通过治疗药物监测实现阿替利珠单抗（atezolizumab）的个体化给药

Background: Currently, intravenous atezolizumab has 3 FDA-approved dosing regimens; 840 mg every 2 weeks or 1,200 mg every 3 weeks or 1,680 mg every 4 weeks which yield steady-state concentrations > 10-fold above the stated minimum effective concentration (MEC) of 6 μg/mL, to ensure adequate exposure for all patients, including patients that may experience lower exposure due to the incidence of anti-drug-antibodies (ADA). Atezolizumab exhibits a flat exposure-response relationship. Exposure-safety analysis showed a trend of a slight increase in adverse events of special interest (AESIs) with increasing exposure. To test the feasibility of reducing drug exposure while maintaining plasma drug concentration at or above MEC, a clinical study was developed. Methods: This is an open-label, single-arm, Phase 1 feasibility study of a therapeutic drug monitoring (TDM)-based method for atezolizumab dosing (NCT06066138). The study will enroll up to 20 evaluable participants with an accrual ceiling of 30. Treatment Plan The participants will start with one of the FDA-approved Atezolizumab dosing for Cycle 1 (C1) and C2. A trough level will be checked on C2D1 using a validated immunoassay and incorporated into a validated population pharmacokinetics (PK) simulation model replicated from a model described in the FDA Center for Drug Evaluation and Research (CDER) review for the NSCLC indication via NONMEM v7.6. Covariate variables (sex, weight, albumin, tumor burden, presence of anti-drug antibodies) will be used to estimate the clearance rate of atezolizumab. From C3D1, all participants will use 840mg. The timing will be determined based on the clearance rate simulated using the C2D1 trough. The timing of subsequent cycles will be determined based on the simulated clearance rate for each cycle in the first 16 weeks. Afterward, the trough will be checked every 3 months. The participants will remain on study for up to 2 years or until unacceptable toxicity or disease progression. Restaging will be done every 12 weeks. Major Eligibility Criteria All participants must be able to provide a written informed consent. Participants who are 18 or older with an advanced or metastatic cancer who are candidates for treatment with atezolizumab, either alone or in combination with other drug(s), are eligible. Participants with chronic viral infection who are well-controlled are eligible. Participants must not have received an immune checkpoint blockade within 28 days prior to the study treatment. Active autoimmune disease or immune stimulatory or immune suppressive medications within 1 month prior to study treatment will result in exclusion.PK measurements will be obtained using an investigator-developed assay and not the manufacturer-validated assay. Assay methodological differences should be considered when interpreting pharmacokinetic comparisons with previously published manufacturer data. Two of the planned 30 patients have been enrolled.