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.

Time frame: Days 1 to 28 for each cohort (28 days)

Population: The DLT evaluable set included all DLT-evaluable participants, defined as participants who received the doses planned for the respective cohort, and completed the DLT window of 28 days for all cohorts unless they dropped out before completion of the DLT window for reasons other than a DLT. Exception: participant had received the planned doses in cycle 1 and dropped out within 1 week of the completion of the DLT period due to progressive disease, that participant was considered DLT-evaluable.

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).

Time frame: Day 1 Cycle 1 to 30 days after last dose of investigational product or end of study; median treatment duration was 0.62 months

Population: For Cohorts 1-15, the safety analysis set included all participants who received at least 1 dose of emirodatamab. For cohorts 16 and 17, the safety analysis set included all participants who received at least 1 dose of emirodatamab or etanercept.

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.

Time frame: Cohorts 1, 2, 3, 4, 5, 6, 7a, 7b, 8, 9, 10, 11, 12, 13, 16 and 17: C1D5; Cohorts 14 and 15: C1D8 (sampling pre-dose up to 72 hours post-dose)

Population: The PK analysis set included all participants who received at least 1 dose of the investigational product and had at least 1 PK sample collected. Participants were included for PK analysis unless the number of data points required for analysis was not enough, or significant protocol deviations had affected the data, or if key dosing or sampling information is missing. Participants with data available at each timepoint are presented.

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.

Time frame: Cohorts 1, 2, 3, 4, 5, 6, 7a, 7b, 8, 9, 10, 11, 12, 13, 16 and 17: C1D5; Cohorts 14 and 15: C1D8 (sampling pre-dose up to 72 hours post-dose)

Population: The PK analysis set included all participants who received at least 1 dose of the investigational product and had at least 1 PK sample collected. Participants were included for PK analysis unless the number of data points required for analysis was not enough, or significant protocol deviations had affected the data, or if key dosing or sampling information is missing. Participants with data available at each timepoint are presented.

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.

Time frame: For all cohorts: from time zero to 14-days following the C1D1 dose (1 cycle= 14 days)

Population: The PK analysis set included all participants who received at least 1 dose of the investigational product and had at least 1 PK sample collected. Participants were included for PK analysis unless the number of data points required for analysis was not enough, or significant protocol deviations had affected the data, or if key dosing or sampling information is missing. Participants with data available at each timepoint are presented.

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%

Time frame: Day 1 Cycle 1 to 30 days after last dose of investigational product or end of study; median treatment duration was 0.62 months

Population: For Cohorts 1-15, the safety analysis set included all participants who received at least 1 dose of emirodatamab. For cohorts 16 and 17, the safety analysis set included all participants who received at least 1 dose of emirodatamab or etanercept.

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.

Time frame: Cohorts 1, 2, 3, 4, 5, 6, 7a, 7b, 8, 9, 10, 11, 12, 13, 16 and 17: Cycle 1 Day 5 (C1D5); Cohorts 14 and 15: Cycle 1 Day 8 (C1D8) (sampling pre-dose up to 72 hours post-dose)

Population: The PK analysis set included all participants who received at least 1 dose of the investigational product and had at least 1 PK sample collected. Participants were included for PK analysis unless the number of data points required for analysis was not enough, or significant protocol deviations had affected the data, or if key dosing or sampling information is missing. Participants with data available at each timepoint are presented.

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.

Time frame: Cohorts 1, 2, 3, 4, 5, 6, 7a, 7b, 8, 9, 10, 11, 12, 13, 16 and 17: C1D5; Cohorts 14 and 15: C1D8 (sampling pre-dose up to 72 hours post-dose)

Population: The PK analysis set included all participants who received at least 1 dose of the investigational product and had at least 1 PK sample collected. Participants were included for PK analysis unless the number of data points required for analysis was not enough, or significant protocol deviations had affected the data, or if key dosing or sampling information is missing. Participants with data available at each timepoint are presented.

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.

Time frame: Cohorts 1, 2, 3, 4, 5, 6, 7a, 7b, 8, 9, 10, 11, 12, 13, 16 and 17: C1D5; Cohorts 14 and 15: C1D8 (sampling pre-dose up to 72 hours post-dose)

Population: The PK analysis set included all participants who received at least 1 dose of the investigational product and had at least 1 PK sample collected. Participants were included for PK analysis unless the number of data points required for analysis was not enough, or significant protocol deviations had affected the data, or if key dosing or sampling information is missing. Participants with data available at each timepoint are presented.

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.

Time frame: Cohorts 1, 2, 3, 4, 5, 6, 7a, 7b, 8, 9, 10, 11, 12, 13, 16 and 17: C1D5; Cohorts 14 and 15: C1D8 (sampling pre-dose up to 72 hours post-dose)

Population: The PK analysis set included all participants who received at least 1 dose of the investigational product and had at least 1 PK sample collected. Participants were included for PK analysis unless the number of data points required for analysis was not enough, or significant protocol deviations had affected the data, or if key dosing or sampling information is missing. Participants with data available at each timepoint are presented.