tbuckley/cabot-search huggingface dataset:
Phase I dose escalation of ibrutinib and buparlisib in relapsed/refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL).
Authors: Connie Lee Batlevi, Paul A. Hamlin, Matthew J. Matasar, Steven M. Horwitz, John F. Gerecitano, Craig H. Moskowitz, David J. Straus, Andrew David Zelenetz, Pamela Drullinsky, Amanda Copeland, Salma Ahsanuddin, Devin Callan, Benjamin Freidin, Robert Porzio, Thu Oanh Dang, Ai Ni, Jurgen Rademaker, Heiko Schöder, Ahmet Dogan, Anas Younes
Journal: Journal of Clinical Oncology (2017)

7544 Background: In vitro studies of BTK and PI3K inhibitors demonstrate synergy in non-Hodgkin lymphoma (NHL). We embarked on a phase I/Ib investigator-initiated clinical trial evaluating the combination of ibrutinib (BTK inhibitor) and buparlisib (pan-PI3K inhibitor) in relapsed/refractory (R/R) NHL. The completed dose escalation is reported. Methods: Patients (pts) were eligible if they had R/R DLBCL, MCL, or FL with ECOG≤2 and adequate organ function. Ibrutinib and buparlisib were given daily by mouth on a 28-day cycle. Dose reductions were permitted after cycle 1. Tumor response was based on Lugano Classification however CR required both PET resolution and ≥ PR by CT. Results: As of Dec 16, 2016, 13 pts were enrolled and evaluated for toxicity (DLBCL 5, FL 2, MCL 6). Dose levels and DLT per table. Six pts discontinued treatment for disease progression (DLBCL 4, FL 2). Hematologic AE ≥ grade 3 are anemia (2), leukocytosis (2), and leukopenia (4). Relevant non-hematologic AEs of any grade ≥ 20% across all pts were fatigue (77%), diarrhea (62%), anorexia (54%), rash (46%), hyperbilirubinemia (46%), gastric reflux (46%), CMV reactivation (31%), mood change (31%), and hypertension (23%). Most common related grade 3/4 toxicity is rash (N = 3). No grade 5 toxicities noted. Serious adverse events (SAE) include: grade 2 pleural effusion and grade 2 nausea (N = 1), grade 1 fever with hospitalization (N = 1), grade 2 confusion and grade 4 hyponatremia (N = 1) were unrelated to therapy. Responses noted in 13 pts: MCL (N = 6: CR 4, PR 2), FL (N = 2: SD 2), DLBCL (N = 5: SD 1). One CR was a MCL pt with CR after 2 cycles on combination therapy and continues in remission on ibrutinib alone because of buparlisib toxicity. Conclusions: Combination of ibrutinib and buparlisib while generally well tolerated has predicted toxicities of both BTK and PI3K inhibitors. The recommended phase 2 dose is ibrutinib 560 mg and buparlisib 100 mg though dose reductions for tolerability may be needed for long term oral therapies. Promising efficacy is observed in MCL. Clinical trial information: NCT02756247. [Table: see text]
Efficacy and safety of nivolumab (NIVO) in patients with advanced melanoma (MEL) and poor prognostic factors who progressed on or after ipilimumab (IPI): Results from a phase II study (CheckMate 172).
Authors: Dirk Schadendorf, Paolo Antonio Ascierto, John B. A. G. Haanen, Enrique Espinosa, Lev V. Demidov, Claus Garbe, Paul Lorigan, Helen Gogas, Christoph Hoeller, Tormod Kyrre Guren, Andree Rorive, Piotr Rutkowski, Eva Muñoz-Couselo, Reinhard Dummer, Ana Carneiro, Geke Hospers, Elena Borisovna Grigoryeva, Rafia Bhore, Paul Nathan
Journal: Journal of Clinical Oncology (2017)

9524 Background: In the phase III CheckMate 037 study, NIVO improved the objective response rate and progression-free survival with less toxicity vs chemotherapy in patients (pts) with MEL who progressed after prior IPI treatment. We report the first efficacy and updated safety data from pts with MEL in CheckMate 172, including those with rare melanoma subtypes (uveal, mucosal), brain metastases, or an ECOG performance status (PS) of 2. Methods: In this ongoing phase II, single-arm, open-label, multicenter study, pts with MEL who progressed on or after IPI were treated with NIVO 3 mg/kg Q2W for up to 2 years until progression or unacceptable toxicity (NCT02156804). We report efficacy and updated safety data from 734 treated pts with ≥1 year of follow-up (database lock: November 2016). Results: Of 734 pts, 50% had LDH&gt;ULN, 7% ECOG PS 2, 66% M1c disease, 15% a history of brain metastases, and 23% received ≥3 prior therapies. Overall, 593 pts (81%) received more than 4 doses of NIVO. Overall, response rate at 12 weeks was 32%, with a complete response in 1% (Table). The 1-year overall survival (OS) rate was 63%. Any grade and grade 3/4 treatment-related adverse events (AEs) occurred in 66% and 17% of pts, respectively. Discontinuations due to treatment-related AEs occurred in 4% of pts. The most common treatment-related select (potentially immune-related) AEs were diarrhea (12%), hypothyroidism (9%), and pruritus (7%). Conclusions: CheckMate 172 is the largest study of NIVO efficacy and safety in pts with MEL who progressed on or after IPI. NIVO demonstrated a safety profile consistent with that of prior clinical trials. Efficacy outcomes were encouraging in some difficult-to-treat subgroups of pts with poor prognostic factors, such as mucosal melanoma and brain metastases. Clinical trial information: NCT02156804. [Table: see text]
Breast cancer resistance protein (ABCG2) as a potential biomarker for gemcitabine and nab-paclitaxel sensitivity.
Authors: Kenneth H. Yu, Mark Ricigliano, Eileen Mary O'Reilly, Maeve Aine Lowery, Brandon Cooper, Christina M. Covington
Journal: Journal of Clinical Oncology (2016)

4129 Background: PDAC is a leading and rising cause of cancer mortality. Despite this, modern cytotoxics (C) can induce tumor responses and extend life. Breast cancer resistance protein (ABCG2) is an ATP-binding cassette (ABC) transporter identified as a molecular cause of multidrug resistance in diverse cancer cells. We have previously shown that expression profiling of circulating tumor and invasive cells (CTICs) can predict response and resistance to C, predominantly 5-FU based. The current study explores the ability to predict treatment response based on the expression of ABCG2 in a uniform population of patients receiving gemcitabine (G) and nab-paclitaxel (Nab). Methods: 33 patients receiving frontline treatment with G and Nab for treatment of metastatic PDAC were enrolled into a prospective trial from Jan 2014 to the present. Six mL of peripheral blood was collected prior to treatment, after 2 months of treatment and at disease progression. CTICs were isolated using a cell-invasion assay, total RNA extracted and expression of 83 genes used as candidate biomarkers of drug response were measured by qPCR. Patients were followed for PFS and OS. Results: CTICs were isolated, and gene expression profiles were obtained in all 33 patients prior to initiating C and in 21 patients at 1st line disease progression. Expression of ABCG2 predicts treatment response and progression free survival. 12/33 (36%) patients were ABCG2 high and 7/33 (21%) were ABCG2 low, the remainder were intermediate. Clinical benefit was seen for patients with low v high ABCG2 expression (PFS 5 mo v 3 mo, p = 0.028, HR 0.15; OS 8.6 mo v 3.4 mo, p = 0.020). Conclusions: Gene expression profiling of CTICs from patients with metastatic PDAC treated with G and Nab identifies ABCG2 expression as a candidate biomarker of response and prognosis. A prospective study to validate these findings is warranted. Clinical trial information: NCT01474564.
Anti-inflammatory effects of roflumilast in chronic obstructive pulmonary disease (ROBERT): a 16-week, randomised, placebo-controlled trial
Authors: Klaus F Rabe, Henrik Watz, Simonetta Baraldo, Frauke Pedersen, Davide Biondini, Nitin Bagul, Guido Hanauer, Udo-Michael Göhring, Debasree Purkayastha, Jonas Román, Vijay K T Alagappan, Marina Saetta
Journal: The Lancet Respiratory Medicine (2018)
The Zinc-Finger Protein ZCCHC3 Binds RNA and Facilitates Viral RNA Sensing and Activation of the RIG-I-like Receptors
Authors: Huan Lian, Ru Zang, Jin Wei, Wen Ye, Ming-Ming Hu, Yun-Da Chen, Xia-Nan Zhang, Yi Guo, Cao-Qi Lei, Qing Yang, Wei-Wei Luo, Shu Li, Hong-Bing Shu
Journal: Immunity (2018)
Association between physical activity (actigraphy) and symptom burden in advanced cancer patients.
Authors: Sriram Yennu, Supakarn Tayjasanant, Diane D Liu, Janet L. Williams, Eduardo Bruera
Journal: Journal of Clinical Oncology (2015)

e20560 Background: Recent studies in early cancer and cancer survivors suggest that higher physical activity (PA) scores are associated with better self-reported physical functioning, general well-being, self-esteem, cancer related fatigue (CRF), depression scores and overall survival. However, for advanced cancer patients (ACP), there is very limited research on the association between objective physical activity and symptom burden. Our primary aim was to determine the association between PA (actigraphy) and CRF (Functional Assessment of Cancer illness therapy –Fatigue). We also examined the association between PA and Hospital Anxiety Depression Scores (HADS), Edmonton Symptom Assessment Scale (ESAS) and overall survival (OS). Lastly, we explored the factors predictive of poor PA in ACP. Methods: We reviewed baseline patient characteristics and symptoms [CRF (FACIT-F), symptom burden (ESAS), anxiety and depression (HADS)], quality of life (FACT-G), mean daytime activity (actigraphy) and OS data collected from 79 patients who participated in a methylphenidate for fatigue clinical trial (NCT00424099) conducted by our team. We determined the association between PA and symptom severity using spearman correlation, multivariate analysis and Kaplan-Meier survival analysis. Results: 79 eligible patients were evaluable. The median age was 58 yrs, the most common cancer type was Gastrointestinal (22%) and Lung (22%). PA was significantly associated with (r, p) FACIT-FWB (0.25, 0.03), HADS-A (0.26, P = 0.02), total sleep time (-0.32, 0.004), ESAS shortness of breath (-0.30, 0.008) and age (-0.37, 0.001). However, there was no significant association between PA and CRF (FACIT-F subscale), ESAS SDS, FACT-G, FACT PWB, FACT EWB scores. There was no significant association between median OS in months and lower PA ( lower PA 14.3 vs higher PA 19.4), p = 0.18. Multivariate analysis found that lower PA was significantly associated with worse FACT-FWB (P = 0.037), HADS-A (p = 0.014), ESAS shortness of breath (p = 0.006) scores. Conclusions: Lower PA was independently associated with lower functional well-being, anxiety, and dyspnea in ACP. Further studies are needed.
Integrated digital error suppression for noninvasive detection of circulating tumor DNA in NSCLC.
Authors: Aaron M. Newman, Alexander F. Lovejoy, Daniel M. Klass, David Matthew Kurtz, Jacob J. Chabon, Florian Scherer, Henning Stehr, Chih Long Liu, Scott Victor Bratman, Carmen Say, Li Zhou, Justin N Carter, Robert B. West, George W. Sledge, Joseph B Shrager, Billy W. Loo, Joel W. Neal, Heather A. Wakelee, Ash A. Alizadeh, Maximilian Diehn
Journal: Journal of Clinical Oncology (2016)

e20500 Background: High throughput sequencing of circulating tumor DNA (ctDNA) promises to revolutionize the detection, treatment, and monitoring of NSCLC. However, low quantities of ctDNA in blood and sequencing errors currently limit ctDNA profiling from clinically practical blood volumes. Methods: To enhance the analytical sensitivity of Cancer Personalized Profiling by deep Sequencing (CAPP-Seq; Newman et al., Nat Med 2014), we developed an integrated digital error suppression (iDES) approach for capture-based sequencing. iDES combines novel methods for efficient molecular barcoding with in silico removal of stereotypical background artifacts. Technical performance was assessed using dilutions containing variants with known allele frequencies. Clinical performance was studied using 172 plasma samples obtained from 54 NSCLC patients and 30 healthy controls. Results: iDES reduced technical errors in cell-free DNA (cfDNA) sequencing data by ~15-fold without impacting molecule recovery. As a result, somatic mutations were noninvasively detectable down to 1–3 mutant copies across hundreds of kilobases. Applied to mutation hotspots in NSCLC, iDES-enhanced CAPP-Seq achieved an area under the curve of 0.94 for the identification of plasma variants that were confirmed in matched tumors. In erlotinib-treated patients with EGFR-mutant advanced NSCLC (n = 37), this approach allowed sensitive, biopsy-free detection of activating mutations (94%) and subclonal T790M resistance mutations (91%) with zero false positives. When interrogating the entire EGFR kinase domain, 92% of tumor-confirmed point mutations were noninvasively detectable with iDES, with high specificity at both the variant-level (> 99.99%) and patient-level (96%). Finally, iDES enabled accurate treatment response assessment in the absence of tumor tissue via biopsy-free tumor genotyping. Conclusions: iDES-enhanced CAPP-Seq significantly reduces cfDNA error rates without sacrificing molecule recovery. Given its advantages, our approach should prove useful for noninvasive ctDNA profiling, with potential utility for genotyping the significant subset of NSCLC patients who are not currently profiled for actionable mutations.
Pancreatic cancer biomarkers among exosome-fractionated circulating miRNAs.
Authors: Atsushi Hagihara, Yoshiki Murakami, Akihiro Tamori, Kenjiro Kimura, Ryosuke Amano, Kosei Hirakawa, Norifumi Kawada
Journal: Journal of Clinical Oncology (2016)

e15671 Background: Pancreatic cancer (PC) is one of the most deadly cancers. Existing tumor markers, such as carbohydrate antigen 19-9 and carcinoembryonic antigen, have relatively poor diagnostic sensitivity and specificity. Intraductal papillary mucinous neoplasm (IPMN) is related to pancreatic carcinogenesis and is treated as a precursor of PC. We analyzed the miRNA expression profiles of exosome-rich fractionated blood of IPMN, PC and control patients to identify biomarkers that would facilitate early diagnosis of PC. Methods: RNA from the exosome-rich fraction was extracted from eight PCs, eight IPMNs and eight non-pancreatic disease controls (NC). Extracted RNA was subjected to miRNA profiling using an Agilent miRNA microarray and Illumina next-generation sequencer (NGS). Results: IPMN and PC patients were discriminated from controls with 91.6% and 95.8% accuracy, respectively, using the expression profiles of 11 and 19 miRNAs determined by microarray and NGS analyses, respectively. Using NGS, 168 novel miRNA candidates were identified. Six candidate miRNAs were detected in patients with PC but not in those with IPMN or NC. One candidate miRNA was detected among all patients with PC but not those with IPMN. Conclusions: The results of our analysis of miRNAs associated with pancreatic disease were highly reproducible. We could identify pancreatic disease with a high probability using the expression profiles of existing miRNAs and novel candidate miRNAs. Therefore, miRNA expression profiles show promise for the early diagnosis of PC at the precancerous stage. (UMIN No.: 000017958)
Inhibition of Wnt signaling as therapeutic option in platinum-resistant ovarian cancer.
Authors: Fabian Trillsch, Valentina Preinfalk, Martina Rahmeh, Marianne Vogel, Bastian Czogalla, Alexander Burges, Udo Jeschke, Sven Mahner
Journal: Journal of Clinical Oncology (2017)

e17050 Background: New therapeutic approaches for platinum-resistant ovarian cancer patients are urgently needed. In this context, Wnt signaling appears to be a promising target so that inhibition of this pathway in platinum-resistant cell lines was aim of the present study. Methods: The ovarian cancer cell line A2780 and its platinum-resistant clone A2780cis were treated with different concentrations of Wnt singaling inhibitors SB216761, XAV939, and triptolides. Metabolic activity and cell viability was estimated by MTT cell proliferation assays. Immunohistochemistry for ß-Catenin visualized activity of the Wnt pathway. Results: MTT proliferation tests revealed an impaired proliferation following treatment with all three agents. While triptolides already led to significantly reduced metabolic activity after 48h, this effect was seen for SB216761 and XAV939 not before 72h. Immunohistochemistry for ß-Catenin confirmed inhibition of Wnt signaling. Following XAV939 treatment of A2780cis, ß-Catenin signals shifted from the nucleus towards the cell membrane. Conclusions: Re-sensitizing platinum-resistant ovarian cancer cells for platinum-based chemotherapy by inhibition of Wnt signaling seems to be mechanism visualized by the translocation of ß-Catenin from the nucleus towards the cell membrane. In this context, a dose-dependent response was noted for XAV939. Inhibition of Wnt Signaling appears to be a prospective therapeutic approach for platinum-resistant ovarian cancer patients.
Early MRD negativity to predict deepening myeloma response in relapsed/refractory multiple myeloma (RRMM) patients treated with bb2121 anti-BCMA CAR T cells.
Authors: Nikhil C. Munshi, Jesus G. Berdeja, Yi Lin, James Kochenderfer, Noopur S. Raje, Michaela Liedtke, Sundar Jagannath, Deepu Madduri, Jacalyn Rosenblatt, Marcela Valderrama Maus, Ashley Turka, Lyh Ping Lam, Kristen Hege, Timothy Brandon Campbell, Monica Massaro, Fabio Petrocca, David Samuel DiCapua Siegel
Journal: Journal of Clinical Oncology (2018)

8024 Background: A high frequency of rapid minimal residual disease-negative (MRD-neg) responses has been seen in CRB-401, a phase I trial of bb2121 CAR T cell therapy for RRMM (Kochenderfer, ASH 2017). We report IMWG responses in MRD-neg patients (pts) and associated factors. Methods: Pts treated with ≥ 150 × 106 BCMA CAR+ T cells in the dose-escalation phase of CRB-401 and evaluable for MRD by Adaptive NGS-based MRD Assay (Adaptive Biotechnologies) were included in this analysis (n = 10 as of 02 Oct 2017; median follow-up: 34 wks; min, max: 7, 67). Results: Nine of 10 evaluable pts were MRD-neg with a sensitivity of 1 in 10-4 nucleated cells (1 pt), 1 in 10-5 (6 pts), and 1 in 10-6 (2 pts). Achievement of MRD negativity was independent of depth of response at first MRD-neg assessment; 2 pts had stable disease, 3 had PR, 2 had VGPR, and 2 had CR / stringent CR. Of 8 evaluable MRD-neg pts, all showed ≥ 85% and ≥ 97% decline in serum BCMA and involved free light-chain levels, respectively, at month (M) 1. Two of 9 MRD-evaluable pts were in CR at MRD-neg assessment and the remaining 7 achieved deeper response over time, 4 with CR or stringent CR, 2 with VGPR and 1 with PR between M1 and M15. One MRD-neg pt became MRD-positive at M12, and 1 MRD-neg pt had progressed as of data cut-off. Achievement of MRD negativity was independent of occurrence of cytokine release syndrome. MRD-neg was observed across all active bb2121 doses (150 [n = 3], 450 [n = 5], and 800 x 106 [n = 1] CAR+ T cells). Of 9 MRD-neg pts, 7 had at least 6M follow-up and 1 had IMWG progression (at M6); 3 had at least 12M follow-up, 1 had become MRD-positive and none had IMWG progression. Attainment of MRD-neg was independent of peak CAR T expansion (vector copy min, max: 93,744, 1,457,070 copies/µg gDNA; n = 9) and was observed in high ( > 50%) bone marrow plasma cells (BMPC; n = 6) and low BMPC (n = 3) tumor burden pts. Eight of 9 MRD-neg pts had cytogenetic abnormalities including del(17), del(13), amp(1q21), or t(11;14). Conclusions: bb2121 induced a high frequency of rapid MRD-neg response, independent of IMWG MM responses. These early MRD-neg responses starting at M1 offer insights into bb2121 kinetics and may portend achievement of deeper responses over time. Clinical trial information: NCT02658929.
Profiling the immune checkpoint pathway in acute myeloid leukemia.
Authors: Paola Dama, Marshall Tang, Noreen Fulton, Justin Paul Kline, Hongtao Liu
Journal: Journal of Clinical Oncology (2018)

7015 Background: The immune checkpoint pathways in AML patients especially during the course of chemotherapy induction were seldom studied. This study was to characterize these pathways in AML patients treated on a prospective clinical trial to combine Selinexor with high-dose cytarabine (HiDAC) with mitoxantrone (Mito) (NCT02573363). Methods: Multi-parameter flow-cytometry was utilized to monitor the changes in expression of immune checkpoint receptors using bone marrow and peripheral blood samples at diagnosis and following remission induction therapy in 26 patients with AML enrolled to the study. Expression of CD47, PD-L1, PD-L2 and Gal-9 was assessed on CD34+ AML blasts and CD34- cell populations. In parallel, we evaluated expression of inhibitory (PD1, CTLA4, LAG3, TIM3) and stimulatory co-receptors (CD28, ICOS, CD137, OX40, CD40L, HLA-DR) on CD4+ and CD8+ T cell subsets. Flow cytometry data were analyzed with FlowJo-10 software. The Mann Whitney Test, Wilcoxon Rank test and Spearman’s rank correlation analysis were applied. Results: The percentage of CD34- Gal9+ cells was significantly higher in patients who experienced treatment failure (TF) after chemotherapy, comparing with those in complete remission (CR), with median of 36.9% (range: 1.7% -98.3%) versus a median of 3.8% (range: 0.18%-60.1%; p < 0.05). There was no difference of PD-L1 expression in these two patient groups. At the time of remission, we observed significant increase of expression of PD-L1 on BM CD34- cells, Tim3 on BM CD4+ and CD8+ T cells, as well as co-stimulatory checkpoint receptors: CD137 (4-1BB), HLA-DR on BM CD4+ cells, and OX40 on BM CD8+ T cells. In peripheral blood, the PD1 expression on CD4 cells was much higher at the time of remission comparing to that at the diagnosis. These data suggested an exhausted T cells status at the time of disease remission on the clinical trial treatment. Conclusions: Our small study demonstrated high level expression of Gal9 in CD34- cells in the BM at diagnosis in patients who failed induction chemotherapy. Increased expression of Tim 3 on CD4 and CD8 T cells in the BM and high PD-1 in peripheral CD4+ T cell at the disease remission suggested an exhausted immune status, which could be targeted with checkpoint inhibitors.