bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of daily administration of MGCD265 to patients with advanced malignancies (Study 265–101)
Authors: Kollmannsberger C. K. , Hurwitz H. , Vlahovic G. , Maroun C. , Dumouchel J. , Reid G. , Martell R. , Shapiro G. 
Published: August 2020

e14525 Background: MGCD265 is a novel multitargeted receptor tyrosine kinase (RTK) inhibitor that targets the mesenchymal epithelial transition (c-Met) and the vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2, and VEGFR3). Additional RTK targets include Tie-2, and Ron. Those kinases are known to be involved in tumor development and angiogenesis. The objective of this Phase I study is to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of daily administration of MGCD265 in patients with solid tumors. Methods: This is a multicenter, open-label, dose escalation study of oral MGCD265 administered as a continuous 21-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: Ten patients with advanced solid tumors have been treated. Characteristics: age range 25–75; gender: 8 M/2F; ECOG: 0 (1 patient); 1 (9 patients). At dose levels of 24, 48 and 96 mg/m2, no DLTs nor grade 2 or greater drug-related AEs during cycle 1 have been reported. Eight patients received treatment for 2 cycles or more. Preliminary PK profile after the first dose of administration shows a dose dependent increase in AUC and Cmax with an approximate mean half-life of 23 hours (see Table below). 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: Daily oral administration of MGCD265 was found to be well tolerated at doses of 24, 48, and 96 mg/m2. Further dose escalation is underway. [Table: see text] [Table: see text]
Phase I study of everolimus (E; RAD001) + low-dose weekly cisplatin (C) for patients with advanced solid tumors: Preliminary results
Authors: Fury M. G. , Sherman E. , Stambuk H. , Haque S. , Lisa D. , Shen R. , Carlson D. , Pfister D. G. 
Published: August 2020

e14527 Background: Preclinical studies demonstrate synergistic anti-tumor activity with the combination of E + C. Methods: Patients received E per oral for days 1–21 of a 28 day cycle. E was dose escalated though 4 planned dose levels (DLs): 2.5 mg/day, 5 mg/day, 7.5 mg/day, and 10 mg/day. Cisplatin dose was fixed at 20 mg/m2 intravenously on days 1, 8, 15. A standard 3 + 3 dose escalation scheme was used. Blood samples for pharmacokinetics were collected on Day 1 and Day 8 of Cycle 1. Response was assessed by RECIST after 2 cycles. Results: 24 patients enrolled: 13 M, 11F; median age 62 (32–77); median number of prior cytotoxic chemotherapy regimens 1 (0–3; 75% with prior RT). At DL1, 3 patients were inevaluable (1 withdrawal of consent prior to treatment, 1 disease progression during cycle 1, 1 recurrent diverticulitis during cycle 1) and were replaced. DL 1 was expanded after a patient with melanoma metastatic to liver had sudden death of unclear cause, and the protocol was amended to exclude patients with hepatic dysfunction. At DL2, one patient experienced grade 3 small bowel obstruction of uncertain etiology, and the dose level was expanded to 6 evaluable patients without additional DLT. No DLTs occurred at DL3. No DLTs have occurred to date among 6 patients enrolled at DL 4. Adverse events per cycle (total n = 63 cycles; 20 patients evaluable for toxicity) include: lymphopenia G3 (19%), AST G3 (3.2%), alkaline phosphatase G3 (3.2%), ALT G3 (1.6%), hyponatremia (1.6%). Median cycles per patient, 2 (range <1 to 10+). Minor response seen in pulmonary carcinoid (n = 1); prolonged SD ≥ 6 cycles seen in pulmonary carcinoid (n=2), basal cell carcinoma (n=1), and esthesioneuroblastoma (n=1). Conclusions: Pending safety analysis at the final planned dose level, the phase II recommended dose is E 10 mg/day (days 1 - 21) + C 20 mg/m2 (days 1, 8, and 15) on a 28-day cycle. [Table: see text]
Bevacizumab (BEV) and continuous low-dose granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid tumors: final results of a prospective clinical trial
Authors: Kurbacher C. M. , Schmidt M. , Kurbacher J. A. , Schäfer S. , Arenz P. N. , Nagel W. J. , Reinhold U. 
Published: August 2020

e14544 Background: BEV is potent inhibitor of VEGF-mediated tumor angiogenesis. VEGF is also crucial in antineoplastic immunortolerance by blocking the generation of dendritic cells (DC). VEGF inhibition may thus result in an improved anti-cancer immune response which may be further augmented by GM-CSF, a powerful stimulator of DC generation. In a previous study, GM-CSF was able to produce clinical responses in patients (pts) suffering from refractory carcinomas (Kurbacher et al., Oncology 2005). In this trial, we investigated BEV+GM-CSF in pts with advanced solid neoplasms. Methods: 26 pts have been enrolled: epithelial ovarian cancer, n=12; breast cancer, n= 6; primary peritoneal carcinoma, n=3; hormone-refractory prostate cancer, n=2; miscellaneous, n=3. All pts have been considered refractory to or non-treatable by chemotherapy due to their baseline bone marrow and/or organ functions. Fourteen pts had previously received BEV as part of other antineoplastic regimens. BEV was applied at a fixed dose of 6 mg/kg q2w. The starting dose of GM-CSF (sargramostim) was 125 μg/d. In cases not responding and/or not achieving moderate leukocytosis (< 20 G/L), GM-CSF was increased every 4 weeks at 25 μg increments up to a maximum of 250 μg/d. Toxicity was documented according to the NCI-CTC score, responses were recorded according to the RECIST or Rustin criteria. Results: Grade (G) 3–4 hypertension was seen in 3 pts, with 1 pt experiencing cerebral stroke 6 weeks after cessation of BEV+GM-CSF. Other G3–4 toxicities were fatigue in two pts, and fever, pain, myalgia, and central nervous symptoms in either one pt. Other side-effects like injection-site reactions, proteinuria, anemia, thrombocytopenia, and constipation did not exceed G1–2. The objective response rate was 31% (1 CR, 7 PR, 10 SD, and 8 PD); the rate of pts benefiting was 69%. Eight pts failing prior BEV benefited from BEV+GM-CSF. Until today, 13 pts have died. The median time to progression is 92 days and the median overall survival is 302 days. Conclusions: BEV+GM-CSF is an active and generally well tolerated non-cytotoxic regimen in pts with advanced solid tumors. Thus, large-scaled studies of this promising treatment are warranted. No significant financial relationships to disclose.
Incidence of thromboembolism in patients receiving vorinostat: Clinical trial and post-marketing data from more than 1,800 patients
Authors: Rizvi S. , Lis J. , Boileau K. , Garcia-Vargas J. 
Published: August 2020

e14547 Background: Thromboembolic events (TEEs) occur in approximately 10–15% of advanced cancer patients. Risk factors include cancer therapy and extent and type of malignancy. Vorinostat, a histone deacetylase inhibitor, has been licensed in the USA for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following two systemic therapies. TEEs were observed in 6/86 patients (7.0%) enrolled in vorinostat CTCL clinical trials at licensure. To gain further insight into the association between TEEs and vorinostat treatment, we analyzed data from vorinostat clinical trials and post-marketing surveillance (PMS) reports. Methods: Serious adverse events (SAEs) reported through November 3, 2008, among patients receiving vorinostat in completed and ongoing clinical trials, PMS reports, and published literature were reviewed for terms consistent with TEEs. A committee of independent (non-Merck employees) academic experts evaluated these reports. Although no safety signals were observed, the committee recommended that d-dimer and/or plasmin-antiplasmin assays should be conducted. This recommendation has been implemented in three ongoing studies ( NCT00486720 , NCT00632931 , NCT006429542) and will provide further information on clotting parameters among patients being treated with vorinostat. Results: During the reporting period, data from >1,845 cancer patients who received vorinostat were reviewed. Irrespective of causality, 107 patients (<5.8%) reported TEE SAEs (Table). Of these, 47 (<2.6%) had TEE SAEs that were rated as related to vorinostat, four of which were fatal. As of the data cut off, review of the special assays in the three studies did not result in any conclusive correlation. Conclusions: The incidence rate of TEEs observed in vorinostat studies is similar to reported rates of TEEs for advanced cancer patients. [Table: see text] [Table: see text]
Non-invasive bioluminescence imaging of caspase-3 activity in Breast Cancer
Authors: Olsen C. C. , Li F. , He Z. , Li W. , Li C. 
Published: August 2020

e14557 Background: Apoptosis is a major form of tumor cells death during cytotoxic therapy. Understanding the kinetics of apoptosis would greatly facilitate development of more effective therapeutic approaches. In order to monitor apoptosis activities in vivo, we developed a novel bioluminescence-based reporter gene to detect caspase 3 activities, which are elevated at the execution phase of apoptosis. Methods: A caspase-3 reporter system was constructed by combining two different reporter proteins; green fluorescent protein (GFP) and firefly luciferase (FL) linked through multiple polyubiquitin domains with a caspase-3 recognition site. Under normal circumstances, the reporter proteins are rapidly degraded by the proteasome system.. During apoptosis, activated caspse 3 cleaves off the multi-ubiquitin domain from the reporter protein. This enable the GFP and luciferase fusion reporter to be stabilized and achieve a significant gain in GFP protein and luciferase activities, which in turn could be monitored both in vitro and in vivo. 4T1 cells transduced with CMV-luc or Caspase-3 reporter xenografts were treated with both chemotherapy and radiation therapy and monitored for apoptosis activity. Results: In vitro experiments demonstrated increased luciferase with increasing radiation dose reflective of apoptosis with background levels nearly undetectable. Taxol was associated with a time-dependent increase from 24 to 72hrs after drug exposure, indicating that apoptosis is a gradual, heterogeneous process. EGFP signal increased from 1.85% in controls to 80.6% in cells treated with 1uM Taxol. Xenografts showed nearly undetectable luciferase background with Cytoxan therapy resulting in a 90-fold increase, 10 Gy a 24 fold increase and fractionated RT (5Gy x3) with a 46-fold increase. Conclusions: We developed a novel in vivo caspase reporter based on the ubiquitous proteosome system of protein degradation and bioluminsecence imaging. This allowed us to assess activation of apoptosis in response to chemoradiation therapy in tissue culture and breast cancer xenografts over the course of 2–3 weeks, which has not been possible with other technologies. No significant financial relationships to disclose.
In vitro and in vivo anti-leukemia activity of CHR-2845, a cell-targeted HDAC inhibitor for use in monocytic leukemia
Authors: Tong W. , Stevenson W. , Cortes J. , Needham L. , Brotherton D. , Davidson A. , Drummond A. , Garcia-Manero G. 
Published: August 2020

e14579 Background: Histone deacetylase inhibitors alter gene expression and induce apoptosis in a wide range of cancer cells including those derived from human leukemias. CHR-2845 is a novel hydroxamic acid derivative histone deacetylase inhibitor (HDACi) which is a selective substrate for the intracellular carboxylesterase hCE-1, whose expression is restricted to cells of the monocyte- macrophage lineage. Methods: We studied the in vitro and in vivo anti-leukemia activity of CHR-2845 using cell proliferation assay, annexin V binding assay, cell cycle analysis, western blot and in vitro primary leukemia cell culture. Results: Both U937 and THP1 cells express high levels of hCE-1 whereas the myeloid cell line, HL60, does not. In comparison to vorinostat, CHR-2845 showed increased anti-proliferative potency (IC50) against monocytic cell lines (THP1, 30 nM vs 700 nM and U937, 30 nM vs 475 nM), compared to a myeloid cell line (HL60, 700nM vs 470 nM). In a broad panel of leukemic cell lines, the potency of CHR-2845 over vorinostat correlated completely with hCE-1 expression. In monocytic cell lines, CHR-2845 induced more apoptosis than vorinostat (THP1: 45±5% vs 11±1% and U937: 23±14% vs 6±1%), as measured by flow cytometry using Annexin V. Biochemical assessment of histone H3 and H4 protein acetylation by Western blot also indicateed that CHR-2845 is at least 10 times more potent than vorinostat in monocytic cell lines but not in HL-60 cells. This increase in histone acetylation was associated with increased phosphohistone H2AX, indicating formation of double-strand DNA breaks induced by this compound. These data for CHR-2845 and vorinostat on apoptosis and histone acetylation in THP1 and U937 versus HL60 cells, confirmed the selectivity of this novel compound for cells of the monocytic lineage. We also studied the anti-leukemia activity of CHR-2845 in primary leukemia cells from 8 patients with acute or chronic myelomonocytic leukemia. CHR-2845 decreased proliferation and induced apoptosis more than an equivalent dose of vorinostat in some of the patients we studied. Conclusions: These results indicated that CHR-2845 has potential to be efficacious in the treatment of patients with monocytic leukemia. [Table: see text]
Correlation of sorafenib plasma concentrations and clinical toxicity: A prospective population pharmacodynamic and pharmacokinetic study
Authors: Billemont B. , Hornecker M. , Ropert S. , Blanchet B. , Jais J. , Blanchard P. , Meric J. , Alexandre J. , Tod M. , Goldwasser F. 
Published: August 2020

e14585 Background: Sorafenib is an angiogenesis inhibitor recently approved for the treatment of metastatic renal cell carcinoma and hepatocarcinoma. This oral multi-targeted kinase inhibitor blocks the VEGF, PDGF receptors, BRAF and c-kit. In clinical trials, severe toxicities included rash, hand-foot syndrome and diarrhea. We investigated the relationship between severe toxicity and sorafenib plasmatic exposure. Patients and methods: From February 2008 to December 2008, 32 patients (pts) were treated with sorafenib (800 mg given daily). Clinical and blood exams were performed at baseline and every 2 weeks. Toxicity events were graded according to National Cancer Institute Common Toxicity Criteria 3.0. The sorafenib area under the plasma concentration-time curve over 12 hours (AUC0–12) was determined every 2 weeks by gradient elution liquid chromatography, data analysis with one-compartment disposition and a population approach using NONMEM software. Grade 3 toxicity free survival was estimated by Kaplan-Meier method. Results: Pts (23 males), ECOG 0–1 (27 pts), median age 62.8 years (range 37–78), with metastatic hepato-carcinoma (11), melanoma (6), thyroid cancer (8), renal cell carcinoma (7), received a median treatment duration of 94 days (range : 7–330). 20 pts experienced grade 3 toxicities with 33 events: hand-foot hyperkeratosis (14), diarrhea (5), cutanous rash (4), asthenia (2), anorexia (2), dyspnea (1), scrotal toxicity (1), post surgical complication (1), hypertension (1), increase creatinine level (1), digestive hemorrhage (1). The median AUC0–12 was 62.4 mg/L.h, ranging from 28.7 to 202.2 mg/L.h. Amongst pts experiencing grade 3 toxicity, two groups of 16 pts were defined with the median AUC0- 12 as cut off: low exposure (Lw) and high exposure (Hi). Six Lw pts experienced grade 3 toxicity versus 14 Hi pts (exact Fisher Test p=0.009). The probability of free grade 3 toxicity survival was higher for Lw (Logrank test p=0.004). Conclusions: These results show that grade 3 toxicity occurrence may be related to high plasma sorafenib exposure. This supports the need for therapeutic drug monitoring to prevent toxicity grade 3 occurrence and therefore optimize the clinical management of patients under sorafenib. No significant financial relationships to disclose.
Single-agent and combination activity of suberoylanilide hydroxamic acid (SAHA, vorinostat) in small cell lung cancer (SCLC) cell lines
Authors: Cubitt C. , Zhang S. , Chiappori A. 
Published: August 2020

e14586 Background: SCLC represents a major therapeutic challenge. Histone deacetylase inhibitors (HDAC-I) are a new class of drugs. Exposure to HDAC-Is results in hyperacetylation of core histone proteins, with subsequent chromatin decondensation, and increased topoisomerase inhibitor (TI) DNA binding, with potentiation of DNA damage and apoptosis. This synergy is only observed when the HDAC-I precedes the TI. We investigated the activity of SAHA, an HDAC-I with broad activity in different cancer cell lines, and the potential synergy between SAHA and TIs, in SCLC cell lines. Methods: TIs were obtained from chemical supply companies and SAHA from Merck. Four different cell lines (DMS-114, NCI-H69, NCI-H82, and NCI-H526) were grown and cryopreserved in the recommended media. Drug activity was determined by a high-throughput CellTiter-Blue cell viability assay. A luciferase based assay (Caspase-Glo 3/7) was used to confirm apoptosis as the cause of cell viability reductions. The Chou and Talalay method was used to optimize the drug doses to use in a combination, and to determine the influence of drug sequencing on any additive or synergistic anti- tumor effect. Results: The 72 hours inhibitory concentration 50 (IC50) values corresponding to each drug and cell line is reported in the Table . Using the CellTiter-Blue cell viability assay, the combination index (CI) for SAHA with each of 2 TIs (topotecan and etoposide) was calculated concurrently and sequentially. The strongest synergism was always detected when SAHA and the TI were combined sequentially (SAHA first). This observation was reproduced when the CI was calculated using the Caspase-Glo 3/7 luciferase based assay. Conclusions: The anti-tumor activity of SAHA in SCLC cell lines is comparable to that of common TIs. The synergism observed between SAHA and TIs is sequence specific and highest when drugs are used sequentially (SAHA first). Clinical confirmation of this synergism is warranted in patients with SCLC. [Table: see text] No significant financial relationships to disclose.
Ex-vivo analysis of the isoform selective histone deacetylase inhibitor entinostat in triple-negative breast cancer tumors
Authors: Ordentlich P. , Tee L. , Huynh Y. , Mee S. , Mamuszka H. , Lee G. 
Published: August 2020

e14597 Background: Triple-negative (ER, PR, HER2 negative) breast cancer represents an unmet need for which novel agents and approaches are essential. Entinostat is an orally available, class 1 isoform selective histone deacetylase inhibitor currently in multiple phase 2 clinical studies including advanced NSCLC and breast cancer. Studies in vitro and in vivo in the triple negative cell line model MDA-MB-231 have established single agent activity of entinostat in inhibiting tumor growth as well preventing bone metastases. In addition, entinostat induces expression of ERα in MDA-MB-231 in vivo and is synergistic with endocrine therapy agents to inhibit tumor growth of ER negative cancer cells. The aim of these studies was to confirm the activity of entinostat in triple negative breast cancers using human breast tumor explants. Methods: Cytotoxicity of entinostat was determined by the Oncotech Extreme Drug Resistance (EDR) proliferation assay using ten cryopreserved breast tumor explants known to lack estrogen receptor, progesterone receptor and HER2/neu expression (i.e. Triple negative) by immunohistochemistry. Results: Dose response curves of entinostat were analyzed and compared to paclitaxel at 2.45 μM in ten triple negative breast tumor explants in the EDR assay. Entinostat was broadly effective in all of the tumors tested, with most samples showing dose-dependent response for the range of concentrations analyzed (0.003 - 10 μM). Two of the breast tumors that were most sensitive to entinostat (IC50 30- 100nM) were also sensitive to paclitaxel. In contrast, entinostat effectively inhibited (IC50 10–270nM) the growth of eight of the tumors that were resistant to paclitaxel (i.e. < 50% growth inhibition). Overall, all breast tumors tested were sensitive to entinostat at clinically achievable concentrations regardless of paclitaxel resistance indicating entinostat may improve the treatment outcome of triple negative breast cancer patients. Conclusions: Entinostat is an effective agent at inhibiting the growth of triple negative breast tumors with clinically relevant IC50's ranging from 10nM to 270nM. A pre-surgical clinical study to assess the activity of entinostat in triple negative breast cancer patients is planned. [Table: see text]
Activity of dasatinib with chemotherapy in triple-negative breast cancer cells
Authors: Tryfonopoulos D. , O'Donovan N. , Corkery B. , Clynes M. , Crown J. 
Published: August 2020

e14605 Background: Triple-negative breast cancers (TNBC) lack expression of oestrogen, progesterone, and are HER-2 normal. TNBC cell lines have displayed greater sensitivity to growth inhibition by the multi-target kinase inhibitor, dasatinib, than luminal or HER- 2 positive breast cancer cell lines. The aim of this study was to assess the direct anti-tumor effects of dasatinib in combination with chemotherapy in TNBC. Methods: Four TNBC cell lines (MDA-MB-231, HCC-1143, HCC-1937, MDA-MB-468) were treated with dasatinib in combination with docetaxel, cisplatin or 5'-5' DFUR. IC50 values were calculated for each drug alone by determining response in a 5-day proliferation (acid phosphatase) assay. Combination index (CI) values were determined, using CalcuSyn, to assess the interaction between drugs. Results: Three of the cell lines (MDA-MB-231, HCC- 1143, HCC-1937) were sensitive to dasatinib (IC50 < 1 μM) whereas MDA-MB-468 was resistant (IC50 > 1 μM) (Table). In MDA-MB-231 and HCC-1143 cells, combined treatment with dasatinib and 5'-5'-DFUR displayed synergy (CI<1.0), whereas the combination was additive in HCC-1937 cells (CI=0.98). Combined treatment with dasatinib and cisplatin was synergistic in the three dasatinib sensitive cell lines (CI<1.0). Dasatinib in combination with docetaxel displayed moderate synergy in MDA-MB-231 and HCC-1937 cells (CI<1.0), but was antagonistic in HCC-1143 cells (CI>1.0). Conclusions: Our findings show that the combination of dasatinib with either 5'-5'-DFUR or cisplatin is synergistic in TNBC cell lines, and suggest that combinations of dasatinib with chemotherapy may improve response in triple negative breast cancer patients. [Table: see text] No significant financial relationships to disclose.