tbuckley/cabot-search huggingface dataset:
Predicting survival in primary resected retroperitoneal soft tissue sarcoma: A specific nomogram built on three major sarcoma center data sets.
Authors: Alessandro Gronchi, Rosalba Miceli, Elizabeth Shurell, Frederick C. Eilber, Frederick R. Eilber, Daniel A. Anaya, Dina Lev, Chiara Colombo, Raphael E. Pollock
Journal: Journal of Clinical Oncology (2012)

10000 Background: To build a specific nomogram for predicting postoperative overall survival (OS) in primary retroperitoneal soft tissue sarcoma (RPS). A few single institutions attempts are already available, but due to the rarity of the disease they are based on limited number of cases with inherent limitations. In an attempt to improve the predictive capability of such a prognostic model we utilized series from 3 major sarcoma centers. Methods: We included patients with primary localized RPS resected with curative intent between 1999 and 2009 at 3 institutions (1 European and 2 North Americans). Univariable (Kaplan Meier plots) and multivariable (Cox model) analyses were carried out. Prognostic covariates were: Age (modeled as continuous covariate using 3 knot restricted cubic spline transformation); Tumor size (modeled as continuous covariate using 3 knot restricted cubic spline transformation); Grade (I,II,III); Histological subtype (Leiomyosarcoma, DD Liposarcoma, WD Liposarcoma, MPNST, Pleomorphic Sa, SFT, Other); Multifocality (no,yes); Quality of surgery (macroscopically complete, incomplete); radiation therapy (RT, done/not done). A backward selection procedure, based on the Akaike Information Criterion (AIC), was applied to select the Cox model covariates. The model discriminative ability was estimated by means of bootstrap-corrected Harrel C statistic. Results: 526 patients were identified. At a median follow-up of 45 months (interquartile range: 22‑72 months) 174 deaths were recorded. 5-yr and 7yr OS (95% confidence interval) were 56.4% (51.1,62.2%) and 50.1% (44.1,57.0%). The backward selection procedure by AIC criterion lead to exclude RT from the covariates set. All other covariates proved to be statistically significant in the final multivariable Cox model. The Bootstrap-corrected Harrell C statistic was 0.74. Of interest, size of the tumor and age of the patient had a bimodal contribution to the risk of death and the combination of histological subtype and grade proved significant. Conclusions: A new multi-institution RPS specific nomogram is now available for prognostication in the clinic and patient selection in clinical trials.
Best supportive care (BSC) in published clinical trials.
Authors: Amy Pickar Abernethy, Ryan David Nipp, David Currow, Nathan Cherny, Florian Strasser, Yousuf Zafar
Journal: Journal of Clinical Oncology (2013)

9560 Background: BSC as a control arm in clinical trials is poorly defined. A systematic review was conducted to evaluate clinical trial concordance with published, consensus-based framework for BSC delivery in trials. Methods: A consensus-based Delphi panel previously identified 4 key domains of BSC delivery in trials: multidisciplinary care; supportive care documentation; symptom assessment at least as often as the intervention arm; and guideline-based symptom management. A systematic review of trials including BSC control arms assessed BSC concordance to the consensus-based domains. Databases were searched from 2002-2012 using search strings: “cancer”; “best supportive care”; “randomized” or “random allocation”; and “supportive” or “palliative.” Exclusion criteria were: no BSC arm, non-human trial, not randomized, not English, not advanced cancer, or not including anticancer therapy. Data were independently extracted by 2 reviewers and scored by 4 reviewers for conformance with consensus-based BSC framework. Results: 373 articles were retrieved, 17 retained after applying exclusion criteria. Overall, trials conformed to &lt;18% of the consensus-based BSC standards. 35% of articles offered a detailed description of BSC. 65% reported baseline and regular symptom assessment, and 47% reported using validated symptom assessment measures. 35% reported symptom assessment at identical intervals in both experimental and BSC arms. None listed an evidence-based guideline for symptom management. None of the multicenter trials reported standardization of BSC across sites. No studies reported educating patients on symptom management or goals of anti-cancer therapy. No studies reported offering access to palliative care specialists, social workers, financial or spiritual counseling. Conclusions: Reporting of BSC in trials is incomplete, resulting in uncertain internal and external validity. Such poorly defined interventions and variation between sites is unacceptable for other aspects of a clinical trial. Unless it is truly best supportive care, such studies may risk systematically over-estimating the clinical effect of the comparator arms. Standardization of a BSC delivery framework is needed to improve trial design and data generalization.
Clinical and molecular determinants of treatment benefit with phase I trials in patients (pts) with advanced pancreatic cancer (PC).
Authors: Helena Verdaguer, Tamara Sauri, Jorge Zeron-Medina, Guillermo Villacampa, Jaume Capdevila, Elena Elez, Maria Alsina, Guillem Argiles, Cinta Hierro, Julieta Grasselli, Ignacio Matos, Jordi Rodón, Josep Tabernero, Rodrigo Dienstmann, Enrique Sanz-Garcia, Teresa Mercade Macarulla
Journal: Journal of Clinical Oncology (2017)

409 Background: PC is the 4th leading cause of cancer-related death, with limited efficacy of systemic treatment (tx) beyond first-line chemotherapy (chemo). We aimed to assess the potential benefit of phase 1 trials in this setting. Methods: From 2011 to 2016, 49 pts were enrolled in 54 phase 1 trials at our institution. Clinical and molecular data were retrospectively extracted from medical records. Time to progression (TTP) was calculated from time of tx start to discontinuation due to progressive disease, and clinical benefit rate (CBr) was defined as partial response or stable disease &gt; 4 months. Results: Median age was 58 (41-75), 69% were male, 60% had metastases in liver. Most pts received gemcitabine-based regimens (47%) or Folforinox (32%) as first-line tx (median TTP of 5.63 months [CI 95% 4.0-8.1]). Median tx line of Phase 1 trial was 3 (range 2-5). Regimens included chemo or immunotherapies (chemo-imm group) in 16 cases (12 and 4, respectively), small molecule inhibitor (SMI) as single-agent in 19 cases (SMI.1 group), and SMI in combinations in 19 cases (SMI.2 group). In 17 cases, tx was matched to genomic profile; most frequent matches were PI3K + MEK SMI or RAF SMI ( KRAS mut in 7 pts), PI3K SMI ( PTEN loss/ PIK3CA mut in 3 pts) and PD1 blockade (PDL1 high in 4 pts). There were 3 (6%) partial responses (PI3K SMI unmatched, RAF SMI matched and anti-PD1 agent matched) and 12 (24%) disease stabilizations. Median TTP in phase 1 trial was 1.9 months [CI 95% 1.6-2.5], without significant differences if matched/unmatched agent (p = 0.5) or tx given as second-line/later regimen (p = 0.5). Median TTP was 2.7 months [CI95% 1.6-10.7] with chemo-imm (control arm), 2.0 months [CI95% 1.8-5.6] with SMI.2 (HR = 1.8, p = 0.13) and 1.4 months [CI95% 1.3-2.8] with SMI.1 (HR = 3.0, p = 0.004). This difference was maintained in a multivariable model (HR = 2.9, p = 0.005). CBr with chemo-imm (38%) or SMI.2 (21%) was higher as compared with SMI.1 (5%; p = 0.06). Conclusions: Selected PC pts are eligible to phase 1 trials and up to one-third derive substantial benefit from the intervention. In our experience, chemo-imm agents or targeted SMI given as combination regimens associate with longer TTP and CBr when compared with single-agent SMI.
Randomized phase II trial comparing two schedules of thoracic radiotherapy (TRT) in limited disease small-cell lung cancer (LD SCLC).
Authors: Bjørn Henning Grønberg, Tarje Onsoien Halvorsen, Øystein Fløtten, Odd Terje Brustugun, Paal Brunsvig, Ulf Aasebø, Roy M. Bremnes, Terje Tollali, Kjersti Hornslien, Bjørg Yksnøy Aksnessæther, Erik Dyb Liaaen, Stein Sundstrøm
Journal: Journal of Clinical Oncology (2012)

7027 Background: Concurrent chemotherapy and TRT is standard therapy for SCLC if all lesions can be included in a radiotherapy field (LD). Several schedules of TRT are used. One study showed that two fractions a day improved local control and overall survival (OS), but this schedule has not been compared to a commonly used 3 wks schedule. Methods: Eligible pts had LD SCLC and PS 0-2. Pleural fluid was accepted if negative cytology. Pts received 4 cycles of PE (cisplatin 75 mg/m 2 IV day 1 and etoposide 100 mg/m 2 IV day 1-3 q 3 wks) and were randomly assigned to 3 wks of 3D conformal TRT [A] 42 Gy (2.8 Gy x 1/day) or [B] 45 Gy (1.5 Gy x 2/day). TRT started 3-4 wks after the first PE. All responders received prophylactic cranial irradiation (PCI) 2 Gy x 15 ≤ 6 wks after last PE. Pts reported health related quality of life (HRQoL) on EORTC QLQ C30 + LC13. Primary endpoint: 1-year local failure. Secondary: OS, toxicity and HRQoL (dysphagia and dyspnea; a difference ≥ 10 points was considered significant). 75 pts were required in each arm to show a 30% improvement of local disease control with α=.05 and β=.8. Results: 159 eligible pts were enrolled at 18 sites in Norway May 05 – Jan 11 (A: 85, B: 74). Median age 60 (40-85); 52% men, 84 % PS 0-1, 11% pleural fluid. Mean no. of PE-cycles was 3.8, 97% completed TRT, 82 % PCI (no difference between arms). Response rates were similar (A: 92%, B: 94%; p=.8), but more pts on Arm B had CR (A: 13%, B: 35%; p=.01). There was no difference in local failure as first site of progression at 1 year (A: 17%, B: 12%; p=.4) or 1-year PFS (A: 44%, B: 50% ; p=.4). There was similar grade 3-4 esofagitis (A: 33%, B: 37 %; p=.7) and pneumonitis (A: 6 %, B: 7 %; p=.9). 2 pts (1 on each arm) died from pneumonitis. Pts in Arm B reported more dysphagia (A: 64 points, B: 73 points), but not more dyspnea (A: 29 points, B: 28 points). 1-year OS was similar (A: 77%, B: 76%; p=.9). Currently, 2-year survival among those followed ≥ 2 years (n=130) favors Arm B (A: 40%, B: 55%; p=.09) and so far (all pts followed ≥ 1-year; 103 events) median OS favors Arm B (A: 18.7 mos, B: 26.6 mos; p=.34). Conclusions: Twice daily TRT resulted in more CRs, slightly more dysphagia, similar 1-year local control and 1-year PFS. There are indications of improved 2-year and median OS in this arm.
The presence of ALK translocation in sarcomatoid carcinoma of head and neck and treatment effect of crizotinib: A case series.
Authors: Sungmin Kim, Jong-Mu Sun, Young Hye Go, Keunchil Park, Chung-Hwan Baek, Yoon-La Choi, young-Ik Son, Myung-Ju Ahn
Journal: Journal of Clinical Oncology (2014)

e17048 Background: Sarcomatoid carcinoma of the upper aerodigestive tract, a variant of squamous cell carcinoma, is a rare biphasic tumor consisting of epithelial and mesenchymal components. Herein, we report a case of 34-year-old woman who had a sarcomatoid carcinoma in maxillary sinus and had been treated with surgery, radiation therapy and multiple lines of palliative chemotherapy. Because ALK translocation is common in sarcoma, ALK FISH was performed on the tumor tissue and showed “break-apart” signal indicative of ALK translocation. Thus, ALK inhibitor, crizotinib was administered to the patient. Although dramatic response was not observed, clinical improvement and stable disease with minimal tumor shrinkage was noted and lasted for 4 months. Methods: To further identify the incidence of ALK rearrangement in sarcomatoid carcinoma of head and neck, ALK FISH was performed on tumor samples of 10 patients. Results: Among them, two patients were positive for ALK FISH. Conclusions: To the best of our knowledge, this is the first case report demonstrating clinical benefit of crizotinib in in sarcomatoid carcinoma of head and neck with confirmed ALK translocation . Our results suggest that ALK FISH test may be suitable and encouraged for patients with sarcomatoid carcinoma of head and neck.
Elevated PDGFRB gene copy number gain as prognostic in resected malignant pleural mesothelioma.
Authors: Anne S. Tsao, Nusrat Harun, Junya Fujimoto, Vikki Devito, J. Jack Lee, Reza J. Mehran, Waun Ki Hong, Milind B. Suraokar, Ignacio I. Wistuba
Journal: Journal of Clinical Oncology (2012)

7078 Background: PDGF/PDGFR pathway has been implicated in malignant pleural mesothelioma (MPM) carcinogenesis. We sought to evaluate the incidence of PDGFRB gene copy number gain (CNG) and PDGFR pathway protein expression by immunohistochemistry (IHC) in the tumor cell cytoplasm, membrane, nucleus, and stroma, and correlate it to patient clinical outcome. Methods: 88 archived tumor blocks from resected MPM with full clinical information were used to perform the analyses. IHC biomarkers for PDGFRα,β and p-PDGFRβ, and fluorescence in situ hybridization were performed for analysis of PDGFRB gene CNG. Spearman’s rank correlation, Wilcoxon rank-sum test or Kruskal-Wallis test, BLiP plots, and Kaplan-Meier method were used to assess the biomarkers and their correlation to clinical outcome. Results: There were several correlations identified between the IHC biomarkers; however, none associated with patient demographics or histology subtype, with the exception of high cytoplasmic PDGFRα occurring in patients with no prior known asbestos exposure (p=0.029). In the CNG analysis, PDGFRB gene CNG in &gt; 10% of tumor cells had lower cytoplasmic p-PDGFRβ (p=0.029), while PDGFRB gene CNG in &gt; 40% of tumor cells had a higher cytoplasmic PDGFRβ (p=0.04). PDGFRB gene CNG status did not associate with patient demographics or tumor characteristics. Patients with PDGFRB CNG &gt; 40% of tumor cells had an improved relapse-free survival (RFS) [HR 0.25 (95% CI 0.09, 0.72), p=0.0096]. In the patients with PDGFRB CNG &gt; 40% of cells, the addition of chemotherapy appeared to also improve RFS (p=0.017). In the multi-covariate analyses for RFS, there was no association with any IHC biomarker. In the overall survival (OS) analysis, having PDGFRB gene CNG &gt; 40% of tumor cells correlated with an improved OS [HR 0.32 (95% CI 0.11, 0.89), p=0.029] and the addition of peri-operative chemotherapy led to a trend towards improved OS (p=0.089). Conclusions: PDGFRB CNG &gt; 40% of tumor cells is a potential prognostic biomarker in surgically resected MPM tumors. Adding chemotherapy to patients with PDGFRB CNG &gt; 40% of cells improved RFS and led to a trend towards improved OS. Future validation of this biomarker in prospective trials is needed.
Phase I study of VGX-100, an anti-VEGF-C monoclonal antibody, with or without bevacizumab, in patients (pts) with advanced solid tumors.
Authors: Gerald Steven Falchook, Jayesh Desai, Ian M. Leitch, Jonathan Wade Goldman, Jennifer J. Wheler, Siqing Fu, Razelle Kurzrock, Megan Baldwin, Lee S. Rosen
Journal: Journal of Clinical Oncology (2013)

TPS2619 Background: The vascular endothelial growth factor C (VEGFEC) induces angiogenesis via activation of both VEGFRE2 and VEGFRE3, as well as lymphangiogenesis via activation of VEGFRE3. VGX-100 is a novel fully human IgG 1 λ neutralizing monoclonal antibody directed against human VEGFEC. Synergism between the VEGF-A inhibitor, bevacizumab and VGX-100 has been documented pre-clinically. It is thought that tumoral escape and relapse following VEGF-A inhibition, may in part be due to increased VEGF-C that signals through VEGFR-2 and VEGFR-3. Therefore the premise of this study is that administration of VGX-100 in conjunction with bevacizumab would block the two key ligands for VEGFRE2 along with blocking VEGFR-3-mediated tumor angiogenesis and lymphangiogenesis, and thus this drug combination will be clinically synergistic. This study (NCT01514123) is enrolling at MD Anderson and UCLA. Methods: Objectives:establish the safety and toxicity, MTD, pharmacokinetic and pharmacodynamic / biomarker profiles, as well as preliminary anti-tumor activity in refractory pts. Eligibility: pts with advanced solid tumors, good organ function, ECOG PS 0-1, any number of prior therapies, no CNS or cerebrovascular haemorrhage, no MI or reversible posterior leukoencephalopathy syndrome associated with prior anti-VEGF/anti-VEGFR therapy. Design: This is an open-label phase I dose escalation study with a standard “3+3” design. The study has two arms: safety data from the 28 day DLT period from Arm A (VGXE100 monotherapy at 6 cohort dose levels: 1, 2.5, 5, 10, 20 and 30 mg/kg, QW) will be available prior to starting the equivalent dose level in Arm B (VGXE100 at 5 cohort dose levels: 2.5, 5, 10, 20 and 30 mg/kg QW with bevacizumab at doses of either 5 or 10 mg/kg, Q2W). Accrual has completed in Cohorts A1 to A5 and B1 to B2. Accrual is underway for Cohort A6 and B3. Clinical trial information: NCT01514123.
A phase I trial everolimus and sorafenib in patients with recurrent high-grade gliomas: Brain Tumor Treatment Collaborative trial 09-01.
Authors: Jeffrey J. Raizer, Sean Aaron Grimm, Marta Penas-Prado, Ivo Tremont-Lukats, W. K. Alfred Yung, Nicholas George Avgeropoulos, Tobias Walbert, Monica Elena Loghin, Mark R. Gilbert
Journal: Journal of Clinical Oncology (2015)

2061 Background: Limited treatment options exist for patients with recurrent Malignant Gliomas (MG), especially after failing Bevacizumab (BEV). Signal transduction pathways involved in gliomagenesis provide therapeutic targets. Everolimus targets mTOR which is an important node downstream from PI3K and Akt. Sorafenib targets Raf, as well as VEGF and PDFG. The rationale for combining these agents is to inhibit two parallel pathways simultaneously. We performed a phase I trial of Everolimus and Sorafenib in patients with recurrent malignant gliomas in preparation for a phase II study. Methods: Patients with recurrent MG > 18 yrs, KPS ≥ 60, adequate hematologic, renal and hepatic function and no history of HIV or hepatitis were eligible. No limit on prior relapses and BEV exposure was allowed. Enzyme inducing seizure drugs were not allowed. A 3 + 3 dose escalation was used to determine the MTD, defined as the highest dose combination resulting in 0/3 or 1/6 patients experiencing a DLT. The starting dose was Everolimus 5 mg a day + Sorafenib 400 mg twice a day with a plan to increase to a maximum dose of 10 mg a day and 800 mg twice a day over several defined dose levels. A de-escalation level was Everolimus 5 mg/day + Sorafenib 400 mg twice a day for 7 days on and 7 days off. Results: 11 men and 2 women were enrolled with a median age of 50 years (19-66) and median KPS of 80 (70-100). All patients had a GBM with 7 receiving prior BEV therapy. In cohort 1, 3 of 6 patients experienced a DLT which were grade 3: fatigue, chest pain, HTN, elevated ALT, hypercholesterolemia and hyperglycemia and one grade 4 hypertriglyceridemia. Dose de-escalation occurred with 1 of 7patients having a DLT of myositis, nausea, fatigue, hypertension and hypercholesterolemia-all grade 3. All patients have died due to disease progression with a median PFS of 4 weeks and OS of 20.9 weeks. Conclusions: This phase I study determined the phase II dose in patients with recurrent malignant glioma to be Everolimus at 5 mg daily and Sorafenib at 400 mg BID 7 days on and 7 days off. A phase II trial is on-going investigating this regimen in Bev naive recurrent anaplastic gliomas and GBMs as well as recurrent GBM who failed BEV. Clinical trial information: NCT01434602.
A phase 1b study of ONT-380, an oral HER2-specific inhibitor, combined with ado-trastuzumab emtansine (T-DM1), in HER2+ metastatic breast cancer (MBC).
Authors: Virginia F. Borges, Erika Paige Hamilton, Denise A. Yardley, Stacy L. Moulder, Gabriel N. Hortobagyi, Luke N. Walker, Ian E. Krop
Journal: Journal of Clinical Oncology (2014)

TPS662 Background: ONT-380 is a selective small molecule inhibitor of HER2 kinase with nanomolar potency. Unlike dual HER2/EGFR agents, it does not inhibit EGFR at clinically relevant concentrations, decreasing the potential for EGFR-related toxicities. In preclinical studies, ONT-380 demonstrated greater than additive activity with trastuzumab, and was active in models of CNS metastases. In a single-agent phase 1 study in 50 patients (pts) with metastatic HER2+ cancer, the MTD was 600 mg BID, with DLT consisting of reversible Grade 3 ALT/AST in 2 of 4 pts treated at 800 mg. In 22 HER2+ breast cancer pts treated at doses ≥ 600 mg BID, the clinical benefit rate (partial response [n = 3] plus stable disease for at least 6 months [n = 3]) was 27%. Based on data supporting dual blockade of HER2, ONT-380 is now being evaluated in combination with T-DM1. Methods: The study objectives are to determine the safety, MTD/Phase 2 dose, and preliminary anti-tumor activity of ONT-380 given in combination with T-DM1 in pts with or without CNS metastases. Potential biomarkers of response and pharmacokinetics will also be assessed. A 3+3 design will evaluate up to four dose levels of ONT-380 (starting at 300 mg PO BID) given with T-DM1 (3.6 mg/kg IV once every 21 days). The study population includes up to 48 adult pts with HER2+ MBC who have received prior trastuzumab and a taxane, but not T-DM1, for metastatic disease. Pts with either treated CNS metastases or asymptomatic untreated CNS metastases are also eligible. Two expansion cohorts are planned, including an MTD/Phase 2 dose expansion cohort, and a cohort of pts with CNS disease, including either untreated, asymptomatic CNS metastases or CNS metastases that have progressed after local therapy. Systemic disease response will be evaluated using RECIST 1.1. CNS response will be evaluated by RECIST 1.1, modified RECIST 1.1, and volumetric criteria. Potential biomarkers of response include the presence of p95 HER2 and HER2 mutations in archived tumor biopsies. Treatment will continue until unacceptable toxicity, disease progression, or withdrawal of consent. Clinical trial information: NCT01983501.