Abstract 4518: Model-based integration of pharmacokinetics, efficacy and safety data for optimizing therapy of inotuzumab ozogamicin in subjects with indolent non-Hodgkin's lymphoma
Authors: Luu Kenneth , Boni Joseph 
Published: August 2015

Abstract
Purpose
This study aimed to develop a quantitative method for optimizing the dose and regimen of inotuzumab ozogamicin (InO) in patients with indolent non-Hodgkin lymphoma (NHL) by simultaneously balancing the safety and efficacy outcome measures
Design
Analysis was based on data from a multi-center, single arm, open-label study of intravenous InO administered at a dose of 1.8 mg/m2, every 4 weeks (Q4W) for at least 4 cycles.
Patients and Methods
Pharmacokinetics (PK), safety, and efficacy data from a phase 2 trial of InO in 81 patients were evaluated by modeling and simulation. PK disposition was described by a 2-compartment model linked to: 1) an exponential tumor growth model of time-dependent tumor size change (efficacy determinant expressed as objective response rate); 2) a precursor-dependent platelet inhibition model to describe time-dependent platelet count change (safety determinant expressed as thrombocytopenia grades). Modeling and simulation was performed using NONMEM version 7.2 (ICON Development Solutions, Ellicott City, MD) and internally validated using study data and safety and efficacy response surfaces generated based on virtual trial simulations, from which a clinical utility index (CUI) contour was constructed and optimal InO dosage regimens were selected.
Results
The model-predicted rate of grade 3 or 4 thrombocytopenia for the studied dose of 1.8 mg/m2 Q4W was 44.2% versus observed of 45.8%. The efficacy-response surface indicated that InO, at the dosage regimen studied in the trial (1.8 mg/m2 Q4W), exhibited near-optimal efficacy, with little improvement gained from alternative dosage regimens. The predicted effective objective response rate was 53.1% versus observed of 55.8%. The safety-response surface indicated that modifying the dosage regimen (without compromising efficacy) modestly improved the safety profile. The CUI contour identified a dosage regimen of 2 mg/m2 administered every 10 to 12 weeks as an optimal InO dosage regimen to consider for patients with indolent NHL.
Conclusion
A novel approach to InO treatment optimization in patients with indolent NHL was developed by simultaneously balancing safety and efficacy outcome measures without technical or subjective bias to one or the other. For patients with indolent NHL, increasing the InO dosage interval may improve the tolerability profile, albeit modestly, without substantially compromising efficacy. This approach has broad utility for oncology because it allows objective identification of an optimal dose and regimen for confirmatory trials based on early clinical trial information.
Citation Format: Kenneth Luu, Joseph Boni. Model-based integration of pharmacokinetics, efficacy and safety data for optimizing therapy of inotuzumab ozogamicin in subjects with indolent non-Hodgkin's lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4518. doi:10.1158/1538-7445.AM2015-4518