Dataset Information

A Phase 2 Study of PCI-27483, a Factor VIIa Inhibitor in Combination with Gemcitabine for Advanced Pancreatic Cancer.

ABSTRACT: OBJECTIVES:Tissue factor overexpression is associated with tumor progression, venous thromboembolism, and worsened survival in patients with cancer. Tissue factor and activated factor VII (FVIIa) complex may contribute to tumor invasiveness by promoting cell migration and angiogenesis. The study objective was to evaluate safety, pharmacokinetics, and efficacy of PCI-27483, a selective FVIIa inhibitor. METHODS:This was an open-label, multicenter phase 2 trial of patients with advanced pancreatic cancer. Part A of the study was an intrapatient dose escalation lead-in portion in patients concurrently receiving gemcitabine, and in part B, patients were randomized 1: 1 to the recommended phase 2 dose combination PCI-27483-gemcitabine versus gemcitabine alone. RESULTS:Target international normalized ratio (between 2.0-3.0) was achieved following PCI-27483 treatment. Overall safety of PCI-27483-gemcitabine (n = 26) was similar to gemcitabine alone (n = 16), with a higher incidence of mostly low-grade bleeding events (65% vs. 19%). Progression-free survival (PFS) and overall survival (OS) were not significantly different between patients treated with PCI-27483-gemcitabine (PFS: 3.7 months, OS: 5.7 months) and those treated with gemcitabine alone (PFS: 1.9 months, OS: 5.6 months). CONCLUSIONS:Targeted inhibition of the coagulation cascade was achieved by administering PCI-27483. PCI-27483-gemcitabine was well tolerated, but superiority to single agent gemcitabine was not demonstrated.

SUBMITTER: Ramanathan RK

PROVIDER: S-EPMC6492608 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A Phase 2 Study of PCI-27483, a Factor VIIa Inhibitor in Combination with Gemcitabine for Advanced Pancreatic Cancer.

Ramanathan Ramesh K RK Thomas Gary W GW Khorana Alok A AA Shah Satish S Zhou Cathy C Wong Sofia S Cole George G James Danelle D Gabrail Nashat Y NY

Oncology 20190307 4

<h4>Objectives</h4>Tissue factor overexpression is associated with tumor progression, venous thromboembolism, and worsened survival in patients with cancer. Tissue factor and activated factor VII (FVIIa) complex may contribute to tumor invasiveness by promoting cell migration and angiogenesis. The study objective was to evaluate safety, pharmacokinetics, and efficacy of PCI-27483, a selective FVIIa inhibitor.<h4>Methods</h4>This was an open-label, multicenter phase 2 trial of patients with advan ...[more]

PMID: 30844808

Similar Datasets

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.

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) remains resistant to chemotherapy and immunotherapy individually because of its desmoplastic stroma and immunosuppressive tumor microenvironment. Synergizing cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint blockade with chemotherapy could overcome these barriers. Here we present results of a phase Ib trial combining ipilimumab and gemcitabine in advanced PDAC.Materials and methodsThis was a single-institution study with a 3 + 3 dose-escalation design. The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included determining the toxicity profile, objective response rate (ORR), median progression-free survival (PFS), and overall survival (OS).ResultsTwenty-one patients were enrolled, 13 during dose escalation and 8 at the MTD. The median age was 66 years, 62% were female, 95% had stage IV disease, and 67% had received at least one prior line of therapy. The primary objective to establish the MTD was achieved at doses of ipilimumab 3 mg/kg and gemcitabine 1,000 mg/m2 . The most common grade 3 or 4 adverse events were anemia (48%), leukopenia (48%), and neutropenia (43%). The ORR was 14% (3/21), and seven patients had stable disease. Median response duration for the three responders was 11 months, with one response duration of 19.8 months. Median PFS was 2.78 months (95% confidence interval [CI], 1.61-4.83 months), and median OS was 6.90 months (95% CI, 2.63-9.57 months).ConclusionGemcitabine and ipilimumab is a safe and tolerable regimen for PDAC with a similar response rate to gemcitabine alone. As in other immunotherapy trials, responses were relatively durable in this study.Implications for practiceGemcitabine and ipilimumab is a safe and feasible regimen for treating advanced pancreatic cancer. Although one patient in this study had a relatively durable response of nearly 20 months, adding ipilimumab to gemcitabine does not appear to be more effective than gemcitabine alone in advanced pancreatic cancer.

Project description:PurposeTH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer.Patients and methodsPatients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m(2)), gemcitabine plus TH-302 240 mg/m(2) (G+T240), or gemcitabine plus TH-302 340 mg/m(2) (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety.ResultsTwo hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (-5,398 v -549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302-related AEs but were not associated with treatment discontinuation.ConclusionPFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979).

Dataset Information

A Phase 2 Study of PCI-27483, a Factor VIIa Inhibitor in Combination with Gemcitabine for Advanced Pancreatic Cancer.

Publications

A Phase 2 Study of PCI-27483, a Factor VIIa Inhibitor in Combination with Gemcitabine for Advanced Pancreatic Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets