Emily Chan

Sarah Cannon Research Institute, Nashville, Tennessee, United States

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Publications (27)181.29 Total impact

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    ABSTRACT: This trial was designed to assess efficacy and safety of erlotinib with sorafenib in the treatment of patients with advanced pancreatic adenocarcinoma. An exploratory correlative study analyzing pretreatment serum samples using a multivariate protein mass spectrometry-based test (VeriStrat®), previously shown to correlate with outcomes in lung cancer patients treated with erlotinib, was performed. Patients received sorafenib 400 mg daily along with erlotinib 150 mg daily with a primary endpoint of 8-week progression free survival (PFS) rate. Pretreatment serum sample analysis by VeriStrat was done blinded to clinical and outcome data; the endpoints were PFS and overall survival (OS). Difference between groups (by VeriStrat classification) was assessed using log-rank P values; hazard ratios (HR) were obtained from Cox proportional hazards model. Thirty-six patients received study drug and were included in the survival analysis. Eight-week PFS rate of 46% (95% confidence interval (CI): 0.32-0.67) did not meet the primary endpoint of a rate ≥70%. Thirty-two patients were included in the correlative analysis, and VeriStrat "Good" patients had superior PFS (HR = 0.18, 95% CI: 0.06-0.57; P = 0.001) and OS (HR = 0.31 95% CI: 0.13-0.77, P = 0.008) compared to VeriStrat "Poor" patients. Grade 3 toxicities of this regimen included fever, anemia, diarrhea, dehydration, rash, and altered liver function. This study did not meet the primary endpoint, and this combination will not be further pursued. In this small retrospective analysis, the proteomic classification was significantly associated with clinical outcomes and is being further evaluated in ongoing studies.
    Cancer medicine. 02/2014;
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    ABSTRACT: Background: Previously, this study showed significant improvement in progression-free survival (PFS) in pmab + FOLFIRI vs FOLFIRI (HR=0.73; 95% CI: 0.59-0.90; p=0.004) and a trend toward improved overall survival (OS; HR=0.85; 95% CI: 0.70-1.04; P=0.12; Peeters et al. JCO 2010). Recently, analysis from 1st-line mCRC PRIME study showed that mutations in RAS genes (KRAS/NRAS exons 2/3/4) predicted a lack of response to pmab (Douillard et al. NEJM 2013). Methods: The primary objective was to assess the tx effect of pmab + FOLFIRI vs FOLFIRI on OS and PFS based on RAS mutation status in the primary analysis population. Bidirectional Sanger sequencing was used to detect mutations in KRAS exons 3, 4 and NRAS exons 2, 3, 4 in patients (pts) with known WT KRAS exon 2 mCRC. Results: In this prospective retrospective analysis, overall RAS ascertainment rate was 85% (n=1008/1186). 18% of the WT KRAS exon 2 pts harbored additional RAS mutations (n=107/597). Efficacy is shown (Table). Tx HR for pts with WT RAS was 0.803 (95% CI: 0.629-1.024; P=0.077) for OS and 0.695 (95% CI: 0.536-0.903; P=0.006) for PFS. Conclusions: Improvements were observed in the tx effect of pmab + FOLFIRI vs FOLFIRI on OS and PFS in the WT RAS group vs the WT KRAS exon 2 group. Pts with MT RAS mCRC are unlikely to benefit by the addition of pmab to FOLFIRI, similar to pts with MT KRAS exon 2 mCRC in this study. These findings are consistent with previously reported outcomes by RAS status and support RAS testing to determine potentially appropriate pts for pmab tx. Clinical trial information: NCT00339183. Pmab + FOLFIRI (N = 303) FOLFIRI (N = 294) HR (95% CI) Descriptive p value WT RAS,a n 204 211 Median OS - mos 95% CI 16.2 14.5, 19.7 13.9 11.9, 16.1 0.803 0.629, 1.024 0.077 Median PFS - mos 95% CI 6.4 5.5, 7.4 4.4 3.7, 5.5 0.695 0.536, 0.903 0.006 MT RAS,b n 299 294 Median OS - mos 95% CI 11.8 10.4, 13.1 11.1 10.2, 12.4 0.914 0.759, 1.101 0.345 Median PFS - mos 95% CI 4.8 3.7, 5.5 4.0 3.6, 5.5 0.861 0.705, 1.053 0.144 WT KRAS exon 2 MT RAS,c n 61 46
    2014 Gastrointestinal Cancer Symposium, San Francisco; 01/2014
  • Emily Chan, Jordan Berlin
    Journal of Clinical Oncology 01/2014; · 18.04 Impact Factor
  • Annals of Oncology. 01/2014; 25(suppl 2):ii5.
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    ABSTRACT: The study 20050181 demonstrated significant improvements in progression-free survival (PFS), objective response, and a nonsignificant trend toward increased overall survival (OS) with panitumumab-FOLFIRI versus FOLFIRI alone for second-line wild-type (WT) KRAS metastatic colorectal cancer (mCRC). Updated long-term data from a prespecified descriptive analysis are reported. Patients receiving one prior mCRC treatment were randomly assigned (1:1) to panitumumab (6.0 mg/kg)-FOLFIRI versus FOLFIRI every 2 weeks. Co-primary end points (PFS and OS) were prospectively analyzed by tumor KRAS status. One thousand one hundred and eighty-six patients were randomly assigned. In patients with WT KRAS tumors, panitumumab-FOLFIRI significantly improved PFS versus FOLFIRI [median 6.7 versus 4.9 months; hazard ratio (HR) 0.82 [95% confidence interval (CI) 0.69, 0.97]; P = 0.023]. A trend toward longer OS was observed (median 14.5 versus 12.5 months; HR 0.92 [95% CI 0.78, 1.10]; P = 0.37). Response rates improved from 10% to 36% (P < 0.0001). From post hoc analyses in patients receiving prior oxaliplatin-bevacizumab, panitumumab-FOLFIRI improved PFS (median 6.4 versus 3.7 months; HR 0.58 [95% CI 0.37, 0.90]; P = 0.014). PFS and OS appeared longer for worst-grade skin toxicity of 2-4, versus 0-1 or FOLFIRI. Safety results were as previously reported and consistent with the known toxicities with anti-epidermal growth factor receptor therapy. These data confirm the primary efficacy and safety findings of this trial and support panitumumab-FOLFIRI as a second-line treatment of WT KRAS mCRC.
    Annals of Oncology 01/2014; 25(1):107-16. · 7.38 Impact Factor
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    ABSTRACT: N (1),N (11)-diethylnorspermine (DENSPM), a synthetic analog of the naturally occurring polyamine spermine, can induce polyamine depletion and inhibit tumor cell growth. The objectives of this phase I study were to assess the safety, maximum-tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity of DENSPM in advanced HCC. Patients with measurable advanced HCC, Child-Pugh A or B cirrhosis, CLIP score ≤3, and Karnofsky score ≥60 % were eligible. DENSPM was given as a short intravenous infusion on days 1, 3, 5, 8, 10, and 12 of each 28-day cycle. The starting dose of 30 mg/m(2) was escalated at a fixed increment of 15 mg/m(2) until the MTD was identified. The plasma pharmacokinetics of DENSPM for the first and last doses given in cycle 1 was characterized. Thirty-eight patients (male 79 %; median age 61 years; Child-Pugh A 84 %; ≥1 prior systemic therapy 45 %) were enrolled and treated. The most common adverse events (AEs) ≥grade 1 were fatigue (53 %), nausea (34 %), diarrhea (32 %), vomiting (32 %), anemia (29 %), and elevated AST (29 %). The most common grade 3-4 AEs were fatigue/asthenia (13 %), elevated AST (13 %), hyperbilirubinemia (11 %), renal failure (8 %), and hyperglycemia (8 %). The MTD was 75 mg/m(2). There were no objective responses, although 7/38 (18 %) patients achieved stable disease for ≥16 weeks. The overall mean (±SD) total body clearance for the initial dose, 66.3 ± 35.9 L/h/m(2) (n = 16), was comparable to the clearance in patients with normal to near normal hepatic function. Drug levels in plasma decayed rapidly immediately after the infusion but remained above 10 nM for several days after dosing at the MTD. N (1),N (11)-diethylnorspermine treatment at the MTD of 75 mg/m(2), given intravenously every other weekday for two consecutive weeks of each 28-day cycle, was relatively well tolerated in patients with advanced HCC including those with mild-to-moderate liver dysfunction. This administration schedule provided prolonged systemic exposure to potentially effective concentrations of the drug. Stable disease was seen in 18 % of patients receiving DENSPM treatment. Further evaluation of DENSPM monotherapy for advanced HCC does not appear to be justified because of insufficient evidence of clinical benefit in the patients evaluated in this study.
    Cancer Chemotherapy and Pharmacology 10/2013; · 2.80 Impact Factor
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    ABSTRACT: To investigate pharmacokinetics (PK) of encapsulated CPT-11, released CPT-11 and the active metabolite SN-38 following administration of IHL-305 and to identify factors that may influence IHL-305 PK. Plasma samples from 39 patients with solid tumors were collected in a phase I study. IHL-305 was administered as a 1 h IV infusion with doses ranging from 3.5 to 210 mg/m(2). Plasma concentrations of encapsulated CPT-11, released CPT-11 and SN-38 were used to develop a population PK model using NONMEM®. PK of encapsulated CPT-11 was described by 1-compartment model with nonlinear clearance and PK of released CPT-11 was described by a 1-compartment model with linear clearance for all patients. PK of the active metabolite SN-38 was described by a 2-compartment model with linear clearance for all patients. Covariate analysis revealed that gender was a significant covariate for volume of distribution of encapsulated CPT-11. Vencap in male patients is 1.5-fold higher compared with female patients. The developed population PK modeling approach is useful to predict PK exposures of encapsulated and released drug and can be applied to the more than 300 other nanoparticle formulations of anticancer agents that are currently in development. The effect of gender on PK of IHL-305 needs to be further evaluated.
    European Journal of Clinical Pharmacology 08/2013; · 2.74 Impact Factor
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    ABSTRACT: OBJECTIVE: This article reviews important complications of targeted drug therapies for solid malignancies that can be identified on diagnostic imaging. Wherever possible, known or proposed mechanistic explanations for drug complications are emphasized. CONCLUSION: Familiarity with the toxicity profiles of different targeted cancer therapies is important for identifying drug-related complications and for differentiating drug effects from disease progression. A mechanistic understanding may be useful for associating individual drugs with their complications and for predicting the complications of emerging agents.
    American Journal of Roentgenology 03/2013; 200(3):475-83. · 2.90 Impact Factor
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    ABSTRACT: Background We evaluated AGS-1C4D4, a fully human monoclonal antibody to prostate stem cell antigen (PSCA), with gemcitabine in a randomized, phase II study of metastatic pancreatic cancer.Patients and methodsPatients with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and previously untreated, metastatic pancreatic adenocarcinoma were randomly assigned 1:2 to gemcitabine (1000 mg/m2 weekly seven times, 1 week rest, weekly three times q4weeks) or gemcitabine plus AGS-1C4D4 (48 mg/kg loading dose, then 24 mg/kg q3weeks IV). The primary end point was 6-month survival rate (SR). Archived tumor samples were collected for pre-planned analyses by PSCA expression.ResultsBetween April 2009 and May 2010, 196 patients were randomly assigned to gemcitabine (n = 63) or gemcitabine plus AGS-1C4D4 (n = 133). The 6-month SR was 44.4% (95% CI, 31.9-57.5) in the gemcitabine arm and 60.9% (95% CI, 52.1-69.2) in the gemcitabine plus AGS-1C4D4 arm (P = 0.03), while the median survival was 5.5 versus 7.6 months and the response rate was 13.1% versus 21.6% in the two arms, respectively. The 6-month SR was 57.1% in the gemcitabine arm versus 79.5% in the gemcitabine plus AGS-1C4D4 arm among the PSCA-positive subgroup and 31.6% versus 46.2% among the PSCA-negative subgroup.Conclusions This randomized, phase II study achieved its primary end point, demonstrating an improved 6-month SR with addition of AGS-1C4D4 to gemcitabine among patients with previously untreated, metastatic pancreatic adenocarcinoma.ClinicalTrials.gov identifier: NCT00902291.
    Annals of Oncology 02/2013; · 7.38 Impact Factor
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    ABSTRACT: Aflibercept, an intravenously administered anti-vascular endothelial growth factor (VEGF) and anti-placental growth factor (PlGF) agent, has recently been approved by the U.S. Food and Drug Administration (FDA) in combination with 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer (mCRC) who have previously received an oxaliplatin-containing chemotherapy regimen. In the phase III VELOUR trial, aflibercept plus FOLFIRI statistically significantly prolonged both progression-free survival (median PFS for the aflibercept plus FOLFIRI arm was 6.90 months versus 4.67 months for the placebo plus FOLFIRI arm) and overall survival (median OS for the aflibercept plus FOLFIRI arm was 13.50 months versus 12.06 months for the placebo plus FOLFIRI arm); however, grade 3 or 4 adverse events were more common with the addition of aflibercept. The addition of aflibercept to 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) in the phase II AFFIRM trial of first-line treatment of mCRC failed to improve PFS or response rate, however. As a decoy vascular endothelial growth factor receptor (VEGFR), aflibercept (VEGF-Trap) has binding affinity for VEGF-A, VEGF-B, PlGF-1 and PlGF-2, and this is a mechanism of significant interest. Optimal strategies for incorporating aflibercept into treatment regimens that include other anti-VEGF and cytotoxic chemotherapeutic agents, as well as development of predictive biomarkers for treatment response, have yet to be defined.
    Clinical Cancer Research 02/2013; · 7.84 Impact Factor
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    ABSTRACT: PURPOSE: The objective of this first-in-human trial included the safety, maximum tolerated dose (MTD), pharmacokinetics, immunogenicity and antitumour effects of KRN330, a novel fully-human monoclonal antibody directed against A33, a membrane bound glycoprotein uniformly expressed in 95% of colorectal cancers. METHODS: Patients with advanced or metastatic colorectal cancer (CRC) refractory to standard therapy were eligible. Twenty-nine patients received weekly intravenous KRN330 (0.1-10mg/kg) for a minimum of 4 weeks in a standard 3+3 design, and nine patients received q2week doses at 3mg/kg with pre- and post-biopsies to evaluate tumour binding and safety on this schedule. RESULTS: The most common KRN330 related adverse events (all grades) were nausea (66%), diarrhoea (61%) and vomiting (47%). The MTD was 3mg/kg weekly, with dose-limiting grade 3 gastrointestinal toxicities at 10mg/kg and the intermediate dose level of 6mg/kg. Pharmacokinetics of KRN330 was linear. Stable disease was reported in 12/38 patients (32%), with a median duration of 155 days. There was no evidence of human anti-human antibodies, and immunohistochemistry on biopsy samples demonstrated that KRN330 remained bound to tumour 2 weeks after dosing. CONCLUSIONS: KRN330 is safe and tolerable at the MTD of 3mg/kg once weekly in patients with advanced CRC. Dosing on alternate weeks is supported by tumour binding. The long treatment durations and lack of immunogenicity warrant further investigation of KRN330 in combination.
    European journal of cancer (Oxford, England: 1990) 01/2013; · 4.12 Impact Factor
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    ABSTRACT: Background Two arms with irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI), with or without cetuximab, were initially included in the randomized phase III intergroup clinical trial NCCTG N0147. When other contemporary trials demonstrated no benefit to using irinotecan as adjuvant therapy, the FOLFIRI-containing arms were discontinued. We report the clinical outcomes for patients randomized to FOLFIRI with or without cetuximab. Patients and Methods Following resection, patients were randomized to 12 biweekly cycles of FOLFIRI, with or without cetuximab. KRAS mutation status was retrospectively determined in a central lab. The primary endpoint was disease free survival (DFS). Secondary endpoints included overall survival and toxicity. Results 106 patients received FOLFIRI and 40 FOLFIRI plus cetuximab. Median follow-up was 5.95 years (range 0.1-7.0). The addition of cetuximab showed trends toward improved DFS (HR 0.53, 95% CI 0.26-1.1; p=0.09) and OS (HR 0.45, 95% CI 0.17-1.16; p=0.10) in the overall group, regardless of KRAS status, and in patients with wild type KRAS. Grade ≥ 3 non-hematologic adverse effects were significantly increased in the cetuximab versus FOLFIRI-alone arm (68% vs. 46%, p = 0.02). Adjuvant FOLFIRI resulted in a 3-year DFS lower than that expected for FOLFOX. Conclusion In this small randomized subset of patients with resected stage III colon cancer, the addition of cetuximab to FOLFIRI was associated with non-significant trends toward improved DFS and OS. Nevertheless, given the limitations of this analysis, FOLFOX without the addition of a biologic agent remains the standard of care for adjuvant therapy in resected stage III colon cancer.
    Clinical Colorectal Cancer 01/2013; · 1.80 Impact Factor
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    ABSTRACT: Over the past few decades substantial improvement has occurred in the diagnosis and treatment of rectal cancers. This disease requires the close cooperation of a multidisciplinary team, including radiologists, gastroenterologists, surgeons, medical oncologists, and radiation oncologists, to provide optimum treatment with minimal morbidity. The widespread use of total mesorectal excision (TME) and improvements in chemotherapy and radiation delivery have resulted in decreases in locoregional recurrence. Large randomized studies have shown a benefit with the use of preoperative chemoradiation for most patients with transmural and/or node-positive disease. Controversy remains, however, regarding whether this treatment paradigm should be applied uniformly to all patients regardless of tumor location. As the risk of local recurrence decreases with high rectal tumors and the benefit in terms of sphincter preservation is not applicable to this subgroup of patients, up-front surgery to allow for more accurate pathologic staging prior to making final treatment decisions is recommended. In patients with pathologically staged T3,N0,M0 tumors of the upper rectum who have undergone TME with 12 or more nodes removed, the addition of chemoradiation has very little benefit.
    Journal of the National Comprehensive Cancer Network: JNCCN 12/2012; 10(12):1567-1572. · 5.11 Impact Factor
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    ABSTRACT: PURPOSE: IHL-305 is a novel PEGylated liposome containing irinotecan. This study examined the safety profile and pharmacokinetics of IHL-305 and established the maximum tolerated dose and recommended phase II dose (RP2D). PATIENTS AND METHODS: In a standard 3 + 3 design, IHL-305 was administered IV on day 1 of a 28-day treatment schedule. Subsequently, a 14-day treatment schedule was also explored. Two patient populations were evaluated separately: Patients with at least one wild-type (wt) allele of UGT1A1 (UDP glucoronosyltransferase 1A1) wt/wt or wt/*28 as one group (referred to as UGT1A1 wt group) and patients with UGT1A1*28 homozygous variant (*28/*28) as another group. RESULTS: Sixty patients were treated: 42 on the 28-day schedule and 18 on the 14-day schedule. Seven patients were homozygous variant (*28/*28). In the UGT1A1 wt group, the MTD and RP2D of IHL-305 was 160 mg/m(2) every 28 days and 80 mg/m(2) every 14 days. DLTs included nausea, vomiting, diarrhea, and neutropenia. The most common adverse events were nausea (75 %), vomiting (52 %), diarrhea (62 %), anorexia (57 %), and fatigue (57 %). At the MTD for both schedules, IHL-305 administration resulted in a high and prolonged exposure of sum total irinotecan, released irinotecan, and SN-38 in plasma. One partial response was observed in a patient with breast cancer and eight patients had stable disease for >6 months. CONCLUSIONS: IHL-305, a novel preparation of irinotecan encapsulated in liposomes, can be safely given to patients in a repeated fashion on a 4- or 2-week dosing schedule.
    Cancer Chemotherapy and Pharmacology 09/2012; · 2.80 Impact Factor
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    ABSTRACT: Cetuximab is a monoclonal antibody against the epidermal growth factor receptor (EGFR). The primary goal of this phase I study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of gemcitabine when combined with cetuximab plus radiation in patients with locally advanced pancreatic cancer. Patients with locally unresectable adenocarcinoma of the pancreas were treated with gemcitabine (200 mg/m(2)/week before dose escalation) plus cetuximab (400 mg/m(2) loading dose, 250 mg/m(2) weekly maintenance dose) concurrent with radiation (50.4 Gy). Nine patients were enrolled in the study. One withdrew due to declining performance status before receiving any therapy. Grade 4 allergic reactions to cetuximab caused the withdrawal of 2 patients. Another patient had elevated liver function test results and a stroke after his loading dose of cetuximab. Grade 3 or 4 toxicity developed in 3 of the remaining 5 patients treated with the level 1 dose. Therefore, no further dose escalations were planned. Grade 3 toxicities included nausea, vomiting, ileus, and pneumonitis. One patient had grade 4 diarrhea. The combination of cetuximab, gemcitabine, and radiation resulted in significant toxicity. A recommended phase II dose could not be determined.
    Gastrointestinal cancer research: GCR 07/2012; 5(4):112-8.
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    ABSTRACT: This phase I study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor effects of sunitinib combined with modified FOLFOX6 (mFOLFOX6). Patients with advanced solid malignancies received mFOLFOX6 in 2-week cycles with escalating sunitinib doses (25, 37.5, and 50 mg/day) on three schedules: 2 weeks on, 2 weeks off (2/2); 4 weeks on, 2 weeks off (4/2); or continuous daily dosing (CDD). Patients received up to 8 treatment cycles (Schedule 2/2 and CDD schedule) or 6 cycles (Schedule 4/2). An expansion cohort enrolled patients with metastatic colorectal cancer at the Schedule 2/2 MTD. Overall, 53 patients were enrolled, with 43 evaluable for dose-limiting toxicity (DLT). On Schedule 2/2 (n = 18), DLTs occurred in three patients at 50 mg/day (grade 4 neutropenia [n = 1]; grades 3 and 4 thrombocytopenia [n = 2]) and two patients achieved partial responses (PRs). On Schedule 4/2 (n = 13), 37.5 mg/day exceeded the MTD with two DLTs (febrile neutropenia and grade 4 hypokalemia, respectively). On the CDD schedule (n = 12), the MTD was 25 mg/day; one DLT (grade 3 stomatitis) was reported and two patients achieved PRs. The most common adverse events were neutropenia, fatigue, and thrombocytopenia. No clinically significant drug-drug interactions were apparent between sunitinib, its metabolite SU12662, and mFOLFOX6. Sunitinib combined with mFOLFOX6 had acceptable tolerability. The MTDs were sunitinib 50 mg/day on Schedule 2/2 and 25 mg/day on the CDD schedule. A MTD for Schedule 4/2 was not established.
    Cancer Chemotherapy and Pharmacology 05/2012; 70(1):65-74. · 2.80 Impact Factor
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    ABSTRACT: Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer. To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wild-type KRAS colon cancer. A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS. A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a hazard ratio (HR) of 1.33 (2-sided α = .05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses. Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity. Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98-1.49; P = .08) in patients with wild-type KRAS, and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86-1.46; P = .38) in patients with mutated KRAS, with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1-2.8; P < .001) and failure to complete 12 cycles (33% vs 23%; OR, 1.6; 95% CI, 1.4-1.9; P < .001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older. Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival. clinicaltrials.gov Identifier: NCT00079274.
    JAMA The Journal of the American Medical Association 04/2012; 307(13):1383-93. · 29.98 Impact Factor
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    ABSTRACT: The epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) pathways play key and often complementary roles in the pathogenesis of colorectal cancer (CRC). This study explores the clinical and biological effects of combined blockade of these pathways. Cetuximab-naive patients with refractory CRC were treated with cetuximab (400 mg/m loading dose followed by weekly cetuximab at 250 mg/m) and celecoxib (200 mg orally twice daily). Urinary PGE-M, a stable metabolite of PGE2 that correlates with in vivo COX-2 activity, and serum TGF-α, a ligand that binds to EGFR, were measured serially to assess the biological effect of COX-2 and EGFR blockade. Seventeen patients accrued in this study. Of the 13 patients evaluable for response, 2 (15.4%) had confirmed partial responses, 4 (30.8%) had stable disease, and 7 (53.8%) had progressive disease. The median progression-free survival for all evaluable patients was 55 days (95% confidence interval, 45-112; range, 10-295 d). This study was terminated early owing to lack of sufficient clinical activity. There were no statistically significant differences in serum TGF-α or urinary PGE-M between cycles in responders or nonresponders. This regimen resulted in response rates similar to those published for cetuximab monotherapy in patients with recurrent CRC. Apart from a higher than expected rate of infusion reactions, no other unexpected toxicities were observed. No differences in serum TGF-α or urinary PGE-M between cycles were seen, suggesting that the appropriate targets may not have been hit.
    American journal of clinical oncology 01/2011; 34(6):581-6. · 2.21 Impact Factor
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    ABSTRACT: Panitumumab is a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS) in chemotherapy-refractory metastatic colorectal cancer (mCRC). This trial evaluated the efficacy and safety of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone after failure of initial treatment for mCRC by tumor KRAS status. Patients with mCRC, one prior chemotherapy regimen for mCRC, Eastern Cooperative Oncology Group performance status 0 to 2, and available tumor tissue for biomarker testing were randomly assigned 1:1 to panitumumab 6.0 mg/kg plus FOLFIRI versus FOLFIRI every 2 weeks. The coprimary end points of PFS and overall survival (OS) were independently tested and prospectively analyzed by KRAS status. From June 2006 to March 2008, 1,186 patients were randomly assigned 1:1 and received treatment. KRAS status was available for 91% of patients: 597 (55%) with wild-type (WT) KRAS tumors, and 486 (45%) with mutant (MT) KRAS tumors. In the WT KRAS subpopulation, when panitumumab was added to chemotherapy, a significant improvement in PFS was observed (hazard ratio [HR] = 0.73; 95% CI, 0.59 to 0.90; P = .004); median PFS was 5.9 months for panitumumab-FOLFIRI versus 3.9 months for FOLFIRI. A nonsignificant trend toward increased OS was observed; median OS was 14.5 months versus 12.5 months, respectively (HR = 0.85, 95% CI, 0.70 to 1.04; P = .12); response rate was improved to 35% versus 10% with the addition of panitumumab. In patients with MT KRAS, there was no difference in efficacy. Adverse event rates were generally comparable across arms with the exception of known toxicities associated with anti-EGFR therapy. Panitumumab plus FOLFIRI significantly improved PFS and is well-tolerated as second-line treatment in patients with WT KRAS mCRC.
    Journal of Clinical Oncology 10/2010; 28(31):4706-13. · 18.04 Impact Factor
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    ABSTRACT: Standard therapy for stage II/III rectal cancer consists of a fluoropyrimidine and radiation therapy followed by surgery. Preclinical data demonstrated that bortezomib functions as a radiosensitizer in colorectal cancer models. The purpose of this study was to determine the maximum tolerated dose (MTD) of bortezomib in combination with chemotherapy and radiation. Patients with locally advanced rectal adenocarcinomas, as staged by endoscopic ultrasound, were eligible. Bortezomib was administered on days 1, 4, 8, and 11 every 21 days for 2 cycles with 5-fluorouracil at 225 mg/m2/day continuously and 50.4 Gy of radiation. Dose escalation of bortezomib was conducted via a standard 3 + 3 dose escalation design. A subset of patients underwent serial tumor biopsies for correlative studies. Nine patients in 2 dose cohorts were enrolled. Diarrhea was the principal dose-limiting toxicity and occurred at the 1.0-mg/m2 dose level. There was no clear evidence of suppression of nuclear factor-kappaB target gene expression in biopsy samples. The MTD of bortezomib in combination with chemotherapy and radiation may be below a clinically relevant dose, limiting the clinical applicability of this combination. Performing biopsies before and during irradiation for determining gene expression in response to radiation therapy is feasible.
    Clinical Colorectal Cancer 04/2010; 9(2):119-25. · 1.80 Impact Factor

Publication Stats

519 Citations
181.29 Total Impact Points

Institutions

  • 2013
    • Sarah Cannon Research Institute
      Nashville, Tennessee, United States
    • Gateway-Vanderbilt Cancer Treatment Center
      Clarksville, Tennessee, United States
  • 2007–2012
    • Vanderbilt University
      • • Department of Medicine
      • • Department of Veterans Affairs
      • • Division of Hematology and Oncology
      Nashville, MI, United States