tbuckley/cabot-search huggingface dataset:
Complete dexrazoxane cardioprotection for cardiac function but incomplete female cardioprotection for cardiac structure in doxorubicin-treated osteosarcoma survivors: Hearts too small for the body.
Authors: Lisa M. Kopp, Mark L. Bernstein, Cindy L. Schwartz, David Ebb, Vivian L Franco, David Hall, Donald A. Barkauskas, Mark D. Krailo, Holcombe E. Grier, Paul A. Meyers, Leonard H. Wexler, Neyssa Marina, Richard B. Womer, Katherine A. Janeway, Richard Greg Gorlick, Steven E Lipshultz
Journal: Journal of Clinical Oncology (2017)

10519 Background: Dexrazoxane is protective for lower-dose doxorubicin ( &lt; 300 mg/m 2 ) cardiotoxicity in childhood cancer, but the effect of dexrazoxane (DXRZ) administered with higher-dose (HD) doxorubicin (DOXO) is unknown. Methods: We evaluated patients from Children’s Oncology Group trials for localized (P9754) and metastatic (AOST0121) osteosarcoma (OS) who received HD DOXO (375-600 mg/m 2 ) preceded by DXRZ (10:1 ratio), methotrexate, and cisplatin; some also received ifosfamide alone or ifosfamide/etoposide ± trastuzumab. Cardiotoxicity was identified by echocardiography and by serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations. Results: 81 DXRZ -treated OS patients ( age at enrollment = 13.7 years; range 3.8 - 23.7 years) had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. Female sex and longer follow-up since DOXO were associated with a significantly smaller LV dimension z-score normalized to BSA (μ = -1.20, 95%CI [-1.70, -0.70]). Similarly, in the one-third of patients treated &gt; 81 days after minimal expected treatment (groups equally partitioned by time), significantly thinner LV posterior wall thickness for BSA (μ = -0.57, [-1.05, -0.09]) was found. Interventricular septal wall thickness (μ = -0.84, [-1.2, -0.48]) and LV mass (μ = -0.73, [-1.06, -0.40]) were significantly smaller for BSA than normal for both sexes. For females, these became significantly more abnormal with increasing length of follow-up. Females also showed progressive increases in NT-proBNP. Conclusions: DXRZ is cardioprotective for HD DOXO in terms of LV function and heart failure. Females had progressive abnormalities of LV structure, leading to smaller hearts for body size. This was associated with increasing cardiac stress, as measured by NT-proBNP. DXRZ protection was incomplete for HD DOXO effects on LV structure, resulting in higher LV stress and risk for late LV dysfunction. DXRZ should continue to be used in this population, including for females who exhibit more cardiotoxicity than males at specific cumulative DOXO doses.
Evaluating the repertoire of immune checkpoint markers expressed on peripheral and ascites CD8<sup>+</sup> T cells in ovarian cancer.
Authors: Stephanie Gaillard, Chelsae Dumbauld, Alyssa Bilewski, Jessie A Ehrisman, Angeles Alvarez Secord, Laura Jean Havrilesky, Andrew Berchuck, Kent Weinhold, Cliburn Chan, John Yi
Journal: Journal of Clinical Oncology (2017)

5571 Background: Understanding the immune checkpoint marker repertoire can facilitate development of therapeutic strategies to improve efficacy of immune-based therapies. We used a novel high-dimensional flow cytometry panel to determine co-expression patterns of immune checkpoint markers and effector function of CD8+ T cells from peripheral blood and ascites of patients newly diagnosed with ovarian cancer. Methods: Peripheral blood and ascites samples were collected from patients with epithelial ovarian cancer (n=8). Cells isolated from peripheral blood and ascites were used for immune profiling by multiparameter flow cytometry of 5 inhibitory receptors (PD-1, LAG-3, TIM-3, TIGIT, and BTLA) on CD8+ T cells, along with 4 functional parameters (production of each of the following: TNF-α, IFN-γ, IL-2, and upregulation of CD107a). A complementary multiplex analysis on plasma and ascites fluid was performed to quantify 14 soluble checkpoint markers. Results: The concentrations of soluble PD-1, TIM-3, LAG-3, CTLA-4, BTLA, IDO, and CD137 were increased in ascites fluid compared to plasma from patients with ovarian cancer. Ascites CD8+ T cells co-express higher levels of inhibitory receptors than peripheral CD8+ T cells. In total, CD8+ T cells in ascites retained the ability to produce effector functions at levels similar to peripheral blood. However, IFN-γ production was retained in PD-1 only expressing CD8+ T cells and decreased in CD8+ T cells co-expressing multiple receptors. Conclusions: High-dimensional flow cytometry allowed for the phenotypic and functional characterization of CD8+ T cells from ovarian cancer patients. The profile of receptor co-expression was distinct in peripheral blood compared to ascites. Collectively, our study suggests that co-expression of factors beyond PD-1 influences CD8+ T cell activity. Thus blocking PD-1 and PD-L1 alone may not be sufficient for CD8+ T cells expressing multiple inhibitory receptors.
Determinants of quality of life and survival in ambulatory oncology patients receiving chemotherapy.
Authors: Derek Gerard Power, Louise Daly, Eadaoin Ni Bhuachalla, Samantha Cushen, Peter Mceneaney, Darren L Dahly, Aoife M Ryan
Journal: Journal of Clinical Oncology (2018)

10120 Background: Identifying prognostic variables that may improve outcome in patients (pts) with cancer is a cornerstone of research. Recently, there has been interest in the prognostic value of nutritional status in pts with cancer. Methods: A prospective cohort study of ambulatory adult oncology pts undergoing chemotherapy between 2012-16 was conducted. A survey was devised, incorporating lifestyle, clinical, nutritional, biochemical [CRP, albumin] and quality of life (QoL) data. Nutritional status was evaluated using the cancer cachexia (CC) consensus definition and body composition was assessed using computed tomography. Skeletal muscle index (SMI) and mean muscle attenuation (MA) were obtained. Random forest algorithms were used to identify predictors of QoL and survival. Partial dependence plots were used to assess the direction and association of these predictors with outcome. Results: 1015 pts with solid tumors participated, 56% male, median age of 64 years [IQR 55-71]. Colorectal cancer was the most prevalent (27%). The majority (54%) of pts had stage IV disease. Overweight and obesity (BMI > 25 kg/m2) was highly prevalent (57%), despite high rates of cachexia (42%), sarcopenia (39%) and low MA (45%). Percentage weight loss was the biggest predictor of global QoL. Weight stable pts had the highest global QoL scores after adjustment for other variables. Significant prognostic variables for survival were cancer site and stage, followed by systemic inflammation, anorexia, weight loss and mean MA, collectively considered hallmarks of CC. Highest predicted 1 and 3 year survival rates were observed in pts with a low CRP, high albumin ( > 38 g/L), without anorexia, who remained weight stable with a high mean MA ( > 36 HU). Conclusions: Malnutrition and abnormal body composition features are common in pts receiving chemotherapy but are often masked by adiposity. WL adversely impacts QoL. Nutritional parameters were more reliable prognostic indicators than many clinical variables, such as performance status, age and smoking status. Identifying significant prognostic variables provides conceptual guidance for the development of evidence based prediction models and tools. Further investigation is warranted.
Phase I dose-finding study of OPB-111077, a novel STAT3 inhibitor, in patients with advanced hepatocellular carcinoma.
Authors: Changhoon Yoo, Jihoon Kang, Kyu-Pyo Kim, Ho Yeong Lim, Jee Hyun Kim, Myung Ah Lee, Tae-You Kim, Baek-Yeol Ryoo
Journal: Journal of Clinical Oncology (2018)

4078 Background: The signal transducer and activator of transcription 3 (STAT3) signaling pathway might be a promising therapeutic target for hepatocellular carcinoma (HCC). Methods: This study was a multicenter, open-label, non-comparative, dose escalating phase I study of OPB-111077, an oral STAT3 inhibitor, in patients with advanced HCC who failed on sorafenib. Continuous dosing (daily administration: 50 mg to 400 mg) and intermittent dosing (4-days on/3-days off administration: 300 mg to 900 mg) regimens were evaluated and the dose-limiting toxicities (DLTs), maximal tolerated dose (MTD), and recommended dose (RD) were the primary endpoints. Results: A total of 33 patients (19 for continuous dosing and 14 for intermittent dosing) were enrolled. One patient experienced a DLT with grade 3 dizziness, but the MTD was identified in neither the continuous nor the intermittent dosing cohorts. The RDs were determined to be 250 mg for the continuous dosing regimen and 600 mg for the intermittent dosing regimen. There was no treatment-related death; 6 patients (18%) had grade 3-4 toxicities including thrombocytopenia (6%), fatigue (3%), and dizziness (3%). No patients achieved complete or partial responses and the median progression-free survival was 1.4 months (95% confidence interval, 0.8-2.8). Conclusions: OPB-11107 was well tolerated in patients with advanced HCC after sorafenib failure, but only showed limited preliminary efficacy outcomes. Further investigation of the role of the STAT3 signaling pathway in HCC and the development of biomarkers for STAT3 inhibitors are warranted. Clinical trial information: NCT01942083.
A phase 2 study of seribantumab (MM-121) in combination with docetaxel or pemetrexed versus docetaxel or pemetrexed alone in patients with heregulin positive (HRG+), locally advanced or metastatic non-small cell lung cancer (NSCLC).
Authors: Lecia V. Sequist, Ian Churchill Anderson, Nathan Demars, Enriqueta Felip, Wael A. Harb, Rudolf M. Huber, Art J. Kudla, Jean Kyung Lee, Sara Mathews, Ty McClure, Jorge J. Nieva, Maurice Perol, Frances A. Shepherd, Alexander I. Spira, Akos Gabor Czibere
Journal: Journal of Clinical Oncology (2016)

TPS9110 Background: The role of the HER3 receptor and its ligand heregulin (HRG) in the progression of multiple cancers has been well established. Seribantumab (MM-121) is a fully human, monoclonal IgG2 antibody that binds to the HRG domain of HER3, blocking HER3 activity. In retrospective analyses of prior seribantumab Phase 2 studies, high levels of HRG mRNA appeared to predict poor outcome when patients received standard of care (SOC) treatment. Addition of seribantumab to SOC improved progression-free survival (PFS) in patients with HRG positive (HRG+) tumors, consistent with the hypothesis that blockade of HRG-induced HER3 signaling by seribantumab can restore sensitivity to SOC impacted by HRG. Methods: In the current randomized, open-label, international, Phase 2 study, NSCLC patients will be screened for HRG using an RNA in situ hybridization assay on a recent biopsy tissue sample. Approximately 560 patients will be screened to support enrollment of 280 HRG+ patients, who will be randomized in a 2:1 ratio to receive seribantumab plus investigator’s choice of docetaxel or pemetrexed, or docetaxel or pemetrexed alone. Patients will be wild-type for EGFR and ALK and will have progressed following one to three systemic therapies for locally advanced and/or metastatic disease, including one platinum-containing regimen and anti-PD-1/PD-L1 where available and clinically indicated. The primary endpoint is overall survival (OS). Secondary endpoints include PFS, objective response rate and time to progression. The study has > 80% power to detect a 33% risk improvement in median OS (hazard ratio ≤ 0.67), using a one-sided, stratified log-rank test at a significance level of 0.025. An interim analysis is planned when 50% of final OS events have been reported. Enrollment was initiated in June 2015. Approximately 80 sites worldwide will be open to enrollment by the end of 2016. Clinical trial information: NCT02387216.
A phase II trial of axitinib plus pembrolizumab for patients with advanced alveolar soft part sarcoma (ASPS) and other soft tissue sarcomas (STS).
Authors: Breelyn A. Wilky, Matteo Maria Trucco, Despina Kolonias, Eric Wieder, Ty Subhawong, Andrew Rosenberg, Deukwoo Kwon, Wungki Park, Vaia Florou, Darcy A Kerr, Efrosyni Sfakianaki, Jaime R. Merchan, Krishna Komanduri, Jonathan C. Trent
Journal: Journal of Clinical Oncology (2018)

11547 Background: Inhibition of programmed-death 1 (PD1) by pembrolizumab (P) produced overall response rates (ORR) of 19% in advanced STS [SARC028]. Vascular endothelial growth factor (VEGF) suppresses the immune microenvironment and may contribute to checkpoint inhibitor resistance. Axitinib (Ax) is a pan-VEGFR inhibitor that prolongs progression-free survival (PFS) in advanced STS [Axi-STS], with striking antitumor activity in combination with P in renal cell carcinoma. We report toxicity, efficacy, and correlative endpoints of combination Ax/P for patients (pts) with advanced STS. Methods: NCT02301039 is an open-label Phase II trial of Ax/P in 30 pts with advanced or metastatic STS, requiring RECIST 1.1 progressing disease, adequate end-organ function and performance status. Pts received Ax 5 mg PO twice daily with concurrent P 200mg IV q21 days. Primary endpoint: 3-month PFS rate (PFS3mo); secondary endpoints: toxicity, ORR and clinical benefit rate (CBR) by RECIST 1.1, and overall survival. Tumor biopsies and peripheral blood samples were obtained for correlative studies of TIL and PBMC at baseline, 3 months on treatment, and at progression. Results: 33 pts received at least one dose of study drugs, with 30 pts evaluable for primary endpoint. Enrolled subtypes: ASPS (36%), UPS (15%), LMS (18%), other (30%). PFS3mo was 70.3% [95% CI 50.7-83.3], with median PFS of 5.4 months [95% CI 3.02-11.6]. Best ORR was 21.9% [95% CI 5.9-33.5]. PFS3mo in ASPS pts was 90.9% [95% CI 50.8-98.7], with best ORR of 45.5% [95% CI 18.1-75.4] and CBR of 72.7% [95% CI 39.3-92.7]. Ax/P was well-tolerated, with similar immune-related toxicity rates to prior studies. Correlative markers were analyzed by a penalized logistic regression model with bootstrapping to predict PFS3mo. Baseline high plasma angiogenic activity, circulating neutrophil:lymphocyte ratio < 4.1, low naïve fraction CD4+ TIL, and low PD1+CD8+ PBMC were associated with lack of progression (AUC 0.878 [95% CI 0.743-1, p = 0.0002]). Conclusions: Combination Ax/P is well-tolerated with promising activity in ASPS pts. Identified immune correlates associated with PFS should be validated in prospective immunotherapy trials. Clinical trial information: NCT02301039.
Effect of a new cancer diagnosis on labor force participation (LFP): Has there been a change over time?
Authors: Amy J. Davidoff, Linda F. Cantley, Deron H. Galusha
Journal: Journal of Clinical Oncology (2017)

e18004 Background: Health shocks, such as a new cancer diagnosis, have been shown to reduce LFP in working adults. Over the past decade, there have economic swings, retirement age has increased, while newer cancer treatments may be less toxic or disabling. We update prior estimates of LFP responses, and assess whether patterns changed over time. Methods: Adults from the 1998-2014 waves of the Health and Retirement Study (HRS) who were aged 51+ yrs and working in 1998 or at HRS cohort entry in 2004 or 2010, were followed until their LFP decreased. Decreased LFP was defined as a switch from fulltime work, or a 10 hour or 25% decrease in hours worked. We created time varying indicators for health conditions (cancer, heart condition, lung disease, stroke) newly reported or worsened since the prior wave, condition history, demographics, net worth, and insurance coverage. We estimated discrete Cox proportional hazard survival models for the full sample, and with person-wave observations stratified pre/post 2008. Results: Among 13,918 working adults, mean age was 56 years, 45% women; health history included 5.3% cancer, 9.5% heart condition, 4.1% lung disease, 1.5% stroke; new health conditions included 2.9% cancer, 4.7% heart, 2.3% lung, and 1.3% stroke. Newly reported or worsened cancer, heart and lung disease were associated with similar risk of LFP decrease (see table). Prior history of lung disease, diabetes, arthritis and psychiatric disorders were associated with LFP decreases, but cancer was not. There was no difference in the effect of a new condition on LFP pre/post 2008. Conclusions: Many working adults reported preexisting health conditions. New diagnoses or worsening of cancer and other serious health conditions were associated with LFP reductions, although a longer term history of cancer was not associated with LFP changes. [Table: see text]
Phase 1/2 study of mRNA vaccine therapy + durvalumab (durva) ± tremelimumab (treme) in patients with metastatic non-small cell lung cancer (NSCLC).
Authors: Leena Gandhi, Kristen Aufiero Ramirez, Paul Schwarzenberger, Toni Ricciardi, Mary J. Macri, Aileen Ryan, Ralph Rudolph Venhaus
Journal: Journal of Clinical Oncology (2018)

TPS9107 Background: Vaccine therapies stimulate the immune system to attack cancer cells (active immunotherapy), whereas checkpoint inhibitors block immune inhibition (passive immunotherapy). Several PD-1 and PD-L1 blocking antibodies are approved for NSCLC. This study combines active and passive immunotherapies to determine if the addition of a mRNA vaccine can enhance the activity of checkpoint blockade. The vaccine BI 1361849 (comprising 6 mRNAs encoding for selected tumor-associated antigens: MUC1, survivin, NY-ESO-1, 5T4, MAGE-C2 and MAGE-C1) is combined with 1 or 2 checkpoint inhibitors (durva [anti-PD-L1] ± treme [anti-CTLA-4]). Methods: This ongoing Phase 1/2, open-label study (NCT03164772) evaluates the safety and efficacy of BI 1361849 when administered with durva (Arm A) or durva + treme (Arm B) in NSCLC patients. In arm A, an initial dose-evaluation phase follows a 3+3 design to determine the dose of durva (1500 or 750 mg) to be given with the vaccine. Arm B uses the durva dose from Arm A, with the addition of 75 mg treme. In the expansion phase, 20 patients are treated in each arm. To aid in the evaluation of immune responses, there is an additional control group (n = 10), which receives the checkpoint inhibitors only. Study treatment is administered over 12 (28-day) cycles. Durva (x 12 doses) and treme (x 4 doses) are administered intravenously every 28 days. The vaccine is administered on 1 to 3 days over each of the 12 cycles using a device that provides a needle-free intradermal administration. The primary endpoint is safety/tolerability per CTCAE, including dose-limiting toxicity during dose evaluation. Secondary endpoints are progression-free survival and objective response rate at 8 and 24 weeks, disease control rate, response duration, and overall survival, with tumor response evaluated by RECIST and immune-related RECIST. Exploratory objectives include effects on tumor microenvironment and evaluation of immune responses. Enrollment opened 20Dec2017. Clinical trial information: NCT03164772.
Phase II trial of pembrolizumab (MK-3475) in metastatic cutaneous squamous cell carcinoma (cSCC).
Authors: Ragini Reiney Kudchadkar, Melinda Lynne Yushak, David H. Lawson, Keith A. Delman, Michael C. Lowe, Monica Goings, Stephanie McBrien, Marjorie Mckellar, Kristin Sieja, Necia Maynard, Mandy Ford, Brian P. Pollack
Journal: Journal of Clinical Oncology (2018)

9543 Background: cSCC is the second most common skin cancer in the U.S. with over 700,000 new cases and 2000 deaths per year. Though most cSCCs are curable with surgery or radiation, 5% metastasize and are treated typically with platinum-based chemotherapy and EGFR inhibitors as standard of care. These agent have overall response rates (ORR) of only10-20%. No current treatments have been shown to improve overall survival. Methods: Clinical activity of pembrolizumab in metastatic cSCC patients not curable by surgery or radiation was evaluated. Primary objective was to establish the ORR of pembrolizumab in metastatic cSCC per RECIST 1.1 Secondary objectives were 6-month progression-free survival (PFS) and 1 year overall survival. The study was conducted with Simon’s optimal two-stage design, with goal of 12 patients in the first stage with 3 or more responses would lead to stage two that would include an additional 13 patients. Patients were treated with pembrolizumab 200mg IV every 3 weeks for up to 2 years. Normal skin, blood, and tumor tissue were obtained for biomarker studies including PD-L1, expression of co-stimulatory and co-inhibitory molecules on and functionality of T cell populations. Results: Ten subjects (2 females) with a median age of 68.7 years are reported. All subjects were Caucasian. ORR was 40%, with 10% (1) complete response (CR),30% (3) partial responses (PR), 10% (1) stable disease (SD) 10% (n = 1), progressive disease (PD) 20% (n = 2), and 3 subjects are not yet evaluable. Three subjects had prior chemotherapy, 2 of the 3 had PD, 1 subject not yet evaluable. All patients with CR, PR, and SD are yet to progress at current follow up. No subject deaths have occurred on study. Two grade 3 related-adverse events were noted, hepatitis and pneumonitis. No unexpected adverse events related to treatment have occurred. Median PFS and OS has not been reached as of February 2018. Further follow up as well as biomarker correlates will be presented. Conclusions: Pembrolizumab has significant clinical activity in cSCC. Expansion into the second stage of the trial is indicated. Further follow up is needed in order to establish survival benefit for these patients. Clinical trial information: NCT02964559.
Effective screening of neoantigen-specific cytotoxic t cells.
Authors: Tatsuo Matsuda, Matthias Leisegang, Jae-Hyun Park, Taigo Kato, Yuji Ikeda, Makiko Harada, Kazuma Kiyotani, Ernst Lengyel, Gini F. Fleming, Yusuke Nakamura
Journal: Journal of Clinical Oncology (2018)

e15061 Background: Current evolution of cancer immunotherapies has implicated neoantigens as major targets of anti-cancer cytotoxic T cells. Adoptive T cell therapy with neoantigen-specific T cell receptor (TCR)-engineered T cells would be an attractive new therapeutic option for advanced cancers where the host anti-tumor immune function is strongly inhibited. Most challenging part of this therapy is generation of neoantigen-specific T cells and identification of neoantigen-specific TCRs. Methods: We first established the pipeline for the rapid expansion of neoantigen-specific T cells and the identification of their TCRs using our own TCR sequencing method. We then chose 14 candidate neoantigen peptides from 7 ovarian tumors to validate our approach. Results: We first stimulated CD8 T cells with neoantigen epitopes identified by exome sequencing for 10 days. Neoantigen-specific T cells (several hundred to a few thousand cells) were enriched using antigen-specific dextramers and TCR sequencing was performed to determine unique TCRs. This step from stimulation of T cells with neoantigen-loaded dendritic cells to the identification of neoantigen-specific TCRs required only two weeks. We successfully induced 3 of 14 neoantigen-specific T cells from one healthy donor and identified their TCR sequences. We confirmed functional activity of the three identified TCRs by generating TCR-engineered T cells recognizing the corresponding neoantigens and showed cytotoxic activity in an antigen-dose-dependent manner. However, one of three neoantigen-specific TCR-engineered T cells showed cross-reactivity against the corresponding wild-type peptide. Conclusions: We established a 2-week protocol for generating and identifying neoantigen-specific TCRs and demonstrated the feasibility of our protocol using clinical specimens of ovarian cancer. We also reveal the importance of careful validation of neoantigen-specific-TCR-engineered T cells to avoid severe immune-related adverse events.