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Deeken J.F.,Inova Comprehensive Cancer and Research Institute | Wang H.,Georgetown University | Subramaniam D.,Georgetown University | He A.R.,Georgetown University | And 7 more authors.
Cancer | Year: 2015

BACKGROUND Acquired resistance to antiepidermal growth factor receptor (anti-EGFR) therapy may be caused by EGFR-v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ErbB2) heterodimerization and pathway reactivation. In preclinical studies, inhibiting ErbB2 blocked this resistance mechanism and resensitized cells to anti-EGFR therapy. Cetuximab targets EGFR, whereas lapatinib inhibits both EGFR and ErbB2. The objective of this phase 1 trial was to assess the safety, dose-limiting toxicities (DLTs), and maximum tolerated doses (MTDs) of cetuximab and lapatinib in patients with solid tumors. METHODS Patients received standard weekly cetuximab with escalating lapatinib doses of 750 mg, 1000 mg, or 1250 mg daily in 3-week cycles. DLTs were monitored through the end of cycle 2. Pretreatment and post-treatment tumor biopsies and germline DNA samples were obtained for correlative studies. RESULTS Twenty-two patients were enrolled, and 18 patients each were evaluable for toxicity and response. Fifty-nine percent of patients had received prior anti-EGFR therapy. Common toxicities included rash and diarrhea. No patient experienced a DLT at the highest dose level, and no grade 4 toxicity was observed. Response included no complete responses, 3 partial responses, 9 patients with stable disease, and 6 patients with disease progression, for an overall response rate of 17% and a clinical benefit rate of 67%. The clinical benefit rate in patients who had previously received anti-EGFR therapy was 70%. The mean treatment duration was 4.7 cycles (range, 1-14 cycles). Decreased expression of EGFR/ErbB2 pathway components after treatment was correlated with response, whereas increased expression in the PI3K, Jak/Stat, and MAPK pathways occurred in nonresponders. CONCLUSIONS The combination of cetuximab and lapatinib was well tolerated, had the expected toxicities, and exhibited notable clinical activity, including in patients who had received previous anti-EGFR therapy. Further clinical study of this combination is warranted. Cancer 2015;121:1645-1653. © 2015 American Cancer Society.


Rudek M.A.,Johns Hopkins University | Moore P.C.,University of Arkansas for Medical Sciences | Mitsuyasu R.T.,University of California at Los Angeles | Dezube B.J.,Beth Israel Deaconess Medical Center | And 11 more authors.
Cancer | Year: 2014

BACKGROUND The treatment of non-acquired immunodeficiency syndrome-defining cancers may be complicated by drug interactions between highly active antiretroviral therapy (HAART) and chemotherapy. This trial is the first by the AIDS Malignancy Consortium to assess targeted therapies and HAART in human immunodeficiency virus-positive patients (ClinicalTrials.gov identifier: NCT00890747). METHODS In a modified phase 1 study of sunitinib, patients were stratified into 2 treatment arms based on whether they were receiving therapy with ritonavir, a potent CYP3A4 inhibitor. Patients in treatment arm 1 (non-ritonavir HAART) received standard sunitinib dosing (50 mg/day). Treatment arm 2 (ritonavir-based HAART) used a phase 1, 3 + 3 dose escalation design (from 25 mg/day to 50 mg/day). Cycles were comprised of 4 weeks on treatment followed by a 2-week break (6 weeks total). The pharmacokinetics of sunitinib and its active metabolite (N-desethyl sunitinib) were assessed. RESULTS Nineteen patients were enrolled and were evaluable. Patients on treatment arm 1 tolerated treatment with no dose-limiting toxicity observed. In treatment arm 2, a dose-limiting toxicity was experienced at a dose of 37.5 mg, and an additional 3 of 5 patients experienced grade 3 neutropenia (toxicity graded as per National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]), an uncommon toxicity of sunitinib. No patient achieved a response, but 10 patients had stable disease, including 8 with prolonged disease stability. Efavirenz, a potent inducer of CYP3A4, resulted in increased exposure of N-desethyl sunitinib, whereas ritonavir caused decreased exposure of the metabolite. Hand-foot syndrome was associated with higher steady-state trough concentrations of sunitinib. CONCLUSIONS Patients receiving non-ritonavir-based HAART regimens tolerated standard dosing of sunitinib. Patients receiving ritonavir-based therapy who were treated with a dose of 37.5 mg/day experienced higher toxicities. Dose reductions of sunitinib to 37.5 mg may be warranted in patients receiving ritonavir. © 2014 American Cancer Society.


Niederhuber J.E.,Inova Comprehensive Cancer and Research Institute | Niederhuber J.E.,Inova Health System | Niederhuber J.E.,Inova Translational Medicine Institute | Niederhuber J.E.,Johns Hopkins University | And 6 more authors.
Abeloff's Clinical Oncology: Fifth Edition | Year: 2013

Practical and clinically focused, Abeloff's Clinical Oncology is a trusted medical reference book designed to capture the latest scientific discoveries and their implications for cancer diagnosis and management of cancer in the most accessible manner possible. Abeloff's equips everyone involved - from radiologists and oncologists to surgeons and nurses - to collaborate effectively and provide the best possible cancer care. © 2014 by Saunders. All rights reserved.


El-Bahesh E.,INOVA Comprehensive Cancer and Research Institute | Finianos A.,INOVA Comprehensive Cancer and Research Institute | Alfaraj A.,George Washington University | Aragon-Ching J.B.,INOVA Comprehensive Cancer and Research Institute
Future Oncology | Year: 2015

Management of metastatic castration-resistant prostate cancer has changed markedly over the last decade with major shifts in the treatment paradigm, although ultimately still will progress despite currently available therapies. The sequencing or combination of these agents is an area of active investigation, since definitive prospective randomized trials to define the optimal choice of drug sequence have yet to be done or resulted. This article will highlight pivotal trials for currently approved therapies for metastatic castration-resistant prostate cancer and a suggestion for sequencing of these agents, as well as highlighting investigations using novel therapies for advanced prostate cancer. © 2015 Future Medicine Ltd.

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