Tumor growth inhibition modeling to support the starting dose for dacomitinib.

Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor for first-line treatment of patients with metastatic non-small cell lung cancer and EGFR-activating mutations. A high rate of dose reductions in the pivotal trial led to an observed inverse exposure-response (ER) relationship with the primary end points. Three ER models were developed to determine if the starting dose from the pivotal trial, 45 mg once daily (q.d.) dose, is appropriate: a longitudinal logistic regression model for adverse event-related dose changes, a Claret tumor growth inhibition (TGI) model, and a Cox model for progression-free survival (PFS) based on the TGI model predictions. This analysis included 266 patients taking dacomitinib with a starting dose of 45 mg (N = 250) or 30 mg (N = 16) q.d. The ER relationships with the time-varying exposure metrics, most recent maximum plasma concentration (Cmax ) and average concentration (Cavg ) from the first dose, were established for the dose reduction and TGI models, respectively. The TGI model characterized the tumor inhibition over time with constant growth rate (kL  = 0.0012 years-1 ) and highly variable kill rate (kD  = 1.002 years-1 /[µg/L]θcavg , coefficient of variation [CV] = 89%) and drug resistance (λ = 14.47 years-1 , CV = 96%) leading to prolonged tumor shrinkage. The ER relationship was characterized using an exposure parameter with a power parameterization (θcavg = 0.454, p < 0.0001). The Cox model found that baseline tumor size (p = 0.0166) and week 8 tumor shrinkage rate (p = 0.0726) were the best predictors of PFS. Simulations of dose reductions and drug interruptions on tumor shrinkage over time showed greater and more prolonged tumor shrinkage with a starting dose of 45 mg q.d.

Exposure-response modeling of the effect of glasdegib on cardiac repolarization in patients with cancer.

PURPOSE: To characterize the effect of glasdegib on cardiac repolarization (QTc) in patients with advanced cancer. METHODS: A concentration-QTc model was developed using data from two glasdegib single-agent, dose-escalation trials. Triplicate electrocardiogram was performed at pre-specified timepoints paired with pharmacokinetic blood collections after a single dose and at steady-state. Changes in QTc from baseline were predicted by model-based simulations at the clinical dose (100 mg QD) and in a supratherapeutic setting. RESULTS: Glasdegib did not affect the heart rate, but had a positive effect on the corrected QT interval, described by a linear mixed-effects model with ΔQTcF (QTc using Fridericia's formula) as the dependent variable with glasdegib plasma concentrations from doses of 5-640 mg QD. The predicted mean QTcF change (upper bound of the 95% CI) was 5.30 (6.24) msec for the therapeutic 100-mg QD dose; at supratherapeutic concentrations (40% and 100% increase over the therapeutic Cmax), it was 7.42 (8.74) and 12.09 (14.25) msec, respectively. CONCLUSIONS: The relationship of glasdegib exposure and QTc was well characterized by the model. The effect of glasdegib on the QTc interval did not cross the threshold of clinical concern for an oncology drug. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01286467 and NCT00953758.

Pharmacokinetic/Pharmacodynamic Modeling to Support the Re-approval of Gemtuzumab Ozogamicin.

Gemtuzumab ozogamicin (Mylotarg; Pfizer, New York, NY) was the first antibody-drug conjugate to be approved for CD33-positive acute myeloid leukemia (AML). However, it was voluntarily withdrawn from the US market due to lack of clinical benefit in the confirmatory phase III trial. In 2012, several investigator cooperative studies using a different dosing regimen showed efficacy, but pharmacokinetic (PK) data were not collected in these trials. Through simulation of expected concentrations for new dosing regimens, PK/pharmacodynamic modeling was able to support the safety and efficacy of these regimens. Significant exposure-response relationships were found for the attainment of complete remission with and without platelet recovery, attainment of blast-free status, the time course of myelosuppression, several grade ≥ 3 hepatic adverse events, and veno-occlusive disease. Gemtuzumab ozogamicin received full approval by the US Food and Drug Administration (FDA) in September 2017 for newly diagnosed and relapsed AML in adult patients and relapsed AML in pediatric patients aged 2-17 years.