tbuckley/cabot-search huggingface dataset:
Phase I trial of dasatinib (D) and lapatinib (L).
Authors: C. Erlichman, M. E. Menefee, D. W. Northfelt, R. Qin, J. M. Reid, M. Oursler, R. Marks, P. Haluska, J. R. Molina, K. Koch
Journal: Journal of Clinical Oncology (2010)

2610 Background: Src transduces HER tyrosine kinase activation and phosphorylates HER to further increase its activity. Src also promotes osteoclast differentiation. We performed a phase I trial of D+L to: 1) determine the maximally tolerated dose (MTD) of D+L; 2) describe the toxicities; 3) assess the pharmacokinetic (PK) interaction of L+D; 4) assess the effect of D+L on circulating osteoclast/macrophage precursor (COMP) activation; 5) correlate the clinical endpoints with the PK parameters, and/or biologic results; and 6) describe the responses of this treatment. Methods: Eligibility criteria included ≥ 18 years of age, incurable solid tumors not amenable to other therapies, adequate organ function, normal K+ and Mg++, life expectancy ≥ 12 weeks, ejection fraction > 50%, ECOG PS 0-2, and able to swallow pills whole. Each agent was administered once daily on a 28-day schedule. At the MTD patients were treated with D day 1, and day 9-28 and L day 2-28. Dose levels (mg) were 1) D 70, L 1,000, 2) D 100, L 1,000, 3) D 140, L 1,000. Results: 12 patients were entered on the dose escalation part of the trial and 15 were entered at the MTD. Characteristics of evaluable patients were: median age, 61; 44% female; PS 0 (8%) 1 (65%), 2 (27%). DLT was seen in 2 patients at dose 3. One patient had grade 3 hypermagnesemia and 1 patient had grade 3 rash. The MTD was 100 mg of D and 1,000 mg of L once daily. Despite large variability in the PK data, it appeared that systemic exposure to D and L were increased by concomitant use in a concentration dependent manner. However, in most patients, the magnitude of this effect was small. No grade 4 or 5 events have been observed. One RCC and 2 CRC patients were stable for 6 months, 1 leiomyosarcoma was stable for 5 months and 1 CRC and 1 esophageal ca were stable for 3 months. COMP levels either increased and persisted or increased initially and then returned to baseline at day 28. Conclusions: D+L are tolerable at clinically relevant doses so the possible PK interaction of L and D may have little clinical significance. D+L affects levels of COMP. Studies of D+L in breast, esophageal, and CRC are warranted. Funded by a grant from GlaxoSmithKline and Bristol-Myers Squibb. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline
A comparison of the Cockroft-Gault (CG) and the modification of diet in renal disease (MDRD) equations for estimating renal function and guiding dose adjustment of oncology-related drugs.
Authors: J. A. Grillo, S. Abraham, A. Khandelwal, Q. Liu, B. Booth, N. A. Rahman
Journal: Journal of Clinical Oncology (2010)

2601 Background: For many drugs, impaired renal function (RF) may alter pharmacokinetics (PK) to an extent requiring dosage adjustment. The CG is commonly utilized in approved product labeling (PI), but the MDRD is also used in clinical practice. The purpose of this study was to assess the relationship between the CG and MDRD equations to predict RF and concordance in the dose modification for oncology-related drugs. Methods: Demographic and pertinent laboratory data (presented as percentage [%] or median [25th, 75th percentile]) was pooled from renal dosing studies submitted to FDA in support 7 oncology related drugs. Four of these drugs ultimately required dose modification for renal impairment in the PI. Creatinine clearance (Clcr) and glomerular filtration rate (GFR) was estimated using the CG and MDRD equations, respectively. The relationship between these two estimates was determined by correlation analysis and a comparison of estimated RF to PK drug exposures for the 7 drugs. Additionally, the agreement between the recommended dosing was assessed for both estimates in determining dosing modifications in the PI of 4 oncology related drugs (lenalidomide [L], peginterferon alfa-2b [PG], pemetrexed [P], and zoledronic acid [Z]). Results: Individual RF estimates were calculated from 493 research subjects (serum creatinine 1.1 mg/dL (0.8, 1.7); race (82% Caucasian, 13% Black); body weight 77.7 kg (65.9, 92.1)). Correlation analysis of CG and MDRD estimates showed r2=0.69 (p<0.0001) for all observations and r2=0.8 (p<0.0001) when RF estimates > 80 mL/min were excluded. Both estimates appeared to have similar correlation with the PK exposure. The same renal dosing modification was made for L, PG, P and Z 83%, 85%, 82% and 81% of the time, respectively. Where recommendations did not agree, CG estimates resulted in a one step higher dose in 2/3 of the disagreements. Conclusions: There is an adequate relationship between CG and MDRD estimates of RF and both achieve reasonably similar renal dosing modifications in the drugs studied. No significant financial relationships to disclose.
Electrospun Contrast‐Agent‐Loaded Fibers for Colon‐Targeted MRI
Authors: Miao Jin, Deng‐Guang Yu, Xia Wang, Carlos F. G. C. Geraldes, Gareth R. Williams, S. W. Annie Bligh
Journal: Advanced Healthcare Materials (2016)

Magnetic resonance imaging is a diagnostic tool used for detecting abnormal organs and tissues, often using Gd(III) complexes as contrast‐enhancing agents. In this work, core–shell polymer fibers have been prepared using coaxial electrospinning, with the intent of delivering gadolinium (III) diethylenetriaminepentaacetate hydrate (Gd(DTPA)) selectively to the colon. The fibers comprise a poly(ethylene oxide) (PEO) core loaded with Gd(DTPA), and a Eudragit S100 shell. They are homogeneous, with distinct core–shell phases. The components in the fibers are dispersed in an amorphous fashion. The proton relaxivities of Gd(DTPA) are preserved after electrospinning. To permit easy visualization of the release of the active ingredient from the fibers, analogous materials are prepared loaded with the dye rhodamine B. Very little release is seen in a pH 1.0 buffer, while sustained release is seen at pH 7.4. The fibers thus have the potential to selectively deliver Gd(DTPA) to the colon. Mucoadhesion studies reveal there are strong adhesive forces between porcine colon mucosa and PEO from the core, and the dye‐loaded fibers can be successfully used to image the porcine colon wall. The electrospun core–shell fibers prepared in this work can thus be developed as advanced functional materials for effective imaging of colonic abnormalities.
Why do port-wine stains (PWS) on the lateral face respond better to pulsed dye laser (PDL) than those located on the central face?
Authors: Wenxin Yu, Gang Ma, Yajing Qiu, Hui Chen, Yunbo Jin, Xi Yang, Xiaojie Hu, Tianyou Wang, Lei Chang, Henghua Zhou, Wei Li, Xiaoxi Lin
Journal: Journal of the American Academy of Dermatology (2016)
SFRP5 Inhibits Early Stages Of B-Cell Differentiation and Modulates Estrogen-Related Changes In The Immune System
Authors: Takafumi Yokota, Kenji Oritani, Takao Sudo, Tomohiko Ishibashi, Yukiko Doi, Yoko Habuchi, Michiko Ichii, Daisuke Okuzaki, Kazuma Tomizuka, Kengo Yamawaki, Akihiko Shimono, Eiichi Morii, Paul W. Kincade, Yuzuru Kanakura
Journal: Blood (2013)
A phase II trial of radiation plus temozolomide followed by adjuvant temozolomide and poly-ICLC in patients with newly diagnosed glioblastoma multiforme (NABTT #0501)
Authors: M. R. Rosenfeld, M. C. Chamberlain, S. A. Grossman, D. M. Peereboom, G. J. Lesser, T. T. Batchelor, S. Desideri, A. M. Salazar, X. Ye
Journal: Journal of Clinical Oncology (2008)

2055 Background: Polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC), is a double-stranded RNA that stimulates a broad variety of host defense mechanisms including T-cell and natural killer cell activation, cytokine release, and also has a potent adjuvant effect and specific antiproliferative and antiviral effects. The objective of this study is to determine the safety and efficacy of poly-ICLC when it is added as an adjuvant treatment for newly diagnosed glioblastoma (GB). Methods: New diagnosed patients > 18 years with histologically proven GB received standard external beam radiation therapy with concurrent low-dose temozolomide (TMZ)(75 mg/m2) followed by adjuvant cycles consisting of TMZ for 5 days (150- 200 mg/m2) (week 1), intramuscular injections of poly-ICLC (20 mcg/kg) 3 times a week (weeks 2–8; total 21 injections), week 9 off. There is no limit to the number of adjuvant cycles and imaging evaluations are performed before every cycle. Results: There were 96 patients enrolled (59 men); median age 57 yrs (range 22–85); median KPS 90 (range 60–100). Fourteen patients did not start adjuvant treatment (5 patient request and 4 investigator withdrawal; 2 progressive disease; 1 death; 1 toxicity; 1 other). The most frequent grade 3–4 toxicities (occurring in > 5% of subjects) possibly related to the study regimen were leukopenia (20%), thrombocytopenia (13%), anemia (13%), neutropenia (9%), and SGPT elevation (7%). The two deaths during adjuvant treatment were considered unlikely related to the regimen. Based on these data and an interim safety evaluation of the first 30 subjects completing 19 weeks of treatment, no safety reason was found to suspend the trial. As of 9/30/07 59 patients are alive and 37 have died; 42 patients remain on study. Conclusions: The addition of poly-ICLC to a modified adjuvant treatment regimen for newly diagnosed GB is well tolerated. Further safety and interim efficacy data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Oncovir Oncovir Oncovir Oncovir
Randomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG9912)
Authors: N. Boku, S. Yamamoto, K. Shirao, T. Doi, A. Sawaki, W. Koizumi, H. Saito, K. Yamaguchi, A. Kimura, A. Ohtsu
Journal: Journal of Clinical Oncology (2007)

LBA4513 Backgrounds: We conducted a 3-arm phase III study to investigate superiority of CP and non-inferiority of S-1 to 5-FU for advanced gastric cancer in the primary endpoint of overall survival (OS) and secondary endpoints of response rate (RR), time to treatment failure (TTF), non-hospitalized survival (NHS) and toxicities. Methods: Treatments with 5-FU (800mg/m 2 /d, ci, d1–5, q4w), CP (irinotecan, 70mg/m 2 , div, d1&amp;15 and cisplatin, 80mg/m 2 , div, d1, q4w) and S-1 (40mg/m 2 , b.i.d., d1- 28, q6w) were continued until disease progression or unacceptable toxicities. Tumors were evaluated every two months. With 230 patients (pts) per arm, this study had 80% power to demonstrate 10% superiority of CP and non-inferiority with 5% margin (hazard ratio, HR=1.16) of S-1 and 0.05 study-wise 1-sided alpha. Results: 704 pts having unresectable or recurrent gastric adenocarcinoma with/without target lesions (TL) were randomized between Nov 2000 and Jan 2006. Final analysis was performed in Feb 2007 when 601 pts (85%) were dead. The results of OS are shown in Table . Median TTF/NHS were 2.3M/7.2M for 5-FU, 3.7M/9.5M for CP, and 4.0M/9.2M for S-1. Incidences (%) of grade 4 neutropenia, grade ≥3 febrile neutropenia, infection with neutropenia, anorexia, diarrhea within 6M, and treatment related death (5- FU/CP/S-1) were 0/37/0, 0/9/0, 0/8/0, 13/33/12, 0/9/8, and 0/1.3/0.4. In the subset having TL, RRs of 5-FU/CP/S-1 (n=175/181/175) were 9%/38%/28%, and their median survival times (MST) were 9.0M/12.1M/10.5M and HRs to 5-FU were 0.78 (95%CI, 0.63–0.98) for CP and 0.85 (0.68–1.06) for S-1. In the subset not having TL, the MSTs of 5-FU/CP/S-1 (n=59/55/59) were 13.5M/14.4M/18.1M and HRs were 1.02 (0.68–1.55) for CP and 0.82 (0.55–1.24) for S-1. Conclusions: S-1 showed a significant non-inferiority to 5-FU. Although CP did not show statistically significant superiority to 5-FU in all pts, it may have a benefit for some subgroups such as pts with measurable metastatic diseases. [Table: see text] [Table: see text]
Explaining differences in chemotherapy utilization in ovarian cancer between health service areas
Authors: D. Polsky, K. A. Armstrong, T. C. Randall, R. N. Ross, X. Zhang, O. Even-Shoshan, J. S. Schwartz, P. R. Rosenbaum, J. H. Silber
Journal: Journal of Clinical Oncology (2004)

6005 Background: Identifying excess variation has proved to be a useful tool to better understand potential strengths and weaknesses of the health care system. This study aims to report on the extent of geographic variation in chemotherapy utilization in ovarian cancer between 38 U.S. Health Service Areas (HSA) utilizing the 11 tumor registries from SEER-Medicare, and to determine HSA characteristics associated with this variation. Methods: Medicare patients with a diagnosis of ovarian cancer between 1990 and 1999 were selected from the SEER registries (N=10,986). After exclusions for HMO status (N=1778), death < 30 days (N=810), and HSAs < 30 subjects (N=466), the sample size was 7932. Chemotherapy within a year of diagnosis was identified by Medicare billing codes. Sociodemographic and disease characteristics were obtained from SEER and Census data. HSA data were obtained from the Area Resource File of the Federal Bureau of Health Professions. Results: In order to study differences across HSAs, we fit a logit model describing each of the 38 HSAs, and explored the variation in the odds of receiving chemotherapy inside HSAs, controlling for patient age, stage and year of diagnosis. There were large and significant differences between HSAs, with ORs varying 4.6-fold, (chi-square for HSA was 151, df=37, p=0.000). In a second model we added race, income, and education. ORs for HSAs now varied by 5.9 fold (chi-square for HSA was 148, df=37, p=0.000). Finally, we removed the 38 fixed effects and replaced them with 7 HSA descriptors (%HMO, pop. density, MD/pop., oncologist/MD, ln pop., N hospitals, %hosp with oncology services). The chi-square for these HSA characteristics was 21 (df=7, p=0.004). The only HSA descriptor with a significant odds ratio was % hospitals with oncology services (OR=1.82, p=.012). Conclusions: Medicare patients with the same age, stage, and year of diagnosis had very different chemotherapy utilization within one year of diagnosis in different geographic areas as defined by the HSAs. An important HSA factor contributing to this excess variation in utilization of chemotherapy between HSAs was the density of oncology facilities inside each HSA. No significant financial relationships to disclose.
Abstract 14676: Evidence for Electromechanical Coupling in Patients With Cardiac Resynchronization Therapy From Vectorcardiography and Echocardiography
Authors: Caroline J van Deursen, Liliane Wecke, Wouter van Everdingen, Marcus Stahlberg, Patrick Houthuizen, Michel H Janssen, Harry J Crijns, Lennart Bergfeldt, Kevin Vernooy, Frits W Prinzen
Journal: Circulation (2013)

Introduction: Experiments in dogs with left bundle branch block (LBBB) showed a strong relation between electrical (QRS-vector amplitude, QRSVampl) and mechanical interventricular dyssynchrony. We ...
Trabectedin (T) in relapsed advanced ovarian cancer (ROC): A pooled analysis of three phase II studies
Authors: S. McMeekin, J. M. del Campo, N. Colombo, C. Krasner, A. Roszak, P. Braly, T. E. Ciuleanu, C. Lebedinsky, M. A. Izquierdo, C. Sessa
Journal: Journal of Clinical Oncology (2007)

5579 Introduction: Trabectedin is a DNA minor groove binding drug with a distinct MoA under development in sarcoma, prostate, breast and ROC. We have performed a pooled analysis of efficacy and tolerability of all phase II trials with T as 2 nd - 3 rd line in ROC. Methods: Three Trabectedin schedules were investigated: two every 3weeks (q3w; A: 1.3 mg/m 2 3-h or B: 1.5 mg/m 2 24-h) and one weekly (C: 0.58 mg/m 2 3-h ×3 q4w). Endpoints were response rate (RR), time to progression (TTP), response duration (RD) and safety. 294 patients from 3 phase II (one randomized A vs B) trials were included: 108 were resistant (R) and 186 sensitive (S) to last platinum, based on progression-free interval &lt;6 months or longer.Results: Overall RR and median TTP were 8% and 2.1mo in R and 34% and 5.8 mo in S patients. Median RD was 5.8 m. Schedules A &amp; B q3w showed significant better RR (33% vs 16%, p=&lt;0.0001) and median TTP (5.8 vs 2.8 m, p=0.0001) than the weekly schedule C. No efficacy difference was seen between 3-h and 24-h q3wk. In patients with = 2 prior platinum-based regimens, RR (R:7% and S:37%) and median TTP (R: 2.5 m and S:6.3 m) were similar than patients with only 1 prior platinum [RR (R:9%; S:33%) and TTP (R: 2 m; S: 5.5 m)]. 1,404 cycles were delivered [median A: 5(1–23), B: 5(1–19), C: 3(1–22)], with similar dose intensity (mg/m 2 /wk) across regimens (0.38, 0.42, 0.39). Most common drug-related AEs of any grade by cycle were (A, B, C) fatigue: 38, 35, 63% and vomiting: 16, 27, 21%. Grade 3/4 lab abnormalities were non-cumulative neutropenia: 21, 28, 1% and ALT increase: 32, 26, 3%. Low incidence of febrile neutropenia, neurotoxicity, stomatitis and alopecia was seen regardless of schedule. Conclusions: Trabectedin as single agent has shown clinical activity in both R and, particularly in S ROC. Activity was fully retained in patients with =2 prior platinum lines. Trabectedin q3w schedules (with no difference between 3 and 24-h) showed higher efficacy than T weekly. Toxicities were manageable and non-cumulative. Trabectedin is a promising new drug for the treatment of ROC and is under evaluation in a phase III trial. No significant financial relationships to disclose.
A phase II trial of cetuximab/irinotecan every 2 weeks in patients with metastatic colorectal cancer (CRC) that expresses wild-type KRAS after failure to first-line therapy with an irinotecan-containing regimen with or without detectable epidermal growth factor receptor (EGFR) expression.
Authors: Y. Hong, M. Kang, S. Kim, J. Baek, J. Lee, H. Chang, S. Jang, Y. Kang, T. Kim
Journal: Journal of Clinical Oncology (2010)

e14112 Background: Cetuximab plus irinotecan has been proven to be effective in patients (pts) with irinotecan-refractory metastatic colorectal cancer (mCRC) which express wild-type (WT) KRAS and EGFR(+). Retrospective analysis revealed that mCRC with undetectable EGFR (EGFR−) by immunohistochemistry (IHC) also showed similar efficacy to cetuximab. There has not been a prospective study to investigate the efficacy of cetuximab for mCRC pts with EGFR−. Methods: This is a prospective, nonrandomized multicenter phase II study. Between Mar. 2008 and Oct. 2009, 40 pts (20 EGFR+ and 20 EGFR− in each study arm, respectively) were enrolled. Main eligibility criteria were histologically proven adenocarcinoma expressing WT-KRAS, failed to first-line irinotecan-containing chemotherapy. EGFR expression was determined by IHC (PharmDx; Dako Corporation, Carpentino, CA, USA). Pts were treated with biweekly cetuximab (500 mg/m2) and irinotecan (150-180 mg/m2) as second-line chemotherapy. Primary endpoint was to investigate response rate (RR), and secondary endpoints were to evaluate toxicity, progression-free survival (PFS) and overall survival (OS). Results: Baseline characteristics were balanced between both arms. The overall RR was 45% (18/40, 95% CI 29.6-60.4), 55% (11/20) in EGFR+ and 35% (7/20) in EGFR− arm. Overall median PFS was 7.1 months (mo) (95% CI 5.2-9.1); 8.3 mo in EGFR+ and 5.8 mo in EGFR− arm. Median OS was not reached yet; 1-year survival rate was 81.1%, 86.6% in EGFR+ and 78.7% in EGFR− arm. Grade 3 or 4 toxicities included neutropenia in 5 pts (12.5%), and febrile neutropenia/asthenia in 2 pts (5%), respectively. Grade 2 or 3 skin rash were observed in 70% of pts (14/20) in EGFR+ and 55% (11/20) in EGFR− arm. Conclusions: Biweekly cetuximab plus irinotecan was feasible and well tolerated as a second-line treatment in mCRC. This combination showed significant anti-tumor activity in irinotecan-refractory mCRC pts with WT-KRAS regardless of EGFR expression of the tumor. No significant financial relationships to disclose.
A phase III study (CheckMate 017) of nivolumab (NIVO; anti-programmed death-1 [PD-1]) vs docetaxel (DOC) in previously treated advanced or metastatic squamous (SQ) cell non-small cell lung cancer (NSCLC).
Authors: David R. Spigel, Karen L. Reckamp, Naiyer A. Rizvi, Elena Poddubskaya, Howard Jack West, Wilfried Ernst Erich Eberhardt, Paul Baas, Scott Joseph Antonia, Adam Pluzanski, Everett E. Vokes, Esther Holgado, David Michael Waterhouse, Neal Ready, Justin F. Gainor, Osvaldo Rudy Aren, Leora Horn, Luis Paz-Ares, Christine Baudelet, Brian Joseph Lestini, Julie R. Brahmer
Journal: Journal of Clinical Oncology (2015)

8009 Background: Treatment options are limited for patients (pts) with advanced SQ NSCLC who fail platinum-based doublet chemotherapy (PT-DC). We report results of a randomized, open-label, global phase III study of NIVO, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, vs DOC in pts with SQ NSCLC and with disease progression (PD) during/after one prior PT-DC regimen. Methods: Pts (N = 272) were randomized 1:1 to receive NIVO 3 mg/kg (n = 135) Q2W or DOC 75 mg/m2(n = 137) Q3W until PD, discontinuation due to toxicity, or other reasons. The primary objective was overall survival (OS). Secondary objectives included investigator-assessed objective response rate (ORR; RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 expression (PD-L1 testing not required for enrollment), quality of life, and safety. Results: Superior OS was observed with NIVO vs DOC (HR = 0.59; 95% CI: 0.44, 0.79; p = 0.00025). NIVO improved PFS vs DOC (HR = 0.62; 95% CI: 0.47, 0.81; p = 0.0004). ORR was 20% (27/135) for NIVO and 9% (12/137) for DOC (p = 0.0083). OS HRs favored NIVO regardless of PD-L1 expression (Table). Grade 3–4 drug-related AEs occurred in 7% (9/131) of NIVO and 55% (71/129) of DOC pts. No deaths were related to NIVO vs 3 DOC-related deaths. Conclusions: CheckMate 017 met its primary objective, demonstrating superior OS of NIVO vs DOC in pts with advanced, previously treated SQ NSCLC and demonstrated PFS and ORR superiority. Tumor PD-L1 status was neither prognostic nor predictive for efficacy endpoints. The safety profile of NIVO 3 mg/kg Q2W is acceptable and favorable vs DOC. NIVO represents a significant improvement in second-line therapy for SQ NSCLC. Clinical trial information: NCT01642004. NIVO (n = 135) DOC (n = 137) mOS, mo (95% CI) 9.2 (7.3, 13.3) 6.0 (5.1, 7.3) 1-yr OS, % (95% CI) 42 (34, 50) 24 (17, 31) Median duration of response, mo (range) Not Reached (2.9–20.5+) 8.4 (1.4+–15.2+) mPFS, mo (95% CI) 3.5 (2.1, 4.9) 2.8 (2.1, 3.5) 1-yr PFS, % (95% CI) 21 (14, 28) 6 (3, 12) PD-1 expression NIVO (n) DOC (n) OS HR (95% CI) ≥ 1% 63 56 0.69 (0.45, 1.05) < 1% 54 52 0.58 (0.37, 0.92) ≥ 5% 42 39 0.53 (0.31, 0.89) < 5% 75 69 0.70 (0.47, 1.02) ≥ 10% 36 33 0.50 (0.28, 0.89) < 10% 81 75 0.70 (0.48, 1.01)