tbuckley/cabot-search huggingface dataset:
First-in-human study of 4SC-205 (AEGIS), a novel oral inhibitor of Eg5 kinesin spindle protein.
Authors: Klaus B. Mross, Dirk Scharr, Heike Richly, Annette Frost, Sebastian Bauer, Babett Krauss, Rolf Krauss, Anna Mais, Bernhard Hauns, Bernd Hentsch, Roland Baumgartner, Max E. Scheulen
Journal: Journal of Clinical Oncology (2014)

2564 Background: 4SC-205 is a potent small molecule inhibitor of the kinesin spindle protein Eg5 with broad anti-tumour activity in vitro and in vivo. Currently, 4SC-205 is the only oral available Eg5 inhibitor at clinical stage. Oral availability allows for flexible dosing in order to determine an optimal therapeutic window. Methods: Patients (pts) with solid tumors were dosed either once weekly (ow) at days 1 and 8 or twice weekly (tw) at days 1, 4, 8, and 11 or continuously (con) within a 21-day cycle. Dose escalation followed a 3+3 design. Primary objectives comprised safety, tolerability, definition of MTD/DLT and pharmacokinetic (PK) characterization. Secondary objectives include assessment of anti-tumour effect, measurement of M30/M65 cytokeratin-18 and pH3 in skin biopsies. Results: 56 Pts were enrolled at dose levels of 25mg (N=3), 50mg (N=3), 100mg (N=6), 150mg (N=6) and 200mg (N=13) ow; at 50mg (N=3), 75mg (N=7), and 100mg (N=5) tw; and at 10mg (N=3), 20mg (N=3) and 30mg (N=4) con. DLT was reached at 200mg (ow) and at 100mg (tw). MTD is established at 150mg (ow) and at 75mg (tw). These findings are in line with a dose proportional PK, resulting in similar cumulative AUCs for DLT and MTD for ow and tw dosing, respectively. The most common dose limiting adverse event was neutropenia. Prophylactic treatment with G-CSF at 200mg (ow) did not result in additional benefit. Interim analysis of exposure-toxicity data using a population PK/PD model for neutropenia suggested an opportunity for continuous dosing. Neutropenia occurred at dose level of 30mg (con). A dose-dependent biomarker response was observed in skin biopsies. Response acc. to RECIST was not observed. 28% of patients were stabilized into follow-up after 6 weeks. The maximum treatment duration was > 300 days. Currently, 3 more patients are entrolled in 20mg con. However,the data of 56 patients allows for reliable evaluation. Conclusions: 4SC-205 could be safely administered up to 200mg (ow), 100mg (tw) and 30mg (con). Neutropenia was the main dose limiting toxicity. The compound exhibits dose-proportional pharmacokinetics with t1/2 ~ 10h. Plasma exposure exceeds average in vitro GI50 20x at the highest dose level over a period of 24h. Clinical trial information: NCT01065025.
Two Distinct Mechanisms Are Responsible for Regulation of Ribosomal Protein S19 Expression Level in Diamond-Blackfan Anemia by NF-κB Pathway.
Authors: Corinne Hurtaud, Aurore Cretien, Valerie Clayette, Didier Pisani, Stephane Giraudier, Thierry Leblanc, Jean Delaunay, Gil Tchernia, Narla Mohandas, Lydie Da Costa
Journal: Blood (2007)
Exposure–safety relationship of trastuzumab emtansine (T-DM1) in patients with HER2-positive locally advanced or metastatic breast cancer (MBC).
Authors: Jin Jin, Bei Wang, Yuying Gao, Meghna Samant, Chunze Li, Chunyan Song, Sandra M. Swain, Michael Untch, Sandhya Girish
Journal: Journal of Clinical Oncology (2013)

646 Background: Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate composed of trastuzumab, the cytotoxic agent DM1, and a stable thioether linker. The effects of T-DM1 exposure on safety in patients with HER2-positive locally advanced or MBC are reported. Methods: The exposure–safety analysis included 618 patients with pharmacokinetic (PK) data who received single-agent T-DM1 3.6 mg/kg q3w from five phase 2 or 3 studies: TDM4258g, TDM4374g, TDM4450g/BO21976, TDM4688g, and EMILIA. Exposure parameters observed in cycle 1 were T-DM1 conjugate AUC, T-DM1 conjugate C max , and DM1 C max , (no PK accumulation). Safety endpoints were worst grade of thrombocytopenia (TCP) or hepatotoxicity (HPT) by protocol definitions. A multivariate logistic regression analysis was conducted to evaluate the association of exposure and clinically relevant covariates with the probability of experiencing TCP or HPT. Platelet counts (PLT), alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin (TBL) versus time profiles were also evaluated by exposure quartiles to further test exposure effect on lab values. A secondary analysis for patients in the EMILIA study alone (n=307) was also conducted. Results: Grade ≥3 TCP and grade≥ 3 HPT were observed in 72 patients and 45 patients in the exposure–safety data set, respectively. Data from the pooled studies showed no statistically significant association between exposure and the incidence of grade ≥3 TCP (T-DM1 AUC P=0.99, T-DM1 C max P=0.97, DM1 C max P=0.72), or grade ≥3 HPT (T-DM1 AUC P=0.25, T-DM1 C max P=0.93, DM1 C max P=0.95). Additionally, no obvious difference was observed for longitudinal PLT, ALT, AST, or TBL profiles across exposure quartiles, with no exposure–safety relationship for the probability that PLT, ALT, AST, or TBL exceeded grade 3 thresholds. Similar results were observed for the EMILIA analysis. Conclusions: For patients with HER2-positive locally advanced or MBC treated with T-DM1 3.6 mg/kg q3w, no exposure–safety relationship was observed for TCP, HPT, PLT, or liver function based on T-DM1 or DM1 exposure.
Clinical significance of plasma fibrinogen level in patients with prostate cancer.
Authors: Xiao-Kun Ma, Jing-Yun Wen, Zhan-Hong Chen, Qu Lin, Xing Li, Min Dong, Li Wei, Jie Chen, Tian tian Wang, Dan-Yun Ruan, Ze-Xiao Lin, XiangBo Wan, Xiang-Yuan Wu
Journal: Journal of Clinical Oncology (2013)

e16077 Background: Most of malignant tumor patients have hypercoagulable state with plasma fibrinogen (Fib) levels increased. In this study, we aimed to investigate correlation of plasma Fib with routine prognostic factors of prostate cancer patients, including Gleason score, prostate specific antigen (PSA), TNM 7th Stage. Methods: From January 2007 to December 2012, 107 patients with prostate cancer and 44 cases of benign prostatic hyperplasia (BPH) were included in our study. Automated coagulation analyzer was used to determine the plasma fibrinogen levels. Results: The patients presented a mean age of 70.6 years, a mean PSA level of 28.73 ng/ml, clinically localized prostate cancer in 47 cases, locally advanced condition in 27cases, and distant metastatic disease in 33 cases. The fibrinogen levels were increased in cancer patients compared to that in patients with BPH (P = 0.031). Higher fibrinogen levels related to metastasis, higher TNM stage and increased PSA (p = 0.000, 0.041 and 0.004 respectively). Fib levels were irrelevant to T state, N state, and Gleason score. Conclusions: Prostate cancer patients displayed increased Fib levels. Plasma Fib is significantly increased in patients with higher PSA level,worse TNM stage and distant metastasis. The patients with high Fib might presented relative worse prognosis and should be monitored closely. [Table: see text]
Phase II trial of intraperitoneal (IP) administration of catumaxomab (C) as consolidation therapy for patients (pts) with relapsed epithelial ovarian cancer (OC) in second or third complete remission: GEICO 1001 study.
Authors: Ignacio Romero, Ana Oaknin, Jose Angel Arranz, Elena García-Martínez, Ana Herrero, Antonio Casado, Ana De Juan, Eva Guerra, Susana Hernando Polo, Ana Santaballa, Andres Poveda, Antonio Gonzalez-Martin
Journal: Journal of Clinical Oncology (2014)

5528 Background: Treatment with the trifunctional anti-EpCAM x anti-CD3 antibody, Catumaxomab, has shown antitumor activity in patients with advanced OC and refractory ascites. We explored prospectively the potential activity of C as consolidation therapy in pts with clinical complete response (CCR) following treatment for relapse. Methods: Pts with 2nd or 3rd CCR (CA-125 < 35 UI/ml and no evidence of disease in CT Scan), received IP C 10 µg day 0, 20 µg d3, 50 µg d7, 200 µg d10 . All pts received premedication with paracetamol and methylprednisolone 20 mg. Primary endpoint was progression-free survival (PFS) defined as time in months (m) from beginning of therapy for the most recent relapse until progression by RECIST criteria in the Intent to treat population (at least 1 dose of C). CA-125 was double-blinded during follow-up. Secondary end-points were safety, 2nd PFS (PFS of pts in 2nd CCR), 3rd PFS (PFS of pts in 3rd CCR) and PFS from first C dose. A median PFS > 14 m would be considered clinically meaningful to assess a confirmatory randomized trial. Results: 46 pts were included, 39 received 1st dose (29 in 2nd and 10 in 3rd CR) and 32pts completed 4 doses. Catheter-related issues preclude 4 pts to receive 1st dose and 3 pts to complete the 4 doses. Median duration of C therapy was 13 d (1-22). Grade 3-4 AE were observed in 29 pts (74.4%) and lead to interruption of C in 4 pts (10.2%). Grade 3-4 AE in > 5% of pts: GGT (35.9%), ALT/AST(20.5%), abdominal pain (12.8%), nausea (10.3%), asthenia (7.7%), Bilirubin (7.7%), diarrhea (5.1%), vomiting (5.1%) and non-neutropenic infection (5.1%). Additionally, pyrexia grade 2 in 33.3% of pts. Median PFS is 17.08 m (CI 95%: 12.9-21.5), 2nd PFS is 17.28 m (CI 95%: 12.9-21.5), 3rd PFS is 17.08 m (CI 95%: 9.26-25.5) and median PFS from first C dose is 8.71 m (CI 95%: 6.01-12.3). Conclusions: Intraperitoneal catumaxomab as consolidation therapy for pts with relapsed OC in 2nd or 3rd CCR is feasible. Median PFS of 17.08 m from most recent relapse and 8.71 m from C first dose may indicate an impact of C in relapsed OC with minimal residual disease after 2nd or 3rd CCR, and should be confirmed in a randomized trial. Clinical trial information: NCT01246440.
Prospective cohort study of serum sialylated glycoprotein (KL-6) as a prognostic marker in patients (pts) with non-small cell lung cancer (NSCLC) receiving gefitinib monotherapy: Okayama Lung Cancer Study Group 0703.
Authors: Hiroshige Yoshioka, Katsuyuki Hotta, Isao Oze, Yoshiro Fujiwara, Hidetoshi Hayashi, Akihiro Nishiyama, Yohei Korogi, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura
Journal: Journal of Clinical Oncology (2013)

e19023 Background: Gefitinib is now crucial in the treatment of EGFR-mutant NSCLC. Its anti-tumor activity could be modulated by MUC1 mucins [Cancer Res 2006], similar to KL-6 in the biochemical property, currently used as an indicator for interstitial lung diseases (ILDs). Our preliminary retrospective study showed the elevated serum KL-6 level is a potential negative prognostic value in pts with advanced NSCLC receiving gefitinib therapy [Lung Cancer 2008]. We conducted an observational study to evaluate this issue prospectively. Methods: Consecutive, EGFR-TKI-naïve NSCLC pts who were to receive gefitinib were enrolled and stratified by pretreatment KL-6 levels (&lt; 500 U/ml: normal group [NG] and ≥ 500 U/ml: abnormally elevated group [EG]). The primary endpoint was overall survival (OS). The planned accrual number of pts was 150, assuming an estimated HR of 2.0, α=0.05, ß=0.10). We also evaluated ILD events during the gefitinib treatment. Results: Between 2007 and 2012, 154 pts were registered (NG: 89 [58%] and EG: 65 [42%] with median KL-6 score of 305 and 1,050 IU/mL, respectively). Those with pretreatment pulmonary fibrosis were similarly distributed between the groups. Median follow-up time was 13.7 months. The EG had significantly worse OS in the univariate analysis (log-rank p=0.0011), which was retained in the multivariate analysis (hazard ratio [HR]: 1.95, 95% confidence interval [95% CI]: 1.34-2.81). Exploratory analyses showed an interaction between EGFR-mutation status and KL-6; HR of KL-6 for OS: 1.96, [1.30-2.97], and HR: 4.80, [1.05-21.95] in pts with EGFR-mutant and wild-typed tumors, respectively (interaction p=0.07). As for ILD event it occurred similarly during the gefitinib therapy (HR: 2.76, [0.62-12.33]). Conclusions: The elevated KL-6 level could predict a poor prognosis in NSCLC pts with gefitinib therapy, and this association seemed modulated by EGFR-mutation status. Further studies are needed to clarify the biological behavior of KL-6 expression on tumor progression especially in the EGFR pathway.
Ductal carcinoma in situ (DCIS): Ethnicity, clinical-pathologic features, and outcome.
Authors: Adam C. Berger, Fran Guiles, Angela Toss, Jocelyn Andrel Sendecki, Nicole Lynn Simone, Pramila R. Anne, Tiffany P. Avery, Rebecca J. Jaslow, Juan Palazzo, Melissa A. Lazar, Theodore N. Tsangaris, Massimo Cristofanilli
Journal: Journal of Clinical Oncology (2014)

e11503 Background: The main goal in treating DCIS remains the prevention of ipsilateral recurrence and contralateral tumors. Known risk factors for recurrence include multifocal disease, tumor size, nuclear grade, presence of comedo necrosis, hormone receptor (HR) and HER-2 status and young age. Despite the similar distribution of molecular characteristics and treatments among ethnic groups, previous research reported that African Americans (AA) have worse outcomes. Methods: We identified 446 patients with DCIS (395) or microinvasive carcinoma (51), treated between 2008 and 2013, in the Thomas Jefferson University Tumor Registry. Associations between recurrence and demographic factors, histology, and treatment were assessed. Student’s t-test was used to compare age between recurrent and non-recurrent patients, Pearson’s Chi-squared test to test associations between recurrence variables with more than two categories, and Fisher’s Exact test for testing associations between recurrence and two-level categorical variables. Results: The median age was 59.5 years with a racial distribution of 65.7% white, 23.5% AA and 7.6% Asian. Moreover, 75.8% were ER positive, 66.8% PR positive and 20% HER2 positive. Mastectomy was performed in 26.7% of patients and 72.9% were treated with conservative surgery. AA and Asian patients were significantly more likely to undergo mastectomy. Adjuvant radiotherapy was utilized in 46.8% of women who underwent conservative surgery. Adjuvant chemotherapy was administered to 3.6% of women, preventive or adjuvant hormone therapy to 33.8%. To date, 22 patients developed a recurrence, 19 of which were in situ lesions. Only one of these patients had microinvasion in primary lesion. Conclusions: Our analysis confirms previously published results demonstrating that the histopathology of DCIS did not significantly differ among ethnic groups, even if AA patients were more likely HR positive and consequently were more frequently offered preventive endocrine therapy. The higher rate of mastectomy in AA, independent of patients’ preferences, may underlie a more aggressive disease biology and greater potential for multifocality requiring future evaluation of prognostic molecular biomarkers.
Safety and feasibility of anticoagulation prophylaxis with enoxaparin in acute lymphoblastic leukemia during asparaginase-based intensification therapy.
Authors: Hassan Abdulmaoula Sibai, Jack Toshimine Seki, Naoko Sakurai, Andre C. Schuh, Karen W. L. Yee, Mark D. Minden, Aaron David Schimmer, Vikas Gupta, Joseph M. Brandwein
Journal: Journal of Clinical Oncology (2015)

7048 Background: Venous thromboembolism (VTE) is a well-known complication in adults receiving asparaginase (ASP) for acute lymphoblastic leukemia (ALL). We previously reported 27.3% VTE rate in patients (pts) receiving a modified Dana Farber Cancer Institute (DFCI) intensification phase. Low-dose enoxaparin (ENOX) was not associated with lower rate of VTE. We describe escalated dose of ENOX in adults treated with this protocol. Methods: 38 pts with ALL treated with a weekly ASP-based modified DFCI intensification for 21-30 weeks, received ENOX 1 mg/kg subcutaneously daily (adjusted-dose group).The result was compared with a similar group of 41 pts receiving ENOX 40 mg for pts weighing < 80 kg, or 60 mg for pts ≥ 80 kg (low-dose group), and to a historical cohort of 99 pts treated with the same protocol, without prophylaxis. Results: There was no significant difference among groups with respect to median age, weight and number of cycles. The actual mean dose of ENOX in the low-dose group was 0.62 mg/kg, as compared to 0.84 mg/kg in the adjusted-dose group. No major bleeding complications were observed. Minor bleeding rate was 5%.VTE rate in the entire cohort was 22.7%.VTE rate in pts receiving adjusted dose ENOX was 18%, as compared to 26.8% in the low-dose group. There was no significant difference in the VTE rate according to age or gender. Sites of VTE in the prophylaxis groups included lower extremity (9), sagittal sinus (3), central line related (5) and pulmonary embolism (8); some pts had > 1 site. Conclusions: Prophylactic ENOX during intensification in adults with ALL was safe: despite dose increase to 1 mg/kg, no increase in bleeding events was observed. There was trend toward a lower rate of VTE with 1 mg/kg ENOX, particularly in patients weighing ≥ 80 kg; however, a larger cohort is needed to determine if the difference is significant. No Prophylaxis n = 99 ENOX low-dose n = 41 ENOX adjusted-dose n = 38 P-value* Rate of VTE 27/99 (27.3%) 11/41 (26.8%) 7/38(18%) 0.42 Weight < 80 kg 18/67 (26.9 % ) 4/26 (15.3%) 5/29 (17.2%) 1 Weight > 80 kg 9/32 (28.1% ) 7/15 (46.7%) 2/9 (22%) 0.38 P value by weight 0.90 0.03 0.53 Minor bleeding events 3 (6.1%) 1 (2.6%) NS *Comparing low dose vs adjusted dose
Preoperative Tru-Cut biopsy (POB) for the diagnosis of retroperitoneal soft tissue sarcomas (RPS) and risk of local recurrence (LR) compared to primary surgery of the tumor.
Authors: Paola Boccone, Lorenzo D'Ambrosio, Danilo Galizia, Erica Palesandro, Sandra Aliberti, Antonio Manca, Ilaria Bertotto, Filippo Russo, Manuela Racca, Marco Gatti, Ymera Pignochino, Massimo Aglietta, Giovanni Grignani
Journal: Journal of Clinical Oncology (2013)

10583 Background: Regardless optimal surgery LR is still a major challenge in RPS affecting 60% of the patients (pts). To improve these results pre-operative radiotherapy +/- chemotherapy are under investigation. This strategy requires to perform a POB. The surgical removal of the whole needle track is mandatory for limb sarcomas, but it can hardly ever be achieved in RPS. We explored whether POB did increase the risk of LR in terms of tumor cell seeding (along the needle track) or in the tumor mass area. Methods: We scanned our prospectively (01/2000 to 12/2010) collected RPS database including 176 pts. Complete information (records, CT scans, biopsy-track, follow up data) were available and retrospectively examined in 100 pts. Pts were divided into: group A (POB), group B (direct surgery). The 7 year probability of disease free survival (DFS) was estimated for each pt (ASCO 2012 abs 10000). T student test and Fisher's exact test were used to compare the estimated DFS and the incidence of LR in the 2 groups, respectively. Kaplan-Meier method was used to estimate DFS and overall survival (OS). Results: In 51 male, 49 female, median age 58 years (22-81) RPS histotype distribution was: lipo 43, leio 28, pleomorphic 9 and other 20. RPS grades were: G1 29%, G2 32%, G3 39%. POB was performed in 25 pts (25%) without major complications. The baseline probability of 7 year DFS was 0.43 and 0.51 (p= .24) for group A and B, respectively. After a median follow up of 71 mos, LR was 8% and 23% (p&gt; .05) for group A and B, respectively. No relapse along the needle track was detected. As expected, liposarcoma was associated with a higher rate of LR (Odds Ratio 5.6 CI 95% 2-13). Median DFS, local DFS and OS were 24, 88 and 71 months, respectively. Conclusions: With the limit of the retrospective nature of our data, we didn’t find any increased risk of LR for POB in RPS. Although surgery is still the standard therapy in RPS, knowledge of histotype and differential diagnosis might encourage to consider inclusion of pts into pre-operative clinical trials and to avoid surgery for other retroperitoneal tumors (e.g. lymphomas, germinal cell tumors, IgG4-related sclerosing disease).
Final overall survival results of a randomized phase III trial comparing weekly docetaxel plus cisplatin (DP) with 3-weekly docetaxel (D) monotherapy in elderly patients (pts) with advanced non-small-cell lung cancer (NSCLC): intergroup trial JCOG0803/WJOG4307L.
Authors: Koji Takeda, Tetsuya Abe, Yuichiro Ohe, Shinzoh Kudoh, Yukito Ichinose, Hiroaki Okamoto, Nobuyuki Yamamoto, Hiroshige Yoshioka, Koichi Minato, Toshiyuki Sawa, Yasuo Iwamoto, Hideo Saka, Junki Mizusawa, Tomonori Mizutani, Shinichiro Nakamura, Masahiko Ando, Akira Yokoyama, Kazuhiko Nakagawa, Nagahiro Saijo, Tomohide Tamura
Journal: Journal of Clinical Oncology (2015)

e19012 Background: The intergroup trial JCOG0803/WJOG4307L demonstrated that overall survival of subject in the doublet arm, treated with weekly DP, was not superior to that of subjects in the D monotherapy arm (hazard ratio [HR], 1.56; 95% confidence interval [CI], 0.98–2.49), and the predictive probability that DP would be statistically superior to D upon final analysis was 0.996% in the first interim analysis (Abe T, et al. J Clin Oncol 2015). These findings led to early study termination (the information time, 24% [73/304]) in elderly pts with advanced NSCLC. This final survival analysis aimed to confirm the result of the first interim analysis. Methods: Chemotherapy-naïve stage III, stage IV, or recurrent NSCLC pts aged ≥ 70 years with performance status of 0 or 1 who were considered unsuitable for bolus cisplatin administration were randomized to receive 60 mg/m2 D on day 1, every 3 weeks, or 20 mg/m2 D plus 25 mg/m2 cisplatin on days 1, 8, and 15, every 4 weeks. The primary endpoint was overall survival. The planned sample size was 380 pts in total, to provide an 80% power to detect a 0.752 HR for DP to D with a 5% one-sided alpha. Results: In total, 276 pts with a median age of 76 years (range, 70–87 years) were enrolled (D, n = 137; DP, n = 139). After 198 deaths of 272 eligible patients (D, 69.4%;DP, 76.1%) were observed with a median follow-up of 23.1 months for alive pts, the median survival time was 14.8 months for the D and 13.3 months for the DP (HR, 1.21; 95% CI, 0.91–1.60). Survival of the DP was not superior in all subgroups, including age subgroup ( = < 74/ > = 75 years). In the EGFR mutated subgroup, DP showed significantly shorter survival than D (HR, 2.69; 95% CI, 1.07–6.77). The progression-free survival was not different between the arms (HR, 0.92; 95% CI, 0.72–1.17). Conclusions: The final survival analysis confirmed the result of first interim analysis. This study failed to demonstrate any survival advantage of weekly DP over D monotherapy as a first-line chemotherapy for elderly pts with advanced NSCLC. Clinical trial information: UMIN000001424.