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1.  FEASIBILITY AND SAFETY OF SEQUENTIAL RESEARCH-RELATED TUMOR CORE BIOPSIES IN CLINICAL TRIALS 
Cancer  2012;119(7):1357-1364.
Background
There has been increasing interest in serial research biopsies in studies of targeted therapies. Definition of patient characteristics and optimal target tissue for safe research tumor biopsy in the era of anti-angiogenic and targeted agents is needed.
Methods
This IRB-approved retrospective study included chart and interventional radiology case review from six phase 1/2 studies at the NCI.
Results
142 of 150 protocol patients approached gave consent for research biopsies. Patients had a median age of 56 yrs (27–78), median BMI 25.8 kg/m2 (14.4–46.2), ECOG PS 0–1, and normal end-organ function. Baseline biopsies were collected in 138/142 patients (97%), and paired specimens in 96(70%). Most patients had metastatic gynecologic cancers (85%) and 78% patients had target disease below the diaphragm of median size 2.7cm (1–14.5cm). Protocol therapies included kinase inhibitors (35%), angiogenesis inhibitors (54%), and olaparib/carboplatin (11%); therapy was not interrupted for biopsies. Adverse events were all uncomplicated and were observed in four patients (liver subcapsular hematoma [1]; vasovagal syncope [2]; pneumothorax [1]). The complication rate in obese patients was similar to that in non-obese patients (3/108 vs.1/34). 67 patients (48%) were receiving bevacizumab at the time of subsequent biopsies. The complication rate in those receiving bevacizumab was not different from those without (3/67 vs 1/71). 95% of biopsies yielded useable material.
Conclusions
Serial percutaneous core needle biopsies can be obtained safely and yield material applicable for multiple translational applications. Obesity and/or concomitant anti-angiogenic therapy, and depth of disease do not increase risk or preclude successful acquisition of useful tissue.
doi:10.1002/cncr.27916
PMCID: PMC3604070  PMID: 23280317
2.  A phase II clinical trial of polyethylene glycol-conjugated L-asparaginase in patients with advanced ovarian cancer: Early closure for safety 
Molecular and Clinical Oncology  2013;1(3):565-569.
The anti-angiogenic activity of L-asparaginase (L-ASP) and the sensitivity of ovarian cancer cell lines to L-ASP has been previously demonstrated by preclinical findings. The aim of this clinical trial was to translate those findings and evaluate the activity of polyethylene glycol-conjugated L-asparaginase (PEG-ASP or pegaspargase) in advanced ovarian cancer. Women with recurrent ovarian cancer and good end-organ function were enrolled in an open-label phase II trial of PEG-ASP at a dose of 2,000 IU/m2 by intravenous infusion every 2 weeks. Patients were evaluated for response every 8 weeks and for toxicity on an ongoing basis. Early stopping rules for toxicity and activity were included. Four patients were enrolled and received a total of 7 treatment cycles. The study ended accrual by invoking an early stopping rule, after excessive toxicity was identified in patients. Drug-related toxicities included grade 2 pancreatitis, fatigue, neutropenia, hypoalbuminemia, weight loss, dehydration, decreased fibrinogen and 1 case of grade 3 hypersensitivity reaction during cycle 2. One patient died during the study. No patients were evaluable for response. PEG-ASP was poorly tolerated in this group of advanced-stage ovarian cancer patients and no conclusions regarding activity may be drawn. Further studies of PEG-ASP in ovarian cancer patients are not recommended.
doi:10.3892/mco.2013.99
PMCID: PMC3916154  PMID: 24649212
ovarian cancer; pegaspargase; L-asparaginase; angiogenesis
3.  Phase 1, open-label study of MEDI-547 in patients with relapsed or refractory solid tumors 
Investigational New Drugs  2012;31(1):77-84.
Summary
Background Targeting the cell-surface receptor EphA2, which is highly expressed in some solid tumors, is a novel approach for cancer therapy. We aimed to evaluate the safety profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of MEDI-547, an antibody drug conjugate composed of the cytotoxic drug auristatin (toxin) linked to a human anti-EphA2 monoclonal antibody (1C1), in patients with solid tumors relapsed/refractory to standard therapy. Methods In this phase 1, open-label study with planned dose-escalation and dose-expansion cohorts, patients received a 1-h intravenous infusion of MEDI-547 (0.08 mg/kg) every 3 weeks. Results Six patients received 0.08 mg/kg; all discontinued treatment. Dose escalation was not pursued. The study was stopped before cohort 2 enrollment due to treatment-related bleeding and coagulation events (hemorrhage-related, n = 3; epistaxis, n = 2). Therefore, lower doses were not explored and an MTD could not be selected. The most frequently reported treatment-related adverse events (AEs) were increased liver enzymes, decreased hemoglobin, decreased appetite, and epistaxis. Three patients (50%) experienced treatment-related serious AEs, including conjunctival hemorrhage, pain (led to study drug discontinuation), liver disorder, and hemorrhage. Best response included progressive disease (n = 5; 83.3%) and stable disease (n = 1; 16.7%). Minimal or no dissociation of toxin from 1C1 conjugate occurred in the blood. Serum MEDI-547 concentrations decreased rapidly, ~70% by 3 days post-dose. No accumulation of MEDI-547 was observed at 0.08 mg/kg upon administration of a second dose 3 weeks following dose 1. Conclusions The safety profile of MEDI-547 does not support further clinical investigation in patients with advanced solid tumors.
doi:10.1007/s10637-012-9801-2
PMCID: PMC3553417  PMID: 22370972
MEDI-547; EphA2; Cancer therapy; Clinical trial; Relapsed/refractory solid tumors
4.  PROGRANULIN IS A POTENTIAL PROGNOSTIC BIOMARKER IN ADVANCED EPITHELIAL OVARIAN CANCERS 
Gynecologic oncology  2010;120(1):5-10.
Purpose
There are few validated relapse prediction biomarkers for epithelial ovarian cancer (EOC). We have shown progranulin (PGRN) and secretory leukocyte protease inhibitor (SLPI) are up regulated, overexpressed survival factors in EOC. We hypothesized they would predict presence of occult EOC.
Methods
PGRN, SLPI, and the known biomarker HE4 were measured in EOC patient plasma samples, prospectively collected every 3 months from initial remission until relapse. Clinical data and CA125 results were incorporated into statistical analyses. Exploratory Kaplan-Meier estimates, dividing markers at median values, evaluated association with progression-free survival (PFS) and overall survival (OS). Area-under-the-curve (AUC) statistics were computed from receiver operating characteristic (ROC) curves to evaluate discrimination ability. A Cox proportional hazards model assessed the association between PFS, OS, and biomarkers, adjusting for clinical prognostic factors.
Results
Samples from 23 advanced stage EOC patients were evaluated. PGRN at 3 months was the only biomarker independently associated with PFS (P<0.0001) and OS (P<0.003). When used to predict progression by 18 months, sensitivity and specificity were 93% and 100%, respectively, with AUC = 0.944. The Cox model hazard ratio for PFS, divided at 59 ng/ml by ROC analysis and adjusted for clinical factors, was 23.5 (95% CI: 2.49–220). Combinations with SLPI, HE4, and/or CA125 did not improve the model.
Conclusions
We report pilot data indicating a potential independent association of PGRN on EOC patient PFS and OS. A validation study will be required to confirm this finding and to inform whether PGRN warrants evaluation as a potential screening biomarker.
doi:10.1016/j.ygyno.2010.09.006
PMCID: PMC2997933  PMID: 20950846
Progranulin (PGRN); biomarkers; progression free survival; overall survival; epithelial ovarian cancer

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