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Liang Fang - One of the best experts on this subject based on the ideXlab platform.
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drug interaction potential of trastuzumab emtansine t dm1 combined with pertuzumab in patients with her2 positive metastatic breast cancer
Current Drug Metabolism, 2012Co-Authors: Dan Lu, Howard A Burris, Bei Wang, Claire E Dees, Javier Cortes, Amita Joshi, Manish Gupta, Joohee Yi, Ted Shih, Liang FangAbstract:Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprised of trastuzumab and the cytotoxic Agent DM1 (derivative of maytansine) linked by a stable linker N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC). T-DM1 targets an epitope located at subdomain IV of human epidermal growth factor receptor 2 (HER2). Pertuzumab is a monoclonal antibody that targets an epitope located at subdomain II of HER2, distinct from the epitope recognized by T-DM1. The pharmacokinetics (PK), safety, and efficacy of T-DM1 combined with pertuzumab were studied in a phase 1b/2 trial in 67 patients with HER2-positive, locally advanced or metastatic breast cancer (MBC). The therapeutic protein-drug interaction (TP-DI) potential of T-DM1 plus pertuzumab was evaluated. The PK of T-DM1–related analytes and pertuzumab were compared with historical PK data. The results show that the exposure of T-DM1 and DM1, as estimated by noncompartmental analyses, was comparable with that reported by historical single-Agent studies in patients with HER2-positive MBC. T-DM1 clearance and volume of distribution in the central compartment, as estimated by population PK analysis, were also comparable between this Study and historical single-Agent studies in patients with HER2-positive MBC. Summary statistics of pertuzumab trough and maximal exposure (concentrations at predose and 15–30 minutes after the end of infusion at cycle 1 and at steady state) were similar with those observed in a representative historical single-Agent Study with the same dosing regimen. The visual predictive check plot by population simulation further confirmed that T-DM1 did not alter pertuzumab PK. Based on these data and the PK and pharmacodynamic properties of T-DM1 and pertuzumab, the risk of TP-DI appears to be low when T-DM1 and pertuzumab are given together.
Dan Lu - One of the best experts on this subject based on the ideXlab platform.
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drug interaction potential of trastuzumab emtansine t dm1 combined with pertuzumab in patients with her2 positive metastatic breast cancer
Current Drug Metabolism, 2012Co-Authors: Dan Lu, Howard A Burris, Bei Wang, Claire E Dees, Javier Cortes, Amita Joshi, Manish Gupta, Joohee Yi, Ted Shih, Liang FangAbstract:Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprised of trastuzumab and the cytotoxic Agent DM1 (derivative of maytansine) linked by a stable linker N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC). T-DM1 targets an epitope located at subdomain IV of human epidermal growth factor receptor 2 (HER2). Pertuzumab is a monoclonal antibody that targets an epitope located at subdomain II of HER2, distinct from the epitope recognized by T-DM1. The pharmacokinetics (PK), safety, and efficacy of T-DM1 combined with pertuzumab were studied in a phase 1b/2 trial in 67 patients with HER2-positive, locally advanced or metastatic breast cancer (MBC). The therapeutic protein-drug interaction (TP-DI) potential of T-DM1 plus pertuzumab was evaluated. The PK of T-DM1–related analytes and pertuzumab were compared with historical PK data. The results show that the exposure of T-DM1 and DM1, as estimated by noncompartmental analyses, was comparable with that reported by historical single-Agent studies in patients with HER2-positive MBC. T-DM1 clearance and volume of distribution in the central compartment, as estimated by population PK analysis, were also comparable between this Study and historical single-Agent studies in patients with HER2-positive MBC. Summary statistics of pertuzumab trough and maximal exposure (concentrations at predose and 15–30 minutes after the end of infusion at cycle 1 and at steady state) were similar with those observed in a representative historical single-Agent Study with the same dosing regimen. The visual predictive check plot by population simulation further confirmed that T-DM1 did not alter pertuzumab PK. Based on these data and the PK and pharmacodynamic properties of T-DM1 and pertuzumab, the risk of TP-DI appears to be low when T-DM1 and pertuzumab are given together.
Ian E Krop - One of the best experts on this subject based on the ideXlab platform.
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abstract p4 15 08 a phase 1b Study of ont 380 an oral her2 specific inhibitor combined with ado trastuzumab emtansine t dm1 in her2 metastatic breast cancer mbc
Cancer Research, 2015Co-Authors: Virginia F Borges, Erika Paige Hamilton, Denise A Yardley, Jorge Chaves, Nathalie Aucoin, Cristiano Ferrario, Luke Walker, Ian E KropAbstract:Background: ONT-380 (also known as ARRY-380) is a potent, selective small molecule inhibitor of HER2 with 500-fold selectivity compared to EGFR. Preclinical studies have demonstrated synergistic activity with ONT-380 and chemotherapy or trastuzumab, as well as superior activity compared to lapatinib and neratinib in models of HER2+ CNS metastases. In a Phase 1 single Agent Study in HER2+ MBC, ONT-380 was well tolerated and provided clinical benefit with minimal EGFR-type toxicities, with an MTD of 600 mg BID using an API-in-capsule formulation. Based on the potential for dual blockade of HER2 to lead to clinical benefit, ONT-380 is being evaluated in combination with T-DM1 in patients previously treated with a taxane and trastuzumab for metastatic disease. Methods: This 3+3 dose escalation Study evaluates escalating doses of ONT-380 in a new tablet formulation combined with T-DM1 at 3.6 mg/kg IV once every 21 days. Prior treatment with trastuzumab and a taxane are required. Prior lapatinib or neratinib therapy and asymptomatic brain metastases (treated or untreated) are allowed. Previous T-DM1 is not permitted. Normal left ventricular ejection fraction and anthracycline exposure ≤ 360 mg/m2 is required. Study assessments include safety, ONT-380 and T-DM1 PK, tumor response by RECIST 1.1, and CNS response by both modified RECIST and volumetric criteria. Dose escalation will be followed by enrollment of expansion cohorts in patients with and without CNS disease. Results: As of 21 May 2014, 7 patients have been treated with ONT-380 at 300 mg BID for 1–5 cycles. One dose limiting toxicity (DLT) of Grade 3 ALT/AST elevation was seen in the ONT-380 300 mg BID cohort, requiring a dose reduction for both Agents with subsequent cohort expansion to 6 patients. No further DLTs have been seen in this cohort, and no other dose reductions have been required. Most toxicities have been Grade 1 or 2, with the most common regardless of attribution being nausea, fatigue, diarrhea, and thrombocytopenia. Two Grade 3 AEs have been reported, including the DLT of ALT/AST elevation, and one event of thrombocytopenia, considered related to T-DM1 but not ONT-380. There has been no Grade 3 diarrhea and no SAEs. In the four patients evaluable for response to date, best response has been 1PR, 2 SD, and 1 PD. Three patients with prior CNS radiation have had continued reduction in CNS lesions on Study. Initial PK data indicate greater ONT-380 exposure is achieved with the new tablet formulation compared to the earlier capsule formulation with no evidence of drug interaction with T-DM1. Conclusions: Treatment with ONT-380 and T-DM1 has been associated with an acceptable safety profile, with only one DLT and minimal Grade 3 toxicity, including no Grade 3 diarrhea or rash. Early evidence of disease control has been seen, including in patients with CNS metastases. Dose escalation continues, and updated results will be presented for additional cohorts. Citation Format: Virginia F Borges, Erika Hamilton, Denise A Yardley, Jorge Chaves, Nathalie Aucoin, Cristiano Ferrario, Luke Walker, Ian Krop. A phase 1b Study of ONT-380, an oral HER2-specific inhibitor, combined with ado-trastuzumab emtansine (T-DM1), in HER2+ metastatic breast cancer (MBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-08.
Javier Cortes - One of the best experts on this subject based on the ideXlab platform.
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drug interaction potential of trastuzumab emtansine t dm1 combined with pertuzumab in patients with her2 positive metastatic breast cancer
Current Drug Metabolism, 2012Co-Authors: Dan Lu, Howard A Burris, Bei Wang, Claire E Dees, Javier Cortes, Amita Joshi, Manish Gupta, Joohee Yi, Ted Shih, Liang FangAbstract:Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprised of trastuzumab and the cytotoxic Agent DM1 (derivative of maytansine) linked by a stable linker N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC). T-DM1 targets an epitope located at subdomain IV of human epidermal growth factor receptor 2 (HER2). Pertuzumab is a monoclonal antibody that targets an epitope located at subdomain II of HER2, distinct from the epitope recognized by T-DM1. The pharmacokinetics (PK), safety, and efficacy of T-DM1 combined with pertuzumab were studied in a phase 1b/2 trial in 67 patients with HER2-positive, locally advanced or metastatic breast cancer (MBC). The therapeutic protein-drug interaction (TP-DI) potential of T-DM1 plus pertuzumab was evaluated. The PK of T-DM1–related analytes and pertuzumab were compared with historical PK data. The results show that the exposure of T-DM1 and DM1, as estimated by noncompartmental analyses, was comparable with that reported by historical single-Agent studies in patients with HER2-positive MBC. T-DM1 clearance and volume of distribution in the central compartment, as estimated by population PK analysis, were also comparable between this Study and historical single-Agent studies in patients with HER2-positive MBC. Summary statistics of pertuzumab trough and maximal exposure (concentrations at predose and 15–30 minutes after the end of infusion at cycle 1 and at steady state) were similar with those observed in a representative historical single-Agent Study with the same dosing regimen. The visual predictive check plot by population simulation further confirmed that T-DM1 did not alter pertuzumab PK. Based on these data and the PK and pharmacodynamic properties of T-DM1 and pertuzumab, the risk of TP-DI appears to be low when T-DM1 and pertuzumab are given together.
Ted Shih - One of the best experts on this subject based on the ideXlab platform.
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drug interaction potential of trastuzumab emtansine t dm1 combined with pertuzumab in patients with her2 positive metastatic breast cancer
Current Drug Metabolism, 2012Co-Authors: Dan Lu, Howard A Burris, Bei Wang, Claire E Dees, Javier Cortes, Amita Joshi, Manish Gupta, Joohee Yi, Ted Shih, Liang FangAbstract:Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprised of trastuzumab and the cytotoxic Agent DM1 (derivative of maytansine) linked by a stable linker N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC). T-DM1 targets an epitope located at subdomain IV of human epidermal growth factor receptor 2 (HER2). Pertuzumab is a monoclonal antibody that targets an epitope located at subdomain II of HER2, distinct from the epitope recognized by T-DM1. The pharmacokinetics (PK), safety, and efficacy of T-DM1 combined with pertuzumab were studied in a phase 1b/2 trial in 67 patients with HER2-positive, locally advanced or metastatic breast cancer (MBC). The therapeutic protein-drug interaction (TP-DI) potential of T-DM1 plus pertuzumab was evaluated. The PK of T-DM1–related analytes and pertuzumab were compared with historical PK data. The results show that the exposure of T-DM1 and DM1, as estimated by noncompartmental analyses, was comparable with that reported by historical single-Agent studies in patients with HER2-positive MBC. T-DM1 clearance and volume of distribution in the central compartment, as estimated by population PK analysis, were also comparable between this Study and historical single-Agent studies in patients with HER2-positive MBC. Summary statistics of pertuzumab trough and maximal exposure (concentrations at predose and 15–30 minutes after the end of infusion at cycle 1 and at steady state) were similar with those observed in a representative historical single-Agent Study with the same dosing regimen. The visual predictive check plot by population simulation further confirmed that T-DM1 did not alter pertuzumab PK. Based on these data and the PK and pharmacodynamic properties of T-DM1 and pertuzumab, the risk of TP-DI appears to be low when T-DM1 and pertuzumab are given together.
