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Disrupting cytokine signaling in pancreatic cancer: a phase I/II study of etanercept in combination with gemcitabine in patients with advanced disease.

ABSTRACT: Etanercept blocks tumor necrosis factor ? (TNF-?), a proinflammatory cytokine that plays a role in cancer-related cachexia and tumor growth. A phase I/II study was conducted to assess the tolerability and efficacy of gemcitabine and etanercept in advanced pancreatic cancer.Twenty-five patients received etanercept 25 mg subcutaneously twice weekly with gemcitabine. A control cohort of 8 patients received gemcitabine alone. The primary end point was progression-free survival at 6 months. Blood specimens were analyzed for TNF-?, IL-1?, IL-6, interferon-?, IL-10, and NF-?? activation. The trial is registered with ClinicalTrials.gov, number NCT00201838.Thirty-eight patients participated in this study. In the gemcitabine-etanercept cohort, grade 3/4 drug-related toxicities included leucopenia (3) and neutropenia (6). There were 3 (12%) patients with partial response and 8 (32%) patients with stable disease. The rate of progression-free survival at 6 months was 28% [n = 7; 95% confidence interval (CI), 20%-36%]. Median time to progression was 2.23 months (95% CI, 1.86-4.36 months) and median overall survival was 5.43 months (95% CI, 3.30-10.23 months). Clinical benefit rate was 33% of the evaluable patients. A correlation was seen between IL-10 levels and clinical benefit.Etanercept added to gemcitabine is safe but did not show significant enhancement of gemcitabine in patients with advanced pancreatic cancer.

SUBMITTER: Wu C

PROVIDER: S-EPMC3664263 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Disrupting cytokine signaling in pancreatic cancer: a phase I/II study of etanercept in combination with gemcitabine in patients with advanced disease.

Wu Christina C Fernandez Soledad A SA Criswell Tamara T Chidiac Tarek A TA Guttridge Denis D Villalona-Calero Miguel M Bekaii-Saab Tanios S TS

Pancreas 20130701 5

<h4>Objectives</h4>Etanercept blocks tumor necrosis factor α (TNF-α), a proinflammatory cytokine that plays a role in cancer-related cachexia and tumor growth. A phase I/II study was conducted to assess the tolerability and efficacy of gemcitabine and etanercept in advanced pancreatic cancer.<h4>Methods</h4>Twenty-five patients received etanercept 25 mg subcutaneously twice weekly with gemcitabine. A control cohort of 8 patients received gemcitabine alone. The primary end point was progression-f ...[more]

PMID: 23429495

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Project description:PurposeLenalidomide have both immunomodulatory and anti-angiogenic properties which could confer anti-cancer effects. The aim of this study was to assess the feasibility of combining lenalidomide with the standard treatment gemcitabine in pancreatic cancer patients with advanced disease.Patients and methodsEligible patients had locally advanced or metastatic adenocarcinoma of the pancreas. Patients received lenalidomide days 1-21 orally and gemcitabine 1000 mg/m2 intravenously (days 1, 8 and 15), each 28 day cycle. Three cohorts of lenalidomide were examined (Cohort I = 15 mg, Cohort II = 20 mg and Cohort III = 25 mg daily). The maximum tolerated dose (MTD) of lenalidomide given in combination with gemcitabine was defined as the highest dose level at which no more than one out of four (25%) subjects experiences a dose-limiting toxicity (DLT). Patients should also be able to receive daily low molecular weight heparin (LMWH) (e.g. dalteparin 5000 IU s.c. daily) as a prophylactic anticoagulant for venous thromboembolic events (VTEs). Twelve patients (n = 4, n = 3 and n = 5 in cohort I, II and III, respectively) were enrolled in this study.ResultsMedian duration of treatment was 11 weeks (range 1-66), and median number of treatment cycles were three (range 1-14). The only DLT was a cardiac failure grade 3 in cohort III. Frequent treatment-related adverse events (AEs) (all grades) included neutropenia, leucopenia and fatigue (83% each, but there was no febrile neutropenia); thrombocytopenia (75%); dermatological toxicity (75%); diarrhea and nausea (42% each); and neuropathy (42%).DiscussionThis phase I study demonstrates the feasibility of the combination of lenalidomide and gemcitabine as first-line treatment in patients with advanced pancreatic cancer. The tolerability profile demonstrated in the dose escalation schedule of lenalidomide suggests the dosing of lenalidomide to be 25 mg daily on days 1-21 with standard dosing of gemcitabine and merits further evaluation in a phase II trial.Trial registrationClinicalTrials.gov NCT01547260.

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Dataset Information

Disrupting cytokine signaling in pancreatic cancer: a phase I/II study of etanercept in combination with gemcitabine in patients with advanced disease.

Publications

Disrupting cytokine signaling in pancreatic cancer: a phase I/II study of etanercept in combination with gemcitabine in patients with advanced disease.

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