tbuckley/cabot-search huggingface dataset:
Phase II study of FOLFIRI + ramucirumab with recurrent colorectal cancer refractory to adjuvant chemotherapy with oxaliplatin / fluoropyrimidine (RAINCLOUD).
Authors: Naotoshi Sugimoto, Chu Matsuda, Taishi Hata, Taroh Satoh, Masakazu Ikenaga, Tsunekazu Mizushima, Kohei Murata, Masayuki Ohue, Yuichiro Doki, Masaki Mori
Journal: Journal of Clinical Oncology (2018)

TPS882 Background: The RAISE study demonstrated the superiority of FOLFIRI + ramucirumab (Ram) to FOLFIRI in second-line metastatic colorectal cancer patients progressed after oxaliplatin, fluoropyrimidine with bevacizumab. But no prospective data is existed that the efficacy and toxicity of FOLFIRI + Ram pretreated oxaliplatin, fluoropyrimidine without an anti-angiogenesis therapy. Methods: RAINCLOUD study is a multicenter single-arm phase II trial. Key eligibility criteria is as follows: histologically or cytologically confirmed colorectal cancer, confirmed recurrent colorectal cancer, refractory to fluoropyrimidine, refractory or intolerant of oxaliplatin without pretreated anti-angiogenesis therapy, has measureable or non-measurable lesion, PS = 0 or 1, has adequate coagulation function, 20 years or older. Primary endpoint of this study is progression-free survival. Secondary endpoints are overall survival, time to treatment failure, response rate, disease control rate and safety. Patients receive FOLFIRI (irinotecan: 180 mg/m2, l-levofolinate: 200 mg/m2, bolus fluorouracil: 400mg/m2, and continuous fluorouracil: 2400 mg/m2) plus Ram (8 mg/kg) every two weeks until progression or the development of unacceptable toxicity. We hypothesized that threshold of PFS in FOLFIRI + Ram is 3.9 months and expected PFS is 6.9 months and designed to have an 80% power to detect clinically meaningful improvement in PFS at the one-sided significance level of 0.05, minimal patient registration number is 44 in order that power 1-β outperforms 0.8. Taking a few ineligibility patients and dropout patients into consideration, number of target patients is set to be 48. Study recruitment started on September 2017. The association of exploratory biomarker study will be planned. Clinical trial information: UMIN000028677.
Final Report of a Phase II Study of Guadecitabine (SGI-110) in Patients (pts) with Previously Untreated Myelodysplastic Syndrome (MDS)
Authors: Guillermo Garcia-Manero, Koji Sasaki, Guillermo Montalban-Bravo, Kristy R. Bodden, Prithviraj Bose, Yesid Alvarado, Naval G. Daver, Gautam Borthakur, Farhad Ravandi, Koichi Takahashi, Jorge E. Cortes, Elias J. Jabbour, Kiran Naqvi, Courtney D. DiNardo, Christopher B. Benton, Naveen Pemmaraju, Tapan M. Kadia, Maro N. Ohanian, Sherry A. Pierce, Hagop M. Kantarjian
Journal: Blood (2018)
Impact of Leukapheresis and Time to Chemotherapy on Outcomes of Newly Diagnosed Patients (pts) with Acute Myeloid Leukemia (AML) Presenting with Hyperleukocytosis: An Analysis from a Large International Patient Cohort
Authors: Maximilian Stahl, Wei Wei, Pau Montesinos, Etienne Lengline, Rory M Shallis, Judith Neukirchen, Vijaya R. Bhatt, Mikkael A. Sekeres, Amir T. Fathi, Heiko Konig, Selina Luger, Irum Khan, Gail J. Roboz, Thomas Cluzeau, David Martínez-Cuadron, Emmanuel Raffoux, Ulrich Germing, Jayadev Manikkam Umakanthan, Sudipto Mukherjee, Andrew M. Brunner, Adam M. Miller, Christine M. McMahon, Ellen K. Ritchie, Rebeca Rodríguez-Veiga, Raphael Itzykson, Blanca Boluda, Florence Rabian, Mar Tormo, Evelyn Gloria Acuna Cruz, Emma Rabinovich, Brendan Yoo, Nikolai A. Podoltsev, Steven D. Gore, Amer M. Zeidan
Journal: Blood (2018)
Phase 2 study investigating the safety, efficacy, and surrogate biomarkers of response to 5-azacitidine (5-AZA) and entinostat in advanced breast cancer.
Authors: Roisin M. Connolly, Rachel Catherine Jankowitz, Cynthia A. Zahnow, Zhe Zhang, Michelle A. Rudek, Shannon Slater, Penny Powers, Stacie Jeter, Adam Brufsky, Richard Piekarz, James Gordon Herman, Nita Ahuja, George Somlo, Agustin A. Garcia, Stephen Baylin, Nancy E. Davidson, Vered Stearns
Journal: Journal of Clinical Oncology (2014)

569 Background: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to re-expression of genes encoding important therapeutic targets including the estrogen receptor. We conducted a multicenter phase II study of 5-AZA and entinostat in women with advanced breast cancer. Methods: Women with advanced HER2-negative (triple-negative [TNBC] or hormone-resistant [HR]) breast cancer received 5-AZA 40 mg/m2 (SQ, ds 1-5, 8-10) and entinostat 7 mg (PO, ds 3,10) q28 ds. Primary endpoint: Objective response rate (ORR) in each cohort. Secondary endpoints: PFS, OS, safety. We obtained mandatory baseline and wk 8 tumor biopsies for gene methylation/expression, and blood samples for pharmacokinetics and pharmacogenetics. At progression, patients were offered optional continuation (OC) with the addition of endocrine therapy. We hypothesized that ORR would be >20% against null of 5% using Simon two-stage design. At least 1 response was required in 1st of 13 patients per cohort to continue accrual to 27 per cohort. Type I error 4%, power 90%. Results: TNBC data were presented at AACR 2013. From 08/2011-09/2013, 27 women enrolled in the HR cohort. Median age 55 ys (33-70), median prior endocrine and chemotherapies 3 each. Median cycles received 2 (1-16). Twelve women continued in OC phase and received median 2.5 additional cycles (range 1-9). We observed 1 partial response with epigenetic therapy alone (ORR 4%, 95% CI, 0-19%) and 1 in OC. At median follow up 6.3 ms, median PFS was 1.8 ms (95% CI, 1.7-1.9), and median OS 11.5 ms (95% CI, 5.5-16.3). In OC phase, median PFS was 1.9 ms (95% CI, 1.7-3.7) and median OS 15.6 ms (95% CI, 5.5-NA) vs PFS 1.8 ms (95% CI, 0.8-1.9) and OS 9.2 ms (95% CI, 2.3-16.3) for event monitoring. Therapy was well tolerated with few grade 3/4 events. We obtained 95% baseline core biopsies, and 58% matched samples. Correlative analyses will be presented. Conclusions: Combination epigenetic therapy was well tolerated but our primary endpoint was not met. OC results suggest that some women benefit from epigenetic therapy and/or reintroduction of endocrine therapy beyond progression. Clinical trial information: NCT01349959.
Impact of National Cancer Institute (NCI)-mandated scientific review on protocol development and content.
Authors: Ning Ning, Jingsheng Yan, Xian-Jin Xie, David E. Gerber
Journal: Journal of Clinical Oncology (2014)

6586 Background: The National Cancer Institute (NCI) requirement that all clinical trials involving cancer patients at NCI-designated cancer centers undergo a scientific review in addition to Institutional Review Board (IRB) review is unique among medical specialties. We evaluated the impact of this process. Methods: We collected data on oncology clinical trials undergoing full board review by the UT Southwestern Protocol Review and Monitoring Committee (PRMC) 2009-2013. We analyzed associations between trial characteristics, PRMC decisions, protocol changes requested, and protocol changes implemented using Chi-square testing, Fisher’s exact testing, and logistic regression. Results: The analysis included 226 trials. Initial PRMC decisions were: approve (40%), approve pending response (52%), defer (7%), and disapprove (1%). Final PRMC decision was approve for 96% of trials. The PRMC requested a total of 270 changes (range 0-17 per protocol). Number of requested changes per protocol was associated with trial type (mean 0.7 for industry-sponsored versus 3.0 for investigator-initiated; P<0.001) and study year (mean 0.7 in 2009 versus 2.4 in 2013; P=0.03). Requested protocol changes included design (53%), intervention (24%), evidence-background-rationale (14%), and population (11%). Compared to those for industry-sponsored trials, PRMC requested changes for investigator-initiated trials were more likely to be implemented (91% versus 83%; P=0.08). A pronounced difference was noted for requested changes related to trial design: among 154 industry-sponsored trials, 28 changes to study design were requested (average 0.2 per trial), of which 29% were implemented; among 52 investigator-initiated trials, 39 changes to study design were requested (average 0.8 per trial), of which 90% were implemented. Conclusions: The NCI-mandated scientific review of cancer clinical trials appears to have a substantial impact on investigator-initiated protocols, but the effect on industry-sponsored protocols is less clear. Given heightened interest in the quality and timeliness of oncology clinical trials, further research into this process is warranted.
Presentation and Outcomes of Pregnancy in Patients With Autoimmune Hepatitis
Authors: Laura-Patricia Llovet, Diana Horta, Maria García Eliz, Marina Berenguer, Emilio Fábrega, Federico Sáez-Royuela, Montserrat García-Retortillo, Yolanda Sánchez Torrijos, Manuel Romero-Gómez, Conrado Fernández, Elena Gómez Domínguez, Albert Parés, Maria-Carlota Londoño
Journal: Clinical Gastroenterology and Hepatology (2019)
Liquid Crystal‐Induced Myoblast Alignment
Authors: Daniele Martella, Lorenzo Pattelli, Camilla Matassini, Francesca Ridi, Massimo Bonini, Paolo Paoli, Piero Baglioni, Diederik S. Wiersma, Camilla Parmeggiani
Journal: Advanced Healthcare Materials (2019)

The ability to control cell alignment represents a fundamental requirement toward the production of tissue in vitro but also to create biohybrid materials presenting the functional properties of human organs. However, cell cultures on standard commercial supports do not provide a selective control on the cell organization morphology, and different techniques, such as the use of patterned or stimulated substrates, are developed to induce cellular alignment. In this work, a new approach toward in vitro muscular tissue morphogenesis is presented exploiting liquid crystalline networks. By using smooth polymeric films with planar homogeneous alignment, a certain degree of cellular order is observed in myoblast cultures with direction of higher cell alignment corresponding to the nematic director. The molecular organization inside the polymer determines such effects since no cell organization is observed using homeotropic or isotropic samples. These findings represent the first example of cellular alignment induced by the interaction with a nematic polymeric scaffold, setting the stage for new applications of liquid crystal polymers as active matter to control tissue growth.
Abstract 16347: The BioMonitor 2 Master Study: Early Experience With a New Insertable Cardiac Monitor
Authors: Georg Noelker, Mathias Busch, Jörn Schmitt, Franz X Roithinger, Glenn Young, Milos Taborsky, Christopher Piorkowski
Journal: Circulation (2017)

Introduction: Insertable Cardiac Monitors (ICM) are becoming widespread for long-term monitoring of the heart rhythm. The BioMonitor 2 (BM2; Biotronik, Germany) is a novel ICM combining low profile...
The Lymphoma Epidemiology of Outcomes (LEO) Cohort Study Reflects the Demographics and Subtypes of Patients Diagnosed with Non-Hodgkin Lymphoma in the United States
Authors: Christopher R Flowers, Brian K. Link, Loretta J. Nastoupil, Timothy J. McDonnell, Brad S Kahl, Kiran R. Vij, Carla Casulo, Jonathan W. Friedberg, Richard Burack, Izidore S. Lossos, Carrie A. Thompson, Kathleen J Yost, Francisco Vega, Sergei Syrbu, Peter Martin, John P. Leonard, Giorgio Inghirami, Leon Bernal-Mizrachi, Karen P. Mann, Cristine Allmer, Julianne Lunde, Matthew J. Maurer, Susan L. Slager, Thomas M. Habermann, David L. Jaye, Andrew L. Feldman, James R. Cerhan
Journal: Blood (2018)
Text, talk, and informed consent: A component analysis.
Authors: Shlomo A. Koyfman, Chandana A. Reddy, Sabahat Hizlan, Angela C Leek, Eric Kodish
Journal: Journal of Clinical Oncology (2014)

e20558 Background: We applied a novel approach of analyzing and comparing the length and readability of transcribed Informed Consent Conversations (ICCs) with Informed Consent Documents (ICD) for phase I pediatric cancer clinical trials. We also assessed how investigators’ years of experience influenced these parameters of the ICC and how frequently they discussed critical elements of the consent process. Methods: ICCs where a pediatric phase I oncology trial was being offered were audio recorded as part of a prospective study of informed consent conducted at 6 institutions. Each ICC was subsequently transcribed and analyzed for word count, Flesch Kinkaid Grade Level (FKGL) and Flesch Reading Ease Score (FRES) using Microsoft Word 2010 software. The paired-sign test was used for comparing the length and readability between the ICD and the transcribed ICC. Years of investigator experience was correlated with these outcomes using spearman correlation coefficients, and with how frequently investigators covered critical consent elements using logistic regression analysis. Results: 69 cases of unique physician/protocol pairs were included in this analysis, 42 of the patients were male (61%) with a median age of 10.6 (range: 1-20). The median years of clinical experience of the investigators was 15 (1-32). While investigators nearly always discussed potential side effects (91%), study purpose (86%), and safety mechanisms (87%), they less reliably discussed other critical elements of consent, including explanation of voluntariness (55%), withdrawal rights (58%), dosing cohorts (44%), dose limiting toxicities (26%) and dose escalation (52%). Overall, ICC used fewer words (4,677 vs. 6,364; p=0.0016), had lower FKGL (6 vs. 9.7; p=<0.0001) and higher FRES (77.8 vs. 56.7; p<0.0001) compared to their respective ICD. Investigator experience did not correlate with FKGL scores or discussing critical consent elements during the ICC. Conclusions: Investigators performed ICC using shorter and simpler language than that used in the corresponding ICD, but more often omitted critical elements of the consent process. Increasing investigator experience was not associated with reduced linguistic complexity or fewer omissions of critical elements of consent.
RANKL circulating levels in the evaluation of bone response in breast cancer (BC) patients.
Authors: Toni Ibrahim, Laura Mercatali, Marianna Ricci, Emanuela Scarpi, Rossana Ricci, Alberto Bongiovanni, Venetia Zavoiu, Nada Riva, Sebastiano Calpona, Chiara Liverani, Devil Oboldi, Elena Amadori, Federico La Manna, Alessandro De Vita, Flavia Foca, Erica Gunelli, Manuela Monti, Patrizia Serra, Dino Amadori
Journal: Journal of Clinical Oncology (2014)

11128 Background: Bone Metastases (BM) are responsible of the high morbidity, low quality of life and poor prognosis of patients with BC. The evaluation of bone response to treatment is still controversial. Methods: This is a prospective study on 36 consecutive BC patients with BM for the evaluation of RANK, RANKL and OPG transcripts by Real-Time PCR and NTX levels by ELISA. Patients enrolled had at first diagnosis of bone metastases and had not previously undergone bone targeted treatment. They underwent the standard Zoledronic Acid schedule of a 4-mg infusion every 28 days and standard antitumor therapy. Patients were monitored for about 1 year and blood samples were collected before the first infusion of ZA and every 4 months. The primary aim was to study the predictive role of different circulating markers in the response to ZA respect to objective response (MD Anderson criteria). Results: The NTX levels were not different in patients that underwent to progression respect to those with stable disease or partial response to ZA Treatment. Instead a decrease of 30% and 15% was observed in OPG and RANKL levels in non responders patients. ROC curves evaluation for all markers showed RANKL was the most accurate, with an AUC of 0.70 (95%CI 0.48-0.93). We observed for RANKL/OPG an AUC of 0.64 (95%CI 0.44-0.84) and for NTX an AUC of 0.60 (95%CI 0.38-0.82). Considering as a cut off a variation of markers of at least 25%, the positive predictive value (PPV) for RANK was 26.6%, 9.1 for RANKL, 30 for OPG and 13.3 for the ratio RANKL/OPG. NPV for these markers ranged from 79.2 to 84.6 %. NTX PPV and NPV were respectively 0 and 84.6%. Conclusions: The most accurate marker for the evaluation of bone response was RANKL, the key molecule in the pathogenesis of BM and the target of Denosumab. NTX, the marker most used up to now, failed to show a predictive power of response with aspecific decrease both in responder and non responder patients. Further research should be done to improve our knowledge in this field.
Fynomer-antibody fusions targeting HER2 and CD3 for selective killing of HER2 overexpressing tumor cells.
Authors: Richard Woods, Simon Brack, Kristina Klupsch, Ulrich Wuellner, Fabian Buller, Roger Santimaria, Isabella Attinger-Toller, Susann Koenig-Friedrich, Irene Zbinden, Julian Bertschinger-Ehrler, Dragan Grabulovski
Journal: Journal of Clinical Oncology (2014)

3066 Background: A promising approach in the immunotherapy of cancer is to recruit T cells to attack tumor cells using bispecific therapeutics targeting a tumor-associated surface antigen and CD3 on T cells. Such therapeutics elicit T cell mediated lysis of tumor cells independent of T cell specificity. Fynomers are small 7 kDa globular proteins derived from the SH3 domain of the human Fyn kinase (Fyn SH3) that can be engineered to bind with antibody-like affinity and specificity to virtually any target of choice. Fynomers can be fused to N-terminal and/or C-terminal ends of antibodies to generate bispecific therapeutics (FynomAbs) with tailored architectures. Here, we describe the generation and characterization of anti-CD3/HER2 FynomAbs. Methods: Using phage display technology we have isolated Fynomers binding to HER2. After genetic fusion of these Fynomers to anti-CD3 antibodies the resulting bispecific fusion proteins were evaluated for their anti-tumoral activity. Results: We have generated novel bispecific FynomAbs which can simultaneously bind HER2 on tumor cells and CD3 on T cells. The bispecific HER2/CD3 targeting FynomAbs potently redirect T cells to HER2 expressing tumor cells showing picomolar tumor cell lysis activity on multiple cell lines. The activity was found to be highly specific, as no lysis of cells was observed in the absence of HER2 expression. In addition, the FynomAbs demonstrate an antibody-like pharmacokinetic profile in mice, which may translate into a convenient administration route without the need for continuous infusion. Conclusions: FynomAbs represent an attractive platform to generate bispecific molecules and can be produced using standard antibody technology (GMP production yield of 3.3 g/L at 1000 L scale achieved). We show here the successful generation of bispecific T cell recruiting FynomAbs with antibody-like biophysical and pharmacokinetic properties that allow the redirection of T cells specifically to tumor cells.
Trends in first-line TKI prescribing preferences (PPrefs) among U.S.-based hematology-oncology physicians (HOPs) for patients with chronic phase chronic myelogenous leukemia (CP-CML).
Authors: Neil P. Shah, Arden Buettner, Maria Lankford, Joanne Willey, Doug B. Neely, Mark R. Green
Journal: Journal of Clinical Oncology (2014)

7085 Background: Imatinib (12/2002), nilotinib (6/2010) and dasatinib (10/2010) are all indicated for first-line treatment of patients (pts) with CP-CML. PPrefs may be influenced by multiple considerations such as assessment of the risk profile of an individual patient’s disease, randomized efficacy data, cross trial comparisons of efficacy and toxicity, associated co-morbid conditions, ease of access to and administration/management of specific agents, cumulative pt out of pocket costs, and physician familiarity with available agents. Methods: Since 2011 we have used a live, extensively validated research tool to assess PPrefs of U.S.-based HOPs related to first-line TKI selection across several risk-based scenarios in pts with a new diagnosis of CP-CML. Lower risk scenario: 2011/2012 - 59 year old male, spleen palpable 7 cm below the left costal margin (LCM); white blood cell count (WBC) 75,000 with 82% mature polys; 3% basophils, no blasts; Hemoglobin (Hgb) 12.0 gms; Platelets (Plts) 430K. 2013: Identical scenario and labs except age of 63 and spleen palpable 5 cm below LCM. Higher-risk scenarios: 2012: Male, age 59, spleen 11 cm below LCM; WBC 96,000 with 3% blasts, 5% basophils; Hgb 11.1 gms; Plts 935K. 2013: Identical scenario except age of 63, basophils 9% and platelets 965K. Results: TKI PPrefs by year and scenario shown in Table. Conclusions: PPrefs among US-based HOPs for pts presenting with a new diagnosis of CP-CML appear to be progressively shifting toward use of FDA indicated second generation TKIs as initial therapy. Blood counts and spleen size at presentation appear to impact HOP PPrefs. In 2013, the majority of PPrefs for the higher risk scenario are for second generation agents and there is an equal split in the lower risk population. Among respondents indicating a PPref for a second generation agent as initial therapy, a trend over several years toward increasing PPref for dasatinib is evident. First-line preference Lower-risk scenario Higher-risk scenario 2011 N=259 2012* N=358 2013* N=366 2012 N=366 2013 N=368 Imatinib 57% 53% 48% 37% 31% Dasatinib 17% 23% 30% 31% 40% Nilotinib 26% 23% 19% 32% 26% Other 0% 2% 2% 0% 3% *May not equal 100% due to rounding.
Heme-Regulated Inhibitor (HRI) Loss and Pharmacologic Treatments Cooperate to Strongly Elevate Fetal Hemoglobin and Reduce Sickle Cell Formation
Authors: Scott A. Peslak, Jeremy D. Grevet, Xianjiang Lan, Osheiza Abdulmalik, Junwei Shi, Gerd A. Blobel
Journal: Blood (2018)
Methods to minimize power loss at interim futility analyses and final analyses due to violations of initial sample size assumptions in oncology clinical trials with survival endpoints.
Authors: Aaron C. Camp, Joseph Walt Adair
Journal: Journal of Clinical Oncology (2014)

e22201 Background: The gold-standard for efficacy in oncology clinical trials is overall survival – a time-to-event endpoint. In phase III trials when interim analyses include a futility component the probability of type II error – stopping the study for futility when the treatment is significantly better than control – is inflated thus reducing the power. Unlike symmetric superiority/futility bounds, one-sided futility bounds can be set without also increasing the chance of stopping for superiority. This is often done to appease parties for whom it is desirable to have a large chance to stop for futility if the treatments are not different. The most commonly used test to compare survival curves is the non-parametric log-rank test. It relies upon an assumption of proportional hazards and is generally assumed to be robust to small departures from this assumption. Methods: Through simulation we show that the log-rank test is not robust to the types of departures from the proportional hazards assumption commonly observed in oncology clinical trials and that these departures can lead to a loss of power, especially when a futility analysis is incorporated into an interim analysis. We examine several methods to minimize the risk of type II error associated with futility analysis of survival data, including composite futility endpoints that rely on the observed hazard ratios at interim as well as the results of the log-rank test. Results: A case-study and several simulations illustrate the issue and potential solutions are discussed. Conclusions: The power loss associated with stopping for futility in scenarios where the final analysis would be successful is typically not provided or accounted for in the final power computed by many commonly used statistical software packages. In cases where the proportional hazards assumption is not met and when incorporating interim futility, simulation should be used to properly calculate sample size and power.