tbuckley/cabot-search huggingface dataset:
Randomized phase II study of 2nd-line FOLFIRI versus modified FOLFIRI with PARP inhibitor ABT-888 (veliparib) (NSC-737664) in metastatic pancreatic cancer (mPC): SWOG S1513.
Authors: E. Gabriela Chiorean, Shannon McDonough, Philip Agop Philip, Elizabeth M. Swisher, Michael J. Pishvaian, Katherine Guthrie, Andrew M. Lowy, Howard S. Hochster
Journal: Journal of Clinical Oncology (2017)

TPS4147 Background: PC is characterized by multiple DNA repair defects, including in BRCA1/ 2, and other homologous recombination (HR) genes such as FANC, ATM, ATR (Waddell N, Nature 2015). Folinic acid/5-fluorouracil/ irinotecan (FOLFIRI) is a 2 nd line therapy option in mPC, but overall survival (OS) averages only 6 mos (Yoo C, Br J Cancer 2009). It is known that PARP facilitates repair from topoisomerase 1-associated DNA damage, and that preclinically PARP inhibitors (PARPi) increase DNA breaks from camptothecins, resulting in synergistic antitumor effects (Smith LM, Clin Cancer Res 2005, Davidson D, Invest New Drugs 2013). PARPi are active in mPC harboring BRCA1/2 mutations. Given the preclinical synergism between ABT-888 with irinotecan, and the safety and preliminary efficacy noted in a phase I trial (Berlin J, J Clin Oncol 2014; abstr 2574), we designed a randomized phase II study of mFOLFIRI /ABT-888 vs FOLFIRI alone for 2 nd line mPC patients (pts). Blood and tumor samples are collected at baseline to retrospectively analyze biomarkers related to DNA repair capacity, including the HRD assay and BROCA-HR, a targeted multi-gene sequencing to detect alterations within the Fanconi Anemia-BRCA (HR), non-homologous end joining (NHEJ), and DNA mismatch repair pathways, and correlate with efficacy. Methods: Phase II study in 143 pts randomized (1:1) to mFOLFIRI/ABT-888 or FOLFIRI. For optimal PARP inhibition, ABT-888 is dosed Days (D) 1-7 and mFOLFIRI (no 5-FU bolus) D3-5 in 14D-cycles. In the control arm, FOLFIRI is dosed D1-3 in 14D-cycles. Primary endpoint: compare OS between treatment arms; secondary endpoints: safety, progression-free survival, response rates; translational: correlate germline/somatic BRCA1/2 mutations, and other DNA repair biomarkers with efficacy in each arm. Standard eligibility criteria apply. Assuming that the addition of ABT-888 will increase OS from 6 to 9 mos, 128 eligible pts (143 pts total) are required, based on a one-sided type 1 error of 10%, and 80% power. Kaplan-Meier methodology will be used to estimate median OS for each treatment arm. This study is open to accrual (NCT02890355). Clinical trial information: NCT02890355.
Dexamethasone for the prevention of transcatheter arterial chemoembolization-induced fever, nausea, vomiting, and anorexia in patients with hepatocellular carcinoma: A randomized, double-blind, placebo-controlled trial.
Authors: Sadahisa Ogasawara, Tetsuhiro Chiba, Yoshihiko Ooka, Eiichiro Suzuki, Naoya Kanogawa, Tenyu Motoyama, Akinobu Tawada, Tomoo Nakagawa, Kazue Nagai, Hideki Hanaoka, Fumihiko Kanai, Osamu Yokosuka
Journal: Journal of Clinical Oncology (2016)

4071 Background: Fever, nausea, vomiting, and anorexia are the most frequent adverse events of transcatheter arterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). In this study the efficacy of dexamethasone in preventing these events was evaluated. Methods: Patients with HCC who had a Child–Pugh score of A or B and who lacked macrovascular invasion/extrahepatic metastasis were included in this study. Patients were randomly assigned to either a dexamethasone regimen [day 1, intravenous dexamethasone (20 mg) and granisetron (3 mg) before TACE; day 2 and 3, intravenous dexamethasone (8 mg)] or a control regimen [day 1, intravenous placebo (saline) and granisetron (3 mg); day 2 and 3, intravenous placebo]. The primary endpoint was a complete response (CR), which was defined as no grade 1 or higher fever, nausea, vomiting, or anorexia, according to CTCAE (version 4.0), and no use of rescue therapy for 120 h after TACE. Results: From October 2010 to June 2013, 120 patients were randomly assigned. One patient randomly assigned to the dexamethasone regimen did not receive TACE and was therefore excluded from analysis. Thus, 59 patients were randomly assigned to the dexamethasone regimen and 60 to the control regimen and underwent intention-to-treat analysis. The overall CR rate was greater with the dexamethasone regimen than with the control regimen (47.5% vs. 10.2%; P < 0.001). The overall incidence of fever, nausea and vomiting, and anorexia within 120 h following TACE were 28.8%, 27.1%, and 33.9% in the dexamethasone regimen and 72.9%, 47.5%, and 78.0% in the control regimen, respectively. The rate of fever, nausea and vomiting, and anorexia were significantly higher in patients receiving the control regimen than those receiving the dexamethasone regimen (fever: P < 0.001, nausea and vomiting: P = 0.022, and anorexia: P < 0.001). Both treatment regimens were generally well tolerated. Conclusions: The dexamethasone regimen was more effective than the control regimen for the prevention of TACE-induced fever, nausea, vomiting, and anorexia in patients with HCC. Clinical trial information: UMIN000004317.
Association Between Aortic Vascular Inflammation and Coronary Artery Plaque Characteristics in Psoriasis
Authors: Aditya A. Joshi, Joseph B. Lerman, Amit K. Dey, Aparna P. Sajja, Agastya D. Belur, Youssef A. Elnabawi, Justin A. Rodante, Tsion M. Aberra, Jonathan Chung, Taufiq Salahuddin, Balaji Natarajan, Jenny Dave, Aditya Goyal, Jacob W. Groenendyk, Joshua P. Rivers, Yvonne Baumer, Heather L. Teague, Martin P. Playford, David A. Bluemke, Mark A. Ahlman, Marcus Y. Chen, Joel M. Gelfand, Nehal N. Mehta
Journal: JAMA Cardiology (2018)

Inflammation is critical to atherosclerosis. Psoriasis, a chronic inflammatory disease associated with early cardiovascular events and increased aortic vascular inflammation (VI), provides a model to study the process of early atherogenesis. Fludeoxyglucose F 18 positron emission tomography/computed tomography (18F-FDG PET/CT) helps quantify aortic VI, and coronary computed tomography angiography provides coronary artery disease (CAD) assessment through evaluation of total plaque burden (TB) and noncalcified coronary plaque burden (NCB), luminal stenosis, and high-risk plaques (HRP). To our knowledge, association between aortic VI and broad CAD indices has not yet been assessed in a chronic inflammatory disease state. Such a study may provide information regarding the utility of aortic VI in capturing early CAD.To assess the association between aortic VI and CAD indices, including TB, NCB, luminal stenosis, and HRP prevalence, in psoriasis.In a cross-sectional cohort study at the National Institutes of Health, 215 consecutive patients with psoriasis were recruited from surrounding outpatient dermatology practices. All patients underwent 18F-FDG PET/CT for aortic VI assessment, and 190 of 215 patients underwent coronary computed tomography angiography to characterize CAD. The study was conducted between January 1, 2013, and May 31, 2017. Data were analyzed in March 2018.Aortic VI assessed by 18F-FDG PET/CT.Primary outcome: TB and NCB. Secondary outcomes: luminal stenosis and HRP.Among 215 patients with psoriasis (mean [SD] age, 50.4 [12.6] years; 126 men [59%]), patients with increased aortic VI had increased TB (standardized β = 0.48; P < .001), and higher prevalence of luminal stenosis (OR, 3.63; 95% CI, 1.71-7.70; P = .001) and HRP (OR, 3.05; 95% CI, 1.42-6.47; P = .004). The aortic VI and TB association was primarily driven by NCB (β = 0.49; P < .001), whereas the aortic VI and HRP association was driven by low-attenuation plaque (OR, 5.63; 95% CI, 1.96-16.19; P = .001). All associations of aortic VI remained significant after adjustment for cardiovascular risk factors: aortic VI and TB (β = 0.23; P < .001), NCB (β = 0.24; P < .001), luminal stenosis (OR, 3.40; 95% CI, 1.40-8.24; P = .007), and HRP (OR, 2.72; 95% CI, 1.08-6.83; P = .03). No association was found between aortic VI and dense-calcified coronary plaque burden.Aortic VI is associated with broad CAD indices, suggesting that aortic VI may be a surrogate for early CAD. Larger prospective studies need to assess these associations longitudinally and examine treatment effects on these outcomes.
Patient experiences with avelumab vs chemotherapy for treating merkel cell carcinoma: Results from protocol-specified qualitative research.
Authors: Howard Kaufman, Jeremy Lambert, Carla Dias Barbosa, Isabelle Guillemin, Lisa Mahnke, Murtuza Bharmal
Journal: Journal of Clinical Oncology (2017)

e21065 Background: Avelumab is a fully human anti–PD-L1 monoclonal antibody that has shown durable responses and a manageable safety profile in patients (pts) with various tumors, including metastatic Merkel cell carcinoma (mMCC). We report findings from qualitative interviews with mMCC pts about their experiences with avelumab or chemotherapy. Methods: Pts with mMCC who progressed after chemotherapy were enrolled in a registrational, single-arm, multicenter, international phase 2 trial (NCT02155647). Protocol-specified semi-structured phone interviews were conducted at baseline (to document experiences with chemotherapy) and during avelumab treatment at Weeks 13 and 25. Interview transcripts were analyzed qualitatively using a thematic approach. Results: Interviews were conducted with 19 pts at baseline and 10 pts at Weeks 13 and 25. At baseline, most pts (n = 12) reported that chemotherapy was initially successful prior to relapse. At Week 13, pts generally were “optimistic,” but “cautious,” and had “high hopes” regarding avelumab treatment. Pts most frequently reported having no or fewer side effects (n = 6) with avelumab vs prior chemotherapy. At Week 13, fatigue was the most frequently reported impact of avelumab (n = 8); at Week 25, 3 pts still reported fatigue, but 5 “felt less tired” than at Week 13. Most pts (n = 12) had experienced fatigue with chemotherapy; having “less energy” was the most-reported effect (n = 4) when compared with avelumab. Most pts did not report any negative impact of avelumab on everyday lives (n = 7); 3 reported a need “to rest more often after activities.” In contrast, only 6/19 pts reported that chemotherapy had no negative impact or a” very small” negative impact on everyday lives. Eight pts reported feeling “slowed down” or “being limited” in physical capacities during chemotherapy. Eight pts thought that chemotherapy had substantial negative impact on their lives, describing it as “very disruptive,” “debilitating,” or “devastating.” Conclusions: Pts had a more positive experience with avelumab than chemotherapy; it had a minimal detrimental impact on their lives. Clinical trial information: NCT02155647.
Randomized phase II trial of trofosfamide vs. adriamycin in elderly patients with previously untreated metastatic soft tissue sarcoma.
Authors: Joerg Thomas Hartmann, Hans Georg Kopp, Viktor Gruenwald, Sophie Piperno-Neumann, Annegret Kunitz, Ralf Hofheinz, Lothar Mueller, Michael Geissler, Marius Horger, Peter Fix, Jens Chemnitz, Robert Eckert, Claus Hann von Weyhern, Sebastian Bauer, Frank Mayer
Journal: Journal of Clinical Oncology (2018)

11507 Background: DOX is still the standard in metastatic STS. We assessed the efficacy and safety of oral TRO. Methods: This is a randomized phase 2 trial at 15 german and 1 french centers. We included pts with metastatic high-grade STS, older than 60 yrs of age, with an ECOG of 0-1. They were randomly (1:2) assigned to either (A) DOX (60 or 75 mg/sqm i.v., on day 1, q 22 d for 6 cycles) or arm B (oral TRO, 300 mg, d1-7, then 150mg daily continuously p.o.) as first-line tx. Randomisation was stratified by presence of liver mets, and PS (0 vs 1). Pts were treated until PD or unacceptable toxicity. Primary aim was a 6-months (mos) PFS rate of at least 20 % in Arm B; secondary: safety, ORR, survival. Results: Between 8/04 and 10/12 40 pts were randomly assigned to arm A and 80 to Arm B, median age 70 yrs (60-89). Median duration of f/u of surviving patients was 18.4 mos (range, 3.8-94.7). Median treatment duration was 2.8 mos (0-4.6) in A and 2.8 mos (0.4-41.4) in B. No difference in terms of ORR with 7.7% (1.6-20.9) in arm A and 6.7% (2.2-14.9%) in arm B (p = 0.99); disease control rate (including disease stabilization) (53.8% (95%-CI, 37.2-69.9%) vs. 41.3% (95%-CI, 30.1-53.3%), p = 0.23), PFS (4.3 mos; 95%-CI, 2.2-5.9 vs. 2.8 mos; 95%-CI, 1.6-3.5), p = 0.99) and OS (9.6 mos; 95%-CI, 6.4-11.6 vs. 12.1mos; 95%-CI, 9.5-16.0), p = 0.59) were seen, without difference in ITT- and per-protocol populations. Duration of response lasted 5.0 mos in arm A (range, 1.3-8.0) and 4.0 mos (0-46.6) in arm B; however, in pts achieving a CR or PR duration was longer in favor of cohort B (0 vs. 27.7 mos resp. 4.3 vs. 8.2 mos). Primary study endpoint (6-mos PFR) was 27.6% in Arm B (95%-CI, 18.0-39.1). Safety analyses in 115 pts showed at least one side effect in 97.4% vs. 96.1% pts (p = 0.99); of note, side effects G3-4 were lower in favor of Arm B (59% vs. 30.3%; p = 0.005). TRO caused more often dyspnoe, fatigue (but only minor degree); DOX leukocyto- and neutropenia as well as mucositis, G1-4. Discontinuation rate other than PD was 15.4% vs. 7.9%. Conclusions: In an elderly population of pts who received either standard Dox or oral TRO for metastatic STS, equal median PFS and OS have been achieved. TRO associated with a more favorable toxicity profile. Clinical trial information: 00204568.
Patterns of PSA versus clinically progressive disease in the E3805 CHAARTED trial.
Authors: Alan Haruo Bryce, Yu-Hui Chen, Glenn Liu, Michael Anthony Carducci, David Frazier Jarrard, Jorge A. Garcia, Robert Dreicer, Maha Hussain, Mario A. Eisenberger, Manish Kohli, Noah M. Hahn, Elizabeth R. Plimack, Nicholas J. Vogelzang, Joel Picus, Robert S. DiPaola, Lauren Christine Harshman, Christopher Sweeney
Journal: Journal of Clinical Oncology (2018)

5046 Background: Recent data has highlighted the high frequency with which metastatic prostate cancer can progress either radiographically or symptomatically without a rise in PSA, so called PSA-Clinical discordance. Recognizing this clinical phenomenon is important to implementing appropriate criteria for disease monitoring during treatment. Methods: 790 men were accrued from 7/28/06 to 11/21/2012 and randomized to ADT or ADT + Docetaxel at 75mg/m2 every 3 weeks for 6 cycles. Patients were prospectively stratified into high volume (HV) vs. low volume (LV) disease. Clinical PD was defined as increasing symptomatic bone metastases, progression per RECIST criteria, or clinical deterioration due to cancer per investigator’s opinion. PSA PD was defined as an increase in PSA of more than 50% above the on-treatment nadir, with two consecutive increases at least 2 weeks apart. Concurrent PSA PD and Clinical PD is defined as both events occurring within 1 month. Results: As of the data cutoff of 4/30/2016 403 men with HV disease and 157 with LV disease had progressed. In HV disease, the most common progression pattern was PSA PD followed by clinical PD in both the ADT + D and ADT arms (39.5 vs 43.2%). Clinical PD without PSA progression occurred in 29.5% and 31.0% of patients. In LV disease, the dominant pattern of progression was Clinical PD without PSA PD, occurring in 44.8% and 34.4% of patients. PSA PD followed by clinical PD occurred in 28.4% and 37.8% of patients. Table 1: Disease progression pattern by treatment arm and disease volume Clinical trial information: NCT00309985. Conclusions: Clinical progression of disease in the absence of a PSA rise is frequent in patients treated for metastatic castration sensitive prostate cancer. The results highlight the need to incorporate imaging into treatment monitoring rather than relying on PSA alone to trigger imaging. Disease progression pattern High volume Low volume ADT+D ADT alone ADT+D ADT alone Concurrent PSA PD and clinical PD 11 (5.8%) 18 (8.5%) 3 (4.5%) 1 (1.1%) PSA PD first and then clinical PD 75 (39.5%) 92 (43.2%) 19 (28.4%) 34 (37.8%) PSA PD only 48 (25.3%) 37 (17.4%) 15 (22.4%) 24 (26.7%) Clinical PD only 56 (29.5%) 66 (31.0%) 30 (44.8%) 31 (34.4%) Total 190 213 67 90
Abstract 13962: Goals of Care Intervention in Advanced Heart Failure
Authors: Cynthia M Dougherty, Ardith Z Doorenbos, Wayne C Levy, J R Curtis
Journal: Circulation (2016)

Introduction: Guidelines for care in Stage D advanced heart failure (HF) include discussions of prognosis, advance care planning, and deactivation of the implantable defibrillator, along with symptom management and quality of life. The purpose of this study was to evaluate, among adults with advanced HF and their HF providers, the effect of a communication intervention designed to improve patient-provider communication about goals of care (GoC) that incorporated prognostic information from the Seattle HF Model (SHFM). Hypothesis: Patients in the GoC intervention will demonstrate increased numbers of GoC conversations, quality of communication, quality of life, with reduced depression and anxiety compared to usual care (UC). Methods: Eighty patients (40/group) with a diagnosis of HFrEF (EF%&lt; 40%), mean age 58.2±11.2 years, 76.3% male, 82.5% Caucasian, EF%=30.3±9.7%, 1 year SHFM scores of 95.1% participated in a RCT comparing GoC to UC. HF providers were physicians and APRNs (N=9) in a tertiary care academic medical center. The GoC intervention: HF education, ICD deactivation information, and the Five Wishes directive, delivered in a nurse-led telephone discussion that preceded a subsequent HF clinic visit. At baseline and after the HF visit, the Quality of Communication (QOC), Kansas City Cardiomyopathy Questionnaire (KCCQ), Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder (GAD-7) scales were completed. Numbers of GoC conversations are verified with medical records. Analysis of variance will be used to determine effects on study outcomes. Results: There was a significant increase in goals-of-care conversations (73% vs, 2.6%, p &lt;0.001) and quality of end-of-life communication ( p =0.03) in the GoC group compared to UC after the intervention. There were no significant differences between groups on quality of life, anxiety, or depression. HF providers noted that having a GoC conversation within a regular HF clinic visit took additional clinic time. Conclusions: The GoC intervention resulted in more GoC conversations and higher quality communication between HF patients and HF providers without increased anxiety or depression. Further studies are needed to assess impact on longer-term quality of care and patient outcomes.
Gemcitabine/nab-paclitaxel (G/A) alternating with 5-FU/leucovorin/irinotecan (FOLFIRI) in 1st line metastatic pancreatic cancer (MPC).
Authors: Vincent J. Picozzi, Bruce Shih-Li Lin, Margaret T. Mandelson
Journal: Journal of Clinical Oncology (2018)

e16218 Background: The use of alternating chemotherapy regimens in cancer therapy may 1)lessen toxicity 2) slow emergence of resistant cancer biology thus improving outcomes and 3) provide a broader platform for the addition of other (non)chemotherapeutic (CT) agents to the base regimen. This strategy using alternating G/A and FOLFIRI in MPC was first tested in the SEENA-1 trial ( Picozzi et.al. GI Cancer Symposium 2017). We sought to extend these observations at our institution. Methods: Eligible patients (pts) had the following characteristics: 1) bx proven de novo MPC, 2) no prior CT , 3) ECOG PS 0/1 , and 4) bidimensionally measurable disease. Treatment (Rx) consisted of 1) gemcitabine 1000mg/m2 and nab- paclitaxel 125 mg/2d 1,(8),15 alternating every 8 weeks (2 cycles) with 5-FU. Pts were radiographically restaged every 8 weeks. Rx was continued for up to 48 weeks, at which time additional therapy was given per physician/patient decision. Results: From 10/1/2015 thru 1/1/2018, 40 pts were treated via this method. Pt characteristics included median age 67, ECOG PS 0/1, 58%/42%. Frequent metastatic disease sites included liver 78%, peritoneum 45%, lung 23%. 33 pts have completed Rx , 7 pts remain on Rx. Toxicity generally was less than typical in either individual regimen (e.g. no ≥ grade 3 neuropathy or diarrhea was seen). Of pts completing Rx, median number of cycles given was 8; 13/33 pts (39%) completed all 48 weeks intended Rx. Disease control rate in 34 currently evaluable pts at 16 weeks was 85% (47% PR/38% SD/15% PD). As of 1/1/2018, median f/u is 9.5 mo; 21/37 evaluable pts remain alive (3 transferred care). PFS is 9.2 mo (95% CI 5.9-10.6 mo), 1-year OS is 61%, median OS is 16.3 mo (95% CI 9.7 mo-NR). Conclusions: 1) The above alternating regimen approach in MPC showed promising results with respect to toxicity and response. 2) This approach offers a platform for further regimen development in MPC. 3) We continue to accrue experience with this regimen.
Large-scale nationwide genomic screening system for small cell lung cancer in Japan (LC-SCRUM-Japan).
Authors: Yukari Ogawa, Shigeki Umemura, Haruyasu Murakami, Masato Shingoji, Nobuaki Kobayashi, Tadasuke Shimokawaji, Haruko Daga, Takashi Seto, Norio Okamoto, Hiromi Aono, Yutaka Fujiwara, Satoshi Hara, Nobuhiro Kanaji, Shingo Matsumoto, Hibiki Udagawa, Kiyotaka Yoh, Koichi Goto
Journal: Journal of Clinical Oncology (2018)

8572 Background: Recent genomic analyses of small-cell lung cancer (SCLC) have provided insights into novel therapeutic targets such as the PI3K pathway. Thus, we prospectively analyzed clinical samples of SCLC using a large-scale nationwide genomic screening project in Japan (LC-SCRUM-Japan) to identify the patients harboring targetable genomic alterations. Methods: Submitted tumor samples were subjected to a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 (ver.1) or 161 (ver.3) cancer-related genes. Results: From July 2015 to January 2018, 544 patients had been enrolled. The median age was 68 years. 76% were male and 95% were smokers. Among 468 samples completed analysis, we identified high prevalence of inactivating TP53/RB1 mutations in 341 (73%) /148 (32%) of cases, respectively. MYC/MYCL1/MYCN amplifications were detected in 18 (4%) /23 (5%) /7 (2%) of cases, respectively. The NGS analysis also showed that 30 (6%) of cases had activating alterations in receptor tyrosine kinase genes: 7 EGFR mutations, 8 KRAS mutations and 15 FGFR1 copy number gains. Mutations in the PI3K pathway were detected in 35 (7%) of the tumors: 13 PIK3CA mutations, 17 PTEN inactivating mutations, 1 AKT mutation and 4 TSC2 inactivating mutations. Among them, 6 cases harboring mutations in the PI3K pathway enrolled in the investigator-initiated phase II study of gedatolisib (UMIN 000020585). Survival data was available in 244 patients receiving platinum-based chemotherapy. Multivariate analysis revealed that the presence of MYC/MYCN amplification or KRAS mutation were significantly associated with poor progression free survival of the first-line chemotherapy (HR, 3.07; 95% CI 1.81 – 5.20; p < 0.001) and unfavorable survival (HR; 2.31; 95% CI 1.26 – 4.22; p = 0.007). Conclusions: To our knowledge, this is the world’s largest prospective genomic screening project for SCLC. This nationwide screening system is helpful for identifying biologically relevant genomic alterations and prognostic prediction in SCLC. This screening program is currently ongoing to screen 800 SCLCs as a final goal. Updated screening results will be presented at the 2018 ASCO Annual Meeting.