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POSEIDON Trial Phase 1b Results: Safety, Efficacy and Circulating Tumor DNA Response of the Beta Isoform-Sparing PI3K Inhibitor Taselisib (GDC-0032) Combined with Tamoxifen in Hormone Receptor Positive Metastatic Breast Cancer Patients.
PURPOSE: The strategy of combining endocrine therapy with PI3K-mTOR inhibition has shown promise in estrogen receptor (ER)-positive breast cancer, but new agents and combinations with a better therapeutic index are urgently needed. Taselisib is a potent, selective, beta-isoform-sparing PI3 kinase inhibitor. PATIENTS AND METHODS: 30 patients with ER-positive, metastatic breast cancer who had failed prior endocrine therapy were treated with escalating doses of taselisib (2 or 4 mg in an intermittent or continuous schedule) combined with tamoxifen 20 mg once daily in this phase 1b study using a "rolling six" design. RESULTS: Taselisib combined with tamoxifen was generally well tolerated, with treatment-emergent adverse events as expected for this class of drugs, including diarrhea (13 patients, 43%), mucositis (10 patients, 33%), and hyperglycemia (8 patients, 27%). No dose-limiting toxicities were observed. Objective responses were seen in 6 of 25 patients with RECIST-measurable disease (ORR 24%). Median time to disease progression was 3.7 months. Twelve of 30 patients (40%) had disease control for 6 months or more. Circulating tumor (ct)DNA studies using next-generation tagged amplicon sequencing identified early indications of treatment response and mechanistically relevant correlates of clinical drug resistance (e.g., mutations in KRAS, ERBB2) in some patients. CONCLUSIONS: Taselisib can be safely combined with tamoxifen at the recommended phase 2 dose of 4 mg given once daily on a continuous schedule. Preliminary evidence of antitumor activity was seen in both PIK3CA mutant and wild-type cancers. The randomized phase 2 part of POSEIDON (testing tamoxifen plus taselisib or placebo) is currently recruiting
Pharmacodynamic modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens
Pharmacometrics for treatment optimization and drug development in oncology
This thesis describes the application of pharmacometrics to optimize treatment with existing therapies and to support development of novel drugs in the area of oncology. In the field of pharmacometrics, data on pharmacokinetic (PK) and pharmacodynamic (PD) properties of drugs are characterized using a combination of mathematical and statistical models. These properties give insight in the fate of a drug in the body (PK) and in its desired and undesired (toxic) effects (PD). Quantification of PK-PD relationships in mathematical and statistical models allows for understanding the characteristics of a drug. Additionally, these models can help answer questions to improve clinical application of drugs and supports decision making in drug development. This thesis describes various examples of applying modeling and simulation methods to improve current treatments and support development of new drugs in oncology. Chapter 1 focuses on the pharmacology of tamoxifen and strategies to individualize dosing of tamoxifen by applying dose adjustments based on endoxifen concentrations. In chapter 2 a pharmacometric approach is used to determine a first-in-human dose for a novel monoclonal antibody and to evaluate its pharmacokinetic properties. In chapter 3 PK-PD modeling is performed to describe pharmacodynamic properties (i.e. toxicity) of different anti-cancer drugs, such as anthracyclines, trastuzumab and docetaxel.This thesis demonstrates that pharmacometrics provides powerful techniques to answer (clinical) pharmacological questions that are often impossible to answer using conventional statistical methods. The examples in this thesis, are applied to the therapeutic area of oncology, though can in part also be applied to answer pharmacological questions in other therapeutic fields and contribute to improved and safer drug treatment in patients
Pharmacometrics for treatment optimization and drug development in oncology
This thesis describes the application of pharmacometrics to optimize treatment with existing therapies and to support development of novel drugs in the area of oncology. In the field of pharmacometrics, data on pharmacokinetic (PK) and pharmacodynamic (PD) properties of drugs are characterized using a combination of mathematical and statistical models. These properties give insight in the fate of a drug in the body (PK) and in its desired and undesired (toxic) effects (PD). Quantification of PK-PD relationships in mathematical and statistical models allows for understanding the characteristics of a drug. Additionally, these models can help answer questions to improve clinical application of drugs and supports decision making in drug development. This thesis describes various examples of applying modeling and simulation methods to improve current treatments and support development of new drugs in oncology. Chapter 1 focuses on the pharmacology of tamoxifen and strategies to individualize dosing of tamoxifen by applying dose adjustments based on endoxifen concentrations. In chapter 2 a pharmacometric approach is used to determine a first-in-human dose for a novel monoclonal antibody and to evaluate its pharmacokinetic properties. In chapter 3 PK-PD modeling is performed to describe pharmacodynamic properties (i.e. toxicity) of different anti-cancer drugs, such as anthracyclines, trastuzumab and docetaxel.This thesis demonstrates that pharmacometrics provides powerful techniques to answer (clinical) pharmacological questions that are often impossible to answer using conventional statistical methods. The examples in this thesis, are applied to the therapeutic area of oncology, though can in part also be applied to answer pharmacological questions in other therapeutic fields and contribute to improved and safer drug treatment in patients
Therapeutic Drug Monitoring of endoxifen as an alternative for CYP2D6 genotyping in individualizing tamoxifen therapy
Different strategies have been proposed to individualize tamoxifen treatment in order to improve recurrence-free survival in estrogen receptor (ER)-positive breast cancer. To date, the debate remains on which strategy should be used. The objective of this viewpoint is to highlight Therapeutic Drug Monitoring of endoxifen, the active tamoxifen metabolite, as the preferred methodology compared to CYP2D6 genotyping for individualizing tamoxifen therapy for ER-positive breast cancer patients treated in the adjuvant setting
Therapeutic Drug Monitoring of endoxifen as an alternative for CYP2D6 genotyping in individualizing tamoxifen therapy
Different strategies have been proposed to individualize tamoxifen treatment in order to improve recurrence-free survival in estrogen receptor (ER)-positive breast cancer. To date, the debate remains on which strategy should be used. The objective of this viewpoint is to highlight Therapeutic Drug Monitoring of endoxifen, the active tamoxifen metabolite, as the preferred methodology compared to CYP2D6 genotyping for individualizing tamoxifen therapy for ER-positive breast cancer patients treated in the adjuvant setting
Therapeutic Drug Monitoring of endoxifen as an alternative for CYP2D6 genotyping in individualizing tamoxifen therapy
Different strategies have been proposed to individualize tamoxifen treatment in order to improve recurrence-free survival in estrogen receptor (ER)-positive breast cancer. To date, the debate remains on which strategy should be used. The objective of this viewpoint is to highlight Therapeutic Drug Monitoring of endoxifen, the active tamoxifen metabolite, as the preferred methodology compared to CYP2D6 genotyping for individualizing tamoxifen therapy for ER-positive breast cancer patients treated in the adjuvant setting
Therapeutic Drug Monitoring of endoxifen as an alternative for CYP2D6 genotyping in individualizing tamoxifen therapy
Different strategies have been proposed to individualize tamoxifen treatment in order to improve recurrence-free survival in estrogen receptor (ER)-positive breast cancer. To date, the debate remains on which strategy should be used. The objective of this viewpoint is to highlight Therapeutic Drug Monitoring of endoxifen, the active tamoxifen metabolite, as the preferred methodology compared to CYP2D6 genotyping for individualizing tamoxifen therapy for ER-positive breast cancer patients treated in the adjuvant setting
Therapeutic Drug Monitoring of endoxifen as an alternative for CYP2D6 genotyping in individualizing tamoxifen therapy
Effects of Pharmacogenetics on the Pharmacokinetics and Pharmacodynamics of Tamoxifen
The antiestrogenic drug tamoxifen is widely used in the treatment of estrogen receptor-α-positive breast cancer and substantially decreases recurrence and mortality rates. However, high interindividual variability in response is observed, calling for a personalized approach to tamoxifen treatment. Tamoxifen is bioactivated by cytochrome P450 (CYP) enzymes such as CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5, resulting in the formation of active metabolites, including 4-hydroxy-tamoxifen and endoxifen. Therefore, polymorphisms in the genes encoding these enzymes are proposed to influence tamoxifen and active tamoxifen metabolites in the serum and consequently affect patient response rates. To tailor tamoxifen treatment, multiple studies have been performed to clarify the influence of polymorphisms on its pharmacokinetics and pharmacodynamics. Nevertheless, personalized treatment of tamoxifen based on genotyping has not yet met consensus. This article critically reviews the published data on the effect of various genetic polymorphisms on the pharmacokinetics and pharmacodynamics of tamoxifen, and reviews the clinical implications of its findings. For each CYP enzyme, the influence of polymorphisms on pharmacokinetic and pharmacodynamic outcome measures is described throughout this review. No clear effects on pharmacokinetics and pharmacodynamics were seen for various polymorphisms in the CYP encoding genes CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5. For CYP2D6, there was a clear gene-exposure effect that was able to partially explain the interindividual variability in plasma concentrations of the pharmacologically most active metabolite endoxifen; however, a clear exposure-response effect remained controversial. These controversial findings and the partial contribution of genotype in explaining interindividual variability in plasma concentrations of, in particular, endoxifen, imply that tailored tamoxifen treatment may not be fully realized through pharmacogenetics of metabolizing enzymes alone