tbuckley/cabot-search huggingface dataset:
Anti-PD-L1 durvalumab combined with cetuximab and radiotherapy in locally advanced squamous cell carcinoma of the head and neck: A phase II study.
Authors: Pierluigi Bonomo, Isacco Desideri, Mauro Loi, Monica Mangoni, Mariangela Sottili, Daniela Greto, Vieri Scotti, Icro Meattini, Lorenzo Livi
Journal: Journal of Clinical Oncology (2017)

TPS6094 Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by prominent immune escape mechanisms. Potentially, the blockade of immune check points such as the PD-1/PD-L1 axis may stimulate the host T-cell activation against tumor cells and favor the FcγRIIIa-mediated, Cetuximab (CTX) induced antibody dependent cellular cytoxicity (ADCC). Durvalumab (DUR) is a humanized monoclonal IgG1, anti-PD-L1 antibody with promising activity in recurrent/metastatic HNSCC (NCT01693562). The aim of our study is to test the hypothesis that a restored ability of the host immune system via blockade of the PD1/PD-L1 axis through DUR may enhance the antitumor activity of both CTX and radiotherapy (RT) in locally advanced HNSCC, a setting with unmet needs for effective treatment options. Methods: In this open-label, multi-center, single-arm, phase II study, enrolled patients will receive RT (69.9 Gy/2.12 Gy fx in 33 fractions over 7 weeks) with concurrent CTX (400 mg/m 2 1 week before RT start followed by 250 mg/m 2 q1w) and DUR (1500 mg q4w starting from RT-CTX week 1) followed by adjuvant DUR (to a maximum of 6 months after completion of RT-CTX). Primary endpoint of the study is 2-year progression-free survival (PFS). Assuming a 2-year PFS of 66% based on historical data from RTOG study 0129, the experimental regimen is hypothesized to yield a 12% absolute increase at 2 years, corresponding to a hazard ratio of 0.6 (α = 0.1, power is 0.80 when the 2-year PFS is 78%). The required sample size with this design is 69 patients. A safety run-in is planned after the enrollment of first 12, 24 and 36 patients. Patients affected by high-risk ( &gt; N2a or &gt; T3, any N) larynx, hypopharynx and HPV negative oropharynx or HPV-positive oropharynx ( &gt; N2b, &gt; 10 pack/years) will be eligible. To avoid potential RT-induced chronic loco-regional immunosuppression, protocol-indications will be undertaken to restrict target volumes to sites of gross disease and subclinical high risk lymph node basins excluding areas deemed at very low risk of disease spread. For this purpose, dose-painting intensity modulated radiotherapy (IMRT) is mandatory for this study. Clinical trial information: 2016-004668-20.
Kinin system and blood plasma inhibitors as factors of pathogenesis of osteolytic metastases from breast cancer.
Authors: Larisa S. Kozlova, Oleg I. Kit, Elena M. Frantsiyants, Artyom Andreevich Barashev, Larisa Nikolaevna Vashchenko, Marina I. Vereskunova, Ludmila Ya. Rozenko, Marina M. Sergeeva
Journal: Journal of Clinical Oncology (2018)

e13106 Background: Bone metastases are associated with characteristics of bone tissues: a good blood supply and constant processes of bone formation and osteolysis. The mechanism of development of osteolytic metastases is poorly studied; their obligatory component is slow inflammation as a result of bone tissue resorption. Our purpose was to study the kinin-kallikrein system (KKS), trypsin-like proteases (TLP), α2-macroglobulin (α2M), and α1-proteinase inhibitor (α1PI) in the blood plasma in solitary osteolytic metastases from breast cancer. Methods: The kinetics of KKS enzymes, α2M and α1PI was studied by spectrophotometry in the citrate blood plasma of 37 patients aged 39-73 years with solitary osteolytic metastases (рT3-4NхM1) and 39 donors (N) before surgery, on days 1 and 7 after surgery and in 1 and 6 months. Statistica 10.0 was used for the statistical processing of the data. Results: Before treatment, kallikrein activity exceeded N, with decreased prekallikrein (PK), without significant changes during the observation period. The kinin destroying enzyme carboxypeptidase N was 2.7 times lower than N, and it continued decreasing on day 1, increasing after 1 and 6 months but still being lower than N. This contributed to the longer existence of bradykinin in circulation, as well as the manifestation of biological properties of bradykinin, kallikrein and other TLPs. Activity of TLPs before treatment exceeded N by 3.4 times and was high during the whole observation period. Activity of α2M before treatment was 2 times decreased (compared to N), was still low after surgery, and increased up to N 6 months after surgery. The α1PI levels were 1.9 times lower than N and were low during the observation period. Insufficient control of proteolysis by endogenous α2M and α1PI promoted breast cancer progression. Conclusions: A prolonged KKS activation in osteolytic metastases from breast cancer results in PK depletion in the blood plasma, high kallikrein activity maintenance and decreased activity of carboxypeptidase N and universal α2M and α1PI inhibitors. The KKS activation and α2M and α1PI deficit are the factors of pathogenesis of osteolytic metastases from breast cancer.
A randomized Bayesian phase 1 design combining an MPS-1 inhibitor with paclitaxel: A strategy to improve determination of the incremental toxicity of a novel compound over a known backbone therapy.
Authors: Florence Atrafi, Oliver Boix, Prabhu Rajagopalan, Anthony W. Tolcher, Patricia LoRusso, Joseph Paul Eder, Kamalesh Kumar Sankhala, Sant P. Chawla, Vivek Subbiah, Jennifer Robinson Diamond, Martin Gutierrez, Ron H.J. Mathijssen, Jian Mei, Jaap Verweij, Ingmar Bruns, Martijn P. Lolkema
Journal: Journal of Clinical Oncology (2018)

2537 Background: Here we present a study combining BAY1217389 (BAY), a potent MPS-1 kinase inhibitor with a backbone chemotherapy paclitaxel. Since we expected overlapping toxicities we sought to improve determination of the maximal tolerated dose (MTD) using a randomized phase 1 design with Bayesian dose modeling. We hypothesized that this approach may determine the MTD of BAY more accurately by limiting the effect of variability of dose limiting toxicities (DLTs) related to paclitaxel. Methods: Patients (≥18 years) were randomized to receive oral BAY with intravenous paclitaxel (experimental arm) or paclitaxel monotherapy (standard arm) in cycle 1. Dose escalation was guided by Bayesian modeling targeting a DLT-rate in the experimental arm of 10% over DLT-rate in the standard arm. PK profiles were determined for both BAY and paclitaxel. Simulations were performed to estimate MTD for several scenarios. Results: We were able to establish an MTD of 65 mg BAY using 50 patients in the dose-escalation part. As expected the main DLTs were hematologic toxicity. Grade ≥ 3 neutropenia was predominantly observed in the experimental arm and was related to higher BAY AUC0-12 on D8 (p<0.001) and not to paclitaxel AUC0-24 (p>0.1). To determine whether the randomization adds value to the study design we ran simulations comparing our randomized strategy using variable toxicity rate (5, 10, 20, 40%) for paclitaxel monotherapy with the 3+3 design. These data showed that the randomized design outperformed the 3+3 design. The 3+3 design underestimated the MTD as dose escalation was terminated more frequently at first dose for higher paclitaxel toxicity rate. Conclusions: Randomized Bayesian phase 1 dose escalation design was feasible with BAY plus paclitaxel. A major advantage of this design is the precise determination of an exposure-toxicity relation for the experimental drug. Moreover, simulations support our hypothesis that the randomized design was able to determine the MTD accurately regardless of variable toxicity rate for paclitaxel. This approach may improve dose determination in phase I combination trials. Clinical trial information: NCT02366949.
Abstract 19024: Regulation of Platelet Reactivity Identified Through MicroRNA Profiling in Acute Coronary Syndrome
Authors: Kristian C Becker, Lydia Coulter, Megan L Neely, Elizabeth Grass, Joesph A Jakubowski, Keith A Fox, Paul W Armstrong, Harvey White, Matthew Roe, E. Magnus Ohman, Simon G Gregory, Svati H Shah, Mark Y Chan
Journal: Circulation (2016)

Introduction: Recent studies suggest an association between changes in platelet-specific microRNAs (miRs) and changes in platelet reactivity. However, molecular pathways that govern platelet reactivity are incompletely characterized. We hypothesize that miRs expressed in plasma are associated with measured platelet reactivity in the TRILOGY-ACS cohort and highlight the genomic regulatory architecture of platelet reactivity. Methods: The study included 712 patients with non-ST elevation acute coronary syndrome (NSTEACS) enrolled in the TRILOGY-ACS trial. Plasma samples collected prior to anti-platelet therapy randomization were used to determine P2Y12 Reaction Units (PRU) measured on the VerifyNow system as well as the concentration of 35 miR species known to be involved in cardiovascular development and disease. We tested for association between PRU and miR expression using multivariable linear regression, adjusting for age, sex, race, prior clopidogrel and aspirin status, diabetes and cytochrome 2C19 gen...
Genomic and proteomic analysis of patient tumors for molecular target selection.
Authors: Shiva Sreenath Andrali, Erlinda Maria Gordon, Sandeep K. Reddy, Shankar Sellappan, John Chang, Esha Sachdev, Sant P. Chawla
Journal: Journal of Clinical Oncology (2018)

e23567 Background: In recent years, molecular diagnostics for personalized cancer treatment has become increasingly popular in the medical community. In this report, information is obtained from the molecular characterization of DNA, RNA and proteins derived from the patient’s own tumor/s to guide treatment strategy. Methods: Archived tumors from sixty-one patients, mostly sarcoma, were processed and evaluated by GPS Cancer, using next generation sequencing and mass spectrometry. The samples were analyzed for genetic aberrations such as amplifications, truncations and single nucleotide polymorphisms. Genomic analysis searched for mutations in oncogenes, tumor suppressor genes, copy number variation, somatic variations and cancer predisposition genes, as well as expression of genomic messages. Proteomic expression analysis of drug response markers and drug resistance markers were also conducted and reported as drugs/treatments that are likely or unlikely to benefit the patient. Results: Comparing germline DNA with tumor DNA helped identify tumor specific somatic mutations that can be specifically targeted. False positives were eliminated by analyzing and correlating the data from DNA, RNA and proteins. A list of chemotherapy and targeted therapies that would likely benefit each patient was generated. These therapies are either FDA approved or still in clinical trials. Proteomic and/or genomic analysis identified 39 of 61 (60%) patients likely to benefit from the use of new drugs, while genomic analysis alone identified 5 out of 61 (8%) patients who were likely benefit from new drugs. Conclusions: Whole genome, whole transcriptome, and targeted proteomic profiling are objective diagnostic tools in the development of patient-specific cancer therapies. Patients who are not found to have benefit from any drugs based on proteomics analysis may have beneficial drugs based on genomics data and vice versa. With improved diagnostics and therapeutic tools, molecular analysis may provide insight into the aggressiveness of the cancer, predict response to cancer treatments and monitor recurrence.
Biomarker selection for patients participating in phase I clinical trials.
Authors: Lauriane Eberst, Clemence Basse, Magali Morelle, Victor Simmet, Catherine Terret, Daniel Pissaloux, Valéry Attignon, Qing Wang, Olivier Tredan, Jean-Yves Blay, Philippe Alexandre Cassier
Journal: Journal of Clinical Oncology (2018)

e24303 Background: Molecular selection is often used for pts orientation towards phase 1 trials (P1T), but the impact of this strategy on PFS is unclear. Methods: All pts treated in a prospective P1T of targeted agent (TA) or immune-oncology (IO) drugs, either as a single agent or in combination, at our institution, from 2012 to 2016, were identified and registered in our database. We sought to determine if the use of a BM (any type) for patient selection improved their outcome in P1T. Results: 229 pts were enrolled in 26 P1T: 100 in IO and 129 in TA trials. Inclusion in a P1T was based on BM in 95 pts: only 11 pts were enrolled in IO trials based on a BM (PD-L1 expression by IHC in all cases), while genomic screening was more commonly used in TA trials (e.g TP53 status, FGFR alterations, PIK3CA mutations, KIT/PDGFRA mutations, etc). In TA trials, BM were activated oncogenes (e.g FGFR, PIK3CA, KIT/PDGFRA) in 38/84 (45%) cases, while negative predictors (e.g wild type TP53) were used in 46/84 (55%) cases. The most frequent tumor types were breast cancer, gastro-intestinal tract cancer, sarcoma (23%, 19% and 15% respectively), followed by head and neck and lung cancers (11%), genito-urinary cancers, biliary/pancreatic tract cancers, and gyneco cancers (less than 10% each) and miscellaneous tumors (11%). Pts received a median of 2 lines of treatment prior to enrolment, and remained on study for a median of 60 days (Min-Max 11- 1149 days). Royal Marsden Hospital (RMH) score at inclusion was 0-1 in 44% of pts. Overall, median PFS was 1.8 mo (95%CI[1.7-2.5]) for BM-selected (BM+) pts, compared to 2.1 mo (95%CI [1.8;2.6], p = 0.6895) for BM- pts. After adjusting on tumor type and classical prognostic factors, BM had no significant effect on PFS (HR: 1.09; 95%CI [0.76; 1.69]). Both RMH score and Neutrophil to Lymphocyte Ratio predicted PFS. In the subgroup of pts treated with TA, there was a trend for longer benefit among pts selected based on an activated oncogene (6 mo PFS-rate n = 9/27 [33%] vs 11/73 [15%] ; p = 0.2701). Conclusions: The use of a BM to enroll patients in P1T yielded a short median PFS, both in IO and TA trials. Few long-term non-progressors were identified. New algorithms, possibly including multiple dimensions and BM, are needed to select patients for P1T.
How far have we really come? Trends in survival and mortality for gliomas between 1973 to 2014 from SEER.
Authors: Shehryar Rahim Sheikh, Tomas Radivoyevitch, Michael A. Vogelbaum
Journal: Journal of Clinical Oncology (2018)

2038 Background: Historical controls are often used as benchmarks for early stage, single arm trials of novel agents. We have investigated whether general or specific changes in the treatment of patients with gliomas drive meaningful changes in outcome and affect the validity of the use of historical control arms. Furthermore, we evaluated factors that impact on selection bias. Methods: We used data from the NCI SEER database and included 92,182 gliomas in our analysis. We identified 4 distinct epochs from 1973 to 2014 and compared survival curves between epochs using 2-year survival, median survival, and Cox-proportional hazards ratio (PHR) analysis. We also compared relative risk of mortality after diagnosis (RRM i.e. risk of death compared to age/sex matched controls) profiles between these periods. Gliomas were stratified by histological grade and age of diagnosis. Results: For low grade tumors, the most significant improvements occurred between the first (1973-1992) and second (1992-2000) epochs (PHR 0.4 and 0.6 for Grades I and II, p < 0.001), while for higher grade tumors it was in between the third (2000-2007) and fourth (2007-2014) epochs (PHR 0.8 for both Grades III and IV, p < 0.001) Since 2005, 2-year survival probability and median GBM survival have increased consistently (slope: 0.3 months/yr, R2: 0.8, p < 0.001); no such trend was discernable in earlier data. RRM profiles for high grade gliomas demonstrate a characteristic pattern that varies with time from diagnosis. RRM rises sharply for the first 1.5 years after diagnosis, and then approaches baseline. Conclusions: The most meaningful improvements in survival measures coincide with the emergence of phase III evidence supporting combined treatment with temozolomide (TMZ) and radiation around 2005. Since at least 2005, there has been a trend of increasing baseline survival in GBM patients; commonly used survival estimates for historical controls may thus be inaccurate and future clinical trials should acknowledge this trend when setting expectations of the control arm. RRM varies as a function of time from glioma diagnosis which may provide a basis for selection bias; patients recruited for clinical trials should be comparable in respect to RRM.
A clinical study on activity of NAMPT and SIRT1 gene expression in neutropenia with cancer chemotherapy.
Authors: Yukari Tsubata, Mika Nakao, Tamio Okimoto, Akihisa Sutani, Michiko Horiguchi, Chikamasa Yamashita, Hiroshi Ohtsu, Takeshi Isobe
Journal: Journal of Clinical Oncology (2016)

e21639 Background: Febrile neutropenia, a fatal side effect, can be appropriately treated if we can predict its risk of development before starting chemotherapy. The nicotinamide phosphoribosyltransferase (NAMPT) activity and sirtuin 1 (SIRT1) gene expression have been reported to be essential for identifying the neutrophils mediated by granulocyte colony-stimulating factor. Methods: We measured the activity of the NAD+-SIRT 1 pathway and vitamin B3 (VB3) levels in cancer patients and examined correlations with grade 4 neutropenia due to chemotherapy. A total of 21 chemo-naïve small and non-small cell lung cancer patients were enrolled. We obtained blood samples before the first treatment, 2 and 4 days after starting treatment, at the nadir, and before starting the second course of treatment. The activity of NAMPT in patient plasma was measured by ELISA, and SIRT1 gene expression in mononuclear fraction was measured by real-time PCR. Results: NAMPT activity before starting treatment was significantly lower in the group with grade 4 neutropenia (N = 9) than in those without neutropenia (N = 12) (0.69 vs 1.63 ng/mL, p = 0.003). SIRT1 gene expression and plasma concentrations of VB3 did not significantly differ between these two groups. On comparison with healthy volunteers, NAMPT activity was significantly higher in cancer patients, however no significant differences were noted between the grade 4 neutropenia group and grade 0-3 neutropenia group. Conclusions: This is the first report to examine the association between the NAD+-SIRT1 pathway and neutropenia in cancer patients. Our finding suggest that NAMPT activity before treatment may be a predictive factor for neutropenia with chemotherapy. We demonstrated the following three points. First, the NAMPT activity was significantly lower in severe neutropenia patients before starting chemotherapy than in those without neutropenia. Second, the SIRT1 gene expression among patients with grade 0 to 3 neutropenia markedly increased in the nadir phase. Third, the NAMPT activity in advanced lung cancer patients was higher than in healthy volunteers. Further studies will be needed to confirm the role of the NAD+-SIRT1 pathway in cancer patients receiving chemotherapy.
Phase II study of BKM120 in patients with advanced esophageal squamous cell carcinoma (EPOC1303).
Authors: Ken Kato, Toshihiko Doi, Takashi Kojima, Hiroki Hara, Shunji Takahashi, Kei Muro, Tomohiro Nishina, Masashi Wakabayashi, Shogo Nomura, Akihiro Sato, Atsushi Ohtsu
Journal: Journal of Clinical Oncology (2017)

4069 Background: BKM120 is an oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, which showed promising activity in breast cancer and squamous cell carcinoma of head and neck. We prospectively investigated clinical activity, safety and biomarkers of BKM120 in advanced esophagus squamous cell carcinoma (ESCC). Methods: We conducted a multicenter phase II study of BKM120 monotherapy in patients with pretreated advanced ESCC. All the patients had a treatment history of fluoropyrimidine and platinum. BKM120 of 100 mg/day was orally administered in a 28-day cycle. A primary end-point was a disease control rate (DCR). Using Simon’s minimax two-stage design, total of 41 patients were required for primary analysis (promising DCR of 60%, non-promising one of 40%, one-sided alpha level of 10% and power of 90%). The response rate (RR), progression-free survival (PFS), overall survival (OS), and safety were also evaluated as secondary endpoints. Tumor samples for all the patients were required for gene alternation analysis in comprehensive genomic profiling assay (FoundationOne). Results: A total of 42 patients (median age, 62.5 years; performance status 0/1 = 28/14) were enrolled. One ineligible patient was excluded from primary analysis. Nineteen and two patients had SD and unconfirmed PR. DCR was 51.2% (95% CI, 35.1% to 67.1%), which met the primary endpoint of the study. Median PFS and OS was 2.0 months (95% CI, 1.8 to 3.2 months) and 9.0 months (95% CI, 6.4 to 11.7 months), respectively. Common grade 3 or 4 adverse events were anorexia, rash, hyponatremia, lipase increased, and abnormal hepatic function (including increased transaminase levels), which were profiles similar to previous studies of BKM120 monotherapy. No treatment-related deaths occurred. Further analyses of the gene alternation are ongoing. Conclusions: BKM120 monotherapy showed promising efficacy and mild toxicity profile in patients with pretreated advanced ESCC. BKM120 is worth evaluating in a further confirmatory study. Result of subgroup analyses with respect to gene alternation status will be presented. Clinical trial information: UMIN000011217.
Abstract 13472: Aortic Valve Reconstruction Using In-body Tissue-Engineered Collagenous Connective Tissue Membranes,BIOSHEETs, in a 3-month Goat Model
Authors: Keitaro Okamoto, Takayuki Kawashima, Yasuhide Nakayama, Hirohumi Anai, Tomoyuki Wada, Satoshi Takebayashi, Takashi Shuto, Satoshi Kozaki, Shinji Miyamoto
Journal: Circulation (2016)

Background and Purpose: Autologous pericardium is widely used for a plastic material in intracardiac structures, pulmonary artery, or aortic valve leaflets. Also in aortic valve reconstruction (AVRec: Ozaki Procedure), inducing excellent clinical results over 6 years, autologous pericardium is used after fixation with glutaraldehyde. In-body tissue architecture (IBTA) based on the tissue encapsulation phenomenon of foreign materials can prepare autologous prosthetic tissues. In this study, we used an IBTA-based collagenous connective tissue sheet (Biosheet) as an aortic valve leaflet material for glutaraldehyde-free AVRec to compare the in vivo valve function and the tissue regeneration with original AVRec in a goat model. Methods and Results: AVRec was performed using two materials, glutaraldehyde-fixed autologous pericardium or Biosheets. The Biosheets were prepared by 2-month embedding of the plastic molds in the dorsal subcutaneous spaces of goats, obtained as completely autologous connective tissue with collagen and fibroblasts, and stored in alcohol before implantaion. AVRec procedure: The heart was exposed via a left thoracotomy at the fourth costal bed. Cardiopulmonary bypass was established with aortic and right atrial cannulations. After resection of native aortic valve cusps, the distance between each commissure was measured using a self-developed sizing instrument. Biosheet or autologous pericardium was trimmed with a self-developed template corresponding to the measured value. The annular margin of the leaflets was sutured to each annulus with monofilament sutures. In a Biosheet model, postoperative echocardiography after surgery showed smooth movement of the leaflets with little regurgitation, similar to that in an autologous pericardium model. Three month after Biosheet implantation, the valve leaflets was very smooth and covered partially with a thin neointima, including endothelial cells without thrombus formation. Biosheet was assimilated in an aortic root than autologous pericardium. Conclusion: An IBTA-based autologous connective sheet, Biosheet, without glutalaldehyde could be used for an AVRec material with high regeneration performance, suggesting that Biosheets have potential clinical use.