tbuckley/cabot-search huggingface dataset:
On-treatment progression-free survival analysis of ziv-aflibercept/FOLFIRI treatment within 28 days of end of treatment in metastatic colorectal cancer: Updated efficacy results from the VELOUR study.
Authors: David Ferry, Tae Won Kim, Tormod Kyrre Guren, Jayesh Desai, Luis Marcelo Villanueva, Michael L. Andria, Eric Van Cutsem, Teresa Macarulla
Journal: Journal of Clinical Oncology (2013)

3573 Background: The phase III VELOUR study demonstrated that adding the novel antiangiogenic agent ziv-aflibercept (known as aflibercept outside the United States) to FOLFIRI in patients with metastatic colorectal cancer previously treated with oxaliplatin significantly improved overall survival, progression-free survival (PFS), and overall response rate vs placebo/FOLFIRI. We performed an additional analysis of PFS “on-treatment,” censoring events that occurred more than 28 days after last treatment dose. Methods: Patients were randomized to receive ziv-aflibercept 4 mg/kg or placebo every 2 weeks in combination with FOLFIRI. An independent review committee determined progression based on radiologic review. PFS was estimated using Kaplan-Meier analysis, with censoring of events after the last dose plus 28 days. Treatment groups were compared using a log-rank test and were stratified by Eastern Cooperative Oncology Group performance status and prior bevacizumab therapy. Hazard ratio (HR) and confidence interval (CI) were estimated using a Cox proportional hazard model. Results: On-treatment analysis showed significantly increased PFS for patients treated with ziv-aflibercept/FOLFIRI compared with placebo/FOLFIRI (Table). More patients were censored in the ziv-aflibercept arm due to adverse events. Conclusions: The on-treatment PFS analysis demonstrates a significantly improved treatment effect of the addition of ziv-aflibercept to FOLFIRI (HR=0.55) over what was observed in the primary analysis suggesting that continuing treatment with ziv-aflibercept up to disease progression provides additional benefit. Clinical trial information: NCT00561470. [Table: see text]
Phase II study of NGR-hTNF plus doxorubicin in relapsed ovarian cancer (OC).
Authors: G. Scambia, D. Lorusso, G. Amadio, N. Trivellizzi, A. Pietragalla, R. De Vincenzo, V. Salutari, M. Di Stefano, G. Mangili, S. Montoli, G. Citterio, A. Lambiase, C. Bordignon
Journal: Journal of Clinical Oncology (2011)

5022 Background: NGR-hTNF consists of tumor necrosis factor fused with the peptide NGR, which selectively binds to a CD13 overexpressed on tumor blood vessels. NGR-hTNF is able to increase the intratumoral doxorubicin distribution by altering tumor vasculature. Methods: OC patients failing at least one prior platinum-taxane line and with platinum-free interval either lower than 6 months (PFI<6) or between 6 to 12 months (PFI<12) received NGR-hTNF 0.8 µg/m2 and doxorubicin 60 mg/m2on day 1 every 3 weeks. Doxorubicin was maintained up to 8 cycles and NGR-hTNF until disease progression. Primary endpoint was response rate. A 2-stage study design assumed that ≥2/17 and ≥6/37 patients with objective response would warrant further testing. Results: Thirty-seven patients (25 with PFI<6; 12 with PFI<12) pretreated with 1 to 5 chemotherapy lines (median 1) were enrolled. Median age was 57 years (range 35-72) and 32 patients presented with a PS of 0. Median PFI was 4.6 months (95% CI 3.4-5.8). Baseline CA125 ranged from 6 to 5,787 U/mL (median 549). Median baseline neutrophil-to-lymphocyte ratio (NLR), an index of systemic host immune response to tumor, was 2 (range 1-17). In total, 172 cycles were given (median 4; range 1-8). Neither increase of doxorubicin-related toxicities nor grade 3-4 NGR-hTNF related toxicity were registered. Common grade 1-2 toxicity were transient chills (58%). After first study stage (n=17), 6 patients showed partial response (2 with PFI<6; 4 with PFI<12) and the trial met its primary endpoint. After study completion (n=37), a total of 17 patients had experienced stable disease (10 with PFI<6; 7 with PFI<12), yielding an overall disease control rate of 66% (92% in PFI<6; 48% in PFI<12). Median progression-free survival (PFS) was 5.0 months (95% CI 4.4-5.6) in overall population, 3.7 months in patients with PFI<6, and 8.2 months in patients with PFI<12. Moreover, median PFS was 7.8 vs 3.4 months (HR=0.37; p=0.01) in patients with baseline NLR lower or higher than the median value, respectively. After a median follow-up of 5.1 months, 31 patients (84%) were still alive. Conclusions: Tolerability and activity of NGR-hTNF plus doxorubicin deserve further randomized testing versus doxorubicin alone in platinum-resistant/refractory OC.
Impact of prior procedures on overall survival following radioembolization in patients with unresectable hepatocellular carcinoma (HCC).
Authors: G. M. Ettorre, B. Sangro, R. Cianni, D. Gasparini, R. Golfieri, S. Ezzidin, F. T. Kolligs, F. Izzo
Journal: Journal of Clinical Oncology (2011)

4099 Background: Radioembolization (RE), which enables the delivery of high dose radiation preferentially to liver tumors, is used in some specialist centers as part of the multimodal treatment of HCC. In this analysis, the impact of prior hepatic-directed procedures on the outcome with RE was evaluated. Methods: A retrospective analysis was conducted of consecutive patients who received RE between 09/2003 and 12/2009 at 8 European centers. Patients who were not suitable for surgery (resection, liver transplantation), local ablation (PEI, RFA, cryoablation) or transarterial therapies (TACE, TAE), or had progressed on prior treatment (surgery, ablation or TACE/TAE) were considered for RE with 90Y resin microspheres (SIR-Spheres). Results: Patients (n=325) were mostly Child-Pugh class A (82.5%), had underlying cirrhosis (78.5%) and a good performance status (ps; ECOG 0-1: 87.7%) but many had multinodular (75.7%) advanced disease (BCLC ‘C’: 56.3%) invading both lobes (52.9%) and/or portal vein occlusion (13.5% branch; 9.8% main). Of these, 182 patients (56.0%) had received RE as first line treatment while 143 patients (44.0%) had had prior hepatic surgery (n=61; 18.8%), ablation (n=29; 8.9%) and/or vascular procedures (n=98; 30.2%), mostly as a single procedure (n=101; 31.1%). The analysis found few differences in baseline characteristics between prior treatment groups, except for baseline bilirubin which was higher in treatment naïve patients (1.2 vs. 1.0 mg/dL; p=0.004). A slightly higher median activity was administered to those who were treatment naïve (1.7 vs. 1.5 GBq; p=0.001) reflecting the higher target tumor volume (253.5 vs. 180 mL). No statistically significant differences were observed in overall survival between the prior procedure and treatment naïve groups (median 13.1 [95% CI 10.9-19.6] vs. 12.5 [10.3-15.9] months; p=0.289); BCLC ‘A’ patients who had received a prior procedure survived longer post-RE than those who received RE first line (33.7 [19.6-46.8] vs. 22.1[15.1-38.1] months; p=0.047). Conclusions: Patients with HCC who had failed prior procedures can be treated effectively with RE and had outcomes similar to those who were treatment naive.
Multicenter retrospective analysis of systemic chemotherapy for advanced poorly differentiated neuroendocrine carcinoma of the digestive system.
Authors: Nozomu Machida, Tomohiro Yamaguchi, Akiyoshi Kasuga, Hideaki Takahashi, Kentaro Sudo, Tomohiro Nishina, Kazutoshi Tobimatsu, Kenji Ishido, Junji Furuse, Narikazu Boku
Journal: Journal of Clinical Oncology (2012)

4046 Background: No standard regimen is yet established for advanced poorly differentiated neuroendocrine carcinoma (PDNEC) although regimens for small-cell lung carcinoma are usually adopted such as irinotecan + cisplatin (IP) or etoposide + cisplatin (EP). Our aim was to respectively investigate outcomes for advanced PDNEC of the digestive system according to patient characteristics and regimens. Methods: Data was collected from patient medical records at 23 hospitals in Japan. The selection criteria were as follows: 1) histologically proven PDNEC, small cell carcinoma, mixed endocrine-exocrine carcinoma with a PDNEC component, or histologically proven neuroendocrine tumor with rapidly progressive clinical course; 2) primary tumor arising from the gastrointestinal tract (GI) or the hepato-biliary-pancreatic system (HBP); and 3) inoperable or recurrent disease treated with systemic chemotherapy (Cx) between April 2000 and March 2011. Results: This study included 258 patients (males/females, 182/76) with median age of 62.5 years. Primary sites were esophagus/stomach/small bowel/colorectum/hepato-biliary system/pancreas in 85/70/6/31/31/35 patients (pts). According to the primary sites, the median overall survival period (mOS) was 13.4/13.3/29.7/7.6/7.9/8.5 months, and that of GI/HBP was 13.0/7.9 months, respectively. Most common regimen was IP (160 pts, 62%), followed by EP (46 pts, 18%). For IP/EP patients, response rates (RR) were 50%/27%, the median progression free survival periods (mPFS) were 5.2/4.0 months. Second line Cx was performed for 88 pts (55%)/28 pts (61%) and mOS from first line Cx were 13.0/7.3 months in IP/EP groups. Multivariate analysis demonstrated that a primary site of HBP (HR=1.96, p=0.003) and performance status of 2 and more (HR=2.32, p=0.01) were independent unfavorable prognostic factors of PDNEC patients treated with systemic Cx, while the hazard ratio comparing IP with EP was 0.79 (p=0.305). Conclusions: PDNEC of HBP had poorer prognosis than GI. IP was the most common treatment regimen and seemed to show better treatment outcomes than EP.
The role of VEGF/mTOR/AKT pathway in patients with advanced urothelial carcinoma of the bladder cancer.
Authors: Rudolf Moritz, Arndt Hartmann, Johannes Giedl, Elke Eltze, Lothar Hertle, Edwin Herrmann
Journal: Journal of Clinical Oncology (2013)

264 Background: Activation of the mTOR pathway can be observed in various tumor entities. In advanced urothelial carcinoma of the bladder (BCA) its role still is unclear. The aim of our study was to examine activation of the mTOR cascade in BCA and its correlation with survival data. Methods: Tissues from 268 patients undergoing radical cystektomy were collected to assess the diagnostic and prognostic value of mTOR, HIF1-alpha, p4EB-P1, pAKT and VEGF using tissue microarray-based immunohistochemistry. Results: Overexpression of mTOR pathway enzymes is frequently detected for HIF1-alpha (29.8%), pAKT (53.2%), mTOR (43.3%), p4EB-P1 (28.4%) and VEGF (58.5%). Overexpression of pAKT was a significant predictor of progression (PFS) in pT1 (p=0.026) and pT2 (p=0.018) tumors. Overall survival (OAS) was significantly shorter for patients with pT1 (p=0.021) and pT2 (p=0.026) tumors in this subgroup. HIF1-alpha overexpression leads to significant earlier recurrence of BCA following radical cystektomie in the subgroup of pT3 tumors (p=0.046). High levels of mTOR were predictive for cancer related death (p=0.021) in pT2-tumors. Conclusions: Activation of mTOR-pathway, especially pAKT is of prognostic value in patients with advanced BCA and might be useful as a target for future therapies.
Gemcitabine (G) + nab-paclitaxel (nab-P) versus G in patients (pts) with advanced pancreatic cancer (PDAC) after FOLFIRINOX: A single center, retrospective review.
Authors: Edmond Mankee Chan, Theodore S. Hong, Jeffrey William Clark, Lawrence Scott Blaszkowsky, Jill N Allen, Andrew Zhu, Lipika Goyal, Janet E Murphy, Eunice L Kwak, Jennifer Y Wo, David P. Ryan, Jason Edward Faris
Journal: Journal of Clinical Oncology (2016)

348 Background: The MPACT study showed that G + nab-P improved OS and PFS over G as first line therapy for metastatic PDAC. However, there is limited data studying this combination after FOLFIRINOX. Here, we compared G + nab-P to G in pts with advanced PDAC previously treated with FOLFIRINOX. Methods: From 3/2010 to 5/2014, we identified all pts treated with FOLFIRINOX for PDAC who later received G +/- nab-P at the MGH. PFS and OS were calculated from the start of G +/- nab-P and analyzed using Kaplan-Meier and Cox-regression analyses. Results: 40 pts received G + nab-P and 36 pts received G. 29 of 36 pts in the G arm started G prior to the FDA approval of nab-P. Baseline characteristics were similar except 7 pts in the G + nab-P arm had locally advanced PDAC at start of G + nab-P while all other pts in both arms had metastatic PDAC. The median OS was 4.8 months (m) for G + nab-P vs 4.2m with G (HR 0.69, 95% CI 0.42 – 1.13). The median PFS was 2.4m for G + nab-P vs 1.8m for G (HR 0.70, 95% CI 0.44-1.12). The median OS did not change when the analysis was restricted to pts with metastatic PDAC – 4.8m vs 4.2m (HR 0.68, 95% CI 0.41-1.14). The median PFS for pts with metastatic PDAC was also similar – 2.7m for G + nab-P vs 1.8m with G (HR 0.69, 95% CI 0.42-1.12). Pts treated with G + nab-P received a median of 4m of treatment vs 2m for pts with G alone. The median relative dose of G was 50% of the maximum anticipated dose over the first 8 weeks for G + nab-P vs 66% with G. The median relative dose for nab-P was 50% of the maximum anticipated dose over the first 8 weeks. The most common reasons for discontinuing therapy were progression (62.5% vs 69%), patient decision (5% vs 11%), and infection (12.5% vs 0%). Conclusions: Although retrospective and limited by a small sample size, our data suggests that G + nab-P could be considered over G for advanced PDAC after FOLFIRINOX. However, G + nab-P affords marginal improvement in median OS and PFS, thus calling for the need to explore other agents in the second-line setting. Moreover, our experience suggests that the addition of nab-P led to a reduction in the achievable dose of G – raising the question of tolerability in combining further agents to G + nab-P in this setting.
Phase I study of S-1 administrated for 14 days in a 21-day cycle in patients with advanced upper gastrointestinal cancer (AUGIC)
Authors: J. W. Clark, A. X. Zhu, D. P. Ryan, J. Meyerhardt, P. Enzinger, C. Earle, C. Fuchs, H. Anbe, M. Houghton, M. Kulke
Journal: Journal of Clinical Oncology (2005)

4066 Background: S-1 is a novel oral fluoropyrimidine drug that combines tegafur, CDHP, and oxonic acid (Oxo). A previous phase I study of S-1 bid for 28 days in a 35-day cycle had late onset grade 3/4 diarrhea as the major DLT. In an attempt to decrease this toxicity and reduce the impact of food intake on Oxo stability, we conducted the following phase I study. Methods: S-1 was administered orally one hour before or after a meal bid for 14 days, followed by a 7-day recovery period. MTD, Pharmacokinetics (PKs) and antitumor activity were evaluated. Key eligibility criteria included adult patients with refractory AUGIC, KPS ≥ 50%, and adequate organ function. Results: Sixteen patients were evaluated at two dose levels (30 mg/m2 and 35 mg/m2): median age = 56, Male/Female = 12/4, KPS 100/90/80/70/50 = 6/3/3/3/1. At 30 mg/m2 dose level, no DLT was observed in the first 3 patients. However, two of the three patients developed DLTs (Grade 3 rash and dehydration) on the 35 mg/m2 dose level. An additional 10 patients were subsequently treated at 30 mg/m2 without DLT. Therefore, 30 mg/m2 was established as the MTD. Common toxicities included anorexia, nausea, diarrhea, skin rash, and fatigue. No grad 4 toxicities were observed. One confirmed partial response (PR) was seen in a patient with gemcitabine refractory pancreatic adenocarcinoma and disease stabilization was seen in 8 patients with the following tumors: pancreatic, gastric and gallbladder carcinomas. AUC and Cmax of 5-FU at the MTD dose level were 855 ± 40 ng/ml respectively. Conclusions: The 30 mg/m2 dose is the MTD of this regimen and was well tolerated. Preliminary antitumor activity was seen in refractory upper GI cancers. 5-FU PK profile in this regimen was comparable to Japanese patients receiving S-1 at 36 mg/m2, suggesting a possible genetic difference in S-1 PK profiles, although further study is needed. Phase II studies have been initiated with this S-1 regimen. No significant financial relationships to disclose.
An evaluation of microRNA signature and response of patients with gastric cancer to cisplatin and fluorouracil.
Authors: H. K. Kim, C. H. Kim, J. Kim, I. J. Choi, D. J. Munroe, J. E. Green
Journal: Journal of Clinical Oncology (2011)

4062 Background: In previous miRNA microarray studies in gastric cancer, adjacent non-tumor tissue was used as the control as opposed to tissue from healthy volunteers. Also, most of previous studies attempting to identify miRNA predictors of clinical chemoresistance in cancer have examined only individual miRNAs. Very few high-throughput microarray analyses have been performed to identify miRNA expression signatures predictive of chemotherapy resistance in metastatic solid tumor patients. In order to identify miRNA signatures for gastric cancer and for predicting clinical resistance to cisplatin/fluorouracil (CF) chemotherapy, a comprehensive miRNA microarray analysis was performed using endoscopic biopsy samples. Methods: Endoscopic biopsy samples were collected prior to chemotherapy from 90 gastric cancer patients treated with CF and from 34 healthy volunteers. At the time of disease progression, post-treatment samples were collected from 8 clinical responders. miRNA expression was determined using a custom-designed Agilent microarray. In order to identify a miRNA signature for chemotherapy resistance, we correlated miRNA expression levels with the time to progression (TTP) after CF. Results: A signature distinguishing gastric cancer from normal stomach epithelium was identified. Fifty-eight miRNAs were significantly correlated with TTP of 82 cancer patients (P<0.05). Prominent among upregulated chemosensitive miRNAs were miRNAs associated with apoptosis. When this 58-miRNA predictor was applied to a separate set of pre- and post-treatment tumor samples from the 8 clinical responders, all of 8 pre-treatment samples were correctly predicted as low-risk, whereas samples from the post-treatment, chemoresistant state were enriched for the 58 miRNA signature, suggesting that selection for the expression of these miRNAs occurred as chemoresistance developed. Conclusions: This study identified a miRNA expression signature that distinguishes gastric cancer from normal stomach epithelium from healthy volunteers, and a chemoreresistance miRNA expression signature that is correlated with TTP after CF, although limited by the small sample size of the validation set.
First-in-human phase I trial of prostate-specific membrane antigen antibody drug conjugate (PSMA ADC) in taxane-refractory prostate cancer.
Authors: P. Kantoff, D. P. Petrylak, M. Pomerantz, R. J. Israel, W. C. Olson, T. Ramakrishna, S. Morris
Journal: Journal of Clinical Oncology (2010)

TPS245 Background: PSMA is a type II transmembrane glycoprotein with abundant and restricted expression on prostate cancer cells. PSMA ADC comprises a monoclonal antibody (mAb) to PSMA linked to the antitubulin agent monomethyl auristatin E (MMAE). PSMA ADC demonstrated potent activity against human prostate tumors in preclinical studies (Ma et al, Clin Canc Res 12:2591). This report describes an ongoing phase I dose escalation study of PSMA ADC in patients (pts) with progressive taxane refractory metastatic prostate cancer (metCRPC). The goals of the trial are to determine a maximum tolerated dose (MTD), identify potential dose limiting toxicities, describe the pK profile of free MMAE and the parent compound, and detect potential antitumor activity of PSMA ADC. Methods: Eligible pts are ≥18 years with metCRPC after failure of a taxane-containing regimen and ECOG status of 0 or 1. PSMA ADC is administered by IV infusion Q3W for up to 4 cycles. Adverse events, pK, PSA, circulating tumor cells, clinical disease progression, and immunogenic response to PSMA ADC or its components are assessed. Serum concentrations of study drug (PSMA ADC) and total antibody (PSMA mAb + PSMA ADC) are measured by an enzyme-linked immunosorbent assay (ELISA) method and serum concentrations of free toxin (MMAE) are measured by a liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) method. Using a modified Fibonacci sequence, dosing began at 0.4 mg/kg in the first cohort. Pts perceived to be benefitting from treatment may be enrolled in an extension study of PSMA ADC at the same dose. Current Status:Fifteen patients have been treated to date; Cohort 1 (0.4 mg/kg), 3 pts; Cohort 2 (0.7 mg/kg), 3 pts; Cohort 3 (1.1 mg/kg), 3 pts; Cohort 4 (1.8 mg/kg), 6 pts. Two pts have enrolled in the extension study. Enrollment is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Progenics Pharmaceuticals, Inc. Progenics Pharmaceuticals, Inc. Progenics Pharmaceuticals, Inc. Progenics Pharmaceuticals, Inc.
Everolimus plus octreotide LAR versus placebo plus octreotide LAR in patients with advanced neuroendocrine tumors (NET): Updated safety and efficacy results from RADIANT-2.
Authors: J. C. Yao, S. Ricci, R. E. Winkler, V. Jehl, M. E. Pavel
Journal: Journal of Clinical Oncology (2011)

4011 Background: In the RADIANT-2 trial, everolimus, an oral inhibitor of mTOR, plus octreotide (E+O) demonstrated a clinically meaningful increase in median progression-free survival (PFS) vs placebo + octreotide LAR (P+O) in patients with advanced low- or intermediate-grade NET and a history of carcinoid syndrome (ESMO 2010 Abstract #LBA8). Updated safety and exploratory biomarker analyses from this trial are presented. Methods: Patients (n=429) received everolimus 10 mg/d + octreotide LAR 30 mg IM q 28 days (n=216) or placebo + octreotide LAR (n=213). The primary endpoint was PFS per adjudicated central review (RECIST v1.0). Results: Median PFS (95% CI) with everolimus was 16.4 (13.7-21.2) mo vs 11.3 (8.4-14.6) mo with placebo (HR=0.77; 95% CI, 0.59-1.00; P=0.026), resulting in an increase of 5.1 mo. Benefit with E+O was observed across all prespecified subgroups (age, sex, PS, tumor grade, primary site, prior somatostatin analog, prior chemotherapy). Biomarker analyses showed baseline CgA to be a significant prognostic marker (HR=0.43; 95% CI, 0.32-0.59; P<0.001). Median PFS for those with elevated (>2x ULN) CgA was 13.9 (11.3-17.1) mo for E+O and 8.4 (7.7-11.1) mo for P+O (HR=0.66; 95% CI, 0.48-0.89; P=0.003). For those with nonelevated CgA, median PFS was 31.3 (19.3-NA) mo for E+O and 20.1 (13.04-NA) for P+O (HR=0.74; 95% CI, 0.42-1.28; P=0.14). Mixed-model analysis demonstrated that E+O led to greater fold reductions of both serum CgA (P=0.004) and urinary 5-HIAA (P<0.0001) vs P+O. Median safety follow-up is now 31.1 mo. Most frequent drug-related AEs (E+O vs P+O, %) were stomatitis (47.4 vs 10.9), rash (37.2 vs 12.3), and fatigue (31.6 vs 24.2) and were consistent with previous experience. Most frequent drug-related grade 3-4 AEs (E+O vs P+O, %) were fatigue (6.5 vs 2.8), diarrhea (6.0 vs 2.4), and hyperglycemia (5.1 vs 0.5). Conclusions: E+O has shown a clinically meaningful increase in median PFS and reduction in tumor and secretory biomarker levels with a favorable safety profile. These findings support the use of everolimus in patients with advanced NET and a history of secretory symptoms associated with carcinoid syndrome.
Outcomes for Adult Lymphoblastic Leukemia (ALL) Are Mainly Influenced by Age and Status of Minimal Residual Disease (MRD) by Multiparameter Flow Cytometry (MFC) After Therapy with the Modified Hyper-CVAD (with or without Rituximab) Regimen
Authors: Deborah A. Thomas, Hagop M Kantarjian, Jeffrey L. Jorgensen, Stefan Faderl, Elias Jabbour, William G. Wierda, Farhad Ravandi, Srdan Verstovsek, Guillermo Garcia-Manero, Charles Asa Koller, Jan A. Burger, Alessandra Ferrajoli, Marina Konopleva, Tapan Kadia, Gautam Borthakur, Steven M. Kornblau, Michael Andreeff, Rebecca Garris, Jorge E. Cortes, Susan O'Brien
Journal: Blood (2011)