389 Combining transcriptomic- and tissue-based immune biomarkers to evaluate GB1275, a CD11b modulator, as a single agent or with pembrolizumab in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A414-A414
Author(s):  
Wells Messersmith ◽  
Drew Rasco ◽  
Johann De Bono ◽  
Andrea Wang-Gillam ◽  
Wungki Park ◽  
...  
Keyword(s):  
Gene Expression ◽  
Solid Tumors ◽  
Peripheral Blood ◽  
Post Treatment ◽  
Transcriptomic Analysis ◽  
Gene Set Enrichment Analysis ◽  
Cancer Center ◽  
Advanced Solid Tumors ◽  
Core Tissue ◽  
Dose Dependent

BackgroundGB1275 is a first-in-class CD11b modulator in development as monotherapy and in combination with pembrolizumab or chemotherapy for the treatment of advanced solid tumors. Nonclinical data show that GB1275 reduced influx of tumor-associated myeloid-derived suppressor cells (MDSCs) and macrophages (TAMs), and repolarized M2 immuno-suppressive TAMs towards an M1 phenotype. We hypothesize that GB1275 administration can alleviate myeloid cell-mediated immunosuppressive effects and improve cancer treatment outcomes. A phase 1 trial evaluating GB1275 as monotherapy and in combination with pembrolizumab in specified advanced tumors in ongoing (NCT04060342).MethodsBlood gene expression variations as well as core tissue biopsies pre- and post-treatment were assessed following GB1275 monotherapy and combination with pembrolizumab. After obtaining informed consent, peripheral blood for MDSCs was collected from 21 patients pre- and two weeks post-treatment; core tissue biopsies were collected from 13 patients pre- and post-treatment. The frequency of MDSCs in whole blood was measured using the Serametrix MDSC FACS Assay. Gene expression transcriptome profiles were generated using NovaSeq platform. CD8 staining was performed at Neogenomics, and tumor infiltrating lymphocyte (TIL) quantification was performed by an independent pathologist.ResultsPreliminary statistical analysis of MDSC immunophenotyping pre- and post- treatment is consistent with the proposed mechanism of GB1275, showing modulation of peripheral blood MDSCs in some patients. Preliminary gene expression analysis in the blood showed dose-dependent clusters following treatment with GB1275 alone. Moreover, the transcriptomic analysis revealed two unique expression patterns for patients treated with GB1275 monotherapy or in combination with pembrolizumab. Gene Set Enrichment Analysis showed that the CD11b pathway is downregulated in patients treated with GB1275. Analyses of TIL count revealed an increase in lymphocyte trafficking into the tumor after treatment with GB1275 alone or in combination with pembrolizumab. CD8 expression and transcriptomic analysis are underway and will be presented.ConclusionsGB1275 alone or in combination with pembrolizumab demonstrates biological activity, which may be dose dependent. The observed increase in TILs after treatment is supportive of the mechanism of action of GB1275. Further biomarker analyses in blood and tissues are ongoing and will be correlated with clinical activity in a larger number of patients.Ethics ApprovalThis ongoing study is being conducted in accordance with the the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. The study was approved by the Ethics Boards of University of Colorado Hospital, Washington University School of Medicine - Siteman Cancer Center, Memorial Sloan Kettering Cancer Center, The Sarah Cannon Research Institute/Tennessee Oncology, South Texas Accelerated Research Therapeutics, and The Royal Marsden NHS Foundation Trust.

287 Safety and antitumor activity of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor KHK2455 in combination with anti-CCR4 monoclonal antibody mogamulizumab in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A313-A314
Author(s):  
Solmaz Sahebjam ◽  
Jameel Muzaffar ◽  
Timothy Yap ◽  
David Hong ◽  
Olivier Rixe ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Overall Survival ◽  
Antitumor Activity ◽  
Combination Therapy ◽  
Adverse Events ◽  
Solid Tumors ◽  
Ex Vivo ◽  
Advanced Solid Tumors ◽  
Grade 3 ◽  
Dose Dependent

BackgroundIDO-1 inhibitors have shown antitumor activity in combination with immunotherapeutic agents in multiple cancers. KHK2455 is a novel and selective oral IDO-1 inhibitor. KHK2455 inhibits IDO-1 apo-enzyme, with long-lasting and potent activity. Mogamulizumab is an anti-C-C chemokine receptor 4 (CCR4) monoclonal antibody that has shown synergy with KHK2455 in preclinical models. Mogamulizumab is approved in the US and EU for treatment of mycosis fungoides and Sézary syndrome.MethodsIn this first-in-human study, patients with advanced solid tumors received escalating oral doses of KHK2455 alone (0.3, 1, 3, 10, 30 and 100 mg once daily) for 4 weeks (Cycle 0), followed by combination with 1 mg/kg weekly of IV mogamulizumab for 4 weeks (Cycle 1), and then on Days 1 and 15 (from Cycle 2 onward) in a standard 3+3 Phase I design. Safety, tolerability, pharmacokinetics and IDO activity (kynurenine [Kyn] and tryptophan [Trp] levels and ex vivo Kyn production) were evaluated.ResultsThirty-six patients were enrolled across all cohorts. One patient with lower esophageal cancer in the 100 mg cohort exhibited dose-limiting toxicity (Grade 3 gastrointestinal necrosis). The most frequent (≥10%) treatment-emergent adverse events (TEAEs) are presented in table 1. Overall numbers of TEAEs, ≥Grade 3 TEAEs, and serious TEAEs related to KHK2455 and mogamulizumab are presented in table 2. Serious KHK2455-related TEAEs included gastrointestinal necrosis (KHK2455 monotherapy), and nausea and drug eruption (combination therapy). In addition, five drug-related TEAEs in combination therapy led to discontinuation; there were no fatal outcomes related to either study drug. Plasma KHK2455 concentrations reached steady state by Day 8 (Cycle 0) and increased dose-dependently. Potent dose-dependent inhibition of IDO activity was demonstrated by plasma Kyn concentration and Kyn/Trp ratio (median inhibition 70.5% and 70.8%, respectively, at 100 mg dose on Day 15, compared to baseline) and ex vivo Kyn production (>95% inhibition at ≥10 mg KHK2455), confirming target modulation. Six of 26 evaluable patients from all dosing groups achieved durable disease stabilization (≥6 months, RECIST 1.1), and one patient with bevacizumab-resistant glioblastoma demonstrated confirmed partial response (43.5% tumor reduction over a 2-year observation period). Median overall survival was 13.4 months, with 30% of subjects surviving for 2 years or longer (figure 1).Abstract 287 Table 1Study 2455-001: Treatment-Emergent Adverse Events (≥10% by Preferred Term)Abstract 287 Table 2Abstract 287 Figure 1Study 2455-001: Overall SurvivalConclusionsKHK2455 in combination with mogamulizumab was well-tolerated and manageable at all doses tested, suppressed Kyn production in a dose-dependent and sustained manner, and demonstrated signals of antitumor activity. These data support the continued development of this combination.AcknowledgementsMedical writing assistance was provided by Susan E. Johnson, PhD, S.E. Johnson Consulting, LLC, New Hope, PA, USA.Trial RegistrationNCT02867007 (www.clinicaltrials.gov)Ethics ApprovalThis study was approved by Ethics Committees at all participating study institutions.

Phase I, dose-escalation study of the investigational drug TAK-733, an oral MEK inhibitor, in patients (pts) with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2528-2528 ◽  
Author(s):  
Alex A. Adjei ◽  
Patricia LoRusso ◽  
Antoni Ribas ◽  
Jeffrey Alan Sosman ◽  
Anna C. Pavlick ◽  
...  
Keyword(s):  
Steady State ◽  
Solid Tumors ◽  
Peripheral Blood ◽  
Human Study ◽  
Mek Inhibitor ◽  
Investigational Drug ◽  
Advanced Solid Tumors ◽  
Post Dose ◽  
Dose Escalation Study ◽  
Grade 3

2528 Background: This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), MTD, and efficacy of TAK-733 – an oral, selective, allosteric inhibitor of MEK1/2 – in pts with advanced solid tumors (NCT00948467; completed study). Methods: Eligibility: age ≥18 y; ECOG PS 0–2; evaluable tumors. Pts received escalating doses of TAK-733 QD in a modified 3+3 design for 21 d in a 28-d cycle to determine the MTD based on DLTs in cycle 1. Plasma (PK) and peripheral blood samples (PD: pERK reduction in PBMCs) were obtained pre-dose (d 1, 8, 15, 21) and post-dose (d 1, 21) in cycle1. Results: 51 pts (median age 58 y; 51% M) received escalating doses of TAK-733 (0.2–22 mg; median 2 cycles, range 1–11 [5 pts ≥6 cycles]). 4 pts had DLTs: grade 3 acneiform dermatitis, 1 each at 11.8 and 16mg; grade 3 pustular rash and grade 2 rash/stomatitis (qualifying as a DLT) at 22mg, leading to the 16 mg dose being selected as MTD. 45 pts (88%) had a drug-related AE; most frequent was acneiform dermatitis (47%). 10 pts (20%) had a grade ≥3 drug-related AE; most frequent were creatine phosphokinase increase and acneiform dermatitis (each n=3, 6%). 7 pts discontinued due to AEs. TAK-733 exhibited a moderately fast absorption with a median Tmax of 3 hr. Steady-state exposure of TAK-733 (0.2–22mg) did not increase in a dose proportional manner based on the power model analysis. The mean terminal t1/2 (11.8, 16, and 22 mg) was 43 hr. Overall mean accumulation ratio was 3.5 following QD dosing for 21 d. On d 21, Emax of blood pERK modulation was 56–99%, and time-averaged modulation over the dosing interval at steady-state was 76–98% at MTD. This range correlates well to the 76–89% for pERK modulation associated with maximal efficacy in xenograft models. 1 pt (16 mg) with melanoma (BRAF L597R) had a confirmed partial response after 4 cycles (treated for 9 cycles). 15 pts had a best response of stable disease (4–11.7 months in 6 pts). Conclusions: From preliminary data, TAK-733 appears generally well tolerated, pharmacodynamically active and shows signs of anti-tumor activity in pts with advanced solid tumors. MTD was associated with significant pERK inhibition in peripheral blood. Clinical trial information: NCT00948467.

Emergency department visits among patients with advanced solid tumors at a cancer center in Mexico City.

2018 ◽  
Vol 36 (34_suppl) ◽  
pp. 52-52
Author(s):  
Miguel Araujo ◽  
Mirza Alcalde Castro ◽  
Enrique Soto Perez De Celis ◽  
Andrea De la O ◽  
Rafael Reyes ◽  
...  
Keyword(s):  
Emergency Department ◽  
Solid Tumors ◽  
Mexico City ◽  
Advanced Cancer ◽  
Palliative Chemotherapy ◽  
Emergency Department Visits ◽  
Cancer Center ◽  
Advanced Solid Tumors ◽  
Newly Diagnosed ◽  
Ed Visits

52 Background: Emergency department (ED) visits are a distressing event for patients with advanced cancer, and identifying planned, unplanned and avoidable ED visits is important for providing better cancer care. We studied the causes for ED visits, as well as potentially avoidable ED visits during palliative chemotherapy, among patients with advanced cancer treated at a public cancer center in Mexico City. Methods: Consecutive patients with newly diagnosed advanced solid tumors treated at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán from 10/2015 to 03/2016 were screened. Patients who visited the ED during that period were included, and their demographic and clinical characteristics recorded. Number and reasons for ED visits were obtained from medical records. Among patients who received chemotherapy within the previous 30 days, the following reasons for ED visits were classified as avoidable: anemia, nausea, dehydration, neutropenia, diarrhea, pain, emesis, pneumonia, fever or sepsis (according to Centers for Medicare and Medicare Services Hospital Outpatient Quality Reporting Program). Results: 77 patients were diagnosed with advanced solid tumors during the study period, of which 53 (69%) had at least one ED visit. Median age was 63 years (range, 19-88), and 47% were men (n = 25). 51% had gastrointestinal, 21% genitourinary and 28% other tumors. Median follow-up was 360 days. 95 ED visits were identified; with a median number of ED visits per patient of 1 (range 1-5). The most common causes of ED visits were: infections (n = 20; 21%), gastrointestinal disorders (n = 18; 19%), pain (n = 15; 16%), ascites (n = 14; 15%), anemia (n = 4; 4%), catheter dysfunction (n = 4; 4%), and other causes (n = 20; 21%). 57% of ED visits among patients who received chemotherapy within the previous 30 days were classified as potentially avoidable. Conclusions: Over two thirds of patients with newly diagnosed metastatic cancer had ED visits in the first year after diagnosis. Furthermore, more than a half of ED visits among patients receiving palliative chemotherapy were potentially avoidable. Strategies aimed at reducing ED visits are needed to improve quality of care for patients with advanced cancer.

scholarly journals Functional Genetic Biomarkers of Alzheimer’s Disease and Gene Expression from Peripheral Blood

2021 ◽  
Author(s):  
Andrew Ni ◽  
Amish Sethi ◽  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Peripheral Blood ◽  
Genetic Variants ◽  
Cell Activation ◽  
Association Studies ◽  
Gene Set Enrichment Analysis ◽  
Machine Learning Techniques ◽  
Genome Wide Association Studies

AbstractDetecting Alzheimer’s Disease (AD) at the earliest possible stage is key in advancing AD prevention and treatment but is challenged by normal aging processes in addition to other confounding neurodegenerative diseases. Recent genome-wide association studies (GWAS) have identified associated alleles, but it has been difficult to transition from non-coding genetic variants to underlying mechanisms of AD. Here, we sought to reveal functional genetic variants and diagnostic biomarkers underlying AD using machine learning techniques. We first developed a Random Forest (RF) classifier using microarray gene expression data sampled from the peripheral blood of 744 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. After initial feature selection, 5-fold cross-validation of the 100-gene RF classifier achieved an accuracy of 99.04%. The high accuracy of the RF classifier supports the possibility of a powerful and minimally invasive tool for screening of AD. Next, unsupervised clustering was used to validate and identify relationships among differentially expressed genes (DEGs) the RF selected revealing 3 distinct AD clusters. Results suggest downregulation of global sulfatase and oxidoreductase activities in AD through mutations in SUMF1 and SMOX respectively. Then, we used Greedy Fast Causal Inference (GFCI) to find potential causes of AD within DEGs. In the causal graph, HLA-DPB1 and CYP4A11 emerge as hub genes, furthering the discussion of the immune system’s role in AD. Finally, we used Gene Set Enrichment Analysis (GSEA) to determine the biological pathways and processes underlying the DEGs that were highly correlated with AD. Cell activation in the immune system, glycosaminoglycan (GAG) binding, vascular dysfunction, oxidative stress, and the neuronal apoptotic process were revealed to be significantly enriched in AD. This study further advances the possibility of low-cost and noninvasive genetic screening for AD while also providing potential gene targets for further experimentation.

scholarly journals System-Level Factors Associated With Use of Outpatient Specialty Palliative Care Among Patients With Advanced Cancer

2019 ◽  
Vol 15 (1) ◽  
pp. e10-e19 ◽  
Author(s):  
Justin A. Yu ◽  
Kristin N. Ray ◽  
Seo Young Park ◽  
Amanda Barry ◽  
Cardinale B. Smith ◽  
...  
Keyword(s):  
Palliative Care ◽  
Travel Time ◽  
Solid Tumors ◽  
Advanced Cancer ◽  
System Level ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Cancer Type ◽  
Advanced Solid Tumors ◽  
Patient Travel

PURPOSE: The proportion of patients with advanced cancer who receive outpatient specialty palliative care (OSPC) is as low as 2.0%. Improved understanding of the system-level factors influencing use of OSPC could inform adaptations to the delivery of palliative care to maximize access. We examined associations between OSPC use among patients with advanced solid tumors and oncology-OSPC clinic colocation and patient travel time to an OSPC clinic. PATIENTS AND METHODS: We conducted a retrospective cohort study of patients with advanced solid tumors receiving oncologic treatment between January 1 and December 31, 2016, within a comprehensive cancer center network with well-established, oncology-specific OSPC clinics. Multivariable logistic regression analysis was used to evaluate the associations of clinic colocation and geographic access with OSPC use. RESULTS: Of 9,485 patients with advanced solid tumors, 478 (5.0%) received OSPC services in 2016. After controlling for age, sex, marital status, cancer type, insurance, treatment intent, and illness severity, patients whose oncologist practices were colocated with OSPC clinics were more likely to use OSPC (odds ratio [OR], 19.2; 95% CI, 14.1 to 26.2). Compared with patients who lived > 90 minutes from an OSPC clinic, patients with travel times of < 30 minutes (OR, 3.2; 95% CI, 2.2 to 4.6) and 31 to 60 minutes (OR, 2.4; 95% CI, 1.6 to 3.6) were also more likely to use OSPC. CONCLUSION: Among patients with advanced solid tumors, colocation of oncology and OSPC clinics and shorter patient travel time were associated with greater odds of using OSPC. Future efforts to increase OSPC use in this population should consider clinic colocation and travel burden.

Phase I dose-finding study of golvatinib (E7050), a c-Met and Eph receptor targeted multi-kinase inhibitor, administered orally QD to patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3030-3030 ◽  
Author(s):  
Gennaro Daniele ◽  
Malcolm Ranson ◽  
Montserrat Blanco-Codesido ◽  
Emma Jane Dean ◽  
Krunal Jitendrakumar Shah ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Gene Copy Number ◽  
Post Treatment ◽  
Dose Finding ◽  
Gene Copy ◽  
Multiple Time ◽  
Advanced Solid Tumors ◽  
Eph Receptor

3030 Background: Golvatinib is a highly potent, small molecule ATP-competitive inhibitor of the c-Met receptor tyrosine kinase and multiple members of the Eph receptor family as well as c-Kit and Ron, based on isolated kinase assays. Golvatinib showed preclinical evidence of anti-tumor activity. This phase 1 study was performed to determine the MTD, safety, PK, PD and preliminary activity of golvatinib. Methods: Patients (pts) with advanced solid tumors, ECOG PS 0-1, ≥ 18 years (yrs) and adequate organ function were eligible. Golvatinib was administered orally, once daily (QD), continuously. Blood samples for PK and PD analysis were collected at multiple time-points. Mandatory tumor biopsies for PD analysis were taken pre and post Cycle 1 in an expanded MTD cohort. Results: 34 pts (M/F: 21/13; median age 63.5yrs [range 32-78]) were treated at 6 dose levels: 100, 200, 270, 360, 450 and 400 mg. Tumor types were colorectal (n=15), lung (n=4), renal (n=4), esophageal (n=2), melanoma (n=2) and others (n=7). Three DLTs were observed: Gr3 GGT and alkaline phosphatase (n=1; 200mg) and repeated Gr2 (n=1) and Gr3 (n=1) fatigue, both at 450mg. The MTD was determined to be 400 mg QD. Frequently occurring adverse events ([AEs]; all grades) were fatigue: 68% (Gr3: 15%), diarrhea: 65%, nausea: 62%, vomiting: 53%, decreased appetite: 47% (Gr3: 9%), ALT increase: 38% and AST increase: 23%. No Gr4 AEs were observed. Best response was stable disease in 6 pts lasting >84 days. PK showed high variability and plasma concentration increased with dose. The Cmax was reached within a median time of 4 hours. Plasma PD analysis showed an increase in soluble c-Met and Ang 2 levels after golvatinib treatment. Tumor PD analysis in 5 pts at 400 mg demonstrated a baseline elevated MET gene copy number, with c-Met overexpression and post treatment decline in phospho(p)-c-Met expression in 1 pt; post-treatment decline in p-c-Met in a 2nd pt, and post-treatment decline in p-ERK in a 3rd pt. Conclusions: Golvatinib at an MTD of 400 mg QD has manageable toxicity. Preliminary PD analysis demonstrated evidence of c-Met target modulation. Further evaluation will continue in phase 2 combination studies.

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