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dc.contributor.authorDean, Emma J
dc.contributor.authorJodrell, Duncan
dc.contributor.authorConnolly, Kate
dc.contributor.authorDanson, Sarah
dc.contributor.authorJolivet, Jacques
dc.contributor.authorDurkin, J
dc.contributor.authorMorris, Stephen
dc.contributor.authorJowle, Debra
dc.contributor.authorWard, Timothy H
dc.contributor.authorCummings, Jeffrey
dc.contributor.authorDickinson, Gemma
dc.contributor.authorAarons, Leon
dc.contributor.authorLacasse, Eric
dc.contributor.authorRobson, Lesley
dc.contributor.authorDive, Caroline
dc.contributor.authorRanson, Malcolm R
dc.date.accessioned2009-06-05T10:09:02Z
dc.date.available2009-06-05T10:09:02Z
dc.date.issued2009-04-01
dc.identifier.citationPhase I trial of AEG35156 administered as a 7-day and 3-day continuous intravenous infusion in patients with advanced refractory cancer. 2009, 27 (10):1660-6 J. Clin. Oncol.en
dc.identifier.issn1527-7755
dc.identifier.pmid19237630
dc.identifier.doi10.1200/JCO.2008.19.5677
dc.identifier.urihttp://hdl.handle.net/10541/69777
dc.description.abstractPURPOSE: To establish the maximum-tolerated dose and evaluate tolerability, pharmacokinetics, pharmacodynamic effects, and antitumor activity of AEG35156, a second-generation antisense to X-linked inhibitor of apoptosis (XIAP) protein, in patients with advanced refractory malignant tumors. PATIENTS AND METHODS: This was a first-in-man, open-label, phase I dose-escalation study. AEG35156 was administered by continuous intravenous infusion over 7 days (7DI) or 3 days (3DI) of a 21-day treatment cycle. Dose escalation started at 48 mg/m(2)/d and continued until consistent dose-limiting toxicity (DLT) was observed. RESULTS: Thirty-eight patients were entered in seven cohorts. Grade 3 to 4 adverse events were uncommon and were predominantly abnormal laboratory values: elevated ALT, thrombocytopenia, and lymphopenia. DLTs comprised elevated hepatic enzymes, hypophosphatemia, and thrombocytopenia. The maximum-tolerated doses were defined as 125 mg/m(2)/d for the 7DI regimen and < or = 213 mg/m(2)/d for the 3DI schedule. AEG35156 area under the plasma concentration curve and peak plasma concentration increased proportionally with dose. Suppression of XIAP mRNA levels was maximal at 72 hours (mean suppression, 21%), and this coincided with a dramatic decrease in circulating tumor cells in a patient with non-Hodgkin's lymphoma. Two further patients had unconfirmed partial responses. Circulating biomarkers of cell death and apoptosis altered in association with drug infusion and toxicity. CONCLUSION: In this first-in-man study, AEG35156 was well tolerated, with predictable toxicities, pharmacokinetic properties, and clinical evidence of antitumor activity in patients with refractory lymphoma, melanoma, and breast cancer. Phase I/II trials of AEG35156 chemotherapy combinations are ongoing in patients with pancreatic, breast, non-small-cell lung cancer, acute myeloid leukemia, lymphoma, and solid tumors for which docetaxel is indicated.
dc.language.isoenen
dc.subjectRefractory Canceren
dc.subjectDrug Therapyen
dc.subjectAntitumour Activityen
dc.subject.meshAntineoplastic Agents
dc.subject.meshFemale
dc.subject.meshGene Expression
dc.subject.meshHumans
dc.subject.meshInfusions, Intravenous
dc.subject.meshMale
dc.subject.meshMaximum Tolerated Dose
dc.subject.meshNeoplasms
dc.subject.meshOligonucleotides
dc.subject.meshOligonucleotides, Antisense
dc.subject.meshX-Linked Inhibitor of Apoptosis Protein
dc.titlePhase I trial of AEG35156 administered as a 7-day and 3-day continuous intravenous infusion in patients with advanced refractory cancer.en
dc.typeArticleen
dc.contributor.departmentChristie Hospital National Health Service Foundation Trust, Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research, and School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK.en
dc.identifier.journalJournal of Clinical Oncologyen
html.description.abstractPURPOSE: To establish the maximum-tolerated dose and evaluate tolerability, pharmacokinetics, pharmacodynamic effects, and antitumor activity of AEG35156, a second-generation antisense to X-linked inhibitor of apoptosis (XIAP) protein, in patients with advanced refractory malignant tumors. PATIENTS AND METHODS: This was a first-in-man, open-label, phase I dose-escalation study. AEG35156 was administered by continuous intravenous infusion over 7 days (7DI) or 3 days (3DI) of a 21-day treatment cycle. Dose escalation started at 48 mg/m(2)/d and continued until consistent dose-limiting toxicity (DLT) was observed. RESULTS: Thirty-eight patients were entered in seven cohorts. Grade 3 to 4 adverse events were uncommon and were predominantly abnormal laboratory values: elevated ALT, thrombocytopenia, and lymphopenia. DLTs comprised elevated hepatic enzymes, hypophosphatemia, and thrombocytopenia. The maximum-tolerated doses were defined as 125 mg/m(2)/d for the 7DI regimen and < or = 213 mg/m(2)/d for the 3DI schedule. AEG35156 area under the plasma concentration curve and peak plasma concentration increased proportionally with dose. Suppression of XIAP mRNA levels was maximal at 72 hours (mean suppression, 21%), and this coincided with a dramatic decrease in circulating tumor cells in a patient with non-Hodgkin's lymphoma. Two further patients had unconfirmed partial responses. Circulating biomarkers of cell death and apoptosis altered in association with drug infusion and toxicity. CONCLUSION: In this first-in-man study, AEG35156 was well tolerated, with predictable toxicities, pharmacokinetic properties, and clinical evidence of antitumor activity in patients with refractory lymphoma, melanoma, and breast cancer. Phase I/II trials of AEG35156 chemotherapy combinations are ongoing in patients with pancreatic, breast, non-small-cell lung cancer, acute myeloid leukemia, lymphoma, and solid tumors for which docetaxel is indicated.


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