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A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients.

ABSTRACT: The aim of this study was to determine whether checkpoint kinase 1 inihibitor (CHK1), LY2603618, and gemcitabine prolong overall survival (OS) compared to gemcitabine alone in patients with unresectable pancreatic cancer.Patients with Stage II-IV locally advanced or metastatic pancreatic cancer were randomized (2:1) to either 230 mg of LY2603618/1000 mg/m2 gemcitabine combined or 1000 mg/m2 gemcitabine alone. OS was assessed using both a Bayesian augment control model and traditional frequentist analysis for inference. Progression-free survival (PFS), overall response rate (ORR), duration of response, pharmacokinetics (PK), and safety (Common Terminology Criteria for Adverse Events [AEs] v 3.0) were also evaluated.Ninety-nine patients (n?=?65, LY2603618/gemcitabine; n?=?34, gemcitabine) were randomized (intent-to-treat population). The median OS (months) was 7.8 (range, 0.3-18.9) with LY2603618/gemcitabine and 8.3 (range, 0.8-19.1+) with gemcitabine. Similarly, in a Bayesian analysis, the study was not positive since the posterior probability that LY2603618/gemcitabine was superior to gemcitabine in improving OS was 0.3, which did not exceed the prespecified threshold of 0.8. No significant improvements in PFS, ORR, or duration of response were observed. Drug-related treatment-emergent AEs in both arms included nausea, thrombocytopenia, fatigue, and neutropenia. The severity of AEs with LY2603618/gemcitabine was comparable to gemcitabine. The LY2603618 exposure targets (AUC(0-?) ?21,000 ng?hr/mL and Cmax ?2000 ng/mL) predicted for maximum pharmacodynamic response were achieved after 230 mg of LY2603618.LY2603618/gemcitabine was not superior to gemcitabine for the treatment of patients with pancreatic cancer.NCT00839332 . Clinicaltrials.gov. Date of registration: 6 February 2009.

SUBMITTER: Laquente B

PROVIDER: S-EPMC5312529 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients.

Laquente Berta B Lopez-Martin Jose J Richards Donald D Illerhaus Gerald G Chang David Z DZ Kim George G Stella Philip P Richel Dirk D Szcylik Cezary C Cascinu Stefano S Frassineti G L GL Ciuleanu Tudor T Hurt Karla K Hynes Scott S Lin Ji J Lin Aimee Bence AB Von Hoff Daniel D Calvo Emiliano E

BMC cancer 20170215 1

<h4>Background</h4>The aim of this study was to determine whether checkpoint kinase 1 inihibitor (CHK1), LY2603618, and gemcitabine prolong overall survival (OS) compared to gemcitabine alone in patients with unresectable pancreatic cancer.<h4>Methods</h4>Patients with Stage II-IV locally advanced or metastatic pancreatic cancer were randomized (2:1) to either 230 mg of LY2603618/1000 mg/m<sup>2</sup> gemcitabine combined or 1000 mg/m<sup>2</sup> gemcitabine alone. OS was assessed using both a B ...[more]

PMID: 28202004

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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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A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients.

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A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients.

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