bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of AMG 655 in combination with paclitaxel and carboplatin (PC) in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Paz-Ares L. , Sánchez Torres J. M. , Diaz-Padilla I. , Links M. , Reguart N. , Boyer M. , Wiezorek J. , Sabin T. , Pan Y. , Van Meerbeeck J. 
Published: August 2020

e19048 Background: AMG 655 is an investigational, fully human IgG1 monoclonal agonist antibody that binds human death receptor 5 (DR5), activates caspases, and induces apoptosis in sensitive tumor cells. The primary objective of this phase 1b study was to determine the maximum tolerated dose (up to a target dose of 15 mg/kg) of AMG 655 that can be safely administered with PC. Methods: Eligibility included: ≥ 18-years old, untreated, advanced NSCLC, and ECOG PS 0 or 1. Patients (pts) were enrolled in sequential dose cohorts of AMG 655 (5 or 15 mg/kg) + P (200 mg/m2) and C (AUC = 6 mg/mL x min) IV every 3 weeks for up to 6 cycles. After completion/discontinuation of PC, pts may continue AMG 655 as monotherapy. Endpoints include: incidence of dose- limiting toxicities (DLT); adverse events (AE); pharmacokinetics (PK); levels of plasma genomic (g)DNA, serum caspase 3/7 activity, and M65 (cell death and apoptosis biomarkers); objective tumor response rate (by RECIST), and progression-free survival (PFS). Results: As of 09/08, 12 pts enrolled and received ≥ 1 dose of AMG 655 + PC. Ten were men; 11 had ECOG 1, and median (range) age = 68.5 (50–83) years. Median (range) time on AMG 655 = 5.2 (0.2–8.3) months; all pts have discontinued treatment. There was 1 DLT: grade 3 hyponatremia (15-mg/kg cohort). Five (42%) pts had grade 3 AE including neutropenia and dyspnea (2 pts each); 3 (25%) had grade 4 AE (2 with neutropenia, 1 with pulmonary embolism). After one 5- or 15-mg/kg dose of AMG 655 + PC, AMG 655 PK values (serum clearance, Cmax, AUC) were similar to the first-in-human study (LoRusso et al. JCO 2007; 25: abstr 3534) indicating no effect of PC on PK of AMG 655. Data also indicate no effect of AMG 655 on PK of PC. Plasma gDNA, serum caspse 3/7 activity, and serum M65 levels increased significantly from baseline 24 h after administration of AMG 655 + PC. Best overall tumor response: 1 complete response, 3 partial responses, 3 stable disease, and 3 progressive disease (2 pts had no on-treatment tumor assessments). Median (95% CI) PFS = 5.1 months (1.5, 7.0). Conclusions: AMG 655 administered with PC appears to be well tolerated with expected PK properties not altered by PC. A randomized phase 2 trial (AMG 655 ± PC) is ongoing. [Table: see text]
Chemosensitivity of newly established human malignant pleural mesothelioma cells: Significant growth inhibition by amrubicin, a novel 9-aminoanthracycline, or cyclooxygenase 2 inhibitor
Authors: Hida T. , Ogawa S. , Park J. , Park J. , Shimizu J. , Horio Y. , Yoshida K. , Sekido Y. 
Published: August 2020

e19060 Background: Malignant pleural mesothelioma is asbestos-related malignancy that is highly resistant to current therapeutic modalities. Survival of patients with malignant mesothelioma is very poor, especially in advanced stage, regardless of a recent advancement of chemotherapeutical modalities of combination with cisplatin and antifolate. Methods: Eleven cell lines derived from malignant mesothelioma were established in our laboratory. Chemosensitivity of these cell lines to nine chemotherapeutic drugs (cisplatin, vinorelbine, irinotecan, gemcitabine, pemetrexed, gefitinib, erlotinib, and amrubicin and its active in vivo substance, amrubicin-13-OH) and four cyclooxygenase 2 inhibitors was tested by MTT assay. Results: Anti-cancer agents, cisplatin, vinorelbine, gemcitabine, gefitinib, or erlotinib, showed little growth inhibition, and pemetrexed and irinotecan showed modest growth inhibition in malignant mesothelioma cells, whereas amrubicin-13-OH showed strong growth inhibition. Cyclooxygenase 2 inhibitors inhibit proliferation of malignant mesothelioma cells in a dose-dependent manner: modest growth inhibition at clinically achievable low concentrations and complete growth inhibition at clinically achievable high concentrations by intrapleural instillation. In addition, enhanced growth suppression was obtained by using amrubicin-13-OH in combination with cyclooxygenase 2 inhibitor. Conclusions: Our study suggests that amrubicin can inhibit proliferation of malignant mesothelioma cells. In addition, the use of a cyclooxygenase 2 inhibitor may be a promising therapeutic approach in the treatment of mesothelioma, because previous studies indicated the presence of increased cyclooxygenase 2 expression in malignant mesothelioma, which is notoriously resistant to chemotherapy. No significant financial relationships to disclose.
Primary chemotherapy, stereotactic radiosurgery, or whole brain radiotherapy in non-small cell lung cancer (NSCLC) patients with asymptomatic brain metastases
Authors: Kim K. , Lee J. , Chang M. , Uhm J. , Yun J. A. , Yi S. , Park Y. , Ahn J. , Park K. , Ahn M. 
Published: August 2020

e19063 Background: Approximately 25 to 30% of patients with lung cancer develop brain metastases at some stage and 12∼18% at the time of initial presentation. Whole brain radiotherapy (WBRT) has long been a mainstay of treatment of brain metastases. Another treatment approach, Stereotactic radiosurgery (SRS) is a method of delivering high doses of focal irradiation to a tumor while minimizing the irradiation to the adjacent normal tissue. However, the prognosis of NSCLC patients with asymptomatic brain metastases, who are not treated with SRS or WBRT, has not been fully investigated yet. This study aimed to analyze the outcome for various treatment modalities in NSCLC patients with asymptomatic brain metastases. Methods: We reviewed the medical records of 129 patients with a histopathologically proven NSCLC and a synchronous brain metastases between January 2003 and December 2007. The patients were categorized as primary chemotherapy, primary SRS, and primary WBRT group: primary chemotherapy (78 patients), primary SRS (24 patients), and primary WBRT (27 patients). Results: With median follow-up of 30.0 months (7.2 -70.7), the median overall survival (OS) for the entire patients was 15.6 months (0.5–50.7) and the progression free survival (PFS) was 6.1 months (0.3- 53.0). The OS was 22.4m for primary SRS group, 13.9m for primary chemotherapy group, and 17.7m for primary WBRT group; p=0.86). However, patients treated with primary SRS showed trend toward prolonged survival compared to those of primary WBRT p=0.06). Subset analysis of 110 adenocarcinoma patients showed that the median OS for patients treated with primary SRS was longer than those of primary WRBT (29.3m vs 17.7m p=0.01) or primary chemotherapy (29.3m vs 14.6m p=0.04). Conclusions: These results suggest that for NSCLC patients with asymptomatic brain metastases at first diagnosis, SRS rather than primary chemotherapy or WBRT might be considered as initial treatment, especially for patients with adenocarcinoma. No significant financial relationships to disclose.
Phase II study of combination chemotherapy with docetaxel and carboplatin for elderly patients with advanced non-small cell lung cancer
Authors: Kim B. , Kim H. , Kim T. , Lee H. , Lee B. , Kim J. , Nam S. 
Published: August 2020

e19073 Background: More than 50% of advanced non-small cell lung cancer (NSCLC) are diagnosed in patients older than age 65 years. Cisplatin-based chemotherapy has been used in patients with advanced NSCLC as standard treatment, and we investigated the efficacy and safety of combination chemotherapy with docetaxel and carboplatin for elderly patients with advanced non- small cell lung cancer. Methods: Chemotherapy-naïve patients (age ≥ 65 years) with stage IIIB or IV NSCLC were enrolled. Patients received docetaxel (75 mg/m2 on D1) and carboplatin (AUC of 5 mg/ml/min on D1) every 3 weeks. End points included response, time to progression, overall survival, and toxicity. Results: Total 37 patients were enrolled between March 2005 and August 2008. Median age was 75 years old (range, 65 to 84 years), and 33 patients (89.2%) had ECOG PS 0 or 1. Twenty two patients (59.5%) had increased Charlson comorbidity index score (CCI ≥1). The median number of treatment cycles was five (range, 1–8), and relative dose intensity was 95.6% in docetaxel and 95.8% in carboplatin. Overall response rate was 51.3% (95% CI 34.9–67.1) with one complete response, and 18 partial responses. The median time to progression was 6.7 months and median overall survival was 12.3 months. In 164 cycles, grade 3 or 4 hematologic toxicities included neutropenia (10.4%), anemia (1.8%), and thrombocytopenia (1.2%). Non-hematologic toxicities were tolerable. Conclusions: The combination chemotherapy with docetaxel and carboplatin was effective with tolerable toxicities in elderly patients with advanced non-small cell lung cancer. No significant financial relationships to disclose.
Treatment of advanced non-small cell lung cancer (NSCLC) with a biweekly schedule of irinotecan (I), paclitaxel, and cisplatinum (P): A phase II study
Authors: Gonzalez M. , Rebollo J. , Rami R. , Belda J. , Farré J. , Azinovic I. , Crespo A. , Brugarolas A. 
Published: August 2020

e19076 Background: Irinotecan, paclitaxel (taxol, T), and cisplatinum are among the most active agents in the treatment of NSCLC, given alone as single agents or in combination. Based in previous data (Proc ASCO 2003 # 2816), we performed a confirmatory phase II study of the activity of a bi-weekly combination of I (120 mg/m2), T(60 mg/m2) and P (40 mg/m2) in advanced NSCLC. Methods: Forty-three patients (pts) (37 male, 6 female) with histologically proven IIIA-IV NSCLC were treated at our institution. Median age was 61 years (33–79). All pts were ECOG 0–2. 14 pts had locally advanced disease (8 IIIA, 6 IIIB) and 29 metastatic disease. Previous treatments included surgery (5 pts), radiotherapy (4 pts), chemotherapy (5 pts), surgery + radiotherapy (3 pts) and surgery + chemotherapy (2 pt). In three cases, treatment was administered as adjuvant after resection of a primary (2 cases) or a metastatic tumor (1 case). Results: A total of 299 courses were administered (median 6, range 2–14). Toxic episodes grade III-IV were neutropenic fever (10/299; 3.3%), anemia (1/299; 0.3%), asthenia (3/299; 1%), diarrhea (5/299; 17%), hemorrhagic colitis (1/299; 0.3%), mucositis (2/299, 0.6%), vomiting (4/299; 1.3%) and peripheral neuropathy (1/299; 0.3%). With a median follow-up of 72 months (9–97), 2 pts (4.6%) presented pathological complete response, 26 (60%) partial response, 11 (25%) stable disease and 1 pt progressed. Four partial responders were rendered free of disease after rescue surgery. Median time to progression was 6 months. Median survival was 10 months. The actuarial 2 and 5-year overall survival are 26% and 13% respectively. Conclusions: I, T and P at the referred doses can be safely administered in a bi-weekly basis, with a good tolerance and response rate in advanced NSCLC pts. No significant financial relationships to disclose.
Metronomic antiangiogenetic biochemotherapy of non-small cell lung cancer patients with fractionated cisplatimum, oral etoposide, and bevacizumab
Authors: Remondo C. , Migali C. , Martellucci I. , Carbone F. , Ricci V. , Addeo R. , Del Prete S. , Fulfaro F. , Francini G. , Correale P. 
Published: August 2020

e19083 Background: Chemotherapy efficacy in advanced non small cell lung cancer (NSCLC) patients may be augmented if combined with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF) with anti-angiogenetic activity. Metronomic chemotherapy is a newest approach which employs cytotoxic drugs at lower doses with very close and regular administrations, which has shown anti-angiogenetic effects, epigenetic attenuation of cancer phenotype and immune-modulation. Metronomic chemotherapy with cisplatinum and oral etoposide (mPE) has been tested in NSCLC patients with promising results. We have thus investigated a newest biochemotherapy regimen with mPE + bevacizumab (mPEBev regimen) in advanced NSCLC patients. Methods: This is a phase IB/II trial designed to evaluate toxicity, anti-tumor and biological activity of bevacizumab given at escalating doses in combination with mPE chemotherapy. Twenty-six patients with inoperable NSCLC and an ECOG≤2 were enrolled in the study and received every 21 days, iv. cisplatinum (30 mg/sqm, days 1–3), oral etoposide (50 mg/sqm, days 1–15) and bevacizumab (day 3) at different dose levels (no antibody/control group; 2.5; 5; 7.5; and 10 mg/kg). Results: The treatment resulted very active in those patients who received bevacizumab with a 95% objective response rate (19/20), with a median time to progression of 7.55 months. There were two early deaths at higher bevacizumab dosages: one due to a cardiovascular accident (7.5 mg/kg) and another to lung hemorrhage (10mg/kg). We reported also 4 cases of psychic depression and 4 cases of pneumonia which evolved into lung cavitation. A magnetic resonance monitoring showed a significant treatment-related blood perfusion reduction in the tumor site. It was also observed a progressive decrease in VEGF, thrombospondin-1 levels which were not dependent upon bevacizumab dose and were not observed in the controls. Conclusions: mPEBev regimen resulted very active in advanced NSCLC patients. Our metronomic biochemotherapy regimen with lower bevacizumab doses (2.5–5 mg/Kg) deserves to be investigated in further phase II-III trials. No significant financial relationships to disclose.
A phase II trial of first-line bevacizumab in combination with pemetrexed and carboplatin in advanced nonsquamous non-small cell lung cancer (NSCLC)
Authors: Skaff Z. G. , Hageboutros A. , Krieger K. , Coakley S. , Somer R. , Stevenson J. 
Published: August 2020

e19091 Background: Combining bevacizumab (Bev) with platinum doublet yields a survival benefit in previously untreated patients with advanced nonsquamous non-small cell lung cancer. Carboplatin with pemetrexed is an efficient combination that is potentially less toxic. This phase II trial evaluates the efficacy and the safety of adding bevacizumab to carboplatin and pemetrexed in advanced non-small cell lung cancer. Methods: This is a single arm, open-label phase II trial. Eligibility stipulated enrollment of patients with stage IIIB/IV non-squamous non-small cell lung cancer with an ECOG PS 0–1 and no other contraindications to Bev. Treatment consisted of pemetrexed 500 mg/m2, carbo AUC 6 and Bev 15mg/kg on day 1, repeated every 3 weeks. If clinical benefit was proven, patients received Bev maintenance until progression. The response was evaluated every two cycles. The primary endpoint was time to progression (TTP); secondary endpoints included overall survival, response rate (RR) and grade 3–4 toxicities. Results: As of September 2008, 27 out of 42 projected patients were enrolled of which, 14 were males and 13 females; median age 68 (72% older than 60); IIIB/IV 5/22; median number of cycles 9 (range 2–33). At the time of analysis, 25 patients were evaluable. Preliminary results show a median time to progression of 7.25 months (95% CI, 6.4 to 8.2). 23 patients (92%) had disease control (95%, CI 82–96%) with an overall response rate of 36% (95%, CI 25–47%).14 patients had stable disease (56%), 8 had partial response (32%) and one achieved a complete response (4 %). Median survival has not yet been reached. Grade 3/4 adverse events include: Cerebral ischemic event (N=1), Anorexia (Gr 3: N= 5/ Gr 4: N= 4), gastrointestinal fistula (N=1), hypertension (Gr3: N=3), epistaxis (Gr 3 N=1), vomiting (Gr 3; N= 3), fever (Gr 4: N=1) and neuropathy (Gr 3: N=2). Conclusion: The addition of bevacizumab to carboplatin and pemetrexed appears to be an active first line treatment with a high disease control rate and an acceptable toxicity profile in the setting of advanced non-small cell lung cancer. No significant financial relationships to disclose.
A phase I trial of S-1 plus vinorelbine in patients with unresectable advanced or metastatic non-small cell lung cancer
Authors: Suyama H. , Shigeoka Y. , Igishi T. , Matsumoto S. , Kodani M. , Takeda K. , Sumikawa T. , Morita M. , Ueda Y. , Shimizu E. 
Published: August 2020

e19098 Background: We reported the efficacy of the combination treatment of tegafur-uracil (UFT) and vinorelbine (VNR) for the elderly patients (pts) (>70) with advanced non-small cell lung cancer (NSCLC) in ASCO 2007 (Abstract - No. 18075). Although the cisplatin-based doublets are still milestone for the pts with advanced NSCLC, non-platinum based doublet regimens remain as a matter of development judging from recent meta-analysis. Tegafur-5-chloro-2,4-dihydroxypyridine-potassium oxonate (S-1), a new oral fluoropyrimidine, has been studied extensively, and appears promising for various kinds of cancers including NSCLC. Thus, we conducted this phase I trial using VNR and new oral fluoropyrimidine, S-1. Methods: Pts with advanced NSCLC, who had received at least one prior platinum-containing regimen, were eligible. In this phase I study, VNR was infused on days 1 and 8, and S-1 was administered from day 2 to day 6 and from day 9 to day 13 of a 3-week cycle. The starting dose of S-1 was 80 mg/m2/day and, if necessary, the dose was decreased to 65 mg/m2/day; VNR was increased from 20 to 25 mg/m2 in this trial. Results: From August 14, 2007 to April 1, 2008, 8 pts enrolled in this study. Median age was 61 (range 49–75). Dose limiting toxicity (DLT) was evaluated during the first 6 weeks of the treatment. No DLT was observed at dose level I (80 mg/m2/day S-1, 20 mg/m2 VNR). At dose level II (80 mg/m2/day S-1, 25 mg/m2 VNR), DLT in the form of neutropenia, hyperglycemia and hyponatremia was observed in 3 of 5 pts. The maximum tolerated dose (MTD) for the present treatment was 80 mg/m2/day S-1 and 25 mg/m2 VNR; the recommended tolerable dose for future phase II trials is therefore 80 mg/m2/day S-1 and 20 mg/m2 VNR. Conclusions: Three-week cycle of VNR (20 mg/m2), infused on days 1 and 8; S-1 (80 mg/m2/day), administered from day 2 to day 6 and from day 9 to day 13, is being examined in our phase II trial for first-or second-line treatment of NSCLC. No significant financial relationships to disclose.
Colloidal cDNA encoding recombinant multimodular proteins rMDVA comprising disintegrin/cysteine rich disulfide bond 2RGD, and C-terminal domain (ammodystatin), metalloprotease-domain (ammodylysin), and dimeric disintegrin/MLD-VGD domain (VADD) isolated from vipera ammodytes, exerted synergistic action with vinorelbine against metastatic NSCLC, circumventing chemotherapy-mediated systemic toxicity
Authors: Dritsas J. , Giannios J. , Michailakis E. , Alexandropoulos N. 
Published: August 2020

e19100 Background: We investigate if venom proteome of vipera ammodytes can induce apoptosis in NSCLC. Methods: We developed a large scale expression system with lung cell line (LCL), which we modified genetically by cloning. We expressed cDNA encoding multimodular disintegrin (rMDVA) comprising 3 domains from the venom of vipera ammodytes. The cDNA of rMDVA was cloned into the plasmid vector pcDNA III, which was transferred into LCL. The multimodular peptide rMDVA was encapsulated in the hydrophilic phase of liposomes termed as LIP-rMDVA. The in-vivo studies with human metastatic NSCLC were performed in an orthotopic xenograft model. Results: The venom proteome contained 140 proteins. We isolated the multimodular disintegrin displaying cysteine rich disulfide bond 2RGD, and C-terminal motif (ammodystatin), the dimeric MLD/VGD motif (VADD) and metalloprotease-domain (ammodylysin). Ammodystatin with the 2 (ARG-GLY-ASP) RGD motifs interacts with integrins avb5, a5b1 inhibiting invasion, angiogenesis/vasculogenesis and blocked the bFGF-induced avb3 integrin, and avb5 downregulating VEGF, and Ras. It also disrupts the actin cytoskeleton inducing G1 DNA replicative phase arrest, and blocks endothelial cell (EC) secretion of MMP-2, MMP-9, and urokinase type plasminogen activator with its receptor inhibiting proteolysis, and dissolution of ECM blocking invasion. Ammodystatin and ammodylysin lead to type I PCD/apoptosis of tumor cells in masses up to 2 mm, and EC. Beyond that size, ammodystatin inhibits the development of the required vascular network according to HUVEC, MVD, and IHC. VADD causes burring and blocked adhesion of a4b1 integrin to VCAM1. LDH, BrdU and MTT exhibited inhibition of tumor and EC proliferation. TEM exhibited apoptotic signs of irreversible D2 stage in tumor and ECs. Conclusions: Novel liposomal formulation LIP-rMDVA is an effective angiostatic, and cytostatic agent against metastatic NSCLC minimizing ST. No significant financial relationships to disclose.
Role of gefitinib (G) in heavily pretreated non-small cell lung cancer (NSCLC)
Authors: Tamburini E. , Tassinari D. , Pasquini E. , Papi M. , Possenti C. , Drudi F. , Castellani C. , Santelmo C. , Carloni F. , Ravaioli A. 
Published: August 2020

e19102 Background: To assess the role of a palliative treatment with gefitinib in advanced and heavily pre-treated NSCLC. Methods: The records of all the consecutive patients treated with G in our department were reviewed; all the patients pre-treated with at least one courses of a platinum-containing regimen were considered eligible and enrolled into the trial. All the patients were treated with G 250 mg/die until progression of the disease or intractable toxicity. All the patients were evaluated every 21 days for toxicity and every 2 months for survival. Primary end point was time to progression (TTP); secondary ones were overall survival (OS) and safety. A sub-analysis comparing TTP and OS on the basis of sex (male/female), smoker status (smoker/never-smoker) and histology (adenocarcinoma/non-adenocarcinoma) was performed using the Log-Rank test. Results: Till today 63 patients were considered eligible and enrolled into the trial; the results are summarised in the table . Toxicity was mild with no haematological side effects, and no grade III-IV non-haematological toxicity. Conclusions: G seems to represent an interesting options in patients with NSCLC heavily pre-treated with chemotherapy. Our data seems to confirm that G is active mainly in female, no-smoker patients with adenocarcinoma, suggesting the need of reintroducing the molecule in the treatment of such a subset of patients. [Table: see text] No significant financial relationships to disclose.