A Phase Ib/II Study of BBI608 in Combination with Pembrolizumab in Patients with Metastatic Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer
PROVIDER: 2638404 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Preclinical studies have shown that combining the LSD1 inhibitor tranylcypromine (TCP) with all-trans retinoic acid (ATRA) induces differentiation and impairs survival in non-APL acute myeloid leukemia (AML). We conducted a Phase 1 clinical trial (NCT02273102) to evaluate the safety and preliminary activity of ATRA in combination with TCP in patients with relapsed/refractory AML and myelodysplasia (MDS). Seventeen patients (11 AML and 6 MDS) received ATRA-TCP therapy with ATRA (45 mg/m2 daily in divided doses) and TCP (3 dose levels: 10 mg twice-daily [BID], 20 mg BID, and 30 mg BID). ATRA-TCP had an acceptable safety profile. The maximum tolerated dose of TCP was 20 mg BID. There were 3 DLTs: dizziness (20 mg BID), asthenia (30 mg BID), and nausea/vomiting (30 mg BID). Best evaluable responses included 1 morphologic leukemia-free state (MLFS), 1 marrow complete remission (CR) with hematologic improvement, 2 stable disease with hematologic improvement, and 2 stable disease. In 13 response-evaluable patients, the overall response rate was 30.8% and clinical benefit rate 46.2%. Gene expression profiling of patient blasts showed that responding patients had a more dormant phenotype compared to non-responders at baseline. In human AML cell lines, we showed that treatment with ATRA-TCP increases differentiation capacity and/or cell death, and that ATRA-TCP regulates the in vitro expression of genes that segregate primary patients by their clinical response. These data indicate that LSD1 inhibition sensitizes AML cells to ATRA-induced differentiation and cell death and may restore clinical responsiveness in subsets of MDS and AML patients.
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Project description:Intervention name : TAS-102
Dosage And administration of the intervention : TAS-102 as a starting dose of 25 mg/m2/dose BID (50 mg/m2/day) is administered orally in a 28-day cycle (2-week cycle of 5 days of treatment followed by a 2-day rest period, and then a 14-day rest period).
Control intervention name : irinotecan
INN of the control intervention : irinotecan
Dosage And administration of the control intervention : Irinotecan is administered by intravenous infusion at a dose of 150 mg/m2 over 90 minutes on day 1 and 15.
Primary outcome(s): Safety
CTCAE (ver.3.0)
Study Design: Open-label, multi-center, phase I study
| 2610898 | ecrin-mdr-crc
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2021-09-09 | GSE183415 | GEO
Project description:Background: Clenbuterol, a beta2-adrenergic receptor agonist, is used therapeutically to treat respiratory conditions in the horse. However, by virtue of its mechanism of action it has been suggested that clenbuterol may also have repartitioning affects in horses and as such the potential to affect performance. Clenbuterol decreases the percent fat and increases fat-free mass following high dose administration in combination with intense exercise in horses. In the current study, microarray analysis and real-time PCR were used to study the temporal effects of low and high dose chronic clenbuterol administration on differential gene expression of several skeletal muscle myosin heavy chains, genes involved in lipid metabolism and the β2-adrenergic receptor. 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The microarrays were evaluated for differential gene expression using Transcriptome Analysis Console (TAC) and for hybridization quality control using Expression Console Software (Affymetrix, Santa Clara, CA). In brief, a total of five Cell Intensity Files were generated per time point, uploaded and normalized under the following conditions: PM (perfect match)-only as a PM intensity adjustment and the Robust Multichip Analysis (RMA) quantification method. For evaluation of the assays performance the number of differentially expressed genes detected between baseline and day 14 (low dose administration) or day 28 (escalating dose regimen) were assessed. Based on the TAC software userâs manual, genes with mean transformed ratios significantly less than -2 and larger than +2 were considered significantly regulated. A number of the significant genes were selected by filtering the genes using an ANOVA (p value < 0.05). A Pearson's correlation coefficient was used to calculate linear dependence between time point and baseline samples to evaluate the correlation coefficient, where 1 was a positive correlation and 0 was no correlation. For each probeset, expression at day 14 (low dose administration) or day 28 (escalating dose regimen) was compared to expression at baseline in the same horse using a paired t-test. Fold changes and their confidence intervals were calculated by exponentiating (base 2) the mean within-horse difference in expression for each gene and the associated t confidence intervals. P-values were adjusted for multiple testing using the False Discovery Rate (FDR) method. Analyses were conducted using the statistical software environment R, version 3.0.2 (R Core Team, 2013).
2016-03-24 | E-GEOD-79559 | biostudies-arrayexpress
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2021-04-17 | GSE172234 | GEO
Project description:Mice rendered obese with high fat diet were treated by IP injection with N-trans caffeoyltyramine (NCT) (200 mg/kg bid) for 14 days, followed by harvesting of the intestine for analysis, including RNA isolation.
2021-06-18 | GSE178435 | GEO
Project description:To examine the effects of GSK199 treatment on antibody responses, a synovial antigen array analysis was performed using day 35 sera derived from mice with CIA treated with 30 mg/kg qd, 30 mg/kg bid GSK199 or saline. The synovial antigen arrays contain nearly 200 peptides and proteins, both citrullinated and uncitrullinated, representing candidate antigens in RA. Significance Analysis of Microarrays identified 7 and 14 autoantibody reactivities that were statistically decreased in CIA mice treated with 30 mg/kg qd or 30 mg/kg bid GSK199 respectively, compared to PBS treatment. By comparison, over 150 native and citrullinated epitopes on the arrays did not exhibit significant differences in reactivity. Sera from mice treated with 30 mg/kg GSK199 qd exhibited decreased IgG reactivity to native epitopes such as peptides from human fibrinogen alpha and beta chains and keratin while sera from mice treated with 30 mg/kg bid GSK199 demonstrated decreased IgG reactivity to native epitopes including collagen IV, heat shock protein 65, peptides from human fibrinogen alpha and beta chains (two of which match those that were decreased in the 30 mg/kg qd group), and vimentin as compared to saline controls (q < 0.1%). Decreased autoantibody reactivity to citrullinated peptides from vimentin and fibromodulin were also observed in sera from mice treated with 30 mg/kg bid GSK199 compared to controls treated with saline (q < 0.1%), but not by GSK199 30 mg/kg qd. There were no differences between treatment with GSK199 or saline alone in the levels of autoantibodies to 38 other citrullinated proteins in the array. These data demonstrated that GSK199 treatment decreases the development of autoantibodies in CIA and impairs epitope spreading to a degree similar to that observed with pan-PAD inhibition.
2015-10-08 | GSE69680 | GEO
Project description:Interventions: investigational material(s)
Generic name etc : TAS-102
INN of investigational material :
Therapeutic category code : 422 Antimetabolic agents
Dosage and Administration for Investigational material : TAS-102 as a starting dose of 25 mg/m2/dose BID (50 mg/m2/day) is administered orally in a 28-day cycle (2-week cycle of 5 days of treatment followed by a 2-day rest period, and then a 14-day rest period).
control material(s)
Generic name etc : irinotecan
INN of investigational material : irinotecan
Therapeutic category code : 424 Antineoplastic preparations extracted from plants
Dosage and Administration for Investigational material : Irinotecan is administered by intravenous infusion at a dose of 150 mg/m2 over 90 minutes on day 1 and 15.
Primary outcome(s): Safety
CTCAE (ver.3.0)
Study Design: Open-label, multi-center, phase I study
| 100929 | ecrin-mdr-crc
Project description:Intervention name : S-1(tegafur + gimeracil + oteracil potassium)/LV/L-OHP/Bevacizumab
INN of the intervention : S-1:tegafur, gimeracil, oteracil potassium LV:folic acid OHP:oxaliplatin Bevacizumab:bevacizumab
Dosage And administration of the intervention : S-1 40-60 mg bid day 1-day 7, LV 25 mg bid day 1-day 7, L-OHP 85 mg/m2 iv. for 2 hr on day 1 of each 2 weeks cycle, Bevacizumab 5 mg/kg iv. for 90 min on day 1 of each 2 weeks cycle.
Control intervention name : null
Primary outcome(s): Response rate(RR)
RECIST
Study Design: Randomized, open-label, comparative study.
| 2610204 | ecrin-mdr-crc