tbuckley/cabot-search huggingface dataset:
A phase II cluster study of single agent AUY922, BYL719, INC280, LDK378, and MEK162 in Chinese patients with advanced non-small cell lung cancer (NSCLC).
Authors: Qing Zhou, Xu-Chao Zhang, Bin Peng, Xiaolu Yu, Mikhail Akimov, Barbara Lynn Weber, Yi-Long Wu
Journal: Journal of Clinical Oncology (2014)

TPS8122 Background: Advanced NSCLC management has evolved toward individual tumor subtyping based on targetable oncogenic drivers. Most molecularly characterized lung adenocarcinoma patients (pts) could thus potentially benefit from targeted treatment. This study investigates the innovative paradigm of allocating pts to specific treatment arms based on their genetic profile. The targeted therapies AUY922 (HSP90 inhibitor[i]), BYL719 (PI3Ki), LDK378 (ALKi), INC280 (METi), and MEK162 (MEKi) will be evaluated in different pt subgroups with appropriate confirmed molecular aberrations, in a single cluster study. Methods: This Phase II, multiple arm, open-label study will enroll pts (aged ≥18 years, ECOG PS ≤2) with advanced (stage IIIB/IV) lung adenocarcinoma bearing different molecular alterations, who have failed prior treatment or are unsuitable for chemotherapy, and have received ≤2 prior lines of therapy. Pts must have locally obtained documentation of a relevant molecular alteration from either a new or the most recent archival tumor sample, using primary genetic profiling. Pts will be allocated to a specific treatment arm accordingly (AUY922, 70 mg/m2 QW: activating EGFR mutation and resistant to EGFR inhibitors; BYL719, 350 mg QD: PIK3CA mutation/amplification [other PI3K pathway alterations may be eligible]; INC280, 600 mg BID: MET-positive tumors [by IHC or FISH]; LDK378, 750 mg QD: ALK or ROS1 rearrangement; MEK162, 45 mg BID: KRAS, NRAS or BRAF mutation). Sample size was calculated based on a Bayesian approach using either a minimally informative prior (BYL719, INC280 and MEK162; N=20 for each) or an informative prior using relevant historical data (AUY922 [N=30] and LDK378 [N=25]). The sample size will allow detection with high likelihood, of statistically and clinically relevant antitumor activity. Each treatment arm is independent from one another and will be analyzed separately. Study treatment is given until disease progression or discontinuation. The primary endpoint is overall response rate; secondary endpoints are overall survival, progression-free survival, disease control rate, duration of response, safety, and pharmacokinetics.
2008년 대한간학회 학술연구기금 당선과제 발표 : 약물유전체학을 이용한 만성 B형간염 환자에서 항바이러스제 치료 후 치료반응 및 내성 발생 등의 부작용과 관련된 유전자 마커 발굴
Authors: 김윤준 ( Yoon Jun Kim )
Journal: Clinical and Molecular Hepatology (2008)
A randomized double-blind phase II study to evaluate same-day vs next-day administration of pegfilgrastim with carboplatin and docetaxel in patients with NSCLC
Authors: C. P. Belani, S. Ramalingam, A. Al-Janadi, E. Eskander, H. Ghazal, L. Schwartzberg, M. Elliott, S. Shahin, L. Dreiling
Journal: Journal of Clinical Oncology (2006)

7110 Background: Combination therapy with carboplatin and docetaxel has demonstrated activity against non-small cell lung cancer (NSCLC), but is associated with at least a moderate risk of febrile neutropenia (FN). Though pegfilgrastim is given only once-per-cycle 24 hours after chemotherapy (CT), administering pegfilgrastim on the same day as CT would be convenient for patients (pts). Methods: Pts ≥18 years with previously untreated stage IIIB or IV NSCLC and ECOG ≤2 who were candidates for carboplatin AUC 6 and docetaxel 75 mg/m 2 were randomized 1:1 to receive pegfilgrastim 6 mg within 4 hours or approximately 24 hours after CT. The primary endpoint was the duration of grade 4 neutropenia (DSN) in cycle 1. Same-day administration was considered noninferior to next-day if the upper 95% confidence interval (CI) limit for the difference in DSN between groups in cycle 1 was &lt;2 days. Results: As planned, 90 pts were enrolled. 88 pts received blinded study drug. Pts in the same-day and next-day groups had comparable mean baseline ANC and similar proportions of pts completed the study (43% vs 45%). In cycle 1, only 5% of pts in both groups experienced grade 4 neutropenia; resulting in a mean DSN of 0 days. Similarly in cycle 4, 10% (lasting for 1 day only) and 0% of pts in the same-day and next-day groups experienced grade 4 neutropenia. No pts experienced FN during the study. 44% of pts in the same-day and 33% of pts in the next-day group experienced serious adverse events. Conclusions: In this study of lung cancer patients receiving carboplatin and docetaxel, use of pegfilgrastim from the first cycle was well-tolerated in both treatment groups. Although the incidence of grade 3/4 neutropenia was lower than previously reported for this regimen, DSN appeared to be similar for patients in the same-day and next-day groups. Additionally, few patients experienced reductions or delays in CT delivery. [Table: see text] [Table: see text]
Transformation of follicular lymphoma in the era of immunochemotherapy: A population-based study from British Columbia.
Authors: Abdulwahab J. Al-Tourah, Laurie Helen Sehn, Alden A Moccia, Randy D. Gascoyne, Joseph M. Connors
Journal: Journal of Clinical Oncology (2012)

8049 Background: Several published series have established that the risk of transformation of follicular lymphoma (FL) to aggressive lymphoma is approximately 3% /year (15%-20% at 5 years). The addition of rituximab (R) to chemotherapy (immuno-chemotherapy) has significantly improved the outcome of patients with FL. The impact of immuno-chemotherapy on the risk of transformation remains unknown. We assessed whether the introduction of immuno-chemotherapy has altered this risk. Methods: We examined the Lymphoid Cancer Database of the British Columbia Cancer Agency for FL patients treated with immuno-chemotherapy. Inclusion criteria: FL grades 1-3A by WHO criteria; only patients requiring treatment at diagnosis were included. Exclusion criteria: FL grade 3B or composite histology (FL and DLBCL) at diagnosis; pts who received anthracycline-based chemotherapy; and HIV positivity. The diagnosis of transformation was confirmed by biopsy when possible (n=19; 79%) but patients who were considered to have transformed based on pre-defined clinical assessment (n=5; 21%) were also included in the analysis. Results: We identified 261 pts with FL grade 1-3A requiring treatment at diagnosis, who received immuno-chemotherapy; median f/u 47 months (0.2-116), median age, 61 y (34-86). Treatment: 243 (93%), R-CVP of which 145 (59%) also received maintenance R; 9 (4%), R-Fludarabine combination. 24 pts developed transformed aggressive lymphoma. The risk of transformation for the entire group was approximately 2% per year or 10% at 5 years. However, pts treated with maintenance R (n=151) had a lower risk of transformation compared to pts who only received R-chemo at induction (n= 110), 8% vs 20% at 5 years respectively, (P= 0.003). The post-transformation outcome remains poor with a median survival of 6 months. Conclusions: We and other groups have demonstrated that the risk of transformation from FL to aggressive lymphoma is approximately 15% to 20% by 5 years. Our study suggests that the introduction of immuno-chemotherapy has reduced this risk to less than 10%. This effect is particularly apparent when patients receive maintenance R. The outcome for patients who develop transformation remains poor.
First-in-human evaluation of the human monoclonal antibody vantictumab (OMP-18R5; anti-Frizzled) targeting the WNT pathway in a phase I study for patients with advanced solid tumors.
Authors: David C. Smith, Lee S. Rosen, Rashmi Chugh, Jonathan Wade Goldman, Lu Xu, Ann Kapoun, Ranier K Brachmann, Jakob Dupont, Robert J. Stagg, Anthony W. Tolcher, Kyriakos P. Papadopoulos
Journal: Journal of Clinical Oncology (2013)

2540 Background: The WNT pathway is a key oncologic pathway in numerous tumor types. Vantictumab is a first-in-class anti-Cancer Stem Cell (CSC) antibody that interacts with the extracellular domain of 5 Frizzled receptors (1, 2, 5, 7, 8) and blocks canonical Wnt signaling (PNAS 109, 11717). In patient-derived xenograft models, vantictumab inhibits growth of many tumor types, reduces CSC frequency, promotes differentiation of tumor cells, and synergizes with many chemotherapeutic agents. Methods: Using a 3+3 design, vantictumab was given intravenously, first every 1 week (q1w) or q2w, and, ultimately, q3w. Objectives were determination of maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Results: 18 patients have been treated in 5 dose-escalation cohorts (0.5 &amp; 1 mg/kg q1w; 0.5 mg/kg q2w; 1 &amp; 2.5 mg/kg q3w). Most common related adverse events (AEs) included Grade 1 and 2 fatigue, vomiting, abdominal pain, constipation, diarrhea and nausea. Only related Grade ≥3 AEs were dose-limiting toxicities of Grade 3 diarrhea and vomiting in 1 patient at 1 mg/kg q1w. Vantictumab clearance was dose-dependent, consistent with target-mediated drug disposition, with the half-life ranging from 1.5 (0.5 mg/kg) to 3 days (2.5 mg/kg). Exposure at highest dosed cohorts correlates with efficacy in preclinical tumor models. PD biomarkers indicate manipulation of WNT pathway in patient tumors and surrogate tissue. 1 patient at 0.5 mg/kg q1w had a bone fracture on Day 110 with an ~4-fold increase by Day 28 of β-C-terminal telopeptide (β-CTX), a marker for bone degradation. A revised safety plan and less frequent dosing enabled further dose escalation. Upon β-CTX doubling, 2 patients received zoledronic acid, and β-CTX returned to baseline. 3 patients with neuroendocrine tumors (NETs) had stable disease (SD) for 7+, 3.5, and 9+ months; ~2-, 4- and 7-fold longer, respectively, than on prior therapy. Conclusions: Vantictumab is well tolerated up to 2.5 mg/kg q3w. Bone toxicity appears manageable and reversible. Prolonged SD in 3 patients with NETs may represent single-agent activity. Dose escalation continues. Clinical trial information: NCT01345201.
Comparison of 200 cGy vs. 400 cGy Total Body Irradiation (TBI) When Used with Fludarabine for Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation (RIC AHSCT).
Authors: Ronald Sobecks, Robert Dean, Lisa Rybicki, Josephine Chan, Karl Theil, Roger Macklis, Steve Andresen, Matt Kalaycio, Brad Pohlman, Christine Ferraro, Kelly Cherni, Laura Bernhard, John Sweetenham, Edward Copelan, Brian Bolwell
Journal: Blood (2007)
Phase 1–2a dose ranging study of TLK286 (a novel glutathione analog) in combination with docetaxel in platinum-resistant non-small cell lung cancer (NSCLC)
Authors: V. Papadimitrakopoulou, P. Boasberg, R. Figlin, R. Zinner, G. Blumenschein, L. King, M. Truong, K. Patel, G. L. Brown, N. Hanna
Journal: Journal of Clinical Oncology (2004)

7140 Background: TLK286 (Telcyta) is a novel glutathione analog prodrug activated by GST P1–1, which is overexpressed in NSCLC, releasing two electrophilic fragments that induce apoptosis. TLK286 has demonstrated significant single agent activity by RECIST in two Phase 2 NSCLC trials. In preclinical models, TLK286 is not cross resistant to docetaxel and shows synergistic inhibition in MCF-7 cells. Methods: The objectives were to determine the MTD of the TLK286/docetaxel combination and the objective response rate (ORR) by RECIST. NSCLC patients (pts) who had failed prior platinum-based therapy were treated with TLK286 at 500, 750 or 960 mg/m2 and docetaxel at 75 mg/m2 every 3 weeks until tumor progression or unacceptable toxicity. Results: At interim analysis, 30 pts (16 M, 14 F), median age 65 (range 46–80), median ECOG performance status 1, median prior regimens 1.5 (range 1–3) have received 103+ cycles (mean 3.4 cycles/pt, range 1–11). Pts failed prior therapies with: platinum (100%), paclitaxel (70%), pemetrexed (17%), EGFR inhibitors (33%), gemcitabine (10%), others (20%). The MTD of 960/75 mg/m2 of TLK286/docetaxel was well tolerated without dose limiting toxicities. Most common adverse events related to the TLK286/docetaxel combination were: Grade 1–2 fatigue, nausea, vomiting, anorexia, alopecia. Grade 3–4 neutropenia (15%), leukopenia (10%) and fatigue (15%) was seen. Febrile neutropenia occurred as expected with docetaxel in 7%. No cumulative toxicity has been seen. Six PRs (ORR=25%) and 11 SDs (DSR=71%) of 24 evaluable pts at TLK286/docetaxel dose of 960/75 mg/m2 were reported. Conclusions: TLK286/docetaxel combination has been well tolerated and is an active regimen in platinum resistant NSCLC. The recommended TLK286/docetaxel combination dose is 960/75 mg/m2 for future studies in NSCLC, ovarian and breast cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Telik, Inc. Telik, Inc. Telik, Inc. Telik, Inc. Telik, Inc.
Long-Term Dosing in Sickle Cell Disease Subjects with GBT440, a Novel HbS Polymerization Inhibitor
Authors: Josh Lehrer-Graiwer, Jo Howard, Claire Jane Hemmaway, Moji Awogbade, Paul Telfer, Mark Layton, John B. Porter, Timothy Mant, Kobina Dufu, Athiwat Hutchaleelaha, Donna Oksenberg, Mira Patel, Margaret Eleanor Tonda, Kenneth Bridges, Eleanor Ramos
Journal: Blood (2016)
Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation
Authors: Jonathan U. Peled, Sean M. Devlin, Anna Staffas, Melissa Lumish, Raya Khanin, Eric R. Littmann, Lilan Ling, Satyajit Kosuri, Molly Maloy, John B. Slingerland, Katya F. Ahr, Kori A. Porosnicu Rodriguez, Yusuke Shono, Ann E. Slingerland, Melissa D. Docampo, Anthony D. Sung, Daniela Weber, Amin M. Alousi, Boglarka Gyurkocza, Doris M. Ponce, Juliet N. Barker, Miguel-Angel Perales, Sergio A. Giralt, Ying Taur, Eric G. Pamer, Robert R. Jenq, Marcel R.M. van den Brink
Journal: Journal of Clinical Oncology (2017)

Purpose The major causes of mortality after allogeneic hematopoietic-cell transplantation (allo-HCT) are relapse, graft-versus-host disease (GVHD), and infection. We have reported previously that alterations in the intestinal flora are associated with GVHD, bacteremia, and reduced overall survival after allo-HCT. Because intestinal bacteria are potent modulators of systemic immune responses, including antitumor effects, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HCT. Methods The intestinal microbiota of 541 patients admitted for allo-HCT was profiled by means of 16S ribosomal sequencing of prospectively collected stool samples. We examined the relationship between abundance of microbiota species or groups of related species and relapse/progression of disease during 2 years of follow-up time after allo-HCT by using cause-specific proportional hazards in a retrospective discovery-validation cohort study. Results Higher abundance of a bacterial group composed mostly of Eubacterium limosum in the validation set was associated with a decreased risk of relapse/progression of disease (hazard ratio [HR], 0.82 per 10-fold increase in abundance; 95% CI, 0.71 to 0.95; P = .009). When the patients were categorized according to presence or absence of this bacterial group, presence also was associated with less relapse/progression of disease (HR, 0.52; 95% CI, 0.31 to 0.87; P = .01). The 2-year cumulative incidences of relapse/progression among patients with and without this group of bacteria were 19.8% and 33.8%, respectively. These associations remained significant in multivariable models and were strongest among recipients of T-cell–replete allografts. Conclusion We found associations between the abundance of a group of bacteria in the intestinal flora and relapse/progression of disease after allo-HCT. These might serve as potential biomarkers or therapeutic targets to prevent relapse and improve survival after allo-HCT.
"Formoterol in patients with chronic obstructive pulmonary disease: a randomized, controlled, 3-month trial". R. Aalbers, J. Ayres, V. Backer, M. Decramer, P.A. Lier, P. Magyar, J. Malolepszy, R. Ruffin, G.W. Sybrecht. Eur Respir J 2002; 19: 936-943
Journal: European Respiratory Journal (2002)
External validity of clinical trials in metastatic melanoma.
Authors: Davis Sam, Gillian Gresham, Kerry J. Savage, Joanna Vergidis, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2015)

e17754 Background: Results from clinical trials are not always generalized to real world patients (pts) by adhering to the studies’ original inclusion and exclusion criteria, due in part to physician and pt discretion as well as institutional differences in treatment policies. We aimed to determine the pattern in which clinical trial findings are applied in a population-based setting and the treatment outcomes of these pts. Methods: We focused on melanoma as several new therapies have been recently introduced. Pts with unresectable or metastatic disease from 2013 to 2014 and referred to any 1 of 5 cancer centers in British Columbia were reviewed. Based solely on eligibility criteria as described in registration trials of vemurafenib (Vem) and ipililumab (Ipi), we classified pts into trial eligible (TE) and ineligible (TI) and those treated and untreated with these agents. During the study period, Vem was approved for 1st line use in BRAF mutant pts and Ipi was funded for 2nd line use. Results: We identified 185 pts with known BRAF status for the Vem analysis and 114 pts for the Ipi analysis: median ages 64 and 59 years, 57% and 61% men, and 89% and 88% ECOG 0 to 1, respectively. For Vem, BRAF wild type was the most common reason for being TI. Of the remaining 86 BRAF mutant pts, 59 (69%) were considered TE of whom 51 (86%) received treatment. For Ipi, poor ECOG including rapidly progressive disease was a prevalent factor for being TI. In the Ipi cohort, 96 (84%) cases were deemed TE of whom 63 (66%) received therapy. Factors most frequently associated with non-treatment in both Vem and Ipi TE pts included comorbidities (41%), pt refusal (23%), and toxicities from prior treatments (14%). Compared to TI pts as well as those considered TE but did not receive treatment, pts deemed TE and received treatment achieved the best survival (HR 0.53, 95% CI 0.28-1.00 for Vem and HR 0.33, 95% CI 0.13-0.83 for Ipi, adjusted for age, gender and ECOG). Conclusions: Uptake of new melanoma treatments was generally favorable, but a significant number of pts were considered TI. Even among TE pts, non-use of novel agents was observed and attributable to physician factors, pt preferences and toxicities, highlighting specific opportunities to further optimize real world effectiveness of these new therapies.
Body mass index (BMI) influence on survival in adult patients with newly diagnosed acute myeloid leukemia (AML)/high-risk MDS: Retrospective study of 130 patients from a single institution.
Authors: Mohamed Abdelfatah, Ali Al-Ameri, Zeyad Kanaan, Ahmed Malkawi, Nairmeen Awad Haller
Journal: Journal of Clinical Oncology (2013)

e18011 Background: The incidence of obesity is increasing worldwide and is associated with numerous adverse health outcomes. In AML high body mass index (BMI) is associated with increased risk of treatment-related complications; the overall survival in patients with acute myeloid leukemia is inferior, with most studies conducted in the pediatric population. Aim: To evaluate the effect of increasing (BMI) in the overall survival (OS) of adult patients with AML/High risk MDS. Methods: After obtaining IRB approval, all adult patients with AML diagnosed and treated at our institution (2002–2010) were studied. Data collection included patient demographics, laboratory tests, bone marrow biopsies, BMI, and survival information. We classified the AML patients into two groups according to BMI (kg/m 2 ) classification by WHO; normal Weight 18-25 kg/m 2 , overweight and obese &gt;25 kg/m 2 . Chi-Square and T-test were used for between group comparisons and Kaplan-Meier test was applied for survival estimates. Results: Adult patients with newly diagnosed AML (n = 130) had a median age of 55 years (range: 19-90), and 43 (56%) patients were older than 75 years. Seventy-two patients (55%) were male and 58 (45%) were female. 45 patients (35%) in total had complex cytogenetics, 20 patients (15%) had AML arise from MDS.Forty-four patients (34%) were considered normal weight; Eighty-six patients (66%) were classified as overweight or obese. Overall median survival was 28 weeks; patients with BMI 18-25 kg/m 2 had a 36-week median survival, while patients with BMI &lt;25 kg/m 2 had a 25-week median survival (p&lt;0.499). Conclusions: Overall survival was low in the study population; survival in obese and overweight patients (BMI&gt;25) was slightly lower than normal weight group (18-25 kg/m 2 ), although this did not translate into a survival benefit. Future large scale studies may be needed to further define the role of BMI in survival benefit for these patients.
Hepatocellular carcinoma (HCC) and bone metastases (Mets).
Authors: James J. Harding, Ghaith Abu Zeinah, Joanne F. Chou, Dwight Hall Owen, Michele Ly, Maeve Aine Lowery, Eileen Mary O'Reilly, Marinela Capanu, Leonard Saltz, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2015)

e15129 Background: HCC bone mets are a known disease complication but their frequency, morbidity, and biology are poorly understood. Screening guidelines for HCC bone mets are not established presently. Methods: HCC patients (Pts) with extrahepatic disease treated from 2002 to 2012 at single-center were identified. Pt demographics, clinicopathologic parameters, date of first bone mets, date of first skeletal-related events (SRE, i.e., pathologic fracture, radiation therapy to bone, or surgical resection), genotype by MSK-IMPACT, and outcomes were extracted. Overall survival (OS) was estimated by Kaplan-Meier methods. Cumulative incidence function estimated the probability of developing SRE/bone mets from the date of extrahepatic disease. Regression models identified risk factors for SRE/bone mets. Results: 459 HCC pts with extrahepatic disease were identified; 128 (27.9%) had bone mets as a first site of extrahepatic disease. In 128 pts who presented with bone mets, 67 had SREs with a median time to SRE of 0.8 months (range 0.03-21). The cumulative incidence of SREs at 6-months was 50%. HBV-related HCC and Asian pts had a significantly higher 6-month incidence of SREs (HBV-related 58% vs non-HBV-related 46%; Asian 66% vs non-Asian 47%). Sorafenib (HR 0.4 95%CI: 0.19-0.77) and bisphosphonates (HR 0.3 95%CI: 0.13-0.64) appeared to protect against SREs. For those 331 pts who presented with non-osseous extrahepatic disease, 23 developed bone mets. The cumulative incidence of bone mets at 1 yr was 6.4% (95%CI: 3.6-9.2%). Asian vs Non-Asians pts (10.8 vs 5.8%, p = 0.07) and HBV-related vs. non-HBV-related HCC (11.4% vs 4.6%, p = 0.02) were more likely to develop bone mets. Bone mets rarely developed after 1 yr from extrahepatic disease diagnosis. OS from the time of extrahepatic disease was not altered by the presence of bone mets. 53 genes were mutated in 8 bone met samples with recurrent mutations in TERT (4), TP53 (2), MCL1 (2), GNAS (2) and CTNNB1 (2). Conclusions: Bone mets are a common and morbid HCC extrahepatic manifestation. Screening is indicated at the initial diagnosis of extrahepatic disease and over the first treatment year. Sorafenib and bisphosphonates are recommended to reduce SREs. Exploration into biologic variants that lead to bone mets is necessary.