bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes from 735 patients with breast cancer brain metastases (BM) according to biological subtype, number of BMs, and systemic treatment after local therapy.
Authors: Niwinska Anna , Pogoda Katarzyna , Rudnicka Halina , Jagiello-Gruszfeld Agnieszka Irena , Rybski Sebastian , Nowecki Zbigniew 
Published: September 2018

2078 Background: To assess survival when BM is detected according to the biological subtype of breast cancer, number of BMs and systemic treatment after local therapy. Methods: Subjects were 735 consecutive breast cancer patients with BM treated during 2003-2015. Whole brain radiotherapy was undertaken in 97%, neurosurgery -19% and systemic therapy was performed in 74% cases. The biological subtypes: triple-negative (TNBC), HER2+ER/PR-, HER2+/ER/PR+ and ER/PR+HER2- (Luminal) were determined in 714 subjects. Survival after BM detection was assessed in the entire group, in patients with a single BM (1 brain lesion regardless of metastases in other organs) and those with a solitary brain metastasis (1 brain lesion but no metastases in other organs). Factors influencing survival upon detecting BM were assessed by Cox multivariate analysis. Results: The median survivals for all patients with TNBC, HER2+ER/PR-, HER2+/ER/PR+ and Luminal breast cancer BM were respectively 4, 8, 10 and 9 months (p < 0.001). In those both treated and untreated systemically within the TNBC, HER2+ER/PR-, HER2+/ER/PR+ and Luminal subtypes survivals were correspondingly 6, 10, 14, 11 and 2, 3, 2, 2 months (p < 0.001). Median survivals of 171 patients with a single BM treated and untreated systemically were respectively 15 and 5 months (p < 0.001). Median survivals of 70 patients with solitary BM treated and untreated systemically were respectively 28 and 6 months (p < 0.001). In patients with solitary brain metastasis, median survival within the TNBC, HER2+ER/PR-, HER2+/ER/PR+ and Luminal subtypes, with systemic treatment was respectively 16, 28, 28, 28 months and without systemic treatment 6, 7, 7 and 7 months (p < 0.001). Conclusions: Patients with TNBC and BM had the worst prognosis. Systemic treatment performed after local therapy is an important factor prolonging survival of patients with breast cancer BM, even in those with solitary brain metastasis. Based on the present evidence and our recent publication, systemic treatment should be performed in all patients with BM after local treatment, even those with brain metastases as an isolated recurrence.
Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT): An MD Anderson precision medicine study.
Authors: Tsimberidou Apostolia Maria , Hong David S. , Cartwright Carrie , Wheler Jennifer J. , Falchook Gerald , Naing Aung , Fu Siqing , Piha-Paul Sarina Anne , Janku Filip , Hwu Patrick , Kee Bryan K. , Kies Merrill S. , Broaddus Russell , Mendelsohn John , Hess Kenneth R. , Kurzrock Razelle ,   ASCO Authors
Published: September 2018

2513 Background: We present outcomes for 637 patients who were referred for phase I trials and were treated under IMPACT. Methods: Patients with advanced, refractory cancer who had tumor genomic analyses were treated with matched targeted therapy (MTT) when available. Results: Overall, 1,179 (82.1%) of 1,436 patients had ≥1 alteration (median age, 59.7 yrs; men, 41.2%); 637 had ≥1 actionable aberration and were treated with MTT (n=390) or non-MTT (n=247). Patients treated with MTT had higher rates of CR and PR (11% vs. 5%; p=.0099) (Table), longer failure-free survival (FFS) (3.4 vs. 2.9 months; p=.0015), and longer overall survival (OS) (8.4 vs. 7.3 months; p = .041) than unmatched patients. Two-month landmark analyses showed that, for MTT patients, FFS for responders vs. non-responders was 7.6 vs. 4.3 months (p<.0001) and OS was 23.4 vs. 8.5 months (p<.0001); for non-MTT patients (responders vs. non-responders), FFS was 6.6 vs. 4.1 months (p=.0005) and OS was 15.2 vs. 7.5 months (p = .43). Patients with both PI3K and MAPK pathway alterations matched to PI3K/Akt/mTor axis inhibitors alone showed outcomes comparable to unmatched patients. Conclusions: Matched versus unmatched patients had significantly better outcomes. For matched responders, median survival reached almost two years. However, matching patients who harbor both a PI3K and a MAPK pathway alteration to only a PI3K pathway inhibitor did not improve outcome. Clinical trial information: NCT00851032. [Table: see text]
Pharmacokinetic-driven phase I study of DCC-2618 a pan-KIT and PDGFR inhibitor in patients (pts) with gastrointestinal stromal tumor (GIST) and other solid tumors.
Authors: Janku Filip , Abdul Razak Albiruni Ryan , Gordon Michael S. , Brooks David Glenn , Flynn Daniel Lee , Kaufman Michael , Pitman Jama , Smith Bryan Douglas , Somaiah Neeta , De Groot John Frederick , Chen Guo , Jennings Julia , Salah Samer , Westwood Deb , Gerstenberger Eric , Rosen Oliver , George Suzanne 
Published: September 2018

2515 Background: DCC-2618 is a potent switch control inhibitor of KIT and PDGFR kinases active in a broad range of mutations. GIST is an important disease to achieve a proof-of-concept due to the heterogeneity of KIT resistance mutations, which emerge on treatment with approved KIT inhibitors. Methods: This was a PK-guided dose escalation study of oral DCC-2618 (QD or BID q28 days) in advanced solid tumors. FDG-PET scans were used to assess changes in FDG uptake in GIST pts after 3 wks of therapy. Next generation sequencing (NGS) of plasma cell-free (cf) DNA was performed throughout the study to assess and quantify KIT and other molecular alterations in drug targets and potential mechanisms of resistance. Results: 38 pts were enrolled (30 GIST; 4 glioma; 1 mastocytosis, 3 other carcinoma) to 8 dose levels: BID doses: 20 (4 pts), 30 (4), 50 (5), 100 (6), 150 (6) and 200 mg (3); QD doses: 100 (5) and 150 mg (4). Safety of evaluable pts is as follows: G3 or G4 adverse effects (regardless of attribution and occurring in > 1 pt) included anemia (5), lipase increase (4), hypertension (2). Two of the G3/4 lipase increase at 100 mg BID and 200 mg BID were DLTs. All G3/4 lipase increase were asymptomatic. G1/2 AEs (considered at least possibly related to DCC-2618) and occurring in ≥15% (n > 5) of pts include fatigue (12), alopecia & lipase increase (7), weight decrease (6). Starting with 50 mg BID dose level, trough concentrations of total drug exceeded the IC90 of the least sentivitive KIT mutations. Plasma concentrations > 5μM were achieved starting at 100 mg BID and the selection of the expansion phase dose is being finalized. Of 18 pts with KIT mutant GIST assessed by FDG PET, 14 (78%) had partial metabolic response per EORTC criteria. RANO/RECIST partial responses (PRs) were reported in 3 patients (1 GBM with PDGFRA/KIT amplifications and 2 GIST with Ex 11 & 17 / Ex 11 & 18 mutations, respectively). NGS of plasma cfDNA revealed 44 KIT mutations in baseline samples from 19 of 21 pts with GIST. Conclusions: DCC-2618 is well tolerated with encouraging preliminary activity in GIST pts with a broad spectrum of mutations and prior therapies. PR was also seen in a pt with GBM with PDGFRA/KIT amplifications. Clinical trial information: NCT02571036.
Phase 1 study of ARQ 761, a β-lapachone analog that promotes NQO1-mediated programmed cancer cell necrosis.
Authors: Gerber David E. , Bisen Ajit Kumar , Beg Muhammad Shaalan , Frankel Arthur E. , Fatunde Oluwatomilade , Fattah Farjana , Arriaga Yull Edwin , Dowell Jonathan , Meek Claudia , Bolluyt Joyce D. , Sarode Venetia , Luo Xin , Xie Yang , Schwartz Brian E. , Boothman David A. , Leff Richard 
Published: September 2018

2517 Background: NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase expressed in multiple tumor types at levels 5- to 200-fold above normal tissue. ARQ761 is a β-lapachone hydroquinone analog that exploits the unique elevation of NQO1 found in solid tumors to cause tumor-specific cell death by eliciting a futile redox cycle generating high levels of reactive oxygen species and ultimately PARP1 hyperactivation-dependent cell death. Methods: 3+3 dose escalation study of 3 schedules (weekly, every other week, 2/3 weeks) of ARQ 761 as a 1-hr or 2-hr infusion. Eligible patients had refractory advanced solid tumors, ECOG 0-1, adequate organ function, and central venous access. Blood samples were analyzed for ARQ761 levels and NQO1 polymorphisms. Archival tumor tissue was analyzed for NQO1 staining intensity and prevalence. After 18 patients were analyzed, enrollment was restricted to patients with NQO1-positive tumors (defined as Histo-score ≥200). Results: A total of 42 patients were treated. Median number of prior lines of therapy was 4. For all schedules, the maximum tolerated dose (MTD) was 390 mg/m2 as a 2-hr infusion. DLT was hemolytic anemia. The most common treatment-related adverse events were anemia (79%), fatigue (45%), hypoxia (33%), hemolysis (17%), nausea (17%) and vomiting (17%). Transient grade 3 hypoxia, due to methemoglobinemia, occurred in 26% of patients. Among 31 evaluable patients, the best response was stable disease (n = 11) and progressive disease (n = 19). For the 18 analyzed cases analyzed prior to NQO1 enrollment biomarker, clinical benefit appeared associated with tissue NQO1 expression: disease control rate was 65% in NQO1-positive tumors and 18% in NQO1-negative tumors ( P=0.06). Analysis of all 31 evaluable patients did not show a significant difference in progression-free survival (PFS) according to NQO1 status ( P=0.26), but 3-mo PFS rate was numerically greater among NQO1-positive cases (40% versus 20%). Conclusions: ARQ 761 has clinical activity in NQO1-positive tumors. Principal toxicities include hemolytic anemia and methemoglobinemia. Combination studies are underway.
Effect of target lesions selection on between-reader variability of response assessment according to RECIST 1.1.
Authors: Kuhl Christiane K. , Alparslan Yunus , Sequeira Bruno , Schmoe Jonas , Engelke Hannah , Keulers Annika , Bruemmendorf Tim , Keil Sebastian 
Published: September 2018

2528 Background: Response-classification-systems, e.g. RECIST1.1, and dedicated oncology software-tools (DOST) are used to standardize response assessment. Expectation is that different readers should yield the same response-classification for any given patient. We investigated real-life variability between readers who, as in clinical practice, were free to select target-lesions (TL). Methods: Prospective study on 316 patients with metastatic disease who underwent 932 CT-studies, yielding a total 616 follow-up occasions (baseline vs. follow-up) for analysis. All CT-studies were independently evaluated by 3 radiologists who used state-of-the-art DOST (MintLesion). Readers were free to select TL in the respective baseline study, and did so independently. Kappa-statistics were used to analyse agreement for RECIST1.1 response-class-assignment depending on whether readers had selected the same or different TL.To investigate possible impact on treatment decisions, agreement was also determined after aggregating response classes into progressive (PD) vs. non-progressive (CR/PR/SD). Results: Readers used the same TL in 38.6 (238/616), different in 61.4% (378/616). Where readers happened to select the same TL, agreement was “almost perfect” (κ = 0.966 [96%-CI: 0.912–1.00] for assignment of individual response-classes, and 0.977 [0.898–1.0] for the distinction progressive-vs-non-progressive). Where readers had selected different TL, agreement was only “moderate” (0.583 [0.541–0.624] for individual response-class-assignment, and 0.644 [0.587 to 0.701] for distinction progressive-vs.-non-progressive). Choice of the same TL was associated with agreement for distinction between progressive-vs.-non-progressive-disease in 97.7 % [95.4%–100.0%] of patients; choice of different TL was associated with disagreement in 44.7% [37.6%–51.8%]. Conclusions: If different radiologists use RECIST1.1 and DOST for response assessment, they will select different TL more often than not. Just depending on whether TL selection was concordant or not, radiologists will exhibit perfect agreement, or substantial disagreement, even for distinguishing progressive vs non-progressive disease.
Validation of RECIST 1.1 for use with cytotoxic agents and targeted cancer agents (TCA): Results of a RECIST Working Group analysis of a 50 clinical trials pooled individual patient database.
Authors: Litière Saskia , Isaac Gaëlle , De Vries Elisabeth , Bogaerts Jan , Chen Alice P. , Dancey Janet , Ford Robert , Gwyther Steve J , Hoekstra Otto S. , Huang Erich , Lin Nancy U , Liu Yan , Mandrekar Sumithra J. , Schwartz Lawrence HOWARD , Shankar Lalitha , Therasse Patrick , Seymour Lesley ,   RECIST Working Group
Published: September 2018

2534 Background: The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 were derived from an international collaborative effort supported by data from clinical trials (16 studies, 9147 patients) on cytotoxic chemotherapy (CT), providing a standard tool for response assessment. RECIST’s role has been questioned for TCA. Using a pooled individual patient database (IPD) from clinical trials performed by industry and cooperative groups, we assessed whether modifications to RECIST are required to evaluate antitumor activity of TCA. Methods: Data were collected from phase 2 and 3 clinical trials testing TCA in solid tumors. To study the occurrence of mixed responses, the variability of response of lesions within patients was studied. Furthermore, response was correlated with survival through landmark analyses and time dependent Cox models. Results: Clinical data were obtained from 23,259 patients, mainly with lung (36%), colorectal (28%) or breast cancer (11%). 15,620 patients (67%) received a TCA, mainly transduction or angiogenesis inhibitors, either as single agent (37%) or combined with other TCAs (7%) or CT (56%); 28% received CT only and 5% best supportive care or placebo. Within-patient variability reduced as the number of lesions used for response assessment increased, and did so similarly for TCAs (+/- CT) and CT. Mixed responses seemed to occur similarly across these treatment categories as well. Landmark analyses showed improving overall survival by % tumor shrinkage and a clear distinction between the effect of tumor shrinkage and progressive disease (PD) according to RECIST 1.1. This was confirmed by time dependent analysis. In addition target lesion growth showed no marked improvement in overall survival prediction over and above the other components of RECIST 1.1 PD (new lesions, non-target PD), regardless of treatment (TCA, CT or both) received. Similar results were seen focusing on major tumor types and classes of TCA. Conclusions: Using a large IPD dataset we demonstrated that RECIST 1.1 performs equally well for response assessment of TCA as for CT. No modifications are required.
The Drug Rediscovery Protocol (DRUP).
Authors: Van Der Velden Daphne Liselotte , Hamming Lisanne C. , Verheul Henk M.W. , Bloemendal Haiko , Grunberg Katrien , Huitema Alwin , Lugtenburg Pieternella J. , De Vos Filip Yves Francine Leon , Gelderblom Hans , Voest Emile E. ,   Center for Personalized Cancer Treatment (CPCT)
Published: September 2018

2547 Background: Bringing precision medicine to cancer patients remains a challenge. For many cancers, the relative contribution of tumor type, mutations or CNV to drug sensitivity remains unknown. In addition, drug access is generally limited to the labeled indication, bypassing rarer disease subgroups for which large trials are not feasible. An innovative trial that facilitates drug access, whilst systematically analyzing treatment outcomes and biomarkers, could help overcome these challenges. Methods: We designed a prospective, non randomized clinical trial in which patients with advanced cancer are treated with targeted or immunotherapy matched to their tumor profile, defined by genetic aberration, microsatellite instability (MSI) or high mutational load (HML). Upon a mandatory pre-treatment tumor biopsy for biomarker research, patients are enrolled in multiple parallel cohorts, each defined by study drug, histologic tumor type and molecular tumor profile. Efficacy is analyzed per cohort, enrolling 8 patients in stage I and 16 more in stage II if ≥1 response is observed in stage I. Study endpoints include objective tumor response (CR or PR), stable disease (SD) at 16 weeks and grade≥3 adverse events. The DRUP is registered at ClinicalTrials.gov (NCT02925234). Results: Since start of recruitment in Sep 2016, 76 patients have been submitted for review (mean per month 15, range 8-17) and 16 (21%) have started treatment in 10 different cohorts, directed at either ATM (n = 1; breast cancer), BRAF (n = 2; salivary duct carcinoma and ACUP), BRCA (n = 1; breast cancer), ERBB2 (n = 2; CRC), HML (n = 2; prostate and CRC), MSI (n = 5; CRC, GBM and urothelial carcinoma), RET (n = 1; NSCLC) or RAS-RAFwt (n = 2; SCC and sarcoma). Out of the 7 patients for whom response evaluation is available, PR (n = 2) or SD at 16 weeks (n = 1) was observed in 3 (43%). Thirteen study drugs (supplied by 6 pharmaceutical companies) are currently available, 6 more are expected soon. Conclusions: Execution of a nationwide multidrug precision oncology trial is feasible. It contributes to oncologists’ education on molecularly targeted therapies and to identification of early signs of activity in rare cancer subsets. Data sharing with similar studies such as TAPUR and CAPTUR will help to enlarge cohorts and affirm conclusions. Clinical trial information: NCT02925234.
Phase I study combining MLN8237 with nab-paclitaxel in patients with advanced solid malignancies.
Authors: Lim Kian-Huat , Lockhart Albert C. , Waqar Saiama Naheed , Govindan Ramaswamy , Morgensztern Daniel , Picus Joel , Tan Benjamin R. , Baggstrom Maria Quintos , Ratchford Emily , Marquez Samantha , Wang-Gillam Andrea 
Published: September 2018

2553 Background: MLN8237 is a potent Aurora A kinase inhibitor which synergizes with paclitaxel in preclinical studies for various solid malignancies. Methods: We conducted a two-part, phase 1 study combining MLN8237 with nab-paclitaxel in patient with advanced, refractory solid malignancies (NCT01677559). The part 1, dose-escalation phase utilizes a standard a 3+3 design for determination of maximum tolerated dose (MTD) and dose limiting toxicities (DLTs), starting from nab-Paclitaxel 100mg/m2/week 3 out of a 4-week cycle, and MLN8237 20mg BID D1-3/week (denoted nP/M 100/20). In the part 2, dose-expansion cohort, patients with advanced pancreatic ductal adenocarcinoma (PDAC) or high grade neuroendocrine tumor (pNET) who progressed on standard chemotherapy were enrolled. Results: Totally 33 patients (17 in part 1 and 16 in part 2) with a median age of 61 were enrolled. In part 1, the most frequent treatment-related toxicities (all Grade/Grade 3-4) were: nausea (65%/6%), neutropenia (61%/18%), fatigue (47%/6%), anorexia (47%/0%), oral mucositis (53%/6%) and anemia (35%/18%). Two of 3 patients experienced a DLT at dose nP/M 100/50 (Grade 4 neutropenia; febrile neutropenia). No treatment-related mortality occurred. MTD was set at nP/M 100/40 for part 2. At data cutoff, totally 20 patients from the entire study were evaluable for treatment response. One patient with small cell lung cancer achieved partial response and is in cycle 29. Nine other patients (9/20, 45%) with the following tumor histology achieved stable disease after two cycles: 1 small cell lung cancer, 1 lung neuroendocrine carcinoma, 1 lung squamous cell carcinoma, 1 PDAC and 5 high grade pNET (range: 3 and ongoing ~ 18 cycles). Conclusions: MLN8237 plus nab-paclitaxel has manageable side effect profile with very promising activity in tumors with high grade neuroendocrine features, warranting further testing. Exploratory studies on pharmacodynamic markers are ongoing. Clinical trial information: NCT01677559.
Final report of a phase I study of 2-hydroxyoleic acid (2OHOA) a novel sphingomyelin synthase activator in patients (pt) with advanced solid tumors (AST) including recurrent high grade gliomas (rHGG).
Authors: Azaro Analia , Plummer Elizabeth R. , Urruticoechea Ander , Rodon Jordi , Haris Noor R Md , Veal Gareth , Perier Antoine , Tur Vicenc , Escriba Pablo V. , Busquets Xavier , Alberti Joan , Sicart Elisabet , Collins Dearbhaile , Fernandez Ricardo , Bettenhaussen Evelyne , Klumper Edwin , Lopez Juanita Suzanne 
Published: September 2018

2554 Background: 2OHOA is an orally bioavailable, first-in-class synthetic hydroxylated fatty acid, that activates SGMS1 and modulates the lipid content of cancer cell membranes. This regulates the localization of key signaling proteins, including Ras and PKC at the plasma membrane, leading to inactivation of Ras/MAPK, PI3K/Akt and PKC/cyclin/CDK signaling pathways. A dose escalation (DE) and partial expansion cohorts (EC) results of the phase 1 study have previously been reported. We now present the final results of the study. Methods: 2OHOA was evaluated in a 3+3 DE design (7 cohorts from 500mg/d to 16000mg/d) and 2 EC at 4000mg TID in 21 days cycles. PK profiles were determined after single dose (fasted [D-7] or fed [D1]) and multiple doses (fed [D21]) during DE phase and only on D1 throughout EC.Safety assessments were based on CTCAEv4.Tumor response was measured by RECIST and RANO every 6 weeks. Results: Overall 54 pt (DE: 32 pt; 21AST/11rHGG; EC: 22 pt; 12 AST/10 rHGG) were treated (median age 60, range 19-78 years). During the EC the most common treatment related G1-G2 toxicities were diarrhea (n = 13;11pt),nausea (n = 7;6pt), ALT increase (n = 6;4pt), pruritus in throat (4pt), fatigue (4pt) and vomiting (3pt). No G3-G4 toxicities or DLTs were reported confirming the MTD from the DE at 4g TID. Food intake did not alter oral 2OHOA bioavailability. Steady state was already achieved at D8. Power model showed dose proportionality in terms of AUC and Cmax, after single and multiple BID dosing. Average t1/2 ranged from1-2h to 8-12h with delayed Tmax and longer half-lives at higher doses. One glioblastoma (GBM) pt had sustained partial response ( > 2,5 years) and 4rHGG pt (3 GBM) achieved stable disease for at least 6 months. They had previously received 2 lines of treatment without bevacizumab. Tumor markers were measured and will be presented. Conclusions: 2OHOA is well tolerated at the P2RD of 4000mg TID PO daily. The preliminary antitumor activity including a sustained PR in heavy pretreated rHGG pt warrants further investigation in a Ph2 study Clinical trial information: NCT01792310.