A phase IV study evaluating QT interval, pharmacokinetics, and safety following fractionated dosing of gemtuzumab ozogamicin in patients with relapsed/refractory CD33-positive acute myeloid leukemia.

PURPOSE: Gemtuzumab ozogamicin (GO) is indicated for treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML). The QT interval, pharmacokinetics (PK), and immunogenicity following the fractionated GO dosing regimen have not been previously assessed. This phase IV study was designed to obtain this information in patients with R/R AML. METHODS: Patients aged ≥ 18 years with R/R AML received the fractionated dosing regimen of GO 3 mg/m2 on Days 1, 4, and 7 of each cycle, up to 2 cycles. The primary endpoint was mean change from baseline in QT interval corrected for heart rate (QTc). RESULTS: Fifty patients received ≥ 1 dose of GO during Cycle 1. The upper limit of the 2-sided 90% confidence interval for least squares mean differences in QTc using Fridericia's formula (QTcF) was < 10 ms for all time points during Cycle 1. No patients had a post-baseline QTcF > 480 ms or a change from baseline > 60 ms. Treatment-emergent adverse events (TEAEs) occurred in 98% of patients; 54% were grade 3-4. The most common grade 3-4 TEAEs were febrile neutropenia (36%) and thrombocytopenia (18%). The PK profiles of both conjugated and unconjugated calicheamicin mirror that of total hP67.6 antibody. The incidence of antidrug antibodies (ADAs) and neutralizing antibodies was 12% and 2%, respectively. CONCLUSION: Fractionated GO dosing regimen (3 mg/m2/dose) is not predicted to pose a clinically significant safety risk for QT interval prolongation in patients with R/R AML. TEAEs are consistent with GO's known safety profile, and ADA presence appears unassociated with potential safety issues. TRIAL REGISTRY: Clinicaltrials.gov ID: NCT03727750 (November 1, 2018).

Development of Highly Optimized Antibody-Drug Conjugates against CD33 and CD123 for Acute Myeloid Leukemia.

PURPOSE: Mortality due to acute myeloid leukemia (AML) remains high, and the management of relapsed or refractory AML continues to be therapeutically challenging. The reapproval of Mylotarg, an anti-CD33-calicheamicin antibody-drug conjugate (ADC), has provided a proof of concept for an ADC-based therapeutic for AML. Several other ADCs have since entered clinical development of AML, but have met with limited success. We sought to develop a next-generation ADC for AML with a wide therapeutic index (TI) that overcomes the shortcomings of previous generations of ADCs. EXPERIMENTAL DESIGN: We compared the TI of our novel CD33-targeted ADC platform with other currently available CD33-targeted ADCs in preclinical models of AML. Next, using this next-generation ADC platform, we performed a head-to-head comparison of two attractive AML antigens, CD33 and CD123. RESULTS: Our novel ADC platform offered improved safety and TI when compared with certain currently available ADC platforms in preclinical models of AML. Differentiation between the CD33- and CD123-targeted ADCs was observed in safety studies conducted in cynomolgus monkeys. The CD33-targeted ADC produced severe hematologic toxicity, whereas minimal hematologic toxicity was observed with the CD123-targeted ADC at the same doses and exposures. The improved toxicity profile of an ADC targeting CD123 over CD33 was consistent with the more restricted expression of CD123 in normal tissues. CONCLUSIONS: We optimized all components of ADC design (i.e., leukemia antigen, antibody, and linker-payload) to develop an ADC that has the potential to translate into an effective new therapy against AML.

Gemtuzumab ozogamicin in acute myeloid leukemia: past, present and future.

After being in the therapeutic wilderness for several decades, acute myeloid leukemia has been recently thrust into the limelight with a series of drug approvals. Technical refinements in production, genetic manipulation and chemical modification of monoclonal antibodies led to growing interest in antibodies-based treatment strategies. Much of the focus of these efforts in acute myeloid leukemia has been on CD33 as a target. On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin for treatment of relapsed or refractory CD33+ acute myeloid leukemia. This signals a new chapter in the long and unusual story of gemtuzumab ozogamicin, which was the first antibody-drug conjugate approved for human use by the Food and Drug Administration. In this review we have analyzed the history of this drug which, among several mishaps, is experiencing a second youth and still represents a field to be further explored.

Population Pharmacokinetics of Gemtuzumab Ozogamicin in Pediatric Patients with Relapsed or Refractory Acute Myeloid Leukemia.

BACKGROUND AND OBJECTIVE: To date, the population pharmacokinetics (popPK) of gemtuzumab ozogamicin (GO), a CD33-directed antibody-drug conjugate consisting of hP67.6 antibody linked to N-acetyl gamma calicheamicin used in the treatment of acute myeloid leukemia (AML), has not been characterized in pediatric patients. This report describes the popPK of GO following intravenous administration in 29 pediatric patients aged ≤ 17 years with relapsed or refractory AML who were enrolled in the 0903A1-102-US phase I/II study. METHODS: The pharmacokinetics (PK) of GO, as represented by total hP67.6 antibody, were described by a two-compartment model with two clearance components: a linear clearance (CL1) and time-dependent clearance that includes a decay coefficient. The PK of unconjugated calicheamicin (UC; payload) were described by a two-compartment model with CL1 and an input rate of formation based on antibody rate of elimination. Allometric scaling was included in both models, with baseline body weight as a fixed effect on CL1 and central volume. RESULTS AND CONCLUSIONS: PK parameters for hP67.6 and UC were not significantly affected by any of the available demographic factors and safety laboratory values tested as covariates (except baseline body weight). Simulations to compare GO dosing regimens (6, 7.5, and 9 mg/m2 on days 1 and 15 versus, 3 mg/m2 fractionated dosing on days 1, 4, and 7) were performed, showing that total antibody and UC trough concentrations were maintained at higher concentrations during treatment following the more frequent dosing than following the original regimen. STUDY IDENTIFIER: 0903A1-102-US.

Population Pharmacokinetic Modeling of Gemtuzumab Ozogamicin in Adult Patients with Acute Myeloid Leukemia.

BACKGROUND AND OBJECTIVE: Gemtuzumab ozogamicin is an antibody-drug conjugate composed of the anti-CD33 monoclonal antibody hP67.6 covalently linked to N-acetyl-gamma-calicheamicin dimethylhydrazide, a potent cytotoxic antibiotic. The aim of this study was to characterize the population pharmacokinetics of gemtuzumab ozogamicin, represented by total hP67.6 antibody and unconjugated calicheamicin, in adult patients with acute myeloid leukemia to support drug dosing strategies and explore intrinsic and extrinsic factors that may influence exposure. Pharmacokinetic data from seven previous phase I and II studies in adult patients with relapsed, refractory, or de novo acute myeloid leukemia were integrated and analyzed using nonlinear mixed-effects modeling. METHODS: The pharmacokinetics of total hP67.6 antibody was described in 407 patients (5643 concentrations) who received gemtuzumab ozogamicin doses ranging from 0.25 to 9 mg/m2 using a two-compartment model with linear and time-dependent clearance components. The pharmacokinetics of unconjugated calicheamicin was characterized in 338 patients (4281 concentrations) using a two-compartment model with an input rate of formation dependent on the amount of hP67.6 eliminated. No statistically significant baseline covariates (sex, albumin, bone marrow, and peripheral blast percentage) demonstrated a clinically meaningful impact. RESULTS AND CONCLUSION: Total hP67.6 antibody disposition did not appear altered in patients with mild or moderate renal disease or hepatic impairment. Gemtuzumab ozogamicin was approved for the treatment of acute myeloid leukemia by the US Food and Drug Administration in September 2017. The model-based simulations described here provided a pharmacokinetic rationale for the approved dosing regimen of 3 mg/m2 on days 1, 4, and 7, and served as the basis for all exposure-response modeling included in the recent Biologics License Application submission. Clinical trials identifiers: 0903A1-101-US; 0903A1-103-JA; 0903B1-201-US/CA (NCT00003131); 0903B1-202-EU; 0903B1-203-US/EU (NCT00003673); 0903B1-205-US/EU/AU (NCT00037596); and 0903B1-206-US/EU/AU (NCT00037583).