Study of Continuous OSI-906 Dosing
Ontology highlight
ABSTRACT:
DISEASE(S): Ovarian Cancer,Advanced Solid Tumors,Non-small Cell Lung Cancer,Colorectal Cancer,Advanced Cancer,Breast Cancer
PROVIDER: 2043046 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:Multicenter, open-label, phase 1, cohort dose escalation study to determine the maximum tolerated dose (MTD) of 3 intermittent OSI-906 dosing schedules.
| 2043067 | ecrin-mdr-crc
Project description:We performed RNA sequencing on tumors harvested from OV5398 (ovarian) PDX treated for 40-50 days with either control vehicle (PEG), 100 mg/kg BID INX-315 or 200 mg/kg QD INX315.
2023-11-22 | GSE243151 | 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:Multicenter, open-label, phase 1, cohort dose escalation study to determine the Maximum Tolerated Dose (MTD) of OSI-906 in combination with erlotinib
| 2060049 | ecrin-mdr-crc
Project description:The purpose of this study is to determine the maximum tolerated dose (MTD) of the combination of OSI-906 and everolimus for the treatment of patients with refractory metastatic colorectal cancer.
| 2091466 | ecrin-mdr-crc
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.
2021-06-21 | GSE151594 | GEO
Project description:Growth factor signaling via insulin receptor (IR) and IGF-1 receptor (IGF1R) plays several important roles in the pathogenesis of metabolic syndrome and diabetes. OSI-906 (linsitinib), an anti-tumor drug, is an orally bioavailable dual inhibitor of IR and IGF1R. To investigate the recovery from metabolic changes induced by the acute inhibition of IR and IGF1R in adult mice, mice were treated with OSI-906 or a vehicle for 7 days and the results were analyzed on the last day of injection (Day 7) or after 7 or 21 days of withdrawal (Day 14 or Day 28). On day 7, the visceral white fat mass was significantly reduced in mice treated with OSI-906 accompanied by a reduced expression of leptin and an increased expression of the lipolysis-related genes Lpl and Atgl. Interestingly, the lipoatrophy and the observed changes in gene expression were completely reversed on day 14. Similarly, liver steatosis and β cell proliferation were transiently observed on day 7 but had disappeared by day 14. Taken together, these results suggest that this model for the acute inhibition of systemic IR/IGF1R signaling may be useful for investigating the recovery from metabolic disorders induced by impaired growth factor signaling.
| S-EPMC5482874 | biostudies-literature
Project description:Importance: Autophagy has been identified as a resistance mechanism to BRAF and MEK inhibition in BRAF mutant melanoma. In the BAMM trial, hydroxychloroquine (HCQ) was used to inhibit autophagy in combination with dabrafenib and trametenib in BRAF mutant melanoma patients. Objective: To a) determine safety and maximal tolerated dose (MTD) of hydroxychloroquine when combined with dabrafenib and trametinib and b) determine antitumor activity of the combination. Design: Open label non-randomized phase I/II clinical trial Setting: Prospective therapeutic clinical trial conducted in 4 centers Participants: Unresectable Stage III or Stage IV BRAF mutant melanoma patients Intrevention: HCQ twice daily, dabrafenib 150 mg twice daily and trametinib 2 mg daily (D+T) Main Outcome: Primary outcomes were safety and 1-year progression-free survival (PFS) rate Results: Between December 2014 and January 2020, 50 patients were screened, 38 patients were enrolled and evaluable for toxicity and 34 patients were evaluable for 1-year PFS rate. Patient demographics were: 29% were ECOG PS 1, 47% had elevated LDH, 52% were Stage IV M1c or M1d and 53% had previously received therapy for advanced melanoma. In the phase I trial there was no dose limiting toxicity of HCQ at either 400 (n=3) or 600 (MTD) mg po bid combined with D+T. For the entire study population, the 1-year PFS rate was 41% (95% CI = ), median PFS was 11.9 months (95% CI = ), overall response rate (ORR) was 85% (95% exact CI=64-95%)and complete response rate of 41% (95% exact CI=25-59%). In a prespecificed subgroup analysis in 18 patients with elevated LDH, the ORR was 88% and median PFS was 8 months Conlusion and Relevance: The combination of HCQ, dabrafenib and trametinib was well tolerated and produced a high response rate but did not meet the prespecified criteria for success with respect to the 1-year PFS rate. In patients with elevated LDH , the response rate and PFS were encouraging. A randomized placebo controlled trial of dabrafenib and trametinib with/without HCQ in advanced BRAF mutant melanoma patients with elevated LDH and previously treated with immunotherapy is being conducted through the National Clinical Trial Network.
2022-01-07 | GSE193157 | GEO
Project description:12 wild-type C57BL/6 (B6) mice were divided into 4 groups: control group, IFN-α group, LPS group, and IFN-α+ LPS group, every group contained 3 mice (n=3). IFN-α was administrated i.p. to IFN-α group and IFN-α+ LPS group once daily (QD) for 7 days at a medium dose of 105units/kg weight, PBS was administrated i.p. to control group and LPS group QD for 7 days at the same volume. LPS group and IFN-α+ LPS group were injected i.v. with 10 μg LPS for one mouse on the 8th day. Control group and IFN-α group were injected i.v. with PBS at the same volume. 6 h later, mice were sacrificed to harvest spleens for protein microarray experiment. Mouse Cytokine Antibody Array 3(62) was purchased from Ray Biotech, Norcross GA, US.
2012-11-10 | GSE42183 | GEO
Project description:In this study we investigated the effect of linsitinib on the reversal of multidrug resistance (MDR) mediated by the overexpression of the ATP-binding cassette (ABC) subfamily members ABCB1, ABCG2, ABCC1 and ABCC10. Our results indicate for the first time that linsitinib significantly potentiate the effect of anti-neoplastic drugs mitoxantrone (MX) and SN-38 in ABCG2-overexpressing cells; paclitaxel, docetaxel and vinblastine in ABCC10-overexpressing cells. Linsitinib moderately enhanced the cytotoxicity of vincristine in cell lines overexpressing ABCB1, whereas it did not alter the cytotoxicity of substrates of ABCC1. Furthermore, linsitinib significantly increased the intracellular accumulation and decreased the efflux of [(3)H]-MX in ABCG2-overexpressing cells and [(3)H]-paclitaxel in ABCC10-overexpressing cells. However, linsitinib, at a concentration that reversed MDR, did not significantly alter the expression levels of either the ABCG2 or ABCC10 transporter proteins. Furthermore, linsitinib did not significantly alter the intracellular localization of ABCG2 or ABCC10. Moreover, linsitinib stimulated the ATPase activity of ABCG2 in a concentration-dependent manner. Overall, our study suggests that linsitinib attenuates ABCG2- and ABCC10-mediated MDR by directly inhibiting their function as opposed to altering ABCG2 or ABCC10 protein expression.
| S-EPMC7670583 | biostudies-literature