Kyle D Holen

University of Wisconsin, Madison, Madison, MS, United States

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Publications (51)181.8 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors. Methods Patients received vorinostat orally once daily on days 1-14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m(2)). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1. Results Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m(2) to 1.5 mg/m(2). The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m(2). DLTs consisted of grade 3 fatigue in three patients (1 mg/m(2),1.3 mg/m(2) and 1.5 mg/m(2)) and grade 3 hyponatremia in one patient (1.5 mg/m(2)). The most common grade 1/2 toxicities included nausea (60.9 %), fatigue (34.8 %), diaphoresis (34.8 %), anorexia (30.4 %) and constipation (26.1 %). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1. Conclusions This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily × 14 days and bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 of a 21-day cycle.
    Investigational New Drugs 10/2013; · 3.50 Impact Factor
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    ABSTRACT: Vorinostat is a small molecule inhibitor of class I and II histone deacetylase enzymes which alters the expression of target genes including the cell cycle gene p21, leading to cell cycle arrest and apoptosis. Patients enrolled in a phase I trial were treated with vorinostat alone on day 1 and vorinostat and bortezomib in combination on day 9. Paired biopsies were obtained in eleven subjects. Blood samples were obtained on days 1 and 9 of cycle 1 prior to dosing and 2 and 6 h post-dosing in all 60 subjects. Gene expression of p21, HSP70, AKT, Nur77, ERB1, and ERB2 was evaluated in peripheral blood mononuclear cells and tissue samples. Chromatin immunoprecipitation of p21, HSP70, and Nur77 was also performed in biopsy samples. In peripheral blood mononuclear cells, Nur77 was significantly and consistently decreased 2 h after vorinostat administration on both days 1 and 9, median ratio of gene expression relative to baseline of 0.69 with interquartile range 0.49-1.04 (p < 0.001); 0.28 (0.15-0.7) (p < 0.001), respectively, with more pronounced decrease on day 9, when patients received both vorinostat and bortezomib. p21, a downstream target of Nur77, was significantly decreased on day 9, 2 and 6 h after administration of vorinostat and bortezomib, 0.67 (0.41-1.03) (p < 0.01); 0.44 (0.25-1.3) (p < 0.01), respectively. The ChIP assay demonstrated a protein-DNA interaction, in this case interaction of Nur77, HSP70 and p21 with acetylated histone H3, at baseline and at day 9 after treatment with vorinostat in tissue biopsies in most patients. Vorinostat inhibits Nur77 expression, which in turn may decrease p21 and AKT expression in PBMCs. The influence of vorinostat on target gene expression in tumor tissue was variable; however, most patients demonstrated interaction of acetylated H3 with Nur77, HSP70, and p21 which provides evidence of interaction with the transcriptionally active acetylated H3.
    Cancer Chemotherapy and Pharmacology 08/2013; · 2.80 Impact Factor
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    ABSTRACT: Chemotherapy has yielded minimal clinical benefit in pancreatic and biliary tract cancer. A high-dose, short course capecitabine schedule with oxaliplatin, has shown some efficacy with a lower incidence of palmar-plantar erythrodysesthesia. Achieving high exposures of the targeted agent sorafenib may be possible with this shorter schedule of capecitabine by avoiding dermatologic toxicity. All patients had pancreatic or biliary tract cancer. Patients in both cohorts received oxaliplatin 85 mg/m2 followed by capecitabine 2,250 mg/m2 PO every 8 h x 6 doses starting on days 1 and 15 of a 28 day cycle, or 2DOC (2 Day Oxaliplatin/Capecitabine). Cohort 1 used sorafenib 200 mg BID, and cohort 2 used sorafenib 400 mg BID. Sixteen patients were enrolled. Across all cycles the most common grade 1 or 2 adverse events were fatigue (10 pts), diarrhea (10 pts), nausea (9 pts), vomiting (8 pts), sensory neuropathy (8 pts), thrombocytopenia (7 pts), neutropenia (5 pts), and hand-foot syndrome (5 pts). Grade 3 toxicites included neutropenia, mucositis, fatigue, vomiting and diarrhea. Cohort 1 represented the MTD. Two partial responses were seen, one each in pancreatic and biliary tract cancers. The recommended phase II dose of sorafenib in combination with 2DOC is 200 mg BID. There were infrequent grade 3 toxicities, most evident with sorafenib at 400 mg BID.
    Investigational New Drugs 12/2012; · 3.50 Impact Factor
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    ABSTRACT: Prognosis remains poor after progression on first-line chemotherapy for colorectal adenocarcinoma, and inactivation of the EGFR pathway with monoclonal antibodies is an effective treatment strategy in selected patients with metastatic disease. Lapatinib is an oral EGFR and HER-2 dual tyrosine kinase inhibitor that has not shown significant activity in metastatic colorectal cancer. However, lapatinib may act synergistically with capecitabine in anticancer effects. This was an open-label, non-randomized phase II study of lapatinib 1,250 mg orally daily and capecitabine 2,000 mg/m(2) by mouth split into twice-daily dosing for 14 days of a 21 days cycle. Inclusion criteria included metastatic or locally advanced adenocarcinoma of the colon or rectum with progression by RECIST on or within six months of receiving a fluoridopyrimidine-, oxaliplatin- or irinotecan-containing regimen. Prior EGFR monoclonal antibody was permitted. K-ras testing was not routinely performed and was not a part of the study protocol. Twenty nine patients (16 M; 13 F) were enrolled in this study. There were no complete or partial responses. 41.4% of patients achieved stable disease as a best response. Median overall survival was 6.8 months, with a 1-year survival rate of 22%, and median progression-free survival was 2.1 months. The combination produced few grade 3 and no grade 4 toxicities. No grade 3 toxicity occurred in more than 10% of patients. Although capecitabine and lapatinib is well tolerated, it is not an effective regimen in patients with refractory colorectal adenocarcinoma.
    Journal of gastrointestinal oncology 06/2012; 3(2):90-6.
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    ABSTRACT: GSK923295 is an inhibitor of CENP-E, a key cellular protein important in the alignment of chromosomes during mitosis. This was a Phase I, open-label, first-time-in-human, dose-escalation study, to determine the maximum-tolerated dose (MTD), safety, and pharmacokinetics of GSK923295. Adult patients with previously treated solid tumors were enrolled in successive cohorts at GSK923295 doses ranging from 10 to 250 mg/m(2). GSK923295 was administered by a 1-h intravenous infusion, once weekly for three consecutive weeks, with treatment cycles repeated every 4 weeks. A total of 39 patients were enrolled. The MTD for GSK923295 was determined to be 190 mg/m(2). Observed dose-limiting toxicities (all grade 3) were as follows: fatigue (n = 2, 5%), increased AST (n = 1, 2.5%), hypokalemia (n = 1, 2.5%), and hypoxia (n = 1, 2.5%). Across all doses, fatigue was the most commonly reported drug-related adverse event (n = 13; 33%). Gastrointestinal toxicities of diarrhea (n = 12, 31%), nausea (n = 8, 21%), and vomiting (n = 7, 18%) were generally mild. Frequency of neutropenia was low (13%). There were two reports of neuropathy and no reports of mucositis or alopecia. GSK923295 exhibited dose-proportional pharmacokinetics from 10 to 250 mg/m(2) and did not accumulate upon weekly administration. The mean terminal elimination half-life of GSK923295 was 9-11 h. One patient with urothelial carcinoma experienced a durable partial response at the 250 mg/m(2) dose level. The novel CENP-E inhibitor, GSK923295, had dose-proportional pharmacokinetics and a low number of grade 3 or 4 adverse events. The observed incidence of myelosuppression and neuropathy was low. Further investigations may provide a more complete understanding of the potential for GSK923295 as an antiproliferative agent.
    Cancer Chemotherapy and Pharmacology 03/2012; 69(3):733-41. · 2.80 Impact Factor
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    ABSTRACT: Bortezomib (PS-341, VELCADE®) is a selective inhibitor of the 26S proteasome, an integral component of the ubiquitin-proteasome pathway. This phase II study evaluated the activity and tolerability of bortezomib in unresectable hepatocellular carcinoma (HCC) patients. The primary endpoint was confirmed tumor response rate (RR) with secondary endpoints including duration of response, time to disease progression, survival and toxicity. Treatment consisted of bortezomib, 1.3 mg/m2 IV bolus on days 1, 4, 8, and 11 of each 21-day treatment cycle. Eligibility included: no prior systemic chemotherapy, ECOG PS 0-2, Child-Pugh A or B, preserved hematologic, hepatic and neurologic function; prior liver-directed therapy was permitted. Thirty-five patients enrolled and received a median of 2 cycles of treatment (range 1-12). Overall, 24 and 4 patients had a maximum severity of grade 3 and 4 adverse events (AEs), respectively. No treatment related deaths occurred. Only thrombocytopenia (11%) was seen in greater than 10% of patients. One patient achieved a partial response, lasting 13 weeks during treatment and progressed 11.6 months later; two patients received treatment for greater than 6 months. Median time-to-progression was 1.6 months and median survival was 6.0 months. This international, multicenter trial evaluated bortezomib as monotherapy in unresectable HCC patients. And, despite the lack of significant activity, this report serves as a baseline clinical experience for the development of future dual biologic approaches including bortezomib.
    Investigational New Drugs 02/2012; 30(1):387-94. · 3.50 Impact Factor
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    ABSTRACT: The transcription factor nuclear factor-kB (NFkB) is implicated in gastric cancer carcinogenesis and survival, and its inhibition by proteosome inhibition is associated with preclinical gastric cancer anti-tumor activity. We examined the single agent efficacy of bortezomib, a selective proteasome inhibitor, in gastric adenocarcinoma. We performed a phase II trial of bortezomib in patients with advanced gastric adenocarcinoma. Bortezomib 1.3 mg/m(2) was administered on days 1, 4, 8, and 11 every 21 days. The primary endpoint was objective response rate(RR); the null hypothesis was RR <1% versus the alternative ≥15%. One response in the first stage(15 patients) was required before proceeding with an additional 18 patients. If at least 2 or more responses out of 33 were observed, further study with bortezomib was warranted. Correlative studies evaluated pre-treatment tumor expression of NFkB, IkB, p53, p21, and cyclin D1. We enrolled 16 patients (15 evaluable for response) from four institutions. No patients demonstrated an objective response(95% CI, 0-22%); one patient achieved stable disease. Fourteen out of 16 patients experienced ≥ grade 2 toxicity. The most common toxicity was fatigue in six patients (n = 4 grade 2, n = 2 grade 3). Seven patients experienced neuropathy (n = 5 grade 1, and 1 each grade 2 and 3). Seven (60%) had high cytoplasmic staining for NFkB. Single agent bortezomib is inactive in metastatic gastric adenocarcinoma and should not be pursued. Future study of proteasome inhibition in gastric adenocarcinoma should be considered in combination with targeted inhibition of other non-overlapping oncogenic pathways as a potential rational approach.
    Investigational New Drugs 12/2011; 29(6):1475-81. · 3.50 Impact Factor
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    ABSTRACT: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are rational targets for therapy in hepatocellular cancer (HCC). Patients with histologically proven HCC and not amenable to curative or liver directed therapy were included in this 2-stage phase 2 trial. Eligibility included an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and Child's Pugh score of A or B, and 1 prior systemic therapy. Patients received erlotinib 150 mg daily and bevacizumab 10 mg/kg on days 1 and 15 every 28 days. Objective tumor response was the primary end point. Twenty-seven patients with advanced HCC (median age, 60 years) were enrolled in this multi-institutional study. The proportion of patients with Child's A classification was 74%. One patient had a confirmed partial response and 11 (48%) achieved stable disease. Median time to disease progression was 3.0 months (95% confidence interval [CI], 1.8-7.1). Median survival time was 9.5 months (95% CI, 7.1-17.1). Grade 3 toxicities included rash, hypertension, fatigue, and diarrhea. In this trial, erlotinib combined with bevacizumab had minimal activity in patients with advanced HCC based on objective response and progression-free survival. The role of targeting EGFR and VEGF in HCC needs further evaluation in molecularly selected patients.
    Cancer 09/2011; 118(9):2424-30. · 5.20 Impact Factor
  • Clinical advances in hematology & oncology: H&O 06/2011; 9(6):492-500.
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    ABSTRACT: Low-grade neuroendocrine tumors (NETs) respond poorly to chemotherapy; effective, less toxic therapies are needed. Glycogen synthase kinase (GSK)-3β has been shown to regulate growth and hormone production in NETs. Use of lithium chloride in murine models suppressed carcinoid cell growth, reduced GSK-3β levels, and reduced expression of chromogranin A. This study assessed the efficacy of lithium chloride in patients with NETs. Eligible patients had low-grade NETs. A single-arm, open-label phase II design was used. Lithium was dosed at 300 mg orally three times daily, titrated to serum levels of 0.8-1.0 mmol/L. The primary endpoint was objective tumor response by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included overall survival, progression-free survival, GSK-3β phosphorylation, and toxicity. Fifteen patients were enrolled between October 3, 2007 and July 17, 2008, six men and nine women. The median age was 58 years. Patient diagnoses were carcinoid tumor for eight patients, islet cell tumor for five patients, and two unknown primary sites. Eastern Cooperative Oncology Group performance status scores were 0 or 1. Two patients came off study because of side effects. The median progression-free survival interval was 4.50 months. There were no radiographic responses. Because of an early stopping rule requiring at least one objective response in the first 13 evaluable patients, the study was closed to further accrual. Patients had pre- and post-therapy biopsies. Lithium chloride was ineffective at obtaining radiographic responses in our 13 patients who were treated as part of this study. Based on the pre- and post-treatment tumor biopsies, lithium did not potently inhibit GSK-3β at serum levels used to treat bipolar disorders.
    The Oncologist 03/2011; 16(4):452-7. · 4.10 Impact Factor
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    ABSTRACT: Metastatic colorectal cancer (mCRC) is a leading cause of cancer-related mortality in the United States, and new treatment options are needed. This phase I study investigated a novel regimen combining 2 chemotherapy drugs with proven efficacy in mCRC (capecitabine and oxaliplatin) with a tyrosine kinase inhibitor (lapatinib). Lapatinib has already been approved by the US Food and Drug Administration for treatment of selected cases of breast cancer. Patients with solid tumors responsive to fluoropyrimidines or oxaliplatin were eligible for enrollment. Treatment was given over a 21-day cycle with a fixed dosing of intravenous oxaliplatin of 130 mg/m(2) on day 1. Capecitabine and lapatinib were given orally at escalating doses, starting at capecitabine 1500 mg/m(2)/day on days 1-14 and lapatinib 1000 mg daily on days 1-21. Ten patients received treatment per study protocol. All had received previous systemic treatment. Diarrhea was one of the most common side effects and accounted for nearly all grade 3/4 toxicity. The starting dose level was determined to be the maximum tolerated dose. One patient with pancreatic cancer had evidence of a partial response. Three other patients demonstrated stable disease. There were no complete responses. Results of this study suggest the regimen of capecitabine, oxaliplatin, and lapatinib has some efficacy in types of advanced or metastatic solid malignancies with known responsiveness to fluoropyrimidines or oxaliplatin. Further research may help determine whether this regimen can improve on the response rates seen with current standard regimens for mCRC.
    Clinical Colorectal Cancer 03/2011; 10(1):57-62. · 1.80 Impact Factor
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    ABSTRACT: The kinesin spindle protein (KSP) is essential for separation of spindle poles during mitosis. Its inhibition results in mitotic arrest. This phase I trial examined safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetic parameters, and anti-tumor activity of MK-0731, a potent inhibitor of KSP. In part 1, patients with advanced solid tumors received MK-0731 intravenously over 24 h every 21 days starting at 6 mg/m(2), escalating until MTD was reached. In part 2, patients with taxane-resistant tumors received the MTD. Plasma samples were collected to analyze the pharmacokinetics of MK-0731. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. In part 1, 21 patients (median age 63 years) were treated with MK-0731 at doses ranging from 6 to 48 mg/m(2)/24 h for median four cycles. The dose-limiting toxicity was neutropenia and the MTD was 17 mg/m(2)/24 h. At the MTD, AUC (±SD) was 10.5 (±7.3) μM × hour, clearance (±SD) was 153 mL/min (±84), and t(1/2) was 5.9 h. In part 2, 22 patients received the MTD and there were no DLTs. Although there were no objective tumor responses, four patients (with cervical, non-small cell lung, and ovarian cancers) had prolonged stable disease. MK-0731 at the MTD of 17 mg/m(2)/day every 21 days in patients with solid tumors had few grade 3 and 4 toxicities with the major DLTs at higher doses being myelosuppression. Anti-tumor efficacy was suggested by the length of stable disease in selected patients with taxane-resistant tumors.
    Investigational New Drugs 03/2011; 30(3):1088-95. · 3.50 Impact Factor
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    ABSTRACT: PURPOSE: 3-AP (3-aminopyridine-2-carboxaldehyde thiosemicarbazone, 3-AP) is a metal chelator that potently inhibits the enzyme ribonucleotide reductase, RR, which plays a key role in cell division and tumor progression. A sub-unit of RR has a non-heme iron and a tyrosine free radical, which are required for the enzymatic reduction of ribonucleotides to deoxyribonucleotides. The objective of the study was to determine whether 3-AP affects its targeted action by measuring EPR signals formed either directly or indirectly from low molecular weight ferric-3-AP chelates. METHODS: Peripheral blood lymphocytes were collected from patients with refractory solid tumors at baseline and at 2, 4.5 and 22 hours after 3-AP administration. EPR spectra were used to identify signals from high-spin Fe-transferrin, high-spin heme and low-spin iron or copper ions. RESULTS: An increase in Fe-transferrin signal was observed, suggesting blockage of Fe uptake. It is hypothesized that formation of reactive oxygen species by FeT(2) or CuT damage transferrin or the transferrin receptor. An increase in heme signal was also observed, which is a probable source of cytochrome c release from the mitochondria and potential apoptosis. In addition, increased levels of Fe and Cu were identified. CONCLUSION: These results, which were consistent with our earlier study validating 3-AP-mediated signals by EPR, provide valuable insights into the in vivo mechanism of action of 3-AP.
    Experimental and therapeutic medicine 01/2011; 2(1):119-123. · 0.34 Impact Factor
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    ABSTRACT: Notch1 has been shown to be a tumor suppressor in neuroendocrine tumors (NETs). Previous in vitro studies in NET cell lines have also suggested that valproic acid (VPA), a histone deacetylase inhibitor, can induce Notch1 and that Notch1 activation correlates with a decrease in tumor markers for NETs. Thus, this study aimed to evaluate the role of VPA in treating NETs and to determine whether VPA induced the Notch signaling pathway signaling in vivo. Eight patients with low-grade NETs (carcinoid and pancreatic) were treated with 500 mg of oral VPA twice a day with dosing adjusted to maintain a goal VPA level between 50 and 100 μg/mL. All patients were followed for 12 months or until disease progression. Notch1 signaling was absent in all tumors prior to treatment and was upregulated with VPA. One patient had an unconfirmed partial response and was noted to have a 40-fold increase in Notch1 mRNA levels. Four patients had stable disease as best response. Tumor markers improved in 5 out of 7 patients. Overall, treatment with VPA was well tolerated. . VPA activates Notch1 signaling in vivo and may have a role in treating low-grade NETs.
    The Oncologist 01/2011; 16(6):835-43. · 4.10 Impact Factor
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    ABSTRACT: 3-AP is a ribonucleotide reductase inhibitor and has been postulated to act synergistically with other chemotherapeutic agents. This study was conducted to determine the toxicity and antitumor activity of 3-AP with irinotecan. Correlative studies included pharmacokinetics and the effects of ABCB1 and UGT1A1 polymorphisms. The treatment plan consisted of irinotecan on day 1 with 3-AP on days 1-3 of a 21-day cycle. Starting dose was irinotecan 150 mg/m(2) and 3-AP 85 mg/m(2) per day. Polymorphisms of ABCB1 were evaluated by pyrosequencing. Drug concentrations were determined by HPLC. Twenty-three patients were enrolled, 10 men and 13 women. Tumor types included seven patients with pancreatic cancer, four with lung cancer, two with cholangiocarcinoma, two with mesothelioma, two with ovarian cancer, and six with other malignancies. Two patients experienced dose-limiting toxicity (DLT) at dose level 1, requiring amendment of the dose-escalation scheme. Maximal tolerated dose (MTD) was determined to be 3-AP 60 mg/m(2) per day and irinotecan 200 mg/m(2). DLTs consisted of hypoxia, leukopenia, fatigue, infection, thrombocytopenia, dehydration, and ALT elevation. One partial response in a patient with refractory non-small cell lung cancer was seen. Genotyping suggests that patients with wild-type ABCB1 have a higher rate of grade 3 or 4 toxicity than those with ABCB1 mutations. The MTD for this combination was 3-AP 60 mg/m(2) per day on days 1-3 and irinotecan 200 mg/m(2) on day 1 every 21 days. Antitumor activity in a patient with refractory non-small cell lung cancer was noted at level 1.
    Cancer Chemotherapy and Pharmacology 10/2010; 66(5):973-80. · 2.80 Impact Factor
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    ABSTRACT: Biliary cancers overexpress epidermal growth factor receptor (EGFR), and angiogenesis has been correlated with poor outcome. Erlotinib, an EGFR tyrosine kinase inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor have each been shown to have activity in biliary cancer. The primary objective of this study was to evaluate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included overall survival (OS), time to progression (TTP), VEGF levels, and molecular studies of EGFR and k-ras. Eligible patients had advanced cholangiocarcinoma or gallbladder cancer. Patients were treated with bevacizumab 5 mg/kg intravenously on days 1 and 15 and erlotinib 150 mg by mouth daily on days 1 through 28. Responses were evaluated by RECIST. VEGF levels were collected, and samples were analyzed for EGFR mutation by polymerase chain reaction. Fifty-three eligible patients were enrolled at eight sites. Of 49 evaluable patients, six (12%; 95% CI, 6% to 27%) had a confirmed partial response. Stable disease was documented in another 25 patients (51%). Rash was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median OS was 9.9 months, and TTP was 4.4 months. Low repeats (< 16) in EGFR intron 1 polymorphism and G>G k-ras Q38 genotype (wild type) were associated with improved outcomes. Combination chemotherapy with bevacizumab and erlotinib showed clinical activity with infrequent grade 3 and 4 adverse effects in patients with advanced biliary cancers. On the basis of preliminary molecular analysis, presence of a k-ras mutation may alter erlotinib efficacy. The combination of bevacizumab and erlotinib may be a therapeutic alternative in patients with advanced biliary cancer.
    Journal of Clinical Oncology 07/2010; 28(21):3491-7. · 18.04 Impact Factor
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    ABSTRACT: Capecitabine has shown similar efficacy to 5-fluorouracil (5-FU); a regimen containing 2 weeks of capecitabine/oxaliplatin (CapOx) has demonstrated noninferiority to infusional 5-FU/oxaliplatin/leucovorin (FOLFOX) for the treatment of metastatic colorectal cancer (mCRC). This phase II study explores the efficacy and safety of a 2-day course of oxaliplatin/capecitabine (2DOC), with oxaliplatin given on day 1 and capecitabine given orally every 8 hours in high doses over 6 doses, mimicking FOLFOX6. This phase II study was conducted by the University of Wisconsin Carbone Cancer Center. Eligible patients with mCRC received oxaliplatin 100 mg/m2 intravenously (I.V.) over 2 hours followed by leucovorin 20 mg/m2 I.V. bolus and 5-FU 400 mg/m2 I.V. bolus on day 1 and day 15. Capecitabine was administered at 1500 mg/m2 orally every 8 hours over 6 doses starting on day 1 and day 15. Results: A total of 45 patients were enrolled; 44 were evaluated for response. Seventeen patients (39%) had objective responses. Median time to progression was 6.8 months, and median overall survival (OS) was 17.5 months. The most common side effects were grade 1/2 neuropathy, fatigue, and nausea. Severe hand-foot syndrome (HFS) was rare. The overall response rate with the 2DOC regimen is similar to published CapOx regimens, and time to progression and OS are similar. The incidence of HFS, diarrhea, and mucositis were lower compared with published results of 2-week schedules of capecitabine. The 2DOC regimen merits further study as a more convenient regimen than infusional 5-FU with less HFS when compared with a 2-week administration of capecitabine.
    Clinical Colorectal Cancer 07/2010; 9(3):157-61. · 1.80 Impact Factor
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    ABSTRACT: ZM336372 is small molecule tyrosine kinase modulator. It has been shown to inhibit glycogen synthase kinase-3beta (GSK-3beta) through phosphorylation of GSK-3beta at Ser 9. GSK-3beta has previously been shown to mediate cell survival in pancreatic cancer cells. Here we determine the effects of ZM336372 on GSK-3beta phosphorylation, apoptosis, and growth in pancreatic adenocarcinoma cell lines. Panc-1 and MiaPaCa-2 cells were treated with ZM336372 or lithium chloride (LiCl) and compared with solvent control. The effects on proliferation for each cell line were determined using the MTT assay. Western blot analysis was performed to examine the effects of treatment on the phosphorylation of GSK-3beta. In addition, western blot was utilized to examine the cleavage of poly (ADP-ribose) polymerase (PARP), a marker of apoptosis. A dose-dependent increase in phosphorylation of GSK-3beta was observed after treatment with both ZM336372 and LiCl. Growth inhibition due to treatment with ZM336372 and LiCl also occurred in a dose-dependent fashion. An increase in cleaved PARP was demonstrated after treatment with both agents, as was seen previously with GSK-3beta inhibition in pancreatic adenocarcinoma cells. This is the first description of growth inhibition and apoptosis in pancreatic cancer cells related to GSK-3beta inhibition through treatment with ZM336372.
    Journal of Surgical Research 06/2010; 161(1):28-32. · 2.02 Impact Factor
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    ABSTRACT: The purpose of this study was to develop a population pharmacokinetic (PK) model for 3-AP, to evaluate the effect of ABCB1 polymorphisms on the pharmacokinetic profile of 3-AP, and to assess the relationship between 3AP disposition and patient covariates. A total of 40 patients with advanced cancer from two phase 1 studies were included in the population PK model building. Patients received 3-AP 25-105 mg/m(2) IV on day 1. 3-AP plasma and erythrocyte levels were sampled at 10 timepoints over a 24-h period and measured by a validated HPLC method. Data were analyzed by a nonlinear mixed-effects modeling approach using the NONMEM system. 3-AP pharmacokinetics were described as a 3-compartment model with first-order elimination, with one compartment representing the plasma and another representing erythrocyte concentrations. Gender was associated with volume of distribution, in which women had a lower V2. The number of cycles administered was associated with clearance; those with decreased clearance were more likely to receive less than 2 cycles before going off study. This study suggests that monitoring 3-AP plasma concentrations in the first cycle and dose adjustment in those with decreased clearance may be helpful in decreasing toxicity associated with the 3-AP.
    Cancer Chemotherapy and Pharmacology 05/2010; 67(2):393-400. · 2.80 Impact Factor
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    ABSTRACT: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of SB-743921 when administered as a 1-h infusion every 21 days to patients with advanced solid tumors or relapsed/refractory lymphoma. Patients who failed prior standard therapy or those without any standard options were eligible. Forty-four patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase. An additional 20 patients were enrolled at the recommended phase II dose to obtain additional safety and pharmacokinetic data. The doses evaluated ranged from 2 to 8 mg/m(2). The pharmacokinetics of SB-743921 was evaluated at 19 time-points over 48 h following during administration during cycle 1. Toxicity was assessed by the NCI Common Terminology Criteria version 3.0. Response evaluation was performed every 6 weeks. The most common and consistent DLT was neutropenia. Other DLTs observed included hypophosphatemia, pulmonary emboli, SVC syndrome, transaminitis, hyponatremia, and hyperbilirubinemia. The MTD of SB-743921 as a 1-h infusion every 21 days was established as 4 mg/m(2). The maximum plasma concentration and area under the plasma concentration time curve appeared to increase proportionally to dose. One durable objective response was seen in a patient with metastatic cholangiocarcinoma who was on treatment 11 months and 6 patients had stable disease for over four cycles. The recommended phase II dose of SB-743921 on this specific schedule of a 1-h infusion every 3 weeks is 4 mg/m(2). The promising efficacy and lack of severe toxicities in this study warrant the continued development of SB-743921.
    Cancer Chemotherapy and Pharmacology 05/2010; 67(2):447-54. · 2.80 Impact Factor

Publication Stats

687 Citations
181.80 Total Impact Points

Institutions

  • 2004–2010
    • University of Wisconsin, Madison
      • Department of Medicine
      Madison, MS, United States
  • 2009
    • University of Texas Health Science Center at San Antonio
      • Cancer Therapy & Research Center
      San Antonio, TX, United States
  • 2001–2003
    • Memorial Sloan-Kettering Cancer Center
      • Department of Medicine
      New York City, NY, United States