tbuckley/cabot-search huggingface dataset:
Enrollment of racial/ethnic minority patients in ovarian and breast cancer trials: An FDA analysis.
Authors: Laura L. Fernandes, Lola A. Fashoyin-Aje, Rajeshwari Sridhara, Patricia Keegan, Richard Pazdur
Journal: Journal of Clinical Oncology (2018)

e18671 Background: Data from the Surveillance, Epidemiology, and End Results database project that ovarian cancer incidence rates are highest in White women, followed by Hispanic, Asian/Pacific Islander, and Black women (12.2, 10.6, 9.5, and 9.4 cases per 100,000, respectively). For breast cancer, while incidence rates are similar between White and Black women, mortality rates are also higher in Blacks (29.2 versus 20.6 cases per 100,000 in Black versus 20.6 in White women). FDA conducted an analysis to describe the demographic characteristics of patients in enrolled in clinical trials (CTs) supporting the approval of new drugs for the treatment of ovarian or breast cancer. FDA conducted an analysis to describe the representation of racial/ethnic minority patients in CTs supporting the approval of new drugs for the treatment of ovarian cancer and breast cancer. Methods: We reviewed the marketing applications of drugs approved 2011- 2018 for the treatment of breast or ovarian cancer. The demographic data were from CT’s providing the primary evidence of safety and efficacy pooled and analyzed in aggregate, for each disease. Results: A summary of the results across four marketing applications for ovarian cancer and five for breast cancer, are shown. Conclusions: Our findings indicate that racial and ethnic minorities and older patients are underrepresented in CTs that supported the approval of new drugs for treatment of breast or ovarian cancer. This trend may limit an adequate assessment of potential differences in the safety and effectiveness of medical products across these demographic subgroups of patients, and limit patients’ access to alternative and/or potentially innovative treatments. Ovarian Cancera Breast Cancerb All n = 3762 US n = 2005 All n = 4663 US n = 1546 % % % % Age < 65 years 88 63 78 79 ≥ 65 years 32 37 22 21 Race American Indian/Alaskan Native < 1 < 1 < 1 < 1 Asian 6 3 14 3 Black/ African American 3 4 2 6 Missing 4 3 2 1 Other < 1 < 1 2 4 Native Hawaiian/ other Pacific Islander < 1 < 1 < 1 < 1 White 86 89 78 86 Ethnicity Hispanic/ Latino 3 5 5 5 Not Hispanic/ Latino 61 79 24 30 Other 1 < 1 - - Missing/Not Collected 34 16 71 65 aOriginal and Supplemental Applications; bOriginal applications only.
Factors associated with allogeneic hematopoietic stem cell transplantation (HSCT) outcomes in patients (pts) with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) treated with inotuzumab ozogamicin (InO) versus (v) conventional chemotherapy (C).
Authors: Partow Kebriaei, Daniel J. DeAngelo, Matthias Stelljes, Nicola Gökbuget, Hagop M. Kantarjian, Anjali S. Advani, Akil Merchant, Tao Wang, Fausto Rodriguez Loberiza, Barbara Sleight, Erik Vandendries, David I. Marks
Journal: Journal of Clinical Oncology (2017)

7007 Background: InO therapy in R/R ALL resulted in superior complete remission (CR)/CR with incomplete hematologic recovery (CRi) rates v C in the Phase 3 INO-VATE trial (NCT01564784; Kantarjian NEJM 2016). More InO v C pts proceeded to HSCT (41% [45/109] v 11% [12/109]; P&lt;0.001). Factors associated with outcomes after HSCT are described. Methods: Full details have been published. Multivariate analyses (MVA) using Cox regression modeling were conducted to determine predictors of non-relapse mortality (NRM) and overall survival (OS). Results: As of 3/8/16, 108/326 pts underwent allogeneic HSCT (InO n=77; C n=31). Baseline characteristics were generally similar, except baseline platelet values were lower in InO v C pts. More InO v C pts achieved minimal residual disease negativity (MRD neg [best status]; 71% v 26%; P&lt;0.0001). Less InO v C pts received additional therapy before HSCT (14% v 55%, P&lt;0.0001). NRM rates were higher in InO v C pts at 1 year (yr; 36% [95% CI 26–47] v 20% [8–36]) and 2 yrs (39% [27–51] v 31% [13–51]), but relapse rates were lower (1 yr, 23% [15–33] v 29% [13–48]; 2 yrs, 33% [22–44] v 46% [24–65]). No significant difference in post-HSCT survival was detected in InO v C pts; however, visual inspection of the curve suggested the survival probability varied before and after 15 months post-HSCT (1 yr, 44% [95% CI 33–55] v 65% [44–79]; 2 yr, 39% [28–50] v 34% [15–54]). Fatal veno-occlusive disease (VOD) was observed in 5 InO pts (all during the first 100 days from the date of HSCT) and no C pts. MVA showed that conditioning regimens without dual alkylators and thiotepa were associated (2-sided; P&lt;0.05) with lower risk of NRM and post-HSCT survival, respectively. Conclusions: Compared with C, InO permitted more pts with R/R ALL to proceed to HSCT in CR/CRi with MRD neg (best status). Despite increased NRM and fatal VOD, long-term survival was attainable in InO pts. In pts previously treated with InO, interventions to reduce NRM and improve OS after HSCT include avoiding dual alkylator conditioning regimens, especially those containing thiotepa. Funding: Pfizer Clinical trial information: NCT01564784.
Prognostic significance of periostin in patients with hepatocellular carcinoma.
Authors: Ahmed Omar Kaseb, Yehia I. Abugabal, Reham Abdel-Wahab, Sahin Lacin, Gehan Botrus, Roberto Carmagnani Pestana, Robert A. Wolff, James C. Yao, Manal Hassan
Journal: Journal of Clinical Oncology (2018)

e16143 Background: Limited data are available about the prognostic significance of Periostin in hepatocellular carcinoma (HCC). Previous studies showed that Periostin is associated with the epithelial mesenchymal transition in cancer and demonstrated enhanced expression of periostin in breast, colon, lung, and pancreas cancer and its correlation with decreased survival and increased recurrence in HCC. Methods: Between 2001 and 2014, total of 766 HCC patients from MD Anderson Cancer Center were enrolled, and baseline patients’ clinicopathologic characteristics were prospectively collected. The normal level of plasma Periostin was defined based on the median among control group ( = 138 mg/ml). Survival analysis included Kaplan Meier statistic and Cox regression analysis were estimated to determine the effect on HCC prognosis. Results: The median value of Periostin was elevated in HCC cases (166 mg/ml) , P < 0.0001. Patients were categorized into two groups: group 1 (N = 267) with normal serum level ( ≤ 138) and group 2 (N = 499) with higher values ( > 138). Median survival (months), 95% CI were 19.5 (16.1 – 22.9) and 10.9 (8.8 – 13) in group 1 and 2 respectively, (P < .0001). Patients in group 2 experienced poor clinical characteristics than group 1 with significantly higher incidence of vascular invasion, portal vein thrombosis and cirrhosis (p < 0.0001). Conclusions: High plasma level of periostin were associated with advanced CLIP staging and poor survival of HCC patients. Recent studies Indicate that a combination of periostin over-expression and micro-vascular invasion in hepatocellular carcinoma was correlated with a poor prognosis and can be a good prognostic marker for hepatocellular carcinoma. Future studies are guaranteed to apprehend the pathways of possible periostin effect on triggering HCC and its progression.
Phase ib study of safety, tolerability and pharmacokinetics of simotinib in patients with advanced non-small cell lung cancer.
Authors: Xingsheng Hu, Xiaohong Han, Li Zhang, Yanhua Ding, Hanping Wang, Hua Mu, Yan Sun, Yuankai Shi
Journal: Journal of Clinical Oncology (2017)

e20642 Background: Simotinib is a novel small molecule agent specifically inhibits EGFR and its downstream signaling pathway. Phase Ia study in healthy volunteers demonstrated that simotinib was well-tolerated at doses up to 500 mg. Here, we report a phase Ib study in NSCLC patients with EGFR sensitive mutations to investigate the safety, tolerability and pharmacokinetics of simotinib (ClinicalTrials.gov identifier: NCT01772732). Methods: Patients with histologically confirmed advanced or metastatic NSCLC with EGFR sensitive mutations, relapsed after first-line platinum-contained chemotherapies were eligible. Patients were orally administered with simotinib twice daily continuously, with assessment of dose-limiting toxicities (DLTs) during the first cycle (28 days). Dose escalation was carried out to determine maximum tolerated dose (MTD) using a 3+3 design and 100 mg as starting dose. Pharmacokinetics of simotinib was assessed on Days 1 and 15, respectively. Tumor response was assessed on Day 29 and every 8 weeks afterwards. Results: Fourty-one patients were enrolled and 40 patients were evaluable for response. Simotinib was well tolerated without DLTs, and MTD was not reached up to dose 650 mg. Thirty-nine (95.1%) patients experienced at least one adverse event (AE), and most of them were mild or moderate. Rash (41.5%) and diarrhea (56.1%) were the most frequent AEs. Within the doses examined, simotinib was rapidly absorbed (Tmax ranged 1-4 hours), and the elimination T 1/2 ranged 6.2-13.0 hours. Exposure to simotinib was approximately proportional with a single dose from 200 mg to 650 mg, but was less than dose proportional after multiple doses. Sixteen (40%) patients achieved partial response (PR). Median progress free survival (PFS) and overall survival (OS) were 9.9 months and 14.6 months, respectively. Notably, 5 of 8 (62.5%) patients with brain metastasis (BM) in dose cohorts of 500 mg and 650 mg achieved PR. Conclusions: Simotinib was well tolerated, with encouraging efficacy observed in NSCLC patients with EGFR sensitive mutations, particularly in those with BM. Further study of simotinib in treatment of NSCLC patients with BM is warranted and on-going. Clinical trial information: NCT01772732.
Altered patterns of global protein synthesis and translational fidelity in RPS15-mutated chronic lymphocytic leukemia
Authors: Gabriel Bretones, Miguel G. Álvarez, Javier R. Arango, David Rodríguez, Ferran Nadeu, Miguel A. Prado, Rafael Valdés-Mas, Diana A. Puente, Joao A. Paulo, Julio Delgado, Neus Villamor, Armando López-Guillermo, Daniel J. Finley, Steven P. Gygi, Elías Campo, Víctor Quesada, Carlos López-Otín
Journal: Blood (2018)
Defining non-inferiority margins for quality of surgical resection for rectal cancer.
Authors: Sergio A Acuna, Tyler R Chesney, Sonali T Amarasekera, Nancy N. Baxter
Journal: Journal of Clinical Oncology (2018)

e18760 Background: A key challenge for non-inferiority randomized clinical trials (NI-RCTs) is the generation of non-inferiority margins (ΔNI). Guidance for the selection of ΔNI is directed to pharmaceuticals with no clear recommendations for NI-RCTs of operative procedures. Quality of surgical resection metrics have been used as surrogates for long-term oncologic outcomes in NI-RCTs comparing laparoscopic and open surgery for rectal cancer. However, ΔNI for these outcomes have not been defined. Methods: A 2-round web-based Delphi process was used to define ΔNI for quality of surgical resection metrics: positive circumferential resection margin (CRM), incomplete plane of mesorectal excision (PME), positive distal resection margin (DRM), and a composite of these outcomes. Between September 2016 and February 2017, 134 international experts in rectal cancer (68 surgeons, 20 medical oncologists, 16 radiation oncologists, and 27 pathologists) were invited to participate. Experts were presented with evidence syntheses summarizing the association between quality of surgical resection and long-term outcomes, and pooled quality of surgical resection outcomes for open surgery. Experts were then asked to provide ΔNI for all outcomes balancing the risk and benefits of minimally-invasive surgery. Results: 72 experts participated: 57 completed the initial questionnaire (Round 1) and 58 the revised questionnaire (Round 2). Consensus was reached for all individual ΔNI but not for the composite. The mean (SD) ΔNI was an absolute difference of 2.33% (1.59) for proportion of positive CRM when comparing surgical interventions for treatment of rectal cancer; 2.85% (1.83) for incomplete PME; 1.28% (1.13) for positive DRM; and 2.71% (2.28) for the composite. However, opinions varied widely for the composite outcome. Conclusions: Delphi processes are a feasible approach to generate ΔNI to evaluate novel surgical approaches. The generated ΔNI for quality of surgical resection metrics for rectal cancer can be used for future NI-RCTs. Outcome Rate for Open Resection (%) Round 1 Mean ΔNI (SD) Round 2 Mean ΔNI (SD) CRM 9.0 2.94 (2.29) 2.33 (1.59 PME 8.6 3.55 (2.66) 2.85 (1.83) DRM 1.5 2.09 (2.36) 1.28 (1.13) Composite 87.4 4.49 (3.09) 2.71 (2.28)
Evaluation of liquid biopsies for molecular profiling in patients with advanced non-small cell lung cancer (NSCLC) in the relapse treatment setting.
Authors: Jordi Remon, Benjamin Besse, Ludovic Lacroix, Laura Mezquita, Cecile Jovelet, Karen Howarth, Vincent Plagnol, Clive D. Morris, Claudio Nicotra, Chloe Pannet, Emma Green, Jean-Charles Soria
Journal: Journal of Clinical Oncology (2017)

11532 Background: Molecular profiling is limited by access to sufficient tumor tissue for comprehensive analysis and due to tumor heterogeneity, the complete range of tumor DNA abnormalities may not be represented nor accurately reflect the clinical evolution of disease. Circulating tumor DNA (ctDNA) can be used as a minimally-invasive liquid biopsy for the detection, quantification and monitoring of molecular abnormalities for personalized treatment strategies. Methods: In a prospectively designed program, to date, we have recruited 227 advanced NSCLC patients having received prior therapy, with unknown molecular profile at time of blood collection. Blood collections (10ml K2-EDTA) were performed to assess molecular profile prior to or at time of relapse. Repeat samples were performed on patients initiated on treatment and followed for up to 18months. Patient samples were analyzed with InVision (enhanced tagged-amplicon sequencing) using a 34 gene panel. Interim analysis performed with full descriptive summary statistical analyses to be presented at conference. Results: ctDNA profiling detected somatic mutations in 182pts (80.2%), predominantly located in TP53 (46%), EGFR (28%), KRAS (11%) and STK11 (7%, half of which had concurrent KRAS). Of note, clinically actionable mutations were detected: T790M (25pts, median 1.4% AF), ERBB2 (8 pts), MET (8pts) and BRAF (4pts) providing eligibility for new therapy options. 20pts including 12 EGFR/T790M+ve were evaluated for ctDNA monitoring up to 18 months (median 10m); correlation between dynamic change in mutation allele fraction and clinical response was observed, especially predictive of relapse to treatment. 10 patients demonstrated SD/PR response to osimertinib treatment with T790M detection at low allele fraction (7/10 &lt; 1% AF with 1pt at 0.08% AF). Conclusions: ctDNA can be used as a non-invasive ‘liquid biopsy’ for molecular profiling of NSCLC patients to detect clinically relevant and actionable mutations when tissue biopsy is unavailable. Liquid biopsies can be repeated as needed where tissue is not feasible, providing real-time information to support personalised treatment.
Improved survival of small cell lung cancer in the veterans health administration from 2000-2010: Association with increasing utilization of PET staging.
Authors: Julian C. Hong, Matthew Boyer, Daphna Spiegel, Christina D. Williams, Betty Caroline Tong, Scott Shofer, Michael James Moravan, Michael J. Kelley, Joseph Kamel Salama
Journal: Journal of Clinical Oncology (2018)

e20571 Background: Accurate staging for small cell lung cancer (SCLC) is critical to selecting appropriate therapy. The impact of positron emission tomography (PET) and stage migration are well-described in non-small cell lung cancer but not SCLC. Temporal trends in PET staging and survival among veterans were analyzed. Methods: Patients diagnosed with SCLC from 2001-2010 were identified by the Veterans Affairs Central Cancer Registry. Rates of PET utilization and overall survival (OS) were assessed over time. The impact of PET staging on OS and lung cancer-specific survival (LCSS) for limited stage (LS) and extensive stage (ES) SCLC was assessed. Results: A total of 10,135 SCLC patients were identified. From 2001-2010, PET utilization increased from 1.1% to 39.2%. Median OS improved for all (6.2 to 7.9 months), LS (10.9 to 13.2), and ES (5.0 to 7.0) patients. Over the study period, LS-SCLC classification increased from 33.1% to 36.2% of all diagnoses and ES-SCLC classification increased from 58.7% to 63.8%. There were 1,536 LS-SCLC patients treated with CRT, with 397 staged by PET. OS and LCSS were greater with PET (median 19.8 versus 14.3 months, p < 0.0001; 22.9 versus 16.7 months, p < 0.0001) which remained with propensity matching. PET was associated with longer OS (HR 0.78; 95% CI 0.68-0.89) and LCSS (0.73; 0.62-0.85). In the 6,143 ES-SCLC patients, PET was also associated with improved OS and LCSS (median 7.8 versus 4.2 months, p < 0.001; 8.6 versus 5.3 months, p < 0.001). Conclusions: In this large cohort, utilization of PET staging increased from 2001-2010. PET was associated with greater OS and LCSS in both LS and ES-SCLC patients. These findings emphasize the importance of PET in SCLC and support its routine use.
Phase I pharmacokinetic and pharmacodynamic results of novel anti-neutropenic factor for the prevention and treatment of febrile neutropenia.
Authors: Ronald Glenn Jubin, Peter Buontempo, Daniel Byczkowski, Hemant K. Misra, Abraham Abuchowski
Journal: Journal of Clinical Oncology (2016)

e14085 Background: Anti-Neutropenia Factor - RHO (ANF-RHO) is a novel pegylated version of native human recombinant G-CSF protein. ANF-RHO has distinct biophysical and biological properties that produce a distinct pharmacokinetic (PK) and pharmacodynamic (PD) profile as compared to pegfilgrastim that may be ideally suited for treating febrile neutropenia. Methods: A phase I clinical study was conducted in healthy subjects to assess the PK/PD profile of ANF-RHO. The randomized, placebo controlled, double blind trial assessed the effect of single, ascending dose, subcutaneous injections of 5 to 50 µg/kg ANF-RHO versus fixed dose 6 mg (80 to 100 µg/kg) pegfilgrastim or placebo on average neutrophil count (ANC) and level of CD34+ hematopoietic progenitor cells. Results: ANF-RHO demonstrated a biphasic ANC response in comparison to pegfilgrastim between days 2-7. Mean ANC counts for all ANF-RHO treated subjects showed a time to Cmax (Tmax ) between 6.8 and 7.4 days in contrast to 2.2 days for pegfilgrastim-treated subjects. Comparison of ANC values showed that ANF-RHO subject neutrophil counts increased in a stable and prolonged manner (over 7 days), in contrast to pegfilgrastim that showed a rapid ANC spike (2 days) and then decreased following administration. Assessment of AUC for the PD curves showed that ANF-RHO at10 µg/kg was equivalent to pegfilgrastim at 80-100 µg/kg, demonstrating a ≥ 8-fold potency effect for ANF-RHO over pegfilgrastim, and with a duration of effect lasting beyond 12 days. Conclusions: Because of the unique PK/PD of ANF-RHO, a significantly lower dose may be given on the same day as chemotherapy administration to achieve neutrophil levels sufficient to mitigate severe neutropenia with fewer dose-related side effects. Planning is underway for a phase II study of ANF-RHO with a focus on reducing or preventing the occurrence and severity of neutropenia resulting from the use of myelo-suppressive chemotherapy. Days Post-Administration Mean AUC Pegfilgrastim 100µg/kg Mean AUC ANF-Rho 10µg/kg 0 3.7 2.86 2 32.6 10.1 7 15.3 16.8 12 5.2 11 %Change from 0 - 12 39 390
Imaging of tumor infiltrating T cells with an anti-CD8 minibody (Mb) 89Zr-IAB22M2C, in advanced solid tumors.
Authors: Michael A. Postow, James J. Harding, Matthew David Hellmann, Michael S. Gordon, Frank Tsai, Joseph A. O' Donoghue, Jason Stuart Lewis, Anna M Wu, William Le, Ronald Lee Korn, Wolfgang Weber, Jedd D. Wolchok, Neeta Pandit-Taskar
Journal: Journal of Clinical Oncology (2018)

e24160 Background: The degree of tumor infiltration by CD8 T cells is associated with favorable outcomes to immunotherapy. Biopsies to assess T cell infiltration are invasive and may not capture heterogeneity among different tumors within an individual patient's tumor burden. Non-invasive CD8 T cell imaging could provide a more comprehensive view of T cell infiltration and potentially be related to treatment responses. Methods: We are conducting a clinical study, imaging with anti-CD8 radiolabeled Mb 89Zr-IAB22M2C in patients (pts) with metastatic solid tumors undergoing checkpoint inhibitor therapy. Pts received 3mCi of 89Zr-IAB22M2C intravenously followed by PET scans at multiple time points. All patients were monitored for adverse events. Clearance of tracer and localization in organs, lymph nodes, and tumor was evaluated. Results: Three pts (1 melanoma, 1 hepatocellular carcinoma (HCC), 1 non-small cell lung cancer (NSCLC)) completed imaging. No immediate or delayed side effects were seen with 89Zr-IAB22M2C. The tracer cleared rapidly from blood. Intense uptake was noted in spleen, liver and bone marrow. Multiple normal lymph nodes were localized in all patients. In the melanoma and HCC pts who had both received checkpoint inhibitors, localization of 89Zr-IAB22M2C was noted in lesions as early as 2h post infusion (PI) and in the majority of lesions by 24h PI. SUVmax in 6 target lesions (1 intramuscular, 2 liver, 3 lymph nodes) ranged 5.85-22.8. One patient with NSCLC did not have radiographically apparent uptake. Conclusions: Preliminary data from this ongoing study show infusing 89Zr-IAB22M2C is safe, has favorable biodistribution and can detect CD8 T cells in tumors with same day imaging. Ongoing dose escalation is underway to better characterize these early proof-of-concept findings. Clinical trial information: NCT03107663.
TCT-581 Diagnostic value of longitudinal flow gradient for the presence of hemodynamically significant coronary artery disease
Authors: Michiel Bom, Roel Driessen, Henk Everaars, Adriaan Lammertsma, Niels van Royen, Juhani Knuuti, Maija Mäki, Ibrahim Danad, Paul Knaapen
Journal: Journal of the American College of Cardiology (2018)