A semi-physiologic population pharmacokinetic/pharmacodynamic (PK/PD) model of thrombocytopenia (TCP) characterizing the effect of trastuzumab-DM1 (T-DM1) on platelet counts in patients with HER2-positive MBC.

Bender, Brendan C.; Stark, F. Schaedeli; Joshi, Avani; Chu, Yan; Rugo, HS; Krop, IE; Girish, Sandhya; Gupta, Manish

doi:10.1200/jco.2011.29.15_suppl.605

Cited by 5 publications

(5 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thrombocytopenia was a DLT for both regimens. While the mechanism of action is currently unknown, population pharmacokinetic modeling and in vitro studies suggest that altered platelet production by megakaryocytes, rather than an effect on circulating platelets, likely accounts for the observed thrombocytopenia 10, 11. In addition to thrombocytopenia, mild‐to‐moderate increases in hepatic aminotransferases were reported on both schedules, which is consistent with findings from studies of T‐DM1 in cynomolgus monkeys (Genentech, data on file).…”

Section: Discussionsupporting

confidence: 82%

A phase 1 study of weekly dosing of trastuzumab emtansine (T‐DM1) in patients with advanced human epidermal growth factor 2–positive breast cancer

Beeram¹,

Krop

Burris

et al. 2012

Cancer

View full text Add to dashboard Cite

BACKGROUND:We conducted a phase 1, multicenter, open-label, dose-escalation study (TDM3569g) to assess the safety, tolerability, and pharmacokinetics of single-agent trastuzumab emtansine (T-DM1) administered weekly and once every 3 weeks in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab. The weekly dose results are described here. METHODS: Patients were administered escalating doses of T-DM1 weekly, starting at 1.2 mg/kg. Additional patients were enrolled at the maximum tolerated dose (MTD) to better characterize tolerability and pharmacokinetics. RESULTS: Twenty-eight patients received weekly T-DM1, and the MTD was determined to be 2.4 mg/kg. In general, T-DM1 was well tolerated, requiring few dose modifications or discontinuations because of adverse events (AEs). Grade !3 AEs were reported in 19 patients (67.9%); treatment-related AEs occurred in 25 (89.3%) patients. Exposure to weekly T-DM1 was dose-proportional at !1.2 mg/kg, and accumulation of T-DM1 and total trastuzumab was observed. Objective partial tumor responses were reported in 13 (46.4%) patients; the median duration of response was 18.6 months, and the 6-month clinical benefit rate was 57.1%. CONCLUSION: The results suggest that a weekly dose of T-DM1 2.4 mg/ kg has antitumor activity and is well tolerated in patients with HER2-positive metastatic breast cancer. Cancer 2012;118:5733-40.

show abstract

Section: Discussionsupporting

confidence: 82%

A phase 1 study of weekly dosing of trastuzumab emtansine (T‐DM1) in patients with advanced human epidermal growth factor 2–positive breast cancer

Beeram¹,

Krop

Burris

et al. 2012

Cancer

View full text Add to dashboard Cite

show abstract

“…A dose-dependent decline in platelet count was observed, with nadirs observed around 8 days after T-DM1 administration and recovery observed by about 15 days. Variability in the degree of thrombocytopenia occurred among individual patients [ 23 ]. Additionally, many patients had serum transaminase increases based on National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 guidelines.…”

Section: Resultsmentioning

confidence: 99%

“…Additional results from the evaluation of clinical pharmacology of T-DM1 are reported elsewhere and include a population PK assessment of demographic and pathophysiologic covariates likely to impact the clearance of T-DM1 [ 22 ], the potential for T-DM1-induced QT interval prolongation [ 21 ], and the potential for drug interaction [ 24 , 25 ]. An integrated modeling and simulation strategy has also been implemented to better understand the PK and pharmacodynamic relationships with T-DM1 [ 22 , 23 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer

Girish¹,

Gupta

Wang³

et al. 2012

Cancer Chemother Pharmacol

235

192

View full text Add to dashboard Cite

PurposeTrastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab and DM1, a microtubule polymerization inhibitor, covalently bound via a stable thioether linker. To characterize the pharmacokinetics (PK) of T-DM1 in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, data from four studies (TDM3569g, TDM4258g, TDM4374g, and TDM4688g) of single-agent T-DM1 administered at 3.6 mg/kg every 3 weeks (q3w) were assessed in aggregate.MethodsMultiple analytes—T-DM1, total trastuzumab (TT), DM1, and key metabolites—were quantified using enzyme-linked immunosorbent assays or liquid chromatography tandem mass spectrometry. PK parameters of T-DM1, TT, and DM1 exposure were calculated using standard noncompartmental approaches and correlated to efficacy (objective response rate) and safety (platelet counts, hepatic transaminase concentrations). Immunogenicity was evaluated by measuring anti-therapeutic antibodies (ATA) to T-DM1 after repeated dosing using validated bridging antibody electrochemiluminescence or enzyme-linked immunosorbent assays.ResultsPK parameters for T-DM1, TT, and DM1 were consistent across studies at cycle 1 and steady state. T-DM1 PK was not affected by residual trastuzumab from prior therapy or circulating extracellular domain of HER2. No significant correlations were observed between T-DM1 exposure and efficacy, thrombocytopenia, or increased concentrations of transaminases. Across the studies, ATA formation was detected in 4.5% (13/286) of evaluable patients receiving T-DM1 q3w.ConclusionsThe PK profile of single-agent T-DM1 (3.6 mg/kg q3w) is predictable, well characterized, and unaffected by circulating levels of HER2 extracellular domain or residual trastuzumab. T-DM1 exposure does not correlate with clinical responses or key adverse events.

show abstract

“…A model of platelet development and circulation was generated and analyzed to better understand the thrombocytopenia associated with T-DM1 [Bender et al . 2011].…”

Section: Toxicity and Patient-focused Perspectivesmentioning

confidence: 99%

“…A model of platelet development and circulation was generated and analyzed to better understand the thrombocytopenia associated with T-DM1 [Bender et al 2011]. Data from the phase I dose escalation study (TDM3569g) and phase II study of single-agent T-DM1 (TDM4258g) were used to generate this model, and data from another phase II study (TDM4374g) were used to validate the model.…”

Section: Thrombocytopeniamentioning

confidence: 99%

The potential for trastuzumab emtansine in human epidermal growth factor receptor 2 positive metastatic breast cancer: latest evidence and ongoing studies

Hurvitz¹,

Kakkar

2012

Ther Adv Med Oncol

View full text Add to dashboard Cite

The treatment of breast cancer that is driven by amplification and overexpression of human epidermal growth factor receptor 2 (HER2) has been drastically improved by the development of HER2-targeted therapies including trastuzumab and lapatinib. While outcomes for patients diagnosed with HER2-positive breast cancer have been greatly impacted by these therapies, treatment resistance is common and toxicity to standard regimens remains a therapeutic challenge. Trastuzumab emtansine (T-DM1) is a novel antibody drug conjugate that consists of the HER2-targeted monoclonal antibody, trastuzumab, joined via a stable linker to a derivative of maytansine, a highly potent cytotoxic chemotherapy. While other antibody drug conjugates have been developed clinically, this is the first in its class that maintains the antitumor properties of the HER2-targeted antibody, trastuzumab, and also avoids release of the chemotherapy until the molecule is taken up inside the HER2-overexpressing cancer cell. Several phase I studies have shown T-DM1 is safe, tolerable and has activity in trastuzumaband lapatinib-pretreated breast cancer. Moreover, phase II studies are now being reported that confirm its safety and clinical efficacy in both the frontline and heavily pretreated settings. Preliminary data from phase II studies evaluating its use in combination with other cytotoxics have also been reported and several large phase III trials are underway to evaluate its use in the HER2-positive metastatic breast cancer setting. This paper aims to provide a detailed review of the preclinical and clinical evidence relating to the mechanism of action, efficacy and safety of T-DM1 for the treatment of HER2-positive breast cancer.

show abstract

A semi-physiologic population pharmacokinetic/pharmacodynamic (PK/PD) model of thrombocytopenia (TCP) characterizing the effect of trastuzumab-DM1 (T-DM1) on platelet counts in patients with HER2-positive MBC.

Cited by 5 publications

References 0 publications

A phase 1 study of weekly dosing of trastuzumab emtansine (T‐DM1) in patients with advanced human epidermal growth factor 2–positive breast cancer

A phase 1 study of weekly dosing of trastuzumab emtansine (T‐DM1) in patients with advanced human epidermal growth factor 2–positive breast cancer

Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer

The potential for trastuzumab emtansine in human epidermal growth factor receptor 2 positive metastatic breast cancer: latest evidence and ongoing studies

Contact Info

Product

Resources

About