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 \[RP2D\]).
This is a first-in-human, open-label, phase 1, sequential dose escalation study. Emerfetamab will be evaluated as a short term intravenous (IV) infusion in adults with relapsed/refractory AML The study will consist of a dose escalation phase and a dose expansion phase. The study was terminated prior to the start of the expansion phase.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
46
Administered by intravenous (IV) infusion.
University of Alabama at Birmingham
Birmingham, Alabama, United States
City of Hope National Medical Center
Duarte, California, United States
University of Texas MD Anderson Cancer Center
Houston, Texas, United States
University of Washington
Seattle, Washington, United States
Number of Participants With Treatment-emergent Adverse Events
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.
Time frame: From first dose of study drug until the end of study; median (minimum, maximum) duration was 1.22 (0.10, 5.98) months.
Number of Participants With Dose-limiting Toxicities (DLT)
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.
Time frame: 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.
Schedule A: Maximum Observed Concentration (Cmax) of Emerfetamab
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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The Alfred Hospital
Melbourne, Victoria, Australia
The Royal Melbourne Hospital
Parkville, Victoria, Australia
Klinikum der Ludwig Maximilians Univeritaet
München, Germany
Time frame: 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.
Schedule A: Time to Maximum Observed Concentration (Tmax) of Emerfetamab
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.
Time frame: 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.
Schedule A: Area Under the Concentration-time Curve From Time Zero to 96 Hours Post-dose (AUC0-96) on Day 1 for Emerfetamab
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.
Time frame: Cycle 1 day 1 at predose and at 1, 6, 24, 48, and 96 hours after the start of infusion.
Schedule A: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for Emerfetamab
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.
Time frame: Cycle 1 day 5 at predose and 1, 6, 12, 24, 48, 72, and 312 hours after the start of infusion.
Schedule A: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) for Emerfetamab
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.
Time frame: Cycle 1 day 5 at predose and 1, 6, 12, 24, 48, 72, and 312 hours after the start of infusion.
Schedule A: AUC Total for Emerfetamab
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.
Time frame: 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.
Schedule A: Terminal Half-life (T1/2,z) of Emerfetamab
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)/λz, where λz is the first-order terminal rate constant estimated via linear regression of the terminal log-linear phase.
Time frame: Cycle 1 day 5 at predose and 1, 6, 12, 24, 48, 72, and 312 hours after the start of infusion.
Schedule A: Clearance (CL) of Emerfetamab
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/λz\*AUCinf.
Time frame: Cycle 1 day 5 at predose and 1, 6, 12, 24, 48, 72, and 312 hours after the start of infusion.
Schedule B: Maximum Observed Concentration (Cmax) of Emerfetamab
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.
Time frame: Cycle 1 day 14 at predose and 1, 6, 12, 24, 48, 72, 96, and 120 hours after the start of infusion.
Schedule B: Time to Maximum Observed Concentration (Tmax) of Emerfetamab
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.
Time frame: Cycle 1 day 14 at predose and 1, 6, 12, 24, 48, 72, 96, and 120 hours after the start of infusion.
Schedule B: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for Emerfetamab
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.
Time frame: Cycle 1 day 14 at predose and 1, 6, 12, 24, 48, 72, 96, and 120 hours after the start of infusion.
Schedule B: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) for Emerfetamab
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.
Time frame: Cycle 1 day 14 at predose and 1, 6, 12, 24, 48, 72, 96, and 120 hours after the start of infusion.
Schedule B: Terminal Half-life (T1/2,z) of Emerfetamab
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.
Time frame: Cycle 1 day 14 at predose and 1, 6, 12, 24, 48, 72, 96, and 120 hours after the start of infusion.
Schedule B: Clearance of Emerfetamab
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.
Time frame: Cycle 1 day 14 at predose and 1, 6, 12, 24, 48, 72, 96, and 120 hours after the start of infusion.
Response Rate
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.
Time frame: 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.
Duration of Response
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.
Time frame: 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.
Time to Response
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.
Time frame: 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.
Time to Progression
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.
Time frame: 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.