tbuckley/cabot-search huggingface dataset:
A phase I study of NC-6004, a micellar formulation of cisplatin, in combination with gemcitabine in Japanese patients with advanced solid tumors.
Authors: Tetsuya Hamaguchi, Toshihiko Doi, Kohei Shitara, Satoru Iwasa, Yasuhiro Shimada, Mitsunori Harda, Kenichiro Naito, Naoto Hayashi, Atsuhiro Masada, Atsushi Ohtsu
Journal: Journal of Clinical Oncology (2016)

e14081 Background: NC-6004 is polymeric micelle containing cisplatin as active moiety. A phase I study of monotherapy in patients with advanced solid tumors confirmed that NC-6004 exhibits lower Cmax and higher AUC compared to an equivalent dose of conventional cisplatin. This phase I study was designed to examine the maximum tolerated dose (MTD) and recommended dose (RD) for phase II of NC-6004 in Japanese patients with advanced solid tumors. Methods: NC-6004 was administered as a 1-h IV infusion every 3 weeks. On cycle 2 or thereafter, gemcitabine at 1000 mg/m2was administered on day 1, 8 every 3 weeks. The renal toxicity profile was also quantitatively evaluated with population PK/PD manner using Indirect Response Model I. Results: Twelve patients received 60 mg/m2 and 90 mg/m2 of NC-6004. Neutropenia and thrombocytopenia were common toxicities. No grade 3 or higher nausea / vomiting was observed without antiemetic premedication. Dose limiting toxicities (DLTs) occurred at 90 mg/m2 of NC-6004. Grade 4 neutropenia and thrombocytopenia were shown in 2 patients, respectively. The disease control rate was 81.8%. The PK profiles of NC-6004 in Japanese were similar to those in non-Japanese patient populations. The PK/PD model well explained the time course of glomerular filtration rate after first dose and the decrease significantly damped through repeated administration. The decrease seemed to reach at saturation over 100 mg/m2. Cisplatin is reported to cause acute kidney injury in almost 70% of patients but NC-6004 causes it in 30% of patients based on PK/PD simulation. Conclusions: RD of NC-6004 in combination with GEM is 90 mg/m2in Japanese patients with advanced solid tumors, which is the same in non-Japanese patients. NC-6004 showed better renal toxicity profile than conventional cisplatin. Estimated population PK/PD model parameters. Parameter Population mean Inter-individual variance [CV%] GFR0 [mL/min/1.73m2] 83.4 26.5 Kout [/day] 0.171 48.7 IC50 [ng/mL] 35.3 211.7 Imax0 0.851 - Imax decrease trend [/day] 0.0273 - IOV (Imax ) [CV%] 53.1 intra-individual variance [CV%] 8.8
OS2.5 Effect of rituximab in primary central nervous system lymphoma - results of the randomized phase III HOVON 105/ALLG NHL 24 study
Authors: J E C Bromberg, S Issa, K Bakunina, M C Minnema, T Seute, G Cull, M J van den Bent, M Gonzales, D de Jong, J K Doorduijn
Journal: Neuro-Oncology (2018)

use of rituximab in Primary Central Nervous System Lymphoma (PCNSL) is based on extrapolation of its impact on survival rates in systemic diffuse large B-cell lymphoma and phase II and retrospective PCNSL studies. We performed an international intergroup randomized phase III study to investigate efficacy of rituximab in PCNSL. newly-diagnosed, non-immunocompromized patients aged 18–70 years with PCNSL and WHO performance status (PS) 0–3 were randomized to induction with 2 cycles of MBVP chemotherapy with (arm B) or without (arm A) rituximab. Patients were stratified for age (≤60 vs ≥61 years) and PS (0–1 vs 2–3). Rituximab (375 mg/m2) was given weekly during MBVP cycle I and every other week during cycle II to a total of 6 administrations. Patients with persistently positive CSF after the first (R-)MBVP cycle received intrathecal MTX; those with at least a partial response received high dose cytarabine consolidation. Patients ≤ 60 years were then consolidated with 30 Gy whole brain radiotherapy (WBRT) with an additional boost of 10 Gy in case of partial remission (PR). Patients ≥61 yrs were not irradiated. Primary end-point was one year event free survival (EFS), where an event was no CR(u) on protocol, relapse or death. Secondary end-points were response rates after induction, consolidation and completion of WBRT, PFS and OS. between August 2010 and June 2016, 200 patients from 24 centers in the Netherlands, Australia and New Zealand were included and randomized; 100 patients to arm A and 99 to arm B, 1 was not eligible and excluded from all analyses. 55% were men. The median age was 61 years (range 26–70), 47% were ≤60 years, 72% had an ECOG PS ≤ 1, 29% had elevated LDH and 30% had positive CSF; the two arms were well balanced at baseline. All patients received cycle I according to randomization, 90% received cycle II and 81% received high dose cytarabine. 16 patients, 8 in each arm, received intrathecal treatment. 70 patients (35%) were irradiated, 34% in arm A and 36% in arm B. A boost was given to 15/34 patients in arm A (44%) and 24/36 patients in arm B (67%). CR/CRu rate was 66% in arm A and 68% in arm B. Overall Response Rate was 87% in both arms. EFS did not differ between the arms: 1 year EFS was 49% in arm A and 52% in arm B; HR 1.00, 95% CI 0.70–1.43, p=0.99 adjusted for age group and WHO. Median OS has not been reached after a median follow-up of 32.9 months (range 3.6–79.2) in the 120 patients still alive but no difference was apparent with an adjusted analysis HR of 0.93 (95% CI 0.59 - 1.44, p=0.74). At database lock 79 patients had died; treatment related mortality was 7% in arm A and 3% in arm B. Grade 3 or 4 adverse events occurred in 59% of patients in arm A, in 63% in arm B. addition of rituximab to HD-MTX-based chemotherapy did not improve response rates, EFS or PFS in PCNSL.
Randomized controlled trials comparing clinical outcomes of 3D versus 2D laparoscopic surgery for gastric cancer: An interim report.
Authors: Changming Huang, Jun Lu, Chaohui Zheng, Ping Li
Journal: Journal of Clinical Oncology (2016)

e15550 Background: The purpose of this study was to evaluate the safety and efficacy of 3D versus two-dimensional(2D) laparoscopic surgery for gastric cancer. Methods: the primary end point was to determine whether there is a difference in the operation time between the two groups. The morbidity and mortality were compared to assess the safety of this trial. The study is registered at ClinicalTrials. Gov, and carries the following ID number: NCT02327481. Results: A total of 342 patients were randomized (3D group 115 patients; 2D group 113 patients) between January 1,2015 and October 1,2015. 7 patients who have exploratory operation were excluded. Finally, a total of 221 patients were analyzed,(3D group 109 cases, 2D group 112 cases). There were no significant differences between the two groups in clinical pathological characteristics, operating time, number of lymph node dissection, time to first ambulation, flatus, liquid diet, soft diet, duration of postoperative hospital stay. The postoperative complication rates of the 3D and 2D groups were 18.3% and 16.1% respectively, P = 0.723.No patients died during postoperative hospital stay. However, the intra-operative blood loss in 3D group was significantly lower than 2D group (58.47±75.00ml vs 78.20±71.76ml, P = 0.047). Conclusions: 3D laparoscopic surgery for gastric cancer is safe and feasible, and can benefit from surgery in reducing blood loss. It is suitable for clinical application and promotion.
Impact of Immune response-associated gene polymorphisms on tumor response in rectal cancer patients treated with capecitabine +/- oxaliplatine and radiation in the ACCORD-12/PRODIGE-2 phase III trial.
Authors: Valerie Boige, Caroline Mollevi, Nathalie Chaput, Sophie Gourgou, David Azria, Jean-François Seitz, Ludovic Bigot, Beata Juzyna, Isabelle Miran, Jean-Pierre Gerard, Pierre Laurent-Puig
Journal: Journal of Clinical Oncology (2017)

e15151 Background: We examined whether 133 germline polymorphisms (SNPs) in 15 candidate genes (CSF1R, IL8RA, TLR4, IL10, IL10RA, CTLA4, IL2, IL2RA, TGF b1, ICOS, IL13, IL13RA2, IFNgR, IL15 and IL15RA) would predict clinical outcome in the ACCORD-12 phase III trial which randomly compared neoadjuvant radiotherapy (RT) plus capecitabine (CAP45) with dose-intensified RT plus capecitabine and oxaliplatin (CAPOX50) in T3-4 Nx M0 resectable rectal cancer. Methods: A candidate-gene association study was conducted in 316 patients (n = 161 in the CAPOX50 and n = 155 in the CAP45 arm). The primary end-point was tumor response according to the Dworak score in each arm. Logistic regressions were used to assess univariate/multivariate associations. The Storey and Tibshirani method based on the control of false discovery rate was used ( q-value &lt; 0.10 (adjusted p-value) considered as true discovery). Multivariate models adjusted on treatment arm and T stage were performed to determine prognostic and predictive values of SNPs for tumor response. Results: In univariate analysis, two SNPs in IL2RA (rs11256456: OR = 5.1 [2.38; 11] and rs706781: OR = 4.2 [1.98 ; 8.74]) were significantly associated with the Dworak score in the CAP45 arm, and one in IL2RA the CAPOX50 arm (rs2104286: OR = 0.11 [0.01 ; 0.90]. All were confirmed in the multivariate analysis. A significant haplotypic effect was observed in the CAP-45 arm (p = 0.0001). Interaction was significant for IL2RA rs11256456 ( p= 0.03) and rs706781 ( p= 0.002) and no significant for IL2RA rs2104286 ( p= 0.722), suggesting a predictive deleterious effect the first two ones for response to oxaliplatin-based chemoRT, and a prognostic effect of the third one for response to chemoRT (+/- oxaliplatin). None of the three IL2RA SNPs were correlated with survival in the multivariate analysis. Conclusions: This pharmacogenetic analysis shows that SNPs in IL2RA have a significant association with response to chemoRT with capecitabine in patients with locally advanced rectal cancer. Their predictive effect may identify patients in whom oxaliplatin addition to chemoRT is deleterious.
P01.028 Tumor treating fields and radiotherapy for newly diagnosed glioblastoma: Safety results from a pilot study
Authors: R Grossman, F Bokstein, C Ben Harosh, D Blumenthal, D Limon, Z Ram
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) are a non-invasive, loco- regional, anti-mitotic treatment comprising low intensity alternating electric fields. In the phase 3 EF14 study in newly diagnosed glioblastoma (ndGBM), TTFields significantly improved survival compared to temozolomide (HR, 0.63; p<0.001). Preclinical data show that TTFields increase glioma cells undergoing cellular death following radiotherapy (RT) by inhibiting DNA damage repair. This suggests TTFields have a radiosensitizing effect and can increase the efficacy of RT. The current study was the first to test TTFields administered concomitant to RT in ndGBM patients. Ten patients with ndGBM were enrolled in this single-arm trial. All had recovered from maximal debulking surgery or biopsy and had KPS ≥70. Patients started TTFields prior to or at the time of RT, and were on stable or decreasing doses of corticosteroids for 7 days before enrollment. TTFields (200kHz) were delivered for 18 hours/day with daily removal of the transducer arrays during delivery of RT. Temozolomide was administered at 75 mg/m2/daily for 6 weeks and RT at a total dose of 60 Gy. The primary endpoint was safety of the combined therapies. Ten patients were enrolled at a single center between April and December 2017. Median age was 59 (range 42–71 years), median KPS was 90 (range 80–100) and 8 (80%) of patients were male. Five patients (50%) underwent gross total resection while the rest had biopsy only. Median dose of RT was 60 Gy (range 52–60 Gy). Six patients (60%) have reported have an adverse event (AE) to-date. The most common AE was TTFields-related skin toxicity, reported in 4 (40%) of the patients. None of these were severe. All other AEs reported occurred in one patient only and could be attributed to the underlying disease or chemotherapy. Two reported serious AEs (seizures and general deterioration) were considered unrelated to TTFields. The proportion of patients with TTFields-related skin toxicity (40%) was similar to that reported for the 466 TTFields patients treated with TTFields in the phase III study (52%), where patients started TTFields > 4 weeks after RT. No other TTFields-related toxicities were reported, nor was there an increase in RT- or temozolomide-related toxicities as a result of combining TTFields with these therapies. To date, TTFields has demonstrated a high safety profile when combined with other therapies in newly diagnosed GBM.
Companion testing using next-generation sequencing as compared with FDA-cleared kits.
Authors: Wanlong Ma, Sally Agersborg, Steve Brodie, Ivan De Dios, Wayne Chen, Shiping Jiang, Maher Albitar
Journal: Journal of Clinical Oncology (2016)

e23146 Background: Companion diagnostic tests are currently recommended for the prescription of multiple therapeutic agents in oncology. Most of these companion tests are FDA-cleared kits. We compared the mutations detected in large number of solid tumors using next generation sequencing (NGS) and confirmation by Sanger sequencing with FDA-cleared testing kits. Methods: Samples from 822 patients were submitted for routine clinical testing for mutations in EGFR, BRAF, and KRAS. This included 442 lung cancers, 168 colorectal, 29 (4%) brain tumors, 33 melanomas, 14 thyroid cancers, and others. All samples were tested by NGS, then confirmed by Sanger sequencing. LNA was used to increase sensitivity of Sanger for EGFR T790M mutation, codons 12/13 for KRAS, and V600 for BRAF mutations. We compared our results with listed detectable mutations in the FDA-approval labeling for EGFR, KRAS and BRAF for cobas tests (Roche, Indianapolis, IN) and Therascreen tests (Qiagen, Germantown, MD). Results: We detected 55 unique EGFR mutations in 99 patients. Of all 99 patients with EGFR mutations, 39 patients (39%) had mutations in codons not covered in the commercial cobas v2 kit and 63 (64%) were not covered by the older cobas v1 kit. Therascreen test also did not cover 64 (65%) mutations detected in EGFR. We detected mutations in BRAF in 114 patients, but only 61 patients had mutations involving codon V600 and 53 (46.5%) patients had mutations involving other codons. These mutations would have been missed if tested using FDA-cleared tests. We detected mutations in KRAS in 320 patients, of which 284 mutations (89%) involved codons 12 and 13. Sixteen (5%) mutations involved codon 61 and 20 (6%) mutations involved other codons. Therefore 6% of patients with KRAS mutation would have been missed if the cobas KRAS test (P = 0.00002) is used and 11% if Therascreen is used. Conclusions: Currently available FDA-cleared kits for testing for mutations in EGFR, KRAS, and BRAF genes are not comprehensive enough and miss significant number of mutations. Genes Detected mutations Missed cases by FDA-Cleared kits Total Unique Cobas V1 Cobas V2 Therascreen EGFR 99 55 63 (64%) 39 (39%) 64 (65%) BRAF 114 42 53 (51%) NA 53 (51%) KRAS 320 30 NA 20 (6%) 36 (11%)
Response to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with de novo epidermal growth factor receptor (EGFR) T790M and S768I resistance mutations.
Authors: Deirdre Kelly, Lisa Mary Prior, Jack Patrick Gleeson, Lynda M. McSorley, Rachel Kearns, Claire Brady, Jane Sze Yin Sui, Mohammed Adam Ibrahim Dawod, Louise Burke, Julie McCarthy, Ray McDermott, John McCaffrey, Derek Gerard Power, Seamus O'Reilly, Deirdre O'Mahony, Stephen P. Finn, Cathal O'Brien, Richard M. Bambury
Journal: Journal of Clinical Oncology (2017)

e20557 Background: Patients with synchronous de novo EGFR sensitising and resistance mutations are rare. Little is known about the response of these patients to EGFR TKIs, especially in a Caucasian population. Methods: We identified NSCLC patients found to have EGFR mutations using PCR-based fragment length analysis, mass spectrometry-based genotyping (Sequenom), and Sanger sequencing using a large multi-institutional database. Baseline clinical characteristics, response rate, progression free survival (PFS) and overall survival (OS) were calculated. Results: From 2008-2015, we observed de novo synchronous EGFR sensitising and resistance mutations in 12 patients representing an overall incidence of 3.6% of EGFR mutants and 0.4% of all NSCLC patients tested. Seven patients were treated using EGFR TKI therapy with erlotinib. In all cases, T790M (n = 4,50%) or S768I (n = 4, 50%) occurred concurrently with another sensitising EGFR mutation, either L858R (n = 4, 34%) or exon 19 deletion (n = 8, 66%). Objective responses were seen in two patients (29%). Three further patients had stable disease lasting 6, 23 and 54 months respectively. The median progression-free survival was 24 months and the median overall survival was 34 months. All patients with baseline EGFR S768I mutations (n = 3) had an objective response or stable disease on erlotinib while two of four patients with T790M demonstrated de novo resistance. Conclusions: This is the largest Irish review of synchronous de novo EGFR mutations. The incidence of co-occurring EGFR mutations was 0.4% and erlotinib demonstrated activity in this cohort of patients. Ongoing trials will determine whether next-generation EGFR TKIs such as osimertinib are preferable as first-line therapy in these patients.
Abstract A019: Heme-oxygenase 1 drives the metabolic fate in prostate cancer
Authors: Valeria G. Antico Arciuch, Florencia Cascardo, Florencia Velazquez, Sofia Lage Vickers, Nicolas Anselmino, Estefania Labanca, Javier Cotignola, Geraldine Gueron, Nora Navone, Elba Vazquez
Journal: Cancer Research (2018)

Abstract Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. Energetic metabolism alterations have become a new hallmark of cancer, since variations in a single gene can orchestrate changes in metabolic pathways and confer an adaptive advantage. Heme-oxygenase 1 (HO-1) exerts an antitumoral role in PCa inhibiting cell proliferation, migration, tumor growth, and angiogenesis. The aim of this work was to assess the role of HO-1 in the metabolic signature of PCa. Through RNA-Seq we found a set of metabolic genes deregulated under pharmacologic induction (hemin treatment) or genetic induction of HO-1 in PC3 cells. STAR and ATP5L2 were upregulated, while HMGCS2, PRODH, and ACOT12 were downregulated. These genes encode for steroid hormone metabolism, ATP synthesis, ketogenesis, proline and lipid metabolism. The analysis of the deregulated genes (2-fold) by Gene Ontology revealed alterations in several metabolic pathways such as steroid, proline and lipid metabolism, and ATP synthesis. Functional analysis highlighted a decrease in oxygen consumption rate and ATP production under hemin treatment. Furthermore, HO-1 induction led to a decrease in the extracellular lactate levels. Bone is the only site of PCa progression, and bone cells are able to produce factors that favor progression. However, the molecular nature of this interaction remains elusive. Our results performed on cocultures of PC3 cells (treated or not with hemin) with Raw264.7 (preosteoclastic) or MC3T3 (preosteoblastic) cells demonstrate that HO-1 directs the metabolic fate of bone precursor cells due to the deregulation of glycolytic genes. HO-1 induction in PC3 cells downregulated PKM2 and LDHA expression in cocultured Raw264.7 and MC3T3 cells (p&amp;lt; 0.05). Based on our results, we propose HO-1 as a key regulator of the metabolic status of PCa cells and a powerful mediator capable of redefining the metabolic signature of bone precursor cells, thus favoring the establishment of a less aggressive phenotype. Citation Format: Valeria G. Antico Arciuch, Florencia Cascardo, Florencia Velazquez, Sofia Lage Vickers, Nicolas Anselmino, Estefania Labanca, Javier Cotignola, Geraldine Gueron, Nora Navone, Elba Vazquez. Heme-oxygenase 1 drives the metabolic fate in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A019.
Autologous (auto) versus matched sibling donor (MSD) or matched unrelated donor (MUD) allogeneic (allo) hematopoietic cell transplantation (HCT) in follicular lymphoma (FL) patients (pts) with early chemoimmunotherapy failure (ECF): A Center for International Blood and Marrow Transplant Research (CIBMTR) analysis.
Authors: James K. Godfrey, Sonali M. Smith, Kwang Woo Ahn, Alyssa Digilio, Timothy S Fenske, Anna M. Sureda, Mehdi Hamadani
Journal: Journal of Clinical Oncology (2017)

7508 Background: Contrary to most FL, high-risk FL pts with ECF (i.e. relapse within 2 yrs of frontline chemoimmunotherapy) have a 5 yr OS of only 50%. (Casulo, JCO 2015). We used the CIBMTR database to compare autoHCT versus either MSD or MUD alloHCT as the first transplant approach in FL pts with ECF. Methods: Adult FL pts (age ≥18) undergoing autoHCT or alloHCT between 2002-2014 and receiving first line rituximab-based chemoimmunotherapies with evidence of ECF (defined as disease relapse or progression within 2 yrs of treatment initiation) were included. The primary endpoint was OS; secondary endpoints were progression-free survival (PFS), relapse and non-relapse mortality (NRM). Results: 440 pts had ECF (auto = 240, MSD = 105, MUD = 95) (Table 1). The 5 yr adjusted probabilities (AjP) of NRM were significantly lower with autoHCT (5%), versus MSD (17%) or MUD (33%) HCT (p&lt;0.0001). 5 yr AjP of relapse were significantly lower with MSD (31%) or MUD HCT (23%), versus autoHCT (58%; p&lt;0.0001). AjP of 5 yr PFS following auto, MSD and MUD HCT were 38%, 52% and 43% (p=.006) respectively. The AjP of 5 yr OS was significantly higher following autoHCT (70%) or MSD HCT (73%) versus MUD HCT (49%; p=0.004). Conclusions: AutoHCT for FL pts with ECF has low NRM and 5 yr OS rates (70%) that are provocatively higher than historical data (~50%). MSD HCT had the lowest relapse rate with similar survival. A prospective trial confirming the role of HCT in ECF FL is warranted. [Table: see text]
P01.136 Safety and adverse event profile of tumor treating fields in elderly patients - a post-market surveillance analysis
Authors: M Glas, S Kebir, W Shi
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) are an established modality for glioblastoma (GBM) treatment administered through the portable Optune system. The efficacy of Optune in newly diagnosed GBM was previously demonstrated in the EF-14 phase 3 trial (n=695). Optune plus temozolomide significantly improved survival in all patient subgroups compared to temozolomide alone, which included those patients ≥ 65 years of age (median OS: 17.1 vs 13.7 months). Here, we report post-marketing surveillance data from elderly patients treated with Optune. A review of adverse events in patients≥65 years of age. Post-market surveillance data were analyzed based on the MedDRA body system (system organ class) preferred terms. A total of 8025 patients were treated with Optune (newly diagnosed glioblastoma 46.1%, recurrent glioblastoma 46.2%, other 7.7%). Of those 2574 patients (32.1%) were ≥ 65 years of age at the time of Optune treatment. 46% of these elderly patients reported ≥ 1 adverse event. Skin reaction was the most prevalent adverse event and occurred in 28% of patients. Similarly, 47% of patients ≥ 18 and <65 years of age (N=5421) experienced at least 1 adverse event and 27% developed skin reaction. The remaining adverse events profile was fairly equally distributed between both age groups. This retrospective analysis demonstrates that Optune is used in patients 65 years of age or older. The adverse event profile in this group of elderly patients is comparable to patients younger than 65 years. The most common adverse event registered was skin reaction, which was also found in the phase 3 EF-11 trial for recurrent GBM and in the EF-14 trial for newly diagnosed GBM patients. In summary, these results underline the safety profile of Optune.