Gemcitabine plus enzastaurin or single-agent gemcitabine in locally advanced or metastatic pancreatic cancer: Results of a Phase II, randomized, noncomparative study

US Oncology Research, Inc., The Woodlands, TX, USA.
Investigational New Drugs (Impact Factor: 2.92). 09/2009; 29(1):144-53. DOI: 10.1007/s10637-009-9307-8
Source: PubMed


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.

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    • "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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    • "This finding emphasises the general importance of defining critical molecular markers that are associated with a potential resistance towards novel targeted therapy compounds, because otherwise it might lead to the treatment of patients that, by their molecular condition, are unable to respond to the novel drug. In fact, this might be one of the explanations as to why initial clinical trials with Enz that were not associated with parallel translational molecular studies at the resected tumour tissue of treated patients, led to initial contradictory results (Casey et al, 2009; Richards et al, 2009; Kreisl et al, 2010; Wick et al, 2010). However, with our results we might give an additional encouragement for the initiation of more tailored-therapy clinical studies, in which putatively essential molecular markers associated with response or resistance are being measured before the decision for a certain combination of therapies in the individual patient. "
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