Comparison of simulated exposure of inotuzumab ozogamicin with and without dose capping in overweight and obese patients with relapsed/refractory acute lymphoblastic leukemia

Abstract Introduction Inotuzumab ozogamacin (InO) is an antibody drug conjugate (ADC) consisting of a CD22-directed monoclonal antibody linked to a cytotoxic payload, calicheamicin. InO is approved for the treatment of patients with relapsed/refractory (R/R) CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL). The labeled starting dose of InO is 1.8 mg/m2/cycle (0.8 mg/m2 on D1, and 0.5 mg/m2 on D8 and D15). While many approved ADCs are dosed based on body weight or body surface area (BSA) (Gogia et al. Cancers 2023; 15:3886), some also implement a maximum dose (dose capping), reducing the potential exposure and safety concerns for patients with larger body sizes. In this analysis, simulations using a final population pharmacokinetic (popPK) model were performed to compare the predicted exposure between the labeled regimen of 1.8 mg/m2/cycle and two capped dose regimens, specifically investigating whether dose capping is needed for InO. Methods A popPK model for InO (Garrett et al. J. of PK & PD 2019; 211-222) was updated to fit adult ALL data from three studies: NCT01363297 (N=72, 1.2–1.8 mg/m2/cycle, Phase 1/2), NCT01564784 (N=162, 1.8 mg/m2/cycle, Phase 3), and NCT03677596 (N=99, 1.2 mg/m2/cycle or 1.8 mg/m2/cycle, Phase 4). The final popPK model, using data from these 333 adult patients, was used to simulate exposure with the labeled and dose capping regimens. The exposure with the labeled regimen was compared to that with two modified dose capping regimens in which patients at or above a specified BSA threshold were simulated with a fixed dose. Two dose capping BSA thresholds were investigated, 1.97 m2 (N=105 >1.97 m2) and 2.14m2 (N=49 >2.14 m2), with thresholds corresponding to previously reported mean BSA values (DuBois formula) for overweight and obese populations, respectively (Verbraecken et al. Metabolism 2006; 55.4:515-524). Simulated InO serum concentrations were used to compute exposure metrics for comparison. The labeled and dose capping regimens were compared using four exposure metrics: cumulative area under the curve (cAUC) at the end of cycle 1 (Day 21, termed cAUC-C1) and cycle 4 (Day 105, termed cAUC-C4), along with the maximum concentration (Cmax, over Days 92-105) and trough concentration (Ctrough, computed on Day 105) for the third dose in cycle 4. The population was further subdivided by BMI <25 kg/m2 (N=152, healthy), 25–30 kg/m2 (N=116, overweight) and >30 kg/m2 (N=65, obese) to understand how regimens affected simulated exposure in overweight and obese subpopulations. Results In general, both capped regimens exhibited only minor reductions in simulated exposure relative to the labeled regimen. For patients with BSA values above the capping thresholds, capped regimens resulted in small percentage decreases in median exposure metrics relative to the labeled regimen, with reductions of 6.9% and 4.5% for Cmax, 8.9% and 3.8% for Ctrough, 3.2% and 3.0% for cAUC-C1, and 4.3% and 8.3% for cAUC-C4, for the >=1.97 m2 and >=2.14 m2 capped regimens, respectively. Patients below the BSA threshold in the capped regimens were simulated with the same dose as the labeled regimen and therefore had no predicted exposure differences. BMI-based partitioning of the population yielded similar findings. For the overweight subpopulation (25–30 kg/m2), the capped regimens had only minor decreases in the median simulated exposure metrics relative to the labeled regimen, with reductions of 0% and 0% for Cmax, 1.7% and 0% for Ctrough, 2.1% and 0% for cAUC-C1, and 1.3% and 0% cAUC-C4, in the >=1.97 m2 and >=2.14 m2 capped regimens, respectively. In the obese subpopulation (>30 kg/m2), the median decrease in exposure metrics in the capped regimens were also small relative to the labeled regimen: 14.7% and 8.5% for Cmax, 10.9% and 10.3% for Ctrough, 7.6% and 5.2% for cAUC-C1, and 14.2% and 12.5% for cAUC-C4, for the >=1.97 m2 and >=2.14 m2 caps, respectively. Conclusion The simulated InO exposures with dose capping were slightly reduced relative to the labeled regimen across BSA and BMI-based patient subpopulations, suggesting that dose capping is not needed. These results support the current labeled BSA-based dosing regimen starting at 1.8 mg/m2/cycle.