Trial Outcomes & Findings for AMG 176 First in Human Trial in Participants With Relapsed or Refractory Multiple Myeloma and Participants With Relapsed or Refractory Acute Myeloid Leukemia (NCT NCT02675452)

Participants were enrolled at 21 study centers in the United States, Canada, Australia, Germany, and Japan, and participated from June 2016 to May 2024. The study was conducted in multiple parts and Part 5 did not enroll any participants due to early termination of the study. Part 2 was removed during a protocol amendment.

Participants with multiple myeloma (MM) or with acute myeloid leukemia (AML) were enrolled into 29 cohorts. Dosing of AMG 176 was from Dose A (lowest) to Dose I (highest).

AMG 176 First in Human Trial in Participants With Relapsed or Refractory Multiple Myeloma and Participants With Relapsed or Refractory Acute Myeloid Leukemia

A DLT was assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v 4.0, and considered by the investigators to be related to AMG 176. A DLT was defined as a grade 3 or higher non-hematological or a grade 4 hematologic adverse event (AE) that occurred during the DLT observation period. CTCAE is graded from grade 1 to 5, with higher grades indicating a worse outcome, and included; grade 1 = mild, grade 2= moderate, grade 3 = severe, grade 4 = life-threatening, and grade 5 = death.

An 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 (AMG 176) up to 30 days after the end of investigational product. Any clinically significant changes in vital signs, electrocardiograms, and clinical laboratory tests were reported as TEAEs. A treatment-related AE was any TEAE that per investigator review had a reasonable possibility of being caused by the investigational product (AMG 176).

Plasma concentrations of AMG 176 were determined using a validated assay. Noncompartmental analysis was performed for estimation of pharmacokinetic (PK) parameters. Concentrations below the lower limit of quantification (LLOQ) of 5.00 ng/mL were set to zero before data analysis.

Plasma concentrations of AMG 176 were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ of 5.00 ng/mL were set to zero before data analysis.

Plasma concentrations of AMG 176 were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ of 5.00 ng/mL were set to zero before data analysis.

Plasma concentrations of AMG 176 were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ of 5.00 ng/mL were set to zero before data analysis.

Plasma concentrations of AMG 176 were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ of 5.00 ng/mL were set to zero before data analysis. Clearance was calculated as Dose/ AUC0-144 for Parts 1A, 3A, and 4; and as Dose/AUC0-168 for Parts 1B, 3 (Cohort 4 only) 3B, 3C, and 3D.

Plasma concentrations of AMG 176 were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ of 5.00 ng/mL were set to zero before data analysis.

A response consisted of any of the following, assessed according to the IMWG-URC: stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minor response (MR), stable disease (SD), or progressive disease (PD) per IMWG-URC. CR: negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, \< 5% plasma cells in bone marrow (BM). sCR: CR and normal serum free light chain ratio and no clonal cells in BM by immunohistochemistry. VGPR: Serum and urine M-protein detectable by immunofixation or ≥ 90% reduction in serum M-protein (urine M-protein level \< 100 mg/24-hrs). PR: ≥ 50% reduction of serum M-protein and reduction in 24-hrs urinary M-protein by ≥ 90% or to \< 200 mg/24-hours; MR: 25-49% reduction in serum M-protein and 50-89% reduction in 24-hr urinary M-protein (\>200 mg/24-hrs); SD: not meeting criteria for CR, VGPR, PR, or PD; PD: ≥ 25% increase in serum or urine M-component, BM plasma cell percentages.

A response was of any of the following, per the ELN criteria: Complete remission (CR) without minimal residual disease (CRMRD-), CR, CR with incomplete hematology recovery (CRi), morphologic leukemia-free state (MLFS), partial remission (PR), SD, PD. CRMRD-: CR with negativity for genetic marker by quantitative reverse transcription (RT-qPCR) or multicolor flow cytometry (MFC); CR: BM blasts \<5% bone marrow, no circulating blasts/ extramedullary disease, ANC \> 1.0 x 10\^9/L, platelets ≥ 100 x 10\^9/L; CRi: CR except for neutropenia (\< 1.0 x 10\^9/L) or thrombocytopenia (\< 100 x 10\^9/L); MLFS: BM blasts \< 5% no blasts with auer rods/extramedullary disease, no hematologic recovery; PR: hematological criteria of CR; decrease BM blast to 5-25%; decrease of BM blast percentage by ≤ 50%; SD: absence of CRMRD-, CR, CRi, PR, MLFS and criteria for PD not met; PD: evidence of increase in BM blast percentage and/or increase of absolute blast count.