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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03541369




Registration number
NCT03541369
Ethics application status
Date submitted
18/05/2018
Date registered
30/05/2018
Date last updated
10/10/2024

Titles & IDs
Public title
Safety, Tolerability, PK, PD, and Efficacy of AMG 427 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia
Scientific title
A Phase 1 First-In-Human Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 427 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia.
Secondary ID [1] 0 0
BB-IND 138440
Secondary ID [2] 0 0
20170528
Universal Trial Number (UTN)
Trial acronym
20170528
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Relapsed/Refractory Acute Myeloid Leukemia (AML) 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - AMG 427

Experimental: Dose Escalation Phase - AMG 427 Dose-finding phase of the study

Experimental: Dose Expansion Phase - AMG 427 MTD identified in dose escalation phase (or lower) will be administered to subjects.


Treatment: Drugs: AMG 427
AMG 427 will be administered as an intravenous (IV) infusion in adult subjects with relapsed/refractory AML.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)
Assessment method [1] 0 0
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.
Timepoint [1] 0 0
Days 1 to 28 for each cohort (28 days)
Primary outcome [2] 0 0
Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) and Treatment-related TEAEs
Assessment method [2] 0 0
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).
Timepoint [2] 0 0
Day 1 Cycle 1 to 30 days after last dose of investigational product or end of study; median treatment duration was 0.62 months
Secondary outcome [1] 0 0
Maximum Observed Concentration (Cmax) of Emirodatamab
Assessment method [1] 0 0
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.
Timepoint [1] 0 0
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)
Secondary outcome [2] 0 0
Time to Reach Cmax (Tmax) of Emirodatamab
Assessment method [2] 0 0
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.
Timepoint [2] 0 0
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)
Secondary outcome [3] 0 0
Minimum Concentration (Cmin) of Emirodatamab
Assessment method [3] 0 0
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.
Timepoint [3] 0 0
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)
Secondary outcome [4] 0 0
Area Under the Concentration-time Curve (AUC) From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) of Emirodatamab
Assessment method [4] 0 0
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.
Timepoint [4] 0 0
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)
Secondary outcome [5] 0 0
AUC From Time 0 to Infinity (AUC0-inf) of Emirodatamab
Assessment method [5] 0 0
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.
Timepoint [5] 0 0
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)
Secondary outcome [6] 0 0
AUC From Time Zero to 14 Days Post-dose (AUC14d) of Emirodatamab
Assessment method [6] 0 0
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.
Timepoint [6] 0 0
For all cohorts: from time zero to 14-days following the C1D1 dose (1 cycle= 14 days)
Secondary outcome [7] 0 0
Terminal Half-life (t1/2,z) of Emirodatamab
Assessment method [7] 0 0
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)/?z, where ?z is the first-order terminal rate constant estimated via linear regression of the terminal log-linear phase.
Timepoint [7] 0 0
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)
Secondary outcome [8] 0 0
Best Overall Response According to Revised International Working Group (IWG) Response Criteria
Assessment method [8] 0 0
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%
Timepoint [8] 0 0
Day 1 Cycle 1 to 30 days after last dose of investigational product or end of study; median treatment duration was 0.62 months

Eligibility
Key inclusion criteria
* Subject has provided informed consent prior to initiation of any study-specific activities/procedures.
* Subjects greater than or equal to 18 years of age at the time of signing consent.
* For relapsed/refractory AML subjects only, AML as defined by the WHO Classification as persisting or recurring following 1 or more treatment courses (exceptions noted in exclusion criteria).
* Myeloblasts greater than or equal to 5% in bone marrow, as confirmed by immunophenotype by flow cytometry.
* Eastern Cooperative Oncology Group (ECOG) Performance Status of less than or equal to 2.
* Renal function as follows: serum creatinine less than 2.0 mg/dL (176.84 µmol/L); estimated glomerular filtration rate (eGFR) greater than 30 mL/min/1.73 m^2.
* Hepatic function as follows: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3.0 x upper limit of normal (ULN); bilirubin less than or equal to 1.5 x ULN (unless considered due to Gilbert's syndrome or hemolysis).
* No active tuberculosis in the setting of anti-tumor necrosis factor (TNF) therapy - National guidelines should be followed for the appropriate tuberculosis screening in the setting of anti-TNF therapy, including a minimum of:

* Subject has a negative test for tuberculosis during screening defined as either:

* Negative purified protein derivative (PPD) (< 5 mm induration at 48 to 72 hours after test is placed) OR
* Negative Quantiferon test
* Subjects with positive PPD and a history of bacillus Calmette-Guérin vaccination are allowed with a negative Quantiferon test.
* Subjects with a positive PPD test (without a history of bacillus Calmette-Guérin vaccination) or subjects with a positive or indeterminate Quantiferon test are allowed if they have all of the following:

* No symptoms, per tuberculosis worksheet provided by Amgen
* Documented history of a completed course of adequate treatment or prophylaxis (per local standard of care) prior to the start of investigational product
* No known exposure to a case of active tuberculosis after most recent prophylaxis
* No evidence of active tuberculosis on chest radiograph within 3 months prior to the first dose of investigational product (substudy subjects only)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Patients with acute promyelocytic leukemia (APML).
* Active extramedullary AML in the central nervous system (CNS)
* Known hypersensitivity to immunoglobulins.
* White blood cells (WBC) greater than 15,000 cells/mcL (15 cells x 10^9/L) at screening (hydroxyurea is permitted to enable eligibility).
* Subjects with a prior or concurrent malignancy whose natural history or treatment is anticipated to interfere with the safety or efficacy assessment of the investigational regimen. Exception: Subjects with prior or concurrent malignancy not anticipated to interfere with the safety or efficacy of the investigational regimen may be included only after discussion with the Amgen Medical Monitor.
* Autologous hematopoietic stem cell transplant (HSCT) within 6 weeks prior to start of AMG 427 treatment.
* Allogeneic HSCT within 3 months prior to start of AMG 427 treatment.
* Any graft-versus-host disease requiring systemic therapy with immunomodulators.
* History or evidence of significant cardiovascular risk including any of the following: symptomatic congestive heart failure, unstable angina, clinically significant arrhythmias (eg, ventricular fibrillation, ventricular tachycardia etc.), recent coronary angioplasty, intra-cardiac defibrillators or any clinically relevant concurrent disorder that may pose a risk to subject safety or interfere with study evaluation, procedures, or completion.
* History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past 3 months.
* Active infection requiring intravenous antibiotics within 1 week of study enrollment (day 1). Antibiotics may be administered for prophylaxis as per institutional standards up to and after enrollment.
* Known positive test for human immunodeficiency virus (HIV).
* Positive for hepatitis B surface antigen (HepBsAg).
* Positive for hepatitis C or chronic hepatitis C. Possible exceptions: acute hepatitis C and completely cleared of the virus (demonstrated by negative viral load), chronic hepatitis C with undetectable viral load defined by sustained virologic response 24 weeks (SVR24) after completion of anti-hepatitis C treatment.
* Live vaccination(s) within 4 weeks before the start of AMG 427 treatment on day 1, during treatment, and until the end of the last study dose.
* Unresolved toxicities from prior antitumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 grade 1 (with the exception of myelosuppression, eg, neutropenia, anemia, thrombocytopenia), or to levels dictated in the eligibility criteria with the exception of alopecia or toxicities from prior antitumor therapy that are considered irreversible (defined as having been present and stable for greater than 2 months) which may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the investigator and sponsor.
* Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted therapy, or investigational agent) within 14 days of day 1. Exception: hydroxyurea to control peripheral blood leukemic cell counts is allowed until start of investigational product treatment. Exception: antitumor therapies with short half-lives only require passing of 5 half-lives from last dose, and after discussion with sponsor.
* Treatment with systemic immune modulators including, but not limited to, non-topical systemic corticosteroids, cyclosporine, and tacrolimus within 2 weeks before enrollment (day 1). Exceptions: physiologic replacement steroids or steroids for treatment of transfusion/hypersensitivity reactions.
* Prior treatment with a fms-like tyrosine kinase 3 (FLT3) targeting chimeric antigen receptor T cell (CAR-T)
* Major surgery within 28 days of study day 1 with the exception of biopsy and insertion of central venous catheter.
* History or evidence of any other clinically significant disorder, condition or disease that, in the opinion of the investigator or Amgen medical monitor would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
* Males and females of reproductive potential who are unwilling to practice a highly effective method(s) of birth control while on study through 4 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).
* Females who are lactating/breastfeeding or who plan to breastfeed while on study through 4 weeks after receiving the last dose of study drug.
* Females with a positive pregnancy test.
* Females planning to become pregnant while on study through 4 weeks after receiving the last dose of study drug.
* Subjects likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject's and investigator's knowledge.
* History of multiple sclerosis or any other demyelinating disease.
* No active hepatitis secondary to alcoholic hepatitis or nonalcoholic steatohepatitis.
* History or evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection unless agreed upon with Medical Monitor and meeting the following criteria:

* Negative test for SARS-CoV-2 RNA by reverse transcriptase-polymerase chain reaction (RT-PCR) within 72 hours of first dose of investigational product
* No acute symptoms of coronavirus disease 2019 (COVID-19) disease within 10 days prior to first dose of investigational product (counted from day of positive test for asymptomatic subjects)

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
14/09/2018
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
21/02/2023
Sample size
Target
Accrual to date
Final
64
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
The Alfred Hospital - Melbourne
Recruitment hospital [2] 0 0
The Royal Melbourne Hospital - Parkville
Recruitment postcode(s) [1] 0 0
3004 - Melbourne
Recruitment postcode(s) [2] 0 0
3050 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Illinois
Country [3] 0 0
United States of America
State/province [3] 0 0
Maryland
Country [4] 0 0
United States of America
State/province [4] 0 0
New York
Country [5] 0 0
United States of America
State/province [5] 0 0
North Carolina
Country [6] 0 0
United States of America
State/province [6] 0 0
Texas
Country [7] 0 0
Canada
State/province [7] 0 0
Ontario
Country [8] 0 0
Germany
State/province [8] 0 0
Dresden
Country [9] 0 0
Germany
State/province [9] 0 0
Muenchen
Country [10] 0 0
Japan
State/province [10] 0 0
Chiba
Country [11] 0 0
Japan
State/province [11] 0 0
Fukui
Country [12] 0 0
Korea, Republic of
State/province [12] 0 0
Seoul

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Amgen
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Public notes

Contacts
Principal investigator
Name 0 0
MD
Address 0 0
Amgen
Country 0 0
Phone 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement


What supporting documents are/will be available?



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT03541369