tbuckley/cabot-search huggingface dataset:
Targeting Aggregation of Wilde-Type p53 and Mutant p53 with ReACp53 As a Novel Therapeutic Concept for AML
Authors: Jianfang Zeng, Alice Soragni, Jo Ishizawa, Vivian Ruvolo, Christopher B. Benton, Teresa McQueen, Peter Ruvolo, Yuan Qi, Xiaoping Su, Jared Burks, David S. Eisenberg, Michael Andreeff
Journal: Blood (2016)
Correlation between phase 2 clinical trial design and subsequent phase 3 outcome.
Authors: Annette E. Hay, Jose Gerard Monzon, Gail T McDonald, Joseph L Pater, Ralph M. Meyer, Eric Xueyu Chen, Bingshu E. Chen, Janet Dancey
Journal: Journal of Clinical Oncology (2014)

2549 Background: Randomized phase 2 (RP2) trials have been postulated to better predict phase 3 (P3) outcome than single arm trials. The aim of this study was to determine which characteristics of P2 trials that led to the conduct of P3 trials are associated with a positive P3 outcome. Methods: Randomized P3 trials testing systemic therapy in patients with malignancy, published in English from 2007 to 2012, were identified through a Medline search. Those of superiority design which cited P2 trials contributing to development of the experimental arm were included. Detailed information regarding design and outcome of P2 and P3 trials was extracted in duplicate. Discrepancies were adjudicated by a third investigator. Positivity was defined as statistical difference between arms for primary endpoint in P3. P2 trials reporting that a pre-stated numeric or statistical target had been met were deemed positive. Statistical analysis was performed using the Generalized Estimating Equation model correlating P2 features with P3 outcome, accounting for any P3 duplication. Results: Of 189 eligible P3 trials 19% were in hematologic malignancies and 81% in solid tumors. The primary outcome was positive in 79 (42%). These were supported by 336 P2 trials (range 1 - 9 per P3 trial); 66 of which were RP2s (29 selection, 21 control, 3 discontinuation, 7 phase 2/3 and a combination of these in 6). RP2 trials were not associated with P3 positivity (see Table, p = 0.44). Positive P2 outcome correlated with positive P3 outcome (p = 0.031). P2 trial features found not to be predictive of P3 outcome included primary endpoint, sponsorship, sample size, similarity in patient population and therapy. Conclusions: We did not find RP2 more predictive than single arm trials. When designing P2 trials consideration should be given to the increased resources required to conduct RP2 studies and anticipated gain for a given disease. 336 phase 2 trials 66 randomized phase 2 270 single-arm phase 2 35 positive 31 not positive* 102 positive 168 not positive* P3 positive P3 negative P3 positive P3 negative P3 positive P3 negative P3 positive P3 negative 14 (40%) 21 (60%) 8 (26%) 23 (74%) 50 (49%) 52 (51%) 61 (36%) 107 (64%) * Numeric or statistical target not stated or not met.
EPAZ: A randomized phase II trial comparing pazopanib with doxorubicin as first line treatment in elderly patients with metastatic or advanced soft tissue sarcoma of the Working Group Medical Oncology (AIO) and German Interdisciplinary Sarcoma Group (GISG).
Authors: Viktor Gruenwald, Annegret Kunitz, Markus Kajo Schuler, Hans-Georg Kopp, Bernd Kasper, Lars Lindner, Jens-Marcus Chemnitz, Alexander Stein, Patrick Schöffski, Bjoern Steffen, Sebastian Bauer, Gerlinde Egerer, Michael Kneba, Martina Crysandt, Armin Koch
Journal: Journal of Clinical Oncology (2015)

TPS10576 Background: 1/3 of STS patients are 60 years and older. Single agent doxorubicin is the mainstay of therapy in metastatic disease, which is frequently associated with hematological toxicity (grade 4 neutropenia in 34%; febrile neutropenia in 9%). We assume that comorbidities in the elderly population may limit tolerability of doxorubicin and novel agents may improve health-related quality of life (HR-QoL), while maintaining efficacy. Methods: This is a randomized, open-label, multicenter phase II study that compares pazopanib 800 mg OD to doxorubicin 75 mg/m2as first line treatment in elderly patients with metastatic or advanced STS (NCT01861951). A total of 120 patients will be recruited and randomized 2:1 to receive either pazopanib or doxorubicin, stratified by performance status (0-1 vs. 2) and histological subtype. HR-QoL (QLQ-C30) and comprehensive geriatric assessment (elderly minimal dataset of EORTC ETF) is determined throughout the course of the study, in order to assess the impact of treatment on the patient’s quality of life and daily living. Key inclusion criteria: age ≥ 60 years; progressive intermediate or high grade STS; ECOG PS 0-2; measurable disease (RECIST 1.1); availability of archived STS tissue; adequate organ function; no prior therapy for metastatic disease. Primary endpoint: Progression free survival (PFS) based on local tumor assessment according to RECIST 1.1. Key secondary endpoints include the incidence of grade 4 neutropenia and febrile neutropenia. For the latter endpoints, sensitivity analyses will be conducted to adjust for primary prophylaxis of granulocytopenia or febrile neutropenia. Other secondary endpoints include: HR-QoL, geriatric assessment, safety and tolerability, overall survival, objective response rate, PFS rate at 12 and 26 weeks, time to onset of response, and predictive biomarkers. The first patient was randomized on October 12, 2012. Currently, a total of 85 patients have been randomized. Clinical trial information: NCT01861951.
Tolerability, humoral immune response, and disease control in phase 1 patients receiving ONT-10, a MUC1 liposomal vaccine.
Authors: John J. Nemunaitis, Ned Adams, Cindi Bedell, Kevin Klucher, Janelle Taylor, Samuel H. Whiting
Journal: Journal of Clinical Oncology (2014)

3091 Background: MUC1 is a high molecular weight glycoprotein overexpressed and aberrantly glycosylated in many cancers. ONT-10, a liposomal vaccine incorporating a synthetic glycolipopeptide MUC1 antigen and the novel synthetic toll-like receptor 4 agonist PET Lipid A, induces strong anti-MUC1 humoral and cellular responses in preclinical models. Methods: This phase 1 study is evaluating ONT-10 safety, immune response, and antitumor activity. Pts with end-stage solid tumors associated with MUC1 expression are eligible. Cyclophosphamide 250 mg/m2IV is given on day -3 followed by ONT-10 (250, 500, 1000, or 2000 µg) SC day 1 and then Q2W for 4 doses or QW for 8 doses using a 3+3 design. Humoral immune response is assessed by ELISA for MUC1 specific antibodies (Ab) and cellular by ELISPOT for MUC1 specific IFN-γ. Tumor response is per RECIST 1.1 and irRC. Pts without progressive disease at week 12 can receive maintenance ONT-10 every 6 weeks Results: 42 pts have been treated: ovarian (n=13), breast (n=6), colorectal (n=6), pancreatic (n=5), endometrial (n=4), lung (n=4), other (n=4), all ECOG 0/1. Median age 62 (35-77); median prior therapies 4 (1-11). There have been no DLTs. All treatment-related AEs have been Grade 1-2, the most common, fatigue (26%) and injection site reactions (16%). MUC1 specific Ab have been seen in the majority of pts at titers up to > 51,200, with the highest IgG responses seen at the higher-dose QW schedules. Cellular analysis is ongoing. Best tumor response has been SD in 23/34 evaluable pts (68%); 12 pts to date have been progression free for > 6 mo (6.4 – 21+ mo). 2 pts with ovarian cancer have had reduced tumor volume (16% at week 9 and 44% at week 34, respectively). 22/36 (61%) eligible pts have gone to maintenance ONT-10. Conclusions: ONT-10 has been well tolerated at all doses with no DLTs. Humoral responses have been seen in most pts, with an apparent dose response for IgG on the QW schedule. Encouraging disease control has been seen with SD in 68% of pts, of whom over half have been progression free for > 6 mo. Clinical trial information: NCT01556789.
Risk factors for development of delayed urticarial reactions in the phase II trial of HER2 peptide vaccines plus GM-CSF versus GM-CSF alone in high-risk breast cancer patients to prevent recurrence.
Authors: Alfred F Trappey, John S. Berry, Timothy J Vreeland, Diane F. Hale, Alan K. Sears, Sathibalan Ponniah, Sonia A. Perez, Guy T. Clifton, Michael Papamichail, Nathan M. Shumway, Elizabeth Ann Mittendorf, George Earl Peoples
Journal: Journal of Clinical Oncology (2013)

3097 Background: We are monitoring the incidence of delayed urticarial reactions (DURs) in our phase II trial evaluating adjuvant HER2-specific vaccines (AE37 and GP2) for the prevention of breast cancer recurrence. Here, we characterize DURs and analyze risk factors for their development. Methods: After completion of standard of care therapy, disease-free node-positive or high-risk node-negative patients (pts) were randomized to receive either a peptide+GM-CSF (VG) or GM-CSF (CG). Pts receive 6 monthly intradermal inoculations during the primary vaccine series (PVS) then four boosters (B) every 6 mos. Immune response is measured by delayed type hypersensitivity (DTH) pre- (R0) and post-PVS (R6) and local reaction (LR) at R1 – R6. Results: Twenty-four (6.1%) of 393 initiated patients report a DUR; 13 VG (vDUR), and 11 CG (cDUR); vDUR - 9 AE37, 4 GP2. Time to onset of symptoms is 9±5 days (d) and is similar in vDUR/cDUR (p = 0.27). DURs manifest as hives/pruritis in all patients. Average duration of symptoms is 32.6 d ± 8.8 d (no difference in vDUR/cDUR [p = 0.23]). Episodes have resolved with antihistamines or IV/oral steroids. Ten (4 cDUR, 6 vDUR) patients have had recurrent episodes that have resolved similarly. 75% of first episodes occur between R6-B3. For DUR patients v. those who have not had a DUR (noDUR), there are no differences in demographics. DTH response is similar in vDUR pts v. noDUR VG pts (R0- p = 0.34; R6- p=0.40). cDUR pts had a greater DTH response v. CG noDUR pts at R6 (13.2 v 4.7 mm, p=0.01). LRs are greater in DUR pts compared to noDUR pts after the second vaccination (R2 – 66.2 v 48.2 mm, p=0.02). LR for DUR pts decrease and are less than noDUR at R6 (45.4 v 57.4 mm, p=0.09). Relative risk for developing DUR for LR &gt; 100 mm at R2 is 3.49 (1.58-7.68, 95% CI [p=0.004]). At 29.9 months median follow-up, there have been no recurrences in VG and CG DUR v. 75.9% DFS for noDUR (p=0.05). Conclusions: DURs occur infrequently and without long-term sequelae. Pts at risk for developing DUR are identified early in the vaccine series using LR. Robust immune response in DUR may explain the survival benefit demonstrated here. Clinical trial information: NCT00524277.
Decline of cognitive functions among elderly localized breast cancer patients after adjuvant treatment: COG-AGE study.
Authors: Florence Joly, Marie Lange, Benedicte Giffard, Sabine Noal, Aurelie Capel, Chantal Rieux, Johan Le Fel, Olivier Rigal, Jean-Emmanuel Kurtz, Christelle Levy, Djelila Allouache, Corinne Veyret, Philippe Barthelemy, Nadine Longato, Benedicte Clarisse, Francis Eustache, Natacha Heutte
Journal: Journal of Clinical Oncology (2014)

9509 Background: Cognitive deficits (CD) have been reported among patients receiving chemotherapy (CT) for cancer.Despite their increased propensity for age-related CD that may worsen during CT, elderly patients have been poorly studied. We assessed the impact of adjuvant treatment as compared to objective and subjective cognitive functions at baseline among elderly localized breast cancer (LBC). Methods: Women >65 years-old with LBC were recruited and compared to a sample of healthy women matched on age and education. Episodic and working memories, executive functions and information processing speed were assessed with neuropsychological tests at baseline and at the end of adjuvant treatment (or at the same interval for healthy women). Questionnaires were used to assess subjective CD, anxiety, depression and fatigue. Geriatric assessment was also performed. Longitudinal neuropsychological scores were analysed with Reliable Change Index of Iverson to control practice effects. Results: Concern 119 elderly LBC (71±4 years) (58 received CT and 61 received only radiotherapy (RT)), and 62 healthy women (71±5 years). Patient characteristics are: mastectomy (28%), stage (I-II: 87%), positive hormonal receptor (88%), positive Her2 (17%); and Activities Daily Living (ADL) and Instrumental ADL means were 6(±0.09) and 0.24(±0.79). After adjuvant treatment, 49% of patients had objective cognitive decline compared to the performances of the healthy women. The main objective CD concerned working and verbal episodic memories (25% and 15%, respectively). No significant difference on CD was observed between CT and RT groups. Only patients treated with CT developed more cognitive and quality of life complaints and fatigue than healthy women (p=0.002, p=0.04 and p=0.008). Conclusions: This is the first large longitudinal study assessing cognitive function after adjuvant treatment in elderly LBC patients. Patients are more at risk to develop objective cognitive impairments during treatment than healthy women. Cognitive and quality of life complaints and fatigue were mainly reported among patients after CT. However we did not find deleterious impact of CT on objective cognitive functions.
Nivolumab dose escalation and expansion in patients with advanced hepatocellular carcinoma (HCC): The CheckMate 040 study.
Authors: Ignacio Melero, Bruno Sangro, Thomas Cheung Yau, Chiun Hsu, Masatoshi Kudo, Todd S. Crocenzi, Tae-You Kim, SuPin Choo, Jorg Trojan, Tim Meyer, Theodore Hobart Welling, Winnie Yeo, Akhil Chopra, Jeffrey Anderson, Christine Marie Dela Cruz, Lixin Lang, Jaclyn Neely, Hao Tang, Anthony El-Khoueiry
Journal: Journal of Clinical Oncology (2017)

226 Background: HCC diagnosed at advanced stages has a poor prognosis. Patients who progress on sorafenib have few options. Nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), has demonstrated clinical and survival benefit in a number of tumor types. Here we report updated interim analyses of safety, efficacy, and exploratory biomarkers in patients with advanced HCC treated with nivolumab in the CheckMate 040 study (NCT01658878). Methods: Patients enrolled had advanced HCC with or without hepatitis C or B virus (HCV or HBV) infection. Prior sorafenib was allowed. Phase 1 dose-escalation evaluated nivolumab (0.1–10 mg/kg) Q2W. Phase 2 dose-expansion was initiated in 4 cohorts: sorafenib naïve/intolerant, sorafenib progressors, HCV infected, and HBV infected. All cohorts received nivolumab 3 mg/kg Q2W. The primary endpoint in the dose-escalation phase was safety/tolerability, and the primary endpoint in the dose-expansion phase was objective response rate (ORR) by RECIST v1.1 (central review). Secondary endpoints included duration of response (DOR), disease control rate (DCR), and overall survival (OS). Biomarkers within pre-treatment tumors were assessed. Results: Across dose escalation and expansion phases, 262 patients have been treated. Grade 3/4 treatment-related adverse events occurred in 20%. No maximum tolerated dose was reached during dose escalation (n = 48). The ORR (investigator-assessed) was 20% (95% CI 15–26) in 214 patients treated in the dose expansion phase with a median DoR of 9.9 months; DCR was 64% (95% CI 58–71). Responses were observed across etiologies and regardless of tumor PD-L1 expression. ORRs of 23% (95% CI 13–36) and 21% (95% CI 11–34) were observed in the uninfected sorafenib-naive and -treated patients, respectively. The 9-month overall survival rate in the expansion phase was 74% (95% CI 67–79). Association between immune-cell biomarkers and clinical outcomes will be presented. Conclusions: In this heavily pretreated population, responses to nivolumab were durable with encouraging overall survival. Safety was manageable and consistent with that observed in other solid tumors with no new safety signals. Clinical trial information: NCT01658878.
Contents Vol. 78, 2009
Authors: Cheryl A. Cockram, Gheorghe Doros, John M. de Figueiredo, Thomas Karger, Nicoletta Sonino, Pio Peruzzi, Piero Porcelli, Antonello Bellomo, Roberto Quartesan, Mario Altamura, Salvatore Iuso, Ida Ciannameo, Massimiliano Piselli, Sandro Elisei, Giovanni A. Fava, Thomas N. Wise, Palmiero Monteleone, Cristina Serritella, Valter Milano, Arcangelo Di Cerbo, Francesco Blasi, Claudio Petrella, Mario Maj, Giovanni Nolfe, K. Domschke, Mark B. Powers, Paul M.G. Emmelkamp, John S. Ogrodniczuk, William E. Piper, Anthony S. Joyce, Allan A. Abbass, Michael Levin, Steven C. Hayes, Elisa Albieri, Dalila Visani, Emanuela Offidani, Fedra Ottolini, Chiara Ruini, Andrew A. Nierenberg, Diane Warden, Madhukar H. Trivedi, Stephen R. Wisniewski, Ira M. Lesser, Jeff Mitchell, G.K. Balasubramani, Maurizio Fava, Kathy Shores-Wilson, Diane Stegman, A. John Rush, R. Berger, M. Gelkopf, K. Pohle, T. Roehrs, V. Arolt, B.T. Baune, Raluca A. Topciu, Xi Zhao, Wan Tang, Marnin J. Heisel, Nancy L. Talbot, Paul R. Duberstein, M. Pasquini, L. Tarsitani, D. Piacentino, G. Moretti, C. Roscioli, C. Leone, M. Biondi
Journal: Psychotherapy and Psychosomatics (2009)
Enzalutamide (ENZA) in men with chemotherapy-Naïve metastatic castration-resistant prostate cancer (mCRPC): Final analysis of the phase 3 PREVAIL study.
Authors: Tomasz M. Beer, Andrew J. Armstrong, Cora N. Sternberg, Celestia S. Higano, Dana E. Rathkopf, Yohann Loriot, Fred Saad, Anthony M. Joshua, Johann Sebastian De Bono, Peter M. Venner, Joan Carles, Paul N. Mainwaring, Christopher P. Evans, Teresa Parli, Harry H. Mansbach, Suman Bhattacharya, Steve Van Os, De Phung, Bertrand F. TOMBAL
Journal: Journal of Clinical Oncology (2015)

5036 Background: PREVAIL (NCT01212991) was a phase 3 trial that investigated the impact of ENZA vs placebo (PBO) on overall survival (OS) and radiographic progression-free survival (rPFS) in asymptomatic or mildly symptomatic chemotherapy-naïve men with mCRPC. ENZA improved OS (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.60–0.84; P < 0.0001) and rPFS (HR 0.19; 95% CI 0.15–0.23; P < 0.0001) in a planned interim analysis after 540 deaths (Sep 16, 2013, data cutoff). On the basis of these results, ENZA was approved for chemotherapy-naïve mCRPC in the US and Europe. Final OS analysis was planned after at least 765 deaths. Methods: Patients (pts) were randomized 1:1 to ENZA 160 mg/day or PBO. OS and rPFS were coprimary endpoints and analyzed in the intent-to-treat population. Planned sample size was 1680 with at least 765 deaths to achieve 80% power to detect a target OS HR of 0.815, with a type I error rate of 0.049 and a single interim analysis. After the interim analysis, eligible PBO pts had the option to crossover to ENZA. All pts were followed in an open-label extension protocol. rPFS was determined by investigator review. The final OS and rPFS results reported here are from Jun 1, 2014, and Jan 15, 2014, data cutoff dates, respectively. Results: 1717 men were randomized (1715 treated) between Sep 2010 and Sep 2012. The final analysis at 784 deaths with a median follow-up of 31 months (mo) confirmed the OS benefits of ENZA with a 23% reduction in risk of death (HR 0.77; 95% CI 0.67–0.88; P = 0.0002) and a 4-mo improvement in median OS (35.3 mo [95% CI 32.2–NYR]) vs 31.3 mo [95% CI 28.8–34.2]). 42% of ENZA and 49% of PBO pts had died; 52% of ENZA and 81% of PBO pts (including 167 pts who crossed over to ENZA) received ≥ 1 subsequent life-extending prostate cancer therapy. A preliminary analysis of rPFS from the Jan 15, 2014, data cutoff showed a significant improvement with ENZA (HR 0.32; 95% CI 0.28–0.36; P < 0.0001). Median rPFS was 20.0 mo (95% CI 18.2–22.1) with ENZA vs 5.4 mo (95% CI 4.2–5.6) with PBO. Conclusions: With longer follow up time, ENZA continued to demonstrate a robust improvement in OS and rPFS in asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC. Clinical trial information: NCT01212991.
Use of DNA repair proteins translated from biomarker screening to predict overall survival in patients with esophageal cancer treated with oxaliplatin chemotherapy.
Authors: Ricky A Sharma, Tom Macgregor, Richard Gillies, Stephanie Hatch, Lonnie Swift, TIM Humphrey, Runjan Chetty, Peter J McHugh, Mark R. Middleton
Journal: Journal of Clinical Oncology (2012)

e13587 Background: Oxaliplatin is first-line chemotherapy for colorectal, gastric, and esophageal cancers. Aim was to identify key determinants of oxaliplatin sensitivity and optimise these biomarkers to select patients for chemotherapy. Methods: High-throughput screening of oxaliplatin sensitivity was performed in a Schizosaccharomyces pombe deletion library of 229 DNA repair strains and Chinese Hamster Ovary (CHO) cell lines with mutations in specific proteins. Biopsies were taken from 50 patients with esophageal cancer, who then received two cycles of oxaliplatin and fluorouracil chemotherapy prior to surgery. Levels of DNA repair proteins were quantified by immunohistochemistry and by qRT-PCR. Results: Twelve lead biomarkers were identified from the preclinical models. In CHO cells, XPF and ERCC1 mutants were approximately 30 times more sensitive than the WT cells (p&lt;0.01). In comparison to WT CHO cells, XPF-deficient cells had prolonged delay in mid-late S-phase after oxaliplatin treatment, and persistence of double strand breaks for at least 48 hours. Modified Comet assay confirmed persistence of inter-strand crosslinks created by oxaliplatin. Cells deficient in DNA polymerase eta (pol eta) also accumulated in S-phase and were 3-fold more sensitive (p&lt;0.01) to oxaliplatin treatment than pol eta-complemented cells. Knockdown of XPF, ERCC1 or pol eta sensitised both oxaliplatin-resistant and oxaliplatin-sensitive HCT116 cells to oxaliplatin. In patients with esophageal cancer, low or absent XPF protein expression predicted complete pathological response to chemotherapy with a sensitivity of 58% and specificity of 72%. Cyclin A protein levels (univariate analysis, p&lt;0.005) and pol eta mRNA levels (multivariate analysis, P&lt;0.005) in pre-treatment esophageal biopsies correlated with overall survival. Conclusions: Results suggest that inter-strand DNA cross-links are the principal cytotoxic lesions created by oxaliplatin. Homologous recombination and damage checkpoint proteins are leading biomarkers for patient selection. In patients with esophageal cancer, XPF and pol eta predict response to oxaliplatin chemotherapy.
Potential effect of centre size on continuity of care and healthcare performance
Authors: Zhe Hui Hoo, Rachael E Curley, Martin J Wildman
Journal: BMJ (2017)

Barker and colleagues show that smaller practices have higher continuity of care, as measured by proportion of contact with the same doctor.1 Quality of the patient-doctor interaction is another aspect of continuity. Dunbar proposed that the number of meaningful stable relationships that can be maintained determines the optimum size of human groups. …