Gemcitabine plus enzastaurin or single-agent gemcitabine in locally advanced or metastatic pancreatic cancer: Results of a Phase II, randomized, noncomparative study
ABSTRACT Gemcitabine (G) is standard therapy for pancreatic cancer. Enzastaurin (E) inhibits PKCβ and PI3K/AKT signaling pathways with a dose-dependent effect on growth of pancreatic carcinoma xenografts. Data suggest that the GE combination may improve clinical outcomes.
Primary objective was overall survival (OS); secondary objectives assessed progression-free survival (PFS), response rate (RR), quality of life (QOL), toxicity, and relationships between biomarker expression and clinical outcomes. Patients were randomly assigned (2:1) to GE or G treatment; GE arm: E 500 mg p.o. daily; loading-dose (1200 mg; Day 1 Cycle 1 only) and G 1000 mg/m(2) i.v. Days 1, 8, and 15 in 28-day cycles; G arm: G as in GE. Biomarker expression was assessed by immunohistochemistry.
Randomization totaled 130 patients (GE = 86, G = 44); 121 patients were treated (GE = 82, G = 39). GE/G median OS was 5.6/5.1 months; median PFS was 3.4/3.0 months. GE responses: 1 complete response (CR, 1.2%), 6 partial response (PR, 7.4%), and 33 stable disease (SD, 40.7%); disease control rate (DCR=CR+PR+SD, 49.4%). G responses: 2 PR (5.3%) and 16 SD (42.1%); DCR (47.4%). No QOL differences were noted between arms. GE/G Grade 3-4 toxicities included: neutropenia (18.3%/28.2%); thrombocytopenia (14.6%/25.6%); and fatigue (11.0%/7.7%). No statistically significant relationships between biomarker expression and outcomes were observed. However, patients with low expression of cytoplasmic pGSK-3β trended toward greater OS with GE treatment.
OS, PFS, QOL, and RR were comparable between arms. Adding E to G did not increase hematologic toxicities. GE does not warrant further investigation in unselected pancreatic cancer patients.
- SourceAvailable from: Clara Natoli
Pancreatic Cancer - Molecular Mechanism and Targets, 12/2011; , ISBN: 978-953-51-0410-0
- "Clinical experience with inhibitors of the PI3K/Akt pathway in PDAC is mostly limited to mTOR or AKT inhibitors. Everolimus and enzastaurin failed to demonstrate significant clinical activity when tested in gemcitabine-refractory (Wolpin et al., 2009) or advanced PDAC (Richards et al., 2011), respectively. "
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ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related mortality in the United States. The prognosis of patients with PDAC is extremely poor with a median survival of 6 months, in part due to the advanced stage at the time of diagnosis and early metastatic spread. A considerable body of evidence points to the involvement of the tyrosine kinase and serine/threonine kinase pathways as major effectors in pancreatic cancer development and as potential targets for intervention. These pathways regulate multiple cellular processes including cell growth, proliferation, migration, invasion and resistance to apoptosis. The relatively recent introduction of novel therapies targeting tyrosine kinase and serine/threonine kinase pathways have yielded dramatic results in certain hematological malignancies, and have resulted in significant advances in our ability to treat patients with melanoma, breast, lung and colon cancer, thereby leading to improved survival and quality of life. Unfortunately, similar therapeutic improvements have not occurred in PDAC. Thus, despite encouraging phase I/II studies, the vast majority of phase-III studies have failed to demonstrate improved efficacy in PDAC. This review will provide an overview on the different kinase signaling pathways in PDAC and the supporting data on targeted therapies available from pre-clinical and clinical studies.Cancer biology & therapy 05/2010; 9(10):754-63. DOI:10.4161/cbt.9.10.11534 · 3.63 Impact Factor
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ABSTRACT: Protein kinase C-beta2 (PKCbeta2) is a splice-variant of the PRKCB1 gene and belongs to a family of serine/threonine-specific kinases that are predominantly activated by diacylglycerol, calcium, and phorbol ester. Cellular functions associated with PKCbeta2 activation include transformation, proliferation, and inhibition of apoptosis. Enzastaurin (LY317615) is an oral, selective, potent inhibitor of the PKCbeta2 kinase. Preclinical activity for this agent was predominantly reported in lymphoma, glioblastoma, and colorectal cancer. In patients with advanced non-small-cell lung cancer (NSCLC) whose previous therapy had failed, 13% of patients had disease control for 6 months with single-agent therapy. We investigated whether biologically relevant variants of PRKCB1 exist in lung cancer cell lines in the context of enzastaurin-induced proliferation and kinase inhibition, using exon sequencing, immunoblotting, and cytotoxicity assays in NSCLC and small-cell lung cancer (SCLC) cell lines. We discovered a total of 6 single-nucleotide variants, but only 1 resulted in an amino acid substitution (T40I). This substitution was not located in the kinase domain of PKCbeta2 and did not affect enzastaurin's antiproliferative or phosphorylation-inhibitory activity. We found enzastaurin to be equally active in NSCLC and SCLC cell lines, with values of the 50% inhibitory concentration in a range of 0.05-0.2 microM. The inhibition of phosphorylation of PKCbeta2 and the downstream molecules glycogen synthase kinase-3beta, S6RP, Akt, and forkhead transcription factor was evident in the same concentration range, which suggests the premise that the determination of phosphorylation levels of these molecules in human tissue specimens may be a useful pharmacodynamic parameter for in vivo target inhibition by enzastaurin.Clinical Lung Cancer 05/2010; 11(3):169-75. DOI:10.3816/CLC.2010.n.021 · 3.22 Impact Factor