tbuckley/cabot-search huggingface dataset:
FLAG-IDA as frontline induction or salvage therapy for patients with high risk and/or relapsed or refractory acute myeloid leukemia (AML).
Authors: Sita Bhella, Eshetu G. Atenafu, Andre C. Schuh, Mark D. Minden, Aaron David Schimmer, Vikas Gupta, Matthew D. Seftel, Naheed Alam, Andrzej Lutynski, Anna Rydlewski, Amr Rostom, Karen W. L. Yee
Journal: Journal of Clinical Oncology (2015)

e18022 Background: Therapy for patients (pts) with high risk and relapsed/refractory AML is unsatisfactory. Since Jan 2011, we have employed FLAG-IDA as first line therapy in pts with high risk AML (i.e. poor risk cytogenetics, antecedent MPN or MDS, or therapy-related AML), or as first salvage in pts with primary refractory/relapsed AML, in an attempt to improve CR rates, OS and to permit more pts to advance to allogeneic stem cell transplantation (alloSCT). Methods: This retrospective review evaluates outcomes of pts with high risk and primary refractory/relapsed AML who were treated with FLAG-IDA between Jan 2011 to Dec 2014 at the Princess Margaret Cancer Centre. Results: 46 pts received FLAG-IDA as first induction [median age 58.5 y (21-76 y)] and 69 pts as salvage [median age 51 y (18-76 y)]. Overall CR rates (CR + CRp) for frontline (n = 43 evaluable) and salvage therapies were 79.1% (88% CR; 11% CRp) and 57.9% (70% CR; 30% CRp), respectively; whereas, CR durations were 3 (0.5-15) mos and 6 (0-58) mos, respectively. CR2 duration for relapsed pts was 4 (1-12) mos. Pts who achieved a CR/CRp had an improved OS (log-rank test, p < 0.0001). Pts who received frontline FLAG-IDA had an improved OS compared to those who received it as salvage (p = 0.0116). Of the 28 (61%) pts who received frontline FLAG-IDA, achieved a CR/CRp and had a donor, 40% (n = 11) underwent alloSCT. Of the 44 (64%) pts who received salvage FLAG-IDA, achieved a CR/CRp and had a donor, 50% (n = 22) proceeded to alloSCT. Median time to plts > 100 x 109/L in the frontline and salvage groups was31 (20-148) days and 36 (17-136) days, respectively. Median time to ANC > 1 x 109/L in the frontline and salvage groups was 30 (14-85) and 33 (17-87) days, respectively. 48% and 62% of pts in the frontline and salvage groups had fungal infections. Median follow up time was 8 (1-64) mos. OS at 1 year in the frontline and salvage groups was 57.8% and 68.6%, respectively. Conclusions: Toxicities associated with FLAG-IDA induction are acceptable and are similar in untreated and pre-treated groups. FLAG-IDA induction can result in durable CR rates, permitting pts with either high risk or primary refractory or relapsed AML to proceed to alloSCT.
The potential prognostic and predictive significance of cell cycle-related proteins Ki-67, p16, p14 and p57 in advanced ovarian cancer
Authors: M. Baekelandt, H. Khouja, G. B. Kristensen, J. Nesland, R. Holm
Journal: Journal of Clinical Oncology (2004)

5042 Background: The level of expression of cell cycle-related proteins has been correlated to differences in disease outcome and response to chemotherapy in several cancer types. The potential significance of Ki-67 and the cyclin-dependent kinase inhibitors p16, p14 and p57 was analyzed in tumor tissue from patients with advanced ovarian cancer (AOC). Methods: Tumor biopsies from 171 consecutive and homogeneously treated patients with stage 3 ovarian cancer were examined immunohistochemically for expression of Ki-67, p16, p14 and p57 proteins. Uni- and multivariate analysis of prognostic factors was performed, and correlations with classical clinicopathological parameters and response to chemotherapy were examined. Response was assessed by second look laparotomy after 4 courses of cisplatin and epirubicin (each 50 mg/m2 q 4 weeks). Results: High levels of expression were detected in 84%, 31%, 1% and 24% of cases for Ki-67, p16, p14 and p57 respectively. Ki-67 expression was correlated to the presence of residual disease after primary surgery (p = 0.019), ascites (p = 0.008), higher FIGO substage (p < 0.001), poor differentiation (p < 0.001) and overexpression of p53 (p < 0.001). p16 expression was related to poor differentiation (p = 0.025) and p53 overexpression (p = 0.002). High expression levels for Ki-67 (p = 0.0001) or p16 (p = 0.005) were associated with poor survival. p14 and p57 expression gave no prognostic information. No correlations were found between expression of any of the proteins and chemotherapy response. Combination of Ki-67 and p16 expression data allowed the patients to be divided into clearly distinct risk groups (p = 0.0002). In multivariate analysis, the presence of residual disease (p < 0.0001), degree of differentiation (p = 0.0002) and the combined expression of Ki-67 and p16 (p = 0.049) were found to correlate with disease-related survival. Conclusions: In stage 3 ovarian cancer, the combination of Ki-67 and p16 expression data gives independent prognostic, but not predictive, information. p14 and p57 expression does not seem to correlate to prognosis in this patient population. No significant financial relationships to disclose.
Time to grade ≥3 adverse events in pts receiving trifluridine/tipiracil (TAS-102).
Authors: Eric Van Cutsem, Atsushi Ohtsu, Natividad Lopez Busto, Akira Kanehisa, Ronan Fougeray, Robert Winkler, Robert J. Mayer
Journal: Journal of Clinical Oncology (2017)

788 Background: The phase 3 RECOURSE showed that treatment with trifluridine/tipiracil in patients (pts) with refractory metastatic colorectal cancer was associated with significantly improved survival versus placebo (7.1 versus 5.3 months, respectively; HR for death 0.68, 95% CI 0.58–0.81, p &lt; 0.001), with few serious adverse events. Trifluridine/tipiracil is administered in 4-week cycles comprising 2 weeks with 5 days at 35 mg/m 2 bid followed by 2 rest days, and then a 2-week rest period. Exploration of timing for AEs, particularly within the first cycle of treatment, is important for pt monitoring in the outpatient setting. Methods: We performed a post hoc analysis of the RECOURSE safety population (533 trifluridine/tipiracil; 265 placebo) to explore timing of hematological and nonhematological AEs. Results: Grade ≥ 3 adverse events (AEs) were more frequent with trifluridine/tipiracil than placebo for both hematological AEs (38% vs 0% neutropenia; 4% vs 0% febrile neutropenia; 18% vs 3% anemia; and 5% vs &lt; 1% thrombocytopenia) and nonhematological AEs (2% vs 1% nausea; 2% vs &lt; 1% vomiting; and 3% vs &lt; 1% diarrhea). The median time to nadir in cycle 1 for hematological events was 28 days (17–31) for grade ≥ 3 neutropenia, 22 days (9–39) for grade ≥ 3 anemia, and 18 days (9–33) for grade ≥ 3 thrombocytopenia; similar values were obtained in subsequent cycles. The median times to nadir and values at nadir over the whole treatment duration (all cycles) are presented in the table for hematological and nonhematological AEs. Conclusions: Hematological and nonhematological AEs with trifluridine/tipiracil appear to be most intense towards the end of treatment cycles, which is reassuring for its use in the outpatient setting. Clinical trial information: NCT01607957. [Table: see text]
A novel K-samII/FGF-R2 autophosphorylation inhibitor is therapeutically useful for scirrhous gastric carcinoma with K-samII amplification
Authors: M. Yashiro, K. Nakamura, T. Sawada, H. Kawajiri, T. Shimizu, A. Miwa, K. Hirakawa
Journal: Journal of Clinical Oncology (2007)

14070 Background: Scirrhous gastric carcinoma, a diffusely infiltrating also known as linitis plastica-type carcinoma, carries the highest mortality of all gastric cancers. Scirrhous carcinoma cells with amplification of the activated K-samII gene, which encodes fibroblast growth factor receptor type 2 (FGF-R2), have a growth advantage during tumor progression The poor prognosis carried by scirrhous gastric cancer is closely associated with amplification of the K-samII/FGF-R2, a tyrosine kinase growth factor receptor. Ki23057, a newly developed small molecule acting K-samII/FGF-R2 inhibitor, is a kinase inhibitor that competes with ATP for the binding site in the kinase, thus strongly blocking phosphorylation of FGF-R2. The aim of the current study is to clarify the possibility of molecular target therapy with Ki23057 for treating scirrhous gastric cancer. Methods: Five human gastric cancer cell lines were used. OCUM-2MD3 and OCUM-8 were derived from scirrhous carcinomas. MKN-7, MKN-45 and MKN-74 cells were derived from non-scirrhous carcinomas. In vitro effects of Ki23057 on cell growth were determined by calculating the number of cancer cells. The influences of Ki23057 on the MAP kinase and PI3 kinase signaling pathways and the apoptosis pathway in the gastric cancer cells were also examined. For in vivo experiments, the Ki23057 was administered orally to mouse models of peritoneal dissemination. Results: K-samII amplification was found in OCUM-2MD3 and OCUM-8 cells, but not in MKN-7, MKN-45, or MKN-74 cells. Ki23057 significantly inhibited the proliferation of scirrhous cancer cells, but not non- scirrhous gastric carcinoma cells. Ki23057 decreased phosphorylation of K-samII/FGF-R2, ERK and Akt, and increased apoptosis in scirrhous cancer lines. The oral Ki23057 administration significantly (p&lt;0.001) prolonged survival of mice with peritoneal dissemination following injection of OCUM-2MD3 scirrhous cancer cells. Conclusions: A novel K-samII/FGF-R2 phosphorylation inhibitor, Ki23057, appears therapeutically promising in scirrhous gastric carcinoma with K-samII amplification. No significant financial relationships to disclose.
Phase 2 clinical study of onapristone (ONA) in patients (pts) with uterine endometrioid adenocarcinoma (EC) expressing the activated progesterone receptor (APR<sup>pos</sup>).
Authors: Jacques Bonneterre, Alexandra Leary, Mario Campone, Antoine Italiano, Marie-Paule Sablin, Anne Floquet, Dominique Berton-Rigaud, Catherine Lhommé, Anne Lesoin, Dorothee Chocteau-Bouju, Michel Fabbro, Laure Favier, Laurence Gladieff, Isabelle Ray-Coquard, Alice Susannah Bexon, Erard M. Gilles, Joseph Bisaha, Alexander Zukiwski, Paul H. Cottu
Journal: Journal of Clinical Oncology (2015)

TPS5616 Background: ONA is a type I PR antagonist, which prevents PR-induced DNA transcription. Presence of transcriptionally-activated PR (APR), seen as an aggregated subnuclear PR distribution pattern, is being explored as a predictive biomarker for ONA activity. The proposed IHC companion diagnostic could select pts with uterine EC most likely to respond to ONA. An extended-release (ER) formulation has been developed to provide constant target exposure to the anti-progestin and address previously-observed liver function test abnormalities. ONA anti-cancer activity has been documented in multiple preclinical models. Pts with APRpos EC, breast and ovarian cancers have experienced clinical benefit (PR or SD ≥ 6 months) on ONA, with excellent tolerability. The current study was designed to test the hypothesis that the APR companion diagnostic identifies the pts most likely to respond to ONA, with 80% power to detect a response rate of 30%. Methods: This is an ongoing multi-center, open-label, randomized, parallel-group, 2-part phase 1-2 study. The randomized phase 1 dose-finding portion is complete (n = 52). Results are presented in separate abstracts. ONA 50 mg ER was selected as the recommended phase 2 dose. The phase 2 portion focuses on post-menopausal female pts ≥ 18 years with recurrent or metastatic uterine EC that is APRpos. APR status is determined by IHC on biopsy at study entry; slides are stained at a central lab using a technically-validated procedure, then centrally interpreted by trained pathologists. PR positivity is defined as ≥ 10% cells PRpos by IHC and APR positivity as ≥ 5% of cells showing the aggregated pattern. Pts are treated with ONA 50 mg ER BID until progressive disease or intolerability. The primary endpoint is objective response rate by RECIST 1.1. Secondary endpoints include relationship between extent of APR expression and ONA activity, safety and tolerability, duration of response, PFS and OS. A Simon 2-stage design includes 10 patients in the first stage. If ≥ 2 pts respond, the study will recruit a further 19 pts (stage 2) to confirm anti-tumor activity. As of February 2015 the study is actively recruiting pts with APRpos uterine EC. Clinical trial information: NCT02052128.
Phase Ib study evaluating safety and pharmacokinetics (PK) of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 monohydrate (LY) when combined with gemcitabine in patients with advanced cancer.
Authors: Mark Kozloff, Rocio Carbonero, Tamara Nadal, Ivelina Gueorguieva, Ann Cleverly, Durisala Desaiah, Michael M. F. Lahn, Sada Pillay, Al Blunt, Josep Tabernero, Teresa Macarulla
Journal: Journal of Clinical Oncology (2013)

2563 Background: Based on animal studies, the combination of a TGF-β inhibitor and gemcitabine is expected to enhance antitumor activity of gemcitabine. Hence, we started a combination study of LY with gemcitabine to assess the safety of this combination therapy. Methods: Gemcitabine was administered as approved and LY was given daily as intermittent dosing (14 days on/14 days off=1 cycle). A dose escalation consisting of 3 cohorts (80 mg/day, 160 mg/day, and 300 mg/day) evaluated the safety of LY in combination with gemcitabine. Toxicity was assessed using the CTCAE, version 4. Pharmacokinetic (PK) profile of LY in combination with gemcitabine was determined. Results: A total of 14 patients were evaluated (cohort 1 [n=5, 4 adenocarcinoma of colon, 1 non-small cell lung cancer, cohort 2 [n=4, adenocarcinoma, 1 each of esophageal, well differentiated, pancreas, lung], cohort 3 [n=5, 3 pancreatic, 2 rectal cancer]) in this study. The median number of cycles was 2 (range (1-6). Regardless of causality, the following treatment-emergent adverse events (TEAEs) were observed in ≥25% of patients: anemia (n=10), nausea (n=8), thrombocytopenia (n=6), neutropenia (n=6), vomiting (n=6), anorexia (n=5), fatigue (n=5), diarrhea (n=5) asthenia (n=5), pyrexia (n=4), AST increased (n=4), and constipation (n=4). Possibly related to LY, (Grade, Gr, 3/4 as mentioned) TEAEs observed were: nausea (n=5), asthenia (n=4), fatigue (n=3, 1 Gr 3), neutropenia (n=3, 1 Gr 3), anemia (n=3, 2 Gr 3 ), and in 2 patients each, thrombocytopenia (both Gr 3), headache, edema peripheral, rash, anorexia, diarrhea (1 Gr 3), mucosal inflammation, vomiting and reversible rhabdomyolysis (n=1, Gr 4). No change in the PK profile of LY was shown when LY was combined with gemcitabine. Conclusions: There were no dose limiting toxicities observed and no clinically meaningful cardiotoxicities were detected. Because of the observed manageable safety profile, LY at 300 mg/day has been advanced into a randomized Phase 2 trial in pancreatic cancer in 1 st line setting to assess the antitumor activity of the combination. Clinical trial information: NCT01373164.
Stereotactic body radiation vs. intensity-modulated radiation for unresectable pancreatic cancer.
Authors: Joseph Junyong Park, Carla Hajj, Marsha Reyngold, Weiji Shi, Zhigang Zhang, John J Cuaron, Christopher H Crane, Eileen Mary O'Reilly, Maeve Aine Lowery, Kenneth H. Yu, Karyn A. Goodman, Abraham Jing-Ching Wu
Journal: Journal of Clinical Oncology (2017)

353 Background: Stereotactic body radiation therapy (SBRT) is an emerging treatment option for unresectable pancreatic cancer, and may be more effective and less toxic than intensity modulated radiation therapy (IMRT). Methods: We retrospectively reviewed unresectable stage I-III pancreatic adenocarcinoma treated with SBRT (5 fractions, 30-33Gy) or IMRT (25-28 fractions, 45-56Gy with concurrent chemotherapy) between 2008-2016 at our institution. The groups were compared with respect to overall survival (OS), local failure (LF), distant failure (DF), any failure (AF), proportion of patients becoming resectable, and incidence of acute toxicity. Competing risks methods were used for univariate (UVA) and multivariate analysis (MVA) for LF, DF and AF. All endpoints were calculated from end of RT. Results: Median follow-up for surviving patients was 12.9 months. 44 patients received SBRT and 226 patients received IMRT. Patients who received SBRT were older (45% vs 29% &gt; 70 years old, p = 0.05). Otherwise there was no significant difference in baseline characteristics, including stage and duration of induction chemotherapy. On MVA, there was no significant difference in OS, LF, DF, or AF between IMRT and SBRT (p = 0.73, 0.81, 0.44, and 0.39 respectively). Median OS was 15.7 months, and the 1-year rate of LF was 34.4% for SBRT and 30.2% for IMRT. Response to induction chemotherapy was associated with longer OS (p = 0.03). There was no significant difference in the proportion of patients who were subsequently resected between IMRT (17%) and SBRT (7%; p = 0.11). Significantly more IMRT patients experienced acute G2+ GI toxicity (24% vs. 7%, p = 0.008), G2+ fatigue (42% vs. 7%, p &lt; 0.0001), and G3+ hematologic toxicity (26% vs. 5%, p = 0.001) compared to SBRT. Conclusions: SBRT achieves similar disease control outcomes as IMRT, and is associated with less acute toxicity. This data suggests SBRT is an attractive technique for pancreatic radiotherapy because of improved convenience and tolerability with equivalent efficacy. However, the lack of observed advantages in disease control with this moderate-dose SBRT regimen suggests a role for increasing SBRT dose, if this can be accomplished without significant increase in toxicity.
EGFR mutation-based phase II multicenter trial of gefitinib in advanced non-small cell lung cancer (NSCLC) patients (pts): Results of West Japan Thoracic Oncology Group trial (WJTOG0403)
Authors: I. Okamoto, T. Kashii, Y. Urata, T. Hirashima, S. Kudoh, Y. Ichinose, N. Ebi, T. Satoh, K. Tamura, M. Fukuoka
Journal: Journal of Clinical Oncology (2006)

7073 Background: Recently several retrospective analyses have reported that somatic activating mutations in the EGFR tyrosine kinase domain underlie responsiveness to gefitinib. In the present study, we have prospectively assessed whether these specific mutations in EGFR gene affect the clinical outcomes of NSCLC pts treated with gefitinib. Method: Pts with a histologically confirmed, recurrent or metastatic NSCLC that harbored EGFR mutations were eligible for the study. Direct sequencing using DNA extracted from paraffin-embedded tumor specimens to detect mutations in EGFR (exons 18, 19 and 21) was performed in a central laboratory. Eligible pts with measurable lesions, ECOG PS of 0–2, adequate organ functions and less than 2 prior chemotherapy regimens were treated with gefitinib 250 mg orally once daily. The primary objective of this study was to determine the objective response rate of single-agent gefitinib in NSCLC pts with EGFR mutations. With the target activity level of 50% and the lowest response rate of interest set at 25%, 23 eligible patients were required with an 80% power to accept the hypothesis and a 5% significance level to reject the hypothesis. Allowing for a 10% loss to follow-up rate, a total of 25 patients with EGFR mutations were planned to enroll. Results: Between March 2005 and December 2005, 104 patients were recruited from fifteen study centers in Japan and screened for the presence of EGFR mutations. EGFR mutations were detected in 28 pts (27%). Twenty-five of the 28 pts have been enrolled onto this study; 12 pts had deletional mutations in exon 19 and 13 pts had missense mutations (L858R) in exon 21. Of the 25 pts with EGFR mutations: adenocarcinoma (24), female (17), never smoker (18), and PS 0–1 (22). Median age was 69 years (range, 54 to 89 years). Previous therapy included surgery in 9 pts (36%), chemotherapy in 7 pts (28%), and radiotherapy in 1 pts (4%). Conclusions: Efficacy and safety data will be mature in March 2006 and will be presented at the ASCO meeting. These are the first prospective studies targeted at NSCLC pts harboring EGFR mutations. No significant financial relationships to disclose.
Gene expression of the MAPK pathway in osteosarcoma.
Authors: Luana Joyce Silva Lopes, Antonio Sergio Petrilli, Francine Tesser-Gamba, Maria Teresa Seixas Alves, Reynaldo Jesus Garcia-Filho, Silvia R. C. Toledo
Journal: Journal of Clinical Oncology (2013)

10534 Background: Osteosarcoma (OS) is the most common malignant bone tumor in adolescents. A feature of the OS is its high risk of lung metastasis. Unlike other sarcomas, OS does not have genetic markers. We suggest that abnormalities in the expression levels of genes involved in important cell signaling pathways, as MAPKs pathway, may contribute to OS progression and aggressiveness. In a recent study, we found an overexpression of MAPK7 gene in prechemotherapy specimens when compared to postchemotherapy specimens and when compared with normal bone. This previous study suggests that MAPK7 overexpression may be contributing to the worse response to treatment and therefore a poor overall survival. To understand the relationship between the OS genesis process and the MAPK pathway, we investigated the expression of genes involved in the regulation of MAPK pathway (MAP2K5, MAP2K6, MAP3K1, MAP3K3, MAP4K3 and DUSP1). Methods: Total RNA was extracted from 68 tumor samples obtained from 28 patients (28 prechemotherapy specimens, 28 postchemotherapy specimens and 12 metastasis specimens) and five normal bone tissues. cDNA was synthesized and expression of the six genes were determined by quantitative real-time PCR. Clinical variables were correlated with gene expression. Results: MAP2K6 and MAP4K3 had a similar gene expression profile. Both genes were overexpressed in postchemotherapy specimens and were strongly associated with important clinical parameters as presence of metastasis (P=0.0159 and P=0.0014, respectively), shorter overall survival (P=0.0040 and P=0.0040, respectively) and disease progression (P=0.0142 and P=0.0109, respectively). DUSP1 overexpression in postchemotherapy specimens was related with metastasis at diagnosis (P=0.0004), worse response to treatment (P=0.0009) and disease recurrence (P=0.0039). MAP2K5, MAP3K1 e MAP3K3 showed no significant correlations in the present study. Conclusions: The overexpression of MAP2K6, MAP4K3 and DUSP1 in postchemotherapy specimens presented a significant association with poor prognosis. The current study suggests that these genes could play an important role in OS tumorigenesis and may be in the future new therapeutic targets in OS treatment.