Phase I multicenter trial of BMS-690514: Safety, pharmacokinetic profile, biological effects, and early clinical evaluation in patients with advanced solid tumors and non-small cell lung cancer

Bahleda, Ratio; Felip, Enriqueta; Herbst, Ronald; Hanna, Nasser H.; Laurie, Scott A.; Shepherd, Frances A.; Armand, Jean‐Pierre; Sweeney, C. J.; Calvo-Aller, E.; Soria, J-C.

doi:10.1200/jco.2008.26.15_suppl.2564

Cited by 15 publications

(12 citation statements)

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“…BMS-690514 is currently under development as an oral agent for the treatment of patients with NSCLC, metastatic breast cancer, and other solid tumor malignancies. BMS-690514 showed evidence of antitumor activity and disease control in a phase I/II study of 62 patients with advanced NSCLC, including those with erlotinib resistance and those with wild-type EGFR, Exon 19-and 21-activating EGFR mutations, EGFR T790M, or K-ras mutations (Bahleda et al, 2008(Bahleda et al, , 2009). BMS-690514 was generally well tolerated with manageable side effects.…”

Section: Introductionmentioning

confidence: 99%

“…dose. The selection of a 200-mg dose was based on the maximum tolerated dose identified in a previous clinical study in patients with cancer (Bahleda et al, 2008). Because biliary excretion was an important pathway for elimination of drug-related radioactivity in rats and dogs and glucuronidation was a major metabolic pathway observed in incubations with human hepatocytes, bile was collected from three subjects to evaluate the role of direct glucuronidation in the overall metabolism of the compound in humans.…”

Section: Introductionmentioning

confidence: 99%

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Metabolism and Disposition of [¹⁴C]BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor, after Oral Administration to Humans

Christopher¹,

Hong²,

Vakkalagadda³

et al. 2010

Drug Metab Dispos

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(3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-3-piperidinol (BMS-690514), an oral selective inhibitor of human epidermal growth factor receptors 1 (or epidermal growth factor receptor), 2, and 4, and vascular endothelial growth factor receptors 1, 2, and 3, is being developed as a treatment for patients with non-small-cell lung cancer and metastatic breast cancer. The disposition of [ 14 C]BMS-690514 was investigated in nine healthy male subjects (group 1, n ‫؍‬ 6; group 2, n ‫؍‬ 3) after oral administration of a 200-mg dose. Urine, feces, and plasma were collected from all subjects for up to 12 days postdose. In group 2 subjects, bile was collected from 3 to 8 h postdose. Across groups, approximately 50 and 34% of administered radioactivity was recovered in the feces and urine, respectively. An additional 16% was recovered in the bile of group 2 subjects. Less than 28% of the dose was recovered as parent drug in the combined excreta, suggesting that BMS-690514 was highly metabolized. BMS-690514 was rapidly absorbed (median time of maximum observed concentration 0.5 h) with the absorbed fraction estimated to be approximately 50 to 68%. BMS-690514 represented <7.9% of the area under the concentration-time curve from time 0 extrapolated to infinite time of plasma radioactivity, indicating that the majority of the circulating radioactivity was from metabolites. BMS-690514 was metabolized via multiple oxidation reactions and direct glucuronidation. Circulating metabolites included a hydroxylated rearrangement product (M1), a direct ether glucuronide (M6), and multiple secondary glucuronide conjugates. None of these metabolites is expected to contribute to the pharmacology of BMS-690514. In summary, BMS-690514 was well absorbed and extensively metabolized via multiple metabolic pathways in humans, with excretion of drug-related radioactivity in both bile and urine.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metabolism and Disposition of [¹⁴C]BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor, after Oral Administration to Humans

Christopher¹,

Hong²,

Vakkalagadda³

et al. 2010

Drug Metab Dispos

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“…BMS-690514, is another pan-HER inhibitor that includes inhibitory activity for all three VEGF receptors [185]. Pharmacokinetic and Phase I studies have been reported identifying the maximum-tolerated dose of 200 mg daily [186][187][188][189][190]. In contrast to AEE788, BMS-690514 appears to have significant antiangiogenic activity by toxicity profile and biomarker analyses [186,191].…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

“…Pharmacokinetic and Phase I studies have been reported identifying the maximum-tolerated dose of 200 mg daily [186][187][188][189][190]. In contrast to AEE788, BMS-690514 appears to have significant antiangiogenic activity by toxicity profile and biomarker analyses [186,191]. There is also evidence for synergism with radiation when BMS-690514 is administered in sequence with radiation [192].…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium

Nelson¹

2014

Clinical Investigation

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“…Of 85 patients treated, 50 (59%) received single-agent targeted phase I therapy [15][16][17][18][19][20][21][22][23], 14 (16%) received a combination of targeted agents, 13 (15%) received chemotherapy combined with targeted agents [24,25], and eight (10%) received chemotherapy alone (Table 2) [26]. None of the patients was treated in a genotype-specific trial such as with anti-epidermal growth factor receptor (EGFR) therapy in patients with tumors harboring EGFR mutations or antianaplastic lymphoma kinase (ALK) therapy in tumors with EML4 -ALK fusion.…”

Section: Treatmentmentioning

confidence: 99%

Outcomes of Patients with Advanced Non-Small Cell Lung Cancer Treated in a Phase I Clinic

et al. 2011

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Results. Eighty-five patients (51 men, 34 women) treated on various phase I protocols were identified. The median age was 62 years (range, 30 -85). The median number of previous systemic therapies was two (range, 0 -5). A partial response was observed in eight patients (9.5%) and stable disease lasting >4 months was observed in 16 patients (19%). The median overall survival time was 10.6 months and median progressionfree survival (PFS) time was 2.8 months, which was 0.6 months shorter than the median PFS of 3.4 months following prior second-line therapy. Factors predicting

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Phase I multicenter trial of BMS-690514: Safety, pharmacokinetic profile, biological effects, and early clinical evaluation in patients with advanced solid tumors and non-small cell lung cancer

Cited by 15 publications

References 0 publications

Metabolism and Disposition of [¹⁴C]BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor, after Oral Administration to Humans

Metabolism and Disposition of [¹⁴C]BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor, after Oral Administration to Humans

HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium

Outcomes of Patients with Advanced Non-Small Cell Lung Cancer Treated in a Phase I Clinic

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Phase I multicenter trial of BMS-690514: Safety, pharmacokinetic profile, biological effects, and early clinical evaluation in patients with advanced solid tumors and non-small cell lung cancer

Cited by 15 publications

References 0 publications

Metabolism and Disposition of [14C]BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor, after Oral Administration to Humans

Metabolism and Disposition of [14C]BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor, after Oral Administration to Humans

HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium

Outcomes of Patients with Advanced Non-Small Cell Lung Cancer Treated in a Phase I Clinic

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Product

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Metabolism and Disposition of [¹⁴C]BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor, after Oral Administration to Humans

Metabolism and Disposition of [¹⁴C]BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor, after Oral Administration to Humans