Trial Outcomes & Findings for Safety, Tolerability, PK, PD, and Efficacy of AMG 427 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia (NCT NCT03541369)

Participants were enrolled at 11 study centers in 5 countries, including Australia, Canada, Germany, Japan, and the United States, and participated from 14 September 2018 to 21 February 2023.

Participants were enrolled into first-in-human (FIH) groups with no step dosing (cohorts 1 - 7a), and with step dosing (cohorts 7b - 13), into extended intravenous (eIV) groups (cohorts 14 -15), and into an etanercept substudy (cohorts 16 - 17). Dosing was from Dose A (lowest) to Dose M (highest).

Safety, Tolerability, PK, PD, and Efficacy of AMG 427 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia

A DLT was any of the following during the DLT window, assessed by Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 except for cytokine release syndrome (CRS) grading: * drug-induced liver injury * any treatment-related death * Grade 2 CRS not resolving to ≤ grade 1 within 7 days; grade 3 CRS not resolving to ≤ grade 1 within 7 days; grade 3 CRS reported at the initial run-in dose; 2 separate grade 3 CRS events * Grade 4 CRS/infusion reactions * Grade 3-5 non-hematologic toxicity not clearly resulting from underlying leukemia except: alopecia, grade 3 rash, fatigue, asthenia, fever, anorexia, or constipation, nausea, vomiting or diarrhea not requiring tube feeding, total parenteral nutrition, or requiring/prolonging hospitalization; infection, bleeding, or other expected complication of cytopenias due to underlying leukemia; grade 3 infusion reaction including CRS; grade 3 tumor lysis syndrome * Grade 4 neutropenia persisting beyond 42 days in absence of leukemia.

An adverse event (AE) was defined as any untoward medical occurrence in a clinical trial participant. A TEAE was an AE that started on or after the first dose of investigational product (emirodatamab) up to 30 days after the end of investigational product or end of study date, whichever was earlier. A treatment-related AE was any TEAE that per investigator review had a reasonable possibility of being caused by the investigational product (emirodatamab).

Serum concentrations of emirodatamab were determined using a validated assay. Noncompartmental analysis was performed for estimation of pharmacokinetic (PK) parameters. Concentrations below the LLOQ (0.05 ng/mL) were set to zero before data analysis.

Serum concentrations of emirodatamab were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.05 ng/mL) were set to zero before data analysis.

Serum concentrations of emirodatamab were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.05 ng/mL) were set to zero before data analysis.

Serum concentrations of emirodatamab were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.05 ng/mL) were set to zero before data analysis. AUC(0-last) was calculated using the linear trapezoidal method.

Serum concentrations of emirodatamab were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.05 ng/mL) were set to zero before data analysis. The AUC(0-inf) was calculated using the linear trapezoidal method.

Serum concentrations of emirodatamab were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.05 ng/mL) were set to zero before data analysis. AUC(14d) was calculated as the sum of AUC values of all dosing days in cycle 1.

Serum concentrations of emirodatamab were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.05 ng/mL) were set to zero before data analysis. t1/2,z was calculated as t1/2,z = ln(2)/λz, where λz is the first-order terminal rate constant estimated via linear regression of the terminal log-linear phase.

A response consisted of any of the following, assessed according to the IWG response criteria: * complete remission (CR): bone marrow (BM) blasts \<5%; no blasts with Auer rods; no extramedullary disease; absolute neutrophil count \>1.0 x 10\^9/L; platelet count \> 100 x 10\^9/L; independence of red cell transfusions * CR with incomplete recovery of peripheral blood counts (CRi): CR except for residual neutropenia (\< 1.0 x 10\^9/L) or thrombocytopenia (\< 100 x 10\^9/L) * complete response/remission with partial hematologic recovery (CRh): ≤5% BM blasts, no circulating blasts/extramedullary disease and partial recovery of peripheral blood counts (platelets \> 50,000/µL, hemoglobin ≥7g/dL and absolute neutrophil count \> 500/µL). * morphologic leukemia-free state: BM blasts \< 5%; no blasts with Auer rods; no extramedullary disease; no hematologic recovery required * partial remission: hematological criteria of CR; decrease BM blast to 5-25%; decrease of pretreatment BM blast percentage by ≤ 50%