tbuckley/cabot-search huggingface dataset:
Trastuzumab emtansine (T-DM1) plus capecitabine (X) in patients with HER2-positive MBC: MO28230 TRAX-HER2 phase 1 results.
Authors: Karen A. Gelmon, Maria Vidal, Marie-Paule Sablin, Rosanne Serpanchy, Jesus Soberino, Javier Cortes, Diego Villa, Mustapha Zoubir, Ulrich Freudensprung, Jian Xu, Charlotte Colthorpe, Veronique Dieras
Journal: Journal of Clinical Oncology (2014)

606 Background: T-DM1, an antibody–drug conjugate composed of trastuzumab, the microtubule inhibitor DM1, and a stable linker, is a newly approved therapy for HER2-positive MBC. Two phase 3 studies have shown significant efficacy in patients previously treated with trastuzumab and a taxane. HER2-directed therapies in combination with X have shown improved efficacy in patients with MBC, and preclinical data show enhanced activity with T-DM1 + 5-fluorouracil. Thus, T-DM1 + X may have increased antitumor activity in patients with HER2-positive MBC. Methods: TRAX-HER2 (NCT01702558) is a phase 1/2 study of T-DM1 + X in patients with HER2-positive MBC (IHC 3+/ISH+) or metastatic gastric cancer. Key inclusion criteria are progression on ≥1 trastuzumab + chemotherapy regimen, ≥1 measurable lesion (RECIST v1.1), and LVEF ≥50%. The primary phase 1 objective for MBC was to evaluate the maximum tolerated dose (MTD) of X with T-DM1 (3.6 mg/kg q3w) using a 3 + 3 design. Safety, tumor response, and PK were also assessed. Results: As of the data cutoff (1/17/14), 7 patients were enrolled in the T-DM1 + X 750 mg/m2 cohort (a 7th patient replaced one that had not met the stable liver enzymes eligibility criterion). Of the 6 DLT-evaluable patients (follow-up: 3.7–13.2 mos), 2 had a DLT (1 grade 3 vomiting, 1 grade 3 elevated ALT and AST, which prohibited start of cycle 2 at 100% dose). After the DLT evaluation period, 2 patients had grade 3 AEs: 1 elevated ALT, 1 keratitis. No grade ≥4 AEs or SAEs were reported. As of the cutoff, 4 of the 6 patients remain on treatment. The best confirmed overall response was a partial response in 4 patients and stable disease in 1 patient; 1 patient was not evaluable (had only 1 assessment). The T-DM1 PK profile was comparable with that observed in single-agent T-DM1 trials; PK of X was similar ± T-DM1. Due to the 2 DLTs, the next cohort was opened with a de-escalated dose of X (700 mg/m2). Three patients have been enrolled (follow-up: 0.5–1.2 mos); no DLTs or grade ≥3 AEs have yet been observed. Conclusions: T-DM1 + X 750 mg/m2 showed encouraging activity. However, due to DLTs, a dose de-escalated cohort (T-DM1 + X 700 mg/m2) was opened. Complete results from this cohort (n=6) will be available at the time of presentation. Clinical trial information: NCT01702558.
HCV/HBV infection in Italian patients (pts) with solid tumor candidates for chemotherapy (CT).
Authors: Fabiola Lorena Rojas Llimpe, Francesca Di Fabio, Claudia Degli Esposti, PierGiorgio Di Tullio, Vita Mutri, Daniela Adua, Stefania Giaquinta, Francesca Sperandi, Bruna Angelelli, Barbara Melotti, Marco Montagnani, Carmine Pinto
Journal: Journal of Clinical Oncology (2014)

e12521 Background: There are few studies dealing with the prevalence of chronic infection by HBV or HCV in Italian pts candidated to CT for solid tumors and on the episodes of hepatitis reactivation during the CT. Methods: Pts referred to S.Orsola-Malpighi Hospital Medical Oncology Unit undergo to blood tests (BT) that include a screening for HBV and HCV infection by testing the positivity for HbsAg and anti-HCV. We examined the records of 564 consecutive new pts from January to December 2012. Pts who performed at least 1 BT were considered elegible: 479/564 (84.9%). Results: Pts screened: 435(90.8%) HbsAg, 397(82.9%) anti-HCV and 397 (82.9%) for both. 24 pts were found positive: 9 (1.9%) HBsAg+, 14 (3.5%) anti-HCV+, 1 (0.3%) HBsAg+/anti-HCV+. Males 16 (66.7%). Primary tumors: 9 (37.5%) liver, 4 (16.7%) lung, 3 (12.5%) head-neck, 3 (12.5%) colon, 2 (8.3%) bladder, 1 (4.2%) anus, 1 (4.2%) breast, 1 (4.2%) gastric, 1 (4.2%) skin. 3/24 pts (12.5%) with abnormal liver function tests at baseline were not treated. 10/24 (41.7%) pts had received previous therapy for hepatitis: 3 (1 HBsAg+, 3 anti-HCV+) interferon(IFN); 5 (anti-HCV+) IFN + ribavirin (rib); 2 (HBsAg+) lamivudine (lam). 3/24 pts were still receiving therapy for hepatitis: 2 with lam (maintained during CT), 1 IFN/rib (suspended at time of CT). After hepatological evaluation 3 pts started prophylactic lam, 5 not received prophylaxis. 17/24 pts (10 HBsAg+, 7 anti-HCV+) underwent CT/oral therapy: 12 platinum compounds, 1 vinorelbine, 1 Nigro regimen, 1 anastrozole, 1 gefitinib, 1 sorafenib. 4/24 pts anti-HCV+ underwent locoregional treatment: 3 ittrium, 1 TACE. 9 (42.86%) pts completed antineoplastic treatment as planned (5HBsAg+, 4 anti-HCV+). 5/24 (23.81%) pts stopped CT because of rapid progression of the neoplastic disease (2 HBsAg+, 2 anti-HCV+, 1 HBsAg+/anti-HCV+). 3 (14.29%) pts had several suspensions of CT until the definitive interruption: 2 neutropenia (1 HBsAg+, 1 anti-HCV+); 1 hypertransaminasemia (HBsAg+). Conclusions: In our series the prevalence of HbsAg and anti-HCV positivity was: 1.9% and 3.5% respectively. CT is feasible in pts with chronic HBV/HCV infection. None of our pts showed viral reactivation although not all received prophylaxis during CT.
A phase I study of oral darinaparsin in patients (pts) with advanced solid tumors (AST).
Authors: Luis H. Camacho, Neil N. Senzer, Wael A. Harb, John A Barrett, Christopher Charles Korth, Dorothea Astl, Jaroslaw Jac, Hagop Youssoufian
Journal: Journal of Clinical Oncology (2012)

e13040 Background: Darinaparsin [Zinapar, ZIO-101(S-dimethylarsino-glutathione)], is a novel organic arsenic compound with in vitro and in vivo anticancer activity in tumor cell lines resistant to arsenic trioxide. An oral formulation is now available. Methods: This study used a 3+3 escalating design, dosing orally for 21 days followed by 7 days off (28 day cycle). Pts with AST refractory to standard therapy, ECOG performance score (PS) ≤ 2 and adequate organ function were treated. Study objectives were safety profile evaluation, pharmacokinetics (PK) and preliminary activity of oral darinaparsin. CTCAE v. 4.0 and RECIST 1.1 were used. Results: A total of 10 pts (8 males, 2 females), with ECOG PS 0=2, 1=8, mean age of 71 years (range: 60-81), median of prior therapies 3 (range: 1-4) were treated. A median of 2 cycles of darinaparsin was administered (range: 1-6). Dose limiting toxicities (DLT) were confusion (n=1; 400 mg), cognitive disturbance (n=1; 400 mg) and encephalopathic syndrome (n=1; 300 mg), reversible with drug discontinuation. The highest tolerable dose was 300 mg per day. Most frequent AEs were: hypokalemia, nausea (40% each), fatigue (30%), anemia, diarrhea, hypophosphatemia, pneumonia, vomiting (20% each). Most frequent grade ≥3 AEs were: hypokalemia, hypophosphatemia (20% each). Best overall response was stable disease (at 2 cycles), observed in 5 pts: adenocarcinoma of colon (2 pts), chordoma, adenocarcinoma of small bowel and carcinoma of tongue. PK analysis of 400 mg cohort (n=4) and 300 mg cohort (n=6) resulted in T max at 9 hr post treatment and C max slightly greater than dose proportional (p&lt;0.05). Steady-state trough levels were achieved on or before Day 5. Approximately 40 % greater C max was observed on D15 compared to D1 for the 300 mg cohort (p&lt;0.05) while unchanged at 400 mg. DLTs were observed when duration of exposure was more than 7 days and serum trough levels were 800 ng/ml or above. Conclusions: Oral darinaparsin is well tolerated at the dosage of 300 mg per day for 21days in a 28 day cycle in pts with AST. Preliminary evidence of clinical activity and a predictable PK profile justify further evaluation of darinaparsin in selected indications.
Folate hydrolase assay of tissue extracts from prostate specific membrane antigen (PSMA) transgenic mice
Authors: Xinning Wang, Dean J. Bacich, Kelley M. Harsch, Warren D. W. Heston
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

4302 

Protein specific membrane antigen (PSMA) is a type II integral membrane protein, predominantly localized to the epithelial cells of the prostate gland. PSMA expression is upregulated in poorly differentiated and advanced prostate cancers. PSMA is also expressed on the tumor vascular endothelium of virtually all solid carcinomas and sarcomas, but not on normal vascular endothelium. PSMA is an established target for imaging and therapy in cancer treatment. In mice, the strongest expression of PSMA is in the kidney with less expression in the brain, but not in the prostate. Transgenic mice that are expressing human PSMA in their prostates have been generated in our lab using prostate specific antigen (PSA) promoter and enhancer. PSMA has two enzymatic activities: folate hydrolase and N-acetylated-alpha linked-acidic dipeptidase (NAALADase). The objective of this study is to perform enzymatic assay of tissue extracts from transgenic mice in comparison with those from wild type mice. The protein was extracted by 1% Triton-100 from fresh tissue homogenates and protein concentrations were measured by BCA assay. The extracts were added to methotrexate diglutamate (MTXGlu2) and incubated at 37°C for 1 hour. The reaction was stopped by adding Na2HPO4. The amount of methotrexate (MTX) and MTXGlu2 were then determined by HPLC using a PRISM RP column. The results are listed in [Table 1][1]. In wild type mice, the highest enzymatic activity was found in the kidney, followed by the brain and anterior prostate (AP), while very low activity was found in the heart and the dorsal, ventral and lateral lobes of the mouse prostate (DP/VP/LP). The folate hydrolase activity of the tissue extracts concurred with the amount of PSMA expressed in the tissues. In transgenic mice, enzymatic activity was also found in the kidney, brain and AP and the values were close to those of the wild type mice. A significant difference was found in the DP/VP/LP, where an enzymatic activity of 5.07 nmol MTX/mg protein/hour was observed compared with 0.71 nmol MTX/mg protein/hour in wild type mice. The results were in agreement with western blot analysis, where expression of PSMA was found in the DP/VP/LP of transgenic mice but not in that of wild type mice. In conclusion, a transgenic mouse that strongly expresses human PSMA in the prostate has been created. Further interest will be to explore how this animal model can be utilized in developing novel imaging and therapeutic strategies.



![Figure][2]  [1]: #F1
 [2]: pending:yes
First-in-human, pharmacokinetic (PK), and pharmacodynamics (PD) phase I study of Debio1143 (AT-406) in patients with advanced cancer: Final results.
Authors: Herbert Hurwitz, Henry Clement Pitot, David C. Smith, Jeffrey Mark Brill, Gregoire Vuagniaux, Elisabeth Rouits, Claudio Zanna, J. Mel Sorensen
Journal: Journal of Clinical Oncology (2014)

2532 Background: Inhibitors of apoptosis proteins (IAPs) modulate multiple processes, including caspases activation and NF-κB signalling. Expression and/or overexpression of IAPs have been reported for a variety of tumour types and are correlated with tumour growth and resistance to apoptosis induced by standard chemo and radiation therapies. The small molecule Debio 1143 (formerly AT-406) is a potent orally-active IAP antagonist able to promote apoptosis in tumour cells by restoring caspase activity, and modulating NF-κB signalling and TNFα effects in various preclinical models. Methods: This first-in-human study in patients with advanced cancer used an adaptive design for dose titration. Debio 1143 was given orally once daily on days 1-5 every 2 or 3 weeks. The starting dose of 5 mg was escalated by 100% in consecutively enrolled single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of 3 and subsequently 6 patients as well as reduction of dose increments to 50%. The MTD was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken. Results: Thirty-one patients received doses from 5 to 900 mg. Only one DLT (G3 reversible ALT elevation) was reported at 180 mg. Most common adverse events of any grade deemed related to study drug were fatigue (26%), nausea (23%), and vomiting (13%). Average tmax and t½ were about 1 and 6 h, respectively. Exposure showed inter-individual variability but increased generally proportionally with dose for doses ranging between 80 mg and 900 mg, without accumulation over 5 days. Degradation of cIAP-1 in surrogate tissue was observed at all doses >80 mg. Plasma MCP-1 increased at 3-6 h post-dose and caspase-cleaved fragment of cytokeratin 18 (M30) significantly increased on day 5. Five patients (17%) had stable disease as best response and 1 patient with metastatic melanoma had an 11% reduction in target lesion dimensions. Conclusions: The MTD was not reached and 900 mg was the highest tested dose. Debio 1143 was safely administered, with confirmed on-target PD effects at dose level >80 mg and signs of antitumor efficacy. Clinical trial information: NCT01078649.
A pilot study of apatinib reversing paclitaxel resistance in heavily pretreated advanced gastric cancer (AGC).
Authors: Rongbo Lin, Shen Zhao, Hui Li, Jie Liu, Nanfeng Fan
Journal: Journal of Clinical Oncology (2017)

89 Background: In vitro or vivo, apatinib can reverse ABC-mediated multidrug resistance not only by inhibiting their transport function, but also by downregulating ABC expression. Methods: The patients with advanced gastric adenocarcinoma were resistant to paclitaxel-containing regimen (disease progression during or within 3 months after chemotherapy) and had measurable lesions received apatinib 850 mg, po, qd combined with paclitaxel alone (80 mg/m 2 d1, d8, and d15, repeated 4-weekly) or POF (reported in 2007, 2008, 2009, 2010 ASCO, paclitaxel 135 mg/m 2 , oxaliplatin 85 mg/m 2 , and leucovorin 400 mg/m 2 , d1; 5-FU 2400 mg/m 2 for 46h, repeat 2-weekly). The choice of regimen was left to clinician discretion in term of performance status and whether the agent that will be given has been resistant. Results: From 14 th August 2015 to 1 st March 2016, seven patients were eligible. The median age was 49 years (range, 43 to 67 years), 5 were males and 2 were females. The prior chemotherapeutic agents were summarized in table. Four patients had disease progression during apatinib. Two PRs, four SDs (unconfirmed), and one early death were observed. At a median follow-up of 238 days, the median progression-free survival was 124 days, the median survival was 194 days (range, 33 to 398+ days). Grade 3 to 4 neutropenia, anaemia, hypertension, fatigue, stomatitis was one patient respectively. No treatment-related death occurred. Conclusions: This study showed promising result that apatinib reverses paclitaxel resistance in heavily pretreated AGC. Clinical trial information: NCT02697838. [Table: see text]
ER as a predictor of early breast cancer (EBC) outcomes in patients.
Authors: Joyce O'Shaughnessy, David M. Loesch, Devchand Paul, Christopher T. Stokoe, John E. Pippen, Joanne Lorraine Blum, Lea Krekow, Frankie Ann Holmes, Svetislava J. Vukelja, Deborah Lindquist, John F. Sandbach, Scot M. Sedlacek, Yunfei Wang, Stephen E. Jones
Journal: Journal of Clinical Oncology (2013)

590 Background: Some ER-negative (ER-) breast cancers express low levels of estrogen receptors and approximately 12% express androgen receptors (Traina, T, et al. ASCO, 2012). Whether young premenopausal women (age &lt;40) with ER- breast cancer (BC) who are more likely to retain ovarian function after adjuvant chemotherapy have a worse outcome than older women with ER- disease has not been widely investigated. Methods: We analyzed 2 adjuvant US Oncology BC studies: 99-016, 1830 BC patients randomized to doxorubicin/cyclophosphamide (AC)→Paclitaxel (P) (AC/P) vs AP→weekly P (no cyclophosphamide [C]) (AP/wP); and 01-062, 2611 patients randomized to AC→docetaxel (T) vs AC→T plus capecitabine (XT). ER+ patients received standard endocrine therapy following chemotherapy. Five-year DFS results did not show significant differences between the treatment arms on either study. The outcomes were analyzed for 5-year DFS by age ≤40yrs and &gt;40yrs and by ER status. Results: In the two studies combined, ER- patients ≤40 had a superior DFS (84%) than ER- patients &gt;40 (80%), while ER+ patients ≤40 had a worse 5-yr DFS (83%) than ER+ patients &gt;40 (89%), although these findings were of borderline significance (see Table below). In 99-016, omitting C did not adversely affect outcomes in either age group, regardless of ER status. Conclusions: We did not observe worse outcomes in ER- patients ≤40 years compared to those &gt;40 years in 2 US Oncology adjuvant chemotherapy trials, suggesting no adverse impact of assumed greater ovarian function following adjuvant chemotherapy in patients ≤40yrs. ER+ patients ≤40 had a worse DFS than ER+ patients &gt;40. Omitting C in ER- patients ≤40 or &gt;40 did not adversely affect outcome. [Table: see text]
Association between vitamin D deficiency and breast cancer histology: A retrospective database review.
Authors: Ranjana S. Bhargava, Yue Zhu, Chana Weinstock, Nader Hanna, Katherine Hanna Tkaczuk, Ting Bao, Saranya Chumsri
Journal: Journal of Clinical Oncology (2012)

1039 Background: Vitamin D (Vit D) deficiency has been shown to be associated with a higher risk of developing breast cancer. Inverse association has also been shown between vit D level and tumor size. However, the association between vit D deficiency and breast cancer histology remains unclear. Preclinical data has suggested that vit D plays an essential role in the terminal differentiation of breast cells. Thus, we hypothesize that vit D deficiency would be associated with estrogen receptor-negative tumors, particularly triple-negative breast cancers (TNBC) which are associated with aggressive clinical course. Methods: We conducted a retrospective database review to obtain information including age, race, tumor histology, size, stage, and vit D levels in newly diagnosed breast cancer patients at University of Maryland Greenebaum Cancer Center. Results: 150 patients presented between July 2008 and August 2011 were included in this analysis. Average age at diagnosis was 57 (range 30-87), and 56% of patients were African American. Overall, 80% of the patients were vit D deficient at diagnosis, with levels &lt; 30 ng/ml. African-American patients were more likely to be severely vit D deficient with levels &lt; 10 ng/ml compared to Caucasians (33% vs. 7.5%, p= 0.0002). Patients with TNBC were more likely to be vit D deficient at diagnosis compared to hormone receptor-positive patients (93% vs. 76%, p =0.015). These patients also had the lowest mean (18) and median (16) of vit D levels compared to all other patients. This difference is also statistically significant in multivariate analysis when adjusted for age, race, and stage (OR 3.96; p=0.04). Regardless of the ER/PR status, Her 2 negative patients were more vit D deficient compared to Her 2 positive patients (86% vs. 61%, p=0.001). Unlike previous studies, no correlation was seen between tumor size and vit D levels. Furthermore, there is also no association between stage, nodal involvement, or Ki67 and vit D level. Conclusions: Vit D deficiency is common among patients with newly-diagnosed breast cancer, particularly African American patients. Patients with TNBC have a significantly higher likelihood of being vit D deficient than patients with other histological subtypes.
Plasma microRNAs: Novel markers of cardiotoxicity in children undergoing anthracycline chemotherapy.
Authors: Kasey Joanne Leger, David Leonard, James A de Lemos, Danelle Nielson, Pradeep P Mammen, Naomi Joan Winick
Journal: Journal of Clinical Oncology (2014)

10083 Background: Early detection of anthracycline cardiotoxicity may allow cardioprotective intervention(s) prior to irreversible damage. microRNA (miRNA) modulation in anthracycline cardiotoxicity has been identified in animal models, however there are no data regarding circulating miR expression following anthracycline-induced cardiac injury in humans. Methods: Plasma miRNA profiling was performed in 25 children before and after a cycle of anthracycline (AC, n=18) or non-cardiotoxic chemotherapy (CTRL, n=7). Samples were screened by qRT-PCR for 25 candidate miRNAs, including miRs -1, 133a/b, 145, 146, 195, 208a/b, 21, 210, 214, 215, 216, 23a, 29a/b/c, 30a, 34c, 423-3p/5p, 361, 367, 499, and let-7g. Candidates were selected based on their established roles in cardiovascular disease or pathways associated with cardiotoxicity. Relative quantification of each miRNA between the pre and post-cycle timepoints (6, 12, and 24 hours) was determined within each group. miRNAs with significant dysregulation from baseline were identified utilizing the paired t-test function within RealTime StatMiner (Integromics). Differences in miRNA regulation over time were compared between groups (AC vs. CTRL) using a mixed effects linear regression model. Results: Three miRNAs were upregulated post-anthracycline therapy, while unchanged after non-cardiotoxic chemotherapy. miR-1 was up by 7 and 5.6-fold at 6 and 12 hours post-anthracycline, respectively (p<0.05). Six hours post-anthracycline, miRs-29b and -499 were up by 10-fold (p<0.01) and 5.1-fold (p=0.04), respectively. In contrast, miRs-1, -29b, and -499 were unchanged at all timepoints after non-cardiotoxic chemotherapy. The difference in post-chemo miRNA dysregulation from baseline was significantly different between AC and CTRL groups at 6 hours for miRs-1, 29b, and 499 (p<0.01) and 12 and 24 hours for miR-499 (p<0.01); Thus it appears this miRNA upregulation is specifically anthracycline-induced. Conclusions: Plasma miR-1, -29b, and -499 are specifically upregulated following anthracycline chemotherapy and may herald acute cardiac injury. Further work is ongoing to evaluate these miRs as early markers of anthracycline-induced cardiotoxicity.
Lenalidomide Plus R-CHOP (R2CHOP) in Patients with DLBCL Is Associated with a Lower Risk of CNS Relapse: Combined Analysis from Two Phase 2 Studies
Authors: Ayed O. Ayed, Annalisa Chiappella, Grzegorz S. Nowakowski, Federica Cavallo, Angela Giovanna Congiu, Gianluca Gaidano, Levi Pederson, Betsy R. Laplant, William R. Macon, Gerardo Musuraca, Alessandro Re, Michele Spina, Thomas E. Witzig, Umberto Vitolo
Journal: Blood (2016)