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Publications (7)43.4 Total impact

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    ABSTRACT: Background. Sorafenib (a VEGFR and multi-targeted kinase inhibitor) and Bortezomib (a proteasome inhibitor) have clinical antineoplastic activities as single agents, and combine synergistically in preclinical models. Methods. This Phase I study was undertaken to define the toxicity and the maximum tolerated doses (MTD) of the combination in patients with advanced solid tumors. Patients with cytologic or histologic proof of unresectable solid tumors were treated with escalating doses of sorafenib (twice daily) and bortezomib (days 1, 4, 8 and 11 intravenously) with 21-day cycles. Results. Fourteen patients (7 males, median age 65, range 24-74), with renal (3), lung (3), pancreas (2), and breast, adrenal gland, melanoma, spindle cell tumor, chronic lymphocytic leukemia and multiple myeloma (1 each) were enrolled. All patients are off treatment, 10 due to disease progression. DLT was seen in two patients (one grade 3 abdominal pain and grade 4 lipase elevation; one with grade 3 vomiting) at sorafenib 200 mg twice daily and bortezomib 1.3 mg/m(2), establishing the MTD. No grade 4 hematologic or grade 5 toxicities were seen. One patient with renal cell cancer had a partial response and 5 patients attained stable disease. Conclusions. The combination of sorafenib and bortezomib was tolerated well. The recommended phase 2 doses are sorafenib 200 mg twice daily continuously with bortezomib 1 mg/m(2) on days 1, 4, 8, 11 (21 day cycles). The combination shows preliminary signs of efficacy, supporting phase 2 studies.
    Investigational New Drugs 07/2013; · 3.50 Impact Factor
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    ABSTRACT: Do colorectal cancer patients with hyperbilirubinemia and liver metastases benefit from chemotherapy? This study entailed a review of 3,019 consecutive patients with colorectal cancer. Within this cohort, 20 met the study's a priori selection criteria, which included a new diagnosis of colorectal cancer, no prior therapy, and a total bilirubin of ≥3.0 mg/dL. All 20 patients had liver metastases, and as a whole the group had a median serum bilirubin of 6.4 mg/dL (range 3.1, 28 mg/dL). Six patients received chemotherapy with an oxaliplatin-containing regimen, and four subsequently sustained a drop in their bilirubin. In one instance, a drop from 27.2 to 2.5 mg/dL occurred. These six patients lived a median of 71 days (range 23+, 283 days), but one treatment-related death occurred. In contrast, patients who received only supportive care lived a median of 28 days. Chemotherapy appears to provide modest benefit to newly diagnosed colorectal cancer patients with severe hyperbilirubinemia.
    Therapeutics and Clinical Risk Management 12/2008; 4(6):1363-6.
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    ABSTRACT: To determine the maximum tolerated dose (MTD), characterize the principal toxicities, and assess the pharmacokinetics of EKB-569, an oral selective irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase, in combination with capecitabine in patients with advanced colorectal cancer. Patients were treated with EKB-569 daily for 21 days and capecitabine twice daily for 14 days of a 21-day cycle. The dose levels of EKB-569 (mg/day) and capecitabine (mg/m(2) twice daily) assessed were 25/750, 50/750, 50/1,000 and 75/1,000. An expanded cohort was enrolled at the MTD to better study toxicity and efficacy. Samples of plasma were collected to characterize the pharmacokinetics of the agents. Treatment efficacy was assessed every other cycle. A total of 37 patients, the majority of whom had prior chemotherapy, received a total of 163 cycles of treatment. Twenty patients were treated at the MTD, 50 mg EKB-569, daily and 1,000 mg/m(2) capecitabine twice daily. Dose-limiting toxicities were diarrhea and rash. No patients had complete or partial responses but 48% had stable disease. The conversion of capecitabine to 5-fluorouracil was higher for the combination of EKB-569 and capecitabine (321+/-151 ng*h/mL) than for capecitabine alone (176+/-62 ng*hours/mL; P=0.0037). In advanced colorectal cancer, 50 mg EKB-569 daily can be safely combined with 1,000 mg/m(2) capecitabine twice a day. A statistically significant increase in plasma levels of 5-fluorouracil for the combination of EKB-569 and capecitabine may be due to the single-dose versus multiple-dose exposure difference, variability in exposure or a potential drug interaction.
    Clinical Cancer Research 10/2008; 14(17):5602-9. · 7.84 Impact Factor
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    ABSTRACT: To evaluate the combination of sorafenib and gefitinib in patients with advanced non-small cell lung cancer. In this dose-escalation trial, patients received oral sorafenib (200-400 mg) twice daily with gefitinib (250 mg orally) once daily to identify the recommended dose for phase II trials (RDP; part A). The pharmacokinetics of the RDP were characterized further in additional patients (part B) receiving single-agent gefitinib or sorafenib for 21 days followed by a 7-day washout with crossover to the other agent for an additional 21 days. Patients then received the combination of sorafenib plus gefitinib in 28-day cycles. Safety, pharmacokinetics, and antitumor efficacy were evaluated. Potential drug-drug interactions and the relationship between pharmacokinetics and toxicity were also assessed. Thirty-one patients were treated (n=12, part A; n=19, part B). Most adverse events were grade 1/2. The most frequent grade 3/4 events included diarrhea and elevated alanine aminotransferase (both 9.7%). One dose-limiting toxicity occurred (part A: elevated alanine aminotransferase at 400 mg twice daily). Gefitinib had no effect on sorafenib pharmacokinetics. However, gefitinib C(max) (26%) and area under the curve (38%) were reduced by concomitant sorafenib. One patient had a partial response; 20 (65%; n=8, part A; n=12, part B) had stable disease >or=4 months. The RDP was sorafenib 400 mg twice daily with gefitinib 250 mg once daily. Sorafenib combined with gefitinib is well tolerated, with promising efficacy in patients with advanced non-small cell lung cancer. Studies to further investigate the significance of the reduction in gefitinib exposure by sorafenib are warranted.
    Clinical Cancer Research 06/2007; 13(9):2684-91. · 7.84 Impact Factor
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    ABSTRACT: This phase I study was conducted to determine the safety, tolerability and maximum tolerated dose of the combination of celecoxib, a selective cyclooxygenase-2 inhibitor, with docetaxel and irinotecan, in patients with advanced solid tumors. Patients with solid tumors received one of three escalating dose levels of daily celecoxib in combination with docetaxel and irinotecan administered on days 1 and 8 of an every 21-day cycle. Toxicities were graded by the National Cancer Institute Common Toxicity Criteria (NCI CTC) and recorded as maximum grade per patient for each treatment cycle. A total of 19 patients received 90 cycles of treatment through three dose levels. Dose-limiting toxicities were nausea and diarrhea. The most common treatment-related toxicities in all cycles of treatment were alopecia, fatigue, diarrhea, nausea, vomiting, anemia, anorexia, and edema.. The maximum tolerated dose was established at celecoxib 400 mg twice a day continuously, weekly docetaxel 30 mg/m2 and irinotecan 50 mg/m2 for 2 weeks every 21 days. Disease stabilization (five or more cycles) was documented in eight patients. The combination of celecoxib with docetaxel and irinotecan did not ameliorate irinotecan-induced diarrhea. Although prolonged disease stabilization was achieved in some patients, we do not recommend combining celecoxib with docetaxel and irinotecan because of lack of activity and the side effect profile of this combination.
    Cancer Chemotherapy and Pharmacology 01/2006; 56(6):623-8. · 2.80 Impact Factor
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    ABSTRACT: Small cell lung cancer is highly sensitive to chemotherapy, and a survival advantage with its use is well established. However, whether chemotherapy also confers such benefits to patients with severe organ dysfunction has not been extensively studied. The goal of this study was to provide further guidance for clinical decision-making. Medical records from small cell lung cancer patients who were seen at a single tertiary care institution between 1994 and 2002 were reviewed. All patients with severe organ dysfunction were identified. The latter was defined as creatinine >/=3mg/dl, total bilirubin>/=3mg/dl, and/or platelet count</=50 x10(6) per milliliter. An in depth review of treatment and outcome in this patient subgroup was then undertaken. A total of 993 small cell lung cancer patients were seen during this period, and 25 (2.5%) had severe organ dysfunction. Eleven had been treated with chemotherapy, 11 had not, and this information was not retrievable in 3. Cyclophosphamide, etoposide (oral or intravenous), paclitaxel, cisplatin, or carboplatin were prescribed as single agents or in combination; 8 of 11 patients received an initial dose reduction. With chemotherapy, three patients normalized their bilirubin, and one manifested a notable drop. Median survival was 150 days for chemotherapy-treated patients but only 10 days for those who did not receive it. One patient died a few days after chemotherapy; three others were hospitalized immediately thereafter; and two were lost to follow up. In five patients, no notable adverse events were noted in the medical record. These preliminary findings suggest that, even in the presence of severe organ dysfunction, a subgroup of small cell lung cancer patients can tolerate chemotherapy, normalize their laboratory parameters, and go on to live for several months.
    Lung Cancer 08/2005; 49(2):209-15. · 3.39 Impact Factor
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    ABSTRACT: We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity. An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A5*3 and NQO1*2 genotypes were determined and correlated with pharmacokinetics and toxicity. Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m(2) were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t(1/2)) of 17-AAG were 11.6 L/h/m(2) and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t(1/2) of 7.63 hours. The CYP3A5*3 and NQO1*2 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance. The MTD of weekly 17-AAG is 308 mg/m(2). 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy.
    Journal of Clinical Oncology 03/2005; 23(6):1078-87. · 18.04 Impact Factor