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Wainberg Z.A.,University of California at Los Angeles | Wainberg Z.A.,Translational Research In Oncology Us Trio Us | Soares H.P.,University of California at Los Angeles | Patel R.,Translational Research In Oncology Us Trio Us | And 18 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2015

Purpose: Our study was designed to evaluate the efficacy and safety of everolimus in patients with pre-treated metastatic gastric and esophagus cancers in a US-based population focusing on biomarker correlation. Methods: Patients with advanced upper GI adenocarcinomas who progressed after 1-2 prior regimens received everolimus 10 mg PO daily. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression-free survival (PFS), toxicity, overall survival (OS) and biomarker correlatives of the mTOR pathway. Target accrual was 50 patients based on one-sided type I error of 10 % and power of 90 %. Results: Forty-five patients were evaluable, 21 gastric, 11 esophagus and 13 from the GEJ. The median age was 64 (range 38-73); all patients had an ECOG of 0 or 1; and 18 patients (40 %) had only 1 prior regimen. The most common grade 3-4 adverse events included fatigue (24 %) and thrombocytopenia (22 %). We observed 1 partial response with 39 % of evaluable patients having stable disease. Median OS was 3.4 months (95 % CI 2.7-5.6 months), and PFS was 1.8 months (95 % CI 1.7-2.2 months). There was a strong correlation between ≥2 + IHC staining for p-S6 in tumor samples with better PFS (p < 0.0001) and DCR (p = 0.0001). Conclusions: Our clinical outcomes were inferior to the Asian studies, which may be explained by disease heterogeneity. However, there was a similar strong correlation between clinical benefit and tumor high pS6. Testing this biomarker in patient samples from the randomized phase III Granite trial may lead to a positive predictive marker. © 2015 Springer-Verlag Berlin Heidelberg. Source

Simon Tchekmedyian N.,Pacific Shores Medical Group | Chen Y.-M.,Novartis | Saad F.,Center Hospitalier Of Luniversite Of Montreal
Cancer Investigation | Year: 2010

Baseline and disease progression characteristics may predict the risk of skeletal-related events (SREs) in patients with bone metastases from various solid tumors. Exploratory analysis of phase III trials compared zoledronic acid with placebo in patients with bone metastases from castration-resistant prostate cancer (N = 643) and lung cancer or other solid tumors (N = 773), adjusted for baseline and time-dependent disease parameters. In all models, more than three bone lesions at baseline correlated with the increased SRE risk. Bone and overall disease progression correlated with increased SRE risk. Overall, cancer progression correlated with increased SRE risks and zoledronic acid was associated with reduced SRE risks versus placebo. © 2010 Informa Healthcare USA, Inc. Source

Barr P.M.,University of Rochester | Saylors G.B.,Charleston Hematology Oncology Associates | Spurgeon S.E.,Oregon Health And Science University | Cheson B.D.,Georgetown University | And 13 more authors.
Blood | Year: 2016

Although agents targeting B-cell receptor signaling have provided practice-changing results in relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), they require prolonged administration and provide incomplete responses. Given synergistic preclinical activity with phosphatidylinositol 3-kinase δ and spleen tyrosine kinase inhibition, this phase 2 study evaluated the safety and efficacy of the combination of idelalisib and entospletinib. Eligible patients with relapsed or refractory CLL or NHL underwent intrapatient dose escalation with each agent. With a median treatment exposure of 10 weeks, 60% and 36% of patients with CLL or follicular lymphoma, respectively, achieved objective responses. However, the study was terminated early because of treatment-emergent pneumonitis in 18% of patients (severe in 11 of 12 cases). Although most patients recovered with supportive measures and systemic steroids, 2 fatalities occurred and were attributed to treatment-emergent pneumonitis. Increases of interferon-γ and interleukins 6, 7, and 8 occurred over time in patients who developed pneumonitis. Future studies of novel combinations should employ conservative designs that incorporate pharmacodynamics/biomarker monitoring. These investigations should also prospectively evaluate plasma cytokine/chemokine levels in an attempt to validate biomarkers predictive of response and toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01796470. © 2016 by The American Society of Hematology. Source

Deeken J.F.,Georgetown University | Shimkus B.,Austin Cancer Centers | Liem A.,Pacific Shores Medical Group | Hill D.,Tri Valley Cancer Research and Treatment Center | And 6 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2013

Purpose: Greater scrutiny is being placed on developing a full understanding of potential cardiotoxicity of therapeutic agents, especially on the potential to prolong the QTc interval which can lead to arrhythmias such as torsade de pointes and sudden death. This trial was designed to specifically evaluate the effect, if any, of cetuximab on the QTc interval in patients with advanced solid tumors. Methods: Cetuximab was administered as an initial dose of 400 mg/m2 on day 1 (week 1) followed by a maintenance dose of 250 mg/m2 weekly thereafter. ECG monitoring was performed at screening, baseline (week 1 preceding dosing), and during week 1 to 5 of treatment. Cetuximab concentration-to-QTc relationship was evaluated based on cetuximab serum samples obtained at the time of each ECG measurement to allow for accurate correlation between any observed QT/QTc changes and cetuximab serum concentration. Results: At the recommended dose (400 mg/m2 on day 1 followed by 250 mg/m2 weekly), cetuximab had no clinically meaningful effect on QTc interval, PR or QRS intervals, or heart rate and there was no apparent concentration-dependent effect of cetuximab on any of these electrocardiogram parameters. Safety observations in patients treated with cetuximab in this study were consistent with the agent's known safety profile. Conclusion: These results suggest that cetuximab can be safely administered as a single agent without risk of effect on QTc interval. © 2013 Springer-Verlag Berlin Heidelberg. Source

Tchekmedyian N.S.,Pacific Shores Medical Group
ONCOLOGY (United States) | Year: 2015

During my first medical school clinical rotation 40 years ago, the professor asked: "What's the most important tool needed to take care of a patient?" His answer: a chair. © 2015, UBM Medica Healthcare Publications. All rights reserved. Source

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