39 research outputs found
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Biomarkers and overall survival in patients with advanced hepatocellular carcinoma treated with TGF-βRI inhibitor galunisertib.
BackgroundTransforming growth factor beta (TGF-β) signalling is involved in the development of hepatocellular carcinoma (HCC). We followed changes in biomarkers during treatment of patients with HCC with the TGF-βRI/ALK5 inhibitor galunisertib.MethodsThis phase 2 study (NCT01246986) enrolled second-line patients with advanced HCC into one of two cohorts of baseline serum alpha-fetoprotein (AFP): Part A (AFP ≥1.5x ULN) or Part B (AFP <1.5x ULN). Baseline and postbaseline levels of AFP, TGF-β1, E-cadherin, selected miRNAs, and other plasma proteins were monitored.ResultsThe study enrolled 149 patients (Part A, 109; Part B, 40). Median OS was 7.3 months in Part A and 16.8 months in Part B. Baseline AFP, TGF-β1, E-cadherin, and an additional 16 plasma proteins (such as M-CSF, IL-6, ErbB3, ANG-2, neuropilin-1, MIP-3 alpha, KIM-1, uPA, IL-8, TIMP-1, ICAM-1, Apo A-1, CA-125, osteopontin, tetranectin, and IGFBP-1) were found to correlate with OS. In addition, a range of miRs were found to be associated with OS. In AFP responders (21% of patients in Part A with decrease of >20% from baseline) versus non-responders, median OS was 21.5 months versus 6.8 months (p = 0.0015). In TGF-β1 responders (51% of all patients) versus non-responders, median OS was 11.2 months versus 5.3 months (p = 0.0036).ConclusionsConsistent with previous findings, both baseline levels and changes from baseline of circulating AFP and TGF-β1 function as prognostic indicators of survival. Future trials are needed to confirm and extend these results
A randomized, phase 2 study of deoxyuridine triphosphatase inhibitor, TAS-114, in combination with S-1 versus S-1 alone in patients with advanced non-small-cell lung cancer
Summary
Introduction TAS-114 is a potent inhibitor of deoxyuridine triphosphatase, which is a gatekeeper protein preventing uracil and 5-fluorouracil (5-FU) misincorporation into DNA. TAS-114 has been suggested to enhance the antitumor activity of 5-FU. This randomized, phase 2 study investigated TAS-114 plus S-1 (TAS-114/S-1) vs. S-1 in non-small-cell lung cancer (NSCLC) patients. Methods Patients with advanced NSCLC, previously treated with ≥ 2 regimens, were randomized 1:1 to receive TAS-114 (400 mg)/S-1 (30 mg/m2) or S-1 (30 mg/m2). Progression-free survival (PFS, independent central review) was the primary endpoint. Secondary endpoints included disease control rate (DCR), overall survival (OS), overall response rate (ORR), and safety. Results In total, 127 patients received treatment. Median PFS was 3.65 and 4.17 months in the TAS-114/S-1 and S-1 groups, respectively (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.71–1.88; P = 0.2744). DCR was similar between groups (TAS-114/S-1 80.3%, S-1 75.9%) and median OS was 7.92 and 9.82 months for the TAS-114/S-1 and S-1 groups, respectively (HR 1.31, 95% CI 0.80–2.14; P = 0.1431). The ORR was higher in the TAS-114/S-1 group than the S-1 group (19.7% vs. 10.3%), and more patients with tumor shrinkage were observed in the TAS-114/S-1 group. Incidence rates of anemia, skin toxicities, and Grade ≥ 3 treatment-related adverse events were higher in the TAS-114/S-1 group compared with the monotherapy group. Conclusions Although the TAS-114/S-1 combination improved the response rate, this did not translate into improvements in PFS. Clinical Trial Registration No. NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016
Clinical Response to Futibatinib in Patients with High-Level FGFR2-Amplified Advanced Gastric Cancer: Two Case Reports
Gastric cancer is the fifth most frequently diagnosed cancer worldwide and the third leading cause of cancer-related deaths [1]. Nearly two-thirds of newly diagnosed gastric cancer patients in Western countries present with advanced disease and are therefore being offered systemic treatments
Population pharmacokinetics and exposure-overall survival analysis of the transforming growth factor-\u3b2 inhibitor galunisertib in patients with pancreatic cancer
PurposeTo evaluate the exposure-overall survival (OS) relationship in patients with advanced pancreatic cancer treated with galunisertib plus gemcitabine (GG) or gemcitabine plus placebo (GP).MethodsGalunisertib 300 mg/day was given orally as intermittent dosing and gemcitabine as per label. Galunisertib exposure metrics for each patient in the GG arm (n=99) of a phase 2 study of pancreatic cancer were calculated. Parametric survival models were used to identify influential baseline and response covariates on OS.ResultsThe population pharmacokinetics dataset included data from 297 patients/healthy subjects (age: 22-84 years, weight: 39-126 kg) across multiple studies, including this pancreatic cancer study. Galunisertib was rapidly absorbed with peak concentrations attained within 0.5-2 h and had an elimination half-life of 8 h. Between-subject variance on apparent clearance was estimated to be 47%. Age was the only characteristic to have a statistically significant effect on apparent clearance. A parametric Weibull survival model with treatment effect (dose) estimated a hazard ratio of 0.796, after adjusting for patient baseline factors that were significantly associated with OS. There was also a flat daily exposure-OS relationship within the observed exposure range, once all significant baseline covariates were included. Response covariates, such as reduction in CA19-9, time on treatment, and cumulative exposure over treatment cycles were also identified as significant factors for OS for patients with pancreatic cancer.ConclusionsThis analysis suggests that 300 mg/day galunisertib administered as 150 mg twice daily for 14 days on/14 days off treatment is an appropriate dosing regimen for patients with pancreatic cancer
Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells
PEP005 (ingenol-3-angelate) is a novel anticancer agent extracted from Euphorbia peplus that was previously shown to modulate protein kinase C (PKC), resulting in antiproliferative and proapoptotic effects in several human cancer cell lines. In Colo205 colon cancer cells, exposure to PEP005 induced a time- and concentration-dependent decrease of cells in S phase of cell cycle and apoptosis. In Colo205 cells exposed to PEP005, a variety of signaling pathways were activated as shown by increased phosphorylation of PKCδ, Raf1, extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase, p38 MAPK, and PTEN. PEP005-induced activation of PKCδ was associated with its translocation from the cytosol to the nucleus and other cellular membranes. Interestingly, PEP005 treatment also resulted in reduced expression of PKCα and reduced levels of phosphorylated active form of AKT/protein kinase B. These data suggest that PEP005-induced activation of PKCδ and reduced expression of PKCα resulted in apoptosis by mechanisms mediated by activation of Ras/Raf/MAPK and inhibition of the phosphatidylinositol 3-kinase/AKT signaling pathways. This study supports ongoing efforts targeting PKC isoforms in cancer therapy with PEP005 alone and in combination with other cytotoxic agents
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A phase 1b study of the Notch inhibitor crenigacestat (LY3039478) in combination with other anticancer target agents (taladegib, LY3023414, or abemaciclib) in patients with advanced or metastatic solid tumors
Notch signaling plays an important role in development and tissue homeostasis. Deregulation of Notch signaling has been implicated in multiple malignancies. Crenigacestat (LY3039478), a potent Notch inhibitor, decreases Notch signaling and its downstream biologic effects. I6F-MC-JJCD was a multicenter, nonrandomized, open-label, Phase 1b study with 5 separate, parallel dose-escalations in patients with advanced or metastatic cancer from a variety of solid tumors, followed by a dose-confirmation phase in prespecified tumor types. This manuscript reports on 3 of 5 groups. The primary objective was to determine the recommended Phase 2 dose of crenigacestat in combination with other anticancer agents (taladegib, LY3023414 [dual inhibitor of phosphoinositide 3-kinase; mechanistic target of rapamycin], or abemaciclib). Secondary objectives included evaluation of safety, tolerability, efficacy, and pharmacokinetics. Patients (N = 63) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 12 patients, mostly gastrointestinal (diarrhea, nausea, vomiting). The maximum-tolerated dose of crenigacestat was 25 mg in Part B (LY3023414), 50 mg in Part C (abemaciclib), and not established in Part A (taladegib) due to toxicities. Patients had at least 1 adverse event (AE) and 75.0-82.6% were ≥ Grade 3 all-causality AEs. No patient had complete or partial response. Disease control rates were 18.8% (Part B) and 26.1% (Part C). The study was terminated before dose confirmation cohorts were triggered. This study demonstrated that crenigacestat combined with different anticancer agents (taladegib, LY3023414, or abemaciclib) was poorly tolerated, leading to lowered dosing and disappointing clinical activity in patients with advanced or metastatic solid tumors. NCT02784795 and date of registration: May 27, 2016
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Phase 1b study of galunisertib and ramucirumab in patients with advanced hepatocellular carcinoma.
BackgroundPreclinical data suggest that vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β signaling interact to stimulate angiogenesis and suppress antitumor immune responses. Thus, combined inhibition of both pathways may offer greater antitumor activity compared with VEGF-targeted antiangiogenic monotherapy against hepatocellular carcinoma (HCC).MethodsThis is a multicenter, open-label, phase 1b study of galunisertib, an inhibitor of TGF-β receptor 1, and ramucirumab, an anti-VEGF receptor 2 antibody, in patients with advanced HCC aiming to define the maximum tolerated dose (MTD). Secondary objectives included safety, pharmacokinetics (PK), antitumor efficacy, and plasma alpha-fetoprotein and TGF-β kinetics. Dose escalation employed a 3 + 3 design. Patients received galunisertib at 80 mg (cohort 1) or 150 mg (cohort 2) orally twice a day on days 1-14 of a 28-day cycle combined with ramucirumab 8 mg/kg intravenously every 2 weeks.ResultsEight patients were enrolled: three in cohort 1 and five in cohort 2 (two patients were unevaluable due to rapid disease progression and replaced). No dose-limiting toxicities were observed. Treatment-related adverse events (AEs) of any grade in ≥2 patients included nausea (25%) and vomiting (25%). There was one Grade 3 treatment-related AE, a cerebrovascular accident possibly related to ramucirumab. Galunisertib exposure was dose-proportional and not affected by ramucirumab. The RECIST version 1.1 objective response rate and disease control rate were 0% and 12.5%, respectively.ConclusionCombination therapy was safe and tolerable and displayed favorable PK. The MTD was established at galunisertib at 150 mg orally twice a day and ramucirumab 8 mg/kg intravenously every 2 weeks. The results do not support the preclinical hypothesis that blocking TGFβ signaling enhances efficacy of VEGF-targeted therapy; thus further clinical development was halted for the combination of galunisertib and ramucirumab
Novel Transforming Growth Factor Beta Receptor I Kinase Inhibitor Galunisertib (LY2157299) in Advanced Hepatocellular Carcinoma
We assessed the activity of galunisertib, a small molecule inhibitor of the transforming growth factor beta (TGF-β1) receptor I, in second line patients with hepatocellular carcinoma (HCC) in two cohorts of baseline serum alpha fetoprotein (AFP)
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Notch pathway inhibition with LY3039478 in adenoid cystic carcinoma (ACC)
6024 Background: ACCs have high levels of Notch-1 receptor expression and activation. LY3039478 (LY) is an orally bioavailable selective Notch inhibitor (Notch 1-4). Here we report on safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of LY in patients (pts) with ACC. Methods: Ongoing, multi-part, phase I trial enrolled pts with advanced or metastatic ACC, measurable disease, ECOG ≤1, and baseline tumor tissue. Eligible pts received LY 50 mg three times per week (TIW), on a 28-day cycle until disease progression. Safety assessments were based on CTCAE V4.0. Tumor responses were assessed using RECIST 1.1. Primary objectives are to confirm the recommended phase II dose of LY and document antitumor activity. Secondary objectives are safety and toxicity, PK and progression-free survival (PFS). Exploratory objectives include assessment for PET metabolic responses. Results: 22 pts have been enrolled and received LY 50mg TIW (13 men, 9 women; median age 60, range 41-82). All pts had metastatic disease; median treatment duration was 3 cycles (range 1-10) with 6 pts continuing on treatment. One pt had an unconfirmed partial response. Disease control rate (DCR) was 16/22 (73%), of which 4 pts had stable disease ≥ 6 months. In the overall group (n = 22) median PFS (mPFS) was 5.3 months (95% CI: 2.4, NE). mPFS was 7.7 (95% CI: 4.0, NE) for pts in second line (n = 7), while mPFS was 2.4 (95% CI: 1.1, NE) for pts in third line or more (n = 9). In pts without prior systemic therapy (n = 6) mPFS could not be estimated since 4 of those patients were censored. In preliminary analysis, 14 pts were assessed by PET, with 2 (14%) achieving partial metabolic response. Most frequent related adverse events (all grades) occurring in ≥20% of pts included diarrhea (55%), fatigue (45%), vomiting (36%), decreased appetite (27%), dry mouth (27%), and dry skin (23%). Grade 3/4 related treatment-emergent adverse events observed in more than one pt were diarrhea (n = 3) and squamous cell carcinoma of skin (n = 2). PK was assessed in 17 pts, with peak concentrations occurring approximately 2 hours post-dose. Biomarker and histologic analyses of pre and post treatment biopsies will be presented. Conclusions: LY showed activity (73% DCR) in ACC with a manageable safety profile. Clinical trial information: NCT01695005