tbuckley/cabot-search huggingface dataset:
Evaluation of toxicities of target therapy phase I and II trials on glioblastoma multiforme patients treated by curative radiotherapy: A meta-analysis.
Authors: Marcos Antonio Santos, Delphine Lefeuvre, Gwenael Le Teuff, Damien Bouda, Céline Bourgier, Julien Domont, Frederic Dhermain, Jean-Charles Soria, Eric Deutsch, Jean-Pierre Pignon
Journal: Journal of Clinical Oncology (2012)

3063 Background: An important limitation of the combination of target therapies (TT) to radiation (RT) is its potentially high level of toxicity. The objective of this study was to describe and quantify the drug related acute adverse events presented by patients taking part in phase I and/or phase II trials on TT combined to curative RT for the treatment of glioblastoma multiforme (GBM). Methods: A meta-analysis of summary data including all phase I, I/II and II trials published between 2000 and 2011 on newly diagnosed GBM patients treated by TT with RT was performed. Pooled incidence rates (IR) of all and specific toxicities were estimated using a generalized linear mixed model with fixed and random study effects. The pooled median of progression-free (PFS) and overall survivals (OS) were also considered. These results were compared to those obtained by patients receiving standard treatment (ST). Results: Twenty-one trials (8 phases I, 3 phases I/II and 10 phases II), testing 9 different drugs, have been selected, including 915 patients. The median follow-up varied from 1.4 to 34.0 months. The estimated pooled IR of all toxicities was 68.6 [53.5-88.0] per 1000 person-months of follow-up, compared to 20.7 [17.6-24.1] on ST (p&lt;0.001). The pooled IRs of thrombocytopenia, neutropenia or leucopenia, fatigue, gastrointestinal events and treatment-related deaths are 11.2 [7.5-16.9], 9.0 [6.1-13.4], 6.4 [4.1-10.0], 5.5 [2.9-10.2] and 3.2 [1.6-6.4], compared to 4.1 [2.8-5.8], 4.9 [3.5-6.6], 4.6 [3.2-6.4], 0.8 [0.3-1.6] and 0.1 [0.0-0.6], respectively, on ST. Median survival times are 7.7 [6.1-9.8] and 13.8 months [11.9-16.1] on TT studies, and 6.9 [5.8-8.2] and 14.6 [13.2-16.8], on ST, for PFS and OS, respectively, without statistically significant difference (p=0.39 and 0.55). The heterogeneity among specific toxicities and survival endpoints may be partially explained by the study design and/or the intake or not of temozolomide. Conclusions: The use of TT combined to RT represented a significative increase in severe adverse events in patients with GBM compared to ST, whereas no significant difference was observed in survival endpoints. Grants from French Cancer League.
EUFORIA study (Eribulin Use for the Treatment of Advanced Breast Cancer: Observational, Retrospective Analysis): Initial experience with eribulin in daily clinical practice in Spain.
Authors: Manuel Ruiz-Borrego, José Ángel Garcia Saenz, Javier Hornedo, Luis Manso, Isabel Calvo, Juan Lao, Antonio González-Martín, Margarita Feijoo, Jesús Florián Gericó, Serafin Morales, Jose J. Illarramendi, Valero Pedro Jimenez, Javier Sánchez-Jiménez, Cesar Augusto Rodriguez, Pedro Sánchez-Rovira, Francisco Ayala, Isabel Alvarez, Juan Antonio Virizuela, Rafael Lopez, Julio Rodríguez-Villanueva
Journal: Journal of Clinical Oncology (2013)

e12015 Background: Spanish MoH authorized eribulin in 04/2011 for use in patients as per license. Pending reimbursement, public hospitals used it through a national compassionate use program. After 1 year, we analyzed the pre-specified patient selection criteria and eribulin efficacy and safety results in a representative sample to confirm whether real world use matched the data from the pivotal phase III study. Methods: An observational, retrospective analysis was proposed to the top 20 hospitals by eribulin use, with at least 3 candidate patients who had/could have received ≥3 cycles of treatment by 03/2012. Patient and disease characteristics, as well as efficacy and safety parameters were obtained. Patient´s data were collected until September 2012. Living patients able to respond at the time of the study signed an informed consent. Study was approved by ethics committees. Results: Out of 112 screened ABC patients in 19 participating hospitals, 104 were enrolled. Median age was 56.6 years and 66% were post-menopausal. Visceral disease occurred in 2/3 of patients. ECOG status was ≤1 in 75,4% of patients. Estrogen receptor expression was found in 64.4% of tumors; 15.4% overexpressed HER2. 49% of patients received 1-5 treatment lines for ABC before eribulin. Mean eribulin treatment duration was 3 months (4,7 cycles). Disease control rate was 48.8% (1.1% CR, 22.1% PR, 25.6% SD). By 09/2012, 64,4% patients were still alive and median PFS was 97 days (95% IC: 81-129). 78.8% of patients reported ≥1 adverse events, being asthenia, neutropenia, anemia, alopecia, nauseas, and mucositis the most frequent ones (≥10%). Grade ≥3 adverse events occurred in ≤5% of patients. Conclusions: The favorable efficacy and safety profile of eribulin observed in this observational study is consistent with the pivotal phase III study (EMBRACE) and confirms its position for the treatment of ABC. Pre reimbursement usage has been restricted to later lines but use per the licensed indication in 3L is expected to yield additional clinical benefit. A confirmatory observational study (EUFORIA-2) is planned.
The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2 diabetes.
Journal: Diabetes Care (1999)

The Diabetes Prevention Program is a randomized clinical trial testing strategies to prevent or delay the development of type 2 diabetes in high-risk individuals with elevated fasting plasma glucose concentrations and impaired glucose tolerance. The 27 clinical centers in the U.S. are recruiting at least 3,000 participants of both sexes, approximately 50% of whom are minority patients and 20% of whom are > or = 65 years old, to be assigned at random to one of three intervention groups: an intensive lifestyle intervention focusing on a healthy diet and exercise and two masked medication treatment groups--metformin or placebo--combined with standard diet and exercise recommendations. Participants are being recruited during a 2 2/3-year period, and all will be followed for an additional 3 1/3 to 5 years after the close of recruitment to a common closing date in 2002. The primary outcome is the development of diabetes, diagnosed by fasting or post-challenge plasma glucose concentrations meeting the 1997 American Diabetes Association criteria. The 3,000 participants will provide 90% power to detect a 33% reduction in an expected diabetes incidence rate of at least 6.5% per year in the placebo group. Secondary outcomes include cardiovascular disease and its risk factors; changes in glycemia, beta-cell function, insulin sensitivity, obesity, diet, physical activity, and health-related quality of life; and occurrence of adverse events. A fourth treatment group--troglitazone combined with standard diet and exercise recommendations--was included initially but discontinued because of the liver toxicity of the drug. This randomized clinical trial will test the possibility of preventing or delaying the onset of type 2 diabetes in individuals at high risk.
Phase I/II trial of intravenous OV001 oncolytic virus in resistant glioblastoma multiforme (GBM)
Authors: A. I. Freeman, J. M. Gomori, E. Linetsky, Z. Zakay-Rones, A. Panet, E. Libson, C. S. Irving, E. Galun, T. Siegal
Journal: Journal of Clinical Oncology (2004)

1515 Background: OV001 (NDV HUJ) is an oncolytic, non-engineered, lentogenic strain of Newcastle Disease Virus (NDV). Following preclinical repetitive dosing toxicity studies, a Phase I/II trial was initiated in GBM determining safety and imaging response. Methods: Patients (11–58yrs, KPS 50–90%) with primary glioblastoma were enrolled 17–49 wks following diagnosis and failure of previous therapy. The first part of the study used an intra-patient dose escalation method with one cycle dosage steps of 0.1, 0.5, 1, 5 and 10 BIU units of OV001 (1 BIU = 1x109 EID50, 50% egg infectious dose). One cycle consisted of 15 min IV infusions on each of 5 consecutive days over a period of 7 d (<1BIU) or 14 d (>=1BIU). Patient reaching 10 BIU received 3 additional cycles of 50 BIU. Patients enrolled in the second part received three cycles of 10 BIU. Patients without progressive disease were maintained with 2 doses of 10 BIU IV weekly. Results: In Phase I, 4/6 patients completed all 3 cycles of 50 BIU of OV001; in the Phase II part, as of Dec 01, 2003, 3/4 patients in Phase II part completed all 3 cycles of 10 BIU. Grade I/II constitutional fever was seen in 5 patients and was the only adverse event related to OV001 administration. MTD was not reached. Patients that did not complete dosing were withdrawn due to disease progression. All tested patients developed anti-NDV hemagglutinin antibodies after 7–14 days. NDV was recovered from one tumor biopsy. One patient has a continuing near complete response 30 weeks after start of dosing. A second patient maintained stable disease between 16–26 weeks. Conclusions: Intravenous OV001 is well tolerated and most excitingly a near complete response provides proof of concept of its therapeutic potential. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OVCure (Israel) Ltd. OVCure (Israel) Ltd. OVCure, Inc. OVCure (Israel) Ltd.
Patient-reported outcomes data from a phase 2 study of idelalisib in patients with refractory indolent B-cell non-Hodgkin lymphoma (iNHL).
Authors: Nina D. Wagner-Johnston, Ajay K. Gopal, Brad S. Kahl, Sven De Vos, Stephen J. Schuster, Wojciech Jurczak, Ian Flinn, Christopher Flowers, Peter Martin, Andreas Viardot, Kristie A. Blum, Andre Goy, Andrew John Davies, Pier Luigi Zinzani, Martin H. Dreyling, Lynne I. Wagner, Bess Sorensen, Wayne Russell Godfrey, Gilles A. Salles
Journal: Journal of Clinical Oncology (2014)

e19554 Background: Idelalisib, a selective oral inhibitor of PI3Kδ, demonstrated considerable anti-tumor activity in patients with relapsed/refractory iNHL in a phase 2 trial (Gopal, 2014). The purpose of this analysis was to evaluate patient-reported outcomes (PRO) data to determine whether drug treatment was associated with a change in health-related quality of life (HRQL). Methods: Eligible iNHL patients (pts) were refractory to both rituximab and an alkylating agent. Idelalisib 150 mg PO BID was administered continuously until disease progression. HRQL was measured by the 42-item Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym), comprising FACT-G subscales: Physical Well-being (PWB), Social/Family Well-being (SWB), Emotional Well-being (EWB), Functional Well-being (FWB), and the Lymphoma Subscale (LymS). Trial Outcome Index (TOI) is PWB + FWB + LymS. Higher scores reflect better HRQL. Minimally important differences (MID) on the FACT-G ranged 3-7 points (2-5 points for subscales). The FACT-Lym was administered every 4 weeks (0-24), then every 6 weeks (30-48), and at week 60. Change from baseline in FACT-Lym was analyzed. Results: Enrolled pts (N = 125) had a median age of 64 years [range 33-87] and were 64% male. With a median follow up 9.4 months, overall response rate (ORR) is 57% (95% CI = 47.6, 65.6) and median DOR is 12.5 months. Median PFS for all pts is 11.0 months. Improvements were noted in the FACT-G, FACT-Lym, and TOI scores during the study, progressively increasing with time. In FACT-G subscales, improvements were noted by 4 weeks for EWB scores. The median best changes from baseline for the FACT-G, FACT-Lym, and TOI total scores were 5.0, 8.3, and 6.0, respectively. LymS change scores exceeded the MID for ≥ 90% of pts indicating a clinically significant improvement in lymphoma-related concerns at some point in the study. The median best change from baseline for the LymS was 5.0 and median time to improvement was 1.9 months. Conclusions: PRO data indicate that clinically significant improvements in HRQL, including lymphoma-related concerns, were noted for most patients. Clinical trial information: NCT01282424.
Development and validation of a predictive model to assess an individual's risk of pancreatic cancer.
Authors: Byung-Ho Nam, Ami Yu, Sang Myung Woo, Hye-Ryung Yang, Jungnam Joo, Woo Jin Lee, Sang Jae Park
Journal: Journal of Clinical Oncology (2013)

4045 Background: Due to the very low survival of pancreatic cancer (PC), early detection is a critical strategy to improve the outcome of PC.Screening individuals with genetic syndromes associated with a high incidence of PC or families predisposed to PC is increasing. However, those populations account for only 10% of all PC cases. A different approach for developing an effective surveillance tool is needed to identify high-risk individuals without hereditary risks. The goal of this study was to develop and validate risk prediction models for filtering purposes as part of the sporadic PC surveillance activities. Methods: Based on an eight-year follow-up of a cohort study involving 1,289,933 men and 557,701 women in Korea who had biennial examinations in 1996-1997, gender-specific risk prediction models were developed using the Cox proportional hazards model. The models were validated using independent data of 500,046 men and 627,629 women who had biennial examinations in 1998-1999. The models’ performance was evaluated with respect to their discrimination and calibration abilities based on the C-statistic and the Hosmer-Lemeshow (H-L) type χ 2 -statistic. Results: Age, height, BMI, fasting glucose, urine glucose, smoking, and age at smoking initiation were included in the model for men. In the model for women, height, BMI, fasting glucose, urine glucose, smoking, and drinking habits were included. Smoking was the most significant risk factor for developing pancreatic cancer in both men and women. Model validation showed excellent model performance with C-statistics (95% confidence interval) of 0.813 (0.800−0.826) and 0.804 (0.788−0.820) for men and women, respectively. The H-L type χ 2 -statistics (P-values) were 7.478 (0.587) and 10.297 (0.327) for men and women, respectively. Five different risk groups could be identified with hazard ratios (HR) greater than 20 in the highest risk group compared to the lowest risk group in both the men and women. Conclusions: Gender-specific individualized risk prediction models for PC were developed and validated with a high level of performance. These models can be used to identify high-risk individuals who may benefit from increased surveillance of PC.
Pioglitazone as a candidate chemoprevention agent for lung cancer: A pilot window trial in early stage NSCLC.
Authors: Dennis A. Wigle, Sumithra J. Mandrekar, Katie Allen-Ziegler, Yaron Gesthalter, Paul Holland, Marie-Christine Aubry, Paul J. Limburg, Spira Avi, Eva Szabo
Journal: Journal of Clinical Oncology (2014)

1581 Background: Multiple lines of evidence support the use of PPARγ ligands in the treatment and prevention of lung cancer. Pioglitazone is a PPARγ ligand that is FDA-approved for type-II diabetes mellitus, and used by millions of diabetic patients worldwide. We evaluated pioglitazone as a candidate chemo-preventive agent for NSCLC by investigating the effects on Ki-67 in NSCLC tumor tissue using a pilot window trial design. Methods: Patients with known or suspected stage IA-IIIA NSCLC who were current or former smokers with a ≥ 10 pack-year smoking history were enrolled. Patients underwent fluorescence bronchoscopy with targeted biopsies (normal, suspicious/dysplastic areas) bronchial brushings, and additional tumor sampling to asses Ki67 staining. Patients also underwent a pre-treatment PET scan, followed by pioglitazone, 45 mg once/day for 14-42 days prior to surgical resection. Ki67 staining along with other secondary biomarker endpoints were assessed in repeat bronchoscopy and surgical resection specimens after pioglitazone treatment. Results: Of the 10 pre-registered participants, 3 did not have biopsy-confirmed NSCLC and 1 had metastatic NSCLC; a total of 6 participants received pioglitazone. Mean age 64.0 years, 5 males, 1 female; with 2nadenocarcinomas, 3 squamous cell carcinomas, and 1 mixed adenosquamous tumor. Median %change in Ki67 staining in the primary tumor of the 5 eligible participants (1 participant excluded with a solitary non-lung cancer metastasis) was -20% (p=0.06), with all patients having a reduction in Ki67 post-intervention. Gene expression analysis of histologically normal bronchial airway epithelium pre- and post-pioglitazone treatment revealed a number of upregulated genes enriched for complement activation and chemokine signaling (GSEA p <0.05). Genes that were repressed were related to inflammatory and B cell survival pathways (GSEA p<0.05). Conclusions: These preliminary data are suggestive of a potential effect for pioglitazone in early stage NSCLC, despite the small sample size. These results need to be confirmed in a larger cohort of patients. Clinical trial information: NCT01342770.
The GALAXY Trial(NCT01348126): A randomized IIB/III study of ganetespib (STA-9090) in combination with docetaxel versus docetaxel alone in subjects with stage IIIB or IV NSCLC.
Authors: Glenwood D. Goss, Christian Manegold, Rafael Rosell, Dean Anthony Fennell, Vojislav M. Vukovic, Iman El-Hariry, Florentina Teofilovici, Aaron S. Enke, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2012)

TPS7613^ Background: Hsp90 is a molecular chaperone required for proper folding and activation of many cancer-promoting proteins and is recognized as a key facilitator of cancer cell growth and survival. In pre-clinical models, Hsp90 inhibition causes degradation of multiple client proteins and leads to cancer cell death. Ganetespib is a resorcinolic Hsp90 inhibitor that has shown potent anti-tumor activity in patients with lung, breast, and other cancers that had progressed on standard treatment agents. Moreover, combination of ganetespib with docetaxel results in synergistic antiproliferative effects in several human non-small cell lung carcinoma (NSCLC) tumor xenografts. Ganetespib is well tolerated and is devoid of severe liver or common ocular toxicities that have been observed with some other Hsp90 inhibitors. Diarrhea is the most common adverse event and is manageable with appropriate supportive care. In a recent report, ganetespib administered at 200 mg/m 2 weekly showed activity in pretreated patients with advanced NSCLC patients with ELM4-ALK translocation and KRAS mutations. Methods: Stage 1 (240 subjects): randomized, international open-label Phase 2B study in subjects that progressed on or after one prior systemic therapy for stage IIIB or IV NSCLC: patients are prospectively stratified for ECOG performance status, histology, total LDH, interval since diagnosis, and smoking status. Co-primary endpoints are PFS in the ITT population, and PFS in patients with KRAS mutations. Main secondary endpoints include ORR, disease control rate, OS and clinical activity in different molecular subtypes, including BRAF, HER2, EGFR, EML4-ALK. Patients on the control arm are treated with docetaxel 75 mg/m 2 on day 1 of a three-week cycle. In the combination arm, ganetespib 150 mg/m 2 is given on day 1 (with docetaxel) and day 15 of a three-week cycle. At the time of submission 90 subjects had been enrolled in Stage 1.
The addition of bevacizumab to temozolomide and radiation therapy followed by bevacizumab, temozolomide, and oral topotecan for newly diagnosed glioblastoma multiforme (GBM).
Authors: Henry S. Friedman, Annick Desjardins, Katherine B. Peters, David A. Reardon, John Kirkpatrick, James Emmett Herndon, April D. Coan, Leighann Bailey, John Howard Sampson, Allan H. Friedman, James J Vredenburgh
Journal: Journal of Clinical Oncology (2012)

2090^ Background: The prognosis for newly-diagnosed GBM is dismal. The addition of temozolomide to radiation therapy improved the median overall survival (OS) to 14.6 months (mos). GBM’s have the highest levels of vascular endothelial growth factor (VEGF). Hypoxia inducing factor-1 alpha (HIF-1 alpha) is an important regulator of VEGF, and topotecan may inhibit HIF-1 alpha. Methods: We performed a phase II trial in newly diagnosed GBM by adding bevacizumab and topotecan to standard therapy. 80 newly diagnosed GBM patients were enrolled between January 2010 and January 2011. Patients received standard radiation therapy and temozolomide. Bevacizumab at 10 mg/kg every 14 days was added a minimum of 4 weeks post-op. Two weeks after radiation therapy was completed, 12 monthly cycles of temozolomide at 150 mg/m 2 /d days 1-5, oral topotecan at 1.5 mg/m 2 for patients not on an enzyme inducing anti-epileptic drug (EIAED) and 2.0 mg/m 2 for patients on an EIAED days 2-6, and bevacizumab at 10 mg/kg on days 1 and 15. Results: The addition of bevacizumab to standard radiation therapy and daily temozolomide was safe. Of the 80 patients, 76 completed radiation therapy. Four patients did not complete radiation, two with clinical decline, one each with a bone flap infection, and a pulmonary embolus. Fifteen patients came off study for toxicity, five with recurrent grade IV thrombocytopenia, three with grade III fatigue, two each with grade 2 CNS hemorrhage, and wound dehiscence requiring surgery and one each with GI perforation, pulmonary embolism and an aortic thrombus. Of the 80 patients, 56 have progressed and 37 have died. The median progression-free survival (PFS) and OS are 11.1 mos (95% CI: 9.4-13.6) and 17.2 mos (95% CI: 15.2) at a median follow-up of 18.4 months. The two year OS is 45.3%. Conclusions: The addition of bevacizumab to temozolomide and radiation followed by temozolomide, bevacizumab and oral topotecan is tolerable. The median PFS and OS are encouraging. The randomized phase III trials with bevacizumab for newly diagnosed GBM patients are essential.