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    <recommendedItem id="20100101_19_260"
                     title="ASCO GI: Agent Targets IGF Receptor in Pancreatic Cancer (CME/CE)"
                     score="0.002"
                     href="http://www.medpagetoday.com/MeetingCoverage/ASCOGI/tb/18124?impressionId=1265755559987"
                     
      &lt;p&gt;ORLANDO  --  A majority of patients with advanced pancreatic cancer had objective responses or stable disease when treated with an inhibitor of the insulin-like growth factor (IGF) receptor, according to data from a small clinical trial reported here.&lt;/p&gt;
&lt;p&gt;A fourth of patients had partial responses that lasted beyond 11 months in some cases. Another third had disease stabilization during treatment with the monoclonal antibody MK-0646, plus chemotherapy and erlotinib (Tarceva).&lt;/p&gt;
&lt;p&gt;&quot;We observed sustained partial responses with two different regimens,&quot; Milind Javle, MD, of M.D. Anderson Cancer Center in Houston, told attendees at the Gastrointestinal Cancers Symposium.&lt;/p&gt;
&lt;p&gt;&quot;Evaluation of MK-0646 is continuing in a randomized phase II study that will include correlative studies to identify predictive markers.&quot;&lt;/p&gt;
&lt;p&gt;Activation of the IGF-1 receptor is associated with an aggressive disease course in pancreatic cancer and acquired resistance to agents that target epidermal growth factor receptor (EGFR) such as erlotinib.&lt;/p&gt;
&lt;p&gt;&lt;/p&gt;
&lt;p&gt; &lt;/p&gt;
&lt;p&gt;Preclinical studies showed that combining an IGF-1 receptor antagonist and cetuximab (Erbitux) had synergistic activity against pancreatic cell lines, Javle said.&lt;/p&gt;
&lt;p&gt;MK-0646 preferentially binds IGF-1 receptor and not the insulin receptor. The antibody inhibits stimulation of IGF-1 receptor by both IGF-1 and IGF-2, Javle continued. MK-0646 downregulates expression of IGF-1 receptor in tumor models and has demonstrated antitumor activity in xenograft models.&lt;/p&gt;
&lt;p&gt;Phase I evaluation of MK-0646 as a single agent showed the antibody was well tolerated and led to downregulation of IGF-1 receptor and other molecules associated with tumor growth. Patients occasionally developed hyperglycemia, which was controlled with oral hypoglycemic agents.&lt;/p&gt;
&lt;p&gt;Javle reported data from a phase I-II study of MK-0646 in combination with gemcitabine (Gemzar) or gemcitabine plus erlotinib. The primary objective of the first phase was to determine the maximum tolerated dose of MK-0646 in combination therapy. Investigators assessed progression-free survival (PFS) of the two combination arms in the second phase.&lt;/p&gt;
&lt;p&gt;The study included patients with stage IV pancreatic adenocarcinoma at least six months after completion of adjuvant chemotherapy.&lt;/p&gt;
&lt;p&gt;Patients were enrolled in a nonrandomized, sequential manner to two treatment arms. One arm had a regimen consisting of weekly gemcitabine plus weekly MK-0646 at either 5 mg/kg or 10 mg/kg. In the second arm, patients received gemcitabine plus daily erlotinib and one of the two doses of MK-0646.&lt;/p&gt;
&lt;p&gt;Dose-limiting hematologic toxicity was defined as grade 4 thrombocytopenia, grade 4 neutropenia lasting at least seven days, or grade 3 or higher neutropenia with fever.&lt;/p&gt;
&lt;p&gt;Dose-limiting nonhematologic toxicity was defined as any grade 3-4 adverse event except rash and controlled hyperglycemia. Delayed dosing was defined as a delay of more than 14 days necessitated by toxicity.&lt;/p&gt;
&lt;p&gt;Of 28 patients enrolled in the study, 23 (82%) required dose adjustment of gemcitabine, and seven had toxicity-associated dose adjustments of erlotinib. Five patients discontinued erlotinib because of toxicity, but no patient withdrew from the study because of toxicity.&lt;/p&gt;
&lt;p&gt;The most frequent grade 3-4 nonhematologic toxicities were hyperglycemia and fatigue (five patients each) and elevated liver enzymes and hypermagnesemia (four each). Half the patients developed grade 3-4 neutropenia and five had grade 3-4 thrombocytopenia. No cases of febrile neutropenia occurred.&lt;/p&gt;
&lt;p&gt;Maximum tolerated dose (MTD) in the first arm was not reached at the 10 mg/kg dose of MK-0646. In the erlotinib arm, MTD was reached at the 5 mg/kg dose of MK-0646.&lt;/p&gt;
&lt;p&gt;Of 24 patients evaluable for response, six (25%) had partial responses and eight (33%) had stable disease. The remaining 10 patients had progressive disease. Response duration ranged from 14 to beyond 44 weeks. Time to progression did not differ between the treatment arms.&lt;/p&gt;
&lt;p&gt;A randomized phase II study of MK-0646 has already begun, said Javle. Patients receive one of three treatment regimens: gemcitabine plus the monoclonal antibody, with or without erlotinib, or control therapy with gemcitabine and erlotinib.&lt;/p&gt;
&lt;p&gt;The activity demonstrated in the study does not constitute an antitumor signal for MK-0646, Philip A. Philip, MD, of the Karmanos Cancer Center in Detroit, said during a formal discussion of the study.&lt;/p&gt;
&lt;p&gt;&quot;Further preclinical and clinical validation of and IGF-1 receptor-based multitargeted strategy in pancreatic cancer must be undertaken,&quot; he said. &quot;Additionally, predictive biomarkers must be developed for patient selection and stratification. We need more data before we begin to design a phase III study.&quot;&lt;/p&gt;
&lt;p&gt;Hyperglycemia with MK-0646 should not come as a surprise, Philip said. The IGF-1 receptor occurring on normal cells has 84% homology with insulin receptor.&lt;/p&gt;
&lt;p&gt;&quot;There will be overlap between IGF-1 receptor and insulin receptor when targeting IGF-1 receptor,&quot; said Philip. &quot;Moreover, up to 40% of patients with pancreatic cancer have diabetes mellitus.&quot;&lt;/p&gt;
&lt;p&gt;In an ongoing intergroup trial involving a different IGF-1 receptor inhibitor, almost half the patients developed grade 1 or 2 hyperglycemia, and 14% developed grade 3 or 4, he added. However, hyperglycemia does not appear to be a dose-limiting toxicity.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The study was supported by Merck.&lt;/p&gt;&lt;p&gt;One or more investigators in the study disclosed relationships with Merck.&lt;/p&gt;&lt;p&gt;Philip disclosed relationships with Bristol-Myers Squibb, ImClone, OSIP, sanofi-aventis, Genentech, Pfizer, Lilly, and Roche.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_154"
                     title="AACR-IASLC: Smoking Boosts Tolerance for EGFR Drug (CME/CE)"
                     score="-0.005"
                     href="http://www.medpagetoday.com/MeetingCoverage/AACR-IASLC/tb/17981?impressionId=1265755559987"
                     
      &lt;p&gt;CORONADO, Calif.  --  Current smokers can tolerate significantly higher doses of the epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors, according to preliminary trial results.&lt;/p&gt;
&lt;p&gt;Smokers&apos; maximum tolerated erlotinib (Tarceva) doses reached up to 525 mg  --  far above the standard 150 mg  --  with a median of 300 mg, found Lynsay Waller, MD, of Wake Forest University in Winston-Salem, N.C., and colleagues.&lt;/p&gt;
&lt;p&gt;Former and nonsmokers in the trial topped out at 225 mg, which was also the median dose (&lt;em&gt;P&lt;/em&gt;=0.03 versus current smokers).&lt;/p&gt;
&lt;p&gt;The key question is whether escalating the dose will improve outcomes for smokers, Waller said.&lt;/p&gt;
&lt;p&gt;That&apos;s something the phase II study aims to eventually determine  --  progression-free survival is the primary endpoint.&lt;/p&gt;
&lt;p&gt;But those results weren&apos;t available for the interim analysis presented here at the Joint Conference on Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.&lt;/p&gt;
&lt;p&gt;While it&apos;s tempting to consider upping the dose for smokers, in the absence of any data showing a benefit, physicians should focus their efforts on getting smokers to quit the habit, commented Paul A. Bunn, Jr., MD, of the University of Colorado Denver.&lt;/p&gt;
&lt;p&gt;Nevertheless, the findings should come as little surprise based on prior studies, he and Waller agreed.&lt;/p&gt;
&lt;p&gt;&quot;Smokers metabolize erlotinib at a faster rate than nonsmokers and require a higher dose to achieve equivalent plasma levels,&quot; she told &lt;em&gt;MedPage Today&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;Smoking appears to elevate levels of a liver enzyme involved in metabolizing the drug, she explained.&lt;/p&gt;
&lt;p&gt;Early studies with erlotinib suggested greater toxicity at higher doses but whether it was accompanied by greater efficacy wasn&apos;t certain, Bunn said.&lt;/p&gt;
&lt;p&gt;Waller&apos;s group designed a rapid dose escalation schema for individualizing erlotinib doses, a task that has proven challenging &quot;due to the frequent progression of cancer prior to achieving each patient&apos;s maximal tolerated dose.&quot;&lt;/p&gt;
&lt;p&gt;Their phase II study included 25 patients with metastatic non-small cell lung cancer given four cycles of dose-dense chemotherapy (75 mg/m&lt;sup&gt;2&lt;/sup&gt; of both docetaxel [Taxotere] and cisplatin [Platinol] on day one of an every two week cycle) with growth factor support.&lt;/p&gt;
&lt;p&gt;Patients then got erlotinib at an initial dose of 150 mg per day for nonsmokers and former smokers or 300 mg daily for current smokers (21% of the cohort). The dose was escalated by 75 mg every two weeks until a grade 2 or higher nonhematologic adverse event occurred.&lt;/p&gt;
&lt;p&gt;Grade 3 or 4 toxicity prompted a hold on dosing until resolution, then dose de-escalation by 75 mg per day.&lt;/p&gt;
&lt;p&gt;This strategy appeared safe, with no grade 4 or 5 toxicity related to erlotinib, the researchers said.&lt;/p&gt;
&lt;p&gt;Maximum tolerated daily erlotinib doses ranged from 300 to 525 mg among smokers and 150 to 225 mg among nonsmokers. Medians didn&apos;t differ by gender.&lt;/p&gt;
&lt;p&gt;The two most common dose-limiting toxicities were grade 2 rash and grade 2 diarrhea (23.5% for each), followed by less severe rash and/or diarrhea (17.6% for each), and finally dehydration (5.9%). Disease progression occurred in 11.8% of cases. &lt;ul&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;These findings would likely generalize to gefitinib (Iressa), which is a similar compound, though not FDA approved, Bunn said.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The study was sponsored by OSI Pharmaceuticals.&lt;/p&gt;&lt;p&gt;Waller reported no conflicts of interest.&lt;/p&gt;&lt;p&gt;Bunn reported having consulted for OSI Pharmaceuticals and Genentech.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
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                     title="Sunlight exposure reduces lymphoma risk"
                     score="-0.006"
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