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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03224819
Registration number
NCT03224819
Ethics application status
Date submitted
3/07/2017
Date registered
21/07/2017
Date last updated
1/09/2023
Titles & IDs
Public title
Study of Emerfetamab (AMG 673) in Adults With Relapsed/Refractory Acute Myeloid Leukemia (AML)
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Scientific title
A Phase 1 First-In-Human Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 673 Administered as Short Term Intravenous Infusions in Subjects With Relapsed/Refractory Acute Myeloid Leukemia
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Secondary ID [1]
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2017-002980-16
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Secondary ID [2]
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20160377
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukemia
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Condition category
Condition code
Cancer
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Leukaemia - Acute leukaemia
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Cancer
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Leukaemia - Chronic leukaemia
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Cancer
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Children's - Leukaemia & Lymphoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Emerfetamab
Experimental: Dose Escalation - The dose-escalation cohorts to estimate the MTD will use 2 schedules of emerfetamab administration: Schedule A (Day 1/Day 5 dosing in 14-day cycles) and Schedule B (once daily dosing for cycle 1 followed by twice weekly dosing in following cycles).
For Schedule A the starting dose for the first cohort will be 0.05 µg emerfetamab administered as short term IV infusions on day 1 and day 5. The doses administered for the following cohorts will be recommended by the Dose Level Review Team (DLRT).
For Schedule B the starting dose will be 72 µg emerfetamab administered as short-term IV infusions daily (QD) during the 14-day cycle 1 after the 72 µg target dose is found to be relatively safe and tolerable by the DLRT for Schedule A.
Experimental: Expansion Phase - For each schedule, upon completion of the dose escalation cohorts, additional participants may be enrolled to receive emerfetamab at a dose at or below the MTD estimated in the dose escalation cohorts.
Treatment: Drugs: Emerfetamab
Administered by intravenous (IV) infusion.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Number of Participants With Treatment-emergent Adverse Events
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Assessment method [1]
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The severity of each adverse event (AE) was graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria, where Grade 1 = mild AE, Grade 2 = moderate AE, Grade 3 = severe AE, Grade 4 = life-threatening and Grade 5 = death due to AE.
A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria:
fatal
life threatening
required in patient hospitalization or prolongation of existing hospitalization
resulted in persistent or significant disability/incapacity
congenital anomaly/birth defect
other medically important serious event.
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Timepoint [1]
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From first dose of study drug until the end of study; median (minimum, maximum) duration was 1.22 (0.10, 5.98) months.
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Primary outcome [2]
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Number of Participants With Dose-limiting Toxicities (DLT)
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Assessment method [2]
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A DLT was defined as any of the events described below occurring in a participant during the DLT window, unless clearly attributable to causes other than emerfetamab:
Any treatment-related death;
Grade 4 neutropenia persisting at 42 days after the last infusion in treatment cycle 1;
Grade 3-5 non-hematologic toxicity not clearly resulting from the underlying leukemia with a few protocol-specified exceptions;
Grade 2 or 3 cytokine release syndrome (CRS) meeting any of the criteria listed below:
Grade 2 CRS that does not resolve, with or without intervention to Grade 1 within 7 days;
Grade 3 CRS that does not resolve, with or without intervention to Grade 2 within 5 days, or grade 1 within 7 days;
Grade 3 CRS reported at the initial dose;
Two separate grade 3 CRS events;
Grade 4 CRS occurring during treatment.
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Timepoint [2]
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Schedule A: From the start of the first infusion on day 1 until day 14. Schedule B: From the start of the first infusion on day 1 to day 28.
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Secondary outcome [1]
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Schedule A: Maximum Observed Concentration (Cmax) of Emerfetamab
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Assessment method [1]
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Serum concentrations of emerfetamab were determined using a validated assay. Noncompartmental analysis was performed for estimation of pharmacokinetic (PK) parameters. Concentrations below the lower limit of quantitation (LLOQ; 0.0015 ng/mL) were set to zero before data analysis.
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Timepoint [1]
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Cycle 1 day 1 at predose and at 1, 6, 24, and 48 hours after the start of infusion, and day 5 at predose and 1, 6, 12, 24, 48, 72, and 312 hours after the start of infusion.
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Secondary outcome [2]
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Schedule A: Time to Maximum Observed Concentration (Tmax) of Emerfetamab
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Assessment method [2]
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Serum concentrations of emerfetamab were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.0015 ng/mL) were set to zero before data analysis.
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Timepoint [2]
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Cycle 1 day 1 at predose and at 1, 6, 24, and 48 hours after the start of infusion, and day 5 at predose and 1, 6, 12, 24, 48, 72, and 312 hours after the start of infusion.
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Secondary outcome [3]
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Schedule A: Area Under the Concentration-time Curve From Time Zero to 96 Hours Post-dose (AUC0-96) on Day 1 for Emerfetamab
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Assessment method [3]
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Serum concentrations of emerfetamab were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.0015 ng/mL) were set to zero before data analysis.
The area under the curve (AUC) from time zero to 96 hours postdose was calculated using the linear trapezoidal method.
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Timepoint [3]
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Cycle 1 day 1 at predose and at 1, 6, 24, 48, and 96 hours after the start of infusion.
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Secondary outcome [4]
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Schedule A: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for Emerfetamab
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Assessment method [4]
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Serum concentrations of emerfetamab were determined using a validated assay. Non-compartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.0015 ng/mL) were set to zero before data analysis.
The area under the concentration-time curve from time 0 relative to the start of the IV infusion to the last quantifiable concentration was estimated using the linear trapezoidal method.
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Timepoint [4]
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Cycle 1 day 5 at predose and 1, 6, 12, 24, 48, 72, and 312 hours after the start of infusion.
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Secondary outcome [5]
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Schedule A: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) for Emerfetamab
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Assessment method [5]
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Serum concentrations of emerfetamab were determined using a validated assay. Non-compartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.0015 ng/mL) were set to zero before data analysis.
The area under the concentration-time curve from time 0 relative to the start of the IV infusion to infinity was estimated using the linear trapezoidal method.
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Timepoint [5]
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Cycle 1 day 5 at predose and 1, 6, 12, 24, 48, 72, and 312 hours after the start of infusion.
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Secondary outcome [6]
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Schedule A: AUC Total for Emerfetamab
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Assessment method [6]
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Serum concentrations of emerfetamab were determined using a validated assay. Non-compartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.0015 ng/mL) were set to zero before data analysis.
The AUC total was calculated as the sum of AUC0-96hr following the Day 1 dose and AUCinf following the Day 5 dose.
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Timepoint [6]
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Cycle 1 day 1 at predose and at 1, 6, 24, and 48 hours after the start of infusion, and day 5 at predose and 1, 6, 12, 24, 48, 72, and 312 hours after the start of infusion.
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Secondary outcome [7]
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Schedule A: Terminal Half-life (T1/2,z) of Emerfetamab
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Assessment method [7]
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Serum concentrations of emerfetamab were determined using a validated assay. Non-compartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.0015 ng/mL) were set to zero before data analysis.
Terminal half-life (t1/2,z) was calculated as t1/2,z = ln(2)/?z, where ?z is the first-order terminal rate constant estimated via linear regression of the terminal log-linear phase.
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Timepoint [7]
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Cycle 1 day 5 at predose and 1, 6, 12, 24, 48, 72, and 312 hours after the start of infusion.
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Secondary outcome [8]
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Schedule A: Clearance (CL) of Emerfetamab
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Assessment method [8]
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Serum concentrations of emerfetamab were determined using a validated assay. Non-compartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.0015 ng/mL) were set to zero before data analysis.
Clearance was calculated as Dose/?z*AUCinf.
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Timepoint [8]
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Cycle 1 day 5 at predose and 1, 6, 12, 24, 48, 72, and 312 hours after the start of infusion.
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Secondary outcome [9]
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Schedule B: Maximum Observed Concentration (Cmax) of Emerfetamab
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Assessment method [9]
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Serum concentrations of emerfetamab were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.0015 ng/mL) were set to zero before data analysis.
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Timepoint [9]
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Cycle 1 day 14 at predose and 1, 6, 12, 24, 48, 72, 96, and 120 hours after the start of infusion.
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Secondary outcome [10]
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Schedule B: Time to Maximum Observed Concentration (Tmax) of Emerfetamab
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Assessment method [10]
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Serum concentrations of emerfetamab were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.0015 ng/mL) were set to zero before data analysis.
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Timepoint [10]
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Cycle 1 day 14 at predose and 1, 6, 12, 24, 48, 72, 96, and 120 hours after the start of infusion.
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Secondary outcome [11]
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Schedule B: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for Emerfetamab
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Assessment method [11]
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Serum concentrations of emerfetamab were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.0015 ng/mL) were set to zero before data analysis.
The area under the concentration-time curve from time 0 relative to the start of the IV infusion to the last quantifiable concentration was estimated using the linear trapezoidal method.
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Timepoint [11]
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Cycle 1 day 14 at predose and 1, 6, 12, 24, 48, 72, 96, and 120 hours after the start of infusion.
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Secondary outcome [12]
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Schedule B: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) for Emerfetamab
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Assessment method [12]
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Serum concentrations of emerfetamab were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.0015 ng/mL) were set to zero before data analysis.
The area under the concentration-time curve from time 0 relative to the start of the IV infusion to infinity was estimated using the linear trapezoidal method.
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Timepoint [12]
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Cycle 1 day 14 at predose and 1, 6, 12, 24, 48, 72, 96, and 120 hours after the start of infusion.
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Secondary outcome [13]
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Schedule B: Terminal Half-life (T1/2,z) of Emerfetamab
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Assessment method [13]
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Serum concentrations of emerfetamab were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.0015 ng/mL) were set to zero before data analysis.
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Timepoint [13]
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Cycle 1 day 14 at predose and 1, 6, 12, 24, 48, 72, 96, and 120 hours after the start of infusion.
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Secondary outcome [14]
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Schedule B: Clearance of Emerfetamab
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Assessment method [14]
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Serum concentrations of emerfetamab were determined using a validated assay. Noncompartmental analysis was performed for estimation of PK parameters. Concentrations below the LLOQ (0.0015 ng/mL) were set to zero before data analysis.
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Timepoint [14]
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Cycle 1 day 14 at predose and 1, 6, 12, 24, 48, 72, 96, and 120 hours after the start of infusion.
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Secondary outcome [15]
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Response Rate
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Assessment method [15]
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Disease response was based upon review of cytogenetics, bone marrow (BM) aspirates/biopsies, and peripheral blood count. Response rate is defined as the percentage of participants with a best overall response of complete remission (CR), CR with incomplete recovery (CRi) or morphologic leukemia-free state (MLFS) according to Revised International Working Group (IWG) response criteria, or CR with partial hematologic recovery (CRh*).
CR: BM blasts < 5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) > 1.0 x 10^9/L; platelet count > 100 x 10^9/L; independence of red cell transfusions.
CRi: All CR criteria except residual neutropenia or thrombocytopenia. MLFS: BM blasts < 5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required.
CRh*: < 5% blasts in BM; no evidence of disease; partial recovery of peripheral blood counts: platelets > 50,000/µl, and ANC > 500/µl; no extramedullary disease.
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Timepoint [15]
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Disease response was assessed on day 14 of every treatment cycle and at the end of study; median (min, max) duration was 1.22 (0.10, 5.98) months.
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Secondary outcome [16]
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Duration of Response
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Assessment method [16]
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Duration of response is defined as the interval from the date of the first disease assessment indicating an overall response to the first documented relapse or death due to any cause, whichever occurred first.
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Timepoint [16]
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Disease response was assessed on day 14 of every treatment cycle and at the end of study; median (min, max) duration was 1.22 (0.10, 5.98) months.
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Secondary outcome [17]
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Time to Response
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Assessment method [17]
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Time to response is defined as the interval from the first administration of study drug to the first documentation of response. Time to response was evaluated only for participants who achieved a response.
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Timepoint [17]
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Disease response was assessed on day 14 of every treatment cycle and at the end of study; median (min, max) duration was 1.22 (0.10, 5.98) months.
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Secondary outcome [18]
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Time to Progression
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Assessment method [18]
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Time to progression (event-free survival) is defined as the interval from first administration of study drug to the earliest of date of treatment failure, relapse for responders, or death due to any cause. For non-responders, the event date for treatment failure was assigned as the date of first administration of study drug.
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Timepoint [18]
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Disease response was assessed on day 14 of every treatment cycle and at the end of study; median (min, max) duration was 1.22 (0.10, 5.98) months.
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Eligibility
Key inclusion criteria
Inclusion Criteria
- Subject has provided informed consent prior to initiation of any study-specific
activities/procedures.
- Subjects = 18 years of age at the time of signing consent.
- AML as defined by the World Health Organisation (WHO) Classification persisting or
recurring following 1 or more treatment courses except promyelocytic leukemia (APML).
- More than 5% myeloblasts in bone marrow.
- Eastern Cooperative Oncology Group (ECOG) Performance Status of = 2.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
Exclusion Criteria
- Known hypersensitivity to immunoglobulins.
- Autologous hematopoietic stem cell transplantation (HSCT) within 6 weeks prior to
start of AMG 673 treatment.
- Allogeneic HSCT within 3 months prior to start of AMG 673 treatment.
- Non-manageable graft versus host disease.
- Known positive test for human immunodeficiency virus (HIV).
- Males and females of reproductive potential who are unwilling to practice a highly
effective method(s) of birth control while on study through 15 weeks after receiving
the last dose of study drug. Acceptable methods of highly effective birth control
include sexual abstinence (males, females); vasectomy; bilateral tubal
ligation/occlusion; or a condom with spermicide (men) in combination with hormonal
birth control or intrauterine device (IUD) (women). Males who are unwilling to abstain
from sperm donation while on study through 5 half-lives after receiving the (last
[multiple-dose studies]) dose of study drug.
- Females who are lactating/breastfeeding or who plan to breastfeed while on study
through 15 weeks after receiving the last dose of study drug.
- Females with a positive pregnancy test
- Females planning to become pregnant while on study through 15 weeks after receiving
the last dose of study drug.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Other
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Other design features
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Phase
Phase 0
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Terminated
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
7/09/2017
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
28/12/2020
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Sample size
Target
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Accrual to date
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Final
46
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
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The Alfred Hospital - Melbourne
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Recruitment hospital [2]
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The Royal Melbourne Hospital - Parkville
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Recruitment postcode(s) [1]
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3004 - Melbourne
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Recruitment postcode(s) [2]
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3050 - Parkville
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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Alabama
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Country [2]
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United States of America
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State/province [2]
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California
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Country [3]
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United States of America
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State/province [3]
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Texas
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Country [4]
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United States of America
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State/province [4]
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Washington
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Country [5]
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Germany
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State/province [5]
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München
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Amgen
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
The primary objectives of this study are to evaluate the safety and tolerability of
emerfetamab in adults with relapsed/refractory acute myeloid leukemia (AML) and to estimate
the maximum tolerated dose (MTD) and/or a biologically active dose (eg, recommended phase 2
dose [RP2D]).
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03224819
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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MD
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Address
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Amgen
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03224819
Download to PDF