumor cell proliferation and induces tumor cell death. Gemcitabine (Gem) and cisplatin (Cis) combination is often used for treatment of solid tumors. Addition of Enz to the regimen has the potential for enhanced clinical benefits without increasing toxicity. Methods: In this phase I, dose-escalation trial, patients (pts) with advanced, refractory, solid tumors received a lead-in treatment (cycle 1) with oral Enz for 14 days to achieve steady-state exposures. Starting with cycle 2, pts received Enz orally (350 mg qd to 500 mg bid) on days 1–21 combined with Gem (1000 or 1250 mg/m2) as a 30-min iv infusion on days 1,8 and Cis (60 or 75 mg/m2) as a 3-h iv infusion on day 1, every 21 days, for up to 7 cycles. Results: 33 pts (22 males, 11 females; ECOG: 0–2), with a median age of 58 yrs (range: 38–79 yrs), were enrolled in 7 dose levels. The MTD was not identified. Two DLTs were reported, 1 grade (Gr) 2 QTc interval prolongation and 1 Gr 3 fatigue, both during cycle 1 in bid cohorts. Laboratory toxicities included Gr 3/4 neutropenia (3/6 pts), thrombocytopenia (1/6 pts), and Gr 3 leukopenia (2 pts), hyperglycemia (1 pt), and creatinine (1 pt). Gr 3 toxicity reported in >1 pt was fatigue (5 pts). Enz bid (≥ 250 mg bid) was associated with more discontinuations in early cycles, more Enz dose adjustments, higher numbers of possibly-related SAEs, and increased numbers of low-grade CTC toxicities compared to the corresponding qd dosing. Exposures of Enz in the presence of Gem and Cis decreased slightly but the decrease was not clinically significant as the mean exposure remained above the targeted exposure of 1400 nM. Gem and Cis exposures were not altered when given in combination with enz, as compared to historical data. Of 24 evaluable pts, 3 pts (pancreatic, head/neck, and ovarian cancer) achieved a partial response, whereas 13 achieved stable disease for ≥ 2 cycles. Conclusions: Based on safety and PK data, the recommended phase II dose is Enz 500 mg qd, Gem 1250 mg/m2, and Cis 75 mg/m2. This regimen is generally well tolerated across all dose levels and there are no significant alterations in PK parameters of any drug, when given in combination.

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A phase I/II study to assess the safety, tolerability and pharmacokinetics (PK) of intravenous (IV) infusion of MB07133 in subjects with unresectable hepatocellular carcinoma (HCC)
Authors: Ma B. , Forbes W. , Venook A. P. , Bissell D. M. , Peterson C. , Niculae I. , Bullough D.
Published: March 2020

2054

Background: MB07133 is a novel cytarabine (araC) prodrug that uses the HepDirect technology to target production of the active form of araC, araC triphosphate (araCTP), to the liver. The study objectives were to determine the maximum tolerated dose, toxicity profile (NCI-CTC 2.0), PK & antitumor activity of MB07133 in patients (pts) with unresectable HCC. MB07133 was given as a continuous IV infusion at escalating doses during the first 7 days of a 28-day cycle until disease progression or unacceptable toxicity occurred. To date, 22 pts with Child-Pugh Class A liver function have been enrolled in 4 cohorts (300, 600, 1200, 1800 mg/m2/d, D1–7), with 3–6 pts/cohort. Enrolled pts had a median age of 57 yrs (range 20–67) & consisted of 21 males, 1 female, 19 Asians & 3 Caucasians. A total of 66 cycles have been administered (maximum 10 cycles in 1 pt) with no dose-limiting toxicities associated with therapy. Most drug-related toxicities (67%) were mild to moderate (gr 1–2 neutropenia, thrombocytopenia & increased ALT). There was 1 gr 3 ascites unrelated to study drug and no gr 4 toxicity. Six pts experienced 10 serious adverse events, all unrelated or unlikely related to study drug. The very low araC concentrations in the plasma (see table ) were consistent with previous animal studies, which demonstrated MB07133 to target araCTP production in the liver. 36% of pts who had ≥ 2 cycles of MB07133 had disease stabilization. Conclusions: MB07133 is well tolerated at doses up to 1800 mg/m2/d in pts with unresectable HCC. Enrollment of a 2400 mg/m2 cohort is ongoing. The disease stabilization observed in this study, although preliminary, warrants further investigation in Phase 2.

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Phase I study of ATN-224 in patients (pts) with advanced solid tumours
Authors: Lowndes S. A. , Adams A. , Timms A. , Middleton M. , Hayward C. , Reich S. D. , Mazar A. P. , Harris A. L.
Published: March 2020

2065

Background: Copper chelation reduces the secretion of many angiogenic factors and reduces tumour growth and microvascular density in animal models. ATN-224 is a second generation analogue of ammonium tetrathiomolybdate, which reportedly can stabilise disease but was limited by the slow onset of copper depletion (50–60 days). Preclinical studies suggest ATN-224 may act primarily by superoxide dismutase 1 (SOD-1) inhibition. The aim of our phase I study was to reduce serum copper levels, as measured by ceruloplasmin (Cp), to 5–15 mg/dl (normal 16–60) in 14–21 days, to determine the pharmacokinetic profile, and to evaluate dose-limiting toxicities. Methods: Cohorts of pts were treated with escalating doses of ATN-224, twice daily, until copper depletion, followed by a titrated maintenance dose. Serum Cp was used as a surrogate marker of copper levels and was titrated to a target range of 5–15mg/dL (normal 16–60). Results: 18 pts have received 54 cycles of ATN-224. Tumours were breast (4), renal (2), melanoma (2), colon (2), and a variety of other types (1 each). Pts received ATN 224 loading doses in cohorts of 1 to 6 pts: 150 (1), 210 (2), 240 (1), 270 (6), 300 (5), and 330 mg/day (3). Mean age was 56 yrs (range 37–78) and PS 0–2. Mean baseline Cp was 39.6 (range 22–63 mg/dL). The maximum administered dose was 330 mg/day where grade 3 lethargy was observed in 3 pts. Of the 4 pts at the maximum tolerated dose of 300 mg/day who have currently completed the loading schedule, all 4 have achieved a reduction of Cp to within 10% of the target range within 21 days. Other toxicities at this dose level included sulphur burps (Gr 1), vomiting (Gr 2), neutropenia (Gr 2), and anaemia (Gr 3). Toxicities reduced in the second and subsequent cycles when doses were titrated downward to maintain Cp levels in target range. PK data indicate greater absorption of ATN 224 and more rapid reduction in Cp with concurrent administration of a proton pump inhibitor. Stable disease of >6 months was observed in 4 pts. Conclusions: Oral ATN-224 is a well-tolerated therapy and at a loading dose of 300 mg/day leads to a reduction of serum Cp levels to 20% normal within 21 days. This will be the recommended starting dose level for phase II study. (Sponsored by Cancer Research UK; funded by Attenuon, LLC).

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Evaluation of the safety of C-1311 administered in a phase I dose-escalation trial as a weekly infusion for 3 consecutive weeks in patients with advanced solid tumors
Authors: Isambert N. , Campone M. , Bourbouloux E. , Drouin M. , Major A. , Loadman P. , Capizzi R. , Grieshaber C. , Fumoleau P.
Published: March 2020

2069

Background: C-1311 is the most active member of a new series of anti-cancer agents, the imidazoacridinones, specially designed compounds developed from research on the structure-activity relationships of other cancer therapies such as the anthracenediones (e.g. mitoxantrone) and the anthracyclines (e.g. doxorubicin). This first-in-man clinical trial was designed to assess the safety profile of C-1311 and determine the recommended dose upon weekly administration for 3 consecutive weeks, within a 28-day cycle. Methods: Patients with advanced solid tumors refractory to conventional therapy were enrolled. The dose escalation scheme was divided into 2 phases: an initial accelerated phase of cohorts of 1 patient at doubling doses and a modified Fibonacci phase of cohorts of 3 pts at 25–33% dose increments. The maximum tolerated dose (MTD) was defined as the dose at which 2/3 or 2/6 pts experienced a dose-limiting toxicity (DLT). The recommended dose (RD) was defined as the dose level below the MTD, confirmed by expansion of the cohort to 9 pts. Results: 16 pts received doses of 15, 30, 60, 120, 240, 480 and 640 mg/m2/wk. The 2 pts treated at 640 mg/m2 experienced a DLT (grade 3 neutropenia preventing the administration of the 2nd and 3rd dose of the first cycle respectively). The RD was defined as 480 mg/m2/wk (cohort of 9 pts). Six additional pts were treated at the RD in an extension study in which one of the first 2 doses was given orally. Overall, 2 serious adverse events have been reported as possibly drug-related, both consisting of post-infusion fever without evidence of infection, resolving within 24 hours. Transient neutropenia was the only recurring grade 3 or 4 drug-related adverse event (AE). Grade 1 or 2 AEs most commonly reported as drug-related were nausea, asthenia, vomiting and diarrhea. Stable disease was observed in 3 patients with advanced malignancy. One pt had a stable course over > 8 cycles, and two had stable courses over 4 cycles. Plasma drug concentrations were linear and proportional to dose. Conclusions: The recommended phase 2 dose of 480 mg/m2, weekly × 3 q 28 days, offers a predictable safety profile and excellent tolerability.

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Phase I combination study of trabectedin (T) and capecitabine (C) in patients with advanced malignancies
Authors: Gore L. , Rivera E. , Lavallee K. , Holden S. , Grolnic S. , Cleere D. , Moulder S. L. , Elsayed Y. A. , Eckhardt S.
Published: March 2020

2079

Background: T binds to the minor groove of DNA, synergizes with functional nuclease excision repair and targets inducible transcription. T is active in several tumor types and exhibits preclinical synergy with C. The primary objective of this study is to determine the maximum tolerated dose (MTD) of T in combination with C. Secondary objectives include safety and pharmacokinetic (PK) analyses. Methods: Pts with advanced cancer, performance status 0–1 and adequate organ function are eligible. Pts received T starting at 0.4 mg/m2 over 3 hours on day 1 followed by C on days 2 through 15. The initial dose of C was 2000 mg/m2/day and was reduced to 1600 mg/m2/day due to GI dose-limiting toxicity. Dose escalation of T continued. Cycles are repeated every 3 weeks, with PK sampling included. Standard “3+3” dose escalation design, definitions of dose limiting toxicity (DLT), and dose modification for toxicity are implemented. Results: To date, 30 patients have received 112 cycles (range 1–12, median 4) of treatment at 7 dose levels. Two of 3 pts at dose level 4 (C 2000 mg/m2/d and T 0.9 mg/m2) and 2/6 pts at dose level 3 (C 2000 mg/m2/d and T 0.75 mg/ m2) developed gastrointestinal DLT (emesis, diarrhea, pancreatitis). C was subsequently reduced to 1600 mg/m2/d and a new T dose escalation was initiated at 0.6 mg/m2. Treatment has been well tolerated with C 1600 mg/m2/d and T up to the current dose of 0.9 mg/m2 (dose level 4a), with 1of 6 subjects experiencing grade 1 alkaline phosphatase. The most frequently reported related grade 3–4 adverse events (AEs) are diarrhea (23%), neutropenia (20%), nausea (16.6%), hand-foot syndrome (16.6%) and vomiting (13%). Anti-tumor activity to date includes a confirmed partial response lasting 8 months (m) in a patient with cholangiocarcinoma, and prolonged stable disease in 2 patients with breast cancer (6 and 7m), ovarian cancer (11m) and chondrosarcoma (9m). Conclusions: The combination of C 1600mg/m2/d and T up to 0.9mg/m2 is tolerable and has promising activity in several tumor types. Dose escalation of T continues at 1.1 mg/m2. Biologic and pharmacokinetic analyses will be presented.

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