tbuckley/cabot-search huggingface dataset:
Phase Ib safety trial of CVX-060, an intravenous humanized monoclonal CovX body inhibiting angiopoietin 2 (Ang-2), with sunitinib.
Authors: Lee S. Rosen, David S. Mendelson, Michael S. Gordon, Jonathan Wade Goldman, Jeffrey Warren Allen, Brendan D. Curti, Charles Chen, Rachelle Perea, Ashwin Gollerkeri
Journal: Journal of Clinical Oncology (2012)

3032 Background: CVX-060 (CVX) is a humanized monoclonal antibody fused to two Ang2 binding peptides. The recommended phase 2 dose (RP2D) is15 mg/kg/wk by intravenous (IV) infusion. Sunitinib (Sun), a kinase with many targets including VEGFR1-3, is dosed 50 mg/day orally x 4/6 wks. Methods: Patients (pts) with solid tumors were to receive CVX at doses of 6, 12, or 15 mg/kg/wk with Sun 50 mg/day x 4/6 wks in successive cohorts. Standard definitions of dose limiting toxicities (DLTs) were used. Serum PK was assessed by ELISA. Results: Thirty-four pts were treated at 5 dose levels (DL) –see table. The median age was 62 years (29-76), ECOG performance status 0-1. The safety of CVX plus lower Sun dose was established in DL 1.1 due to DLTs at the initial cohort. The safety of full dose Sun was further established in 1.2 before further escalating the CVX dose. Overall, DLTs related to CVX and Sun included hemorrhage (DL 1.0), asymptomatic proteinuria (DL 1.2), ischemic colitis/lower GI bleed/recurrent lower GI bleed (DL 3.0) and abdominal pain/microperforation on CT (DL 3.0). The most common adverse events (AEs) related to either agent were fatigue (68%), diarrhea (50%), nausea (47%), hypertension (35%), and dysgeusia (32%). The majority of AEs were Gr 1 to 2. There were no PK interactions between CVX and Sun. Total serum Ang2 (bound plus free) increased with CVX treatment. Of the 34 patients, 24 (71%) remained on study ≥ 8 weeks and 2 patients continue on treatment ≥ 9 months. Anti-drug antibodies were seen in 16 patients at low titers without effects on PK or safety. Conclusions: In pts with advanced disease, CVX is able to be combined at the RP2D with Sun at its labeled dose without exacerbation of Sun-associated toxicities. Combination trials of CVX and other VEGF inhibitors are planned. [Table: see text]
Activity of eribulin on skin metastases in breast cancer patients.
Authors: Nicla Maria La Verde, Anna Moretti, Teresa Gamucci, Karen Borgonovo, Mario Botta, Nello Salesi, Monica Zuradelli, Ida Pavese, Elena Barbieri, Elisabetta Cretella, Tiziana Saladino, Paola Varese, Gianfranco Addamo, Mariangela Ciccarese, Anna Iolanda Rispoli, Arianna Pellegrino, Lucia Mentuccia, Sheila Piva, Gabriella Farina, Massimo Di Maio
Journal: Journal of Clinical Oncology (2013)

e12021 Background: Skin metastases (SM) occur in 20% of metastatic breast cancer (mBC). Clinical trials rarely describe them, even if they affect quality of life and self-perception of the disease. Eribulin (E) is a new drug, approved in mBC, after at least 2 lines of chemotherapy. The aim of this survey is to evaluate the activity of E treatment on SM compared to other metastatic sites, and on cutaneous symptoms (pain, infiltration, bleeding, smell, ulceration). Methods: This multicenter survey was conducted from November 2012 to January 2013 in 14 Italian Cancer Centers. Oncologists completed a database with patient (pts), tumor and treatment characteristics. Descriptive summary statistics were applied. Progression-free survival (PFS) was calculated according to Kaplan-Meier method. Results: 109 pts with mBC on E treatment were considered. 23/109 (21%) pts with SM were identified and analyzed. E was started between January 2012 and October 2012. Median age 63 (31-81). Prior chemotherapy lines: 4 (1-10). Prior hormonal lines: 1 (0-4). Basal Karnofski performance status 90 (50-100). 21/23 pts had other metastases, the remaining 2 had exclusively skin disease. SM were predominantly in the thorax (91%) and presented infiltration in 78%, ulceration in 70%, pain in 43%, bleeding in 43% and smell in 17% of cases. According to RECIST criteria, after E 43% of patients obtained a partial response (PR), 35% stable disease (SD), 22% progressive disease (PD). We evaluated skin response independently and found that 26% obtained a complete response (CR); 22% PR, 39% SD, 13% PD. Skin responses were in complete accordance with overall response in 16/23 (70%) pts, in partial accordance in 4 pts (skin CR, with an overall PR) and were discordant in 3 pts (1 skin SD despite overall PR, and 2 cutaneous CR despite overall PD). We found an improvement in SM symptoms: pain control was gained in 50% (5/10) of pts, as well as improvement in smell (50%, 2/4) and bleeding (50%, 5/10). Infiltration disappeared in 3/18 pts (17%). With a median follow up of 6 months, 21 (91%) pts had PD, median PFS was 4.3 months (95%CI 2.9–6). Conclusions: During E an improvement in skin metastases symptoms was observed; in the majority of cases, the response rate of SM was coherent with systemic responses.
Multicenter, phase II study of trastuzumab and paclitaxel to treat HER2-positive, metastatic gastric cancer patients naive to trastuzumab (JFMC45-1102).
Authors: Satoru Iwasa, Kazuhiro Nishikawa, Akira Miki, Hirokazu Noshiro, Akira Tsuburaya, Yasunori Nishida, Hiroto Miwa, Toshiki Masuishi, Kazuhiro Yoshida, Yasuhiro Kodera, Narikazu Boku, Yasuhide Yamada, Satoshi Morita, Junichi Sakamoto, Shigetoyo Saji, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2013)

4096 Background: The ToGA study indicated that first-line treatment using trastuzumab (T-mab) combined with capecitabine and cisplatin conferred a survival (OS) benefit to patients with HER2-positive metastatic gastric cancer (mGC). However, no reports have described the efficacy and safety of second-line treatment of HER2-positive mGC patients with T-mab who were naïve to the drug. Methods: JFMC45-1102 was a multicenter, Phase II study. Patients positive for HER2 (IHC3+ or IHC2+/FISH+) with gastric adenocarcinoma confirmed histologically; older than ≥ 20 y; who received one or more prior chemotherapies but no prior therapy with T-mab; and normal left ventricular ejection fraction (LVEF ≥ 50%) were eligible. Patients received paclitaxel (80 mg/m 2 on days 1, 8, and, 15 q4w) plus T-mab (8 mg/kg initial dose, followed by 6 mg/kg q3w). Treatment continued until their disease progressed; there was unacceptable toxicity or patient’s refused further treatment. The primary endpoint was overall response rate (ORR) evaluated according to RECIST ver. 1.0. Threshold and expected ORR were estimated at 15% and 30%, and secondary endpoints included progression free survival (PFS), time to treatment failure (TTF), overall survival (OS) and safety. Results: Fourty-six patients were enrolled between September 2011 and March 2012. Patients characteristics were: gender (M/F) 37/9; median age 69; ECOG PS0/1/2, 35/10/1; unresectable/recurrence 25/21; number of prior treatments (1/2), 41/5. The ORR was 37.2% (95% CI: 23.0-53.3%). The median PFS and TTF were 5.2 months (95% CI 3.9-6.6) and 5.2 months (95% CI 3.9-6.6), respectively. The protocol was discontinued for 27 patients (87.1%) for disease progression, and one patient each (3.2%) for severe adverse events, physician’s recommendation, patient refusal, and treatment related death. Conclusions: Combination chemotherapy of paclitaxel plus T-mab showed promising activity and was tolerated well by patients naïve to T-mab who were positive for HER2 and treated previously for mGC. Clinical trial information: UMIN000006223.
Programmed death 1 (PD-1) lymphocytes and ligand (PD-L1) in colorectal cancer and their relationship to microsatellite instability status.
Authors: Zoran Gatalica, Carrie L. Snyder, Kimberly Yeatts, Nianqing Xiao, Daniel Holterman, Henry T. Lynch
Journal: Journal of Clinical Oncology (2014)

3625 Background: PD-1 activation by its ligands (PD-L1 and PD-L2) inhibits T-cell activation and plays a role in cancer progression. PD-L1 is widely expressed in many cell types in tumor microenvironment. In contrast, expression of PD-1 is restricted to a small subset of T-lymphocytes. Inhibition of PD-1/PD-L1 interaction showed no benefit in a small number of colorectal cancers (CRC) studied in clinical trials. We investigated tumor infiltrating PD-1+ lymphocytes and PD-L1 expressing cells in CRC to gain insight in their role as biomarkers. Methods: 77 CRC cases (53 sporadic and 24 hereditary, including 23 Lynch syndrome and 1 FAP) were profiled (Caris Life Sciences) for the presence of PD-1 and PD-L1 expressing cells, mismatch repair proteins, DNA microsatellite instability (MSI) and select cancer genes sequences (NGS). Only intraepithelial PD-1+ lymphocytes (IEL) and aberrantly expressed PD-L1 on carcinoma cells were considered specific. Results: PD-1+ IEL were detected in 47% of sporadic CRC. Microsatellite stable (MSS) cancers were frequently (61%) negative for PD-1. Microsatellite instability-high (MSI-H, both Lynch syndrome and sporadic) were significantly (p<0.03) more frequently infiltrated with PD-1+ IEL than MSS (72% MSI-H vs. 39% MSS). Similarly, PD-L1+ cancer cells were more common in MSI-H (56%) than in MSS (21%, p=0.007), but the expression was patchy in all cases. Concurrent PD1+ IEL and PD-L1 cancer cells were seen in 30% of MSI-H and 5% of MSS cancers (p=0.008). Conclusions: Consideration of immune checkpoint therapies for colorectal cancer needs to consider the presence of PD-1 lymphocytes and cancer cell specific PD-L1 expression. PD-1+ IEL and PD-L1+ cancer cells are more frequent in MSI-H than in MSS colorectal cancers, which are rare in general CRC population.
The ESRD Quality Incentive Program—Can We Bridge the Chasm?
Authors: Daniel Weiner, Suzanne Watnick
Journal: Journal of the American Society of Nephrology (2017)

The ESRD Quality Incentive Program (QIP) is the first mandatory federal pay for performance program launched on January 1, 2012. The QIP is tied to the ESRD prospective payment system and mandated by the Medicare Improvements for Patients and Providers Act of 2008, which directed the Centers for Medicare and Medicaid Services to expand the payment bundle for renal dialysis services and legislated that payment be tied to quality measures. The QIP links 2% of the payment that a dialysis facility receives for Medicare patients on dialysis to the facility’s performance on quality of care measures. Quality measures are evaluated annually for inclusion on the basis of importance, validity, and performance gap. Other quality assessment programs overlap with the QIP; all have substantial effects on provision of care as clinicians, patients, regulators, and dialysis organizations scramble to keep up with the frequent release of wide-ranging regulations. In this review, we provide an overview of quality assessment and quality measures, focusing on the ESRD QIP, its effect on care, and its potential future directions. We conclude that a patient-centered, individualized, and parsimonious approach to quality assessment needs to be maintained to allow the nephrology community to further bridge the quality chasm in dialysis care.
Correlation of<i> PI3KCA</i>and extended<i> RAS</i> gene mutation status with outcomes from the phase III AGITG MAX involving capecitabine (C) alone or in combination with bevacizumab (B) with or without mitomycin C (M) in advanced colorectal cancer (CRC).
Authors: Timothy Jay Price, Maressa Bruhn, Chee Lee, Jenny Hardingham, Amanda Rose Townsend, Kristy Mann, John Simes, Andrew James Weickhardt, Joe Wrin, Kate Wilson, Val Gebski, Bridget Anne Robinson, Guy A. Van Hazel, David Cunningham, Niall C. Tebbutt
Journal: Journal of Clinical Oncology (2014)

3539^ Background: Mutations affecting RAS genes are now established predictive markers of non-response to anti-epidermal growth factor receptor (EGFR) antibodies in advanced colorectal cancer (CRC). PI3KCA (and BRAF) may also be predictive. A previous analysis restricted to KRAS exon 2 has not revealed any role for mutation status as a predictive marker for bevacizumab therapy. This analysis assessed the prognostic and predictive impact of extended RAS and PI3KCA gene mutation status in patients receiving C +/- B +/- M in the randomised phase III MAX study. Methods: DNA was macrodissected from archival formalin fixed paraffin embedded tumor tissue. Mutation status was determined using pyrosequencing and confirmed with Sanger sequencing (for equivocal RAS). Mutation status (Wild type/WT v Mutated/MT) was correlated with efficacy outcomes (RR, PFS & OS). Predictive analyses were undertaken using a test for interaction involving both C vs CB + CBM Results: Patient demographics and clinical outcomes were comparable between the tissue study population (n=281/60%) and the intention to treat population (n=471). MT in KRAS exons 2, 3, 4 and NRAS 2, 3, 4 as follows; 32.4%, 4.3%, 3.9%, 1.4%, 0.7% & 0. There were five patients who had more than one RAS MT (four with KRAS exon 2&4, one KRAS exon 2&3). The total proportion with any RAS MT is 40.9%. PI3K MT rate was 7.5% exon 9, and 3.6% exon 20. All RAS gene mutation status (WT v MT) had no prognostic impact for PFS, HR 0.92 (0.72-1.17) or OS HR 0.97(0.73-1.27). Using the comparison of C v CB + CBM, RAS gene mutation status was not predictive of the effectiveness of B for PFS, HR 0.56 (0.37-0.84) for RAS MT and HR 0.69 (0.49-0.97) for RAS WT, p for interaction 0.51. RR with RAS MT was higher without Bev (C 50% v CB/CBM 37.3%), but RR improved with Bev in the WT group (C 27.3% v CB/CBM 42.3%), p for interaction 0.01. PI3KCA mutation was neither predictive for bevacizumab effect nor prognostic. Conclusions: An additional 12.6% of MAX study patients who were KRAS exon 2 WT had additional RAS mutations. Neither all RAS gene mutation status nor PI3KCA mutation status was prognostic for progression-free survival or overal survival, or predictive of bevacizumab outcome in patients with advanced CRC. Clinical trial information: NCT00294359.
Clinicians preference of adjuvant S-1 versus capecitabine plus oxaliplatin after curative gastrectomy.
Authors: In Gyu Hwang, Se Hoon Park, Jung Hun Kang, Young Saing Kim, Sung Yong Oh, Young-Woong Won, Soonil Lee, Jun Ho Ji, Kyong-Choun Chi, Ha Yeon Lee
Journal: Journal of Clinical Oncology (2015)

e15025 Background: Two recent, randomized, phase III studies (ACTS GC trial and CLASSIC trial) have documented survival benefit for postoperative chemotherapy after D2 lymph node dissection in gastric cancer patients. S-1 and capecitabine plus oxaliplatin (CAPOX) are approved in Korea. We aim to evaluate the trend of clinicians for choosing the S-1 or CAPOX as adjuvant therapy after curative D2 gastrectomy. Methods: We retrospectively reviewed 570 gastric cancer patients who were underwent adjuvant chemotherapy either S-1 or CAPOX after curative D2 gastrectomy between 2007 and 2014. They were recruited from the nine centers in Korea. Clinicopathologic factors and adjuvant treatment were analyzed. Results: Of all 570 patients, 328 (57.5 %) were treated with S-1 and the other 242 (42.5 %) were treated with CAPOX. Median age was 61 years (range, 30−88) in total population. Younger than age 65 patients were more underwent CAPOX than age 65 years or older (75.6 % versus 24.4 %, p < 0.0001). At stage II, 196 (71.0 %) patients took S-1 and 80 (29.0 %) administered CAPOX, however 132 (44.9 %) patients in S-1 and 162 (55.1 %) patients in CAPOX at Stage III (p < 0.0001). Conclusions: Clinicians prefer CAPOX as adjuvant treatment for patients with younger than age 65 and stage III in gastric cancer.
Histological subtype analysis of colon cancer: A population-based study—Different sides and different diseases.
Authors: Francesca Negri, Annamaria De Giorgi, Annalisa Gilli, Maria Michiara, Paolo Sgargi, Enrico Maria Silini, Laura Manotti, Cinzia Azzoni, Lorena Bottarelli, Roberto Sala, Andrea Ardizzoni, Carmine Pinto
Journal: Journal of Clinical Oncology (2015)

e14655 Background: Retrospective analyses and case series showed an unfavourable outcome of mucinous colon cancer and a poorer response to treatment compared with non-mucinous tumours. Contradictory reports suggest that the clinical relevance of this histological type remains unclear. Methods: The authors evaluated incidence, survival and genetic alteration of colon adenocarcinomas in the incident colon cancer population systematically collected by the Parma Province Cancer Registry between 2004 and 2007. An adenocarcinoma was defined as mucinous if > 50% of the lesion was composed of extracellular mucin. Histopathological slides were reviewed for the present analysis. Results: 1077 patients with a diagnosis of stage I to IV colon cancer were analyzed for study purposes: 107 mucinous (10%) and 970 (90%) non-mucinous tumours. A higher proportion of mucinous carcinomas compared with non-mucinous tumours were diagnosed at advanced stage (stage III 38% and stage I 10% vs 29% and 24%, respectively; p = 0.01), showed a higher percentage of poorly differentiated tumours (48% vs 33%; p = 0.002) and high microsatellite instability (44% vs 15%; p = 0.051). The peritoneum was the most common metastatic site in mucinous carcinomas (42%) and the liver in non-mucinous tumours (65%; p = 0.001). In the left colon, non-mucinous tumours were associated with a less advanced stage of disease (stage I 31% vs 8%; p = 0.002). Tumours in the right colon showed an increased incidence of mucinous carcinoma (64% vs 35%; p = 0.001). No difference was observed for 5-years overall survival according to tumour histology (54% vs 58%; p = 0.338). Proximal tumours showed a significantly worse overall survival in non-mucinous tumours (HR = 1.52 [1.24-1.86], p < 0.001) and a trend toward worse survival in the mucinous group (HR = 1.85 [0.97-3.52]; p = 0.061). The female gender was potentially favourable in the mucinous carcinomas (5-years survival 60% vs 48%; p = 0.234), while no difference was observed in non-mucinous tumours. Conclusions: Our results confirm distinctive clinical-pathological and molecular features of mucinous and non-mucinous colon cancers. In non-mucinous carcinomas, tumour location is a strong predictor of survival.
Randomized, double-blind phase II trial of NY-ESO-1 ISCOMATRIX vaccine and ISCOMATRIX adjuvant alone in patients with resected stage IIc, III, or IV malignant melanoma.
Authors: Jonathan S. Cebon, Grant A. McArthur, Weisan Chen, Ian D. Davis, Martin Eric Gore, John F Thompson, Michael Millward, Michael P. N. Findlay, Rod Dunbar, Christian H.H Ottensmeier, Ralph Rudolph Venhaus, Paul D. Nathan, Angus George Dalgleish, Vincenzo Cerundolo, Eugene Maraskovsky, Wendie Hopkins, Jeremy Marsden, B Mark Smithers, Peter Hersey, T.R. Jeffry Evans
Journal: Journal of Clinical Oncology (2014)

9050 Background: The cancer testis antigen NY-ESO-1 (ESO) has been evaluated as a biomarker and a therapeutic immunologic cancer target. Preliminary data from a phase I clinical trial of ESO and ISCOMATRIX adjuvant (ESO vaccine) suggested this treatment could prevent relapse in patients (pts) with high risk resected malignant melanoma (MEL). Methods: We compared ESO vaccine to adjuvant alone in a randomized double-blind phase II study in pts with MEL. Pts with resected stage IIc, IIIb, IIIc, or IV melanoma expressing ESO were randomized 1:1 to ESO vaccine or adjuvant x3 q4w followed by a 4th dose at 6m. Primary endpoint was rate of RFS at 18m in the intent-to-treat (ITT) population and two per protocol (PP) populations, consisting of all relapses regardless of location. Secondary objectives included RFS and Overall Survival (OS) over the entire period of observation (study defined plus off-study follow-up), safety and ESO immunity. Results: Of 111 pts screened with ESO-expressing MEL, 110 comprised the ITT population, with 56 randomized to the ESO vaccine arm and 54 to adjuvant (96% and 87%, respectively, were at stage ≥IIIa at entry). There were no significant differences between the two arms for the ITT population during the 18m observation period for median time to relapse, 139 vs 176 days(p=0.296), or relapse rate, 27 (48.2%) vs 26 (48.1%) (HR=0.913; 95% CI, 0.402 to 2.231), respectively. RFS and OS for the entire period of observation were similar between the two arms. After the third immunization, a significantly larger percentage of pts in the ESO vaccine arm developed a strong positive antibody (Ab) & cellular immune response (IR) to ESO (p<0.001); this difference remained for the duration of the study. A total of 17 out of the 31 pts (55%) who had a vaccine-induced IR (Ab against ESO) and no pre-existing immunity were relapse-free at the end of 18m on study. Conclusions: The ESO vaccine was safe, well tolerated, elicited strong Ab and cellular responses but did not affect relapse free survival. Optimal efficacy may require combining it with other immunotherapy modalities. Clinical trial information: NCT00199901.
Randomized phase III trial of S-1 plus cisplatin versus docetaxel plus cisplatin for advanced non-small-cell lung cancer (TCOG0701).
Authors: Nobuyuki Katakami, Akihiko Gemma, Hiroshi Sakai, Kaoru Kubota, Makoto Nishio, Akira Inoue, Hiroaki Okamoto, Hiroshi Isobe, Hideo Kunitoh, Yuichi Takiguchi, Kunihiko Kobayashi, Yoichi Nakamura, Hironobu Ohmatsu, Shunichi Sugawara, Koichi Minato, Masaaki Fukuda, Akira Yokoyama, Masahiro Takeuchi, Hirofumi Michimae, Shoji Kudoh
Journal: Journal of Clinical Oncology (2012)

7515 Background: Although molecularly targeted therapy improves outcome of selected patients with advanced non-small-cell lung cancer (NSCLC), most of the patients ultimately become candidates of cytotoxic chemotherapy, which is the cornerstone of patient management. S-1 plus cisplatin (SP) has shown activity and good tolerability in phase II settings. Docetaxel plus cisplatin (DP) is the only third-generation regimen that demonstrated statistically significant improvement of overall survival and quality of life by head to head comparison with a second-generation regimen, vindesine plus cisplatin, in patients with advanced NSCLC. Methods: Patients with previously untreated stage IIIB or IV NSCLC, an ECOG PS of 0-1 and adequate organ functions were randomized to receive either oral S-1 80 mg/m 2 /day (40 mg/m 2 b.i.d.) on days 1 to 21 plus cisplatin 60 mg/m 2 on day 8 every 5 weeks or docetaxel 60mg/m 2 on day 1 plus cisplatin 80 mg/m 2 on day 1 every 3 weeks, both up to 6 cycles. The primary endpoint is overall survival (OS). Non-inferiority study design was employed as upper confidence interval (CI) limit for HR&lt;1.322. Secondary endpoints include progression-free survival (PFS), response, safety, and quality of life (QOL). Results: From April 2007 to December 2008, 608 patients from 66 sites in Japan were randomized to SP (n=303) or DP (n=305). Patient demographics were well balanced between the two groups. Two interim analyses were preplanned. At the final analysis, total of 480 death events were observed. The primary endpoint was met. OS for SP was non inferior to DP (median survival, 16.1 v 17.1 months, respectively; HR=1.013; 96.4% CI, 0.837-1.227). PFS was 4.9 months in the SP arm and 5.2 months in the DP arm. Statistically significantly lower rate of febrile neutropenia (7.4% v 1.0%), grade 3/4 neutropenia (73.4% v 22.9%), grade 3/4 infection (14.5% v 5.3%), grade 1/2 alopecia (59.3% v 12.3%) were observed in the SP arm than in the DP arm. QOL data investigated by EORTC QLQ-C30 and LC-13 favored for the SP arm. Conclusions: S-1 plus cisplatin is a standard first-line chemotherapy regimen for advanced NSCLC.