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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.


Naeim A.,University of California at Los Angeles | Ward P.R.,University of California at Los Angeles | Wang H.-J.,University of California at Los Angeles | Dichmann R.,Translational Oncology Research International TORI | And 7 more authors.
Journal of Geriatric Oncology | Year: 2013

Objectives: This study aims to determine the efficacy and tolerability of capecitabine (CAP) plus bevacizumab (BEV) as treatment for frontline metastatic colorectal cancer (mCRC) in frail and/or elderly patients. Materials and Methods: This was an open label, multi-site, single arm, phase II study in frontline mCRC. In this study, patients (pts) who were frail (ECOG 2) or older patients with ECOG 1 performance status (PS) received CAP (1000mg/m2 bid, 14days of every 21days) plus BEV (7.5mg/kg iv once every 21days). The primary objective was progression free survival (PFS). Secondary objectives were overall response rate (ORR) and toxicity. Results: In terms of patients: 50 were enrolled; 5 withdrew consent prior to treatment; 45 were treated, and 41 were evaluable. The mean age was 75.9 (range 54-93) and 62% had an ECOG 2 PS. The median PFS was 6.87. months (95% CI, 5.1-11.5. months) and median overall survival was 12.7. months (95% CI, 6.9-12.7. months). The most common grades 3-4 toxicities were: diarrhea (17.8%), fatigue (13.3%), hand-foot syndrome (13.3%), dehydration (8.9%), hypertension (6.7%) and vomiting (6.7%). Conclusions: The results of this trial support the use of CAP plus BEV as first-line treatment for frail/elderly patients with metastatic CRC. The ORR (40%) is comparable to pooled data in elderly on fluorouracil (5-FU). +. BEV. The median PFS (7.2. months) in this study is slightly lower than that seen with 5-FU. +. BEV but this study had a high percentage of ECOG PS 2 patients. Side effects were manageable with no new safety signals. © 2013 Elsevier Inc.


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.


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.


McKeage M.J.,University of Auckland | Jameson M.B.,Waikato Hospital | Ramanathan R.K.,Virginia G Piper Cancer Center and TGEN | Rajendran J.,University of Washington | And 4 more authors.
BMC Cancer | Year: 2012

Background: The purpose of this phase Ib clinical trial was to determine the maximum tolerated dose (MTD) of PR-104 a bioreductive pre-prodrug given in combination with gemcitabine or docetaxel in patients with advanced solid tumours.Methods: PR-104 was administered as a one-hour intravenous infusion combined with docetaxel 60 to 75 mg/m2 on day one given with or without granulocyte colony stimulating factor (G-CSF) on day two or administrated with gemcitabine 800 mg/m2 on days one and eight, of a 21-day treatment cycle. Patients were assigned to one of ten PR-104 dose-levels ranging from 140 to 1100 mg/m2 and to one of four combination groups. Pharmacokinetic studies were scheduled for cycle one day one and 18F fluoromisonidazole (FMISO) positron emission tomography hypoxia imaging at baseline and after two treatment cycles.Results: Forty two patients (23 females and 19 males) were enrolled with ages ranging from 27 to 85 years and a wide range of advanced solid tumours. The MTD of PR-104 was 140 mg/m2 when combined with gemcitabine, 200 mg/m2 when combined with docetaxel 60 mg/m2, 770 mg/m2 when combined with docetaxel 60 mg/m2 plus G-CSF and ≥770 mg/m2 when combined with docetaxel 75 mg/m2 plus G-CSF. Dose-limiting toxicity (DLT) across all four combination settings included thrombocytopenia, neutropenic fever and fatigue. Other common grade three or four toxicities included neutropenia, anaemia and leukopenia. Four patients had partial tumour response. Eleven of 17 patients undergoing FMISO scans showed tumour hypoxia at baseline. Plasma pharmacokinetics of PR-104, its metabolites (alcohol PR-104A, glucuronide PR-104G, hydroxylamine PR-104H, amine PR-104M and semi-mustard PR-104S1), docetaxel and gemcitabine were similar to that of their single agents.Conclusions: Combination of PR-104 with docetaxel or gemcitabine caused dose-limiting and severe myelotoxicity, but prophylactic G-CSF allowed PR-104 dose escalation with docetaxel. Dose-limiting thrombocytopenia prohibited further evaluation of the PR104-gemcitabine combination. A recommended dose was identified for phase II trials of PR-104 of 770 mg/m2 combined with docetaxel 60 to 75 mg/m2 both given on day one of a 21-day treatment cycle supported by prophylactic G-CSF (NCT00459836). © 2012 McKeage et al.; licensee BioMed Central Ltd.


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.


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.


PubMed | Pacific Shores Medical Group
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

15038 Background: Aromatase inhibitors (AI) are effective therapy for estrogen receptor positive breast cancer. We retrospectively reviewed our experience with AI therapy of 14 advanced ovarian cancer patients.Between March 2001 and January 2006, 14 women with ages ranging from 40 to 80 years received letrozole 2.5 mg orally once a day for periods of 2 to 36 months. All 14 patients had received prior chemotherapy and had recurrent disease. Eleven had received a mean of 2.8 (range 1-7) different chemotherapy regimens for advanced recurrent disease. Six of the 14 patients had received tamoxifen for periods of 1 to 12 months. Thirteen patients had advanced recurrent invasive epithelial ovarian cancer. One patient had advanced progressive ovarian tumor of borderline malignant potential with pleural involvement refractory to chemotherapy. Estrogen receptor status was positive in 13 patients and unknown in 1. CA-125 levels and clinical evaluations were available for all patients.The mean baseline CA-125 level (U/mL) prior to letrozole therapy was 262, and ranged from 4.1 to 2723. The mean lowest CA-125 level after letrozole was started was 143, and ranged from 1.3 to 1158. Five of the 14 patients had CA-125 declines of 50% while on letrozole. Seven of the 14 patients remain on therapy at 2+ to 20+ months. Ten of the 14 patients had sustained clinical improvements or stability and no evidence of disease progression while on AI therapy for a mean period of 12 months with a range of 2 to 36 months. AI therapy was well tolerated.This limited and anecdotal experience suggests that AI therapy may be effective in advanced estrogen receptor positive ovarian cancer, including patients refractory to chemotherapy. AI therapy should be studied further in advanced ovarian cancer and in the adjuvant setting. No significant financial relationships to disclose.

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