tbuckley/cabot-search huggingface dataset:
Phase I/II dose escalation and expansion cohort safety and efficacy study of image guided intratumoral CD40 agonistic monoclonal antibody APX005M in combination with systemic pembrolizumab for treatment naive metastatic melanoma.
Authors: Daniel H. Johnson, Salah E Bentebibel, Srisuda Lecagoonporn, Chantale Bernatchez, Cara L. Haymaker, Ravi Murthy, Alda Tam, Cassian Yee, Rodabe Navroze Amaria, Sapna Pradyuman Patel, Hussein Abdul-Hassan Tawbi, Isabella Claudia Glitza, Michael A. Davies, Wen-Jen Hwu, Patrick Hwu, Willem W Overwijk, Adi Diab
Journal: Journal of Clinical Oncology (2018)

TPS3133 Background: Checkpoint blockade has become a major modality in the treatment of metastatic melanoma (MM). However, durable remission rates remain low. CD40 activation on antigen presenting cells (APCs) initiates their ability to prime and activate CD8+ T-cells through upregulation of co-stimulatory molecules (ie. CD80, CD86) as well as expression of effector cytokines. Furthermore, CD40 activation cause macrophages to develop a tumoricidal phenotype and increase MHC I expression on tumor cells. Direct IT immune modulation utilizes the tumor as a “vaccine site” to generate a tumor specific immune response. We hypothesize that IT injection of a CD40 Agonist (A), will “immunize” patients (Pts) against melanoma neoantigens through “licensing” of APCs for tumor specific T-cell priming and activation. In mouse models, we have shown that IT administration of the recombinant adenovirus encoding CD40L induces CD8+ T-cell-mediated activity against B16 melanoma and, importantly, also augmented the activity of anti-PD-1. Methods: This phase I/II trial (NCT02706353) evaluates the safety, efficacy, and immunological impact of IT administration of APX005M (CD40 A mAb) in combination with pembrolizumab in pts with MM. The phase I escalation is an accelerated 3+3 design. Pts will receive IT APX005M every 3 weeks for a total of 4 doses. Image guidance will allow for injection of visceral, nodal, and soft tissue metastases. The single-arm phase 2 expansion will evaluate the overall response rate (ORR) 12 weeks after treatment initiation. Key inclusion criteria: confirmed, measurable, metastatic cutaneous or mucosal melanoma; and at least 2 injectable lesions. Key exclusion criteria: prior immunotherapy, uveal melanoma, or active autoimmune disease. 26 pts will have 75% power to detect an improvement from a null ORR of 33% to 55%, using a one group chi-square test and assuming a one-sided α–level of 5%. Immune analysis will be performed on pre and on-treatment tumor/liquid biopsies both in injected and non-injected tumors. Dose level 3 of escalation phase has completed with 5 pts enrolled. Clinical trial information: NCT02706353.
Circulating tumor cell (CTC) number as a response endpoint in metastatic castration resistant (mCRPC) compared with PSA across five randomized phase 3 trials.
Authors: Glenn Heller, Robert Thomas Mccormack, Thian Kheoh, Matthew Raymond Smith, Robert Dreicer, Fred Saad, Ronald De Wit, Dana T. Aftab, Mohammad Hirmand, David B. MacLean, Karim Fizazi, Johann S. De Bono, Howard I. Scher
Journal: Journal of Clinical Oncology (2017)

5007 Background: Radiographic progression and overall survival (OS) are the traditional clinical benefit measures for mCRPC trials. Reliable indicators of response that occur early are a critical unmet need in practice and clinical research. We explored a week 13 CTC and prostate-specific antigen (PSA) endpoint relative to baseline in 5 prospective randomized phase 3 registration trials that enrolled 5912 pts. OS was the primary endpoint. Methods: CTC number (CellSearch) and PSA values in patients who survived at least 13 weeks were evaluated as response endpoints in COU-AA-301, AFFIRM, ELM-PC-5, ELM-PC-4 and COMET-1. Pts with missing values at week 13 were considered non-responders. The endpoints considered are shown in Table 1. Results: The discriminatory strength of the response endpoints with respect to OS was estimated using the weighted c-index. To summarize discrimination results for each measure, the mean and the standard deviation based on the weighted c-indices from the 5 studies were computed. Conclusions: CTC0 and CTC conversion endpoints had the highest discriminatory power for OS relative to the % decline in CTC or PSA endpoints. The percent of pts eligible and evaluable for the CTC0 endpoint was significantly higher than the conversion endpoint, 75% vs. 51%, respectively. These two absolute measures of CTC can be considered meaningful response indicators in mCRPC clinical trials. [Table: see text] [Table: see text]
Variability in genomic alterations between right- and left-sided microsatellite stable (MSS) metastatic colorectal cancer and impact on survival.
Authors: Rona Yaeger, Walid Chatila, Marla Lipsyc, Francisco Sanchez-Vega, Jaclyn Frances Hechtman, Andrea Cercek, Zsofia Kinga Stadler, Sumit Middha, Ritika Kundra, Aijazuddin Syed, Ahmet Zehir, Anna M. Varghese, Neil Howard Segal, Efsevia Vakiani, Marc Ladanyi, Michael F. Berger, Nancy E. Kemeny, Jinru Shia, Leonard Saltz, Nikolaus Schultz
Journal: Journal of Clinical Oncology (2017)

3534 Background: Metastatic colorectal cancers (mCRCs) with a right-sided primary site are associated with shorter survival and insensitivity to EGFR inhibitors compared to those originating in the left side of the colon or rectum. Methods: We performed targeted gene sequencing of 928 consecutive MSS mCRCs. Primary tumor site was divided into right-sided for cecum to distal transverse colon (n = 242), left-sided for splenic flexure to rectum (n = 673), or unknown colonic location (n = 13). Histologic subtypes were conventional (adenocarcinoma not otherwise specified), conventional with mucinous features ( &lt; 50% mucinous), mucinous, signet ring, and poorly differentiated. To evaluate receptor tyrosine kinase (RTK) signaling, we analyzed ligand mRNA expression in TCGA. Results: Overall survival from time of metastasis was shorter for right-sided than left-sided primary site (survival at 5 years: 45% v 67%, p &lt; 0.001). Right-sided tumors had more mutations (5.60 v 4.62 per MB, p &lt; 0.001) but fewer copy-number changes (0.18 v 0.22 fraction genome altered, p = 0.001) compared to left-sided tumors. Alterations of KRAS, BRAF, PIK3CA, PTEN, AKT1, RNF43, and SMAD4 were significantly enriched in right-sided tumors, and of APC and TP53 in left-sided tumors. In a multivariate model, APC (HR = 0.7, p = 0.03), BRAF (HR = 3.7, p &lt; 0.001), and KRAS (HR = 1.7, p &lt; 0.01) alterations predicted for survival, but primary site did not (HR = 0.74, p = 0.07). Amphiregulin, epiregulin, neuregulin, and HGF expression was significantly higher in left-sided tumors. We found a higher proportion of conventional histology (83% v 63%) and moderate differentiation (82% v 69%) for left versus right-sided cases. Conclusions: We find that within MSS mCRC there are significantly more oncogenic mutations in right-sided tumors, and the difference in survival between right- and left-sided mCRC is primarily driven by differences in mutations. Left-sided tumors more commonly exhibit a “simpler” conventional histology that is lower grade and may rely on native RTK signaling, such as EGFR, for growth, providing a potential mechanism for the differential sensitivity to EGFR inhibitors seen by primary tumor site.
Association of financial hardship with receipt of necessary medical care among adult cancer survivors.
Authors: Matthew P. Banegas, John F Dickerson, Erin E. Kent, Janet de Moor, Gery P Guy, Donatus U. Ekwueme, Katherine S. Virgo, Zhiyuan Zheng, Stephanie Nutt, Loyce Pace, Lisa Waiwaiole, Alexandra M Varga, Jennifer L Schneider, K Robin Yabroff
Journal: Journal of Clinical Oncology (2016)

e18010 Background: Financial hardship is common among individuals diagnosed with cancer. The purpose of this study was to evaluate the association between financial hardship and the receipt of necessary medical care among adult cancer survivors. Methods: Data on 4,271 adult cancer survivors aged 18-64 years who completed the 2012 LIVESTRONG survey were used in this study. Financial hardship was measured as experiencing any of following items: (1) borrowing money or going into debt, (2) filing for bankruptcy, (3) being unable to cover one’s share of medical care costs, or (4) making other financial sacrifices, because of cancer, its treatment, or lasting effects of treatment. Receipt of necessary medical care was measured by “At any time since you were first diagnosed with cancer, did you get all of the medical care, tests, or treatments that you or your doctor believed were necessary?” Using logistic regression, we evaluated the association between financial hardship with the receipt of necessary medical care. Multivariable models were adjusted for patient age, sex, marital status, insurance, income, employment, caregiver, number of cancer diagnoses and time since last treatment. Results: Approximately, 54% of adult cancer survivors experienced financial hardship and 9% reported not receiving necessary medical care. In adjusted models, adult cancer survivors who reported financial hardship were significantly more likely to report not receiving necessary medical care (OR = 3.04, 95% CI: 2.32–3.97). Female survivors (OR = 1.42; 95% CI: 1.11–1.82), those with multiple cancer diagnoses (OR = 1.32; 95% CI–1.04–1.67), without a caregiver (OR = 1.58; 95% CI: 1.14–2.19), and uninsured (OR = 2.01; 95% CI: 1.38–2.91) were also more likely to report not receiving necessary medical care. Conclusions: Our findings suggest that financial hardship from cancer was a strong predictor of not receiving necessary medical care among adult cancer survivors. Failure to receive medical care, both cancer and non-cancer related, may exacerbate disparities in cancer outcomes and survivorship. Further research is warranted to develop interventions that reduce the financial hardship of cancer, its treatment or lasting effects of treatment.
TCT-584 Long-Term Impact of Improving Drug-Eluting Stent Technology in Patients Undergoing Multilesion Intervention: A Patient-Level Analysis of 19 Randomized Trials
Authors: None Paul Guedeney, Roxana Mehran, Bimmer Claessen, Mengdan Liu, Sabato Sorrentino, Serdar Farhan, Martin Leon, Patrick Serruys, Pieter Smits, Clemens von Birgelen, Ori Ben-Yehuda, Mahesh Madhavan, Bjorn Redfors, Gregg Stone
Journal: Journal of the American College of Cardiology (2018)
Abstract 12770: The Significant Role of Endothelium and Arterial Wall Properties in Patients With Pseudoexfoliative Glaucoma
Authors: Georgia Siasou, Gerasimos Siasos, Marilita M Moschos, Nikolaos Gouliopoulos, Evangelos Oikonomou, Thodoris Paraskevopoulos, Sotiris Tsalamandris, Konstantinos Mourouzis, Stathis Dimitropoulos, Alexios Antonopoulos, Eleni Kokkou, Marina Zaromitidou, Christodoulos Stefanadis, Dimitris Tousoulis
Journal: Circulation (2015)

Introduction: Primary open-angle glaucoma (POAG) is one of the most prevalent causes of irreversible blindness and is associated with endothelial dysfunction and arterial stiffness. Pseudoexfoliative glaucoma (PEG) is another type of glaucoma observed in pseudoexfoliation syndrome. It is characterized by the deposition of pseudoexfoliative material not only to the anterior segment of the eye, but also to the vessels, heart and other organs. Hypothesis: Endothelial function and arterial stiffness are impaired in patients with POAG and PEG supporting the significant role of vascular function impairment in the progression of the disease. Methods: Forty four POAG patients, 22 PEG and 38 healthy subjects (Cl) were included in this study. All subjects were free of cardiovascular or inflammatory diseases. Endothelial function was evaluated by flow-mediated dilatation (FMD). Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as a measure of arterial wave reflections Results: Between the three study groups CL, POAG, PEG there was no difference in age (67±10years vs. 70±9years vs. 66±12yeras, p=0.12) or prevalence of male sex (70% vs. 57% vs. 50%, p=0.21). Importantly, there was a linear impairment of FMD (7.35±2.77% vs. 6.58±3.18% vs. 4.88±3.29%, p=0.006), PWV (7.98±1.56m/sec vs. 9.20±1.84m/sec vs. 9.22±2.16m/sec, p=0.004) and AIx (21.29±8.77% vs. 25.14±5.71% vs. 28.20±8.75%, p=0.002) from CL to POAG and PEG. Interestingly post hoc test after Scheffe correction revealed also that PEG subjects had not only significantly impaired FMD, compared to control subjects, but also compared to POAG subjects (4.88±3.29% vs. 6.58±3.18%, p=0.02). Conclusions: Endothelial function and arterial stiffness are significantly impaired in patients with pseudoexfoliative glaucoma. These findings shed some light in the pathophysiology of pseudoexfoliative glaucoma and support the theory that pseudoexfoliative fibrils may also accumulate and damage the arterial wall.
Use of circulating tumor DNA to predict survival in patients with resected high-risk stage II/III melanoma.
Authors: Rebecca Lee, Gabriela Gremel, Andrea Marshall, Kevin A Myers, Nita Fisher, Philippa Corrie, Janet Dunn, Nathalie Dhomen, Mark R. Middleton, Richard Marais, Paul Lorigan
Journal: Journal of Clinical Oncology (2017)

9583 Background: Patients with high-risk stage II/III resected melanoma commonly develop metastatic disease. Adjuvant high dose interferon and ipilimumab 10mg/kg are associated with survival benefit, but at the expense of toxicity. At present, we cannot differentiate between patients who will progress to stage IV disease or those cured by surgery. Circulating tumor DNA (ctDNA) is a biomarker of disease progression in many cancers including stage IV melanoma, however its utility in the adjuvant setting has not been investigated. Methods: We performed droplet digital polymerase chain reaction to detect BRAF and NRAS mutations in plasma of 161 stage IIB, IIC/III high-risk melanoma patients enrolled in AVAST-M; a randomized study of bevacizumab vs. observation. Baseline plasma samples were collected within 12 weeks of surgery for both arms. Results: Mutant BRAF or NRASctDNA was detectable ( &gt; 1 copy of mutant ctDNA) in 12% (19/161) of patients. Patients with detectable ctDNA had a decreased disease free interval (DFI; hazard ratio [HR] 3.12; 95% confidence interval [CI] 1.79-5.47; p &lt; 0.0001) and distant metastasis-free interval (DMFI; HR 3.22; 95% CI 1.80-5.79; p &lt; 0.0001) vs. those with undetectable ctDNA. One year DFI rate for patients with detectable ctDNA was 26% (95% CI 10-47%) vs. 74% (95% CI 66-81%) for those with undetectable ctDNA. One year DMFI rate for patients with detectable ctDNA was 37% (95% CI 17-57%) vs. 84% (95% CI 77-89%) with undetectable ctDNA. Detectable ctDNA remained a significant predictor after adjustment for N classification and performance status (PS) (DFI HR 3.48; 95% CI 1.95-6.19, p &lt; 0.0001; DMFI HR 3.41, 95% CI 1.88-6.20, p &lt; 0.0001). Five year overall survival (OS) rate for patients with detectable ctDNA was 33% (95% CI 14-55%) vs. 65% (95% CI 56-72%) for those with undetectable ctDNA. OS was significantly worse for patients with detectable ctDNA (HR 2.63; 95% CI 1.4-4.96); p = 0.003) and remained significant after adjustment for PS (HR 2.5, 95% CI 1.32-4.74, p = 0.005). Conclusions: CtDNA is predictive of relapse and survival in high-risk, resected melanoma and can potentially aid stratification of patients for adjuvant therapy.
Improving risk stratification among veterans with newly diagnosed, clinically low-risk prostate cancer using the 17-gene genomic prostate score assay.
Authors: Julie Ann Lynch, Megan Rothney, Raoul Salup, Cesar Emilio Ercole, Sharad Mathur, David Duchene, Joseph W. Basler, Javier Hernandez, Michael Andre Liss, Michael P. Porter, Jonathan L. Wright, Michael Christopher Risk, Mark Garzotto, Olga Efimova, Michael J. Kemeter, Bela Stephen Denes, Phillip G. Febbo, Atreya Dash
Journal: Journal of Clinical Oncology (2016)

e16611 Background: Active surveillance (AS) is a recommended treatment option for low risk prostate cancer (PCa). Studies have shown high rates of AS in the Veterans Administration (VA) yet treatment variation exists between VA medical centers (VAMCs), likely due to concern about missing aggressive disease. The 17-gene Genomic Prostate Score (GPS) has been validated to predict likelihood of favorable pathology (LFP) in men with low risk PCa. This study compares treatment patterns before and after introduction of the GPS to determine if the assay assists in risk-stratification. Methods: Men with PCa who met NCCN criteria for very low (VL), low (L), or intermediate (INT) risk PCa were eligible. Chart review of men across 6 VAMCs established baseline treatment in untested patients in 2013-2014. In 2015, Veterans at the same VAMCs were offered the assay in a prospective study. Treatment recommendations and treatment implemented were captured. Results: There were 200 men in the untested cohort. Characteristics: age (median = 66, range:43-83), Gleason Score (GS) (3+3:64%, 3+4:37%), PSA (mean = 6.6, range:0.7-20), NCCN risk (VL:18%, L:37%, INT:46%). 62% pursued AS. Use of AS varied across VAMCs (range:31%-84%). Among 129 Veterans prospectively enrolled, characteristics were similar. NCCN risk VL: 25%, L: 41%, INT: 34%. GPS ranged from 4-48. GPS identified 13 patients who had more favorable pathology and 11 patients who had less favorable pathology. The change in pathology was found mainly among low-risk patients (12.5% of VL, 75% of L, and 12.5% of INT). Treatment choices were: 94% AS among VL; 75% AS, 25% definitive treatment among L; INT risk patients underwent a variety of treatments: AS (19%), EBRT (24%), prostatectomy (38%), brachytherapy (5.4%), multimodal (14%). Mean LFP in INT patients who received treatment was 56%. Conclusions: Chart review confirmed variation in use of AS. Analysis of 129 Veterans tested showed refined risk estimates after GPS. Results presented at the meeting will demonstrate the ability of the GPS assay to identify men with low risk PCa for AS or immediate therapy using individualized biological information.
Health-related quality of life over time in transplant-ineligible patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone until progression.
Authors: Dan T. Vogl, Michel Delforge, Kevin W. Song, Shien Guo, Craig J Gibson, Annette L. Ervin-Haynes, Thierry Facon
Journal: Journal of Clinical Oncology (2016)

8047 Background: The FIRST trial established a PFS and OS benefit for transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM) treated with lenalidomide + dexamethasone (Rd) to progression vs melphalan + prednisone + thalidomide (MPT) (Benbouker et al, 2013) as well as improved health-related quality of life (HRQoL) over the first 18 mo of treatment (Delforge et al, 2015). HRQoL data were not collected past 18 mo, so we estimated HRQoL during extended Rd therapy using collected data. Methods: Univariate linear mixed-effects regression analyses (n = 535) identified variables collected until progression as predictors of 7 predefined HRQoL domains of interest: EORTC QLQ-C30 (global QoL, GQ; physical function, PF; fatigue, F; pain, P), EORTC QLQ-MY20 (disease symptoms, DS; side effects of treatment, SE), and EQ-5D (health utility, HU). Variables with univariate P< 0.1 were combined into multivariate models for each HRQoL domain; variables with P< 0.1 were retained for final models. Modeled values were validated against observed values prior to 18 mo and extended to extrapolate HRQoL changes from baseline based on observed predictor values beyond 18 mo for Rd pts still on treatment at 24, 30, 36, 42, and 48 mo. Results: All observed changes from baseline fell within the 95% confidence interval of the final predictive models, except month 3 of the DS model. Significant improvements in HRQoL from baseline in the first 18 mo of treatment were maintained through 48 mo of Rd therapy. Key time-varying determinants of final mixed models across multiple domains included ECOG performance status (all domains), ongoing hospitalization (GQ, F, SE, HU), serum albumin (GQ, PF, F, P, SE, HU), RBC transfusion within 30 days (F, P, DS), ongoing AEs (GQ, PF), ongoing grade ≥ 3 pain (PF, F, P, DS, SE, HU), grade ≥ 2 fatigue (F), and grade 3/4 anemia (PF, SE). Conclusions: Our results suggest that the gains in HRQoL over the first 18 mo in Rd-treated NDMM pts are maintained for pts on treatment up to 48 mo. Further analysis is needed to compare these HRQoL results to those of pts treated with Rd or MPT through 18 mo but who have not yet progressed beyond 18 mo. Clinical trial information: NCT00689936.
A phase II trial of durvalumab (Medi 4736) in advanced endometrial cancer: PHAEDRA.
Authors: Yoland Catherine Antill, Martin R. Stockler, Peey Sei Kok, Kristy Pamela Robledo, Kim Gillies, John Stark, Sonia Yip, Linda R. Mileshkin
Journal: Journal of Clinical Oncology (2017)

TPS5614 Background: Advanced endometrial cancer (EC) progressing after 1 or more lines of chemotherapy is an area of unmet need with objective tumour response rates to subsequent lines of chemotherapy of ≤20%. DNA mismatch repair (MMR) deficiency, seen in approximately 15% of EC, is associated with a high mutational load and in addition, up to 90% of ECs are reported to have PDL1/ PD1 expressions. These factors make immune check point inhibition an ideal target for treatment. Methods: DESIGN: Multicentre phase 2 trial in two cohorts. ELIGIBILITY: Advanced, unresectable endometrial cancer that is either MMR-proficient and progressing after 1-3 lines of chemotherapy, or MMR-deficient and progressing after 0-3 lines of chemotherapy. ENDPOINTS: Objective tumour response rate (OTRR) according to iRECIST (primary) and RECIST 1.1, disease control rates at 16 and 24 weeks, progression free survival, overall survival, duration of OTR and DC, adverse events, health related quality of life. Tertiary correlative objectives: Associations between immunologic (including PD-L1), DNA mismatch repair (MMR) and other genetic characteristics with clinical outcomes; and family history of cancer and referral to familial cancer services. INTERVENTION: Durvalumab 1500 mg intravenously every 28 days until disease progression or prohibitive toxicity. STATISTICS: Total of 70 participants in two cohorts (35 each) will have 90% power to distinguish a difference in observed OTRR of ≥20% versus ≤5% (uninteresting rate) using Simon’s 2-stage minimax design with 10% type 1 error rate and allowing 10% ineligibility and missing data. Durvalumab will be considered worthy of pursuit if 4 or more OTR are observed in the first 32 participants in each cohort (OTRR ≥12.5%). BIOSPECIMENS: Tumour tissue and serial bloods (5 time points) will be collected for translational research. PHAEDRA is an investigator-initiated, cooperative-group trial led by ANZGOG, in collaboration with NHMRC Clinical Trials Centre, University of Sydney. Australian New Zealand Clinical Trials Registry: Clinical trial information: ACTRN12617000106336.