PubMed:23632474 JSONTXT

{"project":"DisGeNET5_gene_disease","denotations":[{"id":"23632474-0#23#26#gene3098","span":{"begin":23,"end":26},"obj":"gene3098"},{"id":"23632474-0#72#76#gene2064","span":{"begin":72,"end":76},"obj":"gene2064"},{"id":"23632474-0#86#110#diseaseC0278488","span":{"begin":86,"end":110},"obj":"diseaseC0278488"},{"id":"23632474-15#83#87#gene2064","span":{"begin":2512,"end":2516},"obj":"gene2064"},{"id":"23632474-15#97#110#diseaseC0006142","span":{"begin":2526,"end":2539},"obj":"diseaseC0006142"},{"id":"23632474-15#97#110#diseaseC0678222","span":{"begin":2526,"end":2539},"obj":"diseaseC0678222"}],"relations":[{"id":"23#26#gene309886#110#diseaseC0278488","pred":"associated_with","subj":"23632474-0#23#26#gene3098","obj":"23632474-0#86#110#diseaseC0278488"},{"id":"72#76#gene206486#110#diseaseC0278488","pred":"associated_with","subj":"23632474-0#72#76#gene2064","obj":"23632474-0#86#110#diseaseC0278488"},{"id":"83#87#gene206497#110#diseaseC0006142","pred":"associated_with","subj":"23632474-15#83#87#gene2064","obj":"23632474-15#97#110#diseaseC0006142"},{"id":"83#87#gene206497#110#diseaseC0678222","pred":"associated_with","subj":"23632474-15#83#87#gene2064","obj":"23632474-15#97#110#diseaseC0678222"}],"text":"Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer.\nINTRODUCTION: Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours.\nMETHODS: This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer.\nRESULTS: Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m(-2) on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1-147.3 weeks). Common treatment-emergent adverse events (all grades/grade ≥3) included diarrhoea (92%/29%; none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9-81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan-Meier median progression-free survival was 57.0 weeks (95% CI: 47.7-81.6 weeks). Pharmacokinetic analyses indicated no interaction between neratinib and paclitaxel.\nCONCLUSION: The combination of neratinib and paclitaxel was associated with higher toxicity than that of neratinib as a single agent, but was manageable with antidiarrhoeal agents and dose reductions in general. The combination therapy also demonstrated a high rate of response in patients with HER2-positive breast cancer. A phase III trial is ongoing to assess the benefit and risk of this combination in the first-line setting."}

{"project":"DisGeNET","denotations":[{"id":"T0","span":{"begin":692,"end":696},"obj":"gene:2064"},{"id":"T1","span":{"begin":706,"end":719},"obj":"disease:C0006142"},{"id":"T2","span":{"begin":692,"end":696},"obj":"gene:2064"},{"id":"T3","span":{"begin":706,"end":719},"obj":"disease:C0678222"}],"relations":[{"id":"R1","pred":"associated_with","subj":"T0","obj":"T1"},{"id":"R2","pred":"associated_with","subj":"T2","obj":"T3"}],"namespaces":[{"prefix":"gene","uri":"http://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"disease","uri":"http://purl.bioontology.org/ontology/MEDLINEPLUS/"}],"text":"Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer.\nINTRODUCTION: Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours.\nMETHODS: This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer.\nRESULTS: Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m(-2) on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1-147.3 weeks). Common treatment-emergent adverse events (all grades/grade ≥3) included diarrhoea (92%/29%; none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9-81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan-Meier median progression-free survival was 57.0 weeks (95% CI: 47.7-81.6 weeks). Pharmacokinetic analyses indicated no interaction between neratinib and paclitaxel.\nCONCLUSION: The combination of neratinib and paclitaxel was associated with higher toxicity than that of neratinib as a single agent, but was manageable with antidiarrhoeal agents and dose reductions in general. The combination therapy also demonstrated a high rate of response in patients with HER2-positive breast cancer. A phase III trial is ongoing to assess the benefit and risk of this combination in the first-line setting."}

{"project":"Allie","denotations":[{"id":"SS1_23632474_2_0","span":{"begin":288,"end":326},"obj":"expanded"},{"id":"SS2_23632474_2_0","span":{"begin":328,"end":331},"obj":"abbr"},{"id":"SS1_23632474_5_0","span":{"begin":495,"end":517},"obj":"expanded"},{"id":"SS2_23632474_5_0","span":{"begin":519,"end":522},"obj":"abbr"},{"id":"SS1_23632474_13_0","span":{"begin":1606,"end":1627},"obj":"expanded"},{"id":"SS2_23632474_13_0","span":{"begin":1629,"end":1632},"obj":"abbr"},{"id":"SS1_23632474_13_1","span":{"begin":1647,"end":1666},"obj":"expanded"},{"id":"SS2_23632474_13_1","span":{"begin":1668,"end":1670},"obj":"abbr"}],"relations":[{"id":"AE1_23632474_2_0","pred":"abbreviatedTo","subj":"SS1_23632474_2_0","obj":"SS2_23632474_2_0"},{"id":"AE1_23632474_5_0","pred":"abbreviatedTo","subj":"SS1_23632474_5_0","obj":"SS2_23632474_5_0"},{"id":"AE1_23632474_13_0","pred":"abbreviatedTo","subj":"SS1_23632474_13_0","obj":"SS2_23632474_13_0"},{"id":"AE1_23632474_13_1","pred":"abbreviatedTo","subj":"SS1_23632474_13_1","obj":"SS2_23632474_13_1"}],"text":"Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer.\nINTRODUCTION: Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours.\nMETHODS: This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer.\nRESULTS: Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m(-2) on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1-147.3 weeks). Common treatment-emergent adverse events (all grades/grade ≥3) included diarrhoea (92%/29%; none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9-81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan-Meier median progression-free survival was 57.0 weeks (95% CI: 47.7-81.6 weeks). Pharmacokinetic analyses indicated no interaction between neratinib and paclitaxel.\nCONCLUSION: The combination of neratinib and paclitaxel was associated with higher toxicity than that of neratinib as a single agent, but was manageable with antidiarrhoeal agents and dose reductions in general. The combination therapy also demonstrated a high rate of response in patients with HER2-positive breast cancer. A phase III trial is ongoing to assess the benefit and risk of this combination in the first-line setting."}

{"project":"PubmedHPO","denotations":[{"id":"T1","span":{"begin":344,"end":357},"obj":"HP_0003002"},{"id":"T2","span":{"begin":344,"end":357},"obj":"HP_0100013"},{"id":"T3","span":{"begin":351,"end":357},"obj":"HP_0002664"},{"id":"T4","span":{"begin":374,"end":381},"obj":"HP_0002664"}],"text":"Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer.\nINTRODUCTION: Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours.\nMETHODS: This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer.\nRESULTS: Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m(-2) on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1-147.3 weeks). Common treatment-emergent adverse events (all grades/grade ≥3) included diarrhoea (92%/29%; none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9-81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan-Meier median progression-free survival was 57.0 weeks (95% CI: 47.7-81.6 weeks). Pharmacokinetic analyses indicated no interaction between neratinib and paclitaxel.\nCONCLUSION: The combination of neratinib and paclitaxel was associated with higher toxicity than that of neratinib as a single agent, but was manageable with antidiarrhoeal agents and dose reductions in general. The combination therapy also demonstrated a high rate of response in patients with HER2-positive breast cancer. A phase III trial is ongoing to assess the benefit and risk of this combination in the first-line setting."}